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Side Effects of Drugs Annual 33

HONORARY EDITOR

Prof. M.N.G. Dukes, Oslo, Norway

ADVISORY EDITORIAL BOARD

Prof. F. Bochner, Adelaide, Australia


Prof. I.R. Edwards, Uppsala, Sweden
Prof. G.P. Velo, Verona, Italy
Elsevier
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First edition 2011

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11 12 13 10 9 8 7 6 5 4 3 2 1
Contributors

M.C. ALLWOOD, BPHARM, PHD


Pharmacy Academic Practice Unit, School of Biological, Forensic and
Pharmaceutical Sciences, University of Derby, Mickleover, Derby, UK.
E-mail: M.C.Allwood@derby.ac.uk.

LUIS H. MARTN ARIAS, MD, PHD


Instituto de Farmacoepidemiologa, Facultad de Medicina, 47005 Valladolid, Spain.
E-mail: lmartin@ife.uva.es.

J.K. ARONSON, MA, MBCHB, DPHIL, FRCP, FBPHARMACOLS, FFPM(HON)


University of Oxford Department of Primary Health Care, 2338 Hythe Bridge Street,
Oxford OX1 2ET. E-mail: jeffrey.aronson@clinpharm.ox.ac.uk.

V.V. BANU REKHA


Tuberculosis Research Centre, Mayor VR Ramanathan Road, Chetpet, Chennai 600031,
India. E-mail: banu24@yahoo.com.

ANDREAS J. BIRCHER
Allergy Unit, Department of Dermatology, University Hospital Basel, Petersgraben 4,
4031 Basel, Switzerland. E-mail: andreas.bircher@unibas.ch.

CORRADO BLANDIZZI, MD, PHD


Division of Pharmacology & Chemotherapy, Department of Internal Medicine,
University of Pisa, Via Roma 55, 56126 Pisa, Italy. E-mail: c.blandizzi@gmail.com.

KRISTIEN BOELAERT, MD, PHD, MRCP


School of Clinical and Experimental Medicine, College of Medical and Dental Sciences,
IBR Building 2nd oor, University of Birmingham, Birmingham B15 2TT, UK.
E-mail: k.boelaert@bham.ac.uk.

ALFONSO CARVAJAL, MD, PHD,


Instituto de Farmacoepidemiologa, Facultad de Medicina, 47005 Valladolid, Spain.
E-mail: carvajal@ife.uva.es.

K. CHAN PHD, DSC, FIBIOL, FCP, FRPHARMS, FRSM


Faculty of Pharmacy, The University of Sydney and Centre for Complementary
Medicine Research, University of Western Sydney, Locked Bag 1797, Penrith South DC
NSW 2751, Australia. E-mail: JCTCM@uws.edu.au.

N.H. CHOULIS, MD, PHD


LAVIPHARM Research Laboratories, Agias Marinas Street, 19002 Peania, Attika,
Greece. E-mail: nicoly@otenet.gr.

v
vi Contributors

JAMIE J. COLEMAN, MBCHB, MA (MED ED), MD, MRCP(UK)


Department of Clinical Pharmacology, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
E-mail: j.j.coleman@bham.ac.uk.

NATASCIA CORTI, MD
University Hospital Zurich, Department of Medicine, Division of Infectious Diseases
and Hospital Epidemiology, Rmistrasse 100, CH-8091 Zrich, Switzerland.
E-mail: natascia.corti@usz.ch.

J. COSTA, MD
Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol,
Universitat Autnoma de Barcelona, Ctra. de Canyet s/n, 08916 Badalona, Spain.
E-mail: jcosta.germanstrias@gencat.cat.

NICHOLAS J. COWLEY, MBCHB, MRCP(UK), FRCA


School of Clinical and Experimental Medicine, College of Medical and Dental Sciences,
University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Email: n.j.cowley@bham.ac.uk.

ANTHONY R. COX, PHD


Pharmacy Practice Group, School of Pharmacy, Aston University, Birmingham, B4 7ET,
UK. Email: a.r.cox@aston.ac.uk.

STEPHEN CURRAN, BSC, MBCHB, MMEDSC, MRCPSYCH, PHD


Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe
Lane, Wakeeld, WF1 3SP, UK. E-mail: steve.curran@hud.ac.uk.

GWYNETH A. DAVIES, MD, MRCP


Senior Clinical Lecturer, Asthma & Allergy, School of Medicine, Swansea University,
Swansea, Wales, UK. E-mail: gwyneth.davies@swansea.ac.uk.

S. DITTMANN, MD, DSCMED


19 Hatzenporter Weg, 12681 Berlin, Germany.
E-mail: sd.internat.immun.consult@t-online.de.

IDA DUARTE
Santa Casa de So Paulo Medical School, So Paulo, Brazil.
E-mail: idaduarte@terra.com.br.

M.N.G. DUKES, MD, MA, LLM


Trosterudveien 19, 0778 Oslo, Norway. E-mail: mngdukes@online.no.

RIF S. EL-MALLAKH, MD
Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences,
University of Louisville School of Medicine, MedCenter One, 501 E Broadway, Suite
340, Louisville, Kentucky 40202, USA. E-mail: rselma01@louisville.edu.

M. FARR, MD
Human Pharmacology and Neurosciences, Institut de Recerca Hospital del Mar
(IMIM) Parc de Salut Mar, Universitat Autnoma de Barcelona, Doctor Aiguader 88,
08003 Barcelona, Spain. E-mail: mfarre@imim.es.
Contributors vii

A. FINZI, MD
Istituto di Ricerche Farmacologiche M. Negri,via G La Masa 19, 20156 Milan, Italy.
E-mail: andrea.nzi@marionegri.it.

M.G. FRANZOSI, PHD


Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche
Mario Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail: franzosi@marionegri.it.

S. GALEA, MD, MRCPSYCH, MSC (ADDICTIVE BEHAVIOUR), DIP (FORENSIC


MENTAL HEALTH)
Auckland Community Alcohol & Drugs Services, 50 Pitman House, Carrington Road,
Point Chevalier, Auckland, New Zealand, & Centre for Addiction Studies, St George's
Hospital Medical School, 6th Floor, Hunter Wing, Cranmer Terrace, London SW17
0RE, UK. E-mail: susanna.galea@waitematadhb.govt.nz.

YONGLIN GAO, MD
Mood Disorders Research Program, Department of Psychiatry and Behavioral Sciences,
University of Louisville School of Medicine, MedCenter One, 501 E Broadway,
Suite 340, Louisville, Kentucky 40202, USA. E-mail: ylgao001@gwise.louisville.edu.

A.H. GHODSE, MD, PHD, DSC, FFPH, FRCP, FRCPE, FRCPSYCH


International Centre for Drug Policy, St George's University of London, 6th Floor,
Hunter Wing, Cranmer Terrace, London SW17 0RE, UK.
E-mail: h.ghodse@sghms.ac.uk.

ANDREAS H. GROLL, MD
Infectious Disease Research Program, Center for Bone Marrow Transplantation and
Department of Hematology/Oncology, University Children's Hospital, Albert-
Schweitzer-Strasse 33, 48129 Muenster, Germany. E-mail: grollan@ukmuenster.de.

AVINASH GUPTA, MBBS, BSC, MRCP


University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford
OX3 7LJ, UK. E-mail: Avinash.Gupta@orh.nhs.uk.

ALISON HALL, BSC, MBCHB, FRCA


School of Clinical Science, University of Liverpool, The Duncan Building, Daulby
Street, Liverpool, L69 3GA, UK. E-mail: alih101@yahoo.com.

ALEXANDER IMHOF, MD
University Hospital Zurich, Department of Medicine, Division of Infectious Diseases
and Hospital Epidemiology, Rmistrasse 100, CH-8091 Zrich, Switzerland.
E-mail: alexander.imhof@sro.ch.

M.S. JAWAHAR, MD, MSC, DLSHTM


Tuberculosis Research Centre, Chennai 600031, India.
E-mail: shaheedjawahar@hotmail.com.

NATALIA JIMENO, MD, PHD


Instituto de Farmacoepidemiologa, Facultad de Medicina, 47005 Valladolid, Spain.
E-mail: najimeno@med.uva.es.
viii Contributors

CLARICE KOBATA
Santa Casa de So Paulo Medical School, So Paulo, Brazil.
E-mail: clakobata@yahoo.com.

SARAH LANGENFELD, MD
University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation
Street, Worcester, MA 01605, USA. E-mail: sarah.langenfeld@umassmemorial.org.

M. LARTEY, MBCHB, MSC, FWACP


Department of Medicine & Therapeutics, University of Ghana Medical School,
PO Box 4236, Accra, Ghana. E-mail: mlartey@ug.edu.gh.

R. LATINI, MD
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario
Negri, Via Eritrea 62, 20157 Milan, Italy. E-mail roberto.latini@marionegri.it.

ROSANA LAZZARINI
Santa Casa de So Paulo Medical School, So Paulo, Brazil.
E-mail: lazzarini@fototerapia.com.br.

M. LEUWER, MD
School of Clinical Science, University of Liverpool, The Duncan Building, Daulby
Street, Liverpool, L69 3GA, UK. E-mail: mleuwer@liv.ac.uk.

Z.X. LIN, BSC, PHD


School of Chinese Medicine, Faculty of Science, 1/F Sino Building, The Chinese
University of Hong Kong, Shatin NT, Hong Kong SAR, PR China. E-mail: linzx@cuhk.
edu.hk.

PAM MAGEE, BSC, MSC, MRPHARMS


Fillongley, Coventry, UK. Email: pam.magee@macace.net.

R.H.B. MEYBOOM, MD, PHD


Department of Pharmacoepidemiology and Pharmacotherapy, Faculty of Pharmacy,
Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands.
E-mail: r.meyboom@who-umc.org.

MARK MIDDLETON, PHD, FRCP


University of Oxford, Department of Medical Oncology, Churchill Hospital, Oxford
OX3 7LJ, UK. E-mail: mark.middleton@medonc.ox.ac.uk.

TORE MIDTVEDT, MD, PHD


Department of Microbiology, Tumor and Cell Biology (MTC), Von Eulers v. 5,
Karolinska Institutet, Box 60 400, S-171 77 Stockholm, Sweden.
E-mail: tore.midtvedt@cmb.ki.se.

PHILIP B. MITCHELL, AM, MBBS, MD, FRANZCP, FRCPSYCH


University of New South Wales School of Psychiatry, Prince of Wales Hospital,
Randwick, NSW 2031, Australia. E-mail: phil.mitchell@unsw.edu.au.
Contributors ix

SHABIR MUSA, MBCHB, MRCPSYCH


Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe
Lane, Wakeeld, WF1 3SP, UK. E-mail: shabir.musa@swyt.nhs.uk.

PAUL NESTEL, MD, FRACP


Baker Heart & Diabetes Institute, PO Box 6492, St Kilda Road Central, Melbourne,
Victoria 8008, Australia. E-mail: paul.nestel@bakeridi.edu.au.

JULIE OLLIFF, MBCHB, MRCP, FRCR


Imaging Department, Queen Elizabeth Hospital Birmingham, Mindelsohn Way,
Edgbaston, Birmingham, B15 2WB, UK. E-mail: Julie.Olliff@uhb.nhs.uk.

R.C.L. PAGE, MD, FRCP, MA(ED)


Endocrine Unit, Dundee House, City Hospital, Hucknall Road, Nottingham NG5 1PB,
UK. Email: renee.page@nuh.nhs.uk; rpage@ncht.trent.nhs.uk.

JAYENDRA K. PATEL, MD
University of Massachusetts Medical School, Department of Psychiatry, 361 Plantation
Street, Worcester, MA 01605, and Lake Area Psychiatry, 333 Dr. Michael DeBakey
Drive, Lake Charles, LA 70601, USA. E-mail: jkprjs@gmail.com.

MIKE PYNN, MRCP


Clinical Lecturer, School of Medicine, Swansea University, Swansea, Wales, UK.
E-mail: m.c.pynn@swansea.ac.uk.

ALEXANDER RAYMANN, MD, DESA (DEAA)


Department of Anaesthesiology, Intensive Care and Pain Medicine, Klinikum Region
Hannover Nordstadt, Hannover, Germany. E-mail: AlexanderRaymann@aol.com.

PETER RILEY, MBCHB, MRCP, FRCR


Imaging Department, Queen Elizabeth Hospital Birmingham, Mindelsohn Way,
Edgbaston, Birmingham, B15 2WB, UK. E-mail: Riley.Riley@uhb.nhs.uk.

ANITA ROTTER
Clinic of Dermatology, Santa Casa de So Paulo, So Paulo, Brazil.
E-mail: arotter@terra.com.br.

CARMELO SCARPIGNATO, MD, DSC, PHARMD, FRCP, FCP, FACG


Laboratory of Clinical Pharmacology, School of Medicine & Dentistry, University of
Parma, Via Volturno, 3943125 Parma, Italy. E-mail: scarpi@tin.it.

MICHAEL SCHACHTER, MD
Department of Clinical Pharmacology, National Heart and Lung Institute, Imperial
College, St Mary's Hospital, London W2 1NY, UK. E-mail: m.schachter@imperial.ac.uk.

J.S.A.G. SCHOUTEN, MD
Department of Ophthalmology, Maastricht University Hospital, PO Box 5800, 6202 AZ
Maastricht, The Netherlands. E-mail: J.Schouten@MUMC.nl.
x Contributors

DOMINIK SCHREY, MD
Infectious Disease Research Program, Center for Bone Marrow Transplantation and
Department of Hematology/Oncology, University Children's Hospital,
Albert-Schweitzer-Strasse 33, 48129 Muenster, Germany.
E-mail: Dominik.Schrey@ukmuenster.de.

STEPHAN A. SCHUG, MD, FANZCA, FFPMANZCA


Level 2, MRF Building G Block, Royal Perth Hospital, GPO Box X2213, Perth, WA
6847, Australia. E-mail: stephan.schug@uwa.edu.au.

REGINALD P. SEQUEIRA, PHD, FCP


Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences,
Arabian Gulf University, PO Box 22979, Manama, Bahrain.
E-mail: Sequeira@agu.edu.bh.

OSCAR OZMUND SIMOOYA, BSC, MBCHB, MSC


The Copper belt University, Health Services Division, PO Box 21692, Kitwe, Zambia,
Central Africa. E-mail: oscar.simooya@cbu.ac.zm.

REBECCA SPENCER
Fieldhead Hospital, South West Yorkshire Mental Health NHS Trust, Ouchthorpe
Lane, Wakeeld, WF1 3SP, UK. E-mail: Rebecca.Spencer@swyt.nhs.uk.

D. SPOERL
Allergy Unit, Department of Dermatology, University Hospital Basel, Petersgraben 4,
4031 Basel, Switzerland. E-mail: spoerld@uhbs.ch.

SEBASTIAN STRAUBE, BMBCH, MA, DPHIL


Department of Occupational, Social and Environmental Medicine, University Medical
Center Gttingen, Waldweg 37 B, D-37073 Gttingen, Germany. E-mail: sebastian.
straube@googlemail.com.

P.F.W. STRENGERS, MD
Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam,
The Netherlands. E-mail: p.strengers@sanquin.nl.

ANNE TAEGTMEYER, MD
University Hospital Zurich, Department of Medicine, Division of Infectious Diseases
and Hospital Epidemiology, Rmistrasse 100, CH-8091 Zrich, Switzerland.
E-mail: AnneBarbara.taegtmyer@usz.ch.

K. TORPEY, MD, PHD, MPH


Family Health International, 4401 Wilson Boulevard, Suite 700, Arlington, VA 22203,
USA. E-mail: ktorpey@fhi.org.

LUCIANA TRAMACERE
U.O. Neurologia, Ospedale S Giovanni di Dio, Via Torregalli 3, 50143 Firenze, Italy.
E-mail: luciana.tramacere@asf.toscana.it.

GIJSBERT B. VAN DER VOET, PHD, ERT


Health Council of The Netherlands, Parnassusplein 5 (C709)2511 VX The Hague, The
Netherlands. E-mail: b.v.d.voet@gr.nl.
Contributors xi

P.J.J. VAN GENDEREN, MD, PHD


Department of Internal Medicine, Harbour Hospital and Institute of Tropical
Diseases, Haringvliet 2, 3011 TD Rotterdam, The Netherlands.
E-mail: p.van.genderen@havenziekenhuis.nl.

K.J. VELTHOVE, PHARMD, PHD


Sanquin Blood Supply Foundation, Plesmanlaan 125, 1066 CX Amsterdam,
The Netherlands. E-mail: k.velthove@sanquin.nl.

P. VERHAMME, MD
Vascular Medicine and Haemostasis, University of Leuven, Herestraat, 49, 3000 Leuven,
Belgium. E-mail: Peter.Verhamme@uzleuven.be.

GARRY M. WALSH, MSC, PHD


School of Medicine, Institute of Medical Sciences Building, University of Aberdeen,
Foresterhill, Aberdeen AB25 2ZD, UK. E-mail: g.m.walsh@abdn.ac.uk.

THOMAS J. WALSH, MD
Transplantation-Oncology Infectious Diseases Program, Division of Infectious Diseases,
Weill Cornell Medical College of Cornell University, New York, New York, USA.
E-mail: thw2003@med.cornell.edu.

MANUEL WENK, MD
Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Perth, Australia
& Department of Anesthesiology and Intensive Care, University Hospital Muenster,
Albert-Schweitzer-Str. 33, 48149 Muenster, Germany.
E-mail: manuelwenk@uni-muenster.de.

C. WILLIAMS, BSC, MBCHB, FRCA


Department of Anaesthesia, 12th Floor, Royal Liverpool University Hospital, Prescot
Street, Liverpool, L7 8XP, UK. E-mail: colinwilliams99@yahoo.com.

EILEEN WONG, MD
Harvard Medical School, Massachusetts Mental Health Center, Department of
Psychiatry, Jamaica Plain, MA 02130, USA. E-mail: ewong88@juno.com.

GAETANO ZACCARA, MD
U.O. Neurologia, Ospedale S Giovanni di Dio, Via Torregalli, 50100 Firenze, Italy.
E-mail: gaetano.zaccara@asf.toscana.it.

H.W. ZHANG, BSC, MPHIL, PHD


School of Chinese Medicine, Faculty of Science, 1/F Sino Building, The Chinese
University of Hong Kong, Shatin NT, Hong Kong SAR, PR China.
E-mail: zhanghw@cuhk.edu.hk.
Special reviews

SSRIs and emergent suicidal ideation 26


Antidepressants in pregnancy 27
The uses of lithium 39
Adulteration of street drugs with clenbuterol 53
Flumazenil 79
Typical versus atypical antipsychotic drugs 89
Weight gain and diabetes mellitus due to antipsychotic drugs 94
Suicidality and antiepileptic drugs 127
Lacosamide 139
Visual impairment and vigabatrin 178
An update on adverse events in patients taking COX-2 selective and non-selective 241
NSAIDs
Urinary tract dysfunction after recreational use of ketamine 268
Cartilage toxicity from local anesthetics 281
Tetrabenazine 305
Stress cardiomyopathy and catecholamines 313
Inhaled glucocorticoids and the risk of pneumonia 353
Inhaled glucocorticoids and skeletal adverse effects 355
Long-term safety of long-acting beta2-adrenoceptor agonists (LABAs)an update 357
Cardiovascular risks of inhaled anticholinergic drugs 364
More about amiodarone-induced thyrotoxicosis and its management 382
Dronedarone 386
Nervous system adverse effects of triptans 408
Antihypertensive drugs and their adverse effects in the perioperative period 413
Thimerosal and neurodevelopment in infants 453
Titanium allergy 456
Pro-oxidant effects of deferiprone 468
Disinfectants and bacterial resistance 479
Triphenylmethane dyes 481
Carbapenems and seizures 491
Tetracyclines and the environment 497
Drug-drug interactions with antifungal azoles 545
Adverse metabolic effects of antiretroviral drugs 582
Amantadine and corneal edema 602
Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis 623
Antituberculosis drug treatment in transplant recipients 627
Problems in interpreting interaction studies with protease inhibitors in patients 628
co-infected with tuberculosis and AIDS
Dapsone-induced hematological abnormalities and their management 630
Pandemic inuenza H1N1 vaccines 659
Autism and vaccines 661
The risks of infections from transfusions 669
Vitamin A supplementation in infants at times of immunization 691
Aprotinin and renal function 724

xvi
Special reviews xvii

Cross-reactivity between thiopurines 824


Attitudes to the use of hormone replacement therapy 853
Can HRT activate latent breast cancer? 856
Intrauterine administration of levonorgestrel 865
Abuse of anabolic steroids and the justication of control measures 869
Is there an increased risk of cancer in patients using insulin? 890
Taxanes and other microtubule stabilizing agents 935
Use of carboxypeptidase in the treatment of methotrexate toxicity 950
Cardiotoxicity of mad honey 996
Cumulative indexes of special
reviews, Annuals 1132

1. Index of drugs
Note: the format 32.609 refers to SEDA-32, and ribostamycin, 15.270
p. 609. Amiodarone, dysrhythmias, 25.211
Abetimus, drug development, 29.460 eryptosis, 32.339
ACE inhibitors respiratory toxicity, 15.168
acetylsalicylic acid, interaction, 28.124 thyroid disease, 27.192, 31.327
angioedema, 22.225, 29.207, 31.352, 32.380 Amphetamines, 29.3
cough, 19.211 Amphotericin, liposomal, 17.319
indications, 24.233 nephrotoxicity, 13. 231, 14.229, 27.276
Acetaminophen, see Paracetamol Anabolic steroids
Acetylsalicylic acid, 21.100 abuse, 29.508, 32.751
ACE inhibitors, interaction, 28.124 Analgesics
antithrombotic effectiveness, 12.74 agranulocytosis and aplastic anemia, 11.87
benet to harm balance in preventing strokes choice of drug and dose, 12.63
and heart attacks, 27.109 headache, 21.95
co-medication, 26.423 headaches in children, 23.114
gastrointestinal effects, 17.95, 18.90 nephropathy, 21.98
Reye's syndrome, 11.79, 15.85 Androgens, in women, 24.477
rhinosinusitis/asthma, 17.94 Anesthesia, dental, safety of, 16.122
respiratory disease, 31.193 Anesthetics
sensitivity, 12.75 halogenated, renal damage, 20.106
Acupuncture local, and lipid emulsion, 32.261
incidence of adverse effects, 29.589 local, combinations, 20.121
traumatic effects, 29.590 local, lipid rescue, 31.231
Adenosine, dyspnea and bronchospasm, 32.337 local, neurotoxicity, 21.129, 25.152
Adrenaline, myocardial infarction and ocular, 17.542
vasospasm, 31.259 Angiotensin II receptor antagonists, angioedema
Aerosols, delivery, 27.172 30.238
Albumin, human, anaphylaxis, 14.296 Anisoylated plasminogen-streptokinase
Alcohol, 31.757 activator complex (APSAC), 12.313
vitamin A, beta-carotene, interaction, 24.442 Anorectic drugs
Aldosterone antagonists, in heart failure, 24.246 cardiac valvulopathy 22.3, 23.2, 24.4, 25.5
Alkylating drugs, 31.721 primary pulmonary hypertension, 18.7, 21.2,
Aluminium 23.2, 25.5
in albumin solutions, 23.359 Anthracyclines, 25.533
toxicity in children, 12.185 Antiallergic drugs, ocular treatment, 11.420
tumorigenicity, 31.383 Antibacterial drugs, resistance, 31.413, 32.445
Aminoglycoside antibiotics, 17.304 intrapartum, 32.446
contact dermatitis, 13.225 Anticancer antimetabolites, 29.531
dosage regimens, 20.234, 21.265, 23.264 Anticholinergic drugs, 22.507, 31.273
nephrotoxicity, 15.268, 17.305 cardiovascular risks, 32.318
ototoxicity, 14.222, 18.268 Anticoagulants, oral, skin necrosis, 29.358

xviii
Cumulative indexes of special reviews, Annuals 1132 xix

Anticonvulsants, see Antiepileptic drugs seizures, 18.261


Antidepressants, see also individual agents side chains, 16.264
during and after pregnancy, 21.17 Antioxidant vitamins, 20.363
and emergent suicidality, 32.29 Antiprotozoal drugs
mania, 29.18 African trypanosomiasis, 18.293
overdose, 28.14 toxoplasmosis, 20.262
pregnancy, 32.31 Antipsychotic drugs
relative risks, 11.16 comparisons of different
Antidysrhythmic drugs types 25.53, 27.50
in atrial brillation, 24.197 deaths, 32.89
prodysrhythmic effects, 17.218, 23.196 diabetes mellitus, 28.60
Antiepileptic drugs use in conditions other than schizophrenia,
bone loss, 27.74 27.49
comparison, 25.78 use in elderly patients, 30.59
death, 23.83 weight gain, 26.56
overdosage, 22.84 Antiretroviral drugs, metabolic complications,
psychiatric effects, 22.82, 27.72 28.329
Antiestrogens, genotoxicity and tumorigenicity, Antischistosomal drugs, 12.261
27.429 Antithyroid drugs, pregnancy, 13.377
Antifungal drugs Antituberculosis drugs, 16.341, 31.500
drug interactions (azoles), 24.318, 28.299, children, 32.557
29.282, 30.320, 31.459, 32.497 genetic susceptibility, 28.342
Pneumocystis jiroveci (carinii) pneumonia, hepatotoxicity, 25.363, 26.339, 31.495, 32.555
18.289 Mycobacterium aviumcomplex infection,
Antihelminthic drugs 20.278
Mazzotti reaction, 31.507 transplant recipients, 32.559
pharmacovigilance in developing countries, Appetite suppressants
32.571 cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5
Antihistamines primary pulmonary hypertension, 18.7, 21.2,
cardiovascular adverse effects, 17.196, 22.176, 23.2, 25.5
25.183, 26.180 Aprotinin, market withdrawal, 32.642
drowsiness/sedation, 21.170, 23.171, 26.182 Aripiprazole, 31.70
Antihypertensive drugs, 19.209 Arylpropionic acids, stereoisomers 32.229
in diabetes mellitus, 28.226 Aspirin, see Acetylsalicylic acid
xed-dose combinations, 22.224 Asthma medications, exacerbation of asthma,
individualizing therapy, 17.246 20.165
quality of life, 32.375 Atovaquone, 19.266
Antimalarial drugs, 14.237, 17.325, 20.257 Avoparcin
adjunctive treatments, 24.330 lessons from, 27.242
prophylaxis, 13.239, 23.304 resistance, 29.244
Antimicrobial drugs, see also different types Azathioprine, see Thiopurines
allergic reactions, 23.251 Azoles, see Antifungal drugs
coagulation disorders, 18.258
colitis, 12.216, 17.303 Baclofen, withdrawal syndrome, 26.152
intestinal motility, 13.220 Bambuterol, cardiac failure, 23.181
male fertility, 16.262 Benzodiazepines
new, 13.210 brain damage, 14.36
new, with adjuvants, 17.296 dependence, 12.41
the pill and pregnancy, 24, 274 depression, 17.43
policies and politics, 16.273 medicolegal aspects, 13.33
pregnancy, 11.231 Beta2-adrenoceptor agonists, 18.159
prescribing, 15.254 asthma, 19.178, 21.179
preterm infants, 21.258 asthma deaths, 17.164
prudent use, 25.279 , 27.242, 28. 265 long-acting, respiratory adverse effects,
resistance, 12.206, 13.210, 19.237, 20.228, 30.198, 31.309
21.257, 22.265, 23.250, 24.273, 29.244, long-acting, genetic susceptibility factors,
31.413 30.199, 31.310
xx Cumulative indexes of special reviews, Annuals 1132

Beta-adrenoceptor antagonists systemic brosis, 32.852


arthralgia, 11.164 Corticosteroids, see Glucocorticoids
sexual function, 15.188 Cosmetics
Beta-carotene, see also Vitamin A adverse reactions, 13/117
alcohol, vitamin A, interaction, 24.442 contact allergy, 11.142, 16.150, 19.151
tumorigenicity, 25.454 ingredient labeling 22.159
Beta-lactam antibiotics Co-trimoxazole, hypersensitivity reactions,
effects on eukaryotic cells, 13.212 20.264
immediate hypersensitivity reactions, 14.211 COX-2 inhibitors, 24.115, 25.126, 26.116
pregnancy, 25.280 cardiovascular disease, 29.116, 32.225
Blood, see Transfusions gastrointestinal adverse reactions, 32.225
Botulinum toxin A, use in primary axillary
hyperhidrosis, 27.161 Danaparoid sodium, 32.631
Budesonide, children, susceptibility factors, Daptomycin, muscle damage, 30.309
30.194 Deferiprone, cardiac siderosis, 29.235
Deferoxamine, 16.247
Calcium antagonists, long-term safety, 20.185, bone dysplasia, 23.241
21.208, 22.214 cardiac siderosis, 29.235
Carbamazepine, skin reactions, 32.129 bone dysplasia, 23.241
Carnitine, 13.269 cardiac siderosis, 29.235
Carotenoids, tumorigenicity, 25.454 yersiniosis, 11.215
Ceftriaxone, 15.258 Diamorphine, progressive spongiform
nephrolithiasis, 29.246 leukoencephalopathy, 24.40
Cephalosporins Diclofenac, liver damage, 20.91
immunological reactions, 28.267 Diethylstilbestrol, transgenerational effects,
hypersensitivity reactions, cross-reactivity with 31.657
penicillins, 30.280 Digitalis, in atrial brillation, 24.197
and vitamin K, 12.210 Digoxin, compared with other drugs in heart
Charcoal, activated, in digitalis overdose, 24.201 failure in sinus rhythm, 14.141
Chinese medicines, injectable formulations, compared with other drugs in chronic
32.880 uncomplicated atrial brillation, 14.144
Chloramphenicol, children, 15.267 in atrial brillation, 32.333
Chloroquine, 15.286 in heart failure in sinus rhythm, 18.196
Chondroprotective agents, 14.439 Dimethylfumarate, 32.295
Chymopapain, 11.279, 14.264 Dipeptidyl peptidase IV inhibitors, 30.498
Ciclesonide, 30.196 Diuretics
Ciclosporin, urinary system, 19.348 diabetes mellitus, electrolyte abnormalities,
Clozapine, 15.50 and the ALLHAT trial, 27.219
agranulocytosis, 22.1359 hyponatremia, 29.219
Cocaine interactions with NSAIDs, 12.80
cardiovascular reactions, 18.5 renal cell carcinoma, 23.225
fetotoxicity, 29.41, 30.35 renal insufciency, 25.250
prenatal exposure and perinatal effects, 27.1 thiamine deciency, 32. 401
second-generation effects, 20.24 DNA alkylating drugs, 31.721
Cocamidopropylbetaine, allergy, 19.151 Dofetilide, 26.208
Codeine, breast feeding, 31.154 Dopamine receptor agonists
Complementary and alternative therapies, pathological gambling, 30.174
indirect risks, 27.521 sleep disorders, 26.160, 27.149
esophagus, adverse effects on, 14.442 Doxylamine, overdose and rhabdomyolysis,
Contrast media 31.298
adverse reactions, 13.431, 24.525 Drotrecogin alfa (activated), 32.591
anaphylactoid and allergic reactions, 20.422
delayed reactions, 26.513 Ecstasy, see MDMA
in magnetic resonance imaging, 20.419 EDTA, pseudothrombocytopenia, 21.250
nephrotoxicity, 27.500, 28.556, 29.575, 31.731, Endothelin receptor antagonists, in
31.735, 32. 846 hypertension, 26.233
sialadenitis, 32.845 Enzyme inhibitors, 15.337
Cumulative indexes of special reviews, Annuals 1132 xxi

Epinephrine, see Adrenaline musculoskeletal adverse reactions, 21.417,


Erythromycin, versus the new macrolides, 21.269 32.312
Erythropoietin, pure red cell aplasia, 27.348 osteoporosis and osteonecrosis, 16.447,
status and safety, 16.400 19.377, 20.374, 21.417, 22.182, 28.473
Ethambutol, optic neuropathy, 30.358 preterm infants, 17.445
Ethylene oxide, dialyser hypersensitivity, Glucose solutions, hypophosphatemia, 11.312
11.219 Grapefruit juice, drug interactions 23.519
Etomidate, adrenal suppression, 32.249 Growth hormone
Etoposide, 27.477 adults, 16.501
Etretinate, ossication, 12.127 CreutzfeldtJakob disease, 11.371
Euxyl K 400, contact allergy, 16.150 insulin resistance, 24.504
malignancy, 23.468
Fat emulsions, priapism, 11.313
Felbamate Heparin
aplastic anemia, 19.68, 22.86 low-molecular-weight, 12.311
risk/benet ratio, 23.86 thrombocytopenia, 30.404, 32.626
Fenuramine Hepatitis B vaccine, demyelinating diseases,
cardiac valvulopathies, 22.3, 23.2, 24.4, 25.5 21.331, 22.346, 24.374
primary pulmonary hypertension, 18.7, 21.2, Herbal medicines, warfarin, interactions,
23.2, 25.5 30.400
Fenoterol, safety in severe asthma, 23.182 Heroin, see Diamorphine
Fentanyl, buccal and transdermal Histamine (H2) receptor antagonists, 13.330,
administration, 20.77 15.393
Fertility drugs HIV-protease inhibitors
malignant melanoma, 26.434 insulin resistance, 22.317
ovarian cancer, 24.474 lipodystrophy, 22.317
Finasteride, 30.480 HMG Co-A reductase inhibitors, interactions,
Fish oil, 13.460 25.530, 30.517
Flecainide, in supraventricular dysrhythmias, Hormone replacement therapy
21.200 cardiovascular reactions, 31.659
Fluoroquinolones, 12.250, 18.271 ovarian cancer, 32.740
Fluorouracil, adverse reactions, 23.476 Hormones, sex
Folic acid, dietary supplementation, 19.369 breast cancer 11.346
safety aspects, 27.407 tumors, 22.465
Formoterol, tolerance, 24.187 HRT, see Hormone replacement therapy
Fragrances, contact allergy, 20.149 5-HT, see Serotonin
Hydrochlorothiazide, non-cardiogenic
Gadolinium salts, nephrotoxicity, 28.561, 31.735, pulmonary edema, 31.373
32.852 Hypnotics, 20.30
General anesthetics, see Anesthetics avoiding adverse reactions, 21.37
Germanium, 16.545 Hypoglycemic drugs, combinations of, 27.458,
Glucocorticoids 28.521
bone, 16.447, 22.182, 25.195
contact allergy, 15.139, 21.158 Immunization
effective dose and therapeutic ratio, 23.175 adverse reactions, 24.364
and eyes, 29.481 and autoimmune disease, 27.336
and growth, 14.335 bioterrorism, 25.378, 26.354
inhaled, children, risks in, 27.174 multiple, 27.334
inhaled, effects on mouth and surveillance after, 15.340, 22.333, 23.335,
throat, 29.168 24.364, 25.376, 26.353, 27.334
inhaled, effects on skin, 29.169 Immunotherapy, in leishmaniasis, 15.299
inhaled, fracture risk, 31.307 Incretin mimetics, 29.528
inhaled, growth inhibition, 26.186 Indacaterol, 32.317
inhaled, hypothalamicpituitaryadrenal Indometacin, fetal and neonatal complications,
gland function, 31.305 18.102
inhaled, pneumonia risk, 32.311 Inuenza vaccine, 29.332
inhaled, systemic availability, 24.185, 26.187 Inhalations, 11.151
xxii Cumulative indexes of special reviews, Annuals 1132

Insulin Macrolides, drug interactions, 14.220


edema, 11.364 intestinal motility, 18.269
human, and hypoglycemia, 15.452 Malaria vaccines, 22.306
inhalation, 30.495 Mannitol, 28.236
modes of administration, 26.464 MAO inhibitors, see Monoamine oxidase
resistance, and growth hormone, 24.504 inhibitors
synthetic analogues, 24.489 MDMA (ecstasy)
Interferon ribavirin, 30.344 cognitive reactions, 26.32, 32.63
Interferons, psychological and psychiatric deaths, 24.32
reactions, 29.384 epidemiology of use, 30.37
Interleukin-2, 14.325 Measles immunization, see also MMR
Ipecacuanha, myopathy, 11.422 autism, 23.350
Irinotecan, 27.477 Crohn's disease, 23.350
Iodine, radioactive, 11.358 neurological adverse reactions, 23.348
Iron chelators, combinations, 31.399 subacute sclerosing panencephalitis, 29.335
Isoniazid Mebendazole, hypersensitivity reactions, 12.263
genetic susceptibility factors, 12.257 Melatonin, 25.523
prophylactic, toxicity, 24.352 Mercaptopurine, see Thiopurines
Metamfetamine, 29.3
Kathon CG, 31.134 Metformin
Kava kava contraindications, 28.515
liver damage, 27.518 lactic acidosis, 23.459, 29.526
adverse reactions, 28.579 Methyldibromoglutaronitrile, contact allergy,
Ketoconazole, hepatotoxicity, 12.229 16.150, 19.151
Ketorolac, risk of adverse reactions, 17.110 Methylphenidate, effects at different ages, 31.6
Khat, 30.43 Methylthiotetrazole, 11.226
Mibefradil, drug interactions, 23.210
Lamotrigine, skin rashes, 20.62, 24.88 Midazolam, 15.112
Latex, allergy, 31.761 Midodrine, 26.159
Laxatives, abuse, 13.336 Milrinone, intravenous, acute heart failure,
Leunomide, 29.435 21.196
Leukotriene receptor antagonists, MMR immunization
ChurgStrauss syndrome, 24.183, 27.177, autism, 23.350, 25.387, 28.363
29.174 Crohn's disease, 23.350, 25.387
Levacetylmethadol, 32.193 Mometasone furoate, 30.197
Levodopa, and malignant melanoma, 31.267 Monoamine oxidase inhibitors, 12.8, 13.6, 17.361
Lipid-lowering drugs, 13.402, 15.479 Monofunctional alkylating agents, 32.827
Lithium Morphine, managing adverse reactions, 26.98
adverse reactions, prevention and treatment, Muscle relaxants
13.17, 17.28 emergency medicine, 20.133
benecial uses other than in bipolar disorder, eyes, 21.145
27.19 hypersensitivity reactions, 27.138
efcacy, comparisons with other intensive care, 19.140
agents, 30.23
interactions, 16.13, 18.30 Neuromuscular blocking agents, anaphylaxis,
intoxication, prevention and 29.145
treatment, 17.29 non-depolarizing neuromuscular blockers,
monitoring therapy, 11.24, 18.25 15.127
mortality, 19.14 recovery in intensive care, 12.114
neuroprotection, 32.41 residual paralysis, 27.139
urinary system, 14.18, 19.16 Niacin, extended-release, 16.440
thyroid, 12.26 N-Lost derivatives, 31.721
Local anesthetics, see Anesthetics Nomifensine, 11.15
Loop diuretics, see Diuretics NSAIDs, see also COX-2 inhibitors
Lorenzo's oil, 27.475 acute renal insufciency, 28.122
Lyme disease vaccine, autoimmune disease, blood pressure, 19.92, 27.102
24.366 cardiovascular adverse reactions, 32.225
Cumulative indexes of special reviews, Annuals 1132 xxiii

children, 19.96 infections 22.379


current controversies, 17.102 Penicillins
COX-2 inhibitors, 24.115, 25.126, 26.116 acute desensitization, 23.252
dyspepsia, 28.120 hypersensitivity reactions, cross-reactivity with
gastrointestinal adverse reactions, 14.79, cephalosporins, 30.280
17.95, 18.90, 18.99, 20.86, 21.96, 22.108, immunological reactions, 28.267
23.114, 32.225 Peritoneal dialysis uids, effects on peritoneum,
gastrointestinal damage, role of Helicobacter 22.381
pylori, 27.105 Peroxisome proliferator-activated receptors, see
gastrointestinal damage, reducing, also Thiazolidinediones
30.125 dual agonists, 32.782
gastrointestinal toxicity, prevention, 19.93 Pertussis vaccine, 11.284, 11.285
inammatory bowel disease, 25.131 Phentermine, cardiac valvulopathies, 24.4
inhibiting cardioprotective effects of Pholcodine, 32.206
acetylsalicylic acid, 28.118 Photodynamic therapy, cancers 32.832
interactions with diuretics, 12.80 Phytoestrogens, in foodstuffs, 31.655
intracerebral hemorrhage, 28.119 Pilsicainide, 32.348
necrotizing fasciitis, 28.121 Piroxicam
nephrotoxicity, 11.82, 18.100, 20.89, 24.120, gastrointestinal reactions, 11.97, 12.91
26.111 Pivalic acid, and carnitine, 12.209
osteoarthritis, 11.87 Platinum compounds, 26.490
skin reactions, 13.72 Polio vaccine, AIDS, 23.352
topical, 18.163 Polyaspartic acid, protective against
nephrotoxicity, 17.305
Ocular drugs Polyethylene glycol, electrolyte, mineral, metal,
allergic reactions, 21.486 and uid balance, 29.376
geriatric patients, 16.542 Polystyrene sulfonates, 25.271
risk factors for adverse reactions, 22.507 Polyvinylpyrrolidone, storage disease, 22.522
Omeprazole, tumors, 16.423 PPAR, see Peroxisome proliferator-activated
Opioids receptors
abuse, 29. 44 Pregabalin, 30.86
adverse reactions, frequency, 32.183 Propofol
adverse reactions, prevention, 24.100 infusion syndrome, 26.135
death, 25.37 prevention of pain, 30.143
obstetric use, 24.102 Propolis, allergy, 17.181
routes of administration, 30.106 Proton pump inhibitors, tumors, 23.383
tolerance in neonates, 23.97 Psilocybin, 31.49
Oral contraceptives PUVA, malignant melanoma, 22.166
antimicrobial drugs, and pregnancy, 24.274 Pyrazinamide, in latent pulmonary tuberculosis,
and breast cancer, 15.426 27.323
formulations, 24.472 Pyrimethamine sulfadoxine, prevention of
third-generation, 25.484, 26.442 malaria, 32.523
venous thromboembolism, 23.442
Orlistat, 30.429 Quinidine, versus quinine, 15.295
Oxymorphone, 32.203 Quinine, versus quinidine, 15.295
Paclitaxel, adverse reactions, 21.463
Pancreatic enzyme supplements, brosing Rasagiline, 31.270
colonopathy, 20.322 Rasburicase, 31.203
Renin inhibitors, 30.242
Paracetamol Rhesus anti-D, prophylaxis, 13.297
asthma, 30.129 Ribavirin interferon, 30.344
hepatotoxicity in alcoholism, 12.76 Ribostamycin, and aminoglycosides, 15.270
liver damage, 17.98, 18.94 Rocuronium, allergic reactions, 26.150
overdose, 13.68, 23.117 and pholcodine, 31.249
Parenteral nutrition Rotashield, intussusception, 23.354
bone reactions, 22.378 Rotavirus vaccine, Kawasaki disease, 31.522
cholestasis, 22.376 Rubella vaccine, joints, 11.295
xxiv Cumulative indexes of special reviews, Annuals 1132

Salbutamol, adrenoceptor genotypes, 29.173 Topiramate, cognitive reactions, 26.81


Salmeterol, tolerance, 24.187 Topoisomerase inhibitors, 27.477
Sapropterin, 32.609 Topotecan, 27.477
Sedatives, 29.128 Trocetrapib, 32.816
Sex hormones, tumors, 22.465 Transfusions
Serotonin AIDS, 12.298
receptor antagonists, 15.391 complications, 12.300
selective serotonin reuptake inhibitors, drug Tretinoin, topical, teratogenicity, 18.164
interactions, 22.13 Triazolam, 16.33
selective serotonin reuptake inhibitors, Tricyclic antidepressants
gastrointestinal bleeding, 32.33 endocrine reactions, 11.12
selective serotonin reuptake inhibitors, mania, 13.8
suicidal behavior, 29.19, 31.18 L-tryptophan, eosinophiliamyalgia syndrome,
Smallpox vaccination, 27.339 15.514
Somatostatin, 15.468 Tumor necrosis factor antagonists, infection risk,
Spinal manipulation, adverse reactions, 29.591 29.395, 31.594
SSRIs, see Serotonin Tyrosine kinase inhibitors, 30.520
Statins, see HMG Co-A reductase inhibitors
Steroids, see Glucocorticoids Vaccines, see also individual agents
Stimulants, in ADHD, 31.4 adjuvants, 32.577
Sugammadex, 32.275 autism, 31.516
Sulfonamide derivatives, hypersensitivity combinations, 29.327, 30.369
reactions, 30.252 GuillainBarr syndrome, 31.515
Sumatriptan, 17.171 HIV-infected individuals, 12.269
Suprofen, nephrotoxicity, 12.88 Kawasaki disease, 31.522
Suramin, patients with prostate cancer, 20.283 national compensation systems, 12.271
Surgam, gastric reactions, 12.89 poliomyelitis, 22.352
Suxamethonium, postoperative myalgia, thiomersal in, 28.357
28.155 Valproate, overdose, 32.157
polycystic ovary syndrome, 26.81
Tamoxifen, versus aromatase Vancomycin
inhibitors, 30.475 lessons from, 27.242
Teniposide, 27.477 resistance, 29.244
Tetracyclines Vigabatrin
adverse reactions, 12.212, 26.268 psychosis and abnormal behavior, 18.71
chemically modied, 31.419 visual eld defects, 21.78, 24.95,
comparative toxicity, 22.268 25.98, 26.82
and metalloproteinases, 26.266 Vinca alkaloids, 28.538
non-antimicrobial properties, 30.288 Vitamin A, 17.436
in pregnancy, 25.280 alcohol, beta-carotene, interaction, 24.442
in rheumatology, 23.255 hypervitaminosis, 15.411
therapeutic effects, 24.278 in pregnancy, 21.405
Tetrahydrobiopterin, 32.609 and prostate cancer, 13.346
TGN 1412, 32.642 Vitamin B6, debate, 23.420
Theophylline, asthma, 17.2, 18.1, 18.2 Vitamin E, co-medication, 26.423
Thiazides, see Diuretics Vitamin K
Thiazolidinediones cancer, 23.424
cardiovascular reactions, 31.697 skin reactions, 25.461
musculoskeletal reactions, 32.779 Vitamins, in old age, 22.431
peripheral edema, 29.531
Thiomersal, in vaccines, 28.357 Warfarin, herbal medicines, interactions,
Thiopurines, genetic susceptibility, 31.634 30.400
Thyroid hormones, 29.464
Thyroxine, drug interactions, 24.484 Ximelagatran, hepatotoxicity, 30.411
Tiaprofenic acid, cystitis, 18.106
TNF, see tumor necrosis factor Zidovudine, 13.246
Tolcapone, 32.289 Zileuton, 32.322
Cumulative indexes of special reviews, Annuals 1132 xxv

2. Index of adverse reactions dyspnea, adenosine, 32.337


long-acting beta2-adrenoeceptor agonists,
31.309
Cardiovascular pneumonia, glucocorticoids, 32.311
anticholinergic drugs, 32.318 primary pulmonary hypertension, appetite
atrial brillation, antidysrhythmic drugs, suppressants, 18.7, 21.2, 23.2, 25.5
24.197 pulmonary edema, non-cardiogenic,
atrial brillation, digitalis, 24.197 hydrochlorothiazide, 31.373
cardiac failure, aldosterone antagonists, rhinosinusitis, acetylsalicylic acid, 17.94
24.246 Ear, nose, throat
cardiac failure, bambuterol, 23.181 glucocorticoids, inhaled, 29.168
cardiac siderosis, deferoxamine/deferiprone, Nervous system
29.235 anticholinergic effects, 31.273
cardiotoxicity, antihistamines, 17.196, 25.183, brain damage, benzodiazepines, 14.36
26.180 CreutzfeldtJakob disease, growth hormone,
cardiotoxicity, calcium antagonists, 20.185 11.371
cardiotoxicity, cocaine, 18.5 demyelinating diseases, hepatitis B vaccine,
cardiotoxicity, coxibs, 29.116 21.331, 22.346, 24.374
cardiotoxicity, hormone replacement therapy, drowsiness/sedation, antihistamines, 21.170,
31.659 23.171, 26.182
cardiotoxicity, propofol, 26.135 GuillainBarr syndrome, vaccines 31.515
cardiotoxicity, thiazolidinediones, 31.697 headache, analgesics, 21.95, 23.114
dysrhythmias, antihistamines, 22.176 intracerebral hemorrhage, NSAIDs, 28.119
dysrhythmias, amiodarone, 25.211 neuroleptic malignant syndrome, 11.47, 20.41
hypertension, NSAIDs, 19.92, 27.102 neurotoxicity, anesthetics, local, 21.129
myocardial infarction, acetylsalicylic acid, neurotoxicity, measles immunization, 23.348
27.109 overdosage, antiepileptic drugs, 22.84
myocardial infarction, adrenaline, 31.259 pain, propofol, 30.143
NSAIDs, 32.225 poliomyelitis, vaccines, 22.352
prodysrhythmic reactions, antidysrhythmic progressive spongiform leukoencephalopathy,
drugs, 17.218, 23.196 diamorphine, 24.40
QT interval prolongation, 24.54 seizures, antimicrobial drugs, 18.261
valvulopathies, fenuramine, 22.3, 23.2, 24.4, sleep disorders, dopamine receptor agonists,
25.5 26.160, 27.149
valvulopathies, phentermine, 24.4, 25.5 strokes, acetylsalicylic acid, 27.109
vasospasm, adrenaline, 31.259 strokes, risperidone, 28.76
venous thromboembolism, oral subacute sclerosing panencephalitis, measles
contraceptives, 23.442 vaccine, 29.335
Respiratory tardive dyskinesia, 14.47, 20.38
amiodarone, 15.168 tardive syndromes, 17.54
asthma, acetylsalicylic acid, 17.94, 31.193 transient symptoms, intrathecal anesthetics,
asthma, fenoterol, 23.182 25.152
asthma, paracetamol, 30.129 Neuromuscular
asthma, in pregnancy, 28.186 residual paralysis, neuromuscular blocking
asthma deaths, beta2-adrenoceptor agonists, drugs, 27.139
17.164 Sensory systems
asthma exacerbation, asthma medications, eye reactions, drug abuse, 12.33
20.165 eye reactions, glucocorticoids, 29. 481
beta2-adrenoceptor agonists, long-acting, eye reactions, muscle relaxants, 21.145
30.198 optic neuropathy, ethambutol, 30.358
bronchoconstriction, paradoxical, nebulizer ototoxicity, aminoglycosides, 14.222, 18.268
solutions, 13.134 visual eld defects, vigabatrin, 21.78, 24.95,
bronchospasm, adenosine, 32.337 25.98, 26.82
ChurgStrauss syndrome, leukotriene Psychological
receptor antagonists, 24.183, 27.177, cognitive reactions, MDMA, 26.32, 32.63
29.174 cognitive reactions, metamfetamine, 29.3
cough, ACE inhibitors, 19.211 cognitive reactions, topiramate, 26.78
xxvi Cumulative indexes of special reviews, Annuals 1132

Psychological (cont) polyethylene glycol, 29.376


gambling, dopamine receptor agonists, 30.174 Hematologic
interferons, 29.384 agranulocytosis, analegsics, 11.89
Psychiatric agranulocytosis, clozapine, 22.59
antiepileptic drugs, 22.82, 27.72 aplastic anemia, analegsics, 11.89
autism, MMR/measles immunization, 23.350, aplastic anemia, felbamate, 19.68, 22.86
25.387, 28.363, 31.516 coagulation disorders, beta-lactam antibiotics,
depression, benzodiazepines, 17.43 18.258
mania, antidepressants, 13.8, 29.18 eosinophiliamyalgia syndrome, tryptophan,
interferons, 29.384 15.514
psychosis and abnormal behavior, vigabatrin, hemolytic disease of the newborn, anti-D
18.71 prophylaxis, 12.293
suicidal behavior, antidepressants, 32. 29 hemostasis, cephalosporins, 12.210
suicidal behavior, SSRIs, 29.19, 31.18 pseudothrombocytopenia, EDTA, 21.250
Endocrine pure red cell aplasia, erythropoietin, 27.348
Adrenal suppression, etomidate, 32.249 thrombocytopenia, heparin, 30.404, 32.626
diabetes mellitus, antihypertensive drugs, Mouth
28.226 Glucocoricoids, inhaled, 29.168
diabetes mellitus, antipsychotic drugs, 28.60 Salivary glands
diabetes mellitus, diuretics, 27.219 sialadenitis, iodinated contrast media, 32.845
hypothalamicpituitaryadrenal gland Gastrointestinal
function, inhaled glucocorticoids, 31.305 bleeding, acetylsalicylic acid, 17.95, 18.90
insulin resistance, growth hormone, 24.504 cholestasis, total parenteral nutrition, 22.376
insulin resistance, HIV-protease inhibitors, colitis, antimicrobial drugs, 12.216, 17.303
22.317 Crohn's disease, MMR/measles immunization,
ovarian hyperstimulation syndrome, 23.350, 25.387
valproate, 26.477 dyspepsia, NSAIDs, 28.120
polycystic ovary syndrome, valproate, 26.81 brosing colonopathy, pancreatic enzyme
thyroid disease, amiodarone, 27.192, 31.310 supplements, 20.322
thyroid disease, lithium, 12.26 inammatory bowel disease, NSAIDs, 25.131
tricyclic antidepressants, 11.12 intestinal motility, antimicrobial drugs, 13.220
Metabolism intestinal motility, macrolides, 18.269
antiretroviral drugs, 28.329 intussusception, Rotashield, 23.354
hyperlactatemia, 29.302 NSAIDs, 32.225
hypoglycemia, insulin, 15.452 piroxicam, 12.91
lactic acidosis, metformin, 23.459, 29.526 SSRIs, 32.33
lipoatrophy, 29.302 Surgam, 12.89
lipodystrophy, HIV-protease inhibitors, ulceration, bleeding and perforation,
22.317 NSAIDs, 11.97, 14.79, 16.103, 17.95,
metabolic acidosis, propofol, 26.135 18.90, 18.99, 19.93, 20.86, 21.96, 22.108,
mitochondrial toxicity, 29.302 23.114, 27.105, 30.125
polyvinylpyrrolidone storage disease, 22.522 Liver
weight gain, antipsychotic drugs, 26.56 hepatotoxicity, alcohol/vitamin A/beta-
Nutrition carotene, 24.442
thiamine deciency, diuretics, 32.401 hepatotoxicity, antituberculosis drugs, 25.363,
Electroyte balance 26.339, 31.495, 32.555
electrolyte abnormalities, diuretics, 27.219, hepatotoxicity, diclofenac, 20.91
29.219 hepatotoxicity, kava kava, 27.518
polyethylene glycol, 29.376 hepatotoxicity, ketoconazole, 12.229
Mineral balance hepatotoxicity, paracetamol, 12.76, 17.98,
hypophosphatemia, glucose solutions, 11.312 18.94
polyethylene glycol, 29.376 hepatotoxicity, ximelagatran, 30.411
Metal balance Reye's syndrome, acetylsalicylic acid, 11.79,
polyethylene glycol, 29.376 15.85
Fluid balance Urinary tract
edema, insulin, 11.364 acute renal insufciency, NSAIDs, 28.122
edema, thiazolidinediones, 29.531 cystitis, tiaprofenic acid, 18.106
Cumulative indexes of special reviews, Annuals 1132 xxvii

nephrolithiasis, ceftriaxone, 29.246 rhabdomyolysis, doxylamine overdose, 31.298


nephrotoxicity, aminoglycosides, 15.268, rhabdomyolysis, propofol, 26.135
17.305 postoperative myalgia, suxamethonium,
nephrotoxicity, amphotericin, 13.231, 14.229, 28.155
27.276 Sexual function
nephrotoxicity, analgesics, 21.98 beta-adrenoceptor antagonists, 15.188
nephrotoxicity, anesthetics, halogenated, priapism, fat emulsions, 11.313
20.106 Immunologic
nephrotoxicity, ciclosporin, 19.348 allergic reactions, antimicrobial drugs, 23.251
nephrotoxicity, contrast media, 27.500, 28.556, allergic reactions, contact allergy, cosmetics,
29.575, 31.731, 31.735, 32.846 11.142
nephrotoxicity, gadolinium salts, 28.561 allergic reactions, contact allergy, Kathon
nephrotoxicity, lithium, 14.18, 19.16 CG, 11.134
nephrotoxicity, NSAIDs, 11.82, 18.100, 20.89, allergic reactions, latex, 31.761
24.120, 26.111 allergic reactions, rocuronium, 26.150
nephrotoxicity, suprofen, 12.88 allergy testing, chymopapain, 11.279
renal cell carcinoma, diuretics, 23.225 anaphylaxis, human albumin, 14.296
renal insufciency, diuretics, 25.250 anaphylaxis, neuromuscular blocking agents,
Skin 29.145
contact allergy, 23.160 angioedema, ACE inhibitors, 22.225, 29.207
contact allergy, glucocorticoids, 15.139 aspirin sensitivity, 12.75
contact dermatitis, aminoglycosides, 13.225 autoimmune disease, immunizations, 27.336
cutaneous reactions, NSAIDs, 13.72 autoimmune disease, Lyme disease vaccine,
glucocorticoids, inhaled, 29.169 24.366
necrosis, oral anticoagulation, 29.358 cocamidopropylbetaine, 19.151
rashes, lamotrigine, 20.62, 24.88 contrast agents, 20.422
serious reactions, carbamazepine, 32.129 cosmetics, 16.150, 19.151
systemic brosis, contrast media, 32.852 co-trimoxazole, 20.264
vitamin K1, 25.461 desensitization, penicillin, 23.252
Serosae Euxyl K 400, 16.150
peritoneum, peritoneal dialysis, 22.381 fragrances, 20.149
pleurodesis, 25.189 glucocorticoids, 21.158
Musculoskeletal hypersensitivity reactions, beta-lactam
arthralgia, beta-adrenoceptor antagonists, antibiotics, 14.211, 30.280
11.164 hypersensitivity reactions, ethylene oxide,
arthralgia, rubella vaccination, 11.295 11.219
bone, total parenteral nutrition, 22.378 hypersensitivity reactions, muscle relaxants,
bone dysplasia, deferoxamine, 23.241 27.138
bone loss, antiepileptic drugs, 27.74 hypersensitivity reactions, mebendazole,
bone mineral density, glucocorticoids, 25.195 12.263
eosinophiliamyalgia syndrome, tryptophan, hypersensitivity reactions, rocuronium,
15.514 31.249
fractures, inhaled glucocorticoids, 31.307, hypersensitivity reactions, sulfonamide
32.312 derivatives, 30.252
fractures, thiazolidinediones, 32.779 immune reconstitution disease, 29.315
growth in children, inhaled glucocorticoids, Kawasaki disease, rotavirus vaccine, 31.522
26.186 Mazzotti reaction, antihelminthic drugs,
growth in children, oral glucocorticoids, 31.507
14.335 methyldibromoglutaronitrile, 16.150, 19.151
growth in children, stimulants, 31.4 ocular drugs, 21.486
muscle damage, daptomycin, 30.309 propolis, 17.181
myopathy, ipecacuanha, 11.422 red man syndrome, 17.312
ossication, etretinate, 12.127 Autacoids
osteoarthritis, NSAIDs, 1187 angioedema, angiotensin converting enzyme
osteoporosis and osteonecrosis, inhibitors, 31.352, 32. 380
glucocorticoids, 16.447, 19.377, 20.374, angioedema, angiotensin II receptor
21.417, 22.182, 28.473 antagonists, 30.238
xxviii Cumulative indexes of special reviews, Annuals 1132

Infection risk asthma, 28.186


AIDS, polio vaccine, 23.352 beta-lactams, 25.280
AIDS, transfusions, 12.298 cocaine, 27.1
necrotizing fasciitis, NSAIDs, 28.121 opioids, 24.102
total parenteral nutrition, 22.379 tetracyclines, 25.280
tumor necrosis factor antagonists, 29.395, vitamin A, 21.405
31.594 Teratogenicity
yersiniosis, deferoxamine, 11.215 antibiotics, 11.231
Body temperature tretinoin, topical, 18.164
malignant hyperthermia, 18.112 Fetotoxicity
Trauma cocaine, 20.24, 27.1, 29.41, 30.35
acupuncture, 29.590 diethylstilbestrol, transgenerational reactions,
Death 31.657
antiepileptic drugs, 23.83 indometacin, 18.102
antipsychotic drugs, 32.89 Lactation
calcium antagonists, 22.214 cocaine, 31.154
digoxin, 32.333 Susceptibility factors
ecstasy, 24.32 age, methylphenidate, 31.6
lithium, 19.14 children, aluminium, 12.185
opiates, 25.37, 29.44 children, antituberculosis drugs, 32.557
Drug abuse children, budesonide, 30.194
anabolic steroids, 29.508, 32.751 children, inhaled glucocorticoids 27.174
Drug tolerance children, NSAIDs, 19.96
antimicrobial drug resistance, 11.223, 12.208, elderly patients, antipsychotic drugs, 30.59
19.237, 20.228, 21.257, 22.265, 23.250, genetic susceptibility, antituberculosis drugs,
24.273, 25.279, 29.244, 31.413, 32.445 28.342
opioids in neonates, 23.97 genetic susceptibility, beta-adrenoceptor
Drug dependence agonists, 29.173, 30.199, 31.310
benzodiazepines, 12.41 genetic susceptibility, isoniazid, 12.257
Drug withdrawal genetic susceptibility, thiopurine toxicity,
baclofen, 26.152 31.634
Genotoxicity HIV infection, immunization, 12.269
antiestrogens, 27.429 intensive care, muscle relaxants, 19.140
Tumorigenicity neonatal complications, indometacin, 18.102
alcohol/vitamin A/beta-carotene, 24.442 ocular drugs, 22.507
aluminium, 31.383 old age, vitamins, 22.431
antiestrogens, 27.429 preterm infants, beta-lactam antibiotics,
beta-carotene, 25.454 21.258
carotenoids, 25.454 transplant recipients, antituberculosis drugs,
fertility drugs, 24.474, 26.434 32.559
growth hormone, 23.468 Drug administration
hormone replacement therapy, 32.740 delivery of aerosols, 27.172
levodopa, 31.267 dosage regimens, aminoglycosides, 23.264
omeprazole, 16.423 errors, 28.587, 29.596
oral contraceptives, 11.346, 15.426 formulations, oral contraceptives, 24.472
proton pump inhibitors, 23.383 inhaled glucocorticoids, systemic availability,
PUVA, malignant melanoma, 22.166 24.185
sex hormones, 22.465 inhaled insulin, 30.495
vitamin K, 23.424 intravitreal and parabulbar injection,
Fertility 29.581
fertility, male, antimicrobial drugs, 16.262 labeling problems, cosmetics, 22.159
Pregnancy opioids, 30.106
affective disorders in, 21.17 Drug overdose
antibiotics, 11.231, 32.446 antidepressants, 28.14
antidepressants, 32.31 digitalis, charcoal, 24.201
antimicrobial drugs and the pill, 24.274 paracetamol, 23.117
antithyroid drugs, 13.377 valproate, 32.157
Cumulative indexes of special reviews, Annuals 1132 xxix

Drug formulations monoamine oxidase inhibitors/foods, 13.6


enantiomers and racemates, 13.442 NSAIDs/ACE inhibitors, 28.122
Drugdrug interactions paracetamol, 13.68
acetylsalicylic acid/ACE inhibitor, 28.124 selective serotonin reuptake inhibitors, 22.13
acetylsalicylic acid/NSAIDs, 28.118 thyroxine, 24.484
alcohol/vitamin A/beta-carotene, 24.442 Management of adverse drug reactions
antimicrobial drugs/the pill, 24.274 local anesthetics, lipid emulsion, 32.261
antifungal azoles, 24.318, 28.299, 29.282, Methods
30.320, 31.459, 32.497 ethnopharmacology, 14.429
diuretics/NSAIDs, 12.80 eukaryotic cells, effects of beta-lactams,
grapefruit juice, 23.519 13.212
herbal medicines/warfarin, 30.400 hemolytic disease of the newborn,
HMG Co-A reductase inhibitors, 25.530, prophylaxis, 13.297
30.517 lithium, monitoring, 11.24
lithium, 16.13 local anesthetic toxicity, lipid rescue, 31.231
lithium/selective serotonin reuptake onchocerciasis, treatment, 14.261
inhibitors, 18.30 post-marketing surveillance, 14.210, 15.266,
macrolides, 14.220 24.274
mibefradil, 23.210
Table of Essays, Annuals 132
SEDA Author Country Title

1 M.N.G. Dukes The Netherlands The moments of truth


2 K.H. Kimbel Germany Drug monitoring: why care?
3 L. Lasagna USA Wanted and unwanted
drug effects: the need for perspective
4 M.N.G. Dukes The Netherlands The van der Kroef syndrome
5 J.P. Grifn, P.F. D'Arcy UK Adverse reactions to drugsthe information lag
6 I. Bayer Hungary Science vs practice and/or practice vs science
7 E. Napke Canada Adverse reactions: some pitfalls and postulates
8 M.N.G. Dukes Denmark The seven pillars of foolishness
9 W.H.W. Inman UK Let's get our act together
10 S. Van Hauen Denmark Integrated medicine, safer medicine and AIDS
11 M.N.G. Dukes Denmark Hark, hark, the ctitious dogs do bark
12 M.C. Cone Switzerland Both sides of the fence
13 C. Medawar UK On our side of the fence
14 M.N.G. Dukes, E. Helsing Denmark The great cholesterol carousel
15 P. Tyrer UK The nocebo effectpoorly known but getting
stronger
16 M.N.G. Dukes Denmark Good enough for Iganga?
17 M.N.G. Dukes Denmark The mists of tomorrow
18 R.D. Mann UK Databases, privacy, and condentialitythe effect
of proposed legislation on pharmacoepidemiology
and drug safety monitoring
19 A. Herxheimer UK Side effects: freedom of information and the
communication of doubt
20 E. Ernst UK Complementary/alternative medicine: what should
we do about it?
21 H. Jick USA Thirty years of the Boston Collaborative Drug
Surveillance Program in relation to principles
and methods of drug safety research
22 J.K. Aronson, RE Ferner UK Errors in prescribing, preparing, and giving
medicines: denition, classication, and prevention
23 K.Y. Hartigan-Go, Philippines Inclusion of therapeutic failures as adverse drug
J.Q. Wong reactions
24 I. Palmlund UK Secrecy hiding harm: case histories from the past
that inform the future
25 L. Marks UK The pill: untangling the adverse effects of a drug
26 D.J. Finney UK From thalidomide to pharmacovigilance:
a personal account
26 L.L. Iversen UK How safe is cannabis?
27 J.K. Aronson UK Louis LewinMeyler's predecessor
27 H. Jick USA The General Practice Research Database
28 J.K. Aronson UK Classifying adverse drug reactions in the 21st century
29 M. Hauben, A. Bate USA/Sweden Data mining in drug safety
30 J.K. Aronson UK Drug withdrawals because of adverse effects
31 J. Harrison, P. Mozzicato USA MedDRA: the Tale of a Terminology
32 K. Chan Australia Regulating complementary and alternative medicines

xxx
Mechanistic and clinical
descriptions of
adverse drug reactions
Adverse drug reactions are described in the Side Effects of Drugs Annuals using two com-
plementary systems, EIDOS and DoTS [13]. These two systems are illustrated in Figures 1
and 2. Examples of their use have been discussed elsewhere [48].

