J Autism Dev Disord DOI 10.

1007/s10803-012-1647-0

ORIGINAL PAPER

A Retrospective Study of Amitriptyline in Youth with Autism Spectrum Disorders

Irfan Bhatti Andrew Thome Patricia Oxler Smith Galen Cook-Wiens Hung Wen Yeh Gary R. Gaffney Jessica A. Hellings

Springer Science+Business Media, LLC 2012

Abstract We performed a retrospective chart review of 50 youths with Autism Spectrum Disorder (ASD), prescribed amitriptyline (AMI) for hyperactivity and impulsivity. Data was systematically extracted from 50 outpatient clinic charts, including AMI treatment duration, dose, trough levels and adverse events. Mean age was 9.4 years (4.617.9); 40 were males and 10 females. 30 % had failed atomoxetine and 40 % had failed C3 ADHD medications. Mean dose was 1.3 0.6 mg/kg/day, mean

trough level 114.1 50.5 ng/ml, mean duration 3.4 years. Clinical Global Impressions Scale-Improvement (CGI-I) was B2 in 60 % of patients at the nal visit, and in 82 % of patients for at least 50 % of follow-ups. Cautious use of low dose AMI shows promise for treatment-resistant youth with ASD accompanied by hyperactivity, impulsivity, aggression and self injury. Keywords Amitriptyline Autism Spectrum Disorders Hyperactivity Impulsivity

I. Bhatti Division of Child and Adolescent Psychiatry, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, USA A. Thome School of Medicine M4, University of Missouri-Kansas City, Kansas City, MO, USA P. O. Smith School of Nursing, University of Kansas Medical Center, Kansas City, KS, USA Present Address: G. Cook-Wiens Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA H. W. Yeh Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA G. R. Gaffney Division of Child and Adolescent Psychiatry, University of Iowa Medical Center, Iowa City, Iowa, USA J. A. Hellings (&) The Ohio State University, Nisonger Center, 1581 Dodd Dr, Columbus, OH, USA e-mail: Jessica.Hellings@osumc.edu

Introduction Development of new drugs to treat individuals with Autism Spectrum Disorders (ASD) is minimal, in spite of a growing need. ASD prevalence has increased signicantly since 2002. It is now identied in one in 80 boys, and one in 110 children (CDC Autism Report 2010). In addition, a recent South Korean study identied an ASD in 1 in 38 children, most of whom were not yet diagnosed (Kim et al. 2011). Severe behavior problems associated with ASD include hyperactivity, impulsivity, aggression, property destruction and self-injury which lead to major family and school disruptions as well as lifetime costs estimated at 3.2 million dollars per person (Ganz 2007). Current research emphasis is shifting from symptomatic treatment of the illness to targeting specic molecular causes of ASD. This emphasis shift was based partly on the combating autism act of 2006, which dedicated almost $1 billion to the national institutes of health for basic sciences studies of causes, early detection and possible interventions in ASD. There are likely to be many different molecular causes of ASD, for example deciencies in various mitochondrial enzymes (Dhillon et al. 2011; Frye and Rossignol 2011).

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Given that, advanced etiology-based treatments may still be decades away. A new drug takes up to 15 years to develop for marketing and costs an average of 1.3 billion dollars (Collier 2009). Only two medications are currently approved by the FDA in USA for treating irritability associated with Autistic Disorder. The American Psychiatric Associations Council on Research and Quality Care has identied an urgent and enormous need for autism treatments. The American Academy of Child and Adolescent Psychiatry Research Forum in 2010 identied the need for broader treatment data from unselected patients. Risperidone and aripiprazole are two pharmacologic agents which are relatively well studied in this population and are approved by the FDA for individuals over age 6 years with Autistic Disorder and irritability (Hellings et al. 2006, 2010, 2011; Marcus et al. 2009; Owen et al. 2009; RUPP Autism Network 2002; Zarcone et al. 2004). However, metabolic syndrome, weight gain and associated morbidity are serious risks associated with these medications (Correll et al. 2009; Hellings et al. 2001, 2010). Movement side effects, although less frequent than with rst generation antipsychotics, may also occur with these drugs, including extrapyramidal symptoms, tardive dyskinesias and neuroleptic malignant syndrome. The additional problems of prolactin elevation and related effects are common with risperidone (Hellings et al. 2005, 2010). Hyperactivity, impulsivity, serious aggression and selfinjury are common problematic symptoms in this population, often needing pharmacological interventions (Lecavalier et al. 2006). Since hyperactivity and impulsivity may often respond only partially to antipsychotic agents, use of sequential or combination drug therapy for attention decit hyperactivity disorder (ADHD)-like symptoms may be necessary in many cases, even though more studies are needed. The pros and cons of combination treatments are discussed in a recent editorial by Tamminga (2011), with the conclusion that specic combination studies are needed. Noradrenergic agents may be useful for problematic hyperactivity, impulsivity and aggression, with or without stimulants and antipsychotic agents, in children and adolescents with ASD; although more real-world data and randomized controlled trials are needed. The prefrontal cortex of the cerebral hemispheres is a key brain neural system controlling executive functions and behavioral inhibition, and is primarily noradrenergic, dopaminergic and cholinergic. Prior to, as well as following the marketing of the norepinephrine reuptake inhibitor atomoxetine for ADHD, our group has been cautiously using low doses of the rst-generation TCA amitriptyline (AMI) to target problematic hyperactivity, inattention and impulsivity in youth with ASD. The results have been promising

in many previously challenging and difcult cases, suggesting a need for systematic studies. All tricyclic antidepressants exhibit norepinephrine reuptake inhibition, among other actions (Stahl 2008). TCAs were previously used as second-line agents for ADHD, prior to the development of atomoxetine and long-acting formulations of clonidine and guanfacine. Gordon et al. (1993) performed a double-blind, randomized crossover trial of desipramine, clomipramine and placebo in 24 youths with autism. While clomipramine and desipramine both improved hyperactivity, ratings of irritability increased signicantly in two-thirds of the desipraminetreated subjects. Only clomipramine was statistically superior to placebo in improving repetitive behaviors. Wilens et al. (1996) studied desipramine in a 6-week RCT for adult ADHD with positive ndings. Adults treated with the tricyclic were more likely to continue taking the medication than were those receiving stimulants. In another controlled study conducted by Prince et al. (2000), nortriptyline was found to be safe and effective in reducing ADHD symptoms and oppositionality in youth with ADHD without comorbid ASD. The children and adolescents in that study tolerated nortriptyline well, with few adverse events. The mean dose of nortriptyline was 80 mg per day (1.8 mg/kg/day), resulting in a mean serum level of 81 ng/ml. No signicant adverse events were observed, and children were noted to have some weight gain during the trial. Tricyclic antidepressants have been used for treatment-resistant cases of major depression (Rush 2007), obsessive compulsive disorder (American Medical Association 1991), post-traumatic stress disorder in the general population (Davidson 1990), headaches (Jackson 2010) and neuropathic pain (Max 1987). Amitriptyline (AMI) exhibits anticholinergic action as well as norepinephrine and serotonin- reuptake transporter inhibiting properties (Stahl 2008). In our clinical experience, individuals with ASD with comorbid hyperactivity and impulsivity, who have failed an atomoxetine trial, may respond to low doses of AMI, provided an EKG and blood tests can be obtained. AMI blood level monitoring using trough levels (100250 ng/ml), is essential to prevent cardiotoxicity which may lead to Torsades de pointes and death. Risks of potentially lethal toxicity with AMI overdose require that it should only be used in those youths with responsible parents/caregivers and when close monitoring of pulse, blood pressure, EKG, AMI blood levels and medication compliance can be ensured. We reviewed charts of 50 consecutive clinic outpatients with ASD and comorbid ADHD-like symptoms of hyperactivity and impulsivity, who were treated with AMI. We examined efcacy and safety indicators to inform clinical practice, prospective treatment trials and drug development.