1. EIDOS
The EIDOS mechanistic description of adverse drug reactions [3] has ve elements:

the Extrinsic species that initiates the reaction (Table 1);


the Intrinsic species that it affects;
the Distribution of these species in the body;
the (physiological or pathological) Outcome (Table 2), which is the adverse effect;
the Sequela, which is the adverse reaction.

Extrinsic species This can be the parent compound, an excipient, a contaminant or adulter-
ant, a degradation product, or a derivative of any of these (e.g. a metabolite) (for examples
see Table 1).
Intrinsic species This is usually the endogenous molecule with which the extrinsic species
interacts; this can be a nucleic acid, an enzyme, a receptor, an ion channel or transporter,
or some other protein.
Distribution A drug will not produce an adverse effect if it is not distributed to the same
site as the target species that mediates the adverse effect. Thus, the pharmacokinetics of
the extrinsic species can affect the occurrence of adverse reactions.
Outcome Interactions between extrinsic and intrinsic species in the production of an
adverse effect can result in physiological or pathological changes (for examples see
Table 2). Physiological changes can involve either increased actions (e.g. clotting due to
tranexamic acid) or decreased actions (e.g. bradycardia due to beta-adrenoceptor antago-
nists). Pathological changes can involve cellular adaptations (atrophy, hypertrophy, hyper-
plasia, metaplasia, and neoplasia), altered cell function (e.g. mast cell degranulation in
IgE-mediated anaphylactic reactions), or cell damage (e.g. cell lysis, necrosis, or apoptosis).
Sequela The sequela of the changes induced by a drug describes the clinically recognizable
adverse drug reaction, of which there may be more than one. Sequelae can be classied
using the DoTS system.

xxxi
xxxii Mechanistic and clinical descriptions of adverse drug reactions

1. EIDOS: a mechanistic description 2. DoTS: a clinical description


Drug Dose-relatedness

Drug
Extrinsic
on
u ti
trib
Dis

Intrinsic Outcome Patient Adverse reaction

Patient Adverse reaction Susceptibility factors Time course

Figure 1. The EIDOS and DoTS systems of describing adverse drug reactions.

Dose-relation
(benefit:harm)

Drug

Extrinsic
on
uti
trib

Outcome
Dis

Intrinsic Sequela
Patient Adverse reaction
Susceptibility Time course

Figure 2. How the EIDOS and DoTS systems relate to each other.
Mechanistic and clinical descriptions of adverse drug reactions xxxiii

Table 1 The EIDOS mechanistic description of adverse drug effects and reactions

Feature Varieties Examples

E. Extrinsic species 1. The parent compound Insulin


2. An excipient Polyoxyl 35 castor oil
3. A contaminant 1,1-Ethylidenebis
[L-tryptophan]
4. An adulterant Lead in herbal medicines
5. A degradation product formed Outdated tetracycline
before the drug enters the
body
6. A derivative of any of these Acrolein (from
(e.g. a metabolite) cyclophosphamide)
I. The intrinsic species and the
nature of its interaction with
the extrinsic species
(a) Molecular 1. Nucleic acids
 DNA Melphalan
 RNA Mitoxantrone
2. Enzymes
 Reversible effect Edrophonium
 Irreversible effect Malathion
3. Receptors
 Reversible effect Prazosin
 Irreversible effect Phenoxybenzamine
4. Ion channels/transporters Calcium channel blockers;
digoxin and Na/K-ATPase
5. Other proteins
 Immunological proteins Penicilloyl residue hapten
 Tissue proteins N-acetyl-p-benzoquinone-
imine (paracetamol
[acetaminophen])
(b) Extracellular 1. Water Dextrose 5%
2. Hydrogen ions (pH) Sodium bicarbonate
3. Other ions Sodium ticarcillin
(c) Physical or 1. Direct tissue damage Intrathecal vincristine
physicochemical 2. Altered physicochemical Sulindac precipitation
nature of the extrinsic species

D. Distribution 1. Where in the body the extrinsic Antihistamines cause


and intrinsic species occur drowsiness only if they affect
(affected by pharmacokinetics) histamine H1 receptors in the
brain
O. Outcome (physiological or The adverse effect (see Table 2)
pathological change)
S. Sequela The adverse reaction (use the
Dose, Time, Susceptibility
[DoTS] descriptive system)
xxxiv Mechanistic and clinical descriptions of adverse drug reactions

Table 2 Examples of physiological and pathological changes in adverse drug effects (some categories can be
broken down further)

Type of change Examples

1. Physiological changes
(a) Increased actions Hypertension (monoamine oxidase inhibitors); clotting (tranexamic acid)
(b) Decreased actions Bradycardia (beta-adrenoceptor antagonists); QT interval prolongation
(antiarrhythmic drugs)
2. Cellular adaptations
(a) Atrophy Lipoatrophy (subcutaneous insulin); glucocorticosteroid-induced myopathy
(b) Hypertrophy Gynecomastia (spironolactone)
(c) Hyperplasia Pulmonary brosis (busulfan); retroperitoneal brosis (methysergide)
(d) Metaplasia Lacrimal canalicular squamous metaplasia (uorouracil)
(e) Neoplasia
 Benign Hepatoma (anabolic steroids)
 Malignant
j Hormonal Vaginal adenocarcinoma (diethylstilbestrol)
j Genotoxic Transitional cell carcinoma of bladder (cyclophosphamide)
j Immune Lymphoproliferative tumors (ciclosporin)
suppression
3. Altered cell function IgE-mediated mast cell degranulation (class I immunological reactions)
4. Cell damage
(a) Acute reversible
damage
 Chemical damage Periodontitis (local application of methylenedioxymetamfetamine [MDMA,
ecstasy])
 Immunological Class III immunological reactions
reactions
(b) Irreversible injury
 Cell lysis Class II immunological reactions
 Necrosis Class IV immunological reactions; hepatotoxicity (paracetamol, after
apoptosis)
 Apoptosis Liver damage (troglitazone)
5. Intracellular
accumulations
(a) Calcication Milk-alkali syndrome
(b) Drug deposition Crystal-storing histiocytosis (clofazimine)
Skin pigmentation (amiodarone)

2. DOTS
In the DoTS system (SEDA-28, xxviixxxiii; 1,2) adverse drug reactions are described
according to the Dose at which they usually occur, the Time course over which they occur,
and the Susceptibility factors that make them more likely, as follows:

Relation to dose
 Toxic reactions (reactions that occur at supratherapeutic doses)
 Collateral reactions (reactions that occur at standard therapeutic doses)
 Hypersusceptibility reactions (reactions that occur at subtherapeutic doses in suscep-
tible individuals)
Mechanistic and clinical descriptions of adverse drug reactions xxxv

Time course
 Time-independent reactions (reactions that occur at any time)
 Time-dependent reactions
j Immediate or rapid reactions (reactions that occur only when a drug is administered

too rapidly)
j First-dose reactions (reactions that occur after the rst dose of a course of treatment

and not necessarily thereafter)


j Early reactions (reactions that occur early in treatment and then either abate with

continuing treatment, owing to tolerance, early tolerant, or persist, early persistent)


j Intermediate reactions (reactions that occur after some delay but with less risk

during longer term therapy, owing to the healthy survivor effect)


j Late reactions (reactions the risk of which increases with continued or repeated

exposure)
j Withdrawal reactions (reactions that occur when, after prolonged treatment, a drug

is withdrawn or its effective dose is reduced)


j Delayed reactions (reactions that occur at some time after exposure, even if the

drug is withdrawn before the reaction appears)


Susceptibility factors
 Genetic
 Age
 Sex
 Physiological variation (e.g. weight, pregnancy)
 Exogenous factors (for example, the effects of other drugs, devices, surgical
procedures, food, smoking)
 Diseases

The following reactions are described in SEDA-33 using the EIDOS and DoTS systems:

ACE inhibitors: angioedema 417


Adrenaline: ischemic tissue damage 315
Angiotensin II receptor antagonists: angioedema 418
Antipsychotic drugs: weight gain and diabetes mellitus 94
Benzocaine: methemoglobinemia 289
Bisphosphonates: osteonecrosis of the jaw 1009
Catecholamines: takotsubo cardiomyopathy 313
Cocaine: ischemic cardiac events 58
Contrast media: nephrotoxicity 965
Dapsone: hemolytic anemia and/or methemoglobinemia 630
Diuretics, loop and thiazide: hyponatremia and hypokalemia 439
Dopamine receptor agonists: pathological gambling 322
Dopamine receptor agonists: sleep attacks 322
Ephedrine: ischemic heart disease 317
Ergot-derived dopamine receptor agonists: brotic reactions 321
Ethambutol: optic neuropathy 634
Gadolinium salts: systemic brosis 969
Glucocorticoids: osteoporosis 843
Glucocorticoids, inhaled in COPD: pneumonia 353
Heparin: type II thrombocytopenia 714
Incretin mimetics: nausea and vomiting 896
Iodides: sialadenitis 965
Nitrofurantoin: lung disease 524
Statins: myopathy, myalgia, and rhabdomyolysis 925
Thiazolidinediones: reduced bone density and increased risk of fractures 899
Thionamides: agranulocytosis 884
Vigabatrin: visual eld loss 178
xxxvi Mechanistic and clinical descriptions of adverse drug reactions

The following reactions have also been described in previous editions of SEDA using the
DoTS system:

Adrenaline: hypertension 30.170


Anticoagulants, oral: skin necrosis 29.358
Antituberculosis drugs: hepatotoxicity 31.495
Pseudoephedrine: toxic epidermal necrolysis 30.172
SSRIs: suicidal behavior 29.19
Statins: acute pancreatitis 31.715
Ximelagatran: liver damage 30.411

References
1. Aronson JK, Ferner RE. Joining the DoTS. New approach to classifying adverse drug reactions.
BMJ 2003; 327: 12225.
2. Aronson JK, Ferner RE. Clarication of terminology in drug safety. Drug Saf 2005; 28(10):
85170.
3. Ferner RE, Aronson JK. EIDOS: A mechanistic classication of adverse drug effects. Drug Saf
2010; 33(1): 1323.
4. Callrus T. Use of the dose, time, susceptibility (DoTS) classication scheme for adverse drug
reactions in pharmacovigilance planning. Drug Saf 2006; 29(7): 55766.
5. Aronson JK, Price D, Ferner RE. A strategy for regulatory action when new adverse effects of a
licensed product emerge. Drug Saf 2009; 32(2): 918.
6. Caldern-Ospina C, Bustamante-Rojas C. The DoTS classication is a useful way to classify
adverse drug reactions: a preliminary study in hospitalized patients. Int J Pharm Pract 2010;
18(4): 2305.
7. Ferner RE, Aronson JK. Preventability of drug-related harms. Part 1: A systematic review. Drug
Saf 2010; 33(11): 98594.
8. Aronson JK, Ferner RE. Preventability of drug-related harms. Part 2: Proposed criteria, based on
frameworks that classify adverse drug reactions. Drug Saf 2010; 33(11): 9951002.
How to use this book
THE SCOPE OF THE SIDE EFFECTS OF DRUGS ANNUALS

Volumes in the Side Effects of Drugs Annual (SEDA) series have been published since
1977. The series is designed to provide a critical account of new information relating to
adverse drug reactions and interactions. It complements the standard encyclopedic work
in this eld, Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse
Drug Reactions and Interactions, the 15th edition of which was published in 2006.

PERIOD COVERED

The present Annual reviews all reports that presented signicant new information on
adverse reactions to drugs during the second half of 2008 and the whole of 2009; the next
volume (SEDA-34) will cover 2010. During the production of this Annual, some more
recent papers have also been included; older literature has also been cited when it is rele-
vant. Special reviews (see below) often cover a much wider range of literature.

SELECTION OF MATERIAL

In compiling the Side Effects of Drugs Annual particular attention is devoted to publica-
tions that provide essentially new information or throw a new light on problems already
recognized. Some conrmatory reports are also described. In addition, some authoritative
new reviews are listed. Publications that do not meet these criteria are omitted. Readers
anxious to trace all references on a particular topic, including those that duplicate earlier
work, or to cross-check an electronic search, are advised to consult Adverse Reactions
Titles, a monthly bibliography of titles from about 3400 biomedical journals published
throughout the world, compiled by the Excerpta Medica International Abstracting Service.

Special reviews
The special reviews deal in more detail with selected topics, often interpreting conicting evi-
dence, providing the reader with clear guidance. They are not restricted to literature pub-
lished in the period covered by the volume and are identied by the traditional
prescription symbol and are printed in italics. This volume includes a Cumulative Index of
the Special Reviews that were published in SEDA-11 to SEDA-32 and a list of the Special
Reviews that appear in the current Annual.

CLASSIFICATION OF DRUGS

Drugs are classied according to their main eld of use or the properties for which they
are most generally recognized. In some cases a drug is included in more than one chapter
(for example, lidocaine is mentioned in Chapter 11 as a local anesthetic and in Chapter 17
as an antidysrhythmic drug). Fixed combinations of drugs are dealt with according to their
most characteristic component or as a combination product.
xxxvii
xxxviii How to use this book

NAMES OF DRUGS AND CHEMICALS

Drugs are usually called by their recommended or proposed International Non-proprietary


Names (rINN or pINN); when these are not available, chemical names have been used. If a
xed combination has a generic combination British Approved Name (e.g. co-trimoxa-
zole for trimethoprim sulfamethoxazole) that name has been used; in some cases brand
names have been used instead. When the plus symbol () is used to link drug names (for
example, lopinavir ritonavir), it implies that the two drugs are administered either in
one formulation or in conjunction with one another; otherwise the word plus is used.
Chemicals are named according to the rules of the International Union of Pure and
Applied Chemistry (IUPAC; http://www.iupac.org); for example, we use aluminium,
not aluminum.

SYSTEM OF TAGGING REFERENCES

References in the text are tagged using the following system, which was introduced in
SEDA-24:

M A meta-analysis or other form of systematic review.


A An anecdote or set of anecdotes (i.e. case histories).
R A major review, including non-systematic statistical analyses of published studies.
r A brief commentary (e.g. in an editorial or a letter).
C A major randomized controlled trial or observational study.
c A minor randomized controlled trial or observational study or a non-randomized study.
H A hypothesis article.
E An experimental study (animal or in vitro).
S A statement from an ofcial body (e.g. Governments, WHO), a manufacturer, or a guidelines
group, or a statement about a forthcoming clinical trial.

The various editions of Meyler's Side Effects of Drugs are cited in the text as SED-l4,
SED-15, etc; the Side Effects of Drugs Annuals 132 are cited as SEDA-1, SEDA-2, etc.
References are cited in the bibliography to each chapter using the Vancouver method.
Titles of articles in [square brackets] are English translations of original titles.

INDEXES

Index of drugs: this index provides a complete listing of all references to a drug for which
adverse reactions and/or drug interactions are described.
Index of adverse reactions: this index is necessarily selective, since a particular adverse
reaction may be caused by very large numbers of compounds; the index is therefore mainly
directed to adverse reactions that are particularly serious or frequent, or are discussed in
special detail.
For indexing purposes American spelling has, with a few exceptions, been used, e.g.
anemia and estrogen rather than anaemia and oestrogen.
Abbreviations

The following abbreviations are used throughout the book:

ADP adenosine diphosphate


APACHE acute physiology and chronic health evaluation [score]
ASA American Society of Anesthesiologists
AUC the area under the concentration versus time curve from zero
to innity
AUC0!x the area under the concentration versus time curve from zero to
time x
AUCt the area under the concentration versus time curve during a dosage
interval
bd twice a day (bis in die)
BMI body mass index
CAPD continuous ambulatory peritoneal dialysis
CD [4, 8, etc] cluster of differentiation (describing various glycoproteins that are
expressed on the surfaces of T cells, B cells, and other cells, with
varying functions)
CI condence interval
Cmax maximum (peak) concentration after a dose
Cmin minimum (trough) concentration after a dose
COX-1 and COX-2 cyclo-oxygenase enzyme isoforms 1 and 2
CT computed tomography
CYP [e.g. CYP2D6, cytochrome P450 isoenzymes
CYP3A4]
eGFR estimated glomerular ltration rate
ESR erythrocyte sedimentation rate
FDA [US] Food and Drug Administration
FEV1 forced expiratory volume in 1 second
G6PD glucose-6-phosphate dehydrogenase
HbA1c hemoglobin A1c
HDL, LDL, VLDL high-density lipoprotein, low-density lipoprotein, and very low
density lipoprotein [cholesterol]
HR hazard ratio
IGF insulin-like growth factor
INR international normalized ratio
IQ [range] interquartile [range]
MAC minimum alveolar concentration
MIC minimum inhibitory concentration
MIM Mendelian Inheritance in Man (see http://www.ncbi.nlm.nih.gov/
omim/607686)
MRI magnetic resonance imaging
NNT, NNTB, number needed to treat [for benet, for harm]
NNTH
NSAIDs non-steroidal anti-inammatory drugs
xxxix
xl Abbreviations

od once a day (omne die)


OR odds ratio
PCR polymerase chain reaction
PPAR peroxisome proliferator-activated receptor
RR risk ratio or relative risk
SNP single nucleotide polymorphism
tds three times a day (ter die summendum)
tmax the time at which Cmax is reached
Vmax maximum velocity [of a reaction]
Graham Dukes*

SIDE EFFECTS OF DRUGS ESSAY

Third-generation
oral contraceptives:
time to look again?
It is difcult to say what an essay is . . .. was widely and properly welcomed as con-
Remembering its French origin in essai, stituting a breakthrough in family planning.
perhaps one may call the essay simply The method was simpler and considerably
an attempt to open out a subject. more reliable than anything that had pre-
ceded it. However, within a few years it
Chambers and King [1]
became unhappily evident that these prod-
The history of the oral contraceptives uctstypically comprising up to 5 mg of a
and their association with thromboembolic progestogen (such as norethinodrel, nor-
complications has been repeatedly ethisterone, levonorgestrel, or lynestrenol)
reviewed in these volumes, and with good and 150 micrograms of the estrogen mestra-
reason. No apology is needed for consider- nolwere associated with a signicant inci-
ing the issue anew, since concerns persist, dence of thromboembolic complications.
and it seems that there is remarkably little The response to the problem took time,
solid evidenceperhaps none at allto but it ultimately became clear that consid-
allay them. That, surely, is sufcient reason erable reductions in the doses of both com-
to broach the subject once more in an ponents were both feasible and necessary.
essay, in the hope that others will now take The dose of progestogen was lowered to
a much closer look and succeed in penetrat- 2.5 mg and thereafter typically to 1 mg or
ing to the truth of the matter. less; mestranol was replaced by the more
potent ethinylestradiol, and the dose of
the latter was reduced markedly, in some
cases to a mere 30 micrograms. These
changes proved to be possible without any
THREE GENERATIONS loss of contraceptive effect. The resulting
products were not all of identical composi-
The rst generation of the oral contracep- tion, but the risk of thromboembolic
tive products, introduced in around 1960, complications had clearly been contained,
or at least reduced to a tolerable level. As
a group, the reformulated products became
*Professor M. N. G. Dukes is a physician and inter-
national lawyer who has worked in pharmaceutical
known as the second generation of oral
research management, public health, and develop- contraceptives.
ment aid. He edited Meyler's Side Effects of Drugs So it was in the 1980s, and so it might
from 1975 to 2000 and the Side Effects of Drugs well have remained, but for one element:
Annuals from 1977 to 1992. He is currently the expiry of patents. The estrogen mestra-
External Professor of Drug Policy Studies at the nol enjoyed no patent protection, but
University of Oslo, Norway.

xli
xlii Third-generation oral contraceptives: time to look again?

norethinodrel had been patented in the medical literature, voicing the fear that with
USA as early as 1954, norethisterone in their appearance the risk of thrombo-
1956, and lynestrenol in 1958, while embolic complications had once more
levonorgestrel was patented in Britain in increased. In October 1995 the UK regula-
1961 [2]. Two decades further on such pro- tory authorities informed all physicians
tection would expire, and manufacturers of and pharmacists of three new (and at the
generic products would then be at liberty to time still unpublished) epidemiological
use these substances freely, marketing studies that suggested that combined oral
unbranded products at substantially lower contraceptives of the third generation
costs. By all accounts, therefore, research- caused an approximately twofold increase
based rms with interests in the eld set in the risk of venous thromboembolism; a
about searching for new progestogenic series of precautions with regard to the
molecules that would replace their older use of these products was set out and the
congeners and earn patents of later date, data sheets were revised accordingly [7].
enjoying protection for a further period. Although the regulatory authorities of the
In due course, several such newly synthe- European Union did not follow the British
sized substances, eligible to play this role, lead, considering that further evidence was
emerged. Desogestrel had been developed still needed, matters in Britain came to a
by the Organon company, and patent appli- head in court. Civil actions were brought
cations that were lodged in Germany in against the companies owned in the United
1973 [3] and in the Netherlands in 1974 [4] Kingdom by Schering, Organon, and
were duly granted. It was introduced in Wyeth on behalf of a series of women or
Britain as Marvelon (containing 150 their families who claimed to have suffered
micrograms of desogestrel with 30 micro- the ill effects of the third generation of
grams of ethinylestradiol) and Mercilon products in the form of serious (and in
(with a lower dose of the estrogen). Simi- some instances fatal) episodes of venous
larly, the Schering company developed the thromboembolism.
progestogen gestodene: it introduced it as The litigation, before Mr. Justice Mackay
a component of Femodene (Femovan), in the High Court in London, was consid-
which contained 75 micrograms of the pro- ered in detail in SED-15 (pp. 16512). As
gestogen and 30 micrograms of ethinyl- anyone who was present in court can attest,
estradiol. Other combinations that included the hearings were marked by a series of
gestodene were marketed under licence by direct and sharp conicts between medical
the Wyeth company. As a group these refor- statisticians giving evidence for the plain-
mulated products became known as the tiffs or the defendants. Having considered
third generation of oral contraceptives. the evidence, the learned judge issued on
Even more recently, a further series of 29 July 2002 an extensive judgement on a
progestogens (such as drospirenone) have series of lead cases [8]. Following a critical
emerged, which some workers have consideration of the facts, the contradic-
regarded as comprising a fourth generation tions, and the uncertainties, and the some-
[5, 6], a matter to which we shall return times defective quality of the evidence, he
shortly. came to the conclusion that the products
of the third generation did indeed carry a
greater risk of complications than those of
the second generation. As he put it, The
most likely gure to represent the relative
RENEWED CONCERN risk is around 1.7.
Since the parties had agreed in advance
During the years that followed the market- that the plaintiffs cases should be allowed
ing of the third generation of products, a only if the risk was at least doubled, the
series of publications appeared in the claims for damages failed. Not surprisingly,
Third-generation oral contraceptives: time to look again? xliii

the subsequent press releases by defen- vein thrombosis were compared with 259
dants to the media stressed the failure of control subjects, the highest age-adjusted
the claims, rather than the judge's nding relative risk for thrombosis (with a mean of
that with the introduction of the third-gen- 8.7) was associated with a third-generation
eration products the risk had indeed been product based on desogestrel; lower relative
increased, apparently by some 70%. Here risks (ranging from 2.2 to 3.8) were found
one must pause for a moment to reect on for all other types of oral contraceptive.
what this means. If the learned judge was However, the most striking nding was that
right in his assessment, then among the mil- among carriers of the factor V Leiden muta-
lions of women using the pill the propor- tion the risk of deep vein thrombosis with
tion of users likely to suffer clinically desogestrel-based products was almost
manifest (and sometimes fatal) thrombo- 50 times higher than in non-carriers who were
embolic events must have risen by some not using an oral contraceptive. The risk of
two-thirds once they started to take the using desogestrel products was also higher,
third-generation products rather than those as one might have expected, in women with
of the second generation. One must also a family history of deep vein thrombosis.
realize that no clear added benet The numbers of women in the study popula-
appeared to have been demonstrated with tion using other third-generation products
the new products, such as might have out- were too small to draw conclusions.
weighed the added risk. In theory they Two years later complementary evidence
might have a benecial effect on the lipid was provided by a group working else-
prole, but even in large casecontrol stud- where in the Netherlands on thrombin for-
ies one has seen no reduced incidence of mation [12]. Their ndings were at the
stroke or myocardial infarction [9, 10]. time concisely summarized under three
It would seem that the move to the third headings in a commentary by Vanden-
generation was a matter of patents, prices, broucke and Rosendaal in The Lancet
and prots, no more than that. [13]. To quote them literally,
One, third-generation oral contracep-
tives induce a resistance to the blood's nat-
ural anticoagulation system (APC-
resistance) of almost the same magnitude
PROFILING THE RISK as the resistance induced by a mutation in
coagulation factor V (factor V Leiden);
In the continuing debate about the third
two, second-generation contraceptives
generation of oral contraceptives one rele-
show only part of this effectin that users
vant consideration sometimes appears to
of second-generation pills can be clearly
have received too little attention. That is
demarcated both from women not on oral
the possibilityand even the extreme like-
contraceptives and from women on third-
lihoodthat the thromboembolic risks of
generation pills; three, in women hetero-
the oral contraceptives are particularly pro-
zygous for the factor V Leiden mutation
nounced in a subgroup of users who are
who take oral contraceptives, APC-resis-
identiable in advance and can thus be
tance is as high as that among homozygotes
excluded from exposure to products that
for the mutation.
carry a relatively high risk. In the mid-
To put it simply, this work further delin-
1990s, a team at Leiden University in The
eated the nature of the thromboembolic
Netherlands advanced evidence that such
risk associated with oral contraceptives as
a well-dened subpopulation of individuals
a whole, dened more clearly the suscepti-
at particular risk did indeed exist; it com-
ble groups, and also underlined the particu-
prised carriers of the thrombogenic factor
lar problem attached to products of the
V Leiden mutation [11]. When 126 women
third generation.
of fertile age who had had episodes of deep
xliv Third-generation oral contraceptives: time to look again?

A FOURTH GENERATION? company stood up to assure the audience


that the industry was now aware of substan-
Of the progestogens that have emerged still tial evidence for the safety of the third-gen-
more recently from the laboratory (the so- eration products. To date, unfortunately,
called fourth generation), drospirenone it remains unclear where satisfactory evi-
has been the most prominent, having been dence to this effect is to be found. The most
developed for contraceptive purposes in a widely cited sources for such a view appear
series of combinations with an estrogen. to be two papersfrom 2007 and 2010
One of these, which contains 3 mg of dro- respectivelycommissioned or nanced by
spirenone plus 30 micrograms of ethinyl- Bayer Schering Pharma and published
estradiol, has been marketed under the from Berlin. The rst of these reported a
name Yasmin, with a variant known as European Active Surveillance study on
Yaz. These products have given rise to Oral Contraceptives, commissioned by
various controversies of their own [14], the manufacturer of drospirenone. It was pri-
but again thromboembolism has come to marily concerned with that drug, although it
the fore. In 2003 the suspicion was voiced also involved a series of others and extended
that drosperidone-based contraceptives to issues beyond thromboembolism. Summa-
might be just as likely to cause thrombo- rizing 142 475 women-years of observations
embolism as products of the third genera- [18] its authors concluded in so many
tion [15]; 1 year later, an inter-university words that . . . Risks of adverse cardiovascu-
study group in The Netherlands showed that lar and other serious events in users of a
the combination did indeed increase APC- drospirenone-containing oral contraceptive
resistance, just as the products of the third are similar to those associated with the use
generation had done. Not unexpectedly, a of other oral contraceptives.
subsequent casecontrol study in that same At rst sight the discrepancy between
country showed that the thrombotic risk was this comfortable conclusion and the solidly
at least as high with drospirenone combina- incriminating ndings of the drospirenone
tions as with the third generation, and studies in the Netherlands and Denmark
perhaps rather higher [16]. Almost simulta- seem puzzling, but a closer look provides
neously, a national follow-up study in a series of explanations. First, the work
Denmark independently conrmed these related to a whole series of adverse events,
ndings [17], and as we shall see, there was of which venous thromboembolism was
more to come. One might add that, in both only one; secondly, although a comparison
of these studies and others, similar ndings with levonorgestrel-based products of the
were reported for another product in which second generation was properly included,
the progestogen used was cyproterone. the formulations in use varied, the estrogen
content being either less than 30 micro-
grams or more than 30 micrograms in half
the subjects involved, while a sixth of this
group were using a sequential rather than
THE DEFENDERS a monophasic formulation; thirdly, the reas-
suring general conclusion related to a com-
However concerned one may be, it is only parison of drospirenone formulations with
fair to examine whatever arguments have all others, the latter even including third-
been advanced by those who continue to generation products.
champion either the products of the third Similarly, one experiences certain doubts
generation or those that have emerged still regarding the second of the industry-spon-
later. When, at a drug policy meeting orga- sored Berlin studies, which centred on
nized by Healthy Skepticism in Amsterdam gestodene and was published in 2010 [19].
in October 2010, a speaker pointed to per- To their credit, the authors themselves
sisting concerns about thromboembolism, expressed a series of reservations, because
a medical spokesman for a pharmaceutical of the constraints under which their work,
Third-generation oral contraceptives: time to look again? xlv

in Austria, had been performed. Neverthe- followed by the appearance of two large
less, to quote their cautious conclusion, this nested casecontrol studies from Susan
casecontrol study does not suggest that Jick's group, which have further empha-
there is an increased risk of venous throm- sized the degree of risk attached to the
boembolism for users of oral contraceptives drospirenone products, contrasted with sec-
containing gestodene compared with users ond-generation levonorgestrel combina-
of second-generation oral contraceptives. tions that contain 30 micrograms of
Findings in earlier studies may indeed, as estrogen. The rst study [22], built around
these investigators argued, have been inu- 186 American cases of thromboembolism,
enced to some extent by the time factor; points to a mean relative risk of no less
users of second-generation products had than 2.8 (2.13.8). The second study [23],
commonly taken them for 8 years or more based on 61 British cases plus controls, sim-
at a time when their experiences were com- ilarly showed a relative risk of 2.7 (1.54.7),
pared with those of women taking third- contrasted with the levonorgestrel product.
generation contraceptives, who tended to Differences between the treatment and
be in an earlier phase of treatment. Since, control groups, including age, duration of
in the view of the Berlin group, the risk of contraceptive use, or pre-existing suscepti-
thromboembolic complications may be bility factors, were examined, but none suf-
higher during the early months of use, this ced to explain the striking differences in
could have adversely affected the adverse the risks associated with the two products.
effects data in the third-generation group. In retrospect, one is bound to wonder
Arguments such as these merit consider- whether the originators of drospirenone
ation, although the question remains tested in the early stages its effect in the
whether they could possibly attenuate APC-resistance test; that would have pro-
the impressive and incriminating evidence vided in good time a pointer to its apparent
derived from earlier laboratory and potential for thrombogenesis.
casecontrol studies.

CONCLUSIONS
THE VIEW TODAY
The battle around drospirenone is not the
Two decades have elapsed since the earliest rst to be fought in the eld of oral contra-
expressions of concern that the oral contra- ception, and it seems unlikely to be the last.
ceptives of the third generation might be However, over a longer period one sees
less safe than their predecessors. Many that such dramatic skirmishes have alter-
more grounds for worry have appeared in nated with an uneasy calm, during which
print as the years have gone by. Authorita- the regulators and experts step aside to
tive recent studies only seem to have con- deal with other conundrums; at some
rmed that the risks are at least as great moments one senses a vague belief and
as was estimated in the 1990s; independent hope that, given time, the thromboembo-
reviews appear to have underlined that lism problem will simply go away. Regula-
conclusion [20, 21]. Defence of these prod- tors have been heard justifying their
ucts has at times been vigorous but (per- inaction in the matter, on the grounds that
haps inevitably) awed, with every shot society has a duty to demand absolute
from the ramparts promptly challenged by proof of a problem before taking restrictive
new assaults. At the moment of writing that action; but if that were true, would we not
is most clearly the case where the drospire- still be hopefully treating dyspepsia with
none-based products are concerned. The Mother Seigel's Syrup, which consisted pri-
Berlin studies in their defence have been marily of hydrochloric acid and treacle [24]
xlvi Third-generation oral contraceptives: time to look again?

and consuming a range of quack medicines unanswered and important business unn-
contained conventional treatments (such as ished. This is an area in which we have
opium and ipecacuanha in Dover's pow- much reason to believe that unnecessary
der), poisons (such as hemlock), or nothing harm has been done and may continue to
of value whatsoever [25]? And here and be done unless proper action is taken.
there a faintly protesting voice still argues If we are wrong in that belief, so be it. At
that the pill is no more risky than preg- the very least, society should now try to
nancy. Is that true? And if it is indeed so, penetrate to the truth and accept whatever
is that a sufcient reason to tolerate the consequences that truth may bring with it.
imposition of risks on healthy women,
when they can be avoided or reduced?
It is surely time for patients and pre- Acknowledgements
scribers, regulators and lawyers to demand The author would like to express his
greater clarity in these matters. Issues of indebtedness to senior members of the staff
public health are rarely black and white, of the University of Leiden, who critically
but that is no reason to ignore shades of reviewed an early draft of this essay.
grey. One cannot leave vital questions

References

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[2] Patent data are as cited by Kleemann A, Health of Young Women. BMJ 1997; 315
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Reginald P. Sequeira

1 Central nervous system


stimulants and drugs that
suppress appetite

AMPHETAMINES [SED-15, 180; (CI 1.45, 4.59) in Thailand. The Czech


cohort reported only the standardized mor-
SEDA-30, 1; SEDA-31, 1; SEDA-32, 1]
tality rate, which was 6.22 overall [1C]. This
variation in death rate suggests that mortal-
Note on spelling In International Non- ity among amfetamine users varies geo-
proprietary Names (INNs) the digraph -ph- graphically in important ways. The low
is usually replaced by -f-, although usage is mortality rate in the Czech cohort may have
not consistent, and -ph- is used at the begin- been explained by the absence of AIDS-
nings of some drug names (for example, com- related deaths [2c]. The high death rates in
pare fenuramine and phentermine) or when the Dutch cohort were not consistent with
a name that begins with a ph- is modied by data that suggest that access to both harm
a prex (for example, chlorphentermine). reduction (needle and syringe programs)
For the amphetamines the spellings that and treatment services for general health
are used in SEDA are as follows: amfetamine, care were high during the period of study
benzfetamine,dexamfetamine,metamfetamine [3C]. There is evidence that injection of
(methylamphetamine), and methylenedioxy- amphetamines was associated with a higher
metamfetamine (ecstasy); however, for the mortality than other primary routes of
general term for the group of drugs the more administration [4C]. This is consistent with
common spelling amphetamines is used. the well-documented increased risks in
intravenous users of HIV and hepatitis C
infections, both of which cause substantial
morbidity and mortality [5c]. There was evi-
dence that length of amfetamine use was
Amfetamine and dexamfetamine
associated with a high mortality rate in those
[SEDA-30, 1; SEDA-32, 1]
who had been users for 5 years or more. It is
Systematic reviews A search of 2187 articles unclear how mortality among amfetamine
and 9 grey literature sources identied 72 users varies with age.
studies of amfetamine-related mortality,
seven of which provided data from cohort Cardiovascular There is no evidence at
studies of users. The estimated crude mortal- present to support the use of amfetamine
ity rates ranged from 0 in Australia to 2.95 to enhance recovery after stroke. Despite
a trend to improved motor function, doubts
remain over its safety and it has signicant
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
hemodynamic adverse effects, the conse-
ISSN: 0378-6080 quences of which are unknown. Further-
DOI: 10.1016/B978-0-444-53741-6.00001-5 more, there are insufcient data from which
# 2011 Elsevier B.V. All rights reserved. to draw conclusions regarding the effects of
1
2 Chapter 1 Reginald P. Sequeira

amfetamine on mood or communication or matched group of 564 young people who


quality of life [6M]. Both raised blood pres- died as passengers in motor vehicle trafc
sure and raised heart rate are associated with accidents [11C]. There was a signicant
poor outcomes after stroke [7C], as is association of stimulant use with sudden
impaired baroreceptor sensitivity with unexplained death. The primary exposure
increased cardiac events and dysrhythmias measure was the presence of amfetamine,
[8C]. Despite concerns regarding increasing dexamfetamine, metamfetamine, or methyl-
heart rate and blood pressure, up to a fth phenidate, according to informant reports
of patients with acute strokes have low blood or as noted in medical examiner records,
pressure, and hypotension is associated with toxicology results, or death certicates. In
a poor outcome [9M]. 10 of the sudden unexplained deaths
Cardiomyopathy due to a toxic effect of (1.8%) the youths had taken stimulants,
Adderall, intermediate in onset, with specically methylphenidate; in contrast,
uncertain susceptibility factors such as pre- only two subjects in the motor vehicle acci-
existing coronary artery disease and dent comparison group (0.4%) had used
possibly drugdrug interactions, has been stimulants, and only one case involved
reported [10A]. methylphenidate. As a result of this study,
the US Food and Drug Administration
A 33-year-old man treated with Adderall issued a safety communication, stating
(dexamfetamine amfetamine) for ADHD. that given the limitation of this study, it
Adderall was started initially at 20 mg daily
and two months later increased to 40 mg, was unable to conclude that these data
and uoxetine 20 mg/day was added as a affect the overall benet to harm prole
mood stabilizer. Seven months later the daily of stimulant medications used to treat
dosage of both drugs doubled, and a month ADHD in children [12S]. The FDA advised
later Adderall was again increased to 80 mg
bd. On the higher dose of Adderall, the health-care professionals to follow the
patient experienced increased hyperactivity current prescribing information, including
and irritability. Two months later, he devel- taking a medical history for cardiovascular
oped symptoms of abdominal pain, vomiting, disease and performing a physical exam-
and cough that lasted a month. He was diag- ination focusing on the cardiovascular
nosed as having a cardiomyopathy and
underwent a successful cardiac transplant. system.
Microscopic examination of heart tissue
revealed (a) focally severe coronary athero-
sclerosis of the proximal right coronary artery; Susceptibility factors Genetic Further evi-
(b) cardiomyopathy, mild cardiomegaly, with
biventricular myocyte hypertrophy; (c) mild dence that genetic variants in the SLC6A2
focal nonspecic interstitial myocarditis sug- gene are involved in acute responses to
gestive of hypersensitivity; and (d) fatty inl- amfetamine, which may progress to
tration on the right ventricular myocardium. amfetamine abuse, has been reported [13C].
The contribution of coronary artery athero- In a three-session, double-blind, crossover
sclerosis to the development of cardiomyopa-
thy was uncertain. study, 162 healthy Caucasians (90 men),
aged 1835 years took either a placebo or
There have been eight previously reported oral dexamfetamine (10 or 20 mg). The
cases of cardiomyopathy associated with associations between the degrees of self-
Adderall. Whether an interaction between reported elation and vigor after amfetamine
Adderall and uoxetine would have contrib- and single nucleotide polymorphisms
uted to the cardiomyopathy in this patient is (SNPs) and SNP haplotypes in SLC6A2
uncertain. were determined. SNPs rs36017 and
rs1861647 were associated with signicantly
higher ratings of elation and vigor after
Death In a matched casecontrol study, amfetamine 20 mg. Ratings of vigor after
mortality data from 1985 to 1996 were used amfetamine 20 mg were also associated with
to identify 564 cases of sudden death at a two-SNP haplotype formed with rs1861647
ages 719 years across the USA, and a and rs5569 and a three haplotype formed
Central nervous system stimulants and drugs that suppress appetite Chapter 1 3

with rs36017, rs10521329, and rs3785155. Ecstasy (3,4-


The authors postulated that people with methylenedioxymetamfetamine,
genotype C/C at rs36017 or with genotype MDMA)
A/A at rs1861647 would experience more
profound increases in feelings of vigor and See Chapter 4.
elation after taking amfetamine and would
therefore be more inclined to use
amfetamine again. It is unclear whether the
highly linked polymorphisms are in linkage Metamfetamine [SEDA-30, 2;
dysequilibrium with a functional variant that SEDA-31, 1; SEDA-32, 3]
has not been identied yet or whether these
polymorphisms directly inuence mRNA Cardiovascular It is generally presumed that
processing, stability, or splicing. Neverthe- in patients who develop chest pain after using
less, these ndings add to a growing litera- amfetamine the risk of acute myocardial
ture on the genetic determinants of infarction is increased [15c]. However, in a
responses to amphetamines. Such studies systematic review, although there was a high
are important because acute differences in incidence of acute coronary syndrome in
responses to a drug may contribute to vari- patients with chest pain after metamfetamine
ability in the risk of abuse and drug ingestion, there was no evidence that the inci-
dependence. dence of acute myocardial infarction was
increased [16R]. Evolving diagnostic criteria
[17C] were used: acute coronary syndrome
diagnosis was based on measurement of myo-
Drug overdose Outcomes after accidental cardial creatine kinase (CK-MB) and also
amfetamine ingestion in children under 7 included unstable angina, which is diagnosed
years have been evaluated in a retrospec- in patients with angina and a normal CK-
tive chart review over 4 years (January MB relative index and evidence of myocar-
2003 to December 2007) in 118 patients, dial ischemia on non-invasive cardiac stress
average age 3.1 years (range 8 months to testing or signicant coronary artery disease
7 years), of whom 90 (76%) were nave by coronary angiography.
to the medication and accidentally The prevalence of self-reported illicit use
ingested amfetamine prescribed for sib- of cocaine and/or metamfetamine in
lings [14c]. In all, 28 took a double dose patients with acute decompensated heart
of their normally prescribed medication, failure has been studied, using a multi-
of whom 25 were observed at home and center observational registry, in 11 258
developed no or minimal symptoms; three patients, of whom 594 (5%) had previously
were referred to an emergency depart- used cocaine (96%) and/or metamfetamine
ment with headache or mild agitation but (5%) [18C]. Users had a median age of 50
were subsequently discharged. In all, 76 years compared with 76 years in non-users.
developed symptoms and were evaluated As there were disproportionately more
at a health-care facility; 15 received ben- young AfricanAmerican men with hyper-
zodiazepines for agitation and 16 were tension, left ventricular systolic dysfunction,
observed for more than 12 hours. All and markedly raised B-type natriuretic pep-
the patients had favorable outcomes. tide concentrations, the authors speculated
Although toxic exposure in this study that the severity of cardiac dysfunction in
resulted in mild to moderate symptoms, these young patients would probably result
amfetamine exposure has the potential in higher morbidity, mortality, and health
to cause severe adverse effects. Therefore, costs. Although these patients had a greater
toxic exposure should be evaluated and degree of left ventricular dysfunction (ejec-
treated individually based on the symp- tion fraction <40%), they did not have a
toms each patient has. greater risk-adjusted mortality.
4 Chapter 1 Reginald P. Sequeira

In a casecontrol chart review, 107 6 months, there was memory impairment


metamfetamine users and 114 controls compared with 20 metamfetamine-naive par-
were identied [19C]. The two groups had ticipants [25c]. These memory decits did not
similar sex distribution, length of hospital vary as a function of specic memory task
stay, prevalence of coronary artery disease, demands. Of all the cognitive measures, cog-
diabetes mellitus, hypertension, cigarette nitive inhibition shared greatest variance with
smoking, and alcohol, marijuana, and cocaine group effects on the prospective memory
abuse. The cases were older than the controls measure.
(mean age 38 versus 35 years), had higher Periventricular leukomalacia has been
values of BMI (37 versus 30 kg/m2), and had reported after prenatal metamfetamine
a higher prevalence of renal insufciency exposure [26A].
(13% versus 4.4%). Metamfetamine users
had a 3.7-fold higher odds ratio for A 23-year-old woman gave birth to a male
cardiomyopathy, after adjusting for age, infant weighing 1080 g at 30 weeks of gestation.
She reported using metamfetamine and mari-
BMI, and renal insufciency. LVEF was juana once 3 days before delivery and denied
signicantly lower in cardiomyopathy any other drug use during pregnancy. After
patients with metamfetamine use. cesarean section the infant's Apgar scores were
6 at 1 minute and 7 at 5 minutes. The initial cap-
illary pH was 7.27, with a PaCO2 of 6.9 kPa and
Nervous system Use of metamfetamine is a base decit of 4 mmol/l. A drug screen of
associated with ischemic stroke, intracereb- meconium was positive for metamfetamine
roventricular hemorrhage, and subarachnoid (850 ng/g) and tetrahydrocannabinol (54 ng/
hemorrhage, especially among young indi- g). Cranial ultrasound at 1 week was
viduals. All cases of subarachnoid hemor- unremarkable, but at 6 weeks it was highly
abnormal, with multiple small cysts bilaterally
rhage were aneurysmal, and most were in the subependymal white matter anterior
located in the anterior circulation, as were to the lateral ventricle consistent with
most of the strokes. Although in many cases periventricular leukomalacia. Ophthalmology
imaging conrmed arterial stenosis in the was normal. At 24 months he had severe devel-
opmental delay, with spastic quadriplegic cere-
vascular distribution of the stroke, there bral palsy.
was no evidence that the ischemic stroke
associated with the use of metamfetamine The authors thought that this patient had no
was due to an inammatory cause rather than risk factors for periventricular leukomalacia,
a process of accelerated atherosclerosis [20C]. except for prematurity. They also thought
These conclusions were based on a retrospec- that the cranial ultrasound results at weeks
tive chart review of admissions to a tertiary 1 and 6 were consistent with a history of
care neurovascular service from January metamfetamine exposure at 3 days before
2003 to July 2007; there were 30 cases out of birth. They postulated that metamfetamine
1574 patients who had used metamfetamine, had caused cerebral ischemia and subse-
documented by history or urine toxicology quent destruction of white matter and cyst
screening. There was an apparent selection formation 6 weeks later. However, they
bias in this study: neither the duration nor acknowledged that other factors could have
the severity of substance use was estimated. contributed to the pathophysiology, includ-
Nevertheless, metamfetamine is a susceptibil- ing contamination of metamfetamine.
ity factor for stroke in young adults, consis-
tent with previous reports [21c, 22c]. It is
likely that various stroke subtypes are related Gastrointestinal Occult metamfetamine
to metamfetamine-induced hypertension- abuse should be considered when young
related vascular pathology rather than vascu- patients present with signs and symptoms
litis, as has been suggested before [23R, 24c]. suggestive of ischemic colitis.
In 20 adults with a conrmed history of
A 44-year-old man developed ischemic colitis
metamfetamine use and dependence, curr- after abusing crystalline metamfetamine
ently engaged in rehabilitation and conrmed [27A]. Although a direct causal relation was
to have been abstinent for an average of not established, the temporality in this case,
Central nervous system stimulants and drugs that suppress appetite Chapter 1 5

with the absence of classic susceptibility fac- weight; in men it often improved sex per-
tors, made metamfetamine the presumptive formance. Self-identied gay/bisexual stu-
etiology.
dents were 26 times more likely to have
used crystal meth in the previous year.
Drug abuse In the York Region in Toronto, Street youth reportedly used crystal meth
Canada, a new strategy has been developed as a coping strategy against negative emo-
to curb metamfetamine use, modeling on tions and circumstances. The authors
Vancouver's four-pillar drug strategy (pre- acknowledged that pharmacological treat-
vention, treatment, harm reduction, and ment is challenging, as there is no effective
enforcement) [28S]. However, more than medication for amphetamine abuse; non-
70% of Vancouver's street-involved pharmacological treatments, although
youth have used metamfetamine and effective, may not have enduring effects.
metamfetamine use increased signicantly Bellemare reacted to this article by raising
in intravenous drug users, from 2% to 15% unique child protection concerns that are
in 8 years, despite Vancouver's four-pillar associated with the use and production of
strategy [29r]. It may therefore be crystal meth, which are not relevant to
unjustiably optimistic to anticipating that other drugs [31r]. The specic concerns
the supply of metamfetamine can be were about children who live in places
suppressed, as, unlike other drugs, where metamfetamine is produced. Besides
metamfetamine can be inexpensively pro- neglect of child care by those who are
duced locally, and the likelihood that law actively engaged in metamfetamine produc-
enforcement can successfully curbing the tion, these laboratories can explode, expose
growth in the supply of metamfetamine is children to strangers and drug users, and
exceedingly small. There is also pessimism expose them to drug seeking behaviors,
about the benets of antidrug media cam- including hypersexuality and sexual abuse.
paigns and Drug Abuse Resistance Educa- The author strongly urged clinicians to
tion (DARE) programs. exercise their legal and moral duty to pro-
It has been suggested that D- tect these children by calling the child wel-
metamfetamine hydrochloride, or crystal fare authorities as appropriate.
meth, is more likely to cause dependency
than other forms of metamfetamine [30r]. Teratogenicity In 29 children, aged 34
When smoked or injected it causes an years, who had been exposed to
almost immediate rush, compared with metamfetamine in utero, and 37 unexposed
20 minutes after oral ingestion. It is used children, fractional anisotropy and appar-
rectally as well as snorted. The authors also ent diffusion coefcients were determined
stated that when compared with cocaine, in various parts of the brain [32c]. There
crystal meth . . . can keep the user up were alterations in white matter maturation,
for 12 hours. A user binging in crystal meth involving more compact axons or greater
(on a run) may stay awake for 10 days. dendritic density. The ndings of this study
Prolonged use can lead to tweaking or were confounded by incomplete drug histo-
psychosis with extreme paranoia and result ries from some subjects, which could have
in body scabs from picking at imaginary minimized or exaggerated the effects of
bugs crawling on or under the skin. About metamfetamine. In addition, genetic and
25 million people worldwide may have used environmental inuences cannot be ruled
amphetamine and metamfetamine in 12 out as a source of lower white matter diffu-
months, making it the most widely used sion. It is also not known whether the diffu-
illicit drug after cannabis. Although the sion changes observed in metamfetamine-
authors appreciated the reported decline exposed children remain low, normalize,
in the use of amphetamines among school or become higher with age.
students, they did not believe that it is The molecular mechanisms that might be
enough. The reasons for using crystal meth responsible for metamfetamine neurotoxicity
among women may include a desire to lose include oxidative stress, activation of
6 Chapter 1 Reginald P. Sequeira

transcription factors, DNA damage, (methylenedioxymetamfetamine, MDMA)


excitotoxicity, bloodbrain barrier break- [36A] have been implicated in drug-induced
down, and various apoptotic pathways [33ER]. brotic valvular disease [37R]. 5HT2B receptor
Congenital cataract with triangular mor- activity through activation of protein kinase
phology has been reported in association and potentiation of the effect of transforming
with prenatal metamfetamine exposure growth factor b is thought to result in
[34A]. Although this association was proba- mitogenesis of cardiac valves [38r, 39r]. Inves-
bly coincidental, the morphology of the cata- tigations into individual susceptibility need to
ract and the specic timing of prenatal establish which clinical and demographic fac-
exposure (67 weeks of gestation) suggested tors predict patients at greatest risk of drug-
that further studies would be worthwhile. induced valvular heart disease, and the role
Maternal depressive symptoms are associ- of genetic polymorphisms. It is also important
ated with neurodevelopmental patterns of that new drugs that interact with the serotonin
reduced arousal and increased stress. Among pathways and 5HT2B receptors should be
13 808 screened subjects from Honolulu, assessed at the clinical trials stage, in order
1632 were eligible and 176 mothers were to establish the risk of valvular heart disease
enrolled; prenatal metamfetamine exposure before they are used in clinical practice.
combined with maternal depression was not
associated with any additional neurodeve-
Hematologic In a cross-sectional study,
lopmental differences [35C]. When adjusted
platelet counts in 47 patients with pulmonary
for co-variates, metamfetamine exposure
arterial hypertension (PAH) receiving intra-
was associated with lower arousal and higher
venous epoprostenol were compared with
lethargy scores. Only 136 biological mothers
platelet counts in 44 patients who were taking
with child custody (50 of whom had used
oral agents [40C]. Idiopathic PAH accounted
metamfetamine) had the Addiction Severity
for 69% of cases; the rest were associated
Index (ASI) administered at 1 month. The
with fenuramine (18%), connective tissue
NICU Network Neurobehavioral Scale
disease (10%), or congenital heart disease
(NNNS) was administered to the neonate
(2%). There was thrombocytopenia in 34%
within the rst 5 days of life by an examiner
of the patients who were treated with
blinded to metamfetamine exposure. There
epoprostenol compared with 15% of those
were several limitations to this study. The
who took oral therapy (OR 2.9). Higher
severity of depression in the mothers was
doses of epoprostenol were associated with
assessed not at the neonatal visit but after 1
lower platelet counts than lower doses. The
month. Since only the biological mothers
effects of hemodynamics and epoprostenol
were included in the study, the sample size
were independent and additive, with
was limited, because several infants who had
the highest rates of thrombocytopenia seen
been exposed to metamfetamine were placed
among patients with both severe hemo-
in foster care or the care of relatives, so that
dynamic abnormalities and use of epo-
data from their biological mothers was not
prostenol. Treatment options for
assessed.
thrombocytopenia in PAH are limited, owing
to incomplete understanding of its patho-
physiology; withdrawal of epoprostenol is
Fenuramines [SED-15, 1333; rarely recommended.
SEDA-30, 7; SEDA-32, 7]

Cardiovascular A wide range of drugs,


including those used for migraine prophy- Atomoxetine
laxis (ergotamine, methysergide), appetite
suppressants (fenuramine and dexfen- Observational studies In an open study of
uramine), dopamine receptor agonists the use of atomoxetine for over 4 years in
(pergolide and cabergoline), and ecstasy 384 adults with ADHD, the adverse events
Central nervous system stimulants and drugs that suppress appetite Chapter 1 7

were mainly related to the expected nor- A 13-year-old boy with ADHD was given
adrenergic effects of the drug [41c]. atomoxetine and 5 weeks later developed
changed behavior, disorientation, irrelevant
speech, and self-harming behavior. He was
Systematic reviews In a systematic review very aggressive and hostile towards other chil-
of data from 13 double-blind, placebo- dren and adults. No organic cause was found.
controlled trials and three open extension The boy improved after withdrawal of
studies in 714 children and adolescents with atomoxetine.
ADHD treated with atomoxetine for at
In an extensive review of the literature
least 3 years, under 6% had aggressive/hos-
the authors found no evidence of other
tile behavior and under 1.6% reported sui-
reports of such an effect. However, in one
cidal ideation/behavior; there were no
unpublished study four subjects stopped
clinically signicant effects on growth rate,
taking the drug because of irritability or
vital signs, or electrocardiography [42M].
aggression [48S]. This could be a rare
adverse effect that has not been noticed in
Cardiovascular In children, adolescents,
trials, although a previous meta-analysis
and adults there was a small but signicant
was negative (SEDA-32, 8).
prolongation of the QT interval in electro-
Acute agitation and suicidal ideation
cardiogram when Bazett's correction was
occurred in an 11-year-old boy after he
used but not when the Fridericia formula
started to take atomoxetine [49A]. How-
was used [43c]. The effects of atomoxetine
ever, a previous meta-analysis was negative
on hERG potassium channels have been
(SEDA-32, 8).
studied in human embryonic kidney cells
[44E]. Atomoxetine inhibited hERG cur-
rent with an IC50 of 6.3 mmol/l. The effect Teeth Nocturnal bruxism worsened in a
occurred quickly and was washed out 12-year-old boy with ADHD when he was
quickly. Channel activation and inactiva- given atomoxetine, improved after with-
tion were not affected. Inhibition was drawal, and recurred after rechallenge; it
state-dependent, suggesting open channel responded to the addition of buspirone
blockade. Use dependence was not [50A].
observed.
Drugdrug interactions Methylphenidate
Nervous system In a cohort study of 21 606 In an open study in children aged 617
patients with ADHD treated with years the addition of OROS methylpheni-
atomoxetine and 21 606 treated with other date increased the rates of insomnia, irrita-
medications, the rate ratios were 1.38 bility, and loss of appetite compared with
(95% CI 0.42, 4.54) for the risk of stroke atomoxetine alone [51c].
and 0.31 (95% CI 0.04, 2.63) for the risk
of a transient ischemic attack (TIA) [45C]. Susceptibility factors Alcohol abuse and
There was an increased risk of TIA when dependence increase the risk of
those with ADHD treated with any medi- atomoxetine-related adverse events [52C].
cations were compared with the general
population (HR 3.44; 95% CI 1.13,
11), but no increased risk of stroke.

Sensory systems Mydriasis has been Methylphenidate [SED-15, 2307;


reported in a 15-year-old girl who took SEDA-30, 4; SEDA-3, 3; SEDA-32, 10]
atomoxetine for ADHD [46A].
Observational studies Treatment with rela-
Psychiatric A report of aggression in a boy tively high doses (up to 1.5 mg/kg/day) of
taking atomoxetine has again raised the OROS methylphenidate in 114 adolescents
question of whether this is an adverse effect with ADHD was associated with small but
of the drug [47AM]. statistically signicant mean increases in
8 Chapter 1 Reginald P. Sequeira

blood pressure and heart rate, primarily dur- 1.84 (95% CI 0.05, 10) in patients aged
ing the rst 6 weeks of treatment, without 1521 years. Although the medications
clinically important ECG changes [53C]. may have contributed to the increased risk
Only 57 subjects had completed 6 months of suicide, other factors that can also pre-
of treatment and 19 dropped out because dispose to suicide, such as depression and
of non-cardiovascular adverse events: antisocial behavior, frequently co-exist with
reduced appetite/weight loss (n 6), ADHD [56c, 57R].
reduced appetite/weight loss and irritability
(n 3), mood changes (n 3), stomach ache Placebo-controlled trials In a randomized,
(n 1), headache (n 1), light-headedness double-blind, placebo-controlled crossover
(n 1), and excessive sweating (n 1). trial of methylphenidate in 13 patients with
One subject discontinued medication apathetic Alzheimer's disease stabilized on a
because of recurrent bouts of palpitation cholinesterase inhibitor, methylphenidate
during the rst 6 weeks of treatment. Being produced signicant benet [58c]. There was
an open study, there was no comparison of a positive relation between the acute effects
the cardiovascular end-points with a placebo of dexamfetamine and the response to meth-
or active comparator. Also, since most of the ylphenidate, implicating a role for dopami-
visits occurred at 710 hours after the morn- nergic dysfunction in the development and
ing dose of medication, the timing of blood treatment of apathy in Alzheimer's disease.
pressure measurement may not have A signicantly higher proportion of patients
coincided with the peak action of the had at least one adverse event with methyl-
medication. phenidate compared with placebo; two had
serious adverse events while taking methyl-
Comparative studies Exposure to methyl- phenidate, consisting of delusions, agitation,
phenidate and amfetamine salts carried sim- anger, irritability, and insomnia, which
ilar risks for cardiac emergency department resolved on withdrawal of methylphenidate.
visits in a retrospective cohort study of
claims data from the Florida Medical data Systematic reviews In 26 placebo-con-
on 2 131 953 children and adolescents, trolled trials in 811 adults with ADHD,
between 1994 and 2004, with a diagnosis of methylphenidate was well tolerated in the
ADHD [54C]. However, emergency depart- short-term and produced no serious
ment visits may reect parent concern rather adverse effects [59M]. However, there is lit-
than acute cardiac adverse events. The drug tle information on the long-term safety of
dosages were not considered, because treat- methylphenidate in adults, although the
ment recommendations included dosage number of serious adverse effects reported
titration according to patient response and has so far been low. Methylphenidate is
the occurrence of adverse effects. associated with modest increases in blood
In a study based on the UK General pressure and heart rate. Surveys of the use
Practice Research Database (GPRD) in of stimulants in US universities have shown
patients with ADHD, aged 221 years, that misuse of prescribed medications, for
from 1993 to 2006 with prescriptions recreation or to enhance the ability to
for methylphenidate, dexamfetamine, or study, is fairly common, although the mag-
atomoxetine, there was no increase in the nitude of harm that arises from such prac-
risk of sudden death but there was an tices is unclear.
increased risk of suicide [55C]. Seven Warnings from the FDA and scientic
patients died in a cohort of 18 637 patient- debate surrounding the potential of
years, and cause of death was obtained in psychostimulants to exacerbate tics have
six; none was deemed to be a case of sud- created clinical uncertainty for practitioners
den death (incident rate ratio 1.63; 95% treating ADHD in children with comorbid
CI 0.04, 9.71). The standardized mortal- tics. A meta-analysis of nine studies
ity ratios for suicide were 162 (95% CI involving 477 subjects has suggested that
20, 585) in patients aged 1114 years and among six medications used in ADHD
Central nervous system stimulants and drugs that suppress appetite Chapter 1 9

(the alpha-adrenoceptor agonists clonidine recurred on rechallenge [62A]. It is impor-


and guanfacine, atomoxetine, desipramine, tant to screen and identify psychotic symp-
dexamfetamine, methylphenidate, and toms during stimulant drug treatment,
selegiline), methylphenidate seems to offer because they could be mistaken for deterio-
the greatest and most immediate improve- ration in the symptoms of ADHD and
ment in the symptoms of ADHD and does result in dosage titration upwards, with seri-
not seem to worsen tics [60M]. Alpha ago- ous implications.
nists offer the best combined improvement
in both tics and symptoms of ADHD. Urinary tract A possible association of
Atomoxetine and desipramine offer addi- methylphenidate and enuresis has been
tional evidence-based treatments for reported [63A].
ADHD in children with comorbid tics;
supratherapeutic doses of dexamfetamine An 11-year-old boy with ADHD was given
should be avoided. However, it is important methylphenidate and after the daily dosage
to note that effect size of medications in tri- had been titrated to 20 mg enuresis started
to occur. After 2 months, the medication was
als is inuenced by many factors besides withdrawn and the enuresis stopped immedi-
the efcacy of the medication, including dif- ately. About 1 month later, methylphenidate
ferences in the precision of rating scales. was restarted and the enuresis reoccurred
This difference may have been particularly when the dose reached 20 mg/day. It contin-
inuential in measures of efcacy in ued for about 3 months but immediately
stopped when the medication was withdrawn.
treating ADHD and the inattention and Another rechallenge after 2 months, followed
hyperactivity/impulsive symptom subtypes, by withdrawal of methylphenidate, replicated
because multiple rating scales and raters the response. Other causes of enuresis were
were used. The trials in this meta-analysis excluded and the patient never had daytime
urinary incontinence.
included primarily male subjects and it is
not known how well the results would In previous reports methylphenidate was
apply to girls with ADHD and comorbid reportedly effective in controlling giggle
tics. For several outcomes, there was signif- incontinence [64A, 65A].
icant heterogeneity between studies,
suggesting that differences in trial design
may have inuenced effect sizes. Such dif- Skin The potential for vasculopathy in
ferences in trial design include the type of patients with ADHD taking stimulants has
rating scale and dose and duration of treat- been reported in four patients, two of whom
ment. With a relatively smaller number of were taking methylphenidate and two
studies contributing to this meta-analysis, dexamfetamine [66A]. They developed acral
it is not possible to determine which of cyanosis, livedo reticularis, or Raynaud's
these hypothesized factors contributed to syndrome. Two (one each taking methyl-
heterogeneity. phenidate and dexamfetamine) had positive
Methylphenidate is considered safe for antinuclear antibody titers and one (taking
children who are seizure free. However, dexamfetamine) had histological evidence
a few reports of seizure aggravation in of stratum malpigian necrosis with
methylphenidate-treated children with perivascular lymphocytic inltration on skin
uncontrolled epilepsy have raised concerns biopsy. Both of the patients who were taking
about its use in this group [61R]. methylphenidate had antihistone antibodies.
One patient improved after withdrawal of
Psychiatric Psychosis is an important but dexamfetamine and her medication for
unpredictable adverse effect of stimulant ADHD was changed to bupropion; others
medications and can mimic the symptoms had worsening of their symptoms on higher
of ADHD. Four cases of stimulant-induced doses of medication.
psychosis (three with methylphenidate and
one with Concerta XL) resolved sponta- Genotoxicity Recent studies have added to
neously on withdrawal of medication and the accumulating evidence that therapeutic
10 Chapter 1 Reginald P. Sequeira

concentrations of methylphenidate do not despite withdrawal of methylphenidate. There


cause cytogenetic damage in humans [67C]. was a paternal history of Huntington disease
and a molecular analysis suggested juvenile
In 109 children with ADHD taking methyl- Huntington disease.
phenidate (starting dose 10 mg/day to a
maximum of 60 mg/day) for a total duration This report suggests the possibility that
of 84 days, cytogenetic anomalies were methylphenidate (a dopamine receptor ago-
investigated, including chromosomal aber- nist) in patients with a family history of Hun-
rations, micronuclei, and sister chromatid tington disease may lead to clinical
exchanges in peripheral blood lymphocytes exacerbation of motor symptoms and/or an
in culture. None was signicantly affected unwitting diagnosis in an unprepared family.
by methylphenidate. Since dosage titration Many children who develop the juvenile
was used in the study design, both the daily form of Huntington disease are initially
dose administered and the total cumulative misdiagnosed as having ADHD [75A],
dose over the course of this study differed and one-quarter of those with juvenile Hun-
according to the needs of the patients. tington disease have attention decits [76A].
These results are in marked contrast to pre- Thus, a child with an unrecognized family his-
vious ndings of signicant increases in all tory of Huntington disease presenting with
three end-points with a similar study design isolated cognitive symptoms may be treated
but with a smaller sample size and a behav- with stimulants, and this association may
ior therapy only control group [68c]. Other therefore have been coincidental.
mutational end-points are consistent with
the human and animal cytogenetic data on
methylphenidate [69ER]. Taken together, Drugdrug interactions Fluoxetine Tactile
these ndings show a high degree of consis- and visual hallucinations with the combina-
tency and conrm that methylphenidate tion of methylphenidate and uoxetine
does not induce chromosomal aberrations have been reported [77A].
or other type of genetic damage in children
A 10-year-old boy with ADHD, oppositional
with ADHD [70C]. It is important to note deant disorder, and generalized and separa-
that an epidemiological study of the risk tion anxiety disorders started taking OROS
of cancer among 35 400 methylphenidate- methylphenidate 18 mg/day and uoxetine 10
treated patients with ADHD, who take this mg/day. Four days later, he had an acute epi-
medication before age 20, showed no mod- sode of intense hallucinations 3 hours after
taking the medications. His mother reported
erate or strong association [71c]. that the visual hallucinations lasted about 1
hour and the tactile hallucinations more than
Susceptibility factors Genetic There has 2 hours. Two days later he had a similar epi-
sode. His mother withdrew the medications
been considerable interest in the evaluation for 10 days, during which time he was symp-
of genetic determinants of the response to tom free. When OROS methylphenidate 18
methylphenidate in ADHD. Preliminary mg/day monotherapy was restarted he did
studies have suggested that dopaminergic not report any hallucinations. Mirtazapine 15
genes [72C] and noradrenergic and possibly mg/day was added for symptoms of anxiety
and sleep disturbances. During the next 2
glutaminergic genes [73C] may be involved. months his condition improved and he had
Juvenile Huntington disease with acute no further hallucinations.
onset of motor symptoms coincident with
initiation of treatment with methylphenidate There has been a previous report of
has been reported [74A]. treatment-related hallucinations with the
combination of methylphenidate and uox-
An 8-year-old boy, otherwise healthy, with etine in a 14-year-old girl with ADHD
symptoms of ADHD was given methylpheni- depressive disorder [78A]. The mechanism
date and within 4 weeks had a rapid decline
in ne motor skills, with dysarthria, intention whereby methylphenidate uoxetine
tremor, motor impersistence, and diffusely might cause hallucinations is unclear.
increased tone. His symptoms persisted
Central nervous system stimulants and drugs that suppress appetite Chapter 1 11

Modanil [SED-15, 2369; SEDA-30, 6; Other adverse effects reported at higher


SEDA-31, 7; SEDA-32, 6] doses, such as diarrhea and dyspepsia, were
not seen.
Observational studies Armodanil, the Placebo-controlled studies There was redu-
R-isomer of modanil, produces consis- ced appetite in patients with ADHD treated
tently higher plasma concentrations late in with modanil [81c].
the day than modanil, when compared Gastrointestinal adverse events, such as
milligram for milligram. In two multiple- nausea and dry mouth, were more common
dose pharmacokinetic studies in healthy compared with placebo in cocaine depen-
men aged 1850 years adverse events were dent subjects who took modanil 200 mg/
studied in subjects who completed 7 days day, and one of 70 subjects had an abnor-
of once-daily armodanil (n 34) or mal electrocardiogram, hypertension, chest
modanil (n 18) [79c]. The most common discomfort, a bitter taste sensation, irritabil-
adverse events were headache, palpitation, ity, agitation, anxiety, and tension, and there
nausea, and dizziness with armodanil, were two instances of insomnia, one
and headache, palpitation, insomnia, and instance of sweaty palms, and one case of
anxiety with modanil. With both drugs, upper lip swelling in those who took 400
adverse events were mild or moderate in mg/day [82c].
intensity. While the adverse events were There was exacerbation of psychosis in
similar at lower doses, they were more fre- ve of 83 patients with schizophrenia who
quent with higher doses, requiring with- took modanil compared with two of 70
drawal of the 400 mg dose of armodanil who took placebo [83R].
and the 800 mg dose of modanil after 7
and 3 days respectively. Two subjects who Psychiatric Long-term modanil treatment
took armodanil 400 mg/day had events can rarely cause psychotic symptoms [84A].
that led to withdrawal, one with multiple
events (headache, abdominal pain, pharyn- A 25-year-old woman with a history of narco-
gitis, hypertonia, vasodilatation, nausea, lepsy took modanil, titrated up to 300 mg/
day, and had dry mouth and tachycardia.
insomnia, anorexia, conjunctivitis, anxiety, After 5 days, she continued to take 300 mg/
emotional liability, confusion, and weak- day without any apparent adverse effects.
ness) and one with mild nausea and moder- About 6 months later she had visual and audi-
ate amblyopia. There were clinically tory hallucinations and delusions of reference.
signicant cardiovascular changes, includ- Modanil was withdrawn and her psychotic
symptoms resolved. After restarting modanil
ing sustained hypertension in one subject, on alternate days occasional hallucinations
in those who took modanil 800 mg/day. recurred.
There were no serious adverse events with
armodanil, while two adverse events were There have been other reports of
reported after administration of modanil. modanil-associated psychosis in patients
Both of the subjects with serious adverse with narcolepsy [85A, 86A, 87A].
event required hospitalization for monitor-
ing and evaluation. There were electro-
cardiographic abnormalities in one subject
taking 400 mg/day and anxiety/tachycardia
in one taking 800 mg/day. METHYLXANTHINES
In patients with primary biliary cirrhosis
the dosage of modanil was limited to 200 Caffeine [SED-15, 588; SEDA-30, 5;
mg/day because of the possibility of SEDA-31, 8; SEDA-32, 14]
reduced drug metabolism in this population
[80c]. Despite the low dosage, some Teratogenicity Adenosine receptors are
patients had adverse effects, including nau- among the rst receptors to be expressed
sea, insomnia, headache, and nervousness. in the embryonic brain, and modulation
12 Chapter 1 Reginald P. Sequeira

potentially affects axon formation [88E]. Drug overdose Hemodynamic instability


Intrauterine exposure to 10 or more cups and hypotension after massive caffeine
of coffee per day was associated with a overdose improved with loading doses
threefold increased risk of hyperkinetic dis- followed by continuous infusions of both
order and ADHD [89C]. After adjustment phenylephrine and lidocaine [93A]. Hypo-
for a number of confounding factors, such tension in caffeine overdose is multifactorial:
as smoking, alcohol intake, sex of the child, b2-adrenoceptor agonism causes peripheral
maternal age, a family history of psycho- vasodilatation and b1-adrenoceptor stimula-
pathology and parental socio-economic fac- tion leads to profound tachycardia with
tors, the risk fell and became statistically incomplete diastolic lling. The authors
insignicant (RR 2.3; 95% CI 0.9, suggested that both phenylephrine and lido-
5.9). This study was based on Aarhus Birth caine should be considered in the treatment
Cohort data in Denmark and included of cardiovascular collapse secondary to
24 068 singletons delivered between 1990 methylxanthine poisoning.
and 1998. Linkage was performed with Lactic acidosis has been reported in caf-
three Danish longitudinal registers: the Psy- feine poisoning [94A].
chiatric Central Register, the Integrated
Database for Labor Market Research, and A 17-year-old woman was admitted to the
the Danish Civil Registration System. emergency department 30 minutes after tak-
ing 12 g of caffeine (266 mg/kg) in a suicide
Information about coffee consumption dur- attempt. She had constant nausea with
ing pregnancy was obtained at 16 weeks of repeated vomiting, tremor, anxiety, and
gestation from a self-administered ques- hyperventilation, hypokalemia of 2.4 mmol/l,
tionnaire. A methodological strength of this and a blood lactate concentration of 3.1
mmol/l. The lactate concentration rose to 7.0
study was the community-based sample and mmol/l at 9 hours after ingestion, and no other
disentangling of confounding effects using cause besides caffeine poisoning was identi-
Cox regression analysis. It is important to ed. She was given ondansetron and
pursue a synergistic effect of intrauterine midazolam intravenously for nausea and anxi-
exposure to caffeine and cigarette smoke ety, and the hypokalemia was cautiously
corrected. She was also given propranolol.
on the risk of hyperkinetic disorder and
ADHD. A randomized, controlled trial Excessive sympathetic stimulation with
has shown that the effect of caffeine on increased glycogenolysis and lipolysis and
fetal growth was found only among a secondary rise in pyruvate could explain
smokers [90C]. Moreover, the implications lactic acidosis in caffeine poisoning.
of reduced maternal metabolism of caffeine
during the third trimester [91c] need to be
considered.
In the National Birth Defects Prevention
Study in the USA, a population-based, Theophylline [SED-15, 3361; SEDA-30,
casecontrol study of major birth defects, 5; SEDA-31, 8; SEDA-32, 15]
excluding infants with single-gene disorders
and chromosomal abnormalities, there was Nervous system Status epilepticus has been
no association between maternal dietary attributed to theophylline in two cases.
caffeine intake and orofacial clefts [92C].
This analysis included 1531 infants with A 5-year-old boy with no history of convul-
cleft lip with or without cleft palate, 813 sions had a generalized tonicclonic seizure
after taking oral theophylline for 2 days
infants with cleft palate only, and 5711 followed by non-convulsive status epilepticus
infants with no major birth defects as con- [95A]. The serum theophylline concentration
trols. Maternal caffeine intake was self- was 19.7 mg/l. An intravenous bolus dose
reported. Dietary caffeine intake may have of midazolam 0.26 mg/kg largely restricted
seizure activity to the right hemisphere and
changed during pregnancy, making expo- another 0.24 mg/kg followed by a continuous
sure assessment during the critical period infusion of 0.20 mg/kg/hour completely
for orofacial development difcult. abolished the electrical status.
Central nervous system stimulants and drugs that suppress appetite Chapter 1 13

An 8-month-old boy who had been given oral cocaine abuse, viral myocarditis, aortic
modied-release theophylline and additional dissection, hypercoagulable states, and
aminophylline suppositories developed con-
vulsive status epilepticus [96A]. A combination
autoimmune vasculitis.
of diazepam, lidocaine, and thiopental was
required to stop the convulsion. A pharmaco- Susceptibility factors Genetic Patient selec-
kinetic study showed that the use of the mod-
ied-release formula would have given a tion based on candidate genes may enhance
plasma concentration of no more than 15 mg/ the response to sibutramine in obesity
l, but that the addition of aminophylline would [106C].
have increased it to over 20 mg/l.

Drug overdose Acute pancreatitis has been


reported after severe theophylline overdose
[97A]. Rimonabant [SEDA-32, 19]

Rimonabant has been withdrawn because


of psychiatric adverse effects [107r, 108r,
109r], including, in one case, a major
depressive episode with melancholic fea-
DRUGS THAT SUPPRESS tures that resolved after withdrawal of
APPETITE [SEDA-30, 7; SEDA-31, rimonabant [110A]. In a placebo-controlled
9; SEDA-32, 16] trial in obesity there was an excess risk of
psychiatric reactions (43% versus 28%)
The need for studies of the long-term safety [111C].
and efcacy of antiobesity drugs [98R] and
the regulatory challenges for new drugs to Systematic reviews In a systematic review
treat obesity with comorbid metabolic dis- of 28 randomized placebo-controlled trials
orders [99R, 100R, 101C] have been lasting 1224 months in adults using
reviewed. New central targets for the treat- licensed doses of orlistat (16 trials),
ment of obesity are being explored [102R]. sibutramine (7 trials), and rimonabant (5
trials), the risk ratios (RRs) for withdrawal
because of adverse events were signicantly
increased for rimonabant (2.00; CI 1.66,
Phentermine [SED-15, 2804; SEDA-31, 2.41) and orlistat (1.59; 1.21, 2.08), but not
9; SEDA-32, 17] sibutramine (0.98; 0.68, 1.41) [112M]. Com-
pared with placebo, the risk difference for
Cardiovascular Ventricular tachycardia/ rimonabant was 7% (NNTH 14) and for
brillation in an otherwise healthy 48-year- orlistat 3% (NNTH 39). The most common
old woman who was taking no medications adverse events that led to withdrawal were
other than phentermine was attributed to gastrointestinal with orlistat (40%) and psy-
sympathetic activation [103A]. The cardiac chiatric with rimonabant (47%).
safety concern of phentermine suggested by In another systematic review of nine
these authors has been debated [104r]. published randomized placebo-controlled
trials of rimonabant in 9635 adults,
rimonabant 20 mg/day was associated with
Sibutramine [SED-15, 3131; SEDA-30, increased risks of adverse events (RR
7; SEDA-31, 9; SEDA-32, 17] 1.35; 95% CI 1.17, 1.56), withdrawal
(RR 1.79; 95% CI 1.35, 2.38), psychiat-
Cardiovascular Acute myocardial infarc- ric adverse events (RR 2.35; 95% CI
tion in a 24-year-old man with a low risk 1.66, 3.34), and nervous system adverse
of atherosclerosis, possibly associated with events (RR 2.35; 95% CI 1.49, 3.70);
sibutramine, has been reported [105A]. the NNTH for psychiatric adverse events
Other causes were ruled out, including was 30 [113M].
14 Chapter 1 Reginald P. Sequeira

Cardiovascular Atrial brillation has been subjective mood but did reduce incidental
attributed to rimonabant in two cases [114A]. recall of positive self-relevant adjectives,
an effect opposite to that seen with antide-
A man who took rimonabant for 5 weeks pressants [116c]. Rimonabant did not affect
developed palpitation, fatigue, and exertional other measures of emotional processing.
dyspnea. He had atrial brillation with a ven-
tricular rate of 98135/minute. No other cause
of atrial brillation was found and rimonabant Drugdrug interactions Ciclosporin The
was withdrawn. After 2 weeks his rhythm had interaction of rimonabant with ciclosporin
reverted to sinus rhythm. The patient refused (n 10) and tacrolimus (n 8) has been
re-challenge and 9 months later was still in
sinus rhythm. assessed in stable renal transplant recipi-
After taking rimonabant for 3 weeks a man ents [117c]. Rimonabant increased the
developed dizziness, palpitation, and exer- AUC0!12 of ciclosporin by 20%. The
tional dyspnea. He had atrial brillation, for authors concluded that this effect was prob-
which no other causes were found.
Rimonabant was withdrawn and 10 days later
ably of marginal clinical relevance since
the rhythm had reverted to sinus rhythm with trough concentrations were unaltered.
rst-degree atrioventricular block. Tacrolimus pharmacokinetics were unaf-
fected by rimonabant.
Nervous system Rimonabant has been
reported to cause partial seizures in a
patient with a history of generalized epi-
lepsy [115A] Tesofensine
A 52-year-old obese man with hypertension, Tesofensine is an inhibitor of neuronal
diabetes mellitus, and a history of absences reuptake of dopamine, noradrenaline, and
and two generalized tonicclonic seizures at
ages 415 years, but who had been seizure
serotonin. There has been considerable
free for over 20 years took rimonabant 20 interest in this investigational drug for
mg/day and 2 months later started to have weight reduction as an adjunct to energy
nocturnal partial seizures consisting of a restriction.
stereotypical feeling of falling into a deep
hole, often followed by right leg jerks lasting
3 minutes on average. These seizures were Placebo-controlled studies In a phase II
totally different from the generalized seizures clinical trial of tesofensine in Denmark there
he had had in his youth. After withdrawal of was a signicant reduction in body weight
rimonabant the seizures disappeared. A few compared with placebo [118C]. The common
weeks later he restarted rimonabant and 3 days
later his partial seizures returned. Routine adverse events were dry mouth, nausea, con-
and sleep-deprivation electroencephalography stipation, diarrhea, and insomnia. After 24
showed frequent epileptiform paroxysms, weeks, tesofensine 0.25 and 0.5 mg/day had
consisting of generalized irregular slow waves no signicant effect on systolic and diastolic
intermingled with frontal and temporal spikes blood pressures compared with placebo,
and focal epileptiform abnormalities in the left
temporal lobe, as in previous recordings over but heart rate increased by 7.4/minute. How-
20 years before. The seizures again resolved ever, there is a reduction in blood pressure of
immediately after rimonabant withdrawal, and 35 mmHg systolic and 23 mmHg diastolic
3 months later sleep-deprived electroencepha- with weight losses of 45 kg, and increases
lography showed mainly focal (left > right)
temporal epileptiform discharges and gene- of 1 mmHg in systolic pressure and 23
ralized irregular slow-wave paroxysms. mmHg in diastolic pressure among partici-
pants taking tesofensine 0.5 mg compared
A proconvulsant effect of rimonabant is not with controls seem to suggest that
unexpected, since cannabinoids have anti- tesofensine can increase blood pressure
convulsant properties in animals. [119r]. Drug development in the eld of
weight reduction has regularly faced
Psychological In a double-blind, placebo- pharmacovigilance hurdles, because anorexi-
controlled study in 30 healthy adults, a sin- genic drugs affect various neurotransmitter
gle dose of rimonabant 20 mg did not alter systems and can lead to serious adverse
Central nervous system stimulants and drugs that suppress appetite Chapter 1 15

effects. It has been suggested that the bar reactions from 23 of 289 patients, an inci-
should be set high when new drugs are intro- dence rate of 8%. The major adverse reac-
duced for obesity, in order to avoid repetition tions were ve cases of upper abdominal
of drug scandals related to antiobesity drugs discomfort (1.73%) and two each of anemia,
[120r]. insomnia, delusions, dizziness, and gait dis-
order (0.69%). Serious reactions were one
case each of anemia, anorexia, dizziness,
upper abdominal discomfort, and gait
disorder.
DRUGS USED IN In a study of the effect of donepezil 10 mg/
day the progression of cognitive dysfunction
ALZHEIMER'S DISEASE was slowed [124c]. The incidence of adverse
[SEDA-30, 8; SEDA-31, 10; events was 11.5% lower than the rate of
SEDA-32, 19] 40% or higher recorded during previous
clinical trials. The incidence of adverse
events was 12%, lower than the rate of
Observational study In an open study in 40% or higher that has been recorded during
patients with ADHD rivastigmine produced previous trials in Japan. Seven of the 61
sustained inhibition of acetylcholinesterase patients enrolled in this study were forced
and butyrylcholinesterase, whereas don- to withdraw because of adverse events that
epezil and galantamine did not inhibit occurred within 1 month of treatment with
butyrylcholinesterase and were associated donepezil 10 mg/day. If longer-term
with increases in CSF acetylcholinesterase donepezil treatment is planned, it is appro-
[121c]. The clinical implications of these priate to start with a dose of 5 mg/day and
ndings require evaluation. then increase to 10 mg/day to minimize the
Smell identication function could be use- adverse effects, particularly those that occur
ful as a clinical measure for assessing treat- at the start of treatment
ment response in Alzheimer's disease [122c].
Improved olfaction with donepezil correlated Placebo-controlled studies In a 6-month,
strongly with improvement in Clinician Inter- randomized, double-blind, placebo-con-
view Based Impression of Change plus Care- trolled study of 189 Japanese patients, 68
giver Input (CIBIC-plus), and predicted were given placebo, 69 were given
global improvement better than other mea- donepezil 5 mg/day, and 52 were given
sures, such as cognition. These ndings are donepezil 10 mg/day [125c]. Those who
biologically plausible, because olfaction took donepezil 10 mg/day with little or no
depends on brain regions that are primarily interruption achieved the best long-term
affected by Alzheimer's disease. outcome. Overall, 177 patients (93.7%)
had at least one adverse event. There were
severe adverse events in 15 patients (7.9%)
and serious adverse events in 33 (17.5%).
Donepezil [SED-15, 1179; SEDA-30, 8; Since altered expression of central mus-
SEDA-31, 10; SEDA-32, 19] carinic and nicotinic acetylcholine receptors
in hippocampal and cortical regions might
Observational studies Donepezil improved contribute to cognitive impairment in
cognitive dysfunction in patients with patients with schizophrenia, increasing cho-
Alzheimer's disease, but also ameliorated linergic activity might help improve cogni-
behavioral and psychological symptoms of tion in these patients. With this in mind,
dementia (BPSD), including hallucinations/ donepezil, a cholinesterase inhibitor,
delusions, wandering, and aggression has been examined in a 12-week, multi-
[123c]. Donepezil also alleviated the burden center, placebo-controlled, double-blind,
on care-givers for about 60% of patients. parallel-group study in 250 patients with
There were 30 reports of adverse drug schizophrenia or schizoaffective disorder
16 Chapter 1 Reginald P. Sequeira

who were clinically stabilized on in each arm. All were carried out in China.
aripiprazole, olanzapine, quetiapine, risper- In all, 474 patients were included, 235 in the
idone, or ziprasidone, alone or in combina- huperzine group and 237 in the control group.
tion [126C]. They were randomized to co- The trial durations ranged from 8 to 24 weeks;
treatment with donepezil (5 mg/day for 6 the longer duration resulted in better efcacy
weeks and then 10 mg/day for 6 weeks; on MMSE scores. Adverse symptoms
mean age 41 years; n 121) or with pla- included tachycardia, low energy, dry mouth,
cebo (mean age 40 years; n 124). Adjunc- and hypertension at multiple-dose ranges;
tive donepezil therapy did not signicantly bradycardia, headache, and intense dreams
improve cognitive impairment in moder- at a dose of 400 micrograms bd; muscle
ately ill patients with schizophrenia or cramps at 400 micrograms bd; arthralgia at
schizoaffective disorder maintained on anti- 300400 micrograms bd; and nausea, drowsi-
psychotic drugs. Treatment-emergent ness, and diarrhea.
adverse events were reported by 55% of A meta-analysis has shown that most
those who took donepezil and 61% of those clinical studies of huperzine showed prom-
who took placebo; the frequency of severe ising results in Alzheimer's disease; how-
adverse events was similar in the two ever, most of the studies were found to
groups (8.3% and 8.9% respectively) as have methodological shortcomings [128M],
were serious adverse events (5.8% and further conrmed recently [129R].
5.6%). There were no differences in the
frequency of dosage reduction or tempo-
rary study drug withdrawal because of
adverse events (donepezil, n 3; placebo Memantine [SED-15, 2250;
n 2) or in the frequency of adverse SEDA-32, 20]
event-related withdrawal (donepezil n
10; placebo, n 13). The most common The efcacy and adverse effects of
adverse events were headache and those memantine have been reviewed [130R].
affecting the digestive and nervous systems; The following adverse effects occur in more
treatment groups were comparable with than 2% of patients: fatigue, pain, hyperten-
regard to changes in vital signs and labora- sion, dizziness, headache, constipation,
tory analyses throughout the study. vomiting, back pain, confusion, somnolence,
hallucinations, coughing, dyspnea, agitation,
falls, injuries, urinary incontinence, diarrhea,
bronchitis, insomnia, urinary tract infection,
Huperzine inuenza-like symptoms, abnormal gait,
depression, upper respiratory tract infections,
Huperzine, an alkaloid from the plant anxiety, peripheral edema, nausea, anorexia,
Huperzia serrata, is a potent and highly selec- and arthralgia. Memantine undergoes both
tive, reversible acetylcholinesterase inhibitor. hepatic and renal elimination. In patients
with severe liver or kidney impairment
Systematic reviews In a meta-analysis of the lower dosages are required, but in patients
efcacy and safety of huperzine-A 300500 with mild to moderate renal impairment, no
micrograms/day in Alzheimer's disease, the adjustment is necessary.
estimated effect size on the Mini-Mental
State Examination (MMSE) and Activity of
Daily Living (ADL) increased over the treat-
ment time. Most of the adverse effects were Rivastigmine [SED-15, 3072; SEDA-30,
cholinergic and there were no serious adverse 10; SEDA-31, 11; SEDA-32, 20]
events [127M]. The meta-analysis included
four double-blind, randomized, placebo-con- Observational studies In a multicenter
trolled trials, with more than 20 participants study of a transdermal rivastigmine patch
Central nervous system stimulants and drugs that suppress appetite Chapter 1 17

(9.5 mg/day) for up to 1 year, 870 of 1195 Two months after starting to use a rivastigmine
patients completed the double-blind phase transdermal patch (4.6 mg/day, increased to 9.5
mg/day 1 month later), an 84-year-old woman
and entered the open extension [131c]. developed fatigue, weakness, abdominal
Nausea and vomiting (16% and 14% bloating, yellowish eyes, dark urine, and a tran-
respectively) were the most frequent sient rash. Her other medications included aspi-
adverse effects. Skin tolerability at the site rin, ramipril, and valproic acid. She had a raised
of application was generally good, with no, total bilirubin concentration with a conjugated
fraction of 36 mmol/l, raised aminotransferases,
slight, or mild irritation as the most com- alkaline phosphatase, and gamma-glutamyl
mon application site reaction. Erythema transpeptidase activities, and an eosinophilia.
(7.7%) and pruritus (5.6%) were moderate Tests for hepatic virus markers and autoanti-
or severe reactions to rivastigmine, and bodies were negative. Ultrasonography
showed a normal echogenic liver and no bile
3.7% withdrew owing to reactions at the duct or gall bladder abnormalities.
site of application. There was also a trend Rivastigmine was withdrawn, and the signs
towards an increase in adverse skin reac- and symptoms of hepatitis gradually improved.
tions over time. Rivastigmine was with- She continued taking other medications, and 5
drawn in 73 patients (8.4%) during the weeks after withdrawal of rivastigmine her liver
function tests were normal.
extension phase because of reactions at
the site of application (3.6%) or gastro- The explanation of liver toxicity in this
intestinal disorders (2.9%). patient is uncertain, but a hypersensitivity
In a prospective, non-interventional, post- reaction was possible.
marketing observational study in Taiwan,
rivastigmine 36 mg/day was well tolerated Drug overdose An 80-year-old woman with
by patients with Alzheimer's disease [132C]. Alzheimer's disease had an overdose when
In 261 patients, the mean duration of she used nine 5 cm2 transdermal patches of
rivastigmine exposure was 151 days. Of 253 rivastigmine [135A]. She had fasciculation
patients, 155 (61%) reported at least one of her gastrocnemius and quadriceps mus-
adverse event, the most frequent of which cles bilaterally. The patches were removed
were psychiatric (9.1%) and gastrointestinal and the underlying skin was cleansed with
(8.3%). The most common adverse events soap and water. Although the working diag-
were mild dizziness (5.5%), insomnia nosis was rivastigmine overdose, due to min-
(5.1%), anorexia (4.0%), constipation (4%), imal pulmonary muscarinic ndings,
vomiting (4%), and nausea (3.6%). In all, 12 atropine was not used. She was instead given
patients (4.7%) reported 16 serious adverse pralidoxime 1 g intravenously. Within 30
events, including two deaths, one case of syn- minutes of the end of the infusion her sweat-
cope with head trauma, one peptic ulcer, and ing and miosis had improved and her fascic-
six other hospitalizations. None was reported ulation had resolved.
to be related to rivastigmine. The authors Although the use of pralidoxime is
stressed the importance of starting with a debated, a clinical trial has conrmed a signif-
low dose of rivastigmine and gradually icant advantage for oxime therapy in organo-
increasing the dosage. phosphate poisoning [136C]. In poisoning
with carbamates (such as rivastigmine), the
clinical course tends to be mild and self-limit-
Systematic reviews There is evidence that
ing, because carbamate-induced cholinester-
a lower dose small transdermal patch is
ase inhibition tends to be mild and
associated with fewer adverse effects than
spontaneously reversible. This case of appar-
capsules or a higher dose larger patch, with
ently safe and effective pralidoxime adminis-
efcacy comparable to both [133M].
tration without the use of atropine in a
patient with transdermal rivastigmine toxicity
Liver Hepatotoxicity associated with trans- reinforces recent data demonstrating the
dermal rivastigmine use has been reported potential safety of pralidoxime in carbamate
[134A]. poisoning.
18 Chapter 1 Reginald P. Sequeira

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Philip B. Mitchell

2 Antidepressant drugs

GENERAL antidepressants should be avoided in


those with or at risk of cardiovascular dis-
ease; that reboxetine, duloxetine, and
Comparative rates of adverse effects with venlafaxine increase the blood pressure;
different antidepressants One limitation of and that there is a dearth or absence of
meta-analyses is that they depend on the data about the use of many antidepressants
particular head-to-head comparisons chosen in patients with cardiac disease [2R].
by the researchers, be they industry-based
or academic-based. Multiple-treatments
meta-analysis is a statistical technique that
was developed to extract data from multi-
ple randomized controlled trials to test for
comparative efcacy and tolerability of
agents that were not compared in individ-
MONOAMINE OXIDASE
ual reports. The relative efcacy and
tolerability of 12 different antidepressants INHIBITORS [SED-15, 2371;
have been studied in a multiple-treatments SEDA-32, 32]
meta-analysis, which showed that
escitalopram, sertraline, bupropion, and Moclobemide
citalopram were better tolerated than the
other antidepressants studied [1M]. The
cumulative probabilities of being among Drugdrug interactions Carbamazepine
the most acceptable four treatments were: and valproate The mood stabilizers carba-
escitalopram (28%), sertraline (27%), mazepine and valproate are often used in
bupropion (19%), citalopram (19%), combination with antidepressants in patients
milnacipram (7%), mirtazapine (4%), u- with unipolar or bipolar affective disorder.
oxetine (3%), venlafaxine (1%), duloxetine The effects of valproate and carbamazepine
(1%), uvoxamine (0.4%), paroxetine on the steady-state pharmacokinetics of
(0.2%), and reboxetine (0.1%). moclobemide and two metabolites have been
studied in a non-randomized crossover study
Susceptibility factors Cardiac disease In a in 21 patients with unipolar depression [3c].
comprehensive review of all (old and new) Valproate had no effect, but carbamazepine
antidepressant medications and cardiovas- was associated with a 35% reduction in
cular disease, it was concluded that tricyclic moclobemide AUC, a 28% reduction in Cmax,
and a 41% reduction in clearance after
4 weeks of co-administration. These changes
were interpreted as being due to induction
carbamazepine of the metabolism of
Side Effects of Drugs, Annual 33 moclobemide and its main metabolite. How-
J.K. Aronson (Editor) ever, there was no concurrent loss of efcacy,
ISSN: 0378-6080
DOI: 10.1016/B978-0-444-53741-6.00002-7
throwing into doubt the clinical signicance of
# 2011 Elsevier B.V. All rights reserved. these signicant kinetic effects.

25
26 Chapter 2 Philip B. Mitchell

SELECTIVE SEROTONIN management with placebo. Those allocated


RE-UPTAKE INHIBITORS initially to placebo received open active
treatment as clinically indicated after
(SSRIS) [SED-15, 3109; SEDA-30, 16; 12 weeks, and all subjects were followed
SEDA-31, 18; SEDA-32, 33] for 36 weeks. There were no differences
between the groups in the rates of suicidal
events (suicide attempts, preparation for sui-
Cardiovascular Carotidynia, a focal cervi- cidal behavior, or suicidal ideation) during
cal pain that involves the anatomical terri- either the initial 12-week double-blind phase
tory of the affected carotid artery and or the 36-week open treatment phase. There
often radiates to the ipsilateral side of the were no suicides in either group.
face or ear, has been attributed to uoxe- In the Treatment of SSRI-Resistant
tine and citalopram [4A]. Depression in Adolescents (TORDIA) study
[7C], 334 depressed adolescents, who had
After taking uoxetine 20 mg for 5 months, a
43-year-old man developed left intercostal
not responded to a previous trial with an
pain, which became bilateral, steadier, episodic, SSRI antidepressant, were randomized to
and stabbing on deep breathing and movement either another SSRI or venlafaxine, with or
of the trunk. Two weeks later, he noted a tender without cognitive behavioral therapy. There
swollen mass at the level of the right carotid were no signicant differences between the
bifurcation, accompanied by a severe pulsating
pain, which radiated to the ipsilateral jaw groups in the rates of suicidal and non-sui-
on contralateral head movement. Cervical cidal self-injury, although the signicance
magnetic resonance and angiomagnetic reso- of this was limited by the lack of a placebo
nance studies showed abnormal soft tissue comparison group [8r].
thickening of the right common carotid and its
bifurcation. Fluoxetine was withdrawn and the
In 488 children and adolescents (aged
carotidynia and intercostal pain resolved 717 years) with an anxiety disorder who
completely. Fluoxetine was restarted on two were randomized to 12 weeks of sertraline
further occasions, and the pain recurred within up to 200 mg/day, cognitive behavioral ther-
4 weeks and resolved on withdrawal. The apy, the combination of these, or placebo,
same symptoms recurred after challenge with
citalopram on two occasions. suicidal and homicidal ideation were no
more common with sertraline than placebo;
no child attempted suicide [9C].
Combining the ndings of these child-
hood and adolescent studies, the two large
SSRIs and emergent suicidal placebo-controlled trials [5C, 9C] were con-
ideation sistent in not demonstrating an increased
rate of suicidal thoughts or behavior with
Further data have claried the highly contro- SSRI antidepressants compared with pla-
versial relation between SSRI antidepressants cebo, while Brent et al. [7C] found no differ-
and emergent suicidality. Prior studies have ence between an SSRI and venlafaxine.
suggested that this adverse effect may be more Interpreting these controlled studies conser-
likely to occur in children, adolescents, and vatively, the data suggest either that these
young people than in older adults (SEDA- agents do not increase the risk of suicidal
31, 18; SEDA-32, 29). The ndings of three thoughts or behavior in depressed or anx-
prospective trials of depressed or anxious ious children and adolescents, or that such
children and adolescents have thrown new outcomes are uncommon.
light on this question. With respect to the adult literature, a
Results have been reported from the pooled analysis, by Pzer-employed staff,
Treatment of Adolescents with Depression of sertraline placebo-controlled trials, using
Study (TADS) [5C, 6C], in which 439 ado- the FDA-dened search method, showed
lescents were randomly allocated to 12 weeks no evidence of an increase in the risk of
of uoxetine, cognitive behavioral therapy, suicidality compared with placebo in those
the combination of these, or clinical who took sertraline. In the open citalopram
Antidepressant drugs Chapter 2 27

phase of the STAR*D depression trial [10C] with a signicant reduction in adverse sex-
74% of the 1909 subjects with baseline sui- ual effects [17C]. Secondly, in an 8-week
cidal ideation (i.e. before they started to take open study, mirtazapine produced signi-
citalopram) improved by the nal visit, cant reductions in SSRI-induced sexual dys-
while 4% worsened [11M]. Of 1721 without function in 49 outpatients (men and
baseline suicidal ideation, 7% experienced women) [18c].
emergence of such thoughts by the rst
post-baseline visit, but 63% of these had no
suicidal ideation at their nal visit.
Finally, the effect of the warning issued by Antidepressants in pregnancy
the UK Medicines and Healthcare products [SEDA-30, 16; SEDA-31, 19; SEDA-32, 31]
Regulatory Authority (MHRA) in Decem-
ber 2003, not to prescribe SSRI antidepres- Intense interest in the potential for SSRI
sants, except uoxetine, for those younger antidepressants to have teratogenic and
than 18 years, has been examined [12C]. adverse pregnancy outcomes continues, and
Prescriptions fell signicantly (by 51%) dur- four further major data-based reports have
ing 20002006. However, there were no appeared [19C, 20C, 21C, 22C], as well as a
changes in the rates of non-fatal self-harm report on the management of depression in
or self-poisoning. pregnancy from two leading US professional
bodies [23S] and three leading editorials or
commentaries [24r, 25r, 26r].
Skin SSRI-induced photosensitivity is Previous reports had suggested that SSRIs
uncommon. Three cases have been reported, can cause cardiovascular abnormalities, and
in association with sertraline [13A] and the strongest evidence related to paroxetine.
with uvoxamine and paroxetine [14A]. However, the relative contributions of these
medications and the effect of depressive
Sexual function SSRIs can cause sexual illness have remained uncertain.
dysfunction, particularly reduced libido, In a prospective study of pregnant women
impaired orgasm in women, and inhibition who had contacted teratology information
of ejaculation or erectile difculties in men. services in Israel, Italy, and Germany
There have been two reports of unusual because of rst-trimester exposure to uoxe-
male sexual dysfunction. In two cases of tine (n 346) or paroxetine (n 463),
spermatorrhea (excessive emission of compared with a control group (n 1467)
semen without orgasm or erection) in men who had contacted these services regarding
taking uvoxamine, the problem resolved exposure to non-teratogenic agents during
on drug withdrawal [15A]. Spontaneous the same time period, miscarriage rates were
ejaculations occurred daily in a 27-year- higher after exposure to uoxetine, but this
old man after he had taken citalopram for was not signicantly different from controls
2 weeks [16A]. They were unrelated to after accounting for other factors such
sexual fantasies, arousal, erection, or any as smoking rates and maternal age [19C].
sensation of orgasm and resolved on drug After exclusion of genetic and cytogenetic
withdrawal. They did not recur when he anomalies, there were higher rates of major
took paroxetine. anomalies after exposure to uoxetine
There have been two reports of the man- (4.7%) and paroxetine (5.2%) than in con-
agement of SSRI-induced sexual adverse trols (2.5%), and most of this was related
effects. First, in an 8-week prospective to cardiovascular anomalies (uoxetine
double-blind placebo-controlled trial of sil- 2.8%; paroxetine 2.0%; controls 0.6%).
denal 50100 mg/day in 98 previously sex- After accounting for relevant confounders,
ually functioning premenopausal women uoxetine remained signicantly associated
whose major depression had remitted on with higher rates of cardiovascular anoma-
SSRIs, but who were also experiencing sex- lies (OR 4.47; 95% CI 1.31, 15).
ual dysfunction, sildenal was associated
28 Chapter 2 Philip B. Mitchell

In a prospective observational study the Hospital, the relation between in utero


separate effects of SSRI antidepressants and exposure to SSRIs (at any stage during the
depression in 238 women were assessed at pregnancy) and pregnancy outcome was
20, 30, and 36 weeks of gestation, and neo- examined [22C]. The researchers compared
natal outcomes were determined on blinded outcomes in 329 women exposed to SSRIs,
review of delivery records and infant exami- 4902 with a history of psychiatric illness
nations [20C]. The women were categorized but no SSRIs during pregnancy, and
into three exposure groups: (i) no SSRIs, 51 770 women with no history of psychiatric
no depression (n 131); (ii) SSRI expo- illness or SSRI exposure during pregnancy.
sure, either continuous (n 48) or partial There was a greater likelihood of preterm
(i.e. at some point during the pregnancy; n birth in those exposed to SSRIs compared
23); and (iii) no SSRI exposure, but with women with no history of psychiatric
depression that was either continuous illness (OR 2.0; 95% CI 1.3, 3.2). Neo-
(n 14) or partial (i.e. at some point during nates who had been exposed to SSRIs were
the pregnancy; n 22). Infants who were also more likely than those with no psychiat-
exposed to either SSRIs (RR 3.56; 95% ric history to be admitted to a neonatal inten-
CI 1.40, 9.01) or continuous depression sive care unit (OR 2.4; 95% CI 1.7,
(RR 4.25; 95% CI 1.06, 15) through- 3.4) and to have a low Apgar score (<8)
out the pregnancy were more likely to be born (OR 4.4; 95% CI 2.6, 7.6). There were
before term than infants with no exposure to similar differences in the exposed group
SSRIs or depression. However, after control- compared with those with a psychiatric his-
ling for maternal age and race, only continu- tory but who had not been exposed to these
ous SSRI exposure remained signicantly medications.
related to the risk of preterm delivery (RR What conclusions can be drawn from
5.43; 95% CI 1.98, 15). Neither expo- these four studies? First, the reports of
sure to an SSRI nor depression increased the Diav-Citrin et al [19C] and Pedersen et al
risk of minor physical abnormalities. [21C] conrm prior reports of increased
In a study of a Danish population-based rates of cardiovascular anomalies with
cohort of 493 113 children, in which four SSRIs, suggesting that this is a class effect
nationwide registers were linked (births; rather than specic to paroxetine, as some
medicinal products; fertility; and hospital previous studies had suggested. The report
diagnoses), redemptions for SSRIs during of Diav-Citrin highlights the importance of
early pregnancy (dened as up to 112 days accounting for other potential confounders,
of gestation) were not associated with major such as smoking and maternal age, while
anomalies overall, but were associated with that of Pedersen et al suggests that the main
a greater risk of septal heart defects (OR anomaly is that of septal heart defects and
1.99; 95% CI 1.13, 3.53) [21C]. This that the use of multiple SSRIs may further
was signicant for sertraline (OR 3.25; increase risk.
95% CI 1.21, 8.75) and citalopram (OR Second, the studies of Wisner et al [20C]
2.52; 95% CI 1.04, 6.10), but not for and Lund et al [22C] are consistent in dem-
paroxetine or uoxetine. Rates were also onstrating higher rates of preterm deliveries
higher when there had been redemptions in neonates exposed to SSRIs. Wisner et al
for more than one type of SSRI (OR 4.70; examined for the effect of depression, but
95% CI 1.74, 13). However, absolute found no convincing statistical evidence for
increases in rates of septal heart defects were an additional effect of depression indepen-
low: 0.5% in unexposed children; 0.9% in dent of SSRI exposure. Lund et al extended
those whose mothers redeemed one SSRI; the ndings of higher rates of premature
and 2.1% in those whose mothers redeemed delivery, demonstrating the greater rates of
more than one type of SSRI. poor physical health in exposed neonates,
In a second Danish study, this time focus- who had higher rates of low Apgar scores
ing on outcomes in women who were receiv- and neonatal intensive care admissions.
ing prenatal care at Aarhus University While they could not examine the effect of
Antidepressant drugs Chapter 2 29

depression during pregnancy, Lund et al An 81-year-old man with hypertension, diabe-


found no evidence of an effect of pre-existing tes, end-stage renal disease, and depression,
became dizzy and had an episode of torsade
psychiatric diagnosis. de pointes, with a prolonged QT interval of
In a report from the American Psychiatric 572 ms (QTc 695 ms). An ECG recorded
Association and the American College of 1 month before he started to take citalopram
Obstetricians and Gynecologists, based on a had shown a normal QT interval.
comprehensive review of the literature before
the publication of the above four studies, the The citalopram was withdrawn and the QT
authors concluded that while there had been interval normalized.
reports linking antidepressants to both fetal
anomalies and neonatal dysfunction, the Infection risk In two cases Herpes zoster
effect of confounding factors such as depres- infection occurred within 6 weeks of treat-
sive symptoms during pregnancy had not ment with citalopram [32A]. There have
been adequately investigated [23S]. The been no previous reports of such an associ-
recent studies of Wisner et al and Lund et al ation with any SSRI, and there is no de-
suggest that the effect of SSRI antidepressants nite effect of these agents on immune
is unrelated to current depression or pre- function. The association should therefore
existing psychiatric illness. be regarded as provisional.