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Method Approval for the retrospective chart review was obtained from the University of Kansas Medical Center institutional review board. Parents or guardians of the subjects gave written consent for inclusion of the outpatient record in the review, and when possible, assent from subjects was also obtained. Inclusion criteria were: males and females; age 418 years; diagnosis of Autistic Disorder, Pervasive Developmental Disorder Not Otherwise Specied, or Aspergers Disorder according to DSM-IV-T-R criteria (APA 2000); and treatment with AMI. Exclusion criteria were signicant noncompliance, with having missed multiple medication doses and/or visits, diagnosis of Childhood Disintegrative Disorder and diagnosis of Rett disorder. There was no requirement of a minimum duration of AMI treatment for study inclusion. Data was extracted and checked independently by two separate investigators as follows: Age at AMI treatment initiation, gender, diagnoses including ASD subtype, intellectual disability level and seizure history. Number of prior ADHD medication trials was recorded as an indicator of treatment resistance. AMI treatment duration, nal AMI dose, trough serum levels and any concomitant psychiatric medications prescribed were extracted. Starting and nal blood pressure, pulse, height, weight, QTc interval on electrocardiogram and any adverse events (AEs) elicited by clinical questioning were recorded. Based on the observed high rates of aggression and self-injury in these youth, these symptoms were also extracted in order to inform readers and researchers regarding their co-occurrence with ADHD-like symptomology in youth with ASD and possible impulsive underpinnings. Primary outcome was measured using the Clinical Global Impressions-Improvement scale (CGI-I) (Guy 1976), with treatment response dened as B2 (Much Improved or Very Much Improved). Secondary outcome was measured as percentage of visits rated as: 1 or Very Much Improved, 2 or Much Improved, using the CGI-I. Since many of these subjects received AMI over a period of years, for this outcome measure response was dened as CGI-I score of B2 (Much Improved or Very Much Improved) at 50 % or more of follow-up visits on AMI. The total number of such visits prior to AMI discontinuation or until the time of chart review, was extracted. The majority of CGI-I ratings were performed routinely at the time of the clinic visits by the same board-certied psychiatrist (J.H.), specializing in developmental disabilities. The visits without documented CGI-I scores were rated by the same rater, using the clinic progress notes. The data was analyzed descriptively. Body mass index (BMI) scores were calculated for baseline and end dates, as well as delta z-score values for age and gender. The latter

scores were compared with CDC norms (CDC.gov website: accessed 5/6/2011). In all cases, prior to prescribing AMI, family history was carefully checked for sudden infant death syndrome (SIDS), sudden death of individuals at young ages, familial long QT syndrome and overdose risk in family members. Cardiac history of the child, including any fainting, chest pain, palpitations and shortness of breath with exertion, was carefully elicited. Pulse, blood pressure, height, weight and EKGs to monitor QTc interval were obtained before AMI prescription and every 34 months during the AMI treatment. Cardiology consultation was obtained prior to the AMI trial if there was any suspicion of cardiac problems or QTc prolongation or if tachycardia persisted at 120 bpm, or if other cardiac concerns arose. AMI was tapered and stopped due to increased QTc above 450, as occurred in 3 cases, although this was a conservative precautionary measure. Parents were warned at each visit to lock away all medication including AMI, and the risk of death due to toxicity of AMI in overdose was also discussed. No cases of accidental or intentional overdoses occurred in this series of cases. We used the minimal effective doses of AMI, in order to increase safety, in view also of the potential for drug interactions in combination treatments. AMI was started at doses of 0.5 mg/kg/day or less at bedtime to help with sleep as well as enuresis if present (30 %). Thereafter, AMI dose was increased gradually according to response and side-effects, often divided into 23 low doses daily.

Results This clinic sample represents a signicant number of treatment-resistant youth with ASD all presenting with accompanying hyperactivity and impulsivity, as well as high rates of associated aggression (90 %) and self-injury (50 %). Mean age was 9.4 years (range 4.617.9 years) at AMI treatment initiation; 10 subjects were female and 40 were male. All met DSM-IV criteria for an ASD and presented with ADHD symptoms of hyperactivity and impulsivity. Fifteen subjects were diagnosed with Autistic Disorder, 31 with Pervasive Developmental Disorder Not Otherwise Specied and 4 with Aspergers Disorder. Levels of intellectual disability accessed from the charts were as follows: Mild in 12 subjects, Moderate in 2 subjects, Severe in 1 and Unspecied in 8 subjects. Seventeen subjects were of normal IQ by history and 10 had Borderline Intellectual Functioning. Ninety percent of the subjects also presented with aggression and 50 % with accompanying self-injury. Thirty percent of these youths had failed a trial of atomoxetine in the past, and 40 % had