Susceptibility factors Genetic There has Drug overdose Seizures are a recognized,
been a growing number of reports of attempts albeit uncommon, complication of overdose
to identify genetic predictors of the adverse with a number of SSRI antidepressants, but
effects of SSRIs, largely arising out of two the susceptibility factors have not been elu-
large effectiveness trials, the US STAR*D cidated. Of 241 patients who presented with
[27R, 28R] and the European GENDEP pro- overdose of citalopram, 7.5% had general-
ject. Using the STAR*D dataset, Perlis et al ized seizures [33C]. Co-ingested venlafaxine
looked for genetic predictors of sexual dys- or tricyclic antidepressants increased the
function in depressed patients taking risk substantially (OR 15). In the
citalopram, and found an association with absence of co-ingested drugs, the minimum
the glutamatergic genes GR1A1, GR1A3, citalopram dose associated with seizures
GR1K2, and GR1N3A [29C]. Perroud et al. was 400 mg, with an increase in the odds
from the GENDEP project, looked for ratio for seizures of 1.1 for every 100 mg
genetic predictors of treatment-emergent sui- increment in citalopram dose.
cidal ideation during treatment with
escitalopram or nortriptyline [30C]. Polymor- Drugdrug interactions Propafenone A
phisms in BDNF (the gene for brain-derived possible interaction of citalopram and the
neurotrophic factor) were signicantly associ- class 1C antidysrhythmic drug propafenone
ated with an increase in suicidal ideation. (which is metabolized by CYP2D6) has
While they are of substantial interest, both been reported [34A].
of these reports should be regarded as prelim-
inary, in the absence of replication in inde- An 80-year-old white woman took
propafenone 900 mg/day for more than
pendent datasets. 10 years for paroxysmal atrial brillation with-
out adverse effects. She then took citalopram
20 mg/day for 3 months for anxiety attacks
and began to have episodes of chest tightness
and dizziness, which became more frequent
Citalopram and escitalopram during the following months, causing several
falls and requiring visits to the emergency
Cardiovascular Long QT syndrome is asso- department. However, no coronary event
was diagnosed. The dose of propafenone was
ciated with an increased risk of life-threaten- then halved while the citalopram was contin-
ing cardiac dysrhythmias. Torsade de pointes ued. She recovered and had no further symp-
has been attributed to citalopram [31A]. toms 1 year later.
30 Chapter 2 Philip B. Mitchell

Paroxetine reduced its clearance in heterozygotes but


had no effects in homozygotes [37C]. The
Psychological There has been continuing CYP2D6*10 allele is one of the most com-
debate within professional circles and the mon intermediate metabolism alleles in East
public about the effect of the newer antide- Asians.
pressants on personality, though there have Delirium occurred in a 69-year-old
been few data to throw light on this conten- woman who had been taking paroxetine
tious issue. In one of the few controlled regularly for 5 years after she took
studies, personality (as measured by neu- ecainide for atrial brillation for 2 weeks;
roticism and extraversion on the NEO her serum ecainide concentration was
Five-factor inventory) was examined in a markedly raised and the delirium resolved
placebo-controlled study of paroxetine for 3 days after ecainide withdrawal [38A].
depression [35C], in which 120 subjects
were randomized to paroxetine, 60 to
placebo, and 60 to cognitive therapy.
There was normalization of personality Sertraline
measures, i.e. reduced neuroticism and
Musculoskeletal Rhabdomyolysis has again
increased extraversion, with paroxetine
been attributed to sertraline [39A].
compared with placebo (after statistically
accounting for changes in degrees of A 71-year-old woman took sertraline 50 mg/day
depression). These ndings suggest that for depression and 2 months later was found
SSRIs may have a pharmacological effect to have markedly increased creatine kinase,
on personality distinct from their antide- lactate dehydrogenase, and aspartate amino-
transferase activities and serum myoglobin
pressant action. There was no evidence of concentration. These abnormalities resolved
any pathological effect on personality. within 1 week of sertraline withdrawal, but
recurred dramatically 2 weeks after re-introduc-
Susceptibility factors Genetic Impaired tion of sertraline. Once again, everything
resolved after withdrawal of sertraline. She was
platelet function due to SSRIs has been successfully treated with escitalopram without
well-documented, and is associated with recurrence of the biochemical disturbances.
clinical evidence of an increased bleeding
tendency. The mechanism is related to the Liver Hepatotoxicity has again been attrib-
effect of SSRIs on the serotonin transporter uted to sertraline (SEDA-30, 16) [40A]. In
(5-HTTLPR) in the platelet membrane, this case report, it presented within 6 months
which leads to reduced platelet serotonin of treatment in a 17-year-old boy with no
concentrations; however, there have been other demonstrable explanation.
no studies of the relation of genetic poly-
morphisms of 5-HTTLPR to this pharma-
cological action. In a prospective prepost
trial of paroxetine, the effect of paroxetine
was most pronounced in patients with no
LA alleles or only a single allele, and was
SEROTONIN AND
most marked in those with the S/S genotype NORADRENALINE
[36C]. RE-UPTAKE INHIBITORS
(SNRIS)
Drugdrug interactions Flecainide Fleca-
inide, a class 1C antidysrhythmic agent, is
metabolized by CYP2D6. In a study of the Psychiatric Mania and hypomania due to
interaction of the CYP2D6*10 allele and SNRIs have been reviewed in the light of
paroxetine in an open crossover study in a case of duloxetine-induced hypomania in
healthy Korean subjects, paroxetine signi- a non-bipolar patient [41Ar]. The data
cantly increased the AUC of ecainide and suggest that SNRIs, especially venlafaxine,
Antidepressant drugs Chapter 2 31

can induce mood switching in patients [51A]. Such behavior might be related to
with bipolar depression and in certain altered serotonin function.
patients with unipolar depression, and that
duloxetine and milnacipran can also cause
Electrolyte balance Hyponatremia has
manic or hypomanic symptoms. The authors
been attributed to duloxetine [52A].
suggested starting treatment with a low dose
and titrating upwards as required. An 85-year-old woman with major depression
was given duloxetine 30 mg/day and
within 6 days developed an unstable gait and
reduced vigilance. Her serum sodium concen-
tration was 110 mmol/l, the serum osmolality
Duloxetine [SEDA-32, 34] 234 mOsm/kg, and urine osmolality (310
mOsm/kg), suggesting the syndrome of inap-
Placebo-controlled studies In a placebo- propriate antidiuretic hormone secretion
controlled study of 1491 patients nausea (SIADH). She recovered after withdrawal of
duloxetine.
was more frequent in those who took
duloxetine (30% versus 7.1%) and weight
loss was signicantly greater; all of those Sexual function Increased sexual desire
who withdrew because of an adverse event has been attributed to duloxetine [53A].
were taking duloxetine (22%) [42C].
A 36 year-old man who had had a right parie-
tal lobe stroke took duloxetine 30 mg/day
Systematic reviews In a systematic review for 1 week and developed mild nausea and
of 36 experimental and observational stud- sedation were mentioned. The dose was
ies duloxetine caused nausea, vomiting, increased to 60 mg/day and he started to have
and dry mouth more often than comparator increased sexual desires and masturbated 34
times a day, even in front of his children
drugs, but these differences did not lead to or wife. There were no other hypomanic,
higher withdrawal rates than in patients manic, or obsessivecompulsive symptoms.
taking SSRIs [43M].
Drug overdose Overdose with duloxetine
Cardiovascular Symptomatic tachycardia
has been described in a 38-year-old man
has been attributed to duloxetine 20 mg/day
who had become suicidal within 4 days
in a 26-year-old man; it resolved on with-
after having switched from escitalopram
drawal and recurred after rechallenge; it
20 mg/day to duloxetine 30 mg/day [54A].
responded to treatment with propranolol
He was unconscious and severely hypoten-
while the duloxetine was continued [44A].
sive but recovered after treatment in inten-
An apical cardiomyopathy has also been
sive care. The authors discussed the
attributed to duloxetine [45A].
possibility that duloxetine had made him
feel suicidal, although such an effect has
Nervous system Shock-like sensations in not emerged in clinical trials.
the head (encephalastrapy [46r]) have A 30-year-old woman with major depres-
occasionally been reported in association sion and multiple sclerosis took duloxetine
with antidepressants, and particularly after 1680 mg, pipamperone 380 mg, amitripty-
withdrawal of venlafaxine [47Ar]. Another line 250 mg and became unconscious,
report has now implicated withdrawal of had a seizure, and became delirious with
duloxetine [48A]. agitation and hallucinations; her plasma
Serotonin syndrome has been attributed duloxetine concentration was >2000 ng/ml
to duloxetine [49A, 50A]. and the CSF concentration was 15 ng/ml
[55A]. Despite the very high plasma
Psychiatric Binge eating has been attrib- concentration, she survived. The authors
uted to duloxetine 90 mg/day in a 37-year- suggested that active transporters (the
old woman; the behavior resolved when bloodbrain barrier) had protected
the dosage was reduced to 60 mg/day the brain.
32 Chapter 2 Philip B. Mitchell

Pregnancy and lactation A 29-year-old subjects with major depressive disorder,


woman took duloxetine for depression 7% of those taking desvenlafaxine 100 mg/
during the second half of an otherwise day withdrew because of adverse events
uncomplicated pregnancy, gave birth at [60C]. The most frequent adverse effects
term to a healthy girl, and breastfed her were: nausea (23%), insomnia (14%), som-
without incident while continuing to take nolence (11%), fatigue (10%), reduced appe-
duloxetine [56A]. tite (9%), constipation (7%), hyperhidrosis
(6%), blurred vision (5%), vomiting (4%),
abnormal dreams (2%), and yawning (1%).
Drugdrug interactions Warfarin In 15 On withdrawal by tapering at the end of the
healthy subjects taking warfarin 29 mg/ study, 27% described withdrawal symptoms,
day with a stable international normalized the most common being dizziness (10%),
ratio (INR) of 1.52.0, duloxetine 60 mg headache (5%), and nausea (5%).
for 14 days or 60 mg for 4 days then
120 mg for 10 days had no clinically or Liver Fulminant hepatic failure has been
statistically signicant effect on the steady- attributed to a combination of venlafaxine
state pharmacodynamics or pharmacokinet- and trazodone [61A].
ics of warfarin [57C].
A 48-year-old woman with normal liver func-
Venlafaxine and desvenlafaxine tion took venlafaxine 75 mg/day and trazo-
done 200 mg/day for depression and
[SED-15, 3614; SEDA-30, 19; SEDA-31, 4 months later developed increasing jaundice
22; SEDA-32, 35] and encephalopathy. She had markedly raised
transaminases and bilirubin. There were no
Desvenlafaxine, the major active metabo- other explanations for her hepatic failure,
lite of venlafaxine, has been relatively and she received an urgent liver transplanta-
tion. The pathology showed severe acute hep-
recently introduced as an antidepressant atitis compatible with toxic acute liver failure.
[58R]. It has been approved for marketing She recovered fully, and had normal liver
in the USA but not Europe. function tests 1 year later.

Placebo-controlled studies In an 8-week Drug overdose There has been growing


placebo-controlled exible-dose (200400 awareness of the cardiac adverse effects
mg/day) study in 235 subjects with major of venlafaxine (SEDA-32, 35). A 51-year-
depressive disorder treatment-emergent old woman with no known risk factors
adverse effects were reported by 96% of for coronary artery disease had an episode
those taking desvenlafaxine and 86% of those of non-ST-elevation myocardial infarction
taking placebo; 12% of those taking in association with an overdose of
desvenlafaxine withdrew because of adverse venlafaxine [62A].
effects, nausea being the most common However, in a case series of 273 patients
[59C]. Adverse effects reported by at least who took an overdose of venlafaxine,
5% and at a frequency of at least twice that overdose caused only minor abnormalities
of the placebo control group were: nausea in the QT and QRS intervals, and was
(36%), dry mouth (31%), hyperhidrosis unlikely to be associated with major dys-
(20%), insomnia (16%), somnolence (15%), rhythmias, except possibly with large doses
reduced appetite (15%), tremor (11%), (> 8 g) [63C]. The commonest cardiovas-
blurred vision (10%), yawning (9%), sedation cular effects were tachycardia (54% of
(9%), vomiting (9%), mydriasis (9%), middle patients) and mild hypertension (40%).
insomnia (8%), initial insomnia (6%), erectile
dysfunction (6%), constipation (6%), feeling Drugdrug interactions Desvenlafaxine has
jittery (5%), and dyspepsia (5%). been reported to have minimal effect on
In an 8-week, randomized, placebo- CYP2D6 in a comparison with duloxetine, a
controlled comparison of desvenlafaxine moderate inhibitor of CYP2D6, in a random-
(50 or 100 mg/day) and duloxetine in 638 ized, open, crossover study in healthy
Antidepressant drugs Chapter 2 33

subjects, in which desvenlafaxine had a mini- bupropion during the rst 3 years of its mar-
mal effect on desipramine pharmacokinetics keting in France was associated with 475 seri-
[64C]. ous adverse reactions (SARs), including 21
deaths [69C]. The most common SARs were
cutaneous or allergic reactions (31%
OTHER of SARs), including angioedema and serum
ANTIDEPRESSANTS sickness-like reactions. Serious neurological
reactions were frequent (23% of SARs),
mostly comprising seizures.
Agomelatine
Agomelatine is an agonist at melatonin Drug overdose The incidence and nature
(MT1/MT2) receptors and an antagonist at of seizures after overdoses of bupropion
5-HT2C receptors; it shares the latter action XL have been reported in a study of 117
with other antidepressants, such as patients who presented to ve poison cen-
mirtazapine [65R, 66R]. ters in the USA [70C]. Seizures occurred
in 32%, and the median dose of those
Comparative studies In a 12-week ran- who had a seizure was 4350 mg, compared
domized controlled trial in 276 depressed with 2400 mg in those who did not. One-
patients allocated to agomelatine 50 mg/ third had delayed initial convulsions,
day or venlafaxine (titrated to a target dose dened as occurring more than 8 hours
of 150 mg/day), of those randomized to after the overdose. This suggests the need
agomelatine 20% reported treatment-emer- for a minimum observation period of
gent adverse effects, the most common 24 hours after overdosage with bupropion.
being nausea (12%), headache (10%), and
upper respiratory tract infections (7%); 2% Drugdrug interactions The inhibitory
withdrew because of adverse effects [67C]. effect of bupropion on CYP2D6 metabo-
The rate of treatment-emergent sexual lism has been previously demonstrated
dysfunction (reduced libido in males and in vivo, for example by inhibition of dextro-
impaired orgasm in females) was lower than methorphan metabolism (SEDA-30, 20).
in those who took venlafaxine. An in vitro study using desipramine as sub-
strate has suggested that this effect is due
Placebo-controlled studies In a 24-week to the metabolites erythrohydrobupropion
placebo-controlled study in 339 patients with and threohydrobupropion, which were
major depressive disorder there was a with- much more potent inhibitors of CYP2D6
drawal rate of 2%; most of the adverse than hydroxybupropion or bupropion
events were of mild to moderate intensity itself [71E].
[68C]. The most common adverse effects of
agomelatine, which occurred more fre-
quently than with placebo, were headache
(8%), back pain (6%), neck pain (2%), con- Mirtazapine [SED-15, 2356;
stipation (2%), dyspepsia (2%), and initial SEDA-32, 36]
insomnia (2%). There were no symptoms
associated with abrupt withdrawal. Nervous system There have been two
reports of movement disorders induced by
mirtazapine. Most of a case series of 14
Bupropion (amfebutamone) patients with restless legs syndrome
[SED-15, 108; SEDA-30, 20; SEDA-31, 22; presented within a few days of starting
SEDA-32, 35] treatment, and the symptom occurred more
often in those who also took tramadol or
Observational studies In a study of 698 000 dopamine receptor antagonists, such as
individuals using the French Pharma- antiemetics [72c]. In one case, severe
covigilance Database 20012004, the use of akathisia developed within 4 hours of a rst
34 Chapter 2 Philip B. Mitchell

dose of mirtazapine and required treatment Trazodone


with intravenous diazepam [73A].
Somnambulism [74A] and severe night- Drugdrug interactions Clarithromycin
mares [75A] have been attributed to Trazodone is predominantly metabolized
mirtazapine. by CYP3A4, which is inhibited by
clarithromycin. In a double-blind crossover
Electrolyte balance Mirtazapine can cause study in healthy volunteers, co-administra-
hyponatremia (SEDA-32, 37) and many tion of clarithromycin increased the AUC
reports of antidepressant-induced hypo- of trazodone, prolonged its half-life,
natremia have been in elderly patients. A increased its Cmax, and reduced its oral
76-year-old man developed delayed onset clearance [78C]. There was a concomitant
of hyponatremia, and developed worsening increase in self- and observer-rated seda-
lethargy and confusion after taking tion and ratings of feeling spacey,
mirtazapine for 2 months [76A]. suggesting that this kinetic effect was clini-
cally signicant.
Skin StevensJohnson syndrome has been
attributed to mirtazapine [77A]. Declaration of potential conicts of interest
Philip Mitchell has received remuneration
A 29-year-old man developed a disseminated
pruritic eruption with conuent red macules for lectures or advisory board membership
and bullous lesions after taking mirtazapine from AstraZeneca, Eli Lilly & Co,
15 mg/day for 3 weeks. The lesions involved Janssen-Cilag, and Lundbeck in the last
1015% of his body and there were severe oral 5 years. He has not been a member of an
and genital erosions. He became generally
unwell and lost 5 kg. The lesions improved after industry advisory board since late 2007
withdrawal of mirtazapine and treatment with and has accepted no remuneration from
topical glucocorticoids for 1 week. industry since early 2009.

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38 Chapter 2 Philip B. Mitchell

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Rif S. El-Mallakh and Yonglin Gao

3 Lithium

The uses of lithium Antipsychotic drugs are more often used


in the treatment of bipolar illness. Lithium
Acute mania In a review of 60 years of data was equivalent to aripiprazole, and both
examining lithium use in bipolar disorder, were superior to placebo, in a 3-week, dou-
Grof and Muller-Oerlinghausen noted that ble-blind, randomized, placebo-controlled
despite being the psychotropic drug with the study of acutely manic patients [5C]. The
best demonstrated efcacy, lithium is also improvement was maintained for an addi-
the most contested [1R]. Many studies con- tional 9 weeks (a total of 12 weeks), with a
tinue to demonstrate its efcacy and superior- 12.7 point drop in Young Mania Rating
ity or equivalence to alternative agents. In a Scale score for lithium and a 14.5 point drop
12-month retrospective clinical audit of two for aripiprazole. The most common adverse
adult psychiatric units in Auckland, New events with aripiprazole were headache,
Zealand, lithium was the drug of choice in nausea, akathisia, sedation, and constipation
33% of acutely manic patients [2C]. and with lithium nausea, headache, consti-
In clinical practice in the treatment of bi- pation, and tremor.
polar disorder, many agents are used. Com- In a 4-week randomized, double-blind
parative or adjunctive efcacy are important study of 50 patients with acute mania, lith-
considerations. In an open 12-week, random- ium and verapamil produced equivalent
ized assignment study valproate was com- signicant improvement in mania versus
pared with lithium in 300 patients with acute baseline [6c].
mania [3C]. Overall the two drugs reduced Combined treatment approaches are
manic symptoms equally well, but valproate becoming the standard of care, but these
was superior to lithium in the number of sub- approaches are only now being examined.
jects who achieved remission (72% versus In a 6-month augmentation study, lithium
66%, dened as a Young Mania Rating Scale alone was equivalent to lithium divalproex
score of less than 12). Both drugs were associ- in the prevention of mood recurrence in rap-
ated with a 44% adverse effect rate. idly cycling patients with type I and II bipolar
Similarly, the authors of a review of affective disorder with co-morbid substance
published randomized comparisons of lith- abuse [7C]. Of 149 patients, most withdrew
ium and carbamazepine concluded that the early (79%: poor adherence 42%, non-
two drugs are equivalent in both acute and response 26%; adverse effects 10%). Of the
prophylactic efcacy [4M]. Carbamazepine 31 who remained in the study 55% relapsed
was associated with fewer withdrawals due into an abnormal mood state.
to adverse effects in acute mania, while with A more novel approach has been exam-
lithium there were fewer discontinuations ined in a 4-week double-blind, randomized,
during maintenance treatment. placebo-controlled study of lithium alone
(n 60) or lithium allopurinol (n 60)
[8C]. Lithium reduced manic symptoms,
Side Effects of Drugs, Annual 33
but the combination was more effective.
J.K. Aronson (Editor)
ISSN: 0378-6080 The improvement in allopurinol-treated
DOI: 10.1016/B978-0-444-53741-6.00003-9 patients correlated positively with a reduc-
# 2011 Elsevier B.V. All rights reserved. tion in plasma uric acid concentrations.
39
40 Chapter 3 Rif S. El-Mallakh and Yonglin Gao

Animal models of mania help explain Table 1 Patients reporting adverse reactions in
the mechanisms of lithium action. Positron cases in which there were signicant between group
emission tomography (PET) was used differences (% of 45 patients in each group) [13C]
to study glucose utilization (using
18
F-uorodeoxyglucose) in the ouabain Adverse reaction Lithium Lamotrigine
animal model of mania [9E]. Motor hyper-
activity induced by intracerebroventricularly Dry mouth 53 20
Thirst 49 7.3
administered ouabain was associated with
Nausea/vomiting 47 24
reduced cerebral glucose utilization. Lithium Upset stomach 43 20
administration normalized glucose uptake. In Tremor 41 9.8
the D-amphetamine model of mania, hyper- Increased urinary 33 2.4
activity is associated with lipid peroxidation frequency
and DNA damage. Treatment with either lith- Dizziness/ 31 7.3
ium or valproate ameliorated both the lipid lightheadedness
peroxidation and DNA damage [10E]. Drowsiness/panic 31 9.8
Increased appetite 29 4.9
Cognitive slowing 27 7.3
Bipolar depression The acute efcacy of Word nding 25 4.9
lithium has been compared with that of other Increased weight 23 4.9
agents in three studies in bipolar depression. Impaired memory 20 0
In a 12-week, open study of 83 depressed Feeling dull 18 2.4
patients with type II illness who were random- Reduced sexual 16 2.4
interest
ized to either venlafaxine (n 43) or lithium
Ringing in ears 12 0
(n 40), improvement in depressive symp-
toms was signicantly greater with
venlafaxine [11C]. The rate of mood switches Unipolar depression In an open ran-
was not different between treatments in either domized study in 46 subjects with unipolar
rapid cycling or non-rapid cycling patients.
depression examined over 3 weeks lithium
Therapy was prematurely discontinued in 26
augmented mirtazapine successfully (n 13),
patients, 11 because of lack of efcacy, 13 but carbamazepine was ineffective when
because of adverse events, two because of added to mirtazapine (n 10) compared with
non-compliance; another seven were lost to
mirtazapine alone (n 23) [14C]. Lithium
follow-up. There was one serious adverse augmentation in treatment-resistant depres-
event, an increase in suicidal ideation, during sion remains among the best studied successful
lithium therapy, judged to be unrelated to the
interventions [15C].
drug. Polydipsia, polyuria, and tremor were
the most common adverse events during
lithium therapy. Prevention of recurrence of affective disor-
In a double-blind, placebo-controlled, der Insight into how best to use lithium to
multicenter trial of type I and II depressed reduce the recurrence of new mood episodes
patients treated with either lithium alone continues to accrue. In long-term prospec-
(plus placebo) or lithium plus lamotrigine, tive study in ve centers, the International
improvement was greater with combination Group for the Study of Lithium-Treated
treatment [12C]. Patients examined the relative stability of
In a randomized, blind-rater 16-week patients with predominantly atypical features
comparison in 90 patients, lithium and (n 100; e.g. mixed states or rapid cycling)
lamotrigine were associated with similar sig- or more typical bipolar features (n 142)
nicant improvements over baseline, but the over a mean of 10 years [16C]. There were
early drop-out rate was high at 42% [13C]. no differences in the overall measures of
Adverse events were more common in those morbidity in the two groups.
taking lithium than in those taking This was not consistent with the results of
lamotrigine (Table 1). another study in which 100 patients were
Lithium Chapter 3 41

studied retrospectively over 3 years of use of apoptotic and up-regulating BCL-2, which
life charting [17C]. Atypical features, such as is protective [24E].
mixed episodes and rapid cycling, were less At the organ level, lithium has been asso-
likely to be associated with remission and ciated with an increase in cortical
more predictive of greater severity of dura- grey matter as examined using structural
tion of episodes. magnetic resonance imaging (MRI) [25R]
In a 2-year randomized double-blind and an increase in N-acetyl-aspartate,
study of the comparative efcacy of a mood a derivative of aspartic acid, which is a
stabilizer alone (lithium or valproate plus marker of neuronal health, measured by
placebo) or a mood stabilizer added to magnetic resonance spectroscopy [26C].
quetiapine in 628 bipolar subjects, combina- These neuroprotective characteristics of
tion treatment resulted in fewer mood epi- lithium may reduce the risk of dementia.
sodes (20%) versus a mood stabilizer alone In an observational cohort study using
(52%), and mania and depression were national medical databases in Denmark,
prevented to an equal degree [18C]. patients who had received a prescription
Serum lithium concentrations may be for lithium at least once (n 16 238) had
related to the polarity of recurrence. In an a higher rate of subsequent dementia than
18-month maintenance trial, relapses or those who had never used lithium (n 1
recurrences of depressive episodes were pre- 487 177) (RR 1.47; 95% CI 1.22,
ceded by serum concentrations above the 1.76), but long-term use of lithium was asso-
mean, both when evaluated individually or ciated with a dramatic reduction in the likeli-
across the entire study population [19C]. hood of eventual dementia [27C]. By
The authors concluded that lower concentra- contrast, the use of anticonvulsants was
tions were adequate for preventing depres- associated with a signicantly increased risk
sion, and that higher concentrations of dementia and the risk increased with
prevented episodes of mania and hypo- long-term use.
mania. However, the data can also be For all these reasons, it is not surprising
interpreted in the opposite mannerthat that lithium has independently been pro-
higher lithium concentrations are required posed in Alzheimer's disease as a potential
to prevent depression. agent for prevention [28R] and treatment
[29R]. The effects of lithium have been stud-
ied for up to 1 year in 22 patients with
Dementia Lithium has neuroprotective Alzheimer's disease, of whom 14 stopped
properties in vivo. In human endothelial cell the study early, in three cases because of
and rat cortical astrocyte cultures, lithium adverse effects [30R]. The Mini-Mental State
0.2 mmol/l increased phosphorylation of Exam (MMSE) score did not change in
GSK-3b (inactivation of GSK-3b) and pro- those who took lithium compared with the
moted secretion of vascular endothelial controls. In a 10-week, randomized, pla-
growth factor (VEGF) [20E]. The effect on cebo-controlled study of lithium in 71 sub-
GSK-3b may be more general, since lithium jects with mild dementia (MMSE 2126; 38
also reduced GSK-3b concentrations in pri- placebo, 33 lithium) there was no change in
mary cultures of rat cortical and hippocam- cognition, mood, GSK-3b activity in lym-
pal cells [21E] and in neural precursor cells phocytes, or phosphorylated tau concentra-
[22E]. This effect on GSK-3b expression tions in the cerebrospinal uid [31C].
and activity is probably related to the obser-
vation that lithium treatment of primary cul- Amyotrophic lateral sclerosis The neuro-
ture cortical cells reduces both tau protein protective effects of lithium suggest that it
concentrations and tau phosphorylation might be useful in other neurodegenera-
(tau is phosphorylated by GSK-3b) [23E]. tive or neurodestructive conditions. Amy-
Similarly, in PC12 cells, lithium 1.2 mmol/l otrophic lateral sclerosis (ALS), a disease
reduced morphine-induced apoptosis by of wasting of the motor neurons of the spinal
down-regulating the BAX, which is pro- cord, is of particular interest. In a mouse Au1
42 Chapter 3 Rif S. El-Mallakh and Yonglin Gao

model of ALS, the combination of lithium symptom complexconduct disorderwho


and valproate was more effective in delaying were followed for an average of 8.4 months,
disease onset and reducing neurological def- 29 had at least a 50% reduction in the Mod-
icits than either lithium or valproate alone ied Overt Aggression Scale score or were
[32E]. rated as much improved or very much
improved on the Clinical Global Impres-
HIV infection Imaging was used in an open sion scale [39C]. Ten took lithium alone
study for 10 weeks in 15 subjects with and 19 took a concomitant atypical antipsy-
human immunodeciency virus (HIV) and chotic drug. Less severely affected children
evidence of cognitive decline; there was no generally did better.
evidence of improvement in either cognition
or mood [33C].
Cardiovascular Lithium generally does not
Multiple sclerosis Lithium was effective in a have signicant cardiac effects. However,
mouse model of experimental autoimmune lithium toxicity has been associated with
encephalomyelitis (a model of multiple scle- transient electrocardiographic changes.
rosis). It reduced neurological symptoms if
administered both before and after induction In a 46-year-old man who had had confusion
of the illness and the animals rapidly and ataxia for 2 days the serum lithium con-
centration was 4.69 mmol/l [40A]. The electro-
relapsed if lithium was withdrawn [34E]. cardiogram was normal but there was ST
segment elevation in the anterior leads and
Cerebral ischemia Lithium was efcacious biphasic T waves. Although these changes
in a rat model of cerebral ischemia; given suggested ischemia, the cardiac enzymes were
normal as was echocardiography. The patient
alone or in combination with prostaglandin was hemodialysed and the electrocardio-
E1 it reduced infarct size and cerebral graphic normalized over several days.
edema [35E]. In a 39-year-old woman with signs of lithium
toxicity, the serum lithium concentration was
Use in children The Collaborative Lithium 2.96 mmol/l and the potassium 2.72 mmol/l
[41A]. Her electrocardiographic showed ST
Trials (CoLT) is a large multicenter study segment depression in leads V2 and V3, wide-
that has been initiated at seven sites to exam- spread T wave inversion, and prolongation of
ine the best practices in using lithium in chil- the P wave (180 msec), QRS complex
dren with mania [36r]. Data are currently (120 msec), QT interval (640 msec), and PR
interval (320 msec). She improved rapidly
being gathered and analysed. and the electrocardiographic with normalized
The rst randomized, double-blind, pla- after hemodialysis reduced her serum lithium
cebo-controlled trial of severe mood concentration to 0.57 mmol/l and normalized
dysregulation (SMD) in youths has been the potassium.
performed. SMD is a proposed disorder that
distinguishes children who have persistent While lithium may have played a role in
severe irritability and hyperarousal and the second case, the signicant hypo-
who do not t the criteria for current disor- kalemia may have been responsible.
ders [37R]. Children aged 717 years were Lithium can also be associated with
assigned to lithium (n 14) or placebo changes in cardiac conduction [42A].
(n 11) after a 2-week single-blind placebo
A 57-year-old woman developed acute mental
run-in phase and were followed for 6 weeks status changes. Her serum lithium concentra-
[38C]. Nearly half (45%) of the children tion was 2.2 mmol/l and the creatinine
improved during the 2-week placebo period 187 mmol/l. She was hypotensive (70/
and were not randomized. Among the 45 mmHg) and bradycardic (37/minute).
An electrocardiogram showed complete atrio-
remaining 25 subjects, lithium was not dif- ventricular block. Her hemodynamic status
ferent from placebo in reducing the patients normalized when she cleared the lithium.
mood or behavior symptoms.
In a retrospective study of the effective- While the AV block in this case may seem
ness of lithium in 60 youths with a similar to have been related to lithium toxicity,
Lithium Chapter 3 43

the presentation was more consistent with a A complicated case of thyroiditis and
rise in the serum lithium concentration due Hashimoto's encephalopathy has been asso-
to reduced renal clearance after the onset ciated with lithium [51A].
of heart block.
A 61-year-old woman with type II bipolar ill-
ness, who was taking levothyroxine for thy-
Nervous system In 16 patients with acute roiditis, developed an encephalopathy within
lithium intoxication treated on a toxicologi- 40 days of starting to take lithium. Her serum
antithyroid antibodies were raised and anti-
cal unit, intensity was mild in 25%, moder- thyroid antibodies were detectable in the cere-
ate in 50%, and severe in 25% [43C]. brospinal uid. She improved with a course of
Over one-third required hemodialysis. methylprednisolone.
Mean length of hospitalization was 16 days,
of which 4.8 were spent in acute care and The authors suggested that lithium-induced
11.2 in recovery. There was long-lasting antibodies can have a shared target in both
ataxia in two subjects. the thyroid and the brain, although how an
Severe lithium toxicity is associated with ion can induce such antibodies is not clear.
seizures. In two cases, seizures were associ- Lithium can affect peripheral nerves, but
ated with high lithium concentrations deleterious consequences are rare.
(4.86 mmol/l in a 25-year-old woman and
2.5 mmol/l in a 48-year-old man) [44A]. A A 73-year-old man taking lithium for bipolar
II disorder (serum concentration 0.8 mmol/l)
third case occurred in a 20-year-old man developed confusion, dysarthria, gait distur-
whose lithium concentration was only bance, muscle stiffness, and twitching [52A].
0.8 mmol/l [45A]. Status epilepticus that A brain CT scan was consistent with vascular
lasted 45 minutes occurred in a middle- encephalopathy. Peripheral electromyography
(EMG) showed many intermittent spontane-
aged woman undergoing electroconvulsive ous motor unit discharges in doublets, triplets,
therapy (ECT) while she had therapeutic and multiplets, consistent with peripheral
serum concentrations of lithium and was nerve hyperexcitability. The EMG normalized
also taking agents that reduce the seizure after withdrawal of lithium.
threshold (clomipramine and quetiapine)
[46A]. It has been previously proposed that Severe lithium toxicity can have perma-
ECT can cause the intracellular concentra- nent or long-lived sequelae. This has been
tion of lithium to rise without a concomi- called the syndrome of irreversible lithium-
tant rise in serum concentration [47H]. effectuated neurotoxicity (SILENT) [53A].
In three cases lithium was associated
A 44-year-old woman continued to have
with nervous system toxicity. dyscoordination 1 year after an overdose of
lithium 6 g (lithium concentration not stated).
A 24-year-old woman who was 24 weeks preg- In another case a maximum lithium concentra-
nant and had pregnancy-related hyponatremia tion 1.9 mmol/l was associated with dysmetria
and mood symptoms was given lithium and and unsteady gait, which persisted for 3 years
developed diabetes insipidus, which rapidly after the episode of toxicity, and 2 years later
corrected her hyponatremia and caused cen- a brain MRI scan showed prominent cerebel-
tral pontine and extrapontine myelinolysis lar atrophy [54A].
[48A].
An 11-year-old boy who had taken lithium for
6 months developed pseudotumor cerebri with Psychological The effect of lithium on cog-
secondary visual eld loss [49A]. nition remains unclear. Most studies have
A 42-year-old woman developed dementia in
the setting of atrophy and multiple diffuse found minimal drug-related cognitive de-
areas of brain calcication when she took lith- cits. When 40 euthymic bipolar I patients
ium for antidepressant drug-associated mania were compared with 40 healthy controls,
[50A]. She became semi-comatose, with dysar- the only neuropsychological abnormalities
thria and right-sided dystonia. Her serum lith-
ium concentration was only 0.57 mmol/l, but were in patients who were taking antipsy-
her neurological signs resolved when lithium chotic drugs; they had reduced semantic u-
was discontinued. ency, verbal learning, recognition memory,
44 Chapter 3 Rif S. El-Mallakh and Yonglin Gao

and planning abilities [55C]. Patients who retrospective study of patients who had
were taking only mood stabilizers (includ- taken lithium for at least 1 year, laboratory
ing lithium, n 14) were not affected. Sim- personnel monitored the frequency of serum
ilarly, in 44 patients with bipolar I disorder, calcium determinations [64C]. Of 100
22 of whom were drug free, all the cogni- patients, 43 had had at least one serum cal-
tive symptoms that were noted (delayed cium concentration measurement. Of these,
verbal recall and perseverations during the ve had raised calcium concentrations.
ve-point test) became insignicant after However, lithium also increases bone
control of residual depressive symptoms density [65C] and reduces the risk of bone
[56C]. Finally, in 33 patients with bipolar fracture [66C] (see Musculoskeletal).
depression taking lithium or valproate, 32 In six cases of lithium-associated hyper-
taking no medication, and 52 controls, parathyroidism, four had parathyroid ade-
those taking the medications had greater nomas [67A, 68A]. The authors suggested
response latency and made more errors in that lithium can help uncover pre-existing
tasks of sustained attention [57C]. parathyroid disease, although there does
In a meta-analysis of 12 studies (539 sub- appear to be an increased incidence of
jects, of whom 276 took lithium for an aver- multiglandular or multiadenomatous dis-
age of 3.9 years), in which patients were ease in patients taking lithium. Surgical
comparable for medication, mood state, treatment is often curative when adenomas
educational level, cognitive abilities, and are discovered. When hypercalcemia per-
medications, lithium was associated with sists, cinacalcet, a calcimimetic can be used
reduced immediate verbal learning, effectively.
reduced verbal memory, and reduced crea-
tivity [58M]. Longer duration of lithium
Diabetes insipidus In a retrospective chart
treatment was associated with reduced psy-
review of 116 subjects taking lithium, in
chomotor performance. Many aspects were
whom 24-hour urine collections had been
unaffected, including delayed verbal mem-
performed, 46 had polyuria; 12 of these were
ory, visual memory, attention, executive
also taking serotonergic antidepressants,
function, and processing speed.
compared with only 10 of the 70 subjects
who did not have polyuria, a signicant
Endocrine Thyroid A woman with thyroid difference (OR 2.86; 95% CI 1.00,
carcinoma who was taking lithium for bipolar 8.21) [69C].
disorder discontinued her thyroid hormone When diabetes insipidus occurs, amiloride
replacement in preparation for radioactive can be an effective treatment. In 87 subjects
iodine (131I) treatment [59A]. Within 3 weeks (45 taking lithium and 42 taking other psy-
she developed severe lithium toxicity, which chotropic drugs) there was impaired urinary
the authors attributed to renal insufciency concentrating ability and reduced urinary
associated with hypothyroidism [60R]. Lith- excretion of aquaporin 2 and cyclic AMP;
ium was not withdrawn in this patient, because 11 were given amiloride 10 mg/day for
of an earlier suggestion that lithium can be 6 weeks in a double-blind, crossover design,
used as an adjunct in 131I treatment [61R]. and when they were then given 40 micro-
In an in vitro study using follicular thyroid grams of desmopressin (dDAVP), amiloride
carcinoma cell lines, lithium 1020 mmol/l was associated with an increase in urinary
induced expression of NR4A1 and FOSB, osmolality and aquaporin 2 excretion [70C].
genes whose underexpression is associated The authors concluded that this effect was
with malignancy [62E]. mediated by increased responsiveness to
the ability of desmopressin to increase
Parathyroid In some individuals lithium translocation of aquaporin 2 to the apical
can increase serum calcium and parathy- membrane in principal cells of the collecting
roid hormone concentrations [63M]. In a duct.
Lithium Chapter 3 45

Hematologic Lithium increases bone mar- associated with an increased risk of psoria-
row neutrophil production, protects bone sis (OR 1.68; 95% CI 1.18, 2.39) [78C].
marrow hemopoietic stem cells after expo-
sure to anticancer drugs or radiation, and
Musculoskeletal Lithium is associated with
increases platelet count [71R]. These effects
increased bone density. In 75 patients with
suggest several potential uses in medicine,
mood disorders taking lithium and 75 with-
such as concomitant use in patients who
out mood disorders and no lithium expo-
have clozapine-induced neutropenia.
sure, mean bone density was an average
A 26-year-old AfricanBrazilian man with of 4.57.5% higher in those taking lithium
paranoid schizophrenia improved with cloza- [66C]. Furthermore, in a 10-year adminis-
pine 400 mg/day, but his absolute neutrophil trative database study in which subjects
count fell to 600  106/l; coadministration of older than 50 years in Manitoba 15 792 sub-
lithium (serum concentration 0.6 mmol/l)
allowed clozapine to be used in a dose of jects with bone fractures were compared
600 mg/day while maintaining an absolute with a matched sample of 47 289 without
neutrophil count of 2.53.0  109/l [72A]. fractures, there was a signicantly reduced
risk of fractures in those taking lithium
(OR 0.63; 95% CI 0.43, 0.93). By con-
Gastrointestinal In the acetic acid-induced
trast, antidepressant drug treatment
colitis rat model for inammatory bowel
increased the risk (OR 1.15; 95% CI
disease, lithium 20 mg/kg given 1 hour
1.07, 1.24; serotonin reuptake inhibitors
before the acetic acid ameliorated the mac-
had the highest risk: OR 1.45; 95%
roscopic and microscopic gut abnormalities,
CI 1.32, 1.59) as did benzodiazepines
including reduced neutrophil inltration,
(OR 1.10; 95% CI 1.04, 1.16).
reduced myeloperoxidase activity, and
reduced lipid peroxidation [73E].
Drug withdrawal Lithium withdrawal can
Urinary tract The association of lithium cause neurological adverse effects. Recur-
with renal dysfunction has again been con- rent night-time headaches are frequently
rmed in a retrospective record review of referred to as alarm clock headaches or
59 out-patients [74C]. There was a positive hypnic headaches, and this has now been
association between duration of lithium reported after lithium withdrawal [79A].
treatment and serum creatinine concentra- A 54-year-old woman with bipolar disorder
tion, but the duration of treatment was also who had taken lithium for 6 years
greater in older patients (14.2 years for (600900 mg/day with serum, concentrations
those over 65 years of age and 6.9 years of 0.81.5 mmol/l) stopped taking lithium
for those under 65 years of age). because of renal dysfunction. About 1 month
after withdrawal she began to have nocturnal
Lithium was associated with an increased headaches about 4 hours after going to sleep.
incidence of kidney microcysts (12 mm They were of mild to moderate intensity,
diameter) in patients taking lithium, in both lasted for 34 hours, and resolved spontane-
the cortex and medulla of the kidneys ously. The headaches persisted for 1 month
and then ended without treatment.
and more prevalent in areas of atrophy or
brosis [75r]. Sudden lithium withdrawal also causes
mood disorders to recur. A retrospective
Skin Lithium is associated with an review of 310 charts yielded 53 cases of
increased risk of psoriasis [76R, 77R]. In a withdrawal [80C]. Recurrence of a mood
10-year database study using the UK-based episode after lithium withdrawal was
General Practice Research Database highest at 86% within 3 months. With-
(GPRD) 36 702 subjects with psoriasis drawal of antipsychotic drugs (64%) and
were compared with an equivalent matched antidepressants (58%) were associated with
group without psoriasis; long-term use of lower rates of recurrence. More than half of
lithium (ve or more prescriptions) was these episodes required hospitalization.
46 Chapter 3 Rif S. El-Mallakh and Yonglin Gao

Teratogenicity In a review of all English lithium concentration had fallen to


language literature published between 0.84 mmol/l. This was followed by continuous
veno-venous hemoltration, which prevented
1969 and 2005, a total of 24 pregnancies in rebound, and the lithium concentration con-
women taking lithium were reported, but tinued to fall over the next 14 hours to
only eight included women who took only 0.3 mmol/l. Some of her neurological symp-
lithium. The most common ndings were toms improved quickly, but her lethargy did
larger infant size, transient lithium toxicity not clear for a further 3 weeks.
with concentrations in the infants higher
In the rst case, a young, otherwise
than in their mothers, and two cases of con-
healthy woman, with normal renal function,
genital heart abnormalities (Ebstein's
conservative treatment was adequate. In
anomaly and patent ductus arteriosus)
the second case, with rapidly rising concen-
[81R]. Similarly, registry data (n 225)
trations hemodialysis produced recovery
had also reported an increased risk of car-
within 4 hours, since lithium had not had
diovascular defects (8%, n 18) among
an opportunity to accumulate in the intra-
the 25 (11%) with any congenital defect,
cellular compartment. The third patient
an increased risk of prematurity (36%),
required aggressive treatment because of
and increased size for gestational age
her age and the slow onset of toxicity, which
(37%). However, prospective studies that
conspired to slow her recovery.
do not pick reporting due to outcome (as
is the case for published reports and regis-
try data) have generally shown no change Drugdrug interactions Angiotensin
in the risk of malformations compared with converting enzyme (ACE) inhibitors ACE
controls (2.7% in lithium-treated mothers, inhibitors can increase lithium concen-
n 377, versus 3.2% in controls). Lithium trations, and in one case this combination
is not benign in pregnancy, but the risk of caused dyspnea and bradycardia [85A]. In
teratogenicity may have been exaggerated. another case the addition of a loop diuretic
and an ACE inhibitor precipitated lithium
Drug overdose Treatment of lithium over- toxicity within 3 days [86A].
dose must be individualized to the clinical
condition. Three case reports have Non-steroidal anti-inammatory drugs
highlighted the number of options that are Non-steroidal anti-inammatory drugs can
available to clinicians. reduce lithium renal clearance and increase
lithium concentrations.
A 47-year-old woman with somnolence and a
serum lithium concentration of 3.5 mmol/l A 76-year-old woman took lithium 1000 mg/
was treated with an infusion of isotonic saline day and several over-the-counter pain medica-
200 ml/hour [82A]. Over the next 25 hours tions [87A]. Diclofenac 75 mg bd was added,
her concentration fell to 0.9 mmol/l and her and after 1 week, she developed a confusional
mental status normalized; intravenous uids state, a raised serum creatinine, and a serum
were withdrawn. After 48 hours her lithium lithium concentration of 2.43 mmol/l. She
concentration had fallen to 0.3 mmol/l. recovered completely 4 days after withdrawal
A 47-year-old woman took an overdose of of lithium and diclofenac and then tolerated
lithium [83A]. Her initial serum lithium con- reintroduction of lithium at a lower dosage
centration was 1.62 mmol/l, but it rose to (400 mg/day).
2.77 mmol/l 8 hours later, despite intravenous
uids, and she was lethargic and nauseated.
She was given sustained low-efciency hemo- Management of adverse drug reactions
dialysis for 8 hours. The lithium concentration
fell quickly and remained at under 1.0 mmol/l Guidelines, 19 in all from seven countries,
for the duration of her course. for treating toxicity have been evaluated
An 80-year-old woman became obtunded using the Appraisal of Guidelines Research
after slowly deteriorating over the previous and Evaluation (AGREE) instrument;
week. Her serum lithium concentration was
3.4 mmol/l and her creatinine was 125 mmol/l there were deciencies in nearly every sin-
[84A]. Because of poor diuresis (10 ml/hour) gle guideline [88M]. Many had missing
she was hemodialysed for 4 hours until her information. For example, none highlighted
Lithium Chapter 3 47

the importance of taking a psychiatric his- while patients with depression had more (an
tory and only one suggested psychiatric average of 4.6) compared with euthymic
evaluation. Only two provided information patients (an average of 3.3).
regarding monitoring during hemodialysis However, measuring lithium concentra-
and only ve provided information about tions can be problematic. In neonates, an
discharge. In more general terms, 60% pro- inadequate sample of blood can lead to a
vided information regarding supportive falsely high lithium concentration [91A].
care, 53% regarding diagnosis, 76% regard- Alternatively, there may simply be labora-
ing appropriate treatment, and 20% regard- tory error [92A], suggesting that the clinical
ing discharge and follow-up. The authors presentation is important.
recommended frequent updating of treat- Lithium concentrations appear to have
ment guidelines to improve their utility. seasonal variation. In a retrospective chart
review of 101 patients, there was 25% vari-
Monitoring therapy One of the predictors of ability in lithium concentrations over the
lithium clearance, and consequently lithium seasons; plasma concentrations (anti-
toxicity, is creatinine clearance [89c], and lith- coagulant not specied) were highest in the
ium concentrations are closely associated summer (about 0.55 mmol/l) and lowest in
with its adverse effects. In a study of 186 the autumn and winter (about 0.42 mmol/l),
patients who were followed between 1973 although doses did not vary [93c].
and 2000 (an average of 5.7 years/patient) in Measuring erythrocyte lithium concen-
which nine specic adverse effects were trations does not appear to offer
recorded monthly in a standardized manner any advantages over serum lithium deter-
(diarrhea, nausea, vomiting, stomach ache, minations in the management of lithium
tiredness, concentration decits, tremor, toxicity [94R].
polyuria, and polydipsia), the frequency of One would expect that brain lithium con-
adverse effects increased as a function of lith- centrations might be related to effects of
ium concentration as did their intensity lithium. When brain lithium concentrations
[90C]. The mean number of adverse effects were measured with 7Li magnetic resonance
increased from 3.3 at a concentration of spectroscopy, in older subjects (>50 years)
0.6 mmol/l to 3.8 in patients with a concentra- brain concentrations correlated with
tion of 1.2 mmol/l. However, there was also a higher somatic symptoms on the Hamilton
relation between mood state and adverse Depression rating scale and frontal lobe dys-
effects. Patients with manic symptoms had function [95C].
fewer adverse effects (an average of 2.0),

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50 Chapter 3 Rif S. El-Mallakh and Yonglin Gao

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Lithium Chapter 3 51

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Jayendra K. Patel, Sarah Langenfeld, and
Eileen Wong

4 Drugs of abuse

Adulteration of street drugs which included a request to report all poten-


with clenbuterol tially exposed cases to regional poison centers.
There were 34 patients from ve centers in
Street drugs are often modied by substitution, USA that met the case denitions or proba-
dilution, contamination, or adulteration [1rc]. ble clenbuterol poisoning over a period of
6 months. Thirteen cases met criteria for con-
Substitution involves complete replacement of rmed exposure. The initial nine cases or the
one drug by another one. index cases were listed with the 21 probable
Dilution involves the addition of pharmacolog-
ically inert or dissimilar compounds to reduce exposures, even though they tested positive
the content of active drug in the product. Typi- for clenbuterol, as the test was done by the
cal diluents used are sugars, starches, talc, and law ofcers. The mean age of the patients was
quinine. 34 years, and 31 were men. The results of a
Contamination involves unintentional inclusion
of a foreign substance, often a by-product of urine drug screen were reported in 27 of the
the process of synthesis. 34 cases, and eight were positive for cocaine.
Adulteration involves the intentional addition All the patients survived and were discharged.
of a pharmacologically active substance in an Clenbuterol is a potent, long-acting b2-
attempt to use less of the intended product with- adrenoceptor agonist with unique b3-
out making the user aware.
adrenoceptor agonist effects. It is often used
These changes may go unnoticed or can on illegally by ranchers to increase the lean mass
occasion cause morbidity and/or mortality. of cattle and by body builders for its anabolic
From 28 January to 2 February 2005, nine effects. The authors suggested that as
cases of atypical reactions to heroin were clenbuterol causes excessive stimulation of b-
reported from a county in New Jersey, USA. adrenoceptors, it can cause hypokalemia and
The patients had nausea, chest pain, palpita- hyperglycemia. As this was often observed in
tion, agitation, anxiety, tachycardia, hypoten- these cases, the authors suggested a possible
sion, hyperglycemia, hypokalemia, and diagnostic value to these observations. Cardiac
metabolic acidosis with increased lactate con- markers were documented in 14 of 34 patients;
centrations. Cyanide poisoning was suspected, six had evidence of myocardial injury, as
but cyanide was not found and specic treat- evidenced by increased troponin concentra-
ment was ineffective. However, clenbuterol tions. Two of these also had metabolites of
was identied as an adulterant in a sample of cocaine in the urine. The authors cited previous
heroin obtained by the police. A public health reports of clenbuterol-associated myocardial
alert was issued using the USA Centers for Dis- infarction. The clinicians used b-adrenoceptor
ease Control and Prevention's EPI-X system antagonists to treat 10 patients before
clenbuterol was identied or suspected in these
cases; no adverse events were reported.
Side Effects of Drugs, Annual 33 Thus, adulteration of heroin by clenbuterol
J.K. Aronson (Editor) was associated with sympathomimetic effects,
ISSN: 0378-6080 metabolic acidosis, and myocardial injury.
DOI: 10.1016/B978-0-444-53741-6.00004-0 However, collaborative efforts among the
# 2011 Elsevier B.V. All rights reserved.

53
54 Chapter 4 Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

poison control centers using the CDC Epi-X A 33-year-old man who both sold and was
system rapidly led to identication of the dis- known to have used the same heroin as patients
2 and 3 above reported palpitation, shaking,
ease outbreak. In another paper, with some and muscle tightness involving the face, neck,
of the same authors involved in the report and shoulders within minutes of insufating
mentioned above, a small epidemic of an heroin. He had mild resting tremor in the arms
atypical neuromuscular syndrome in ve and hyper-reexia without clonus. He refused
individuals who had used clenbuterol-tainted serum laboratory studies but agreed to a urine
drug test. He was given lorazepam and left.
heroin has been described [2cr]. His urine was negative for strychnine but posi-
tive for morphine, 6-MAM, and clenbuterol.
A 47-year-old man injected heroin and devel- A 45-year-old man developed nausea,
oped diffuse muscle cramping that progressed vomiting, and leg shaking within 5 minutes of
over 16 hours. He had severe pain, agitation, insufating heroin. He had mild distress, anxi-
sweating, and opisthotonos. His mental status ety, hyper-reexia, and ankle clonus. His potas-
was clear with no focal motor decits. Limited sium was 5.8 mmol/l and creatine kinase
physical examination was unremarkable. His activity 296 U/ml. Urine testing was negative
potassium was 3.3 mmol/l, glucose 7.2 mmol/l, for strychnine but positive for clenbuterol, mor-
creatine kinase 5539 U/l; troponin concentra- phine, 6-MAM, and codeine.
tions and the cerebrospinal uid were normal.
To achieve adequate sedation, he required The authors reported that these patients
endotracheal intubation, and after sedation
had intermittent spasms of his legs, hyper- had an unusual neuromuscular syndrome
reexia, and clonus. Strychnine poisoning and (which has not previously been described),
tetanus were suspected. He was intubated for characterized by muscle spasms and hyper-
8 days and recovered completely. However, reexia that lasted between 2 and 8 days.
his urine and blood were negative
for strychnine. Subsequent testing revealed
They reported that though clenbuterol toxicity
clenbuterol in urine, blood, and CSF. has been reported to cause muscle tremors
A 40-year-old opioid-dependent man currently and myalgia, previous patients did not have
taking methadone maintenance treatment tetany, muscle spasms, or hyper-reexia.
developed nausea, vomiting, and bilateral spas- None of the drug screens detected strychnine,
modic leg pain. He had insufated heroin
3 days before admission and reported symptoms which is a common contaminant of heroin.
within 2 hours of drug use followed by diffuse They concluded that this novel neuromuscu-
crampy muscle aches and right ank pain. He lar syndrome was probably due to
reported that friends who had used the same her- clenbuterol-adulterated heroin, but acknowl-
oin had had similar symptoms. He was in mod-
edged that there could be other possible expla-
erate distress, with akathisia, muscular spasm
of both hamstrings, hyper-reexia throughout, nations/contaminations that were not
and clonus in the knees and ankles. The creatine detected.
kinase activity was 9734 U/l. He was treated with
midazolam, ketorolac, lorazepam, and
ondansetron and subsequently admitted to
intensive care. His condition improved 24 hours
later and the creatine kinase fell to 2398 U/l. He
was discharged 36 hours after admission and
Benzylpiperazine and related
later his urine was found to be negative for compounds [SEDA-32, 55]
strychnine but positive for clenbuterol. Heroin
metabolites were absent. Placebo-controlled studies In a random-
A 35-year-old woman with a history of mild
asthma and substance abuse insufated heroin
ized, double-blind, placebo-controlled
and rapidly developed diffuse muscular pain study in 27 healthy, right-handed, non-
and spasms involving the face, neck, arms, and smoking women, mean age 22 years,
chest. She reported that other friends had had benzylpiperazine increased blood pressure
similar experiences. She had mild physical dis- and heart rate, euphoria, and dysphoria,
tress, was anxious, and had hyper-reexia with-
out clonus. Her creatine kinase activity was and sociability and drug liking [3c].
395 U/l. She received 1 liter of isotonic saline
and intravenous lorazepam and improved
symptomatically. She was discharged. Her urine
was negative for strychnine but positive for Nervous system In 178 individuals who
clenbuterol, morphine, 6-MAM, and codeine. were reviewed in hospital after having
Drugs of abuse Chapter 4 55

taken benzylpiperazine, 69% had also taken 164 serious events, 21 (13%) were relapses
other substances, most commonly ethanol of multiple sclerosis, 16 (9.8%) were
[4c]. In those who took benzylpiperazine vomiting, and 15 (9.1%) were urinary tract
alone, increased plasma benzylpiperazine infections. The rate of non-serious adverse
concentrations were associated with events was higher among those randomized
increased seizure frequency. Ethanol co- to cannabinoids versus controls (RR 1.86;
ingestion reduced the incidence of seizures, 95% CI 1.57, 2.21); there was no differ-
but signicantly increased the likelihood of ence in serious adverse events between the
confusion and agitation. two groups. The most common non-serious
adverse event (714 events, 15.5%) was dizzi-
Drugdrug interactions Benzylpiperazine ness. The median exposure time was 2 weeks
and its analogue 3-triuoromethylphenyl- (range 8 hours to 12 months). The authors
piperazine are often used in combination concluded that while the short-term use of
[5c], mimicking the effects of ecstasy. The medical cannabinoids increases the risk of
combination can cause dissociative-type non-serious adverse events, it does not seem
symptoms, nausea, and signs consistent with to increase the risk of serious events. They
sympathomimetic toxicity [6A]. Both com- found little information about long-term
pounds inhibit CYP2D6, CYP1A2, and risks of exposure. Others have commented
CYP3A4 [7E, 8E], and mutual inhibition of that these ndings support the use of canna-
metabolism occurred when the two com- binoids to treat acute medical conditions
pounds were co-administered in seven such as pain, but for longer term use more
healthy volunteers, with reduced production data is needed [11r]. They also noted that
of their metabolites, 3-hydroxybenzylpiper- none of the trials involved smoked cannabis,
azine and hydroxytriuoromethylphenyl- which may have its own set of adverse
piperazine [9c]. effects. They also drew attention to the need
to examine the risks as they apply to older
adults, for example, risks of cardiovascular
disease, cancer, and any differences in the
risk of dependence.
In another systematic review of the evi-
CANNABINOIDS [SED-15, 614; dence for using cannabinoids in the manage-
SEDA-30, 31; SEDA-31, 33; ment of chemotherapy-induced nausea and
SEDA-32, 55] vomiting in patients with cancer, nabilone,
dronabinol, and levonantradol was superior
to placebo and neuroleptic drugs [12M].
Systematic reviews Serious and non-seri- However, the cannabinoids caused adverse
ous adverse events associated with medical effects in some patients, even when they
cannabinoids in 321 reports, as reported were given orally and their use was limited
during the last 40 years, have been system- to 24 hours. Some untoward reactions
atically reviewed [10M]. Those that focused occurred almost exclusively in patients who
on recreational cannabis were excluded, and were exposed to them: paranoid delusions
23 randomized controlled studies and eight (5%), hallucinations (6%), and dysphoria
observational studies, describing 4779 and/or depression (13%). Although the
adverse events, were included. Serious patients had more adverse effects and
events were dened as those that were life- greater intensity of symptoms during treat-
threatening or resulted in death, or required ment with cannabinoids, most of the drop-
admission to a hospital or prolonged a cur- outs, which were responsible for almost
rent admission, or resulted in persistent or 30% of the nearly 400 dropouts in all the
signicant disability or incapacity, or were studies included in the systematic review,
congenital malformations. Of the adverse were probably not due to cannabinoid
events, 4615 (96%) were not serious. Of the toxicity.
56 Chapter 4 Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

Cardiovascular Preliminary results from a screens throughout the study. The Positive
cohort study in adults recruited after hospi- and Negative Symptom Scale (PANSS)
talization for myocardial infarction have was used to assess symptoms. The canna-
suggested that cannabis use may increase bis-using patients had a larger gray matter
the risk of death among people with coro- volume loss than the healthy controls and
nary heart disease [13R]. Of 1913 patients, non-cannabis-using patients. Non-canna-
52 reported cannabis use during the previ- bis-using patients also experienced some,
ous year. During the mean follow-up time but less, volume loss than the healthy con-
of 3.8 years, 317 died. Compared with those trols. The cannabis-using patients also had
who did not report cannabis use, those who more marked enlargement of both the third
had used it at least weekly had a hazard ventricle and the lateral ventricles than the
ratio of 4.2 (95% CI 1.2, 14). The age- controls and the non-cannabis-using
and sex-adjusted risk for any use was patients. There was no difference in overall
greater for both cardiovascular mortality positive and negative symptoms between
(HR 1.9; 95% CI 0.6, 6.3) and mortal- those who did or did not use cannabis, nor
ity from non-cardiovascular causes (HR any difference in the overall cumulative
4.9; 95% CI 1.6, 15). The authors length of hospitalization, but those who
suggested that the effects of cannabis that did not use cannabis had a slightly greater
may affect the cardiovascular risk include: improvement in their positive and negative
increased heart rate and blood pressure, symptoms. Increased ventricular size corre-
reduced oxygen uptake (due to carbon lated with a greater need for help with daily
monoxide exposure) at a time when functioning and with a lower GAF score;
increased heart rate increases oxygen however, there was no apparent direct cor-
demand. However, they also noted relation with cannabis use. The authors
the increased risk of mortality from non- provided several potential explanatory
cardiac causes. They cautioned that these mechanisms, not directly demonstrated in
results should be viewed as preliminary, this study: cannabis might augment vulner-
given, for example, the small proportion ability to the gray matter changes that are
of cannabis users in the study and the wide associated with schizophrenia by direct
condence intervals; additionally, although effects, by heightening psychotic symptoms
they controlled for important clinical char- (which in turn might facilitate loss of gray
acteristics, such as alcohol and nicotine matter volume), or by reducing adherence
use, there may have been more complex to medications that would otherwise atten-
confounders from lifestyle or other factors. uate the brain changes. Limitations of this
study included the relatively small number
Nervous system Both cannabis use and of patients, the lack of a cannabis-using
schizophrenia have been linked to progres- otherwise healthy control group, and dif-
sive loss of gray matter and cannabis use culty in quantifying the amount of cannabis
has also been associated with poorer clini- exposure (since amounts were based on
cal outcomes in people with schizophrenia. patient and family recall and since there
From the results of a longitudinal MRI are differences in the amount of tetra-
study in 51 patients with recent-onset hydrocannabinol in cannabis preparations).
schizophrenia and 31 sex- and age-matched
healthy subjects, the authors hypothesized Psychological The cerebellum contains
that loss of gray matter volume in people the highest density of cannabinoid recep-
with schizophrenia who use cannabis may tors in the brain, but little is known about
be greater than in non-users [14Cr]. Of the the effects of cannabis on cerebellar-depen-
51 subjects with schizophrenia, 19 used can- dent learning. The long-term effects of can-
nabis over the 5-year study period and 32 nabinoids on the cerebellum have been
did not. Cannabis use was assessed using assessed based on Eyeblink conditioning,
the Composite Diagnostic Interview an associated motor learning task that
(CIDI) and random urine toxicology pairs a conditioned stimulus (tone) to an
Drugs of abuse Chapter 4 57

unconditioned stimulus (a puff of air), lead- supplemented with a computerized version


ing to a conditioned eye blink; the cerebel- of the Symbol Digit Modalities Test, which
lum is critically involved in this process. tests processing speed and working mem-
Current cannabis users (n 14) and ory. Among cognitive variables, the canna-
healthy drug-naive controls (n 10) were bis users performed less well in the
evaluated [15C]. The cannabis users had measure of performance time for visual
used cannabis at least once a week in the working memory. The authors noted that
past month, had a positive urine toxicology direction of causality could not be deter-
screen, and had used no other illicit drugs mined and pointed out that differences
in the past 6 months. The cannabis users may not be direct differences due to canna-
had fewer conditioned responses and their bis use, if, for example, cannabis use is a
conditioned responses were poorly timed; marker for some other risk factor. The lim-
however, they had normal unconditioned itations of the study included the small sam-
responses, and the problem seems specic ple size, self-reporting of cannabis use, and
to acquisition of the conditioned response. lack of urine toxicology conrmations, but
Limitations of this study included the small it has provided information about an area
sample size and the lack of information not previously examined.
about whether or not a period of absti-
nence could improve these effects. Teeth An association between cannabis use
Cannabis use may worsen cognitive func- and periodontal disease has been reported
tion among patients with multiple sclerosis from a prospective cohort study of 903 indi-
and may affect emotional functioning. viduals born in Dunedin, New Zealand,
Cognitive impairment, most commonly between 1972 and 1973 [17c]. Cannabis use
impaired attention and slower processing, data were collected at ages 18, 21, 26, and
is an important predictor of quality of life 32 and dental examinations were done at
for both patients and families. Of 140 con- ages 26 and 32. After controlling for tobacco
secutive community patients with multiple smoking, sex, irregular use of dental ser-
sclerosis, 10 (7.7%) were current cannabis vices, and dental plaque, the cannabis users
users (using at least once a month) and had a higher relative risk of periodontal
had a slower mean processing time [16c]. combined attachment loss: 1.6 (95% CI
While the cannabis users were younger, 1.2, 2.2) for having one site or more with
there were no signicant differences 4 mm or greater combined attachment loss;
between the users and non-users in sex, 3.1 (95% CI 1.5, 6.4) for having one site
education, disease course or duration, or or more with 5 mm or greater combined
physical disability (as measured by the attachment loss; and 2.2 (95% CI 1.2,
Expanded Disability Status Scale). Because 3.9) for having incident attachment loss
age could affect cognitive status indepen- (compared with those who had never smoked
dent of cannabis use, the 10 cannabis users cannabis). There was a doseresponse
were each age-matched to four subjects relation.
who did not use cannabis. Using the Struc-
tured Clinical Interview IV, there were no Liver Daily cannabis use may be a suscep-
differences in the percentages of patients tibility factor for steatosis in chronic hepat-
who met current criteria for any diagnosis, itis C, an important consideration, since
although the cannabis users had a higher steatosis has been reported to increase
rate of lifetime psychiatric diagnoses. The brosis and reduce the rate of viral eradica-
subjects were assessed using the Neuropsy- tion. In 315 consecutive patients with
chological Battery for multiple sclerosis chronic hepatitis C undergoing liver biopsy
(NPBMS), which includes the Selective collected, the patients were categorized as
Reminding Test, the 7/24 Spatial Learning non-users (64%), occasional users (12%),
Test, the Paced Auditory Serial Addition and daily users (24%) [18c]. After alcohol
Task, and the Controlled Oral Word intake and viral genotype were controlled
Association Test. The NPBMS was for, marked steatosis (at least 30% of
58 Chapter 4 Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

hepatocytes with cytoplasmic fat vacuoles) literature on cocaine-associated chest pain


was more frequent in daily cannabis users and myocardial infarction and has provided
than in non-users (OR 2.1; 95% CI guidance on diagnosis and clinical manage-
1.01, 4.50). ment [20R].
Cardiovascular toxicity due to cocaine
Infection risk A 56-year-old woman with abuse forms a spectrum of adverse medical
underlying COPD, a past cigarette smoker conditions. The pathophysiology of cardio-
and current cannabis smoker, had multiple vascular events has been reviewed [21R].
pulmonary nodules seen in a routine chest Ischemia and vasospasm are adrenergically
X-ray [19A]. Biopsy of the nodules showed mediated and there is a prothrombotic effect
cavitary lesions and invasive pulmonary due to increased platelet aggregability. In
aspergillosis. Aspergillus can be found in sam- the setting of hypoxia, intracoronary throm-
ples of marijuana and chronic cannabis use bosis can occur.
probably predisposed her, perhaps owing to In the acute setting of cocaine-induced
impairment in mucociliary activity and alveo- chest pain, assessment includes the possible
lar macrophages function. While prior reports diagnosis of acute myocardial infarction.
of invasive pulmonary aspergillosis have been However, cocaine may independently affect
documented in immunocompromised indi- cardiac biomarkers [22r]. Recent cocaine use
viduals who use cannabis, she was not may alter the specicity of measurement of
immunocompromised. serum creatine kinase and its MB fraction.
Among cocaine users, increased serum crea-
tine kinase activities and increased mean
myoglobin concentrations are common.
Increased skeletal muscle activity and rhab-
domyolysis are often present, possibly
COCAINE [SED-15, 848; SEDA-30, because of cocaine-induced hyperthermia.
31; SEDA-31, 37; SEDA-32, 58] Troponin I concentrations are more reliable
cardiac biomarkers for detecting cocaine-
induced myocardial infarction and are asso-
Cardiovascular ciated with a poor prognosis.
Ischemic cardiac events due to cocaine Aortic dissection is an uncommon cardio-
vascular complication of cocaine use. In a
retrospective chart review of 164 patients
EIDOS classication:
with acute aortic dissection [23c] 16 (9.8%)
Extrinsic moiety: Cocaine
had used cocaine or crack cocaine within
Intrinsic moiety: Alpha-adrenoceptors
24 hours before the onset of symptoms and
Distribution: Myocardium and platelets
148 (90%) had no history of cocaine use. In
Outcome: Vasospasm and increased
the cocaine group, 11 had inhaled intrana-
platelet aggregability
sally and ve had smoked crack cocaine.
Sequela: Ischemic cardiac events due to
The length of time between cocaine use
cocaine
and the onset of aortic dissection was 424
DoTS classication: (mean 13) hours. The cocaine users were
Dose-relation: Toxic younger, were more often men, and had
Time-course: Time independent more co-morbid polysubstance abuse. In
Susceptibility factors: Not known those who had surgery there was a higher
rate of pulmonary complications in the
cocaine users. The authors suggested that
In the USA, cocaine is the illicit recrea- this may have been due to lung impairment
tional drug that leads to the most emer- caused by smoking cocaine; many cocaine
gency room visits and chest pain is the users were also cigarette smokers.
most common complaint. The American Painless aortic dissection has been attrib-
Heart Association has reviewed the current uted to cocaine use [24A].
Drugs of abuse Chapter 4 59

A 48-year-old man had sudden paralysis of his left-sided chest pain. The white blood cell
legs with loss of bowel control. His medical his- count was 14.7 109/l, a chest X-ray showed
tory included hypertension, post-traumatic a left-sided pneumothorax, and a CT scan
stress disorder, depression, and cigarette showed ve cavities in the right lower lung
smoking. His blood pressure was 60/40 mmHg lobe, the largest being 5 cm in diameter. Gram
and his pulse 56/minute. His muscle strength stain of the sputum showed Staphylococcus
was 0/5, and there was areexia in the legs. aureus. The diseased lobe was excised and his-
From the umbilicus down there was loss of sen- tology showed diffuse alveolar damage, pneu-
sation to touch. Rectal tone was absent. The monic inltration, thrombosis in subsegmental
serum creatinine was 186 mmol/l, lactic acid arteries, areas of pulmonary infarction, and
9.5 mmol/l, and serum alcohol 78 mmol/l, and brinopurulent material in the pleura.
a urine screen was positive for cocaine. The
electrocardiogram showed sinus bradycardia Cocaine powder has a direct effect on the
at 60/minute. A chest X-ray showed a widened lungs and there is an indirect effect via
mediastinum. There was a moderate pericardial
effusion with right ventricular collapse, severe vasoconstriction. Barotrauma was the most
aortic regurgitation, and extensive aortic dissec- likely cause for the pneumothorax and
tion starting from the aortic valve. After cardiac pneumomediastinum in this case.
surgery he developed spinal cord damage. An uncommon pulmonary inltrate called
exogenous lipoid pneumonia occurs second-
Severe gangrene of all four limbs due to
ary to aspiration or inhalation of fat-like sub-
cocaine-associated peripheral vasospasm
stances, such as oil-based laxatives.
has been reported [25A].
Exogenous lipoid pneumonia has been
A 43-year-old woman developed reduced attributed to inhalation of crack cocaine
mental responsiveness after using crack mixed with petroleum jelly [28A].
cocaine the previous night and repeatedly in
previous weeks. Her hands and legs were cya- A 42-year-old AfricanAmerican man with
notic. She developed bilateral hand compart- paranoid schizophrenia who smoked crack
ment syndrome and required emergency cocaine mixed with petroleum jelly and ciga-
fasciotomy and carpal tunnel release. Despite rettes developed progressive shortness of
anticoagulant and antithrombotic therapy her breath. His medications included uticasone,
condition deteriorated and she developed dry ipratropium, and salbutamol inhalers, haloperi-
gangrene of eight digits and the legs below dol, quetiapine, trihexyphenidyl, and celecoxib.
the knees, requiring digital and above-knee His oxygen saturation fell from 93% on room
amputations. There was no evidence of auto- air to 88% after 1 minute of walking. There were
immune disorders or vasculitis. ne inspiratory crackles in both lung bases. A
chest X-ray showed diffuse reticular inltrates.
The authors suggested that cocaine-induced Pulmonary function tests showed a combined
peripheral vasospasm with associated restrictive and obstructive ventilatory defect
with a reduced diffusion capacity. A course of
delayed and persistent vasospasm was a high-dose glucocorticoids was ineffective. A
probable mechanism for this outcome. The wedge biopsy showed exogenous lipoid pneu-
vasospastic action of cocaine peaks at 1 hour monia, with lipid vacuoles surrounded by inam-
after use and correlates with an increased matory inltrates.
serum concentration of cocaine
The prevalence of self-reported illicit use
(benzoylmethylecgonine). Delayed and per-
of cocaine and/or metamfetamine in
sistent vasospasm can occur, as the major
patients with acute decompensated heart
metabolites of cocaine, benzyolecgonine
failure has been studied, using a multi-
and ecgonine methyl ester, can also report-
center observational registry, in 11 258
edly cause vasospasm [26r].
patients, of whom 594 (5%) had previously
Respiratory Cocaine use is associated with used cocaine (96%) and/or metamfetamine
various pulmonary complications. Pneumo- (5%) [29C]. Users had a median age of
thorax, lung cavitation, and pleural empy- 50 years compared with 76 years in non-
ema have been reported [27A]. users. As there were disproportionately
more young AfricanAmerican men with
A 32-year-old chronic cocaine user developed hypertension, left ventricular systolic dys-
a cough, shortness of breath, fever, and function, and markedly raised B-type
60 Chapter 4 Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

natriuretic peptide concentrations, the A transnasal biopsy showed a non-specic,


authors speculated that the severity of car- non-granulomatous inammation and coloniza-
tion with Staphylococcus aureus. There was a
diac dysfunction in these young patients strongly positive C-ANCA titer (320 U/l) with
would probably result in higher morbidity, specicity for human neutrophil elastase-specic
mortality, and health costs. Although these anti-neutrophil cytoplasmic antibodies (HNE-
patients had a greater degree of left ventric- ANCA); PR3-ANCA was negative. These
ular dysfunction (ejection fraction < 40%), results ruled out Wegener's granulomatosis
and a diagnosis of cocaine-induced HNE-
they did not have a greater risk-adjusted ANCA associated panhypopituitarism was
mortality. made. He stopped using cocaine and 2 years
later the ANCA titers were repeatedly negative.
Musculoskeletal Osteonecrosis of the calca-
neus following cocaine injection in the foot Skin The adverse effects of cocaine on the
has been reported [30A]. skin include vasculitides, purpura, urticar-
ial, and non-specic eruptions. The delu-
A 49-year-old man developed pain, redness, sion of parasitosis or formication, the false
and swelling in his left foot 3 days after having belief that insects are crawling underneath
injected cocaine into veins on the top of his
left foot. He had a fever of 39.4 C, edema, the skin, has also been described. Two
and erythema of the lower third of the left other reactions have been described in a
leg, with supercial blisters and skin excoria- review [32Ar].
tion. The white blood cell count was
24  109/l and an X-ray and MRI scan showed A 37-year-old woman developed numerous
sclerosis of the navicular bone, suggestive of discrete papular erythematous excoriations
osteonecrosis, soft tissue swelling around the with overlying crusts on the lower legs, thighs,
ankle, consistent with cellulitis, and osteo- and forearms. She also had worsened
arthritis of the talonavicular joint, with a dental caries and unexplained weight loss of
subchondral cyst at the head of the talus. 18 kg. A urine test was positive for
The fever and ankle swelling persisted despite benzoylecgonine.
intravenous antibiotics, and aspiration of A 39-year-old man had itchy skin and weight
the ankle joint yielded a purulent uid. As loss of 1418 kg over 3 months and described
blood cultures were positive for meticillin a whitish, hairy substance that protruded from
resistant Staphylococcus aureus (MRSA), he burning skin lesions. He had erythematous,
was given intravenous vancomycin. The excoriated papules on the arms, legs, the front
wound and ankle joint were debrided and irri- of the trunk, and buttocks. A urine test was
gated several times. Bone histology showed positive for cocaine.
focal areas of necrotic bone with calcication
surrounded by vascularized brous tissue in
the bone marrow, consistent with healing of
The authors recommended that when a
infarcted bone. patient presents with chronic skin lesions,
a vague medical history, negative ndings
The calcaneus has a rich vascular supply during previous examinations, labile affect,
and is an uncommon site of infarction. and delusional behavior, a drug screen
should be obtained to check for cocaine use.
Endocrine Panhypopituitarism with posi-
tive autoimmune serology secondary to Fetotoxicity Cocaine exposure in utero may
cocaine use has been reported [31A]. have a direct effect on autonomic nervous
system regulation, cardiac control mecha-
A 41-year-old man who habitually inhaled nisms, and cardiovascular functioning in
cocaine developed severe fatigue, cold intoler- neonates [33C]. In 21 prenatally cocaine-
ance, anorexia, and weight loss of 20 kg over
6 months. He had low serum concentrations exposed infants and 23 non-exposed con-
of TSH, free thyroxine, and free triiodothyro- trols, studied within 120 hours of birth, there
nine, FSH, LH, ACTH, cortisol, prolactin, and was a positive interaction between prenatal
testosterone. MRI and CT scans showed a cocaine exposure and orthostatic stress.
normal sized pituitary gland within a dense,
edematous, contrast-enhancing mass. The Whereas both exposed and non-exposed
nasal septum was destroyed, and there were infants had increased heart rates and heart
no conchae and severely eroded sinus walls. rate variability, the responses of the exposed
Drugs of abuse Chapter 4 61

infants to orthostatic stress were both were mainly in the posterior and inferior
delayed and prolonged. The responses of brain regions, including the occipital cortex
the non-exposed infants were immediate and thalamus. In addition, the cocaine-
but transient. The authors suggested that exposed group had increased relative cere-
cocaine exposure in utero may alter develop- bral blood ow in the anterior and superior
ment of the sympathetic and parasympa- brain regions, such as the prefrontal, cingu-
thetic systems and thus lead to altered late, insular, amygdala, and superior parie-
neonatal cardiovascular function. tal cortex. These ndings suggest that
Cocaine exposure in utero and its possi- there may be compensatory mechanisms
ble effect on language development has for reduced global cerebral blood ow due
been studied in a prospective, longitudinal to a prenatal cocaine effect during neural
study in 398 children (209 cocaine-exposed ontogeny.
and 189 non-exposed), who were evaluated In the second study volumetric MRI data
at birth, 1, 2, 4, and 6 years of age [34C]. of brains were collected in 35 children,
Cocaine exposure had a negative effect on mean age 12 years, with intrauterine expo-
all language domains during the rst 6 years sure to cocaine, alcohol, tobacco, and mari-
of life. Over time, the cocaine-exposed juana (14 cocaine-exposed and 21 non-
group showed stable language growth but cocaine-exposed) [37c]. The children with
did not catch up in the areas of linguistic cocaine exposure had lower mean cortical
decits. The authors also mentioned that gray matter, total parenchymal volumes,
the cumulative risk of language decits is and smaller mean head circumference. As
also based on other variables, such as other the number of exposures to prenatal sub-
toxic exposures and environmental, genetic, stances grew, these specic measured areas
and social factors. showed further reductions in size. Even
The effect of cocaine exposure in utero though the sample size was small, this study
on subsequent growth has been studied by has provided relevant information on the
enrolling mothers from a prenatal clinic adverse effect of prenatal drug exposure
and interviewing them at the end of each among older children.
trimester about their use of cocaine and Fibromuscular dysplasia has been reported
other substances; follow-up assessments of in a child with in utero cocaine exposure
the offspring were done at 1, 3, 7, and [38A].
10 years [35C]. This study was the rst to
conduct longitudinal growth-curve analysis A 21-month-old boy began vomiting daily. He
using four time-points and to extend into had been exposed to cocaine in utero. His
childhood. The offspring who were exposed symptoms improved initially and then deterio-
to cocaine during the rst trimester rated, with loss of consciousness. He devel-
oped pneumonia, a dilated cardiomyopathy,
grew at a slower rate than non-exposed and presumptive myocarditis, had a respira-
controls. At 7 and 10 years, but not at 1 tory arrest and renal failure and died. Post-
or 3 years, children with prenatal cocaine mortem ndings were consistent with dilated
exposure were smaller on all growth cardiomyopathy and the major coronary arter-
ies had moderate luminal narrowing by inti-
parameters than the children who had not mal broplasia. Histology showed changes of
been exposed. intimal broplasia diffusely present in the
There have been two radiological studies intramyocardial coronary artery branches,
of the effect of in utero cocaine exposure consistent with intimal broplasia, a rare vari-
on neurocognitive development in older ant of bromuscular dysplasia. There was no
evidence of myocarditis.
offspring. In the rst study, 24 cocaine-
exposed adolescents and 25 matched non- Fibromuscular dysplasia is an idiopathic
cocaine-exposed controls underwent struc- disease of small and medium sized arteries.
tural and perfusion functional MRI during The authors postulated that cocaine had
resting states [36C]. The cocaine-exposed altered transforming growth factor beta,
adolescents had signicantly reduced global which had caused intimal broplasia.
cerebral blood ow. The affected areas
62 Chapter 4 Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

Ecstasy (3,4-methylene- Sensory systems Vision Acute bilateral


dioxymetamfetamine, MDMA) angle closure and transient myopia has
[SED-15, 180; SEDA-30, 37; SEDA-31, 41; been attributed to MDMA [40A].
SEDA-32, 61; for other amphetamines see A previously emmetropic 39-year-old healthy
Chapter 1] man developed bilateral angle closure and
transient myopia after using MDMA for
2 weeks. He had painless progressive reduc-
Cardiovascular Based on reports that tion in vision in both eyes over 2 days, bilat-
eral myopic refraction, and an intraocular
in vitro MDMA can cause proliferation of pressure of 4041 mmHg in both eyes, with
cardiac valvular interstitial cells, the authors bilateral ciliochoroidal effusions. Bilateral
of a study recruited 29 subjects who were neodymium-doped yttrium aluminium garnet
using or had used MDMA, mean age 24 years, peripheral iridotomy was performed, but the
and 29 sex- and age-matched controls to intraocular pressures remained high. His
vision improved following treatment with
evaluate the occurrence of cardiac valvular brimonidine 0.2% and timolol maleate 0.5%
disease in Belgium from December 2004 to topically and then oral acetazolamide for
February 2006 [39c]. Subjects who had used 4 days.
drugs that could cause valvulopathy and sub-
jects with any current or past cardiac disease The authors suggested that uid movement in
were excluded. Eight users had abnormal choroidal effusion could have been related to
echocardiograms using the US FDA criteria drug-induced membrane potential changes or
for appetite suppressant-induced valvular a possible idiosyncratic reaction. The acute
heart disease, compared with none in the con- myopia was probably due to forward displace-
trol group. Users with valvular regurgitation ment of the lens caused by superciliary effu-
of  2/4 for mitral and tricuspid valves or any sion, although ciliary body swelling and lens
aortic regurgitation had used on average thickening could also have played a role. They
higher cumulative doses of MDMA than also postulated that the ciliary effusion in this
those with lower grades of regurgitation. Six case could have been due to the serotonergic
had mitral regurgitation of 1/4 and four of effects of MDMA.
2/4, compared with none in the control
group. Tricuspid regurgitation of  2/4 was
present in 13 MDMA users and absent in Psychological The effects of four different
the controls. Four MDMA users had mild single intranasal doses of metamfetamine (0,
aortic regurgitation. There were valvular 12, 25, and 50 mg/70 kg) on a broad range of
strands, dened as thin, mobile, lamentous behavioral and physiological measures have
projections attached to the valvular leaets, been studied in 11 non-treatment seeking
in six MDMA users and none in the controls. metamfetamine abusers in a double-blind
The authors described these strands as wit- study [41c]. Metamfetamine concentrations
nesses of an abnormal underlying valvular rose progressively for 4 hours after adminis-
structure. They observed that this was the rst tration. The cardiovascular and subjective
time valvulopathy in young adults using effects increased and peaked about
MDMA has been reported. They speculated 515 minutes after administration. Cognitive
that the possible mechanism may be activa- performance and less complicated tasks
tion of serotonin 5HT2B receptors and improved on all active doses, whereas perfor-
induction of mitogenic responses in human mance in more complicated tasks was
valvular interstitial cells. They proposed that improved only by the intermediate doses.
this might explain the fact that intermittent The authors proposed that the rapid action
use in these young patients could give rise on subjective well-being probably contributes
to cardiac valvulopathy. They were also to increased abuse liability, as may the perfor-
concerned that valvular strands are associated mance enhancing effect. However, they were
with ischemic stroke in young individuals. puzzled by the rapidity of the subjective
Drugs of abuse Chapter 4 63

effects and the effects on performance, which did not vary as a function of specic pro-
occurred before the plasma concentrations spective memory task demands. The
had peaked. They quoted previous data that authors suggested that these decits were
suggest that metamfetamine is commonly not secondary to the effects of other illicit
abused in multiple dose cycles, with an inter- drug use. They found prospective memory
dose interval of 0.53 hours and may continue impairment in those who had used
for several days, suggesting that binging may metamfetamine but had been abstinent on
result in for very high, potentially toxic, average for 6 months, suggesting that the
plasma concentrations of amphetamines. neurocognitive decits were not transient.
They further contrasted the effects of cocaine The authors made the case that failure to
and metamfetamine: the cardiovascular respond was the most common type of
effects of cocaine last 3050 minutes while error made by both groups, but across all
those of metamfetamine last more than tasks. The metamfetamine users had signif-
240 minutes, making metamfetamine poten- icant impairment of retrospective memory
tially more toxic. and executive functioning. However, the
Prospective memory, which involves cross-sectional design, small sample size,
remembering future intentions, has been and other factors limited their conclusions.
reported to be negatively affected by In a comparison of 29 current MDMA
MDMA in a double-blind, placebo-con- users, 10 previous users, and 46 non-users,
trolled, two-way crossover study of a single using tests of working memory MDMA users
dose of MDMA 75 mg in 12 recreational performed worse than non-MDMA users in a
MDMA users [42C]. A single dose of letter comparison task, although the overall
MDMA increased the number of prospec- difference was not signicant [44c]. Current
tive memory failures, which correlated with MDMA users made signicantly more errors
plasma MDMA concentration. Functional in pattern recognition task than the other
imaging showed that MDMA decreased groups. When the results were combined, cur-
BOLD activation in the left thalamus, left rent MDMA users made signicantly more
putamen, left precuneus, and the bilateral errors than non-users. Working memory de-
inferior parietal lobules. The authors con- cits were signicantly greater in both MDMA
cluded that loss of deactivation in the inferior groups compared with the controls. Although
parietal lobules may account for increments MDMA users made more errors in informa-
in memory failures observed during MDMA tion processing speed and in letter compari-
intoxication. The effect of MDMA on mem- son tasks at all levels of complexity
ory was small. The detrimental effect of compared with non-MDMA users, the differ-
MDMA did not correlate with lifetime use. ences were not statistically signicant. The
There was a threefold intersubject variability authors suggested that age-related impair-
in plasma concentrations of MDMA, imply- ment of information processing is more global
ing that pharmacokinetic variables may play in nature and is characterized by more global
an important part in these effects. The slowing, compared with the MDMA-related
authors speculated that MDMA suppresses impairment, which appears to be more spe-
brain processes that are normally involved cic and localized, perhaps reecting some
in prospective memory. kind of attentional decit among current
Prospective memory has been assessed in users. They acknowledged that MDMA users
20 adults with amfetamine abuse/depen- had used a range of other drugs, making it dif-
dence who were abstinent for an average cult to attribute the results unambiguously to
period of 6 months and 20 MDMA alone.
metamfetamine-naive participants using MDMA has been suggested to alter cogni-
Virtual Week, a laboratory measure that tive function and impulsivity, but the data
closely approximates the type of prospec- have often been tainted by the concurrent
tive memory tasks that actually occur in use of other drugs of abuse. Decision-making,
everyday life [43c]. Metamfetamine users self-reported impulsivity, and drug use have
were signicantly impaired, and the decits been studied in 22 abstinent MDMA users,
64 Chapter 4 Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

30 other drug users, and 29 healthy non-drug [47M]. The preclinical and clinical data sug-
controls [45c]. Users of MDMA and other gest that adult women are more susceptible
drugs had comparable patterns of decision- than men to the acute and subacute psycho-
making and impulsivity. However, both drug logical and physical adverse effects of
groups had poorer decision-making and MDMA. However, men appear to be more
impulsivity than controls. Poorer decision- sensitive to the physiological effects of
making was related to heavier drug use in MDMA. The authors suggested that these
the past year, heavier weekly alcohol use, data are consistent with what has been
and lifetime substance use disorder, while reported with amphetamines and cocaine.
increased impulsivity was associated with They also commented on the relevance of
heavier drug use, heavier weekly alcohol these data to the preponderance of mood dis-
use, more lifetime substance use disorders, orders, especially depression, in women.
and more self-reported depression. MDMA Specically, they raised concerns that
users had heavier patterns of drug use in gen- women who use MDMA and have a history
eral, making a specic role of MDMA use in of depression may be at greater risk of future
reward-related decision-making and impul- psychological difculties, such as relapse of
sivity questionable. No particular drug class depression. As MDMA consumption occurs
emerged as being most strongly associated at dance parties, and can be associated with
with decision-making decits. unprotected sexual activity, they expressed
the concern that users are at increased risk
Immunologic Death from a possible ana- of accidental gestation, since gestational
phylactic reaction to MDMA has been exposure to MDMA can increase the risk of
reported [46A]. abnormal neurodevelopment. They
acknowledged that there is much that is not
A healthy 13-year-old girl took MDMA and known about why there are sex differences
had swelling of her lips. A few weeks later in responses to MDMA. They postulated
she took 1 tablets of MDMA and soon after
complained of nausea and took an antiemetic that the reasons for these differences are:
containing zingerone, without much effect. (1) regulation by MDMA of gonadal hor-
After about 4 hours she became apneic, coma- mone responses in women by altered seroto-
tose, hypothermic (33 C), hypotensive, and nin and dopamine neurotransmission or by
tachycardic. She died 30 hours after ingestion. regulation of gene expression; (2) sex-based
Autopsy showed massive brain edema with
tonsillor and transtentorial herniations and pharmacokinetic variables affecting the
anoxic/ischemic encephalopathy. Her lungs systemic availability and distribution of
were congested and she had laryngeal edema. MDMA; (3) sex differences in brain
There was zingerone in the urine and MDMA structures, which may afford different
blood concentrations were too low to explain
death by acute intoxication alone. Concomi- vulnerability.
tant intoxication from alcohol and other drugs
was excluded. There was no evidence of dis-
seminated intravascular coagulopathy, rhab-
domyolysis, hyponatremia, acute renal or
liver failure, or water intoxication. A friend
had taken a similar formulation of MDMA
Gamma-hydroxybutyric acid
and had had no reaction. (sodium oxybate) and analogues
[SED-30, 1479; SEDA-32, 68]
The authors concluded that this was most
probably a case of anaphylactic reaction to Systematic reviews The tolerability and
MDMA or an adulterant or contaminant abuse liability of gamma-hydroxybutyric
and did not nd any other similar published acid (GHB) have been reviewed [48M].
reports. GHB is abused by a small percentage of
people (<1%) as a club drug and is com-
Susceptibility factors Sex Sex differences monly associated with enhanced sexual
associated with the effects of MDMA as experiences (65%), euphoria (41%), somno-
reported in 28 studies have been reviewed lence (71%), and confusion (24%).
Drugs of abuse Chapter 4 65

Although it can be associated with serious Khat [SEDA-30, 43; SEDA-31, 48;
coma, there have been few reported deaths. SEDA-32, 69]
Formal studies of its abuse liability do not
suggest that it has a high abuse propensity, The experimental and clinical pharmacol-
mainly because oversedation and dizziness ogy of khat, models of addiction, and its
at high doses are unpleasant. Years of clin- adverse effects have been thoroughly
ical use in narcolepsy do not support the reviewed [53R]. In a special edition of the
development of tolerance or withdrawal journal Substance Use and Misuse the
symptoms in the absence of substance moral, political, cultural, and economic
dependence. inuences of khat in Kenyan society have
been reviewed, dealing with the complex
question of whether khat should be consid-
Nervous system Fixed, dilated, asymmetric ered an illicit drug [54c]. Other articles
pupils developed in two patients during included a review of the impact of khat on
continuous intravenous therapy with women's economic independence and
gamma-hydroxybutyrate, in the absence of moral standing in East Africa [55A], a case
cerebral herniation [49A]. study of a London neighborhood's
response to the use of khat [56c], and an
analysis of the public discourse regarding
Drug abuse The incidence of craving for the role of khat in Ethiopia [57c].
and abuse of gamma-hydroxybutyric acid
has been studied in four groups of patients:
pure alcoholics, alcoholics with a sustained Cardiovascular Perioperative considera-
full remission from cocaine dependence, tions specic to habitual khat chewers have
alcoholics with a sustained full remission been reviewed [58c]. Given the sympathomi-
from heroin dependence, and alcoholics in metic effects of khat and its potential for car-
a methadone maintenance treatment pro- diac toxicity, the author recommended
gram [50c]. All were given oral gamma- vigilant monitoring of perioperative cardio-
hydroxybutyric acid 50 mg/kg tds for vascular function and the selection of anes-
3 months. There was signicantly more thetics with fewer sympathomimetic or
craving for gamma-hydroxybutyric acid in cardiovascular effects. Acute use of khat
those in remission from cocaine depen- (within 4 hours before surgery) can lead to
dence than in the pure alcoholics and in increased anesthetic requirements, whereas
those in remission from heroin dependence chronic users, if their catecholamines are
than in those taking methadone. The depleted, may need less anesthesia and are
authors recommended that gamma- at risk of perioperative hypotension.
hydroxybutyric acid should not be used in
alcoholics with sustained full remission
from heroin or cocaine dependence. Psychiatric Susceptibility factors, including
use of khat, associated with violent expres-
sion have been studied among 1294 male
Drug overdose Two deaths and one non-
college students in Ethiopia [59c]. A self-
fatal intoxication following ingestion of
administered survey asked for numbers of
gamma-butyrolactone, a precursor of
violent acts, dened as an intentional act
gamma-hydroxybutyric acid, have been
of physical force or power, threatened or
reported; in another case a 36-year-old
actual, against another, with a high likeli-
woman obtained gamma-butyrolactone
hood of resultant physical or psychological
from nail polish remover pads [51A].
harm. The authors collected socio-
A 25-year-old drug addict died from an
demographic information and asked about
overdose of gamma-butyrolactone after mis-
hypothesized susceptibility factors, includ-
taking it for water in preparing a dilution
ing the style of anger expression (measured
[52A].
by the Spielberger Anger-Out Expression
66 Chapter 4 Jayendra K. Patel, Sarah Langenfeld, and Eileen Wong

Scale), negative life events, and substance reported in three cases, pulmonary edema in
use (whether or not the person labelled two, and intracerebral hemorrhage in one.
themselves as a user of khat, alcohol, and/ Common adverse effects were headache,
or tobacco). They found that 54% of the nausea, vomiting, hypertension, tachycardia,
students surveyed had committed at least chest pain, and myalgia. There was no associ-
one violent act in the past academic year. ation between the number of capsules
While alcohol and cigarette use did not ingested and the intensity of the poisoning;
increase the risk of violence, the use of khat however, this might have been due to the
increased the risk signicantly (OR 1.46; small number of cases. The authors estimated
95% CI 1.02, 2.08). Having a moderate that a typical khat session involves 100200 g
or high level of anger expression and hav- of leaves (about 3672 mg of cathinone);
ing more than four negative life events in this difference in amount ingested, as well as
the past year was more highly associated the faster absorption of hagigat, probably
with violent acts. This study was limited modies the clinical effects.
by the lack of details about any immediate
temporal relation between violence and
the use of khat, the amount or frequency
used, and the use of any substances other
than khat, alcohol, or tobacco. The authors
suggested that schools should implement OPIOID ANALGESICS
screening for violence and prevention
programs that target the susceptibility fac- See Chapter 8, in which both therapeutic
tors of stress, anger management, and sub- and abuse aspects of the opioids are
stance use. covered.

Pregnancy In an analysis of data from the


1997 Yemen Demographic and Maternal
Health Survey (7343 women who had at least Psilocybin [SEDA-31, 49; SEDA-32, 69]
one live birth in past 5 years), 41% of the
women surveyed answered yes when Drug overdose A 28-year-old man with a
asked if they had smoked khat while preg- history of drug and alcohol abuse came to
nant [60c]. There were associations between hospital on several occasions during
khat smoking during pregnancy and lack of 2 months with a variety of symptoms,
education, poverty, and living in a rural area. including altered mental status, vomiting,
The authors did not comment on how this sweating, and mydriasis, which resolved
pattern may have changed over the years spontaneously on each occasion; each time
since that 1997 survey. he required a high level of care [62A]. He
later admitted using mushrooms.
Of 742 patients with acute intentional
Drug overdose Hagigat, which contains exposures to mushrooms, 59 (7.9%) were
200 mg of cathinone (one of the compo- admitted to hospital, 17 of whom required
nents of khat leaves), approximately equiv- admission to a critical care unit and four
alent to 555 g of khat, are marketed in required in-patient psychiatric admission
Israel in capsules as a natural stimulant. [63c]. Their average age was 21 years and
Reports to Israel's poison control center there was a male-to-female predominance
of exposure to hagigat have been analysed of 3.3:1. The actual mushroom was identi-
[61c]. During the 10-month data collection ed in 11 cases, 10 of which involved psilo-
period, there were 34 reports about cybin. The most common symptoms were
patients aged 1654 (median 25) years, 24 vomiting (n 34), nausea (n 19), altered
men and 10 women. In two cases the drug mental status (n 17), abdominal pain
was inhaled. Myocardial ischemia was (n 13), and diarrhea (n 10).
Drugs of abuse Chapter 4 67

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Rebecca Spencer, Stephen Curran, and Shabir Musa

5 Hypnosedatives and
anxiolytics

Comparative studies Experience and Reported prescribing practices were often at


perceptions of using Z drugs (zaleplon, variance with the licence for short-term use.
zolpidem, and zopiclone) and benzodiaze-
pine hypnotics in the community have been
studied in a cross-sectional survey of general
practice patients [1c]. Patients who had
received at least one prescription for a Z drug AZASPIRONES [SEDA-28, 52;
or a benzodiazepine in the previous 6 months
were sent a postal questionnaire. Of 1600 sur- SEDA-32, 75]
veys posted, 935 responses (58%) were
received, of which 705 (75%) were from Buspirone [SED-15, 575; SEDA-32, 75]
patients taking drugs for insomnia. Of those
705 patients, 88% rst received a prescription Placebo-controlled studies In a placebo-
for a hypnotic from their GP, and 95% had controlled study of the use of buspirone
taken a sleeping tablet for 4 weeks or more. (maximum 60 mg/day for 12 weeks) and
At least one adverse effect was reported in motivational interviewing in 50 subjects with
42%; 19% wanted to stop taking the hypnotic; marijuana dependence, all the adverse events
and 49% had tried to stop. Compared with were mild to moderate in intensity [2C]. Most
those taking benzodiazepines patients who of those who took buspirone (96%) had at
were taking Z drugs were more likely to least one adverse event compared with 78%
express a wish to stop (23% versus 12%; OR of those who took placebo. Dizziness was
1.67; 95% CI 1.13, 2.49), or to have more common with buspirone (RR 3.52;
attempted to stop (52% versus 41%; OR 95% CI 1.08, 11). Dry mouth (RR 2.35),
1.54; 95% CI 1.12, 2.12). The two groups ushing/sweating (RR 2.93), and cold-like
did not differ signicantly in respect of bene- symptoms (RR 2.35) were also more
ts or adverse effects. There were no signi- common with buspirone than placebo, but
cant differences in patients perceptions of not signicantly so.
efcacy or adverse effects. Adverse effects
were commonly reported, which may have
contributed to a high proportion of
responders, particularly patients taking Z
drugs who wanted to stop or who had previ- BENZODIAZEPINES [SED-15,
ously tried to stop taking the medication.
429; SEDA-30, 49; SEDA-31, 57;
SEDA-32, 75]
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
ISSN: 0378-6080 Nervous system In a study of the relation
DOI: 10.1016/B978-0-444-53741-6.00005-2 between the blood concentration of benzo-
# 2011 Elsevier B.V. All rights reserved. diazepines and their effects on performance
71
72 Chapter 5 Rebecca Spencer, Stephen Curran, and Shabir Musa

in eld sobriety tests, a retrospective case ventricular and atrial septal defects, were
le evaluation was conducted to select 171 recorded in the infants of mothers who
drivers who had been tested positive for had used an SSRI alone, a benzodiazepine
benzodiazepines only in the period from alone, or the combination, and were com-
January 1999 to December 2004 [3c]. pared with outcomes after no exposure.
Drivers were grouped into those with The risk of a major congenital anomaly or
subtherapeutic, therapeutic, or high con- congenital heart disease increased after
centrations. The outcomes of the tests combined SSRI benzodiazepine expo-
(walking, walking after turning, nystagmus, sure compared with no exposure. However,
Romberg's test, behavior, pupils, and orien- using a weighted regression model, control-
tation) were binomial. Observations of ling for maternal illness characteristics,
behavior (n 137), walking (n 109), combination therapy risk was signicantly
walking after turning (n 89), and associated only with congenital heart dis-
Romberg's test (n 88) were signicantly ease. The risk of an atrial septal defect
related to the benzodiazepine concentra- was higher after SSRI monotherapy com-
tion. There was no signicant relation pared with no exposure, after adjustment
between benzodiazepine concentration for maternal covariates. Daily dose was
and pupil size, nystagmus, or orientation. not associated with an increased risk.
These results suggest a relation between Infants who had been exposed to prenatal
the concentration of benzodiazepines and SSRIs in combination with benzodiazepines
the results of some performance tests. The had a higher incidence of congenital heart
authors concluded that more effort is disease compared with no exposure, even
needed to standardize the tests and to after controlling for maternal illness charac-
determine their sensitivity and specicity. teristics. SSRI monotherapy was not associ-
ated with an increased risk of major
Psychiatric In a prospective study of the congenital anomalies, but was associated
use of benzodiazepines or opioids in rela- with an increased incidence of atrial septal
tion to the incidence and duration of delir- defect.
ium in 304 admissions to an intensive care
unit, 72% of patients had delirium on their
rst day of admission and lasting a median
of 3 days [4c]. After controlling for baseline
Clobazam [SED-15, 806]
dementia, use of haloperidol, and health
status, the use of either a benzodiazepine Skin StevensJohnson syndrome has been
or an opioid within 48 hours was associated reported in a patient taking a combination of
with the duration of delirium and in those clobazam, lamotrigine, and valproic acid [6A].
without pre-existing dementia, there was a
142% increase in the rate of delirium.

Teratogenicity The incidence of congenital Clonazepam [SED-15, 815]


anomalies after prenatal exposure to selec-
tive serotonin reuptake inhibitor antide- Psychological The relation between clo-
pressants (SSRIs) used alone and in nazepam plasma concentrations after a sin-
combination with benzodiazepines has gle oral dose of 4 mg and impairment of
been studied [5C] by linking population psychomotor performance has been studied
health data, maternal health, and prenatal in 23 healthy volunteers [7c]. Clonazepam
prescription records to neonatal records, reduced psychomotor performance by up
representing all live births (British Colum- to 72% at 1.54 hours after administration
bia, Canada, n 119 547) during 39 months and there was time-dependent tolerance.
(19982001). The incidence and risk differ- However, there was too much
ences (RD) for major congenital anomalies interindividual variation to allow individual
and congenital heart disease, including prediction of these effects.
Hypnosedatives and anxiolytics Chapter 5 73

Hair Hair loss has been reported in associ- Diazepam [SED-15, 1103; SEDA-30, 50;
ation with clonazepam [8A]. SEDA-31, 57; SEDA-32, 75]

Drug withdrawal Withdrawal of benzodia- Drug resistance P glycoprotein can confer


zepines is associated with a risk of features drug resistance on cells by allowing them to
such as rebound insomnia, anxiety, percep- export drugs. In a study of the binding of
tual changes, convulsions, or delirium [9A]. some benzodiazepines (bromazepam, chlor-
Malignant catatonia has also rarely been diazepoxide, diazepam, and urazepam) to
reported, as another case illustrates. P glycoprotein in proteoliposomes and their
effects on its transport function and ATPase
A 60-year-old man developed acute confusion, activity in the human cancer cell line, KB-
grimacing, stereotypy, refusal of food and V1, the toxicity of the benzodiazepines
water, muscle rigidity, mutism, and extreme
negativism after abruptly discontinuing all towards the KB-V1 cells was rst evaluated
psychotropic medications. He was given loraz- and the non-toxic drug concentrations were
epam and then clonazepam was re-started. His used to assess drug efux and ATPase activity
catatonic symptoms and autonomic instability [12E]. Using ow cytometry, accumulation
resolved completely.
and efux of daunorubicin were studied by
The mechanism by which catatonia is pre- measuring the daunorubicin-associated geo-
cipitated by benzodiazepine withdrawal is metric mean uorescence intensity. Vana-
not known; the authors speculated that it date was used as a comparative inhibitor.
may involve a rapid reduction in GABA Flurazepam inhibited daunorubicin efux
transmission. in 80%. ATPase activity showed that
urazepam inhibits P glycoprotein-linked
enzyme activity, indicating coupling between
Drug abuse Clonazepam is often used as a drug transport and ATP hydrolysis. Brom-
drug of abuse and to treat drug addicts. In azepam, chlordiazepoxide, and diazepam
cases referred to the Section of Forensic activated P glycoprotein-linked ATPase
Chemistry at the University of Copenhagen activity, suggesting a role as transported sub-
in 20022007 clonazepam and its metabolite strates, but they did not interfere with dauno-
7-aminoclonazepam were detected in 297 rubicin transport.
cases after trafc accidents (median
0.067 mg/kg), in 92 perpetrators or victims of
Drug administration route Intranasal and
a crime (median 0.071 mg/kg), and in 140
intravenous diazepam have been compared
postmortem cases (median 0.115 mg/kg)
[13A]. The tmax and half-life were similar after
[10c]. In 27 of the postmortem cases with high
5 and 10 mg intranasally and the systemic
concentrations other drugs had been taken,
availability was 75%. There were no adverse
but clonazepam was thought to have been
events, although many subjects reported
the primary cause of death in ve (concentra-
swallowing much of the preparation. All
tions 0.260.54 mg/kg).
reported transient pain and watery eyes.
The extent of abuse of clonazepam has
been assessed in a French study, in which
deliveries of clonazepam to individuals who
had had a prescription reimbursed were mon-
itored for 9 months [11c]. There was an Flunitrazepam [SED-15, 1394;
increase of 82% in participants who had a SEDA-31, 58]
delivery of clonazepam between 2001 and
2006, and some deviant participants were Cardiovascular Accidental injection of
identied; they included a higher proportion unitrazepam tablets dissolved in tap water
of men, benzodiazepine users, and into the left femoral artery by a 22-year-old
buprenorphine users. The proportion of devi- drug abuser caused acute ischemia of the
ant participants increased between 2001 and leg with severe rhabdomyolysis within
2006 from 0.86% to 1.38%. 5 hours [14A]. There was acute occlusion
74 Chapter 5 Rebecca Spencer, Stephen Curran, and Shabir Musa

of the posterior tibial artery, which resolved Lorazepam [SED-15, 2163; SEDA-30,
with intra-arterial urokinase and prostaglan- 51; SEDA-31, 58; SEDA-32, 76]
dins and intravenous anticoagulation.
Sexual function Greatly enhanced sexual
Nervous system The risk of road trafc desire has been attributed to lorazepam
accidents in individuals who have lled a [17A].
prescription for unitrazepam, nitrazepam,
zolpidem, or zopiclone has been studied A 62-year-old married woman with carcinoma
[15c]. All Norwegians aged 1869 years of the breast was given lorazepam 1 mg at
(3.1 million) were followed from January bedtime for insomnia. At her next follow-up
appointment, she reported with some embar-
2004 until the end of September 2006. rassment how she felt after taking the rst
Information on prescriptions, road trafc dose. Over the next hour, she had developed
accidents, and emigration/death was a strangely intense sexual desire, an over-
obtained from three Norwegian popula- whelming pleasant sensation climbing over
her inner thighs, progressing to the genitalia,
tion-based registries. The rst week after followed by the sensation of having sexual
the hypnotics had been dispensed was con- intercourse, which she repressed before get-
sidered to be the exposure period. Stan- ting an orgasm. She said that for the rst time
dardized incidence ratios (SIRs) were in some years she had seriously thought about
calculated by comparing the incidence of waking up her husband to initiate intercourse.
I had not felt like this in years. It was like
accidents in the exposed person-time to having sexual intercourse without wanting it.
the incidence of accidents in the unexposed I could not help myself feeling an intense but
person-time. During exposure, 129 acci- unwanted pleasure. The sensations faded
dents were registered for zopiclone, 21 for gradually over the next few hours. The symp-
toms were repeated when she took a dose on
zolpidem, 27 for nitrazepam, and 18 for the next evening.
unitrazepam. The SIRs were: Z hypnotics
(zopiclone zolpidem) 2.3; nitrazepam The authors suggested that this could have
2.7; and unitrazepam 4.0. The highest been explained by inhibition of the action
SIRs were found among the youngest users of serotonin in the septal and amygdaline
for all hypnotics. Thus, users of hypnotics nuclei.
had a clearly increased risk of road trafc
accidents, and the risk for unitrazepam
was particularly high. Drug formulations Propylene glycol is used
as a solvent for many liquid formulations of
drugs, including lorazepam. There is a high
risk of propylene glycol toxicity during the
administration of large doses of lorazepam
Flurazepam intravenously, as has been reported in criti-
cally ill adults [18c]. This has been studied
Nervous system The residual effects of in 35 adults who received any dose of par-
gaboxadol 10 mg and urazepam 30 mg enteral lorazepam and in 14 patients who
on the day after bedtime administration received lorazepam in doses of 1 mg/kg/
have been compared in a crossover, dou- day or more [19c]. The osmolar gap (mea-
ble-blind, randomized, placebo-controlled sured serum osmolality minus calculated
study in 25 healthy elderly subjects [16c]. osmolarity) was used as a measure of toxic-
Flurazepam signicantly impaired choice ity. The serum propylene glycol concentra-
reaction time, the threshold for critical tion was measured when the osmolar gap
icker fusion, digit symbol substitution, exceeded 10. In phase 1, 35 patients were
and speed of compensatory tracking, but monitored for 186 patient-days; 10 devel-
did not alter immediate or delayed word oped an osmolar gap greater than 10, but
recall or the eyes-closed endpoint of the only one had a propylene glycol concentra-
body sway test. Gaboxadol had no deleteri- tion over 180 mg/l. In phase 2, 14 patients
ous effects. received lorazepam in a median dose of
Hypnosedatives and anxiolytics Chapter 5 75

631 mg (interquartile range 437972 mg) Midazolam [SED-15, 2337; SEDA-30,


over a median of 5.5 days. Nine patients 51; SEDA-31, 59; SEDA-32, 77]
had propylene glycol concentrations over
180 mg/l and six of them developed tran-
Observational studies In a prospective
sient acute kidney injury, metabolic acido-
study of 516 children undergoing CT scans,
sis, or both. There was a correlation
who received midazolam 0.212 mg/kg, there
between the osmolar gap and the propyl-
was adequate sedation in 5.9 minutes and
ene glycol concentration. An osmolar gap
only a few patients required additional
of 10 or greater had a likelihood ratio of
boluses [22c]. There were adverse effects
4.4 to predict a propylene glycol concentra-
in 9.1% of patients, including desaturation
tion over 180 mg/l; an osmolar gap of 12 or
in 6.9%, all of whom were treated success-
greater had a likelihood ratio of 2.7 to pre-
fully with oxygen, hiccups in 1.4%, and agi-
dict the development of propylene glycol
tation in 0.79%. All the adverse effects
toxicity. The authors concluded that the
were self-limiting.
osmolar gap may be helpful in screening
In 41 adults undergoing transesophageal
for propylene glycol toxicity in patients
echocardiography, who received
who are receiving intravenous lorazepam
midazolam either alone (2.5 mg bolus plus
in doses of 1 mg/kg/day or more.
1 mg increments as required) or in combi-
nation with remifentanil (midazolam 0.5 mg
Drugherb interactions The dangers of
remifentanil 0.08 micrograms/kg/
herbal medicines have been highlighted by
minute), the median time to an acceptable
the case of a man who self-medicated with
Aldrete score (a measurement of readiness
Valeriana ofcinalis and Passiora incarnata
for discharge) was much slower after
while he was also taking lorazepam and
midazolam than remifentanil midazolam
developed shaking hands, dizziness, throb-
(30 versus 5 minutes) [23c]. There were sig-
bing, and muscle fatigue [20A]. The authors
nicant reductions in blood pressure but not
suggested that the active principles in vale-
heart rate in both groups and there were no
rian and passionower might increase the
adverse respiratory events.
inhibitory effects of benzodiazepines.
In a study of sedation during local anes-
thesia for bone marrow aspiration, 46 adults
were randomized to midazolam 2 mg every
Lormetazepam [SED-15, 2167; 2 minutes (n 21) until conscious sedation
was achieved or Entonox (n 25) delivered
SEDA-32, 77]
by the patient [24c]. Amnesia was induced by
Drug overdose Although benzodiazepine midazolam in 55% compared to 4% with
overdose is rarely fatal, a very large over- Entonox. There was greater pain and dizzi-
dose can be [21A]. ness with Entonox, but midazolam caused
desaturation in 19% of patients. Midazolam
A 34-year-old woman was found dead in her reversal was required in 10 patients for
bed with evident traces of vomit and feces. either desaturation or prolonged sedation
No medicinal products or drugs of abuse were (after a mean dose of 0.08 mg/kg).
found around the body and there was no evi-
dence of injury or trauma. At the autopsy,
3 days later, external examination was Respiratory The effect of oral midazolam
unremarkable and there were no signs of 0.3 mg/kg on respiratory function has been
chronic drug abuse. Internal examination
showed pulmonary edema and severe vascular studied in 18 children (median age
congestion in all internal organs. Toxicological 78 months) without cardiorespiratory dis-
analysis of blood, urine, and bile samples ease undergoing elective surgery [25c].
showed the presence of lormetazepam and its There was a reduction in tidal and minute
metabolite lorazepam in traces. This, together
with the absence of other drugs or alcohol, volume but not respiratory rate or expiratory
strongly suggested that death was due to acute times. There was a 6.5% reduction in func-
overdose of lormetazepam only. tional residual capacity and corresponding
76 Chapter 5 Rebecca Spencer, Stephen Curran, and Shabir Musa

increases in LCI, respiratory resistance, and 10 minutes at both intranasal doses and
elastance (7.8%, 7.4%, and 9.2% respec- the systemic availability was 60%. The
tively) 20 minutes after pre-medication. maximum concentration was dose-depen-
There were no episodes of desaturation. dent but half-life was not affected by dose
or route of administration. The most com-
Nervous system Extrapyramidal adverse mon adverse events were pharyngitis
effects have been attributed to midazolam (n 11), rhinitis (14), and taste distur-
[26A] and hypothesized to have been due bances (11), but all were transient and
to inhibition of ring in the substantia nigra lasted only 214 minutes. There were no
secondary to an effect on a3-containing serious adverse events or changes in endo-
GABAA receptors [27r]. scopic nasal examination.