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J Autism Dev Disord Table 1 Demographics and Challenging Behaviors in addition to Attention Decit Hyperactivity Disorder-like symptoms

Subject #

Age at AMI start (years) 10.2 13.6 9.2 7.6 11.3 5.8 10.9 7.3 8.4 6.4 7.2 10.6 11.7 6.1 10.2 8.7 17.9 14.9 4.6 8.5 7.6 7.5 10.6 6.1 8.1 7.5 9.5 11.4 5.9 12.4 12.2 8.7 6.9 6.1 9.3 11.0 6.9 12.1 10.4 11.1 6.2 9.9 7.0 12.8 12.4 7.5 10.0 9.3 11.3 10.1

Race

Gender

MR level

Autism type

Aggression

Self injury

01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

c c c c Asian c Mixed aa c c c c c c c c c c c Hispanic c c c aa Mixed c c c c c c c aa c c Mixed c c Laotian c c c Korean c c c c c c c

Male Male Female Male Female Male Male Male Male Male Male Male Male Male Male Male Male Male Female Male Male Female Female Female Male Female Male Male Male Male Female Male Male Female Male Male Male Male Male Male Male Male Male Male Male Male Female Male Male Male

Unspec Mild Mild Unspec BIF BIF Unspec Mild BIF Mild Severe BIF BIF BIF Mod Mild Mild Unspec Mild Mild BIF Mild Unspec Unspec Mild BIF BIF BIF Mild Mild Mod Unspec Unspec

PDD-NOS Aspergers PDD-NOS PDD-NOS AD PDD-NOS PDD-NOS PDD-NOS AD PDD-NOS PDD-NOS AD PDD-NOS PDD-NOS AD AD PDD-NOS PDD-NOS PDD-NOS Aspergers PDD-NOS PDD-NOS AD AD PDD-NOS PDD-NOS AD PDD-NOS PDD-NOS PDD-NOS PDD-NOS Aspergers PDD-NOS AD AD PDD-NOS AD PDD-NOS PDD-NOS PDD-NOS PDD-NOS AD PDD-NOS PDD-NOS AD Aspergers PDD-NOS AD AD PDD-NOS

H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H

H H H H H H H H H H H H H H H H H H H H H H H H H

m missing; c caucasian aa African American ad autistic disorder PDD-NOS pervasive developmental disorder-not otherwise specied

48 49 50

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J Autism Dev Disord Table 2 Amitriptyline dosing, treatment outcomes and side effects

Subject #

Final AMI dose (mg/kg/ day) 0.71 0.53 1.86 0.80 1.28 0.61 1.55 1.14 3.01 1.57 1.70 1.67 0.50 2.15 1.21 2.18 1.70 1.11 1.66 1.25 2.50 0.21 0.68 1.40 0.61 0.93 0.95 1.21 1.01 1.57 1.31 1.08 1.52 1.02 1.19 0.98 0.77 1.46 1.30 0.67 2.36 0.72 0.93 0.50 0.41

Final AMI blood level (lg/dl) 152.00 m 126.00 116.00 121.00 m 191.00 114.00 52.00 57.00 81.00 175.00 m 33.00 142.00 182.00 m m 160.00 64.00 126.00 45.00 60.00 109.00 32.00 77.00 25.00 112.00 183.00 145.00 100.00 155.00 156.00 156.00 173.00 79.00 116.00 m 153.00 m 99.00 133.00 59.00 60.00 61.00

CGI severity start 5 5 5 5 5 6 6 6 6 5 5 4 5 4 6 4 6 6 4 4 5 4 5 5 4 6 6 5 4 5 5 5 5 7 5 6 5 4 6 5 4 4 5 5 6

CGI improvement

Ad/E leading to dose reduction/ discontinuation of AMI

01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

2 3 3 4 3 1 3 3 2 2 2 3 2 3 2 2 2 2 3 4 2 2 3 3 4 2 3 2 2 2 3 2 2 2 3 2 3 2 2 2 3 2 2 2 2 Borderline QTc prolongation Equivocal seizures, neurologist discontinued AMI. Tachycardia 120/min. Shaking/tremors of hands Dose lowered by family, not due to A/E per their report. QTC prolongation, increased appetite, and increased tics Sedation Tachycardia Behavioral activation Worsening of behaviors Sleep episodes? volitional QTc Prolongation; discontinued Aggression increase; discontinued Dry mouth Behavior worsened on 25 mg QID