Acidbase balance A severe Drugdrug interactions Antifungal azoles


hyperchloremic metabolic acidosis with a Posaconazole inhibits CYP3A4, by which
normal anion gap occurred in a 9-year-old midazolam is metabolized. The effects of
girl who was given a high-dose continuous oral posaconazole 200 mg bd for 7 days
intravenous infusion of midazolam for and ketoconazole 400 mg od for 7 days on
refractory status epilepticus and resolved the pharmacokinetics of oral and intrave-
within 5 hours of withdrawal [28A]. The nous midazolam have been studied in 12
authors suggested that it was due to the healthy volunteers [32c]. Both azoles
use of hydrochloric acid in the parenteral reduced the clearance and prolonged the
formulation. half-life of midazolam, ketoconazole more
so than posaconazole. Seven subjects
Drug administration route Intranasal reported at least one adverse event during
midazolam is used widely and successfully the study (ve with posaconazole alone
as pre-medication, particularly in children, and four with posaconazole midazolam).
avoiding rst-pass metabolism and increas- The most common adverse events were
ing systemic availability [29A]. diarrhea (n 3 with posaconazole alone,
In a double-blind, crossover, randomized two with ketoconazole alone, and one with
trial in 10 healthy volunteers midazolam posaconazole midazolam) and atulence
0.2 mg/kg was given by nebulizer and liquid (one with posaconazole alone and one with
instillation nasally 5 days apart [30c]. midazolam alone).
Plasma concentrations were greater after
intranasal midazolam. Nasal instillation Opioids Drugdrug interactions with
caused increased sedation but no difference midazolam have been studied in 7431
in the time to sedation. There were no patients in a Brazilian hospital (28% of all
respiratory adverse events. Blood pressure the patients who had been admitted to the
and oxygen saturation fell in both groups hospital) [33c]. Flumazenil was given to 26
(peak reduction at 15 minutes) but none patients within 24 hours after midazolam
required extra oxygen. Mean heart rate and there were clinically signicant
and diastolic pressure were increased. The drugdrug interactions resulting from pre-
incidence of unpleasant adverse effects scriptions of drugs preceding the use of
was greater after intranasal midazolam, umazenil in 23 cases. The most common
and nasal stinging, eye irritation, hiccups, interactions were related to central nervous
and excessive secretions were common. system depressants (22 cases), mainly
One patient with asthma became wheezy opioid agonists.
after intranasal administration.
Intranasal midazolam 2.5 and 5 mg have Protease inhibitors The effects of multiple
been compared with intravenous doses of ritonavir-boosted saquinavir
midazolam 2.5 mg in a crossover study in (100 mg 1000 mg bd for 2 weeks) on
18 healthy volunteers [31c]. The tmax was the pharmacokinetics of a single oral dose
Hypnosedatives and anxiolytics Chapter 5 77

of midazolam 7.5 mg have been studied in Drugherb interactions Interactions of


18 healthy volunteers [34c]. Saquinavir midazolam with herbal medicines have
ritonavir increased the Cmax of midazolam been reviewed [36R].
4.3-fold and the AUC 12.4-fold; the half-life
was prolonged from 4.7 to 15 hours. The
Cmax and AUC of 10 -hydroxymidazolam
were reduced by about sevenfold and two-
Temazepam [SED-15, 3312;
fold respectively. The combination resulted SEDA-30, 52]
in prolonged sedation.
Susceptibility factors Age Temazepam
15 mg and diphenhydramine 50 mg for 14
Drug overdose Between November 2004 nights have been compared in elderly indi-
and November 2008, UK health-care staff viduals with insomnia (mean age 74, range
reported 498 dosing errors for midazolam 7089 years) in a randomized, placebo-con-
to the National Patient Safety Agency trolled, crossover study [37c]. Primary out-
(NPSA); there were three deaths [35S]. come measures were subjective assessments
The following problems were reported: of sleep recorded on sleep diaries. Secondary
measures were the morning-after psychomo-
drawing up part content of a high-strength tor impairment, using the digital symbol sub-
injection ampoule (10 mg in 2 ml or 10 mg in stitution task and the manual tracking task,
5 ml) or giving the whole ampoule by mistake; and the morning-after memory impairment,
failing to titrate the dose to the needs of the
individual patient;
using a free-recall procedure. Temazepam
not understanding the risks of combining improved sleep quality, total sleep time,
midazolam with other drugs, such as opioids; number of awakenings, and sleep-onset
widespread use of, and possible over-reliance latency compared with placebo. Diphenhy-
on, the reversing agent, umazenil. dramine improved the number of awaken-
ings only. The numbers of adverse events
The Agency made the following
were similar after all treatments, although
recommendations:
there was one fall during temazepam treat-
remove high-strength midazolam from all but ment. This suggests that temazepam is more
dened clinical areas (such as general anesthe- effective than diphenhydramine, although
sia, intensive care, and palliative care) and this advantage is mitigated by the risk of falls.
replace with low-strength alternatives; The choice of agent to use in elderly people
review training needs;
identify a lead (usually an anesthetist) for
must consider these relative benets and
sedation policy and auditing the use of harms.
umazenil locally;
routinely use the safer 1 mg/ml strength
(in 2 ml or 5 ml ampoules) rather than high-
strength midazolam in general areasfor Triazolam [SED-15, 3486; SEDA-31, 60;
example, where outpatient diagnostic proce-
dures are performed; SEDA-32, 79]
do not use part-ampoules or part-phials of
high-strength midazolam; Nervous system The effects of triazolam
do not rely on umazenil to reverse 0.375 mg, and zolpidem 10 mg, two
oversedation by midazolam, but aim to pre-
vent oversedation in the rst place; however,
GABAA allosteric activators, on sleep-
if you need to use umazenil, audit its use; dependent motor skill memory consolida-
continue to use high-strength midazolam for tion have been studied in a placebo-con-
general anesthesia and intensive care seda- trolled study in 12 healthy men [38C].
tion, and for palliative care when syringe Triazolam was associated with longer total
drivers are used; in the latter case undertake
a formal risk assessment, especially when dif- sleep time and increased stage 2 sleep. Both
ferent strengths of midazolam are stocked for zolpidem and triazolam were associated
different indications in a single clinical area. with an increased latency to rapid eye
78 Chapter 5 Rebecca Spencer, Stephen Curran, and Shabir Musa

movement (REM) sleep. Overnight motor tabulated. Combining controlled trials for
learning correlated with total sleep time the four drugs, there were 6190 participants
after placebo but not after triazolam or who had taken hypnotics and 2535 who had
zolpidem. Motor performance was signi- taken placebo in parallel. There were eight
cantly impaired overnight by triazolam only. mentions of incident non-melanoma skin
cancers among participants who took hyp-
Drug overdose A 76-year-old woman died notics but no comparable mentions of can-
after taking a combination of triazolam and cers among those receiving placebo. There
promazine in overdose [39A]. Post-mortem were also four mentions of incident tumors
triazolam and promazine concentrations of uncertain malignancy among those who
were respectively: blood 1100 and 3450 ng/ml; took hypnotics but none among those who
gastric contents 1300 and 5800 ng/ml. took placebo. FDA les showed that all four
of the new hypnotics were associated with
cancers in rodents. Three had been shown
to be clastogenic. Together with epidemio-
logical data and laboratory studies, the avail-
BENZODIAZEPINE-LIKE able evidence suggests that new hypnotics
may increase the risk of cancers.
DRUGS
Drug overdose A case of zaleplon over-
Zaleplon [SED-15, 3710; SEDA-29, 57]
dose has been described [42A].
Psychiatric Perceptual disturbances have
A 24-year-old woman took 28 or so tablets of
been attributed to zaleplon [40A]. zaleplon. The time of ingestion was
undetermined but it was probably more than
A 20-year-old Caucasian woman with DSM- 4 hours earlier. She was confused and sleepy.
IV diagnoses of major depressive disorder She looked pale and her mouth and lips were
and borderline personality disorder reported stained blue-green. Soon after arrival she
insomnia characterized by difculty falling vomited dark blue-green stomach contents.
asleep, but no difculty maintaining sleep, for Although a complete neurological examination
6 months. She was given zaleplon 10 mg cap- was difcult to perform, there were no major
sules and advised to take one at bedtime as abnormalities. Her blood pressure was low but
needed. She was also taking uoxetine 60 mg responded to 20 ml/kg of isotonic saline. The
od, ziprasidone 40 mg/day, and the oral con- electrocardiogram showed sinus tachycardia. A
traceptive Alesse. When her insomnia urine sample was strongly blue-green in color
persisted the dose of zaleplon was increased and a urine drug screen for opioids, benzodiaze-
to 20 mg and she took it about six times during pines, cocaine, amphetamines, barbiturates,
the next month. On three of those occasions methadone, and cannabinoids was negative.
she had had some unusual perceptual experi- She subsequently became restless, was confused,
ences, including seeing tree branches moving and had visual hallucinations and intermittent
closer to her, seeing movements of water and myoclonus. The next day she was alert and co-
re in a painting on a wall, and seeing people operative and a complete examination was
moving and talking to her on another picture. normal.
After each episode, she had fallen asleep and
wakened the next morning with no unwanted The authors concluded that the blue-green-
after-effects.
ish discoloration of the vomit and urine could
be an important sign of zaleplon overdose.
Tumorigenicity Data from controlled trials
have been analysed to determine whether
hypnotics can cause cancer [41M]. The US
Food and Drug Administration (FDA)
Approval History and Documents were Zolpidem [SED-15, 3723; SEDA-30, 53;
accessed for zaleplon, eszopiclone, SEDA-31, 61; SEDA-32, 80]
zolpidem, and ramelteon. Incident cancers
that occurred during randomized adminis- Nervous system Sleep walking has been
tration or placebo administration were attributed to zolpidem [43r].
Hypnosedatives and anxiolytics Chapter 5 79

A 51-year-old, white, married woman experi- BENZODIAZEPINE


enced two episodes of somnambulism with
amnesia while taking zolpidem 10 mg at bed- ANTAGONISTS
time. During these episodes, she walked down
the steps from her second-storey bedroom to
the kitchen and ate normal amounts of food. Flumazenil
She stopped taking zolpidem and had no
further problems. Flumazenil is a benzodiazepine antagonist
used to reverse the effects of benzodiaze-
Cases of sleep driving associated with the pines in the treatment of poisoning or in
use of non-benzodiazepine hypnotics anesthesia [46c, 47R, 48R, 49A]. It reduces
reported to the US Food and Drug Admin- the risks of complications from drug over-
istration (FDA) Adverse Events Reporting dose, obviating the need for invasive inter-
System have been summarized [44c]. On 1 ventions such as mechanical ventilation and
March 2006, the FDA Adverse Events invasive hemodynamic monitoring [50c].
Reporting System was searched for However, it is not effective in reversing the
postmarketing reports of sleep driving asso- amnesic effects of midazolam [51A]. It has
ciated with zolpidem, zaleplon, and also been used to reverse the effects of
eszopiclone. Each identied case was evalu- zaleplon [52A], zolpidem [53A, 54A, 55C],
ated to ensure that it met the general zopiclone [56A, 57A], antihistamines such
requirements for sleep driving. There were as promethazine [58A, 59A], baclofen
14 cases, 13 of which involved zolpidem. [60A], cannabis [61A], carisoprodol [62A],
Of these 13, eight involved concomitant chloral hydrate [63A], chlorzoxazone
use of a psychotropic drug (benzodiaze- [64A], carbamazepine [65A], gabapentin
pine, alcohol, or a narcotic). Zolpidem was [66A], paclitaxel [67A], propofol [68C], and
the most commonly implicated drug in thiopental [69C]. Guidelines for its use have
sleep driving, but it is unclear whether this been summarized [70R].
is attributable to a greater risk of sleep The problems in using umazenil are
driving with zolpidem, more widespread those of dose adjustment, the risks of panic
use of the drug, or other factors. Concomi- anxiety, seizures, or other signs of exces-
tant use of other psychotropic drugs could sively rapid benzodiazepine withdrawal. Its
have potentiated the effect of zolpidem. use is also commonly associated with
vomiting and headache, and rarely with psy-
chosis or sudden cardiac death [71A], espe-
cially in mixed overdoses. It can
Zopiclone [SED-15, 3710; SEDA-31, 62] occasionally cause a benzodiazepine with-
drawal reaction [72C].
In 17 patients who were given umazenil to
Nervous system The residual effects at reverse the effect of midazolam after upper
1011 hours after evening doses of gastrointestinal endoscopy, it reversed the sed-
temazepam 20 mg and zopiclone 7.5 mg on ative effects in under 2 minutes but did not
driving performance in a standardized high- affect the ventilatory effects [73c]. However,
way driving test have been evaluated in 18 in a randomized, double-blind, placebo-con-
healthy elderly drivers in a double-blind, trolled crossover study in 12 healthy volunteers
three-way, placebo-controlled crossover intravenous umazenil 1.0 mg restored respi-
study [45C]. Driving performance did not dif- ratory function within 3 minutes [74C].
fer between temazepam and placebo but was Since umazenil has a short half-life (about
signicantly impaired after zopiclone. The 1 hour) compared with the longer half-lives of
magnitude of the impairment was compara- most benzodiazepines, its benecial effects
ble with that found before in younger can wear off before the effects of the benzodi-
volunteers. azepines [75R]. Re-sedation occurs in about
80 Chapter 5 Rebecca Spencer, Stephen Curran, and Shabir Musa

65% of patients, usually within 0.53 hours 5% and 3.3%. Similar results were obtained in
after the rst dose, the shorter interval being a study of 236 patients with grade IVa hepatic
associated with poisoning with combinations encephalopathy [91C].
of drugs; repeated doses of umazenil, some- In a single-dose, crossover, double-blind,
times followed by continuous infusion are placebo-controlled study of umazenil and
effective [76M]. In 50 patients who were given placebo in 16 subjects with Parkinson's dis-
intravenous placebo or umazenil 15 minutes ease, scores on the Unied Parkinson's Dis-
after injection of unitrazepam 0.03 mg/kg in ease Rating Scale tended to improve, but the
a randomized, double-blind study, effect was not signicant; the most common
umazenil promptly reversed sedation for adverse events were light-headedness or diz-
30 minutes, hypotonia for 45 minutes, and ziness [92C].
anterograde amnesia for 60 minutes, and Flumazenil is not anxiolytic after alcohol
improved orientation and collaboration for withdrawal [93C].
60 minutes; however, anterograde amnesia It is not generally helpful to measure ben-
recurred after 60 minutes and sedation after zodiazepine plasma concentrations, but they
90 minutes [77C]. In a placebo-controlled can assist in the diagnosis of overdose and
study in 30 patients who had received thus guide the use of antagonists [94c].
midazolam followed by intravenous
umazenil, subcutaneous umazenil did not Placebo-controlled studies In a double-
prevent the rebound sedation that occurred blind, randomized, placebo-controlled study
after 90 min; adverse effects included nausea in 105 unconscious adults with suspected
and vomiting [78C]. However, a continuous drug overdose, 73 of whom had taken ben-
infusion of umazenil 0.5 mg/hour can pre- zodiazepines, umazenil caused adverse
vent re-sedation [79C]. effects in nine cases: agitation (n 3), a
Paradoxical adverse effects of benzo- depressive mood (n 3), nausea and
diazepines, such as aggressive behavior, can vomiting (n 1), shivering (n 1), and
occur [80r] and can be reversed by umazenil one severe adverse reactiona sudden fall
[81A, 82A, 83A, 84A, 85A]. In 58 patients under- in blood pressure in a 28-year-old woman
going surgery under spinal or epidural anes- in deep coma after combined poisoning with
thesia, umazenil 0.1 mg over 10 seconds benzodiazepines and maprotiline [95C].
abolished the agitation without reversing seda- In a multicenter, double-blind, placebo-
tion (total dose range 0.10.5 mg) [86cr]. In 30 controlled study of the effects of intravenous
patients who had been given midazolam, umazenil 0.7 mg in reversing the effects of
umazenil 0.150.5 mg resulted in cessation midazolam, 82% of 131 umazenil-treated
of the agitation without reversal of sedation patients had complete reversal of sedation,
[87A]. Adverse effects of umazenil were not compared with 15% of 65 placebo-treated
reported in these studies. patients. However, umazenil reversed
Flumazenil has been used as a non-specic midazolam-induced amnesia in only 60%
treatment in patients with hepatic encephalopa- of patients. Dizziness (10%) and nausea
thy [88c, 89R]. However, it was effective in only (9%) were the most common adverse effects
some subjects in a double-blind, placebo-con- [96C]. Similar results were obtained in a
trolled, crossover study in 527 patients with cir- double-blind, placebo-controlled study in
rhosis and hepatic encephalopathy grade III patients who had been given midazolam
and IVa, of whom 265 received umazenil plus an opioid (fentanyl, pethidine, or mor-
and 262 received placebo [90C]. There was phine) [97C], intravenous diazepam [98C],
improvement of the neurological score in 18% or diazepam plus an opioid [99C].
of the patients with grade III encephalopathy
and in 15% of those with grade IVa compared Cardiovascular Multifocal ventricular extra
with 3.8% and 2.7% respectively of those beats with short runs of ventricular tachycar-
who received placebo; electroencephalography dia occurred within seconds after the admin-
improved in 28% and 22% compared with istration of umazenil to reverse oxazepam
Hypnosedatives and anxiolytics Chapter 5 81

toxicity in a 30-year-old woman [100A]. She Opisthotonos after umazenil has been
had also taken chloral hydrate, which may reported [115A].
have sensitized the heart. Ventricular brilla-
tion has also been reported in a 60-year-old A healthy 17-year-old man received an
man [101A]. interscalene brachial plexus block using
mepivacaine 600 mg and bupivacaine 150 mg.
In another case co-administration of a tri- He became disorientated and showed signs of
cyclic antidepressant may also have local anesthetic toxicity, for which he was given
increased the risk of dysrhythmias [102A]. midazolam 5 mg. Flumazenil 0.5 mg was given
23 minutes after the end of the procedure, causing
A 57-year-old woman took an overdose of loraz- opisthotonos.
epam and amitriptyline and became deeply
unconscious. She had a nodal rhythm and fre- Ballismus has also been reported [116A].
quent multifocal ventricular extra beats, ventric-
ular couplets and triplets, and salvos of
ventricular tachycardia. She was given intra-
Psychiatric Oral umazenil was used in a
venous umazenil in divided doses to a total of woman who had had several episodes of
500 micrograms. Her respiratory rate increased hepatic encephalopathy, in an attempt to pre-
to 20/minute and after 5 minutes she had general- vent deterioration into coma, but after 2 days
ized tonicclonic convulsions, followed in 15 sec- she had an acute psychosis; the symptoms
onds by ventricular tachycardia, with no cardiac
output, which reverted to sinus rhythm with resolving rapidly when umazenil was with-
direct current cardioversion. The convulsion drawn [117c].
ended spontaneously after 30 seconds but
recurred within 2 minutes, again followed by Endocrine The effects of umazenil and
sustained ventricular tachycardia. This pattern
of events recurred and nine cardioversions were midazolam on adrenocorticotrophic hor-
required. The convulsions eventually resolved mone and cortisol responses to a cortico-
with intravenous diazepam and thiopental. trophin-releasing hormone challenge have
been assessed in eight healthy men [118c].
Complete heart block occurred when Flumazenil signicantly caused reduced adre-
umazenil was given to a woman who had nocorticotrophic responses compared with
taken an overdose of paracetamol and midazolam or placebo, but had no effects on
temazepam [103A]. cortisol secretion. The authors suggested that
this agonist effect of umazenil on the pitui-
Nervous system Seizures have been attri- tary-adrenal axis might account for the anxio-
buted to umazenil [104A, 105A, 106A, 107A, lytic activity of umazenil, which has been
108A, 109A, 110A, 111R], including status observed during simulated stress.
epilepticus [112A, 113A], which can be fatal.
However, it has been suggested that seizures Susceptibility factors Age The usefulness
are not a toxic effect of umazenil, but are in and relative safety of midazolam in children
many cases instead due to unmasking of the have been reviewed [119R]. Myoclonic-like
anticonvulsant effect of the benzodiazepine movements associated with midazolam in
or to a severe benzodiazepine-withdrawal syn- three full-term newborns were reversed by
drome; furthermore, in some cases they may be umazenil [120A].
due to other drugs taken at the same time, such The pharmacokinetics of umazenil are
as tricyclic antidepressants [114c]. Thus, it has not altered in elderly people [121c].
been recommended that umazenil should
not be given to patients who have used benzo- Drug withdrawal In individuals who have
diazepines for seizure disorders or to patients taken long-term benzodiazepines, umazenil
who have taken other drugs that increase the can provoke acute withdrawal reactions
risk of seizures (e.g. bupropion, ciclosporin, [122C, 123C] and extreme anxiety [124A].
cocaine, cyclic antidepressants, isoniazid, lith- Duration of exposure to the benzodiazepine
ium, methylxanthines, monoamine oxidase does not affect the intensity of withdrawal
inhibitors, and propoxyphene). beyond the rst week of exposure [125C].
82 Chapter 5 Rebecca Spencer, Stephen Curran, and Shabir Musa

In a placebo-controlled study in 34 cause excitation; a case has been reported


chronic users of diazepam 520 mg/day for with chloral hydrate [129A].
528 years, a single-dose of umazenil
caused anxiety reactions; in nine of 15 sub- Drug overdose Unintentional administra-
jects with a history of panic attacks, panic tion of a 10-fold dose of chloral hydrate
attacks were precipitated [126C]. (667 mg/kg) in a 3-month-old girl resulted
in respiratory depression, requiring intuba-
Drug administration route In six patients tion and ventilation [130A]. There were also
undergoing elective surgery during general esophagitis and gastric ulcers. The serum
anesthesia endotracheal umazenil 1.0 mg trichloroethanol concentration was 89 mg/l
in 10 ml of saline therapeutic blood concen- 6 hours later and fell to 20 mg/l within
trations were rapidly achieved [127c]. 24 hours and dialysis was not required.
In 11 patients aged 26 years undergoing
general anesthesia for dental surgery intra-
nasal drops of umazenil resulted in plasma
concentrations similar to those reported after Ramelteon [SEDA-32, 79]
intravenous administration [128c].
On 8 September 2008 the European Medi-
cines Agency announced that Takeda, the
manufacturers of ramelteon, had with-
drawn its application for marketing authori-
OTHER HYPNOSEDATIVES zation for ramelteon for the treatment of
primary insomnia in patients over the age
Chloral hydrate [SED-15, 705; SEDA- of 18 years with a view to extending its clin-
30, 52; SEDA-31, 60; SEDA-32, 79] ical programme to address outstanding
questions on the benet to harm balance;
Nervous system Paradoxical reactions to this followed a negative recommendation
hypnosedatives occur occasionally and can from the regulators in June 2008 [131r].

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zodiazepine effects by umazenil after copy. Endoscopy 1991; 23(1): 53.
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pam and opioids: report of a double-blind Fatal seizures after umazenil administra-
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[100] Short TG, Maling T, Galletly DC. Ventric- [114] Spivey WH. Flumazenil and seizures: anal-
ular arrhythmia precipitated by umazenil. ysis of 43 cases. Clin Ther 1992; 14(2):
Br Med J (Clin Res Ed) 1988; 296(6628): 292305.
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[101] Katz Y, Boulos M, Singer P, Rosenberg B. Taguchi N. Opisthotonos after umazenil
Cardiac arrest associated with umazenil. administered to antagonize midazolam
BMJ 1992; 304(6839): 1415. previously administered to treat develop-
[102] Marchant B, Wray R, Leach A, Nama M. ing local anesthetic toxicity. Anesth Analg
Flumazenil causing convulsions and ven- 1998; 86(3): 6778.
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(6703): 860. Flumazenil-induced ballism. J Korean
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efter umazenil [Convulsions after [118] Strhle A, Wiedemann K. Flumazenil atten-
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contractile seizure in poisoning by a com- [119] Aviram EE, Ben-Abraham R,
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[120] Zaw W, Knoppert DC, da Silva O. [126] Bernik MA, Gorenstein C, Vieira
Flumazenil's reversal of myoclonic-like Filho AH. Stressful reactions and panic
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kinetics in the elderly. Eur J Clin new route of administration for benzodiaz-
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Schwam EM. Intravenous umazenil fol- Kinahan AM, Dunn GS, Bourne RA,
lowing acute and repeated exposure to lor- McCormack JP. Plasma concentration of
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[123] Mintzer MZ, Stoller KB, Grifths RR. A [129] Slatt KA. Crazy with chloral hydrate: a
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Alfonso Carvajal, Luis H. Martn Arias, and
Natalia Jimeno

6 Antipsychotic drugs

GENERAL [SED-15, 2438; Dosage was a key variable in optimizing


SEDA-32, 83] effectiveness of both rst- and second-genera-
tion antipsychotic drugs. In contrast to their
relatively similar efcacy in treating positive
Typical versus atypical symptoms, there were substantial differences
antipsychotic drugs between rst- and second-generation antipsy-
chotic agents with regard to their propensity
Data from two major government-funded to cause extrapyramidal, metabolic, and other
studies of comparative antipsychotic drug adverse effects: second-generation agents are
effectiveness in schizophrenia contradict the less likely to cause acute extrapyramidal
widely prevalent belief that the newer sec- symptoms and tardive dyskinesia but have a
ond-generation medications are vastly supe- tendency to cause greater metabolic adverse
rior to the older rst-generation drugs effects than rst-generation agents.
[SEDA-30, 56; SEDA-31, 65]. The World
Psychiatry Association Section on
Pharmacopsychiatry has reviewed the litera-
ture on the comparative effectiveness of dif- Observational studies Psychiatrists attit-
ferent antipsychotic drug treatments for udes to and actual practices in using typical
schizophrenia and has issued a statement and atypical antipsychotic drugs in elderly
[1R]. They reported that antipsychotic drugs people have been audited in 321 patients
are very heterogeneous, with substantial dif- (mean age 76 years) in 18 old-age psychiatry
ferences in adverse effects proles from drug units across Australia, in which the attitudes
to drug. Second-generation antipsychotic of a sample of 57 prescribing doctors (mean
drugs were also found to be inconsistently age 46 years) were assessed [2c]. Over 96%
more effective than rst-generation agents of the doctors reported that adverse events
in alleviating negative, cognitive, and depres- were obstacles to prescribing typical anti-
sive symptoms, and were less likely to cause psychotic drugs; the most common concerns
tardive dyskinesia; these modest benets with typical drugs were related to acute
were principally driven by the ability of sec- extrapyramidal symptoms (86%), tardive
ond-generation antipsychotics to provide dyskinesia (80%), sedation (35%),
equivalent improvement in positive symp- hyperprolactinemia (18%), and weight gain
toms along with a lower risk of causing (18%). With regard to atypical drugs, 33%
extrapyramidal adverse effects. Clozapine of the doctors reported that weight gain
was shown to be more efcacious than other was an obstacle to prescribing, and they
agents in treatment-refractory schizophrenia. were concerned about olanzapine (91%),
clozapine (60%), oral risperidone (32%),
and quetiapine (25%). Despite these con-
Side Effects of Drugs, Annual 33
J.K. Aronson (Editor)
cerns, psychiatrists used the full repertoire
ISSN: 0378-6080 of antipsychotic drugs for a range of mental
DOI: 10.1016/B978-0-444-53741-6.00006-4 illness in elderly people, including more than
# 2011 Elsevier B.V. All rights reserved. 20% of off-label indications. Antipsychotic
89
90 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

drugs are currently used off-label in demen- 5.2%), dyslipidemia (11% versus 4.2%),
tia [SEDA-31, 65]. cardiovascular conditions (3.4% versus
Antipsychotic drug-induced short-term 14.2%), neurological/sensory symptoms
serious events have been assessed in a retro- (14% versus 65%), and digestive/urogenital
spective cohort study in older adults with problems (71% versus 93%); the odds of
dementia [3C]. A serious event was a com- obesity/excessive weight gain, type 2 diabetes
posite outcome dened as an event serious and dyslipidemia, digestive/urogenital prob-
enough to lead to an acute care hospital lems, and neurological/sensory symptoms
admission or death within 30 days of starting were higher in girls and those for whom
therapy. Older adults with dementia, some multiple antipsychotic drugs had been pre-
living in the community (n 20 682) and scribed. Multiple antipsychotic drugs were
others living in a nursing home (n 20 559) prescribed in 42% of the treated cohort, in
were identied. Propensity-based matching whom the adjusted OR was 2.6 (95% CI
was used to balance differences between 1.5, 4.7) for metabolic adverse events
the drug exposure groups in each setting. and 1.7 (95% CI 1.12.7) for cardio-
Among 6894 community-dwelling older vascular conditions.
adults taking atypical antipsychotic drugs, Metabolic and cardiovascular adverse
960 (14%) were classied as having had events were further studied by the same
any serious event; of those, 186 (2.7%) authors in the same sample of children
died. Relative to community-dwelling older and adolescents [7C]. Compared with the
adults with dementia who did not receive a pre- controls, the treated cohort had a higher
scription for antipsychotic drugs (n 6894), prevalence of obesity (OR 2.1), type 2
similar older adults who did receive atypical diabetes mellitus (OR 3.2), cardiovascu-
antipsychotic drugs (n 6894) were 3 lar conditions (OR 2.7), and orthostatic
times more likely (adjusted OR 3.2; 95% hypotension (OR 1.6). In the treated
CI 2.8, 3.7), and those who received a con- cohort, those who had been exposed to mul-
ventional antipsychotic drug (n 6894) 3.8 tiple antipsychotic drugs had a signicantly
times more likely, to have a serious adverse higher risk of incident obesity/weight gain
event within 30 days of starting therapy (OR 2.3), type 2 diabetes mellitus (OR
(adjusted OR 3.8; 95% CI 3.3, 4.4). The 2.4), and dyslipidemia (OR 5.3). Incident
pattern of serious events was similar but less cardiovascular events were more likely with
pronounced among older adults living in a the use of conventional antipsychotic drugs
nursing home. In a survey, only two of six (OR 4.3) and mood stabilizers (OR
published randomized controlled trials of anti- 1.3). Incident orthostatic hypotension was
psychotic drug therapy for dementia gave data more prevalent in those co-prescribed selec-
on any adverse event [4c]; in two of these trials tive serotonin reuptake inhibitors (OR
there was no information about deaths. The 1.8) and mood stabilizers (OR 1.3).
risk of death in elderly users of antipsychotic People with schizophrenia have substan-
drugs has previously been reviewed [5C]. tially increased rates of mortality than the
The incidence rates for six categories of general population because of chronic ill-
adverse events of antipsychotic drug use ness, particularly cardiovascular disease
have been compared in a retrospective [8M]. In an 11-year follow-up study of mor-
cohort study of 4140 children and adoles- tality in patients with schizophrenia (n 66
cents (mean age 10 years) and 4500 children 881), the gap in life expectancy between
(mean age 7.2 years) with similar service patients with schizophrenia and the general
encounters but not treated with psychotropic population in Finland did not widen
drugs [6c]. Six atypical and two conven- between 1996 (25 years) and 2006 (23 years)
tional antipsychotic drugs were studied. [9C, 10r]. During that time, the proportion of
The overall incidence/prevalence rates in use of second-generation antipsychotic drugs
the control and treated groups differed dra- rose from 13% to 64%. Compared with cur-
matically in obesity/weight gain (8.6% ver- rent use of perphenazine, the highest risk of
sus 20%), type 2 diabetes (1.9% versus overall mortality was recorded for
Antipsychotic drugs Chapter 6 91

quetiapine (adjusted HR 1.4; 95% CI Pzer, and Sano-Aventis, there were no


1.1, 1.8) followed by haloperidol (HR 1.4; differences between atypical antipsychotic
95% CI 1.1, 1.7) and risperidone (HR drugs and haloperidol after 1 year [12c].
1.3; 1.1, 1.6), and the lowest risk for cloza- More of those who took haloperidol had
pine (HR 0.7; 95% CI 0.6, 0.9). signs of parkinsonism than those who took
Long-term cumulative exposure (711 years) an atypical antipsychotic drug; in contrast,
to any antipsychotic drug was associated the proportion of patients who were over-
with a lower mortality than with no drug weight was higher with olanzapine than with
use (HR 0.8; 95% CI 0.77, 0.84). It is haloperidol. With haloperidol 72% of
said that the difference in mortality between patients discontinued treatment for any cause
clozapine and other antipsychotic drugs within the 12 months (dose range 14 mg/day;
might be attributable to more intensive mon- n 103), with amisulpride 40% (dose range
itoring during clozapine treatment, the 200800 mg/day; n 104), with olanzapine
greater effectiveness of clozapine, the poor 22% (520 mg/day; n 105), with quetiapine
safety of other drugs, or all these causes. 53% (200750 mg/day; n 104), and with
According to the authors, current results ziprasidone 45% (40160 mg/day; n 82).
raise the question of whether clozapine Rates of admission to hospital were 723%
should be used as a rst-line treatment, and did not differ signicantly between treat-
because it seems to be the safest antipsy- ments. Since the study was open, the psychia-
chotic drug in terms of mortality and is also trists expectations could have led to
the most effective. haloperidol being withdrawn more often.
The authors stated that it cannot be concluded
Comparative studies First- and second- that second-generation antipsychotic drugs
generation antipsychotic drugs have been are more efcacious than haloperidol in the
compared in 119 children and adolescents treatment of these patients.
(aged 819 years) with early-onset schizo-
phrenia and schizoaffective disorder [11C], Placebo-controlled studies In a study of the
who were randomized to olanzapine effect of long-term treatment with neuro-
2.520 mg/day, risperidone 0.56 mg/day, leptic drugs on global cognitive decline and
or molindone 10140 mg/day, plus neuropsychiatric symptoms in patients with
benzatropine 1 mg/day for 8 weeks; some Alzheimer's disease, 64 patients were
subjects were excluded because of a previous randomized to continue treatment with
history of non-response to a study drug. thioridazine, chlorpromazine, haloperidol,
There were no signicant differences among triuoperazine, or risperidone and 64 to pla-
the treatment groups in response rates, cebo [13c]. There was no signicant differ-
which were low in all three groups ence in global cognitive functioning or
(molindone: 50%, n 40; olanzapine: neuropsychiatric symptoms between the
34%, n 35; risperidone: 46%, n 41) or groups after 6 months. There was a higher
in the magnitude of symptom reduction. risk of parkinsonism in the treated patients,
Olanzapine and risperidone were associated but the differences were not signicant.
with signicantly greater weight gain.
Olanzapine had the greatest risk of weight Systematic reviews First-generation and
gain (average 6.1 kg) and signicant second-generation antipsychotic drugs in
increases in fasting cholesterol, low density patients with schizophrenia have been com-
lipoprotein, insulin, and liver transaminases. pared in a meta-analysis [14M] (for an in-
Akathisia led to treatment discontinuation in depth review, see SEDA-27, 50). The study
two participants taking molindone and in included 150 double-blind, mostly short-
one taking risperidone. term, randomized clinical trials with 21 533
In an open randomized study in patients participants. Four second-generation anti-
with schizophrenia, supported by the mar- psychotic drugs (amisulpride, clozapine,
keting authorization holders of some of the olanzapine, and risperidone) were better
antipsychotic drugs studied, AstraZeneca, than rst-generation ones for overall
92 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

efcacy, with small to medium effect sizes, Olanzapine was superior to aripiprazole,
which is similar to the results of a previous quetiapine, risperidone, and ziprasidone,
meta-analysis [15M]. The overall results are and its efcacy was similar to that of
not consistent with the view that second-gen- amisulpride and clozapine; risperidone was
eration drugs improve negative symptoms, more efcacious than quetiapine and
depression, and quality of life. Second-gen- ziprasidone. Clozapine and olanzapine,
eration antipsychotic drugs caused fewer followed by quetiapine and then risperidone,
extrapyramidal adverse effects than haloper- were the most likely to cause weight gain
idol (even at low doses), but only clozapine, and glucose and lipid abnormalities.
olanzapine, and risperidone caused fewer Amisulpride and risperidone carried a risk
extrapyramidal adverse effects than low- of extrapyramidal symptoms and substantial
potency rst-generation antipsychotic drugs. increases in prolactin concentrations. The
With the exception of aripiprazole and effect sizes ranged between 1.9 (olanzapine
ziprasidone, second-generation antipsych- versus risperidone) and 8.3 (olanzapine ver-
otic drugs produced more weight gain, in sus ziprasidone) PANSS points, and the
various degrees, than haloperidol but not clinical relevance of the difference between
than low-potency rst-generation drugs. olanzapine and risperidone (1.9 PANSS
The authors concluded that second-genera- points) based on a large sample size
tion antipsychotic drugs differ in many (n 2404) is particularly doubtful. For per-
properties and are not a homogeneous class. spective, the average difference between
They also suggested that public institutions second-generation antipsychotic drugs and
could save costs by funding studies to dene placebo in another meta-analysis was only
selected old compounds accurately, because 10 PANSS points [18M]. A sensitivity analy-
they were not rigorously studied at the time sis was also performed with sponsor, dose,
they were introduced. This meta-analysis study quality, treatment resistance, study ori-
merited an editorial, in which some points gin, and trial duration as moderators, and
were further emphasized [16r]; thus, the there were only a few differences; excluding
name second-generation antipsychotic studies sponsored by pharmaceutical com-
drugs would be inaccurate, as this group panies did not change the result. This is sim-
of drugs is in fact a heterogeneous mixture ilar to the result of another meta-analysis of
of compounds, some being superior to the effects of several potentially biasing fac-
others. Accordingly, the spurious invention tors (e.g. industry support, extrapyramidal
of the atypical drugs can be regarded as an adverse effects) on drug efcacy in compar-
invention, cleverly manipulated by drug ison of second-generation and rst-genera-
companies for marketing purposes. The tion antipsychotic drugs [19M].
authors mentioned that using an inadequate The effectiveness of second-generation
comparator (haloperidol) favors the atypical antipsychotic drugs has been addressed in
drugs. a systematic review of 16 randomized
Different second-generation antipsychotic head-to-head comparisons of second-gener-
drugs have been compared in another ation antipsychotic drugs [20M]. The trials
meta-analysis [17M]. The primary outcome were categorized as effectiveness studies if
measure was the change in total score on there was a statement from the authors that
the Positive and Negative Syndrome Scale a naturalistic, pragmatic, practical, or real-
(PANSS); secondary outcome measures life study design was used, or if the methods
were subscores for positive and negative section was presented in corresponding
symptoms and rates of dropout because of terms. There were differences in sample
inefcacy. The analysis included 78 random- sizes, inclusion criteria, follow-up periods,
ized studies, at least single-blind, with 167 and sources of funding. In acute episodes
relevant arms and 13 558 participants; 49 and rst episodes there were no differences
studies were mainly sponsored by pharma- between the second-generation antipsychotic
ceutical companies, 22 were publicly funded, drugs in relief of symptoms; during long-
and in seven funding was uncertain. term treatment those who used olanzapine
Antipsychotic drugs Chapter 6 93

had longer times to discontinuation of treat- Nervous system A re-analysis of the


ment and better treatment adherence com- CATIE study (n 1443) has been
pared with those who used other atypical performed in order to compare the incidence
drugs. Olanzapine was associated with of treatment-emergent extrapyramidal
more metabolic adverse effects than other effects between second-generation anti-
second-generation antipsychotic drugs. psychotic drugs and perphenazine in people
with schizophrenia [23R]. There were no sig-
nicant differences in the incidence of par-
Cardiovascular Extensive data link the kinsonism, dystonia, akathisia, or tardive
typical antipsychotic drugs with an dyskinesia. The probabilities of tardive
increased risk of sudden cardiac death dyskinesia event within 1 year in people
[SEDA-24, 54; SEDA-30, 56]. The adjusted with no tardive dyskinesia at baseline, with
incidence of sudden cardiac death among adjustment for baseline co-variates, were:
current users of single antipsychotic drugs olanzapine 0.01 (95% CI 0.002, 0.03); per-
has been estimated in a retrospective phenazine 0.03 (95% CI 0.01, 0.07);
cohort of Tennessee Medicaid enrolees quetiapine 0.02 (95% CI 0.001, 0.06);
[21C]. Current users of both typical drugs and risperidone 0.01 (95% CI 0.004,
(n 44 218) and atypical drugs (n 0.04). There were greater rates of concomi-
46 089) had greater rates of sudden cardiac tant antiparkinsonian medication among
death than non-users (n 186 600), with individuals taking risperidone and lower
adjusted incidence-rate ratios for use of rates among individuals taking quetiapine;
2.0 (95% CI 1.7, 2.3) and 2.3 (1.9, 2.7) there were lower rates of withdrawal
respectively. For typical antipsychotic drugs because of parkinsonism among people tak-
the risk increased from 1.3 (1.0, 1.8) for low ing quetiapine or ziprasidone. There was a
doses to 2.4 (1.9, 3.1) for high doses; for trend to a greater likelihood of concomitant
atypical agents the risk increased from 1.6 medications for akathisia among individuals
(1.0, 2.5) for low doses to 2.9 (2.2, 3.6) for taking risperidone and perphenazine. The
high doses. The incidence-rate ratios for authors suggested that previous reports of a
atypical versus typical antipsychotic drugs relatively lower incidence of extrapyramidal
was 1.1 (0.3, 1.4). The authors suggested symptoms with second-generation anti-
that antipsychotic drugs increase the risk psychotic drugs were likely to be related to
of serious ventricular dysrhythmias, proba- the use of higher dosages of the high-
bly through blockade of potassium potency rst-generation antipsychotic drug,
channels and prolongation of cardiac haloperidol. One of the limitations pointed
repolarization. out in the study was the relatively short dura-
Changes in the 10-year risk of coronary tion of exposure.
heart disease have been compared between Neurological adverse events associated
treatment groups in 1125 patients followed with antipsychotic drug use in children and
for 18 months or until treatment discontinu- adolescents have been studied retrospec-
ation in the Clinical Antipsychotic Trials tively using medical and pharmacy claims
of Intervention Effectiveness (CATIE) from one state's Medicaid program [24C].
in schizophrenia [22C]. The mean change The incidence rates for these events in
in 10-year coronary heart disease risk dif- 4140 children who were taking anti-
fered signicantly between treatments. psychotic drugs (mean age 10 years) and
Olanzapine was associated with a 0.5% an untreated sample of 4500 children
increase and quetiapine with a 0.3% (mean age 7.2 years) were compared. The
increase, while the risk fell in patients who treated cohort had a higher prevalence of
used perphenazine (0.5%), risperidone involuntary movements (OR 6.2; 95%
( 0.6%), and ziprasidone (0.6%). The CI 4.5, 8.3), sedation (OR 1.8; 95%
difference in 10-year coronary heart disease CI 1.2, 2.3), and seizures (OR 6.2;
risk between olanzapine and risperidone 95% CI 5.3, 7.7). The odds of incident
was statistically signicant. involuntary movements were signicantly
94 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

higher in those taking aripiprazole, risperi- Weight gain and diabetes mellitus
done, haloperidol, and multiple antipsy- due to antipsychotic drugs
chotic drugs; the odds of incident seizures
were greater for those taking risperidone
and multiple antipsychotic drugs; the odds EIDOS classication:
of incident sedation were greater for those Extrinsic moiety Antipsychotic drugs
taking ziprasidone, risperidone, quetiapine, Intrinsic moiety [?]H1, M3, and 5-HT2C
and multiple antipsychotic drugs. Exposure receptors
to risperidone and multiple antipsychotic Distribution Adipocytes and other cells
drugs consistently confers a higher risk Outcome Altered physiology (leptin
of a range of neurological adverse events secretion, insulin resistance,
in young patients, especially those with impaired glucose tolerance)
pre-existing central nervous system or car- Sequela Weight gain and diabetes
diovascular disorders or mental retardation. mellitus due to antipsychotic drugs
Levetiracetam, the levorotary stereo-
isomer of an ethylated congener of pirace- DoTS classication:
tam, was effective in the treatment of Dose-relation Collateral reaction
tardive dyskinesia in a randomized, double- Time-course Intermediate
blind, placebo-controlled study [25c]. The Susceptibility factors Genetic
levetiracetam/placebo difference reached a (AfricanAmerican origin; the
trend level by week 4 and was statistically sig- 102T allele of HTR2A, the 825T
nicant at weeks 6, 9, and 12; at week 12 the allele of GNB3, the 23Cys allele of
AIMS total score model-estimated marginal HTR2C, and the 64Arg/Arg
mean in the levetiracetam group dropped genotype of ADRB3; see Table 1);
44% from baseline, and the placebo group sex (male)
estimated mean fell 19%. Overall adverse
effects were similar in the two groups; since
there have been reports of leukopenia, The potential interactions between atypi-
neutropenia, pancytopenia, and thrombo- cal antipsychotic drugs and several hor-
cytopenia in patients taking levetiracetam, mones that affect appetite regulation and
particular attention was given to these reac- carbohydrate metabolism have been
tions: in no patient did the white blood cell reviewed [27r]. The effects of atypical anti-
count fall below 2.8  109/l, the neutrophil psychotic drugs on carbohydrate intolerance
count below 1.0  109/l, or the platelet count and the development of diabetes show that
below 75  109/l. they produce abnormalities in glucose toler-
ance by altering appetite regulation, insulin
secretion and action, and the release of insu-
Sensory systems Typical antipsychotic lin counter-regulatory hormones, in particu-
drugs, mainly phenothiazines, have been lar leptin and ghrelin; high concentrations of
associated with cataract formation [SEDA- those hormones have been observed in
24, 57]. There were lenticular opacities in patients taking atypical antipsychotic drugs.
21 of 52 patients who used typical anti- Receptor-binding proles of different anti-
psychotic drugs and in 5 of 28 patients psychotic drugs may also help explain the
who used atypical antipsychotic drugs occurrence of some metabolic adverse effects
[26c]. Patients who used typical antipsy- associated with each drug [28r]. Thus, drug
chotic drugs had earlier mental illness afnity at histamine H1 receptors is linked
onset, had used antipsychotic drugs for lon- to weight gain; this is consistent with data
ger periods, had used higher doses, and demonstrating that histamine H1 receptor
were older. No pigment deposition was antagonism promotes feeding in rodents
found, neither in the cornea nor in the ret- and that H1 knockout mice are susceptible
ina of these patients. to weight gain. It has also been observed that
atypical orexigenic antipsychotic drugs
Antipsychotic drugs Chapter 6 95

reverse the actions of leptin, an anorexigenic ( 0.25 mmol/l) compared with ziprasidone
hormone. Drug afnity for H1, M3, and ( 0.35 mmol/l).
5-HT2C receptors correlates with an Consistent results were found in a study
increased risk of diabetes. The receptor- carried out in India, in which all consecutive
binding proles that correlate with antipsy- drug-nave patients with a rst episode of
chotic drug-associated dyslipemia are not schizophrenia (n 99) were recruited into
well understood; however, it has been a randomized, double-blind, controlled
suggested that peroxisome proliferator-acti- study; the prevalence of metabolic syndrome
vated receptor (PPAR) agonists may convey after 6 months (10% and 18% as assessed
therapeutic benet. by ATPIA and International Diabetes Fed-
eration criteria respectively) was ve times
Metabolic syndrome The metabolic syn- as high compared with the matched healthy
drome is highly prevalent among patients control group [31c]. Olanzapine had a max-
with schizophrenia, due in part to medica- imum prevalence of metabolic syndrome at
tions. The metabolic syndrome is a cluster 2025% (n 35), followed by risperidone
of metabolic abnormalities (glucose intoler- at 924% (n 33) and haloperidol at
ance, hypertension, obesity) in a single 03% (n 31).
subject. These abnormalities dene a contin- In a prospective study, fasting serum and
uum of risk, and those who have more fea- anthropometric measures were obtained
tures of this syndrome appear to be more from 45 patients with rst-episode psychosis
predisposed to type 2 diabetes mellitus and and 41 healthy adults of similar age, ethnic-
cardiovascular disease. The nding of differ- ity, and sex [32c]. At baseline, the distribu-
ential metabolic proles for atypical anti- tions of cardiovascular risk markers were
psychotic drugs has been conrmed in similar and the percentages of young
numerous prospective studies [29R]; accord- patients with rst-episode psychosis and
ingly, the parameters that are most healthy controls who were overweight/obese,
inuenced by treatment with metabolically dyslipidemic, hyperglycemic, and
offending medications are weight, serum tri- hyperinsulinemic did not differ. At 24 weeks,
glycerides, and measures of glycemic con- compared with baseline, 16 of the patients
trol, with substantially less effect on serum with psychosis who continued to take the
HDL cholesterol or blood pressure. same antipsychotic medication had statisti-
The change in the proportion of subjects cally signicant increases in BMI, glucose,
with the metabolic syndrome and individual insulin, cholesterol, leptin, and E-selectin,
criteria has been compared between anti- and a reduction in adiponectin.
psychotic drugs, along with mean changes Patients with bipolar disorder and schizo-
for individual criteria in phase 1 of the phrenia who are treated with second-genera-
CATIE schizophrenia study [30C]. Among tion antipsychotic drugs had similar high
all subjects whose metabolic syndrome sta- rates of the metabolic syndrome in a retro-
tus could be determined at 3 months (n spective comparison of different metabolic
660), the prevalence of the metabolic syn- parameters [33c]. The prevalence of meta-
drome increased for olanzapine (from 35% bolic syndrome in a matched and randomly
to 44%), but decreased for ziprasidone selected sample was 43% in bipolar disorder
(from 38% to 30%). Although effect sizes (n 74) and 46% in schizophrenia
varied across subgroups, at 3 months (n 111).
olanzapine and quetiapine had the largest
mean increases in waist circumference (0.7
inches for both) followed by risperidone Diabetes mellitus [SEDA 28, 60; SEDA-30,
(0.4 inches), compared with no change for 58; SEDA-31, 67; SEDA-32, 87] The preva-
ziprasidone and a reduction in waist lence of detected diabetes in the general pop-
circumference for perphenazine (0.4 ulation is around 34%; type 2 diabetes
inches). Olanzapine also had signicant accounts for 8590% of all cases and results
effects on fasting triglycerides at 3 months from a combination of insulin resistance and
96 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

relative insulin deciency. The prevalence of taking second-generation antipsychotic


type 2 diabetes in patients with schizophre- drugs, owing to greater clinical awareness.
nia has been estimated at 9% [34C]. Atypical
antipsychotic drugs have been linked to a Triglycerides Atypical antipsychotic drugs
higher risk of glucose intolerance, and con- have been linked to hyperlipidemia [SEDA-
sequently development of type 2 diabetes 30, 58]. Taking advantage of the data gath-
mellitus. The acute effects of oral administra- ered in the CATIE study [SEDA-30, 56],
tion of olanzapine and ziprasidone on whole- the effects of antipsychotic drugs on triglycer-
body insulin sensitivity in healthy subjects ides have been explored [38R]. In 246 subjects
have been investigated [35c] using the stan- there were signicant treatment differences in
dardized hyperinsulinemic euglycemic clamp the 3-month change from baseline; the
technique in 29 healthy male volunteers who greatest increases in median and adjusted
took either olanzapine 10 mg/day (n 14) mean non-fasting triglycerides concentrations
or ziprasidone 80 mg/day (n 15) for were seen among those randomized to
10 days. Olanzapine caused a signicant quetiapine (mean 0.62 mmol/l) and
reduction in mean whole-body insulin sensi- olanzapine (mean 0.26 mmol/l).
tivity from 5.7 ml/hour/kg at baseline to Ziprasidone had no effect. There were reduc-
4.7 ml/hour/kg; ziprasidone had no effect tions with risperidone (mean 0.21 mmol/l)
(5.2 ml/hour/kg versus 5.1 ml/hour/kg). and perphenazine (mean 0.1 mmol/l).
In another study, medication-nave Raised triglycerides due to olanzapine
patients with schizophrenia were ran- usually involve weight gain accompanied
domized to olanzapine (n 35), risperi- by insulin resistance. However, serum tri-
done (n 33), or haloperidol (n 31) glyceride concentrations can rise without
[36c]. After 6 weeks, there were signicant weight gain or abnormal glucose metabo-
increases in weight, fasting blood sugar, lism [39A, 40A].
and 2-hour postprandial blood sugar
between the matched healthy control group Weight gain [SEDA-32, 87] In the CATIE
(n 51; mean age, 28 years) and the treat- study (see SEDA-30, 56), there was weight
ment group as a whole (n 99; mean age gain of 7% or more in 30% of patients with
26 years). There was also a signicant schizophrenia taking olanzapine 7.530 mg/
increase in the incidence of diabetes mellitus day; the amount of weight gain induced by
at end-point by the WHO criteria (10%; olanzapine was much greater than that
olanzapine, n 3; risperidone, n 3; halo- induced by quetiapine, risperidone, or
peridol, n 3). ziprasidone. There were statistically signi-
The risks of diabetes with different anti- cant differences in weight gain at 3 months
psychotic drugs have been compared in a with olanzapine, risperidone, and haloperi-
meta-analysis of 11 studies in people with dol in a randomized study of drug-nave
schizophrenia or related disorders, including patients [41C]. At 3 months there were
cross-sectional studies, casecontrol studies, increases of 3.8 kg for haloperidol (n 46),
cohort studies, and controlled trials [37M]. 5.9 kg for risperidone (n 52), and 8.4 kg
The relative risk of diabetes in patients with for olanzapine (n 49); after 1 year, the
schizophrenia taking one of the second-gen- difference in weight gain had disappeared:
eration versus rst-generation antipsychotic 9.7 kg for haloperidol (n 24), 8.9 kg for
drugs was 1.3 (95% CI 1.1, 1.5). risperidone (n 35), and 10.9 kg for
According to the authors, there were meth- olanzapine (n 36). The ndings, contrary
odological limitations in most of the studies, to those reported in other studies, were
leading to heterogeneity and difculty in explained by the authors as being due to
interpreting the data; they pointed out that differences in follow-up periods.
one residual confounder not reported in The effects of antipsychotic drugs (halo-
any of the studies was whether an increased peridol, olanzapine, and risperidone) on
amount of screening occurred in those peptides involved in energy balance (insulin,
Antipsychotic drugs Chapter 6 97

ghrelin, leptin, adiponectin, visfatin, and 23Cys allele of HTR2C, and the 64Arg/Arg
resistin) have been studied in 70 drug-nave genotype of ADRB3, were signicantly
patients with a rst episode of psychosis associated with olanzapine-induced weight
[42C]. There were signicant increases in gain. Stepwise regression analysis showed
weight (10.2 kg), body mass index (3.56 kg/ that the baseline BMI predicted 13% of the
m2), and fasting plasma insulin (3.93 mU/ weight gain, and the two latter genetic factors
ml), leptin (6.76 ng/ml), and ghrelin (15.47 added 6.8%. The patients with double and
fmol/ml) concentrations. The increments in triple genetic risk factors had 5.1% and
insulin and leptin concentrations correlated 8.8% increases in BMI respectively; the
with the increments in weight and body mass patients with a single or no risk factor had
index and seem to have been a consequence about a 1% increase.
of higher fat stores; the three antipsychotic In a review of the use of pharmacogenetic
drugs had similar effects on all the parameters testing to predict the likelihood of some
evaluated. The authors suggested that the adverse drug reactions the authors empha-
unexpected increase in ghrelin concentrations sized that the mechanisms of olanzapine-
might have been causally related to weight induced weight gain may involve the gene
gain from antipsychotic drugs. for 5-HT2C receptors; other candidate genes
Prescription of second-generation anti- that may be associated with olanzapine-
psychotic drugs has increased dramatically induced weight gain include CYP2D6, the
in recent years in children [SEDA-31, 66], synaptosomal-associated protein of 25 kDa
in whom metabolic effects, and weight gain (SNAP25), G-protein beta 3 subunit gene
in particular, are supposed to be greater than (GNB3), the alpha2a-adrenergic receptor
in adults. The metabolic and hormonal (ADRA2A), leptin (LEP), and the leptin
adverse effects in children and adolescents receptor (LEPR) [45R]. For a summary of
(mean age 15 years) after 6 months of treat- other genetic factors that have been investi-
ment have been evaluated [43c]. After gated in relation to antipsychotic drug-
6 months, BMI increased signicantly in induced metabolic reactions, see Table 1.
those taking olanzapine (baseline 22.7 kg;
change 3.7 kg; n 20) and risperidone Management The effects of lifestyle inter-
(baseline 21.8 kg; change 1.4 kg; n 22), vention and metformin, alone and in combi-
but not in those taking quetiapine (baseline nation, for antipsychotic-induced weight
21.5 kg; change 0.9 kg; n 24). Mean total gain and abnormalities in insulin sensitivity,
cholesterol concentrations increased signi- have been evaluated in a randomized con-
cantly in patients receiving olanzapine trolled trial in adult Chinese patients with
(baseline 4.1 mmol/l; change 0.27) and schizophrenia [53c]. Those who gained
quetiapine (baseline 4.2; change, 0.38). more than 10% of their predrug weight
within the rst year of treatment with cloza-
Susceptibility factors Genetic factors associ- pine, olanzapine, risperidone, or sulpiride
ated with olanzapine-induced weight have were assigned to one of four groups, in
been studied in Japan [44C]. Patients with which patients continued their antipsychotic
schizophrenia (n 164) took olanzapine drug treatment and were randomly assigned
(mean dose 15.5 mg/day) for 824 weeks. for 12 weeks to placebo (n 32), 750 mg/
BMI rose by a mean of 4.3%. Olanzapine- day of metformin alone (n 32), 750 mg/
induced weight gain correlated negatively day of metformin and lifestyle intervention
with baseline BMI and positively with clini- (n 32), or lifestyle intervention only
cal global improvement and the length of (n 32). All patients with rst-episode
olanzapine treatment, but did not correlate schizophrenia maintained relatively stable
with the daily dose of olanzapine, concomi- psychiatric improvement. The lifestyle-plus-
tant antipsychotic drugs, sex, age, or metformin group had a mean reduction in
smoking. Among 21 polymorphisms exam- BMI of 1.8 (95% CI 1.3, 2.3), the metfor-
ined, four genetic variants, the 102T allele min-alone group had a mean reduction in
of HTR2A, the 825T allele of GNB3, the BMI of 1.2 (95% CI 0.9, 1.5), and the
Table 1 Genetic factors and antipsychotic drug-induced metabolic reactions

Antipsychotic
drug/reaction Genetic factor No. Comments Ref.

Several antipsychotic 5-HT2C receptors 123 Conicting results SEDA-27, 53


drugs/weight gain
Olanzapine/weight gain CYP2D6 11 Association SEDA-27, 61
Olanzapine/weight gain 5-HT2C receptors (759C/T) 42 Possible protective effect of the T allele SEDA-30, 66
Clozapine/weight gain ADRA2A (1291C/G) 91 GG associated with a higher risk SEDA-30, 63
Olanzapine/weight gain ADRA2A (1291C/G) 62 G allele associated with a higher risk SEDA-31, 85
Olanzapine/weight gain Apolipoproteins E and A4 and scavenger 67 Weight proles signicantly associated SEDA-32, 103
receptor class B, member 1
Olanzapine/weight gain L/S promoter (SERTPR) and l/s intron 2 (SERTin2) 94 S SERTPR allelic variant and SS genotype was SEDA-32, 103
genetic variants of serotonin transporter (SERT) associated with signicantly higher weight gain
polymorphisms
Olanzapine/weight gain 102T allele of HTR2; 825T allele of GNB3, the 23Cys 164 Association [44c]
allele of HTR2C; 64Arg/Arg genotype of ADRB3
Olanzapine/weight gain Leptin gene (LEP) (AG 2548) 74 Weight gain was signicantly higher for patients with [46c]
the AG genotype than for those with the AA genotype
(Korean patients)
Olanzapine/weight gain LEP- and LEPR 200 LEPR Q223R polymorphism may be associated with [47c]
obesity in women with a psychotic disorder treated
with atypical antipsychotic drugs
Atypical drugs/metabolic 5-HT2C receptors (759C/T) and leptin 134 Higher risk in those carrying the leptin 2548A/G [48c]
disturbances (2548A/G) allele within the high risk group carrying the
5-HT2C receptor gene 759C/CC
Several atypical drugs/ Acetyl-coenzyme A carboxylase alpha SNP 357 These genes may be promising candidates for studies [49c]
hyperlipidemia, direct (rs4072032); neuropeptide Y (rs1468271); of the direct effects of some antipsychotic drugs on
effects ACCbeta (rs2241220) hyperlipidemia
Atypical drugs/metabolic MTHFR 677C/T and 1298A/C genotype 58 MTHFR 677C/T variant may predispose patients to [50c]
syndrome metabolic complications
Clozapine/weight gain Genes involved in the SREBP activation of fatty 160 Strong association between three markers localized [51c]
acids and cholesterol production (SREBF1, within or near the INSIG2 gene (rs17587100,
SREBF2, SCAP, INSIG1, and INSIG2) rs10490624, and rs17047764) and antipsychotic drug-
related weight gain
Several antipsychotic Alpha1A-adrenoceptor gene (563C/T, 4155G/C, 427 The results do not support a major role of alpha1A- [52c]
drugs/obesity and 4884A/G) adrenoceptor genetic variants in obesity
Antipsychotic drugs Chapter 6 99

lifestyle-plus-placebo group had a mean INDIVIDUAL DRUGS


reduction in BMI of 0.5 (95% CI 0.3,
0.8); however, the placebo group had a Amisulpride [SED-15, 173; SEDA-31,
mean increase in BMI of 1.2 (95% CI
69; SEDA-32, 92]
0.9, 1.5). There were no signicant differ-
ences in the frequencies and types of adverse
Observational studies In an open study, 29
effects among the groups.
patients were treated with a wide range of
The benecial effect of metformin alone
doses of amisulpride (501200 mg/day) [58c].
had already been seen in a previous dou-
After 2 weeks, brain single photon emission
ble-blind study by the same authors [54c],
tomography scans were performed 2 hours
in which 40 in-patients with schizophrenia
after intravenous injection of 185 MBq of
were randomized for 12 weeks to
(123I)IBZM iodobenzamide. D2 receptor
olanzapine 15 mg/day plus metformin
blockade correlated with doses and plasma
750 mg/day (n 20) or olanzapine 15 mg/
concentrations of amisulpride; there was no
day plus placebo (n 20). Of the 40
correlation between the clinical response
patients, 37 completed treatment; all had a
and striatal D2 occupancy. There were extra-
restricted diet. Metformin attenuated the
pyramidal adverse effects, which had to be
increases in weight (0.5 kg versus 5.4 kg),
treated with biperiden, in 31% of the patients.
BMI (0.1 versus 1.8), waist circumference
(0.3 cm versus 1.2 cm), and waist-to-hip
ratios (0.003 versus 0.184).
In a meta-analysis of randomized controlled
trials adjunctive non-pharmacological inter- Aripiprazole [SEDA-30, 61; SEDA-31,
ventions, either individual or group interven-
70; SEDA-32, 93]
tions or cognitive-behavioral therapy, and
nutritional counselling were similarly effective
Placebo-controlled studies In a 6-week
in reducing or attenuating antipsychotic drug-
multicenter, double-blind, randomized,
induced weight gain and treatment effects were
placebo-controlled study, patients aged
maintained during follow-up [55M].
1317 years with schizophrenia were
assigned to aripiprazole (10 mg/day,
n 100; 30 mg/day, n 102) or placebo
Urinary tract Drug-induced urinary reten- (n 100) [59C]. At the end of the study,
tion has been reviewed, emphasizing the both doses of aripiprazole signicantly
anticholinergic activity of some anti- reduced PANSS total scores. Adverse
psychotic drugs [56r]. events that occurred in more than 5% of
subjects in either aripiprazole group and
Sexual dysfunction Ischemic priapism, pain- with a combined incidence at least twice
ful and persistent penile erection unrelated the rate for placebo were extrapyramidal
to sexual desire or stimulation, has been disorders, somnolence, and tremor. Mean
described in association with antipsychotic changes in prolactin concentrations were
drugs [SEDA-24, 59; SEDA-28, 64]. Four 8.5, 12, and 15 ng/ml for placebo and
men aged 2555 years developed priapism for 10 and 30 mg of aripiprazole respec-
while taking antipsychotic drugs tively. Mean body weight changes were
(amisulpride, clozapine, levomepromazine, 0.8, 0.0, and 0.2 kg for placebo and for
olanzapine, pipotiazine, risperidone, or 10 and 30 mg of aripiprazole respectively.
zuclopenthixol) [57A]; they were treated Aripiprazole has been previously com-
with aspiration and irrigation of the corpora pared with placebo in patients with bipolar
cavernosa with sympathomimetic drugs, I disorder [SEDA-31, 74]. Now the results
followed in one case by a surgical distal of several studies in such patients have
cavernoglandular shunt; all cases resolved. emerged. In a 100-week, double-blind, pla-
cebo-controlled study in 28 patients with
100 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

rapid-cycling bipolar disorder the most signicantly more frequently among those
common adverse reactions to aripiprazole taking aripiprazole (19%) than among those
( 10% incidence and twice the placebo taking placebo (5.4%). There were no signi-
rate) were anxiety (n 4), sinusitis (n 4), cant differences between treatments in weight
depression (n 3), and upper respiratory changes.
infection (n 3) [60C]. One patient with- The efcacy and safety of adjunctive
drew because of akathisia. There were no aripiprazole added to standard antidepres-
signicant between-group differences in sant therapy in 736 patients with major
mean changes in weight or metabolic depressive disorder with anxious/atypical
parameters. However, the results of this features at baseline have been evaluated
study were seriously limited by the fact that [63C]. Data from two identical 14-week
only 12 patients completed the initial 26- studies (an 8-week prospective antidepres-
week treatment period and only three com- sant treatment phase and a 6-week random-
pleted the 100-week double-blind period. ized, double-blind phase) were used.
Re-analyses of the results of two random- Patients who took aripiprazole had signi-
ized, 3-week, exible-dose, double-blind, cantly greater improvement in Montgom-
placebo-controlled trials in subpopulations ery-Asberg Depression Rating Scale
of patients with acute mania or mixed epi- (MADRS) total scores than patients taking
sodes of bipolar I disorder have been placebo. Treatment-emergent adverse
performed [61C]. Aripiprazole signicantly effects that occurred in 5% of patients
reduced mean Young Mania Rating Scale were akathisia (25% aripiprazole; 4% pla-
(YMRS) total scores at end-point compared cebo), restlessness (12% versus 2%), fatigue
with placebo and in three subgroups (8% versus 4%), insomnia (8% versus 2%),
stratied by baseline severity of depressive and blurred vision (6% versus 1%). An
symptoms using the Montgomery-Asberg analysis of weight change over the course
Depression Rating Scale (MADRS). In the of double-blind treatment showed that the
overall population, the most common increase was greater with aripiprazole
adverse reactions to aripiprazole (n 263), (1.611.83 kg) than placebo (0.220.48 kg).
which occurred in  5% of patients and were In a 12-week, multicenter, randomized,
at least twice the rate of the placebo group (n double-blind, placebo-controlled trial of
260) were somnolence (aripiprazole 21% aripiprazole in the treatment of alcoholism
versus placebo 8%), dyspepsia (19% versus in 295 subjects, aripiprazole produced more
9), akathisia (14% versus 5%), and acciden- positive subjective effects and less overall
tal injury (9% versus 2%). severity of alcohol dependence than pla-
In a multicenter study, out-patients were cebo, although there was no difference
randomly assigned to adjunctive between aripiprazole and placebo on the pri-
aripiprazole (15 or 30 mg/day; n 253) mary end-point, possibly because of dose-
or placebo (n 131) for 6 weeks [62C]. related attrition (treatment was started at
They had had a manic or mixed episode 2 mg/day and titrated to a maximum
(with or without psychotic features) with of 30 mg/day at day 28). Withdrawals
partial non-response to lithium/valproate (40% versus 27%) and treatment-related
monotherapy and with target serum con- adverse effects (83% versus 64%) were
centrations of lithium (0.61.0 mmol/l) more common with aripiprazole. The most
or valproate (50125 mg/l). Improvement common treatment-related adverse events
was signicantly greater with aripiprazole that differed signicantly between
than with placebo. Withdrawal rates due aripiprazole and placebo were: fatigue,
to adverse reactions were higher with insomnia, restlessness, somnolence, anxiety,
aripiprazole than with placebo (9% versus and altered attention; serious adverse reac-
5% respectively). Akathisia was the most fre- tions attributed to aripiprazole were chest
quently reported extrapyramidal symptom- pain, cellulitis, migraine, and thrombosis;
related adverse reaction, and it occurred extrapyramidal adverse reactions attributed
Antipsychotic drugs Chapter 6 101

to aripiprazole were akathisia (6%), tremor other antipsychotic drugs [SEDA-31, 76].
(3.4%), and dyskinesias (1.4%). In a new case, neuroleptic malignant syn-
drome occurred when aripiprazole was
Observational studies In a 6-week, pro- added to olanzapine [67A].
spective, unrandomized, open study in 20
patients with acute bipolar depression, In a 33-year-old man taking olanzapine 10 mg/
aripiprazole up to a maximum of 30 mg/ day aripiprazole and benzatropine were
added; after 2 weeks the dose of aripiprazole
day improved Montgomery-Asberg was increased from 5 to 10 mg/day and shortly
Depression Rating Scale (MADRS) and afterwards the patient developed sweating, a
Mania Rating Scale (MRS) scores signi- raised temperature, tachycardia, and muscle
cantly [64c]. The most frequent adverse rigidity, with raised alanine aminotransferase,
aspartate aminotransferase, and creatine
reactions were nausea and akathisia; two phosphokinase (peak 3210 U/l).
patients withdrew because of akathisia.
In an open 16-week study of the efcacy Reduced choreiform movements have been
and tolerability of aripiprazole in 85 reported when a 47-year-old man with
patients with bipolar disorder and acute Huntington's disease was given aripiprazole
depression inadequately responsive to a 20 mg/day for 2 weeks; his gait became sta-
mood stabilizer there were signicant ble, enabling him to walk smoothly without
reductions in mean MADRS and Clinical assistance [68A].
Global Impression-Severity (CGI-S) scales
[65c]. Three patients withdrew because of
Endocrine Aripiprazole is said to stabilize
adverse reactions, the most common of
the dopaminergic system and thus amelio-
which was akathisia, which occurred in
rate schizophrenic symptoms without
21% of subjects; there was also a statisti-
increasing serum prolactin [SEDA-31, 76].
cally non-signicant weight gain (0.9 kg).
Prolactin concentrations and sexual func-
The effectiveness and cognitive effects of
tion in schizophrenic patients have been
aripiprazole (mean dose 6.7 mg/day) have
evaluated in an open, 26-week, multicenter
been assessed in a 6-week, open study in
study, in which 555 patients were random-
23 children with attention-decit/hyper-
ized to aripiprazole (n 284) or standard
activity disorder [66c]. There was overall
care (olanzapine, quetiapine, or risperi-
signicant improvement from baseline on
done; n 271) [69C]. At 8 weeks, those
attention-decit/hyperactivity disorder and
who took aripiprazole reported signicantly
functional outcome measures. The most
greater improvement in sexual function.
common adverse events were sedation
Baseline mean serum prolactin concentra-
(n 18), headache (n 11), nausea (n
tions were similar in the two groups (434
7), increased appetite (n 6), musculoskele-
and 423 mg/l respectively); however, at
tal pain (n 6), stomach ache (n 5), hic-
week 26, the mean fall in serum prolactin
cups (n 4), and u-like symptoms (n
was 342 mg/l with aripiprazole compared
4). There was a signicant increase in
with 133 mg/l with the other treatments.
weight, with an increase from a mean of
37.6 kg at baseline to a mean of 39.6 kg at
end of the study. Susceptibility factors Hepatic or renal
impairment Two open, single-dose studies
Nervous system Aripiprazole has been pre- have been conducted to investigate whether
viously associated with neuroleptic malig- the pharmacokinetics of aripiprazole are
nant syndrome but with doubts about the altered in individuals with hepatic or renal
validity of the diagnoses. However, impairment [70c]. In study 1, six subjects with
postmarketing pharmacovigilance schemes normal hepatic function and 19 with hepatic
in Australia have collected a higher propor- impairment (mild, n 8; moderate, n 8;
tion of cases of neuroleptic malignant syn- severe, n 3) received a single dose of
drome with aripiprazole compared with aripiprazole 15 mg. The same dose was used
the total number of reports received for in study 2, in seven patients with normal
102 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

renal function and six with severe renal Clozapine [SED-15, 823; SEDA-30, 61;
impairment. There were no differences in SEDA-31, 78; SEDA-32, 94]
aripiprazole pharmacokinetics in either
study. Comparative studies Clozapine and
olanzapine The efcacy and safety of cloza-
Drugdrug interactions pine (300 mg/day; n 18) and olanzapine
(up to 30 mg/day; n 21) have been evalu-
Cocaine Six cocaine-dependent subjects
ated in a 12-week double-blind study of
were given aripiprazole 15 mg/day and pla-
treatment-refractory children and adoles-
cebo for 10 days in counterbalanced order
cents with schizophrenia aged 1018 years
before assessment of the physiological and
[73C]. Signicantly more clozapine-treated
subject-rated effects of intranasal cocaine
adolescents met response criteria (66%)
[71c]. Intranasal cocaine produced proto-
compared with the olanzapine-treated sub-
typical stimulant-like effects (for example,
jects (33%); clozapine was also superior to
increased blood pressure and heart rate,
olanzapine in terms of reductions in the psy-
increased subject ratings of Like Drug and
chosis cluster scores and negative symptoms
Stimulated) and aripiprazole enhanced
from baseline to end-point. Signicant weight
these effects. The authors concluded that
gain and metabolic abnormalities were major
although these results suggest that
problems associated with both treatments.
aripiprazole is safe and tolerable when
Five of 39 subjects (three taking clozapine
combined with cocaine, enhancement of
and two taking olanzapine) gained more than
the effects of cocaine during maintenance
7% of their baseline body weight, and nine
is not desirable.
(four taking clozapine and ve taking
olanzapine) had newly emergent fasting tri-
Metamfetamine The results of a double- glyceride concentrations over 1.24 mmol/l.
blind study of potential interactions of Furthermore, ve patients, all taking cloza-
intravenous metamfetamine (15 and pine, had serious adverse events and/or
30 mg) with oral aripiprazole (15 mg) have discontinued treatment because of adverse
been published [72C]. The effects of reactions neutropenia, upper bowel obstruc-
aripiprazole on abstinence-related craving tion, increased thirst and polyuria, weight
and cue-induced craving were also evalu- gain (3.2 kg), and drug-induced diabetes (glu-
ated. Participants included non-treatment- cose 8.0 mmol/l). Subsequently, 33 patients
seeking metamfetamine-dependent patients (14 taking clozapine and 19 taking
who took aripiprazole (n 8) or placebo olanzapine) were available for a 12-week
(n 8) for 2 weeks. Aripiprazole had no open extension study [74c]. The incidence of
effect on cue-induced metamfetamine crav- hypertriglyceridemia, dened as fasting tri-
ing, but was associated with increased crav- glycerides over 1.41 mmol/l (10/14), and the
ing independent of metamfetamine dose, incidence of prediabetes, dened as a fasting
euphoria, and amphetamine-like effects blood glucose of 5.5 mmol/l or more (4/
after metamfetamine. Aripiprazole reduced 14 29%), at week 24 in the clozapine-
the increase in systolic blood pressure treated subjects were high. However, 7 of 10
after metamfetamine, but it had no other young patients with schizophrenia who failed
effects on cardiovascular responses to treatment with olanzapine responded in a 12-
metamfetamine. Aripiprazole did not alter week, open trial of clozapine.
the pharmacokinetics of metamfetamine.
The adverse events tended to be equally dis-
tributed between the two groups, except for Clozapine, olanzapine, and haloperidol In
tremor (n 4) and restlessness (n 3), a randomized, double-blind, parallel-group,
which were more common in those who took 12 week study, 100 physically aggressive
aripiprazole. in-patients with schizophrenia were given
clozapine (n 33), olanzapine, (n 34),
Antipsychotic drugs Chapter 6 103

or haloperidol (n 33) [75C]. Olanzapine Iloperidone


was associated with better cognitive func-
tion relative to haloperidol and clozapine, Iloperidone is a novel antipsychotic drug
and this improvement was associated with which is a mixed dopamine D2/serotonin
a reduction in aggressive behavior. There 5-HT2A receptor antagonist. In 2008, the
were no differences among the groups in US Food and Drug Administration
adverse effects, including sedation and required Vanda Pharmaceuticals, the man-
extrapyramidal effects; however, those ufacturers, to carry out a comparison of
who took haloperidol were also given iloperidone with placebo and an active
benzatropine. comparator such as olanzapine or risperi-
done [80S]. It was nally approved in the
USA in May 2009.
Cardiovascular Clozapine has been associ-
ated with venous thromboembolism. The
mortality rate associated with pulmonary Comparative studies Iloperidone has been
embolism has been estimated to be about compared with haloperidol in patients with
28 times higher than in the general popula- schizophrenia using data from three
tion of similar age and sex; it is not clear prospective multicenter studies, each with
whether pulmonary embolism can be attrib- a 6-week stabilization period followed by
uted to clozapine or some characteristic of a 46-week, double-blind, maintenance
its users [SEDA-28, 65]. A new case of pul- phase [81M]. In all, 1644 patients were ran-
monary embolism has been reported [76A]. domized to iloperidone 416 mg/day or hal-
operidol 520 mg/day; of the 1326 patients
A 45-year-old man became acutely confused who completed the 6-week phase and who
after taking an overdose of clozapine, which improved, only 473 (iloperidone, n 359;
he had previously been taking for 6 months.
He had acute dyspnea due to bilateral pulmo- haloperidol, n 114) were included in the
nary emboli. He was not overweight, but was long-term efcacy analysis; mean doses at
a heavy smoker; plasma concentrations of clo- end-point were 12.5 mg/day in both groups.
zapine are lower in smokers than in non- Mean time to relapse was 90 (median 50)
smokers [SEDA-31, 81].
days with iloperidone and 102 (median 78)
days with haloperidol; relapse rates were
Hematologic Agranulocytosis, leukopenia, slightly higher with iloperidone than with
and neutropenia associated with clozapine haloperidol (44% and 41% respectively).
have been extensively studied and The adjusted mean change from baseline
discussed [SED-15, 829; SEDA-32, 97]. to end-point in PANSS-T score (last obser-
vation carried forward) was  16.1 for
A 55-year-old man developed neutropenia iloperidone and 17.4 for haloperidol. For
after taking clozapine 750800 mg/day for the safety analysis, a total of 489 patients
12 years [77A]. Valproic acid 1500 mg/day
had been added 2 years before. When
(iloperidone, n 371, mean age 35 years,
donepezil was added his white blood cell and 64.4% men; haloperidol, n 118, mean
neutrophil counts fell. age, 35 years, 60.2% men) were included.
In the maintenance phase, serious adverse
Of 26 Korean children and adolescents events were reported by 18% of patients
with refractory early-onset schizophrenia who took iloperidone and by 16% of those
(mean age 14 years) nine developed neutro- who took haloperidol; exacerbation of psy-
penia; there was no agranulocytosis [78c]. chotic symptoms was the most frequent
adverse event (iloperidone, 11%; haloperi-
Drugdrug interactions Benzodiazepines dol, 5.9%). Of all the patients who were eval-
In 152 patients who concomitantly took clo- uated, 224 (18%) of those who took
zapine and benzodiazepines from 2001 to iloperidone were hospitalized, and there were
2006 there were no reports of deaths [79c]. four deaths (0.3%); two other patients treated
with iloperidone died in the rst month after
104 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

the study ended. Of those who took haloperi- gain was observed in 29 patients; mean
dol, 56 (14%) were hospitalized; there was weight gain from baseline to week 6 was
one death (0.2%). The most common adverse 5.1 kg (n 76) and from baseline to
events in the maintenance phase were insom- 24 weeks 11.7 kg (n 32); the mean BMI
nia (18%), anxiety (11%), and aggravated rose from 21.2 at baseline to 22.8 at week
schizophrenia (8.9%) with iloperidone; and 6 and to 25.0 at week 24; 24 patients had
insomnia (17%), akathisia (14%), tremor a 7% or greater weight gain. There were
(13%), and muscle rigidity (13%) with halo- higher-than-normal prolactin concentrations
peridol. Mean changes in Fridericia's QTc (boys 16 mg/l; girls 29 mg/l) in 28% at baseline,
interval at end-point were 10.3 ms for 82% at week 2, and 59% at week 6; there was
iloperidone and 9.4 ms for haloperidol; meta- a similar pattern of prolactin concentrations,
bolic changes were minimal in both groups. with a peak of 27 mg/l at week 4 in the boys
(n 58) and 45 mg/l in the girls (n 26).
Placebo-controlled studies In a randomized, One patient discontinued treatment because
placebo-controlled, multicenter study, with a of weight gain and one girl because of
1-week titration period and a 3-week dou- galactorrhea.
ble-blind maintenance period, 593 patients In a prospective open trial in 40 boys with
with acute exacerbations of schizophrenia autism (mean age 12 years) who took
were randomized to iloperidone 24 mg/day, olanzapine (mean dose 7.5, range 510 mg/
ziprasidone 160 mg/day as an active control, day) for 13 weeks, there were signicant
or placebo [82C]. Like ziprasidone, improvements in scores on the Aberrant
iloperidone produced signicant improve- Behavior Checklist scale [84c]. Extrapyrami-
ment compared with placebo. Iloperidone dal symptoms and dyskinetic symptoms did
was associated with higher rates of weight not change from baseline to end-point.
gain, tachycardia, orthostatic hypotension, diz- There were no signicant increases in
ziness, and nasal congestion. There was hepatic enzymes or any serum chemistry.
similar QT interval prolongation with both There were transient mild adverse reactions
active treatments, although no patient had such as drowsiness and sedation, when treat-
a treatment-emergent corrected QT in- ment was begun (13% of patients). Mean
terval of 500 ms or greater. The incidence body weight was 52.5 kg before treatment
of clinically relevant changes in labora- and 52.8 kg after treatment.
tory parameters was comparable between In an open 6-week trial mean weight
iloperidone and ziprasidone. Iloperidone increased by 4.1 kg (range 1.17.7 kg) in 12
was associated with a low incidence of extra- children and adolescents with Tourette's syn-
pyramidal symptoms. drome (age range 714 years; 11 boys) [85c].
Of 278 adults (mean age 36 years, 180
men) with acute psychosis and agitation,
148 took oral olanzapine monotherapy
Olanzapine [SED-15, 2598; SEDA-30, (mean dose 12 mg/day); only mild adverse
64; SEDA-31, 81; SEDA-32, 99] events were observed, including brady-
cardia, dry mouth, sedation, hypertension,
Observational studies The use of anti- hypotension, and orthostatic hypertension
psychotic drugs in children and adolescents (one case each) [86c].
is of particular concern. In a 24-week, mul-
ticenter, open study supported by Eli-Lilly,
the marketing authorization holder, 96 ado- Comparative studies Olanzapine and clo-
lescents with schizophrenic disorder (mean zapine The efcacy and safety of clozapine
age 16 years; 68% boys) were given (300 mg/day; n 18) and olanzapine (up to
olanzapine 10 mg/day [83c]. BPRS scores 30 mg/day; n 21) have been evaluated in
fell from baseline to week 6 by a mean of a 12-week double-blind study of treatment-
17. The most common adverse events were refractory children and adolescents with
weight gain and increased prolactin. Weight schizophrenia aged 1018 years [73C].
Antipsychotic drugs Chapter 6 105

Signicantly more clozapine-treated adoles- in measures of efcacy, nausea, or akathisia


cents met response criteria (66%) compared [89c].
with the olanzapine-treated subjects (33%);
clozapine was also superior to olanzapine in Olanzapine and lithium Chinese patients
terms of reductions in the psychosis cluster with bipolar manic or mixed episodes were
scores and negative symptoms from baseline randomized to olanzapine (mean daily dose
to end-point. Signicant weight gain and 18 mg/day; mean age 31 years; n 69) or
metabolic abnormalities were major prob- lithium carbonate (mean daily dose
lems associated with both treatments. Five 1110 mg/day; mean age 34 years; n 71)
of 39 subjects (three taking clozapine and for 4 weeks in a multicenter, double-blind,
two taking olanzapine) gained more than controlled study [90c]. Patients in both
7% of their baseline body weight, and nine groups improved in different psychopatho-
(four taking clozapine and ve taking logical assessments. Treatment-emergent
olanzapine) had newly emergent fasting tri- adverse events during the study occurred
glyceride concentrations over 1.24 mmol/l. in 55% with olanzapine and 42.3% with
Furthermore, ve patients, all taking cloza- lithium; the most common events with
pine, had serious adverse events and/or olanzapine were constipation (13%), nau-
discontinued treatment because of adverse sea (7.2%), and somnolence (7.2%); with
effects: neutropenia, upper bowel obstruc- lithium they were nausea (13%) and
tion, increased thirst and polyuria, weight nasopharyngitis (5.6%). More of those
gain (3.2 kg), and drug-induced diabetes who took olanzapine reported adverse
(glucose 8.0 mmol/l). Subsequently, 33 events relating to the following MedDRA
patients (14 taking clozapine and 19 taking system organ classes: metabolism and nutri-
olanzapine) were available for a 12-week tion disorders (olanzapine 5.8%; lithium
open extension study [87C]. The incidence 1.4%), nervous system disorders
of hypertriglyceridemia, dened as fasting (olanzapine 13%; lithium 5.6%), and psy-
triglycerides over 1.41 mmol/l (10/14), and chiatric disorders (olanzapine 5.8%; lithium
the incidence of prediabetes, dened as a 0.0%). There were no serious adverse
fasting blood glucose of 5.5 mmol/l or more events or deaths during this study; one
(4/14 29%), at week 24 in the clozapine- patient taking lithium withdrew because of
treated subjects were high. However, 7 of abnormal hepatic function. Mean weight
10 young patients with schizophrenia who increased during the 4-week study in both
failed treatment with olanzapine responded groups but was signicantly higher with
in a 12-week, open trial of clozapine. olanzapine (1.85 kg versus 0.73 kg). In
Olanzapine and clozapine were effective addition, signicantly more of those who
in a 6-month, double-blind study in treat- took olanzapine had a clinically signicant
ment-resistant schizophrenia patients [88c] weight increase (7% of baseline weight)
who were randomized to olanzapine mean compared with lithium (16% versus 2.9%).
dose 34 mg/day (n 19) or clozapine mean The blood glucose concentration increased
dose 564 mg/day (n 21). Mean weight in one patient taking olanzapine (baseline:
gain was 1.6 kg in patients taking clozapine 5.6 mmol/l; end-point: 10.8 mmol/l) and
and 7.2 kg in those on olanzapine; there total cholesterol increased in four patients
was no signicant relationship between (three taking olanzapine and one taking
olanzapine dose and change in weight. lithium).

Olanzapine and droperidol In a ran- Olanzapine, quetiapine, and risperidone In


domized non-blinded clinical trial, patients two studies olanzapine, quetiapine, and ris-
attending an emergency department for pri- peridone had similar efcacies in patients
mary headache were given either intramus- with psychoses but differed in adverse
cular droperidol 5 mg (n 42) or off-label effects.
olanzapine 10 mg (n 45). There were no In a comparative study, 75 in-patients
signicant differences between the groups with schizophrenia were randomized to
106 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

olanzapine (mean dose at end-point 15 mg/ obsessivecompulsive disorder who


day; mean age 35 years; n 25), underwent a 16-week rst phase of treat-
quetiapine (mean dose at end-point ment with SSRIs, 50 were judged to be
590 mg/day; mean age 39 years; n 25), resistant and were randomized to addi-
or risperidone (mean dose at study end- tional risperidone (mean age 36 years;
point 5.1 mg/day; mean age 43 years; mean daily dose 2.1 mg; n 25) or
n 25) [91c]. After 8 weeks, there were olanzapine (mean age 34 years; mean daily
signicant clinical improvements in all dose 5.3 mg; n 25) in an 8-week, single-
treatment arms, with no signicant differ- blind, second phase [93c]. Adverse experi-
ences. There were 14 withdrawals: ve on ences were reported by 52% of those who
olanzapine, four on quetiapine, and ve took additional risperidone and 64% of
on risperidone. At the nal visit there was those who took olanzapine; adverse events
a 7% increase in baseline body weight motivated withdrawal in two patients tak-
in 8%, 8%, and 29% with quetiapine, ris- ing olanzapine (reduced sexual desire and
peridone, and olanzapine respectively. weight gain).
Extrapyramidal symptoms were signi-
cantly worse with risperidone than both
olanzapine and quetiapine at week 3 and Placebo-controlled studies Subjects with
compared with quetiapine thereafter. borderline personality disorder (n 314)
In the Child and Adolescent First-Epi- have been treated off-label with olanzapine
sode Psychosis Study (CAFEPS), a longitu- (modal dose 7.1 mg/day) in a 12-week ran-
dinal multicenter study, 110 patients aged domized, double-blind, placebo-controlled
917 years were treated for a rst psychotic trial [94C]. Olanzapine and placebo pro-
episode [92c]. Only patients who received duced similar signicant improvements,
one antipsychotic drug from baseline to but time to response was signicantly
6 months of follow-up were included in shorter with olanzapine. Withdrawal rates
the safety analysis (risperidone, n 50; because of adverse events were 11% for
quetiapine, n 18; olanzapine, n 16). both olanzapine and placebo. Increased
Using the baseline score as a co-variate, appetite and weight gain were signicantly
there were no signicant differences in the greater with olanzapine (mean weight gain
reductions in any of the four clinical scales 2.8 kg versus  0.4 kg); olanzapine also pro-
in patients who took risperidone, quetiapine, duced signicantly larger increases in
or olanzapine for 6 months. As expected, fasting total cholesterol, fasting LDL choles-
olanzapine caused signicantly greater gains terol, total and direct bilirubin, hepatic
in weight and BMI than the other two drugs enzymes, and prolactin. There were serious
(mean body weight gain 12 kg for olanzapine adverse events in 15 patients: six taking
versus 6.0 kg for quetiapine and 6.1 kg for olanzapine (suicidal ideation, n 4;
risperidone; mean BMI increase 3.9 for aggression, agitation, alcoholism, drug mis-
olanzapine versus 1.4 for quetiapine and 1.9 use, impulsive behavior, self-mutilation,
for risperidone), even after controlling and self-injurious ideation, n 1 each)
for initial weight or BMI. The percentage and nine taking placebo (suicidal ideation,
of patients with hypokinesia/akinesia was n 4; aggression, anxiety, exacerbation of
signicantly higher with risperidone than borderline personality disorder symptoms,
with olanzapine or quetiapine (50% versus n 2 each; and depressed mood, fatigue,
15% and 13%); there was dystonia in one and weight reduction, n 1 each).
patient taking risperidone. Increased appetite and signicantly more
weight gain (2.7 kg versus 0.1 kg) were also
Olanzapine and risperidone Atypical anti- found in 42 patients with pathological gam-
psychotic drugs are occasionally used bling who were randomized in a 12-week
off-label for obsessive symptoms. From an study to olanzapine (mean dose 8.9 mg/
initial sample of 96 Italian patients with day) or placebo [95c].
Antipsychotic drugs Chapter 6 107

In a double-blind, placebo-controlled 3 weeks later had a second episode of pulmo-


study, 34 patients with anorexia nervosa nary embolism, which was attributed to non-
adherence to the anticoagulant treatment.
were randomly assigned to either However, 16 weeks later he had a third episode;
olanzapine plus day-hospital treatment following exhaustive investigations, anti-
(n 16) or placebo plus day-hospital treat- psychotic drugs (olanzapine and risperidone)
ment (n 18) [96c]. At 10 weeks, body remained the most probable causal factor.
weight had increased in both groups, He improved with anticoagulation and
amisulpride 400 mg/day. Paroxetine 20 mg/day
although the achievement of target body and valproate 2 g/day were maintained
mass index was greater and earlier in those throughout these episodes.
who took olanzapine.
Nervous system Abnormality of P300
Cardiovascular Clozapine, which is close waveforms of event-related potentials has
related to olanzapine, has been implicated been suggested to represent an aspect of
as an independent susceptibility factor for the pathophysiology of schizophrenia; low
pulmonary embolism [SEDA-28, 65]. A resolution electromagnetic tomography
possible association between olanzapine analysis (LORETA) has been used to
and pulmonary thromboembolism has also obtain current density images of P300 in 16
been described [SEDA-32, 102]. New cases patients with schizophrenia taking
have been reported [97A, 98A]. olanzapine and 16 healthy controls [99c].
The patients had signicantly smaller
A 47-year-old woman with schizophrenia was LORETA values in several brain regions
found dead in her apartment. She had been on the left side, particularly in the superior
taking lithium and olanzapine. Autopsy
showed an acute pulmonary embolus in the temporal gyrus, middle frontal gyrus, and
left main pulmonary artery, with extension precentral gyrus, than control subjects. After
into the lobar branches and an adherent treatment for 6 months with olanzapine the
thrombus in the left popliteal vein. There P300 source density increased signicantly
was no evidence of other pathology. Post-
mortem toxicology conrmed the presence of only in the left superior temporal gyrus,
olanzapine and showed no other substances. suggesting positive changes in cortical activ-
There were no other risk factors, such as obe- ity; however, the small sample size pre-
sity, a sedentary lifestyle, a history of smoking, cluded rm conclusions.
recent trauma or immobilization, use of estro-
gens, or a family history of thrombotic events;
factor V Leiden and prothrombin mutations Drug withdrawal Switching patients from
were negative. one antipsychotic drug to another is a com-
mon practice; three strategies for changing
In previous cases, identied by specic
olanzapine to risperidone have been
searching, one subject had two known risk
assessed in a 6-week, randomized, open
factors for pulmonary embolism (obesity
study in 123 patients with schizophrenia or
and a recent ankle fracture), one had one
schizoaffective disorder: (i) an abrupt strat-
risk factor (obesity), and three had none.
egy, in which olanzapine was withdrawn
A 23-year-old man, not overweight, a smoker of when risperidone was started; (ii) a gradual
1 pack/day, with an early-onset schizoaffective strategy, in which olanzapine was given at
disorder was given olanzapine 20 mg/day, par- 50% entry dose for 1 week after risperi-
oxetine 20 mg/day, and valproate 2000 mg/ done was started and then discontinued;
day. After 12 weeks, he suddenly developed
back pain radiating to the left anterosuperior and (iii) a very gradual strategy, in which
part of the thorax; over the next few hours he olanzapine was given at 100% entry dose
became dyspneic and had an episode of hemop- for 1 week, then at 50% in the second
tysis. Arterial blood gases were normal. Bilat- week, and then withdrawn [100c]. All-cause
eral pulmonary embolism was conrmed by a treatment withdrawal was lowest (12%) in
CT scan. Olanzapine was withdrawn and oral
anticoagulation was given for 6 months. As his those with the slowest olanzapine dosage
psychotic symptoms recurred 12 weeks reduction; adverse events accounted for
later, he was given risperidone 3 mg/day and withdrawal in 5% of patients on the abrupt
108 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

and very gradual strategies, and in 15% of upper end of the recommended ranges:
those on the gradual strategy. paliperidone modied-release, 9 or 12 mg/
day, and quetiapine, 600 or 800 mg/day.
Management of adverse drug reactions In Six-week completion rates were 78% with
a second phase of the previous study, 71 paliperidone modied-release, 67% with
patients with a BMI over 26 kg/m2 were quetiapine, and 64% with placebo.
enrolled in a weight-loss program while Improvement in mean PANSS total change
taking risperidone and randomly assigned score was greater with paliperidone
to 14 weeks of a behavioral treatment pro- modied-release than with quetiapine from
gram for weight reduction (n 34) or day 5 (11 versus 8.2) to the mono-
usual care (risperidone modal dose therapy phase end-point (23.4 versus
4.5 mg/day; n 37), there was signicant 17.1). At the 6-week end-point, there
weight loss in both treatment groups after was signicantly greater improvement with
14 weeks: mean changes were 2.0 kg in paliperidone than quetiapine or placebo,
the subjects enrolled in the behavioral pro- despite similar use of additive therapy (pre-
gram and 1.1 kg in the control group dominantly other antipsychotic drugs).
[100c]. The authors concluded that specic Over the entire study period, serious
weight-loss behavioral programs might pre- adverse events were reported by 13
vent weight gain associated to olanzapine. (8.2%) patients taking paliperidone, 7
(4.4%) taking quetiapine, and 2 (2.5%) tak-
ing placebo; the most common adverse
event was schizophrenia (3.8%, 1.9%, and
0.0% respectively). There were signicantly
Paliperidone higher values for changes in prolactin with
paliperidone; the values at end-point were
Paliperidone, or 9-hydroxyrisperidone, is 32, 6.7, and 4.5 ng/ml respectively.
the major active metabolite of risperidone. Elderly patients with schizophrenia
It binds to both dopamine D2 and serotonin (mean age 70 years; n 114) who took
5-HT2A receptors, and antagonism at these paliperidone in a 6-week double-blind, pla-
receptors is thought to account for its ther- cebo-controlled study followed by a 24-
apeutic activity in schizophrenia. It was week open extension with paliperidone
approved by the US Food and Drug (mean doses 7.4 and 8.5 mg/day respec-
Administration in 2007 for acute and main- tively) treatment-emergent adverse events
tenance treatment of schizophrenia; it is were similar (71% with placebo and 67%
available in modied-release tablets. The with paliperidone), as were withdrawal
available literature on the pharmaco- rates because of adverse events (8% and
dynamics, pharmacokinetics, clinical ef- 7% respectively) [103c]. There were serious
cacy, and tolerability of paliperidone has adverse events in three patients taking pla-
been extensively reviewed [101R]. cebo and in two taking paliperidone (acute
coronary syndrome and mania, n 1
Placebo-controlled studies Paliperidone each); there was also an age-related
modied-release, quetiapine, and placebo increase in the incidence of somnolence.
have been compared in patients with There was a higher incidence of tachycardia
recently exacerbated schizophrenia requir- with paliperidone in both phases, increases
ing hospitalization in a 6-week double-blind being more pronounced in patients aged
study [102C]. In-patients were randomly 7075 years compared with those aged
assigned to paliperidone modied-release 6469. There was prolongation of the QTc
(n 160), quetiapine (n 159), or pla- interval to over 500 ms in the rst phase,
cebo (n 80). A 2-week monotherapy leading to discontinuation (n 2), and in
phase was followed by a 4-week additive- the second phase (n 1); these three
therapy phase; target doses were at the patients had histories of QT interval
Antipsychotic drugs Chapter 6 109

prolongation. In the double-blind phase, neuroleptic malignant syndrome, or other


there were raised prolactin concentrations severe symptoms.
in 45% of the men and 49% of the women
taking paliperidone, but they returned to Cardiovascular Paliperidone has been
normal at the end of the study; prolactin associated with seizures and atrial brilla-
concentrations also rose in patients taking tion [105A].
paliperidone who had previously taken pla-
cebo. The incidence of extrapyramidal A 46-year old man with bipolar disorder, dia-
symptoms was low throughout the study; betes mellitus, hypertension, hyperlipidemia,
and tobacco use took metformin hydrochlo-
during the second phase, medication for ride 2 g/day, insulin glargine 64 units/day,
treatment of this effect was used in 27% insulin lispro 44 units/day, simvastatin 20 mg/
and 22% respectively. day, enalapril maleate 5 mg/day, escitalopram
In a re-analysis of different short-term 30 mg/day, lamotrigine 200 mg/day, and
clonazepam 2 mg as needed. Owing to stress
studies, the efcacy and tolerability of modi- at work, he was given paliperidone 3 mg
ed-release paliperidone have been assessed orally on day 1 and 6 mg/day thereafter.
in patients with acute schizophrenia [104M]. After 4 days he had a possible tonicclonic sei-
Patients were randomly allocated to zure, a headache, palpitation, and mild dys-
paliperidone 3 mg/day (n 123), 6 mg/day pnea. An electrocardiogram showed atrial
brillation, a ventricular rate of 151/minute, a
(n 234), 9 mg/day (n 245), 12 mg/day QTc interval of 461 ms, and no signicant
(n 240), 15 mg/day (n 113), or placebo changes in the ST segment or T wave. Sinus
(n 351); mean ages were 3639 years. All rhythm recurred after the administration of
doses of paliperidone were signicantly bet- single oral doses of potassium chloride
20 mmol and diltiazem 10 mg. The heart rate
ter than placebo. There were treatment- and QTc interval normalized to 68/minute
emergent adverse events in 6677% in those and 392 ms.
who took paliperidone and in 6% of those
who took placebo; serious adverse events In this case pharmacogenetic testing revealed
occurred in 56% of patients in all groups, CYP2D6 alleles *4 and *10 and CYP3A4
the most common being exacerbation of psy- alleles *16B and *1F, which are associated
chotic symptoms. Orthostatic hypotension with poor-to-intermediate CYP2D6 activity
occurred from 1% at 6 mg/day to 4% at and reduced CYP3A4 activity in vitro.
12 mg/day. A higher proportion of patients
assigned to paliperidone above 6 mg/day Drugdrug interactions In September 2008,
had extrapyramidal symptoms; one patient the FDA Center for Drug Evaluation and
with a previous history of tardive dyskinesia Research changed the information in the
with clozapine had an episode after taking section included in the safety labelling of
paliperidone for 4 days. Glucose-related paliperidone [106S], as follows:
adverse events were reported in both groups
(paliperidone, 1%; placebo, 1%). Mean Potential for Invega (paliperidone) to affect
body weight increased by 0.6 kg with other drugs Paliperidone is a weak inhibitor
of P-glycoprotein at high concentrations. No
paliperidone 3 mg/day and 1.9 kg with in vivo data are available and the clinical rele-
15 mg/day, and fell by 0.4 kg with placebo. vance is unknown.
Median prolactin concentration increases Potential for other drugs to affect Invega
were larger among women (81 ng/ml) In vitro studies have shown that paliperidone
is a P-glycoprotein substrate.
than men (24 ng/ml) when all paliperidone
groups were combined; the magnitude Co-administration of Invega 6 mg once
of this effect increased with increasing daily with carbamazepine 200 mg twice
drug doses and there were prolactin-related daily caused a decrease of approximately
adverse events in 12% of patients taking 37% in the mean steady-state Cmax and
paliperidone 312 mg and 4% of those tak- AUC of paliperidone.
ing 15 mg. There were no deaths, cases of
110 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

Quetiapine [SED-15, 2995; SEDA-30, had dyskinesias, dizziness, and somnolence


67; SEDA-31, 87; SEDA-32, 104] and required dosage reduction. The most
common adverse events were somnolence
Quetiapine has been approved in the USA (26%), orthostatic hypotension (22%), diz-
for the treatment of schizophrenia in ado- ziness (15%), and sedation (7.4%); the
lescents aged 1317 years, bipolar mania heart rate increased by more than 145/
in children and adolescents aged minute in four patients. One of the adults
1017 years, and as adjunctive therapy for withdrew because of agitation, and there
treatment of major depressive disorder were treatment-related adverse events in
[107S]. 19, including orthostatic hypotension (about
50%), dizziness (45%), anxiety (24%), leth-
argy (21%), and dry mouth and insomnia
Observational studies In 477 patients with (both 17%); the heart rate increased by
schizophrenia (mean age 38 years), who more than 120/minute in 17 patients; all
were switched from their medication to hematological tests were within the refer-
quetiapine (mean median dose 575 mg/ ence ranges.
day) because of insufcient efcacy (66%) Quetiapine has been used in very small
or insufcient tolerability (34%) in a 12- numbers of patients for off-label indications:
week, multicenter, open-label study prevention of migraine (75 mg/day; mean
supported by AstraZeneca, the marketing age 39 years; n 34) [111c] and cocaine
authorization holder of quetiapine common dependence (mean dose 429 mg/day; mean
adverse events included somnolence age 47 years; n 22) [112c]. In the rst study
(18%), sedation (15%), and dizziness and the most common adverse events, which
dry mouth (14% each), and extrapyramidal occurred in nine patients, were worsening
symptoms (8.0%) [108C]. There were headache, drowsiness, somnolence, increased
higher glucose concentrations both at base- appetite, weight gain, and nausea. In the
line (n 8) and end-point (n 12). The second study, all the subjects had seda-
mean body weight change was 1.0 kg. tion at some time during treatment, and
In a 12-week, open, exible-dose study several dropped out because of it; weight
of quetiapine in 40 out-patients with gener- increased signicantly and other reactions
alized anxiety disorder who had not were dry mouth, orthostatic faintness, and
achieved remission after at least 8 weeks constipation.
of adequate doses of standard therapy, the
most common adverse reactions were seda-
tion (n 29), dry mouth (n 12), and sex- Comparative studies Quetiapine and lith-
ual dysfunction (n 10) [109c]. Mean total ium In a 4-week, multicenter, double-blind
weight gain from pre-treatment to week 12 study, Chinese patients with bipolar mania
was about 0.5 kg and 14% of patients had were randomized to quetiapine (mean
a 7% weight gain. Seven patients withdrew dose, 648 mg/day; mean age, 33 years; n
because of adverse events: sedation 77) or lithium (mean serum concentration
(n 5), panic attacks (n 1), and bilateral 0.80 mmol/l; mean age 34 years; n 77)
iritis (n 1). [113c]. The proportion of patients with at
Adverse reactions to quetiapine have least one adverse event during the study
been studied in 13 children aged was higher with quetiapine (78%) than lith-
1012 years, 14 adolescents aged ium (69%). The most common (5%)
1317 years, and 29 adults, mean age adverse events with quetiapine were consti-
37 years, with a psychotic disorder, in a pation (35%), dizziness (15%), diarrhea
study that was supported by AstraZeneca, (10%), increased alanine aminotransferase
the marketing authorization holder; (9.0%), bouts of palpitation (9.0%), in-
quetiapine was titrated up to 400 mg/day creased aspartate aminotransferase (7.7%),
over 12 days [110c]. None of the children pharyngolaryngeal pain (6.4%), upper respi-
withdrew because of adverse events, two ratory tract infections (6.4%), and dry mouth
Antipsychotic drugs Chapter 6 111

(5.1%). In those who took lithium the most dysregulation (59% versus 19%) and seda-
common adverse events were nausea (17%), tion (50% versus 6%) were the most fre-
constipation (13%), vomiting (13%), quent adverse events [115c]. Other effects
nasopharyngitis (12%), dizziness (6.5%), were dry mouth (27% versus 13%) and
diarrhea (6.5%), and upper respiratory tract headache (23% versus 19%). Adverse
infections (6.5%); one patient had bone mar- events were the most frequent reason for
row depression and three had adverse events discontinuation only in the quetiapine
(pruritus, vomiting, and depressed level of group. Adverse events leading to with-
consciousness and dizziness) that led to with- drawal in patients taking quetiapine
drawal. Tachycardia, bradycardia, and minor included abnormal electroencephalo-
conduction block occurred in both groups. graphic signs of arousal, suicide attempt,
There were transient increases in hepatic and lymphedema (one each), and body
enzyme activities in ve patients taking weight changes (mean 4.5 kg in patients
quetiapine and in two taking lithium. There taking quetiapine and 2.7 kg in those taking
were high blood glucose concentrations in valproate).
three patients in each group. Mean weight
gain was 1.5 kg with quetiapine and 0.3 kg Drug abuse [SEDA-30, 68; SEDA-32,
with lithium. Extrapyramidal symptoms (dys- 107] Quetiapine abuse has again been
tonia, akathisia, tremor, and extrapyramidal described [116A].
disorder) were similar with quetiapine
(5.1%) and lithium (6.5%). A 29-year-old man reported that the local
police were disturbing his sleep by electroni-
cally monitoring his testicles; he also said he
Quetiapine and risperidone In a 12-month had schizophrenia and was being treated with
multicenter, non-randomized study in quetiapine 600 mg nightly. He received his
patients with acute schizophrenia who were usual dose and slept soundly. The next
given quetiapine (mean age 37 years; mean morning he was still somnolent without
dose 719 mg/day; n 367) or risperidone thought or mood disturbance. His urine toxi-
cology screen was negative. A pharmacy
(mean age 36 years; mean dose 7.0 mg/ review revealed that he had received different
day; n 125), serious adverse events with and excessive amounts of quetiapine from sev-
quetiapine (n 3) were death by suicide, eral sources during the past few months. On
tachycardia, and dystonia; and with risperi- confrontation, he admitted both excessive use
and sale of quetiapine.
done (n 3), severe rigidity/dysphagia,
sedation, and acute dystonia [114C]. Ortho-
static hypotension was more frequent with
quetiapine than with risperidone (14% ver-
sus 6.7%); male sexual dysfunction (loss of
libido 22% versus 11%; erectile dysfunction Risperidone [SED-15, 3052; SEDA-30,
21% versus 9.4%; and impaired ejaculation 69; SEDA-31, 90; SEDA-32, 107]
18% versus 6.9%) were more common with
risperidone. Extrapyramidal symptoms In a review of the use of risperidone in
(including rigidity and hypokinesia) autistic disorder in children and adolescents
occurred in 33% and there were no signi- it was stressed that somnolence, increased
cant differences between the two groups appetite, increased prolactin concentrations,
in female sexual dysfunction, somnolence, and fatigue were the most common adverse
constipation, reduced salivation, headache, events [117R].
dyspepsia, tachycardia, or weight gain.
Observational studies In an open study,
Quetiapine and valproate In a 12-month 232 children and adolescents (mean age
comparison of quetiapine (mean dose 11 years) with disruptive behavioral disor-
465 mg/day; n 22) and valproate (mean ders were followed during 1 year in an
dose 720 mg/day; n 16) in patients with extension period with risperidone, having
rapid-cycling bipolar disorder, orthostatic been previously randomized to risperidone
112 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

or placebo in a double-blind, 6-month with- Other common events were constipation


drawal study [118C]. Weight gain and extra- (risperidone 29%; haloperidol 23.1%) and
pyramidal symptoms (most frequently nocturnal enuresis (20% and 23%
dystonia, n 7) were each reported by 10 respectively).
subjects. Prolactin concentration increased There were greater increases in prolactin
with risperidone; median prolactin concen- concentrations with risperidone in a 12-
trations at baseline were 237 mU/l in week, double-blind study, in which children
women and 175 mU/l in men; at end-point and adolescents with autistic disorder were
the values were 356 and 238 mU/l respec- assigned to either risperidone (mean age
tively. There was gynecomastia in two men 10 years; n 15) or haloperidol (mean
and transient dysmenorrhea in one woman. age 11 years; n 15); the mean doses were
Twenty had serious adverse events, includ- 2.6 mg/day for both drugs [122c].
ing psychiatric aggravation in 10.
In a retrospective study of male delin- Combination studies Herbal preparations
quents, mean age 16 years, with childhood are occasionally used as adjunctive treat-
onset and persistent conduct disorder ments to antipsychotic drugs. In an 8-week,
treated either with psychosocial treatment randomized, double-blind, placebo-con-
and risperidone (mean dose 2.5 mg/day; n trolled study of warm-supplementing kid-
60) or cognitive-behavioral treatment ney yang capsule 2.7 g/day added to
alone (n 69), the most common adverse risperidone in 200 patients with schizophre-
events in the patients taking risperidone nia [123c]. Performance on the Wisconsin
were somnolence (26%), weight gain Card Sorting Test was signicantly higher
(18%), increased appetite (17%), and con- in the group of patients taking the combina-
stipation (14%); mean body weight tion than in those taking placebo; there
increased by 6.8 kg during a mean time of were no signicant differences in adverse
9 months [119c]. events; tremor, akathisia, weight gain, and
insomnia occurred in more than 10% of
patients in both groups.
Comparative studies Risperidone and
divalproex In a retrospective study of 28 Placebo-controlled studies In 86 non-
patients aged 514 years with bipolar disor- psychotic patients who presented with
der who had been treated with risperidone aggressive challenging behavior from 10
(n 16) or divalproex (n 12), risperi- centers in England and Wales and one in
done was associated with faster clinical Queensland, Australia, who were randomly
improvement and signicantly more weight assigned to haloperidol (n 28), risperi-
gain than divalproex (mean changes 2.46 kg done (n 29), or placebo (n 29), aggres-
versus 0.43 kg); however, the small sample sion was substantially reduced by all three
size precluded denitive conclusions [120c]. treatments after 4 weeks; the placebo group
showed the greatest change (a median
Risperidone and haloperidol In a 24-week reduction in the modied overt aggression
study (12-week double-blind and 12-week scale score) after 4 weeks of 9 for placebo
open), 28 children and adolescents with (79% from baseline); 7 for risperidone
autistic disorder were treated either with (58% from baseline); and 6.5 for haloperi-
risperidone (mean age 10 years; n 13) dol (65% from baseline) [124c]. There were
or haloperidol (mean age 11 years; n 15), no important differences between the treat-
both in doses of 0.010.08 mg/kg/day [121c]. ments, including adverse effects; patients
There were signicant mean weight gains who took placebo had no evidence at any
from baseline to end-point (4.2 kg with ris- time of a worse response than patients
peridone and 6.3 kg with haloperidol). who had been assigned to either of the anti-
However, there were no signicant differ- psychotic drugs. The authors suggested that
ences in weight and prolactin concentra- antipsychotic drugs should no longer be
tions between the two groups at end-point. regarded as acceptable in the routine
Antipsychotic drugs Chapter 6 113

treatment for aggressive challenging behav- and galactorrhea in two; amenorrhea


ior in people with intellectual disabilities. and delayed menses in one); there was one
The authors of an accompanying editorial case of menorrhagia with haloperidol and
pointed out that the sample size in this one case of gynecomastia with oral risperi-
study was impressive, in view of the practi- done. The percentage of dropouts for any
cal, legal, and cultural problems associated reason was 20% for injectable risperidone
with recruitment for such research [125r]. compared with 49% for the oral
Off-label uses of risperidone have been medications.
assessed in two studies. In a double-blind In 529 patients (mean age 39 years)
study, elderly patients with depression treated with long-lasting injectable risperi-
resistant to citalopram, who had previously done (modal dose 25 mg), the median
responded to adjunctive therapy with time to discontinuation was 16 months
risperidone, where randomly allocated to [131C]. A total of 13% (n 69) withdrew
continue with adjunctive therapy with ris- because of an adverse event, including
peridone (modal dose 0.8 mg/day; n 32) disease exacerbation and delirium
or to receive placebo (n 31) [126c]. Three (n 4 each); mean body weight increased
patients taking risperidone reported by 1.0 kg from baseline to end-point; glu-
headache. cose-related events were reported by four
In a 12-week, double-blind study, patients. The most common treatment
cocaine-dependent men were randomized adverse events were anxiety (24%), insom-
to risperidone (n 16) or placebo (n nia (19%), weight increase (14%), depression
15); mean weight changes were 2.9 kg (11%), exacerbation of disease (10%), head-
and 0.2 kg respectively, one patient tak- ache (7.7%), relapse (7.4%), tremor (6.0%),
ing risperidone withdrew because of tardive and weight reduction (5.5%); 94 patients
dyskinesia [127c]. gained >7% of their body weight and six
reported pain or injection-site reactions.
Nervous system Impaired sensorimotor In 50 patients with newly diagnosed
function was observed in 33 antipsychotic schizophrenia (mean age 25 years) who
drug-nave patients with schizophrenia were treated with injectable risperidone
after they were given risperidone (n 29) 2550 mg every 2 weeks for 2 years [132c],
or olanzapine (n 4); mean doses at 6 prolactin concentrations increased in 18
and 26 weeks were 3.9 and 3.2 mg/day for patients, four of whom reported possible
risperidone and 11.3 and 15 mg/day for prolactin-related adverse events (amenorrhea
olanzapine [128c]. in one; galactorrhea in one; amenorrhea and
galactorrhea in one; amenorrhea and
Drug formulations Long-acting injectable delayed menses in one). Mean increase in
risperidone is commonly used in patients body mass index was 4.8 kg/m2; 10 subjects
with psychoses. There have been two stud- required anticholinergic medication, and
ies sponsored by Janssen Cilag, the risperi- one developed persistent dyskinesia.
done marketing authorization holder. In
the rst, an observational study in 842 indi- Management of adverse reactions The
viduals (mean age 41 years), 27% had with- herbal preparation Peony-Glycyrrhiza
drawn after 6 months because of adverse Decoction 45 g/day for 4 weeks increased the
events (mean dose at end-point 36 mg) efcacy of bromocriptine 5 mg/day in reducing
[129c]. risperidone-induced hyperprolactinemia in 20
In the second study, which lasted 2 years, women with hyperprolactinemia (serum pro-
long-acting injectable risperidone (n 50) lactin concentration >50 mg/l), who were
was compared with oral risperidone currently experiencing oligomenorrhea or
(n 47) and haloperidol (n 47) [130c]. amenorrhea; one patient withdrew after
Prolactin-related adverse events occurred taking bromocriptine for 5 days because of
in four of those who received injectable ris- worsening of facial acne [133c].
peridone (galactorrhea in one; amenorrhea
114 Chapter 6 Alfonso Carvajal, Luis H. Martn Arias, and Natalia Jimeno

Sertindole [SED-15, 3120; SEDA-30, 72; gained 7% of their baseline weight.
SEDA-32, 110] There were no changes in Fridericia-
corrected QT intervals by more than
Cardiovascular Sertindole has been associ- 60 ms from baseline.
ated with prolongation of the QT interval In 70 patients with schizophrenia and per-
in clinical trials; it was withdrawn from the sistent symptoms or troublesome adverse
market because of an excessive relative effects who were assigned to a exible dos-
reporting rate of sudden deaths in 1998 age (40160 mg/day) in a 12-month open
and then re-introduced in 2001 in Europe trial of ziprasidone looking for cognitive
under certain restrictions [SEDA-26, 66]. improvement, there were signicant
Some re-analyses, sponsored by H improvements in executive functions, atten-
Lundbeck A/S, the marketing authorization tion, and information processing domains,
holder, have been published [134c, 135c]; but the effect sizes were moderate [138c].
they have not added any substantial infor-
mation to that already published from the
European Sertindole Safety and Exposure Cardiovascular It is unknown to what
Survey [SEDA-32, 110]. extent QT interval prolongation due to
ziprasidone increases cardiovascular risk;
particular attention has been devoted to
sudden death [SEDA-31, 95]. In an open,
Ziprasidone [SED-15, 3721; SEDA-30, randomized, postmarketing study
72; SEDA-31, 94; SEDA-32, 111] (the Ziprasidone Observational Study of
Cardiac OutcomesZODIAC), whose pri-
Observational studies Numerous open stud- mary outcome measure was the rate of mor-
ies of ziprasidone promoted by Pzer, the tality, 18 094 patients with schizophrenia
marketing authorization holder, have previ- were randomly assigned to either
ously been published [SEDA-32, 111] and ziprasidone or olanzapine [139c]. Baseline
further studies, similarly promoted, have data suggested that this population had a
emerged. Of 185 subjects who were switched substantial prevalence of cardiovascular risk
from olanzapine or risperidone to factors, and concomitant medications were
ziprasidone, 72 completed a 1-year extension often used, but no other data were released.
study [136c]. The most common adverse
effects were insomnia (23%) and somnolence
(11%); no patient had a corrected QT inter-
val over 500 ms at any time during the study. Zotepine
In 63 subjects aged 1017 years in an
open study of oral ziprasidone, consisting
of a 3-week xed-dose period and a subse- Sexual function Spontaneous ejaculation
quent 24-week exible-dose period, related to zotepine therapy has been
adverse effects occurred mostly during dose reported, supposedly for the rst time
titration and in the high-dose (160 mg/day) [140c].
group [137c]. The most common adverse A 38-year-old man with schizophrenia was
effects during the rst period were sedation given a combination of zotepine 100 mg/day
(32%), somnolence (30%), and nausea and haloperidol ester 100 mg every 2 weeks
(25%), and during the exible-dose period and complained of spontaneous ejaculation,
sedation (30%), somnolence (30%), and which became more severe when the dosage
of zotepine was increased to 150 mg/day.
headache (25%). The incidences of move- Zotepine was discontinued and the spontane-
ment disorders were 22% and 16% during ous ejaculation no longer occurred with halo-
the rst and second periods. Adverse peridol monotherapy. A combination of
effects caused withdrawal in 6% haloperidol 100 mg every 2 weeks and
quetiapine was then used, and spontaneous
during the xed-dose period and in 20% ejaculation did not recur.
in the exible-dose period. One-third
Antipsychotic drugs Chapter 6 115

Zuclopenthixol [SED-15, 3722; zuclopenthixol (n 49), responders were


SEDA-32, 112] randomly assigned to continue (n 19) or
discontinue (n 20) zuclopenthixol during
Placebo-controlled studies The effects of a 12-week, double-blind, placebo-controlled
zuclopenthixol on aggressive behavior in period. Zuclopenthixol was superior to pla-
patients with intellectual disabilities have cebo. In the placebo-controlled period, one
previously been investigated [SEDA-32, patient in each group withdrew because of
112], and a secondary parameter analysis adverse events; adverse effects were reported
of the results of this study has been by six patients taking zuclopenthixol group
published [141R]. After open treatment with and by ve patients taking placebo.