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J Autism Dev Disord Table 2 continued

Subject # 46 47 48 49 50 Mean

Final AMI dose (mg/kg/day) 0.98 1.10 0.79 1.74 1.41 1.27

Final AMI blood level (lg/dl) 158.00 m 46.00 247.00 50.00 114.1

CGI severity start 5 6 4 6 5

CGI improvement 2 4 2 3 2

Ad/E leading to dose reduction/ discontinuation of AMI

Weight gain and anger outbursts, discontinued

m missing

failed 3 or more previous ADHD drug treatment trials (Tables 1, 2). Mean nal AMI treatment dose was 68.5 mg/day or 1.27 0.59 mg/kg/day; mean 12-h trough blood level was 114.1 50.5 ng/ml. The mean duration of AMI treatment was 3.4 years (range 0.1410.9 years). Thirty individuals (60 %) met the primary outcome response measure at the time of chart analysis, based on CGI-I ratings of B2. Fortyone individuals (82 %) had CGI-I ratings of B2 (Much Improved or Very Much Improved) for at least 50 % of follow-ups; 52 % had CGI-I ratings of B2 at 66 % or more of their follow-up visits. This measure was included as an indicator of long-term outcomes. The mean total number of visits was 15.6 11.1; visits were usually attended quarterly after stabilization of AMI dosage and blood levels, based on response. 32 % of youth received concomitant stimulants (dextroamphetamine in 24 %; other stimulants included: mixed salts of dextroamphetamine, methylphenidate and long-acting methylphenidate). 48 % received concomitant risperidone (see Table 3). Only two of the fty subjects received AMI monotherapy, Subjects 13 and 21. Subject 13 was an 11 year old Caucasian male with PDD-NOS and mild ADHD-like symptoms of hyperactivity and inattention without comorbid aggression or self-injury. He was rated as Much Improved on AMI 20 mg HS. According to parental report, his focus signicantly improved on AMI, together with his school grades. Subject 21 was a 7 year old Caucasian male with PDD-NOS and ADHD-like symptoms who was previously unable to tolerate a trial of atomoxetine due to decreased appetite and only partial behavioral improvement. He was treated with AMI 50 mg HS, for 20 months, with ongoing CGI-I ratings of Much Improved, and improved school and social functioning together with some mild residual anxiety. No cases of intentional or accidental AMI overdose occurred. AMI dose was reduced due to an elevated trough blood level ([250 ng/ml) in 3 cases. Cardiology consultations were obtained prior to the AMI trial in 3 individuals due to prior cardiac histories and in 6 individuals during AMI treatment for concerns regarding tachycardia or QTc

interval prolongation. On electrocardiogram, QTc interval increased in 63 % of individuals but remained within the normal range in all except in one subject. Mean QTc interval was 403.1 25.5 at baseline and 422.1 30.3 at end. Twelve subjects required a reduction in their AMI dose due to AEs, including tachycardia, sedation or behavioral activation, and remained on the lower dose with resolution of the side effects. AMI was discontinued in a total of 4 subjects due to lack of response in one, weight gain and lack of response in one, QTc prolongation of [450 in one, and by a neurologist in one subject due to equivocal seizures. Sedation was documented in 6 subjects (12 %). One additional subject had atypical sleep episodes varying from minutes to hours in duration. One episode was witnessed in clinic and judged most likely volitional with no cause found on neurological or cardiac work-up. Behavioral worsening related to AMI dose adjustment occurred in 4 individuals but resolved in 3, after a dosage decrease, allowing continuation of AMI treatment. Weight gain was not recorded as problematic in most cases, even though adjunctive risperidone was also used in 48 % of cases. Mean BMI at baseline was 18.9 6.0; and at end was 21.5 5.8. Mean BMI z-score at baseline was 0.2 1.6; and at end 0.5 1.4. Mean BMI percentile at the beginning was 59.4 35.6; and at end was 64.8 32.6. Based on a paired t test, there is not a signicant change in BMI z-score between start and end (Mean change = -0.23, SD = 0.86, t = -1.63, p = 0.11).

Discussion In the 1980s and 1990s, to most effectively treat youths attending the University of Kansas Autism Clinic we considered all possible treatments that were then available. Classical antipsychotics, such as haloperidol, although effective (Perry et al. 1989; Cohen et al. 1980) were generally reserved for the most severely agitated youth with Autistic Disorder, related to side effects including

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J Autism Dev Disord Table 3 Concomitant medications Subject # 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 VPA liquid 125 ml am ? 250 ml HS, SERT 25 mg 1/2 HS Clonidine 0.1 mg HS Clonidine 0.1 mg 1/2 Tid ? 1 HS Mixed amphetamine salts 10 mg/10 mg/5 mg, QUET 25 mg Bid VPA 250 mg Bid, DEX MPH 5 mg am & noon, guanfacine 0.5 mg am, clonidine 0.1 mg HS, trazodone 50 mg HS, OLZ 2.4 mg HS Loxapine 5 mg HS MPH-ER 54 mg daily VPA 500/125/125/250, Eskalith CR 450 mg QAM, RIS 0.25 mg Qid, clonidine 0.1 mg QID, MPH 7.5 mg/5/5/5 mg VPA ER 750 mg am, mixed amphetamine salts 10 mg am, noon VPA ER 500 mg HS, MPH 5 mg Tid Guanfacine 1 mg Tid, mixed amphetamine salts 10 mg Tid, melatonin 3 mg HS SERT 75 mg am, RIS 0.5 mg Bid, HS VPA 250 mg am, noon, 500 mg HS, RIS 0.5 mg Tid, felbamate 800 mg am 400 mg 3 pm, ditropan 5 ml/5 ml/3 ml (Tid) Mixed amphetamine salts 15 mg/10 mg/15 mg, gabapentin 400 mg Tid, clonidine 0.1 mg HS Clonidine 0.35 mg/day, hydroxyzine 40 mg HS, trazodone 75 mg HS, glucophage 1000 mg Bid, RIS 0.5 mg Bid VPA 400 mg Bid, ARI 5 mg am, RIS 1 mg HS MPH-ER 27 mg am, tiagabine 2 mg Bid MPH-ER 36 mg am, OLZ 2.5 mg HS,RIS 0.5 mg Bid 0.5 mg PRN MPH-ER 54 mg am, VPA ER 1000 mg Bid RIS 0.25 mg Bid VPA 500 mg Bid, RIS 0.5 mg AM ? 1 mg HS RIS 0.5 mg Bid, melatonin 3 mg HS, DEX 7.5 mg at 8 am ? 11am, 5 mg Q3PM MPH ER 18 mg Am, quetiapine 25-25-100, carbamazepine 500 mg Bid, lamotrigine 125 mg Bid RIS 0.5 mg am, VPA 250 mg Bid VPA ER 500 mg HS, RIS 1 mg am0.5 mg pm1 mg HS SERT 12.5 mg am, clonidine 0.02 mg HS, guanfacine 1 mg Bid am ? 3 pm Escitalopram 10 mg AM, clonidine 0.05 mg HS, RIS 0.5 mg Tid ARI 5 mg daily SERT 25 mg daily RIS 1 mg Bid SERT 25 mg PO am, 50 mg HS, RIS 1 mg HS DEX 15 mg am15 mg noon RIS 0.5 mg Bid, MPH-ER 36 mg q am, MPH 10 mg q 4 pm SERT 75 mg daily, clonidine 0.05 mg Tid Concomitant med name and dose RIS 0.25 mg HS, vasopressin 0.2 mg HS Clonidine 0.1 mg HS, DEX 15 mg am and noon RIS 0.5 mg Tid FLX 10 mg daily, mixed amphetamine salts 10/10/5, TPM 50 Tid, gabapentin 400 Tid, melatonin 6 mg HS, ARI 2.5 mg HS Molindone 2.5 mg am, 5 mg HS, RIS 0.5 mg 0.25 mg, melatonin 3 mg HS