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Long-acting injectable risperidone in the Disruptive Behavior Study Group. A dou-
treatment of subjects with recent-onset psy- ble-blind placebo-controlled discontinua-
chosis: a preliminary study. J Clin tion study of zuclopenthixol for the
Psychopharmacol 2008; 28(2): 2103. treatment of aggressive disruptive
[133] Yuan HN, Wang CY, Sze CW, Tong Y, behaviours in adults with mental retarda-
Tan QR, Feng XJ, Liu RM, Zhang JZ, tionsecondary parameter analyses.
Zhang YB, Zhang ZJ. A randomized, Pharmacopsychiatry 2008; 41(6): 2329.
Gaetano Zaccara and Luciana Tramacere

7 Antiepileptic drugs

GENERAL Higher scores in each adverse reaction


class were associated with lower QOLIE-89
Clinicians have only recently realized that scores, and Cognition/Coordination scores
chronic adverse effects of antiepileptic were the strongest predictor. A subgroup of
drugs, mainly those involving central ner- 62 subjects met criteria for a prospective ran-
vous system, may be more disabling to the domized trial on the value of using the
patient than the seizures themselves. Up Adverse Event Prole score in clinical man-
to a few years ago, the historical belief that agement. They were randomly assigned to a
seizure frequency is the major determinant group in which treating physicians had
of health-related quality of life and that access to adverse events prole scores at
adverse reactions are merely a secondary each visit or to another group in which
end-point was the prevalent opinion. It these data were not made available.
has been shown that changes in seizure rate Improvements in Cognition/Coordination,
among patients with drug-resistant epilepsy Mood/Emotion, and Tegument/Mucosa
are only modestly correlated with quality of scores were associated with improvements
life, while adverse reactions and depression in QOLIE-89 scores and improved Cogni-
are critical determinants of subjective tion/Coordination was the only predictor of
health status [1C]. improved QOLIE-89.
Using a questionnaire to assess com-
plaints of adverse reactions to antiepileptic
Observational studies In an attempt to
drugs, an active intervention policy has
dene specic patterns of adverse reactions
been studied in a randomized controlled
and their clinical relevance to subjective
study in 111 adults with epilepsy who had
health status, 200 subjects with epilepsy
had moderate to severe complaints [3C].
completed validated self-report health
Drug therapy was either continued
assessments, including the Adverse Event
unchanged (n 58) or adjusted by reduc-
Prole and Quality of Life in Epilepsy
ing the dose or switching to other anti-
Inventory (QOLIE)-89 [sic] [2C]. The mean
epileptic drug (n 53). After 7 months,
number of adverse reactions per subject
the relative chance of improvement in qual-
was 6.5. Factor analysis segregated all
ity of life was 1.80 (1.043.12) for the inter-
adverse reactions into ve classes:
vention group compared with the controls
cognition/coordination; and the relative chance of a reduction in
mood/emotion; the number of complaints was 1.34 (0.88
sleep; 2.05).
weight/cephalalgia; Different strategies for detecting adverse
tegument/mucosa.
effects have been compared in a cross-sec-
tional epidemiological study in standard
clinical practice in 579 patients: spontane-
Side Effects of Drugs, Annual 33
ous reporting by the patient and a checklist
J.K. Aronson (Editor)
ISSN: 0378-6080 of possible treatment-related adverse reac-
DOI: 10.1016/B978-0-444-53741-6.00007-6 tions completed by the patient34%
# 2011 Elsevier B.V. All rights reserved. reported adverse reactions spontaneously
125
126 Chapter 7 Gaetano Zaccara and Luciana Tramacere

and 65% did so through the checklist [4C]. disordered lipid proles, and increased
Signicant adverse reactions were an lipoprotein(a) serum concentrations, as
important reason for modifying treatment well as thyroid hormone deciency, with
in patients who reported higher degrees of particular emphasis on the clinical implica-
discomfort. tions, have been reviewed [8R].
In an open, long-term, observational Measurement of intima media thickness
study, retention in the study, the percent- at the wall of the common carotid artery by
age of patients who withdrew because of B mode ultrasonography has been per-
adverse events, and the percentage of formed in 195 patients taking long-term anti-
patients who achieved seizure freedom epileptic drugs and 195 healthy age- and
were assessed in 1066 epileptic patients tak- sex-matched control subjects [9C]. The
ing lamotrigine (n 336), levetiracetam intima media thickness was signicantly
(n 301), or topiramate (n 429) in a sin- increased in patients with epilepsy, more in
gle epilepsy center [5C]. Two-year retention men than in women. Furthermore, whereas
rates were 69%, 46%, and 38% respectively. body mass index, homocysteine, C-reactive
Seizure freedom rates were lowest for lamo- protein, and thiobarbituric acid reactive
trigine and highest for levetiracetam. The substances were signicantly raised,
numbers of patients who withdrew because folic acid and thiols were signicantly
of adverse events were 154/429 (36%) with reduced in the patients with epilepsy. In
topiramate, 52/336 (15%) with lamotrigine, addition, the log-transformed common
and 68/301 (23%) with levetiracetam. carotid artery intima media thickness
The technique of event symmetry analysis increased linearly with duration of anti-
has been used to identify adverse reactions epileptic drug therapy after adjustments
from a population of 479 000 subjects [6C]. for age, sex, and thiobarbituric acid reactive
All prescription data from the Odense Uni- substance concentration.
versity Pharmacoepidemiological Database Total plasma homocysteine concentrations
for the period August 1990 to December and other cardiovascular risk factors
2006 and diagnoses from the County Hospi- have been evaluated in 60 children taking
tal register for the period 1994 to 2006 long-term carbamazepine or valproate [10c].
were used. The method assesses the distribu- Plasma total homocysteine, urine methyl-
tion of disease entities and prescription of malonic acid, and lipoprotein(a) were signi-
other drugs, before and after antiepileptic cantly higher in children taking these drugs
treatment, as asymmetry in these distribu- than in controls. Lower serum vitamin B12,
tions may indicate adverse reactions serum folate, and ApoB were also found in
to antiepileptic drugs. All incident anti- children taking antiepileptic drugs. High
epileptic drug users during the study period homocysteine concentrations were signi-
(n 24 882) were identied. Known adverse cantly associated with urine methylmalonic
events (for example, constipation, nausea, acid.
hyponatremia, and osteoporosis) were
detected. Unanticipated signals from analy- Psychological Children with new-onset,
sis without any preselection of drugs and idiopathic epilepsy have been evaluated at
diagnoses were the association of topiramate baseline and at 6 months (n 45) and 12
with dopaminergic agents, of gabapentin months (n 31) after starting antiepileptic
with glaucoma, and of valproic acid with drug therapy [11c]. Cognitive functioning
hypothyroidism. after 12 months of treatment was signi-
Studies of the contribution of specic cantly improved. However, there was a
adverse reactions to impaired health-related transient drop in performance of children
quality of life have been reviewed [7R]. with generalized seizures after the 6
months, which may have been caused by
Cardiovascular Major atherogenic risk persistent seizures or by the drug used
factors among epileptic children, including (mainly ethosuximide). There was also
altered metabolism of homocysteine, worsening of reaction time and reaction
Antiepileptic drugs Chapter 7 127

time variability in those with focal seizures In January 2008, the FDA issued an alert
at 12 months, which was attributed to the that a meta-analysis had shown a signi-
medications used, mainly carbamazepine. cantly increased risk of suicidality associated
The clinical aspects of the cognitive adverse with all antiepileptic drugs. Suicidality
effects of antiepileptic drugs have been occurred in 4.3 per 1000 patients taking anti-
reviewed [12R]. In an overview of studies that epileptic drugs in the active arm compared
highlighted cognitive evaluation in adults and with 2.2 per 1000 patients in the comparison
children with epilepsy, it emerged that arm [19S]. This represents a risk difference
although aspects of cognitive dysfunction, risk of 2.1 per 1000 (95% CI 0.7, 4.2). This
factors, and consequences have been investi- analysis had grouped data from 199 ran-
gated in many studies, the mechanisms of domized clinical trials, including 43 892
contribution of epilepsy-related variables, patients with epilepsy, psychiatric disorders
including antiepileptic drugs, to patients cog- and other disorders, predominantly pain.
nition have largely been unexplored [13R]. Eleven drugs had been evaluated: carba-
The differential effect of antiepileptic drugs mazepine, felbamate, gabapentin, lamotri-
on mature and immature brains and the gine, levetiracetam, oxcarbazepine,
mechanisms that underlie epilepsy and the pregabalin, tiagabine, topiramate, valproate,
adverse effects of antiepileptic drugs on cog- and zonisamide.
nition are discussed. For many clinicians, the FDA alert was
particularly surprising, because antiepileptic
drugs were considered to be a class (dened
as all drugs that share the ability to reduce
the frequency of seizures) despite their dif-
ferent mechanisms of action, and conse-
Suicidality and antiepileptic quently all of them were considered to be
drugs associated with this risk. This procedure
has been criticized. In fact, analyses for sin-
Up to a few years ago, the association gle antiepileptic drugs were also done and
between the risk of suicidal ideation and showed a signicant protective effect on sui-
behavior and the use of antiepileptic drugs cidality for carbamazepine and divalproex
had been explored in very few studies. In while all other antiepileptic drugs had odds
an observational study of 517 consecutive ratios greater than 1, indicating an
patients taking levetiracetam, four (0.7%) increased risk, although the increase
reported suicidal ideation [14C]. The inci- reached statistical signicance only with
dence of suicidal ideation and behavior lamotrigine (OR 2.08; 95% CI 1.03,
resulting from antiepileptic drug exposure 4.40) and topiramate (OR 2.53; 95% CI
in clinical trials is unknown, because most 1.21, 5.85). Other methodological prob-
published data group all psychiatric adverse lems should be considered. For example,
events together rather than reporting suicid- the FDA included only 33% of these trials
ality by itself [15R, 16R, 17R]. in the main analysis, because trials without
In 2005, in a sponsor's report of a double- reports of suicidality were excluded.
blind study, there was a slightly higher risk It has also been considered that although
of suicidality in the antiepileptic drug-treated the question of suicidality with these drugs is
patients compared with those taking placebo controversial, the adverse effects of failing to
and there were also reports of suicidality control epilepsy are not. If antiepileptic drugs
related to the branded formulation of gaba- are less frequently prescribed or taken, sei-
pentin [18r]. zure control may worsen, with associated
These data prompted the US Food and increases in accidents and mortality, or sud-
Drug Administration (FDA) to reanalyse den unexplained death from seizures [20R].
all data on the risk of suicide in controlled In a large study of people with epilepsy it
studies of antiepileptic drugs. has been reported that 21% had an accident
128 Chapter 7 Gaetano Zaccara and Luciana Tramacere

during the study, of which 24% were seizure- The reaction of neurologists to the FDA
related [21C]. Sudden unexpected death in alert concerning suicidal ideation or behav-
epilepsy (SUDEP) occurs in 0.352.7 per ior and antiepileptic drugs has been
1000 people with epilepsy in population- explored in a study of 175 of 780 partici-
based studies [22R] and is more common in pants who answered a questionnaire via e-
people with uncontrolled seizures [23R]. mail on the approach to suicidality and
Even if the FDA analysis is correct, the risk depression in patients with epilepsy [37c].
of suicidality, predominantly suicidal idea- Although 98% warned about behavioral
tion, is only 3.4/1000 in people with epilepsy adverse effects when starting antiepileptic
taking the 11 antiepileptic drugs. drugs, only 44% warned specically about
The rate of completed suicides in the gen- suicidal ideation or behavior. More than
eral population is 12.0/100 000 [24C], with half were not aware of patients who
a marked predominance in men [25C], attempted to commit suicide or who had
while the lifetime prevalence of suicide committed suicide.
attempts is 0.64.9% overall [26C], with a In 47 918 patients with bipolar disorder
preponderance in women. Epilepsy is co- suicide attempt rates were studied before
morbid with suicidality [27C] and with and after treatment with antiepileptic drugs
major depression [28C]. After a diagnosis and the results were compared with a medi-
of epilepsy, the risk of completed suicide cation-free control group [38C]. There was
increases: the overall standardized mortality no signicant difference in suicide attempt
ratio ranges from 3.5 to 5.0 and is higher in rates in patients taking an antiepileptic drug
the presence of a known psychiatric diagno- (13 per 1000 person-years) compared with
sis [29C]. In addition, suicidal ideation and patients not taking an antiepileptic drug or
behavior have been identied as psychiatric lithium (13 per 1000 person-years). In anti-
phenomena in patients with drug-resistant epileptic drug-treated subjects, the rate of
epilepsy [30C]. suicide attempts was signicantly higher
After the FDA alert, several reviews ana- before treatment (72 per 1000 person-years)
lysed data on the association between suicidal- than after treatment (13 per 1000 person-
ity and psychiatric compliance in patients with years). In patients taking no concomitant
epilepsy, and hypotheses have been proposed. treatment with an antidepressant or an anti-
For example, it has been suggested that forced psychotic drug, antiepileptic drugs were sig-
normalization, although rare, may be an epi- nicantly protective relative to no drug
lepsy-related process that could result in treatment (3 per 1000 versus 15 per 1000 per-
increased suicidality [31C]. It consists of the son-years). The authors concluded that in this
development of depressive or psychotic epi- population of patients, the use of antiepileptic
sodes in patients who become seizure-free after drugs reduces suicide attempt rates.
having suffered chronic drug-resistant epilepsy There has been a longitudinal, retrospec-
[32C]. tive cohort study of all individuals who
This alert can be expected to cause con- obtained anticonvulsants (valproic acid, car-
cern among patients and family members. bamazepine, oxcarbazepine, or lamotrigine;
Accordingly, clinicians should provide a n 9952) or lithium (n 6693) from 1995
comprehensive explanation of the alert, to 2001, and who also obtained anti-
describing this drug-related suicidality risk psychotic drugs at least once [39C]. Among
in the context of the complexity of suicidality the patients who obtained an antipsychotic
in this disease [33R, 34r, 35r]. drug at least once during the study period,
It is likely that in the future a prospective more consistent purchasing of anticonvul-
investigation of suicidality in every regula- sants (at least 6 prescriptions) was associated
tory trial will be required, and it is also pos- with a substantial reduction in the risk of
sible that patients will need to be screened suicide compared with individuals who
for suicidality, depression, and anxiety received only a single anticonvulsant
before randomization [36R]. prescription.
Antiepileptic drugs Chapter 7 129

Metabolism The relation between weight maculopapular and/or erythrodermic in


gain and the homeostatic hormones leptin 77% of patients, bullous in 19%, and erythe-
and insulin has been explored in 70 treated matopustular in 3.2%. Fever and peripheral
and 20 untreated patients with epilepsy lymphadenopathy were detected in 61%
[40C]. Body mass index, serum leptin, and and 55% of cases respectively. Hepatic
serum insulin were signicantly raised in enzymes were raised in 71% and there was
patients taking valproate compared with a leukocytosis in 43% and a peripheral eosin-
untreated patients and those taking carba- ophilia in 64%.
mazepine or lamotrigine. In those taking
valproate, serum insulin correlated with
body mass index, leptin, treatment dura- Musculoskeletal Hip bone mineral density
tion, and drug dosage, and serum leptin was measured in 4222 older community-
correlated with age, body mass index, dwelling men at baseline and at an average
serum insulin, treatment duration, and drug of 4.6 years later, of whom 62 were
and valproate dosage. taking enzyme-inducing antiepileptic drugs,
100 were taking non-enzyme-inducing anti-
Liver The pathogenesis and clinical charac- epileptic drugs, and 4060 were taking no
teristics of drug-induced liver injury associ- antiepileptic drugs [43C]. The average rate
ated with antiepileptic drugs has been of change in total hip bone mineral density
reviewed [41R]. Reactive metabolites can, was  0.35%/year among non-users com-
in some cases, lead to direct cytotoxicity pared with  0.53%/year among users of
and liver cell necrosis, whereas in other non-enzyme-inducing antiepileptic drugs
cases they can cause neoantigen formation, and 0.46%/year among users of enzyme-
inducing immunoallergic mechanisms. In inducing antiepileptic drugs. In these old
fact, hypersensitivity features are found in people, the use of non-enzyme-inducing
more than 70% of patients with pheny- antiepileptic drugs was independently asso-
toin-induced liver injury, whereas this is ciated with increased rates of hip bone loss.
only observed in 30% of carbamazepine- Bone mineral density has been assessed
associated hepatotoxicity and very rarely in 96 children with epilepsy taking anti-
with valproate-induced liver injury. No spe- epileptic drugs and in 63 healthy children
cic therapy is of proven value in these and adolescents [44c]. There was abnormal
cases. However, carnitine, which is an bone mineral density in 56, with values doc-
important co-factor in mitochondrial beta- umenting osteopenia in 42 and osteoporosis
oxidation of fatty acids, is recommended in 14. There was a signicant difference
in valproate-associated liver injury, and N- between patients with epilepsy and con-
acetylcysteine is an appropriate treatment trols. Lack of autonomous gait, severe men-
in patients with liver injury due to pheny- tal retardation, a long duration of
toin and carbamazepine. Liver transplanta- antiepileptic drug treatment, topiramate
tion may be required for patients with the adjunctive therapy, and less physical activ-
most severe liver reactions. ity correlated signicantly with abnormal
bone mineral density.
Skin The clinical and laboratory ndings of In a casecontrol study using data from a
anticonvulsant hypersensitivity syndrome hip fracture register of a US county with a
have been retrospectively evaluated using population of almost 500 000 inhabitants,
the medical records of 31 patients over a 12- 7557 patients were admitted to county hospi-
year period [42C]. The syndrome was related tals with a hip fracture [45C]. Controls (n
to carbamazepine in 48% of all cases, phe- 27 575) were frequency matched by age
nytoin in 35%, and lamotrigine in 9.6%, and sex. Fracture risk was increased with
and in co-treatment with lamotrigine and ever use of any antiepileptic drug. The risk
valproic acid in 6.5% of cases. Symptoms was also increased in those who used only
appeared at 286 (mean: 36) days after the enzyme-inducing drugs, and not in those
start of treatment. The rashes were who used non-inducing antiepileptic drugs.
130 Chapter 7 Gaetano Zaccara and Luciana Tramacere

Fracture risk was higher with recent use and Teratogenicity The mental and motor
high daily dosages. developmental quotients of 395 infants of
The adverse effects on bone caused by mothers with epilepsy have been prospec-
chronic anticonvulsant drug therapy have tively evaluated [50C]. Infants not exposed
been reviewed [46R]. to antiepileptic drugs (n 32) had a higher
Bone mineral density at the left femoral mental developmental quotient (mean 92;
neck and spine has been measured in 130 95% CI 81, 103) and motor developmen-
Thai patients with epilepsy who had been tal quotient (mean 95; 95% CI 85, 105)
taking long-term antiepileptic drugs, either than those who had been exposed to anti-
as monotherapy (n 79) or polytherapy epileptic drugs (mean 89; 95% CI 86, 92
(n 51) [47c]. Bone mineral density at the and mean 90; 95% CI 87, 93 respec-
femoral neck had a mean Z-score of tively). Those exposed to polytherapy had
0.15 and at the lumbar spine 0.56. signicantly lower developmental quotients
There was osteopenia in the spine in 31 than those exposed to monotherapy. On
patients and in the femoral neck in 30. multiple regression analysis, polytherapy
Three patients had osteoporosis of the was a stronger predictor of lower develop-
spine and one had osteoporosis of the fem- mental quotients than dosage. Valproate
oral neck. monotherapy was associated with signi-
In a cross-sectional observational study of cantly lower mental and motor develop-
the effects of antiepileptic drug treatment on mental quotients.
vitamin D status and markers of bone turn- All births delivered in Norway from 1999
over in 38 children with epilepsy, the results to 2005 (n 372 128) have been analysed,
were compared with those obtained in 44 and 2805 pregnancies in women with a cur-
healthy controls [48c]. More than 75% of rent or past history of epilepsy (0.8%) and
the patients were vitamin D decient and 362 302 pregnancies in women without a
21% had insufcient vitamin D. Serum con- history of epilepsy were selected [51C].
centrations of osteocalcin and bone alkaline Women with epilepsy had an increased risk
phosphatase were signicantly raised, but of mild pre-eclampsia and delivery before
the concentrations of C terminal telopeptide week 34. Antiepileptic drugs were used in
of type I collagen were signicantly reduced. 233 of the pregnant women with epilepsy
There were signicantly lower concentra- (94%). These patients had an increased risk
tions of vitamin D and C terminal telopep- of mild pre-eclampsia, gestational hyper-
tide of type I collagen and higher activities tension, vaginal bleeding late in pregnancy,
of bone alkaline phosphatase in those taking and delivery before 34 weeks of gestation.
polytherapy. There was no signicant increase in the risk
of these complications in women with epi-
lepsy who were not using antiepileptic
drugs.
Sexual function The effects of oxcarbaz- All 2861 deliveries by women with epilepsy
epine monotherapy on sexual function have recorded in Norway in a certain period were
been studied in 673 men with partial epi- compared to all 369 267 non-epilepsy deliver-
lepsy [49C]. In 181 (79%) of 228 patients ies observed in the same period [52C]. Most of
with pre-existing impairment, sexual func- those with epilepsy (n 1900) did not use
tion improved; 23 had no impairment at antiepileptic drugs during pregnancy, while
the nal visit. The improvements were most in 961 pregnancies there was exposure. Com-
marked in patients who stopped taking pared with non-epilepsy controls, antiepilep-
enzyme-inducing antiepileptic drugs after tic drug-exposed infants were signicantly
starting to take oxcarbazepine. The authors more often preterm and more often had low
suggested that enzyme induction has nega- birth weights (<2500 g), low head circum-
tive effects on sexual function and that sub- ferences (< 2.5 percentile), and low Apgar
stitution with less inducing drugs may be scores. The frequency of major congenital
benecial. malformations was 2.8% (n 81) in the
Antiepileptic drugs Chapter 7 131

epilepsy group versus 2.5% in the controls. Furthermore, exposure to valproate in utero
An increased risk of major malformations seems to be associated with poorer postnatal
could be demonstrated only for exposure to cognitive development.
valproate (5.6%) and polytherapy (6.1%). The available evidence on the manage-
Cesarean section was performed more ment of women with epilepsy during preg-
often in maternal epilepsy, regardless of drug nancy, including the risk of pregnancy-
exposure. associated complications or other medical
The use of antiepileptic drugs in 4798 problems, have been discussed by a commit-
pregnancies in women with epilepsy has tee of the American Academy of Neurology
been prospectively studied using data from [62S, 63S]. For women with epilepsy taking
38 countries. Exposure to second-genera- antiepileptic drugs, there is probably no sub-
tion antiepileptic drugs ranged from 3.5% stantially increased risk of cesarean delivery
in India and 7.3% in Italy to 75% in Den- or late pregnancy bleeding, and probably
mark. The use of second-generation drugs no moderately increased risk of premature
has increased over time (for lamotrigine, contractions or premature labor and deliv-
from 9.9% of all pregnancies before 2001 ery. However, smoking may increase the
to 30% after 2003) [53C]. risk. Seizure freedom for at least 9 months
In an interim analysis of cognitive out- before pregnancy is probably associated with
comes at 3 years of age in 309 children whose a high likelihood (8492%) of remaining
mothers who took a single antiepileptic seizure-free during pregnancy. Preconcep-
agent (carbamazepine, lamotrigine, pheny- tional folic acid supplementation was possi-
toin, or valproate) during pregnancy in the bly effective in preventing major congenital
USA and the UK, children who had been malformations in the children of women with
exposed to valproate had signicantly lower epilepsy taking antiepileptic drugs [64S, 65S].
IQ scores than those who had been exposed Supplementation with vitamin K was not
to other antiepileptic drugs [54C]. After considered useful, because there is no evi-
adjustment for maternal IQ, maternal age, dence of an increased risk of hemorrhagic
antiepileptic drug dosage, gestational age at complications.
birth, and maternal preconception use of
folate, the mean IQ was 101 in children
exposed to lamotrigine, 99 in those exposed Lactation Concerning transfer of anti-
to phenytoin, 98 in those exposed to epileptic into breast milk, it was judged that
carbamazepine, and 92 in those exposed primidone and levetiracetam transfer into
to valproate. The association between breast milk in clinically important amounts,
valproate use and IQ was dose-related. This and that valproate, phenobarbital, pheny-
nding supports a recommendation that toin, and carbamazepine probably are not
valproate should not be used as a rst-choice transferred in clinically important amounts
drug in women of childbearing potential. [64S, 65S]. During pregnancy, there is an
The consequences of exposing fetuses to increase in the clearance of lamotrigine,
antiepileptic drugs during pregnancy have phenytoin, and to a lesser extent carbamaz-
been discussed in several reviews and cor- epine, and possibly reduced concentrations
respondences [55R, 56r, 57R, 58R, 59R, 60R]. of levetiracetam and of the active metabo-
All new information on the teratogenic lite of oxcarbazepine. Supplementing with
effects of the most frequently used anti- at least 0.4 mg of folic acid before preg-
epileptic drugs has been reviewed [61R]. nancy and monitoring lamotrigine, carba-
The prevalence of major congenital malfor- mazepine, and phenytoin concentrations
mations associated with exposure to carba- and probably also levetiracetam and the
mazepine or lamotrigine was only monohydroxy derivative of oxcarbazepine
marginally increased from expected, while is recommended.
malformation rates with valproate have been
reported to be 24 times higher. This adverse Susceptibility factors Genetic Genetic pre-
outcome appears to be dose-related. dictors of susceptibility to adverse reactions
132 Chapter 7 Gaetano Zaccara and Luciana Tramacere

to antiepileptic drugs and their molecular Management of adverse drug reactions


mechanisms have been reviewed [66R]. The clinical characteristics and treatment
of the anticonvulsant hypersensitivity syn-
drome have been reviewed. Treatment with
Drug overdose Of 16 796 toxic exposures
N-acetylcysteine and intravenous immuno-
to antiepileptic drugs (phenytoin, valproic
globulin is suggested. The rationale for this
acid, and carbamazepine) in the USA in
relies on the scavenging properties of N-
2006, 12 resulted in death, as reported by
acetylcysteine and on modulation of the
the US Toxic Surveillance System [67c].
over-reactive immune system by immuno-
Some specic problems determined by over-
globulin [71R].
dose of some old and new antiepileptic
drugs have been briey reviewed. For exam-
ple, topiramate can cause a signicant meta-
bolic acidosis, lamotrigine StevensJohnson
syndrome, oxcarbazepine hyponatremia, Carbamazepine [SED-15, 627; SEDA-
and levetiracetam psychosis. Possible adop- 30, 78; SEDA-31, 107; SEDA-32, 126]
tion of guidelines for critical care manage-
ment of overdose are discussed. Observational studies In a long-term,
open, observational study, the long-term
Drugdrug interactions In a pharmaco- retention rate and adverse effects of carba-
epidemiological study, the likelihood of rel- mazepine (n 105) were evaluated and
evant drug interactions of antiepileptic compared with topiramate (n 41) in
drugs with other drugs has been analysed infants and toddlers with epilepsy [72c].
through inspection of a medical and phar- After 6 months, 73% of those who had
maceutical claims database. All the data of been treated with topiramate and 63% of
adults with epilepsy and taking any anti- those who had been treated with carbamaz-
epileptic drug during the period from 1 July epine were improved. Topiramate was
2001 to 31 December 2004 were extracted withdrawn because of adverse effects in
and analysed for concomitant non-anti- only one case (2.4%), whereas carbamaze-
epileptic drugs used after the start of pine was withdrawn because of adverse
antiepileptic drug therapy. Concomitant effects in 6.7% of patients.
medications were used in every age group
and use increased with age in both men Comparative studies Carbamazepine and
and women. Polypharmacy with non-anti- oxcarbazepine as adjunctive therapy in 52
epileptic drug medications was common in patients with bipolar I and bipolar II affec-
both men and women and was not unique tive disorder taking lithium maintenance
to elderly patients with epilepsy. These treatment have been compared in an 8-
ndings suggest that clinicians must be week, double-blind, randomized, parallel-
mindful of potential interactions of anti- group, single-center study [73c]. Several
epileptic and non-antiepileptic drugs in adverse events were signicantly more fre-
patients of all age groups [68C]. quent with carbamazepine: sedation (n
Interactions of antiepileptic drugs with 16), increased appetite (n 13), weight gain
drugs that are usually prescribed in the (n 11), tremor (n 5), constipation (n
postsurgical care of transplant recipients 3), nausea/vomiting (n 3), dry mouth (n
have been reviewed [69R]. 2), and insomnia (n 2). Hyponatremia,
The possible adverse consequences of hypertension, tachycardia, diplopia, rush,
CYP isoenzyme induction have been and electrocardiographic abnormalities
reviewed and the authors suggested that were not observed.
new treatment for epilepsy be started with
non-inducing antiepileptic drugs unless Systematic reviews A systematic analysis
there is a clear indication for one of the of seven randomized controlled trials
inducing drugs [70R]. assessing the comparative efcacy of
Antiepileptic drugs Chapter 7 133

carbamazepine and lithium in the treatment drugs, the blood pressure improved only after
of acute mania and in the maintenance withdrawal of carbamazepine.
phase of bipolar disorder has been per-
formed [74M]. In three acute studies with- A lesion in the splenium of the corpus cal-
drawals due to adverse effects and the losum occurred 10 days after sudden carba-
numbers of subjects with at least one mazepine withdrawal and resolved 2
adverse effect were not different between months later; this could have been coinci-
carbamazepine and lithium. In four studies dental [77A].
of maintenance treatment the number of
withdrawals because of adverse effects was Endocrine The effects of long-term carba-
signicantly higher with carbamazepine. mazepine (n 18) and valproate (n 14)
on thyroid function in newly diagnosed
Cardiovascular A retrospective electrocar- children with epilepsy have been evaluated
diographic study in elderly patients (>65 in a prospective open comparison with 32
year old) with newly diagnosed epilepsy sex- and age-matched controls [78c]. At
and randomized to sustained-release carba- baseline evaluation, thyroid function was
mazepine or lamotrigine in 108 patients normal. At the 3rd, 6th, and 12th month
who had been previously included in an evaluations, patients taking carbamazepine
international randomized double-blind, 40- had serum thyroxine (T4) and free thyrox-
week trial, excluding patients with signi- ine (fT4) concentrations signicantly lower
cant unpaced atrioventricular conduction than baseline and control subjects; valpro-
defects, there were no signicant changes ate had no such effect.
in QRS duration or QT intervals between In a prospective, randomized study of
baseline and treatment visit, but heart rate thyroid function in 160 men and women
fell and PQ intervals increased slightly with with epilepsy both before and after dou-
both treatments. There were no differences ble-blind withdrawal of antiepileptic drug
between the groups in changes from base- monotherapy, serum samples were
line to treatment visit and no relations obtained from 130 [79C]. After drug with-
between individual electrocardiographic drawal, there were signicant increases in
changes and serum drug concentrations, free thyroxine serum concentrations in
except for QTc intervals, which shortened those who had taken carbamazepine.
slightly with increasing carbamazepine
concentrations. Metabolism A role of carbamazepine in
the pathogenesis of hyperammonemia was
Respiratory Acute interstitial pneumonitis suspected in a 26-year-old man with bipolar
with atypical features has been attributed disorder [80A].
to carbamazepine in a patient with post-
A 26-year-old man with bipolar disorder, sei-
herpetic neuralgia [75A]. zures, and mild mental retardation, who had
started taking carbamazepine for aggression
Nervous system Drug-resistant hyperten- and seizure control 3 weeks before, developed
severe agitation and aggressive behavior.
sion with leukoencephalopathy might have Other medications, which had been stable for
been due to carbamazepine [76A]. at least 6 months, included topiramate, olanza-
pine, quetiapine, guanfacine, and desmopres-
A 21-year-old man who took carbamazepine sin acetate. All laboratory examinations and
for idiopathic trigeminal neuralgia for several vital signs were normal. The serum carbamaz-
days developed arterial hypertension (from epine concentration was 3.9 mg/l and serum
110/60 to 170/126 mmHg) followed by distur- ammonia 127 (reference range 1960) mg/l.
bance of consciousness. An MRI scan showed Carbamazepine was withdrawn and he was
transient hyperintense lesions in the bilateral given oral lactulose. His serum ammonia con-
fronto-parieto-occipital subcortical white mat- centration returned to normal after 4 days.
ter, suggesting the presence of vasogenic This patient had previously a raised serum
edema caused by hypertension. Despite the ammonia concentrations while taking valproic
administration of various antihypertensive acid.
134 Chapter 7 Gaetano Zaccara and Luciana Tramacere

Serum leptin and insulin concentrations was raised, with an eosinophilia, and there
have been measured in 56 epileptic patients was liver dysfunction. On day 21 after the start
of symptoms anti-HHV6 IgM was detected.
who had been on monotherapy with carba- About 1 month later, the skin eruption, fever,
mazepine for at least 6 months and in 42 lymphadenopathy, liver dysfunction, and
control healthy subjects [81c]. Body mass eosinophilia progressively disappeared.
index and leptin and insulin concentrations
were not different in those taking carba- A patient who had had carbamazepine-
mazepine compared with controls. induced DRESS presented with the same
clinical picture after taking lamotrigine for
52 days. The authors discussed cross-reac-
Hematologic It has been suggested that tivity between carbamazepine and lamotri-
carbamazepine may have caused a fatal gine, which are aromatic and non-aromatic
case of anaplastic large cell lymphoma in a anticonvulsants [89A].
73-year-old man with diabetic neuropathy HLA allele B*1502 is a marker for an
and rapidly progressive erythematous skin increased risk of carbamazepine-induced
lesions [82A]. StevensJohnson syndrome and toxic epi-
dermal necrolysis in Han Chinese. The
Skin Drug reactions with eosinophilia and FDA has therefore changed the carbamaz-
systemic symptoms (DRESS) in patients epine label, recommending genotyping in
taking carbamazepine have been reported all Asians [90S].
[83A]. Involvement of internal organs was Carbamazepine-induced toxic epidermal
often characterized by liver injury [84A, necrolysis has been reported in a child
85Ar]. [91A].
In four cases drug hypersensitivity syn- The possible association between HLA-
drome was triggered by carbamazepine in B*1502 and carbamazepine- or phenytoin-
the presence of concomitant active human induced StevensJohnson syndrome or
herpesvirus (HHV-6), demonstrated by maculopapular eruptions has been explored
positive PCR for viral DNA and an in 31 Thai subjects who had these antiepi-
increased anti-HHV-6 IgG titer. In one of leptic drug-induced complications between
these patients, drug-specic lymphocytes 1994 and 2007 and in 50 antiepileptic
were detected by a lymphocyte transforma- drug-tolerant controls [92c]. There was a
tion test when the virus was active. Further- strong association between HLA-B*1502
more, two genetic factors previously and phenytoin- and carbamazepine-
associated with intolerance to carbamaze- induced StevensJohnson syndrome. How-
pine were detected: the allele HLA-A*3101 ever, some patients with HLA-B*1502 had
(a genetic variant of human leukocyte anti- had carbamazepine-induced StevensJohn-
gen) and a homozygous variant allele of son syndrome and were tolerant of pheny-
SNP rs1051740 of the peroxide hydrolase toin and vice versa, which suggests that
gene [86c]. One patient with carbamazepine other factors contribute to this adverse
hypersensitivity syndrome had a strongly reaction.
positive prick and patch skin tests 6 The association between HLA-B*1502
weeks after complete recovery. The useful- and carbamazepine-induced Stevens John-
ness of skin tests in diagnosing carbamaze- son syndrome and toxic epidermal necroly-
pine-induced DRESS has been emphasized sis has been investigated in eight Indian
[87A]. patients, of whom six had the HLA-
B*1502 allele, conrming the association
A 34-year-old man with epilepsy who was tak- in Indian patients [93c].
ing valproic acid and phenobarbital was also The risk of erythema multiforme, Stevens
given carbamazepine and 34 days later devel- Johnson syndrome, or toxic epidermal necro-
oped hyperthermia and cervical lymph- lysis in 72 patients with bipolar disorder tak-
adenopathy and subsequently a generalized
cutaneous eruption (exfoliative conuent mac- ing carbamazepine, valproate, or other
ules and papules) [88A]. The white cell count medications has been analysed using a large
Antiepileptic drugs Chapter 7 135

database [94C]. Both carbamazepine (OR However, a multivariate model, incorporat-


3.7; 95% CI 2.0, 6.8) and valproate (OR ing age and specic genotypes of the
2.2; 95% CI 1.2, 4.2) were associated. EPHX1 gene encoding microsomal epoxide
In a young patient with carbamazepine- hydrolase, showed a signicant association
induced toxic epidermal necrolysis, blister with the maintenance dose of
uid was analysed for protein, chemical, carbamazepine.
and mineral contents [95A]. There was a
threefold increase in albumin and protein Drug formulations In a 3-month, random-
compared with burns blisters. ized, blinded study in patients with type I
or type II bipolar affective disorder, who
Musculoskeletal In a young patient a ten- were already taking carbamazepine or
don sheath abscess was considered a possi- who were starting to take it, immediate-
ble complication of severe carbamazepine release or extended-release carbamazepine
hypersensitivity [96A]. capsules were substituted. Autonomic and
gastrointestinal adverse events were signi-
Sexual function Sexual function has been cantly less common in those who took the
investigated in patients with epilepsy (aged extended-release formulation [99C].
1845 years) taking carbamazepine (63
men/30 women), lamotrigine (37 men/40 Drug overdose In 115 of 130 poisoned
women), or levetiracetam (30 men/26 patients aged 1459 years plasma carba-
women) monotherapy and in healthy con- mazepine concentrations were above the
trols (36 men/44 women) [97c]. In women usual target range [100C]. There was acute
using carbamazepine, steroid hormone- pulmonary failure in three cases. There
binding globulin concentrations were was a positive correlation between plasma
higher and progesterone concentrations carbamazepine concentrations and both
lower. Arizona Sexual Experience Scale systolic blood pressure and heart rate.
scores suggested that women taking lamo-
trigine and levetiracetam have better sexual Drugdrug interactions Aripiprazole The
function than those taking carbamazepine pharmacokinetic interaction of carbamaze-
and controls. In men, carbamazepine was pine with aripiprazole has been studied in
associated with lower free androgen indices 18 in-patients with schizophrenia [101c].
and dehydroepiandrosterone sulfate con- One week after co-administration of carba-
centrations and higher concentrations of mazepine 400 mg/day plasma concentra-
steroid hormone-binding globulin, follicle- tions of aripiprazole and its metabolite
stimulating hormone, and luteinizing hor- dehydroaripiprazole fell by 64% and 68%
mone. Arizona Sexual Experience Scale respectively.
scores for men were similar in all groups.
Paracetamol A pharmacokinetic inter-
Susceptibility factors Genetic Polymorphic action was suspected in a 34-year-old man
variants in various genes involved in the taking carbamazepine for complex partial
pharmacokinetics and pharmacodynamics seizures, who developed acute liver and
of carbamazepine have been investigated renal failure after taking less than 2.5 g a
in 70 patients with epilepsy who had day of paracetamol [102A].
beneted from carbamazepine monother-
apy [98C]. Known variants in drug-metabo- Tacrolimus The metabolism of tacrolimus
lizing enzyme genes and a sodium channel is largely via CYP3A4, and all agents that
polymorphism in SCN2A were screened induce or inhibit this enzyme can change
using polymerase chain reaction-restriction its blood concentration. The interaction of
fragment length polymorphism or direct tacrolimus with carbamazepine has been
sequencing. No single genetic variable was studied in a patient who underwent heart
of sufcient power to inuence carbamaze- transplantation [103A]. The dose-corrected
pine dosing requirements independently. AUC0!12h of tacrolimus 11 days after
136 Chapter 7 Gaetano Zaccara and Luciana Tramacere

carbamazepine treatment was about 50% Gabapentin [SED-15, 1465; SEDA-30,


of the value before carbamazepine, and 80; SEDA-31, 110; SEDA-32, 131]
about 70% after 3 months.
Observational studies In an open study in
75 patients with chemotherapy-induced
neuropathic pain, gabapentin monotherapy
800 mg/day caused mild somnolence in
Ethosuximide about 25%, but none stopped taking the
drug [106c].
Immunologic Systemic lupus erythematosus
with an increase in anti-double-strand
DNA antibodies has been attributed to Comparative studies In a 6-week, double-
ethosuximide [104A]. blind, double-dummy, crossover trial in 56
patients with diabetic polyneuropathy or
A woman with refractory absence epilepsy at post-herpetic neuralgia, daily oral gaba-
age 8 years developed arthritis with an pentin, nortriptyline, and their combination
increase in anti-double-strand DNA anti- were compared and drug doses were
bodies while taking ethosuximide and carba-
mazepine. Both drugs were withdrawn and titrated to the maximum tolerated dose
the symptoms were ascribed to carbamaze- [107C]. There was less pain with combina-
pine. At age 24, because of numerous absence tion treatment than with gabapentin or nor-
seizures, ethosuximide 1000 mg/day was again triptyline alone. During dose titration,
prescribed and 1 month later she had arthral-
gia and fever and the antinuclear antibody moderate or severe dry mouth was signi-
concentration was were 80 UI/ml. Etho- cantly more frequent with nortriptyline or
suximide was continued and 3 weeks later combination treatment than with gaba-
the antinuclear antibodies were 640 UI/ml pentin, whereas an inability to concentrate
and the anti-double-strand DNA antibodies was signicantly more frequent with gaba-
were 33 IU/ml. Ethosuximide was withdrawn
and the antibodies normalized and the arthral- pentin. At the maximum tolerated dose,
gia and fever abated. moderate or severe dry mouth was signi-
cantly more frequent with nortriptyline or
This case was unusual, since drug-induced combination treatment than with gabapen-
lupus is usually associated with antibodies tin. There were no serious adverse events.
to single-stranded, not double-stranded, Gabapentin and lorazepam have been
DNA. compared in the treatment of alcohol with-
drawal symptoms in a double-blind study in
100 patients, who were randomized to two
doses of gabapentin (900 mg/day tapering
to 600 mg/day or 1200 mg/day tapering to
Felbamate [SED-15, 1328] 800 mg/day) or lorazepam (6 mg/day taper-
ing to 4 mg/day) for 4 days [108C]. There
was a tendency for lorazepam to cause
Observational studies In a retrospective
more sedation and for gabapentin more
chart review study of felbamate in 53 chil-
pruritus. One patient who used gabapentin
dren under 4 years, 16 reported at least
was withdrawn because of urticaria. Two
one adverse event while taking felbamate
participants who stopped taking gabapentin
and none required drug withdrawal [105c].
600 mg had probable withdrawal seizures
The events were somnolence (n 7), loss
and one had a syncopal event. No patients
of appetite (n 6), sleep disturbance (n
had delirium tremens.
5), behavioral changes (n 4), and vomit-
In a double-blind, 4-week, placebo-con-
ing (n 1). There were no serious adverse
trolled trial, 214 men with hot ushes, on
effects during the study and no signicant
a stable androgen deprivation therapy pro-
laboratory changes in liver or renal func-
gram for prostate cancer, were randomized
tion or hematology.
to placebo or gabapentin at target doses of
Antiepileptic drugs Chapter 7 137

300, 600, or 900 mg/day, without benet Gabapentin-induced myoclonus occurred


[109C]. The only adverse effects that were in an elderly patient with no other medical
signicantly different between the com- conditions that could have caused it [113A].
bined gabapentin arms and the placebo A patient with end-stage renal disease
arm were loss of appetite and constipation, developed an encephalopathy a few days
which were more common with placebo. after taking gabapentin in usual adult
Gabapentin and controlled-release oxy- doses. Gabapentin is excreted unchanged
codone have been used for acute pain in in the urine and its half-life, normally 59
87 patients with herpes zoster in a 28-day, hours, increases to up to 132 hours in
double-blind, placebo-controlled trial, start- anuria [114A].
ing within 6 days from the onset of the rash, Chorea in an elderly patient with anxiety
with only modest benet from gabapentin resolved completely after gabapentin was
during the rst week [110C]. There were withdrawn [115A].
signicantly more withdrawals among those
taking oxycodone. Four of those who took A 75-year-old man with anxiety disorder
gabapentin did not complete the study developed choreiform movements involving
the neck, trunk, upper and lower limbs, and
because of adverse effects or serious tongue after taking gabapentin 300 mg three
adverse effects (two with imbalance and times a day (tds) for 1 month. He had no fam-
dizziness, one with tremulousness and dizzi- ily history of Huntington's disease or other
ness, and one with fever). The NNTH for conditions that might have caused chorea.
The symptoms resolved within 2 days of gaba-
withdrawal because of adverse effects or pentin withdrawal.
serious adverse effects was 5.8 for con-
trolled-release oxycodone and 9.7 for In a retrospective study in 162 patients
gabapentin. with epilepsy taking gabapentin, pre-existing
myoclonus was worsened in two cases within
2 weeks of starting gabapentin; in another
Systematic reviews In a systematic review case it occurred de novo [116c]. Withdrawal
of four randomized placebo-controlled of gabapentin or clonazepam add-on treat-
studies of gabapentin in women with hot ment resulted in resolution of myoclonus
ushes after natural or tamoxifen-induced with no serious sequelae in all three cases.
menopause, dropouts due to adverse events
were more frequent in those who took
Sensory systems Hearing loss was attributed
gabapentin, particularly two adverse
to high concentrations of gabapentin in a
effects, dizziness/unsteadiness and fatigue/
patient with renal insufciency [117A].
somnolence [111M].
A 46-year-old woman with a 6-year history of
diabetes mellitus and previously normal renal
Nervous system Bilateral ballismus has function developed anuria, hearing loss, myoclo-
been observed in a woman with Parkinson's nus, and confusion with hallucinations. She was
taking lisinopril, hydrochlorothiazide, furose-
disease after the administration of gabapen- mide, atorvastatin, omeprazole, salmeterol/uti-
tin; it resolved fully after drug withdrawal casone and salbutamol by inhalation,
[112A]. metformin, insulin, oxycodone, alprazolam, ven-
lafaxine, and gabapentin 300 mg tds. The gaba-
An 83-year-old woman with Parkinson's dis- pentin blood concentration was 17.6 mg/l. All
ease was given gabapentin for neuropathic her symptoms improved after one session of
pain and after 5 days developed generalized hemodialysis and had resolved at the time of dis-
dyskinetic movements involving all four limbs, charge 4 days later.
which were so severe that they prevented her
from standing. Her mental function was nor-
mal and she had no other neurological signs. Skin A xed drug eruption has been associ-
A CT scan of the brain and laboratory tests ated with gabapentin [118A].
were normal. Gabapentin was withdrawn and
within 4 weeks the involuntary movements A 44-year-old man with post-herpetic neural-
resolved completely. gia was given amitriptyline and gabapentin
138 Chapter 7 Gaetano Zaccara and Luciana Tramacere

300 mg tds. After 2 days he developed a 1847 U/l (240480 U/l), and the serum potas-
mildly itchy and painful bullous eruption in sium concentration was 6.3 mmol/l (3.55.5
the mouth; it soon ruptured leaving an ero- mmol/l). There was myoglobin in the urine.
sion. Gabapentin was withdrawn. The lesion Electromyography conrmed a myopathy.
healed slowly in 810 days. He was subse- She underwent emergency hemodialysis. A
quently treated with pregabalin which was muscle biopsy showed changes of myopathy.
well tolerated. Repeated patch testing was Gabapentin was withheld. She was given par-
always negative. However, oral provocation enteral uids and furosemide and gradually
with gabapentin 300 mg produced the same improved.
bullous lesion at the same site after 4 hours.

An urticarial rash has been attributed to Susceptibility factors Renal disease Un-
gabapentin [119A]. recognized gabapentin toxicity, mainly
characterized by a signicant deterioration
Hair Acute alopecia developed in a patient in consciousness, occurred in a patient with
who took gabapentin for neuropathic pain acute renal impairment [123A]. During epi-
[120A]. sodes of acute renal insufciency the dose
of gabapentin should be reduced.
A 28-year-old woman took gabapentin 1800
mg/day for a continuous sharp pain and a
burning sensation with allodynia and hyper- Drug formulations Gabapentin has a short
algesia in her right shoulder blade. After 1
week she noticed signicant hair loss with pat- half-life and a saturable mechanism of
chy areas of alopecia among areas of normal absorption, with consequent lack of propor-
hair growth. Hematological tests, plasma elec- tionality between doses and concentrations.
trolytes, blood iron and ferritin concentra- New formulations have therefore been
tions, thyroid hormones, cortisol, and
adrenocorticotropic hormone were all within developed. An extended-release formula-
normal limits. Pregnancy, fever, malnutrition, tion may overcome the problems of satura-
dermatological problems, and autoimmune ble absorption and short half-life. When
disorders such as systemic lupus erythemato- administered with a meal, this formulation
sus were excluded. Gabapentin was with- gradually expands and releases the drug to
drawn, and hair shedding stopped 2 months
later, followed by gradual regrowth. the upper gastrointestinal tract over an
extended period of time. This enables it to
Psychiatric A 38-year-old male physician be taken once or twice a day compared
developed delirium and gabapentin depen- with three times a day or more for immedi-
dence after high self-administered doses ate-release gabapentin.
[121A]. In a double-blind, placebo-controlled
study of extended-release gabapentin in
Musculoskeletal Gabapentin can rarely 147 patients with painful diabetic neuropa-
cause a myopathy and rhabdomyolysis. thy, the patients were randomized to pla-
Myoglobinuria, causing acute renal insuf- cebo or gabapentin 3000 mg, either as a
ciency, has been described in a patient with single evening daily dose or as two divided
painful diabetic neuropathy [122A]. doses (1200 mg in the morning and 1800
mg in the evening) for 4 weeks. The inci-
A 63-year-old woman took gabapentin for dence of adverse events was low: dizziness
painful diabetic neuropathy and after 3 weeks in 17%, 12%, and 0% and somnolence in
developed fatigue, gait instability, diffuse mus- 13%, 4.1%, and 0% of patients in the gaba-
cle pain, muscle weakness in her legs, and pentin extended single-dose, divided-dose,
reduced urine output with a reddish color.
She was taking insulin, irbesartan, and gaba- and placebo groups respectively [124C].
pentin 900 mg/day. She had proximal muscle Gabapentin enacarbil is another attempt
tenderness and weakness. The ankle reexes to overcome the problem of gabapentin sat-
were both absent and vibration sensation was urable absorption. It is a prodrug that is
reduced in both feet. There was acute renal
insufciency (creatinine concentration 700 actively transported and provides predict-
mmol/l). Creatine kinase activity was 75 680 able dose-proportional gabapentin expo-
U/l (26167 U/l), lactate dehydrogenase activity sure and oral availability of about 70%.
Antiepileptic drugs Chapter 7 139

In a randomized, double-blind, placebo- Lacosamide


controlled, crossover study, extended-
release gabapentin enacarbil 600 mg tablets The antiepileptic drug lacosamide, a functio-
were given as single oral doses of 2400, nalized amino acid, has a novel mechanism
3600, 4800, or 6000 mg to 32 healthy volun- of actionselective enhancement of slow
teers. Gabapentin exposure in blood was inactivation of voltage-gated sodium chan-
proportional to the dose of gabapentin ena- nels, resulting in stabilization of hyperexcita-
carbil over the range 24006000 mg (equiva- ble neuronal membranes [128R].
lent to 12503125 mg of gabapentin). In August 2008, lacosamide was granted
Blood concentrations of intact gabapentin market authorization by the European
enacarbil were low and transient. The Commission as an adjunctive therapy for
most commonly reported adverse effects, partial-onset seizures with or without sec-
mild to moderate in intensity, were ondary generalization. It was approved by
dizziness and nausea (50% and 25% of sub- the FDA as an adjunctive therapy for par-
jects respectively). Two subjects had treat- tial-onset seizures in October 2008 [129r].
ment-emergent adverse effects rated as It is also effective against neuropathic pain
severe: psychomotor retardation, vertigo, attributed to distal diabetic neuropathy
and sedation (after a dose of 4800 mg) and [130R]. It is available as oral or intravenous
somnolence (after 6000 mg). There were formulations.
no clinically signicant changes in laboratory The apparent lack of sedative effects
parameters, vital signs, or electrocardiogra- makes lacosamide attractive for patients
phy; QTc intervals did not exceed 480 ms or who are likely to develop somnolence with
change from baseline by more than 30 ms other antiepileptic drugs. Reports of poten-
at any dose of gabapentin enacarbil [125C]. tial electrocardiographic changes with laco-
In a 14-day, double-blind, controlled samide suggest that caution is needed
trial, 96 subjects with restless legs syndrome before using it in patients with pre-existing
were randomized to the prodrug gabapen- cardiac disease and in those taking class I
tin enacarbil 1200 or 600 mg/day or pla- antidysrhythmic drugs or drugs that cause
cebo, with benet by day 14 [126C]. The PR interval prolongation. When used as
most common treatment-emergent adverse short-term replacement for oral lacosamide,
events were somnolence (gabapentin ena- intravenous lacosamide is well tolerated
carbil: 1200 mg, 36% and 600 mg, 14%; pla- when administered as a 15-, 30-, or 60-
cebo, 15%) and dizziness (18%, 14%, 3%), minute infusion.
most of which were rated mild or moderate
in intensity.

Observational studies In a 6-month, open


Drug overdose Patients with impaired study, lacosamide was given to 25 patients
driving who were positive for gabapentin with drug-resistant focal epilepsy [131c].
and were submitted to a Toxicology Labo- One patient became seizure-free for 5
ratory between 2003 and 2007 have been months and two for 1 and 4 months. Eight
reviewed [127c]. The concentrations of patients reported a greater than 50% reduc-
gabapentin in blood in 137 cases ranged tion in seizure frequency. Thirteen patients
from <2.0 to 24.7 mg/l, with a mean of 8.4 reported adverse effects during the titration
mg/l. In four cases gabapentin was the only period. In ve patients the adverse effects
drug detected as a possible cause of driving disappeared during the maintenance phase
impairment. The subjects had characteristic and/or with dosage reduction. Most fre-
clinical symptoms (horizontal gaze nystag- quently observed were fatigue (n 6), dou-
mus, poor performance on standardized ble vision (n 5), depression (n 5),
eld sobriety tests, dilated pupils, low body dizziness (n 4), nausea (n 3), irritability
temperature, and increased heart rate and (n 2), word-nding difculties (n 2),
blood pressure). tremor (n 2), and coordination problems
140 Chapter 7 Gaetano Zaccara and Luciana Tramacere

(n 2). Two patients lost more than 10% of respectively) nausea (n 4, 14, 9, and 25),
their body weight. and headache (n 8, 14, 10, and 18). Ver-
In an open study of lacosamide in 69 tigo was reported in eight patients and
patients with painful diabetic neuropathy blurred vision in seven of those taking 600
the initial dose was followed by escalation mg/day. Other neurological adverse events,
by 100 mg/day up to a maximum of 400 such as somnolence and behavioral or cog-
mg/day [132c]. Patients then entered a 20- nitive effects, were relatively uncommon.
week maintenance period after which they Nine subjects in the placebo group (n
could opt to continue for up to about 2.5 65), 17 in the lacosamide 200 mg/day group
years. The most commonly reported adverse (n 141), 30 in the 400 mg/day group (n
events that were considered possibly related 125), and 58 in the 600 mg/day group (n
to the trial medication were headache 137) withdrew because of an adverse event,
(7%), dizziness (7%), tremor (4%), fatigue the most common of which were dizziness
(6%), and diarrhea and nausea (4%). The and nausea. One patient in the lacosamide
adverse events occurred most often during 600 mg group died in cardiac arrest. How-
the titration period. Seven patients withdrew ever, this was considered unlikely to have
because of adverse effectselectrocardio- been related to the trial medication rather
graphic changes (n 2), dizziness and nau- than pre-existing cardiac disease. There were
sea (n 1), chest pain and nausea (n 1), changes in laboratory measurements, weight
dizziness, fatigue, and tinnitus (n 1), pos- gain, and peripheral edema in very few sub-
sible stroke and convulsion (n 1, this was jects. Lacosamide had no effect on the QT
considered a serious adverse event), acciden- interval, but there was a small prolongation
tal overdose (n 1). in the mean PR interval (mean change 5.1
milliseconds in the lacosamide 200 mg/day
Placebo-controlled studies Lacosamide 200, group, 13 milliseconds in the 400 mg/day
400, or 600 mg/day has been studied in three group, and 12 milliseconds in the 600 mg/
randomized, placebo-controlled trials with a day group, compared with 2.3 millisec-
12-week maintenance period, in which onds in the placebo group). There was a
about 1300 patients with partial-onset seizures slight prolongation in mean QRS duration
were included [133M]. There was a statistically in patients taking lacosamide. First-degree
signicant reduction in 28-day seizure fre- atrioventricular block (PR interval > 200
quency compared with placebo. Lacosamide ms) was reported in under 2% of patients
was generally well tolerated in adult patients in any treatment group. There was one case
with partial-onset seizures, and most treat- of second-degree atrioventricular block in a
ment-emergent adverse events were of mild or patient with a normal baseline PR interval
moderate intensity. Dizziness was the most in the lacosamide 600 mg/day group 5 days
common treatment-related adverse event after the last dose.
[134R]. In a multicenter, randomized, placebo-
In a double-blind, randomized, placebo- controlled, double-blind trial in 495 patients
controlled trial, oral lacosamide (200, 400, with painful diabetic neuropathy who took
and 600 mg/day) was given to 654 patients lacosamide 200, 400, or 600 mg/day for 12
with painful diabetic neuropathy for 12 weeks after a 6-week titration phase, the
weeks after a 6-week dose titration period lacosamide 400 mg/day group had signi-
[135C]. The proportions of patients with cant improvement in the primary efcacy
treatment-emergent adverse effects that were measure [136C]. The most common treat-
considered to be at least possibly related to ment-emergent adverse events included diz-
the trial medication were 31% for placebo, ziness, nausea, fatigue, headache, and
39% for lacosamide 200 mg/day, 53% at tremor and all appeared to be dose-related.
400 mg/day, and 68% at 600 mg/day. The For example, the incidence of dizziness was
most common included dizziness (n 3, 8, 5% at 400 mg/day and 22% at 600 mg/day.
27, and 39 in those treated with placebo, There was nausea in 5% of patients taking
lacosamide 200, 400, and 600 mg/day 400 mg/day and 12% of those taking
Antiepileptic drugs Chapter 7 141

600 mg/day. Fatigue was present in 2% that most often led to withdrawal were diplo-
and 7% of patients respectively, and tremor pia (2.2%), vertigo (1.6%), and vomiting
in 2% and 6%. Other central nervous system (1.2%). There were no effects on QT inter-
adverse effects, specically somnolence and val or QRS duration. Lacosamide was asso-
behavioral or cognitive effects, were relatively ciated with a dose-related increase in mean
uncommon. For example, somnolence PR interval (4.6 msec at the end of mainte-
occurred in 3% and memory impairment in nance with 400 mg/day). Laboratory ana-
2%. There were 8, 8, 21, and 37 withdrawals lyses were not affected and body weight did
in patients treated with placebo, 200, 400, or not change.
600 mg lacosamide respectively, and most
occurred early in the study. Dizziness, nau-
sea, and disordered balance were the most
common adverse events that led to drug with-
drawal. The incidence of edema was low (3% Lamotrigine [SED-15, 1990; SEDA-30,
with lacosamide, 4% with placebo). There 80; SEDA-31, 113; SEDA-32, 134]
were no effects on laboratory measurements
attributable to the experimental drug. There Observational studies Lamotrigine has
were no effects on heart rate or QT interval; been evaluated in a study that included an
the placebo-subtracted mean maximum open, 1-week screening phase, a 20-week
change from baseline in PR interval was 6.1 escalation phase, and a 12-week mainte-
milliseconds with lacosamide 200 mg/day, nance phase in 54 children aged under 13
8.3 milliseconds with 400 mg/day, and 9.8 mil- years who had newly diagnosed absence
liseconds with 600 mg/day. The incidence epilepsy and had not previously been trea-
of rst degree atrioventricular block was ted with antiepileptic drugs [138c]. Rash
similar in all the groups and there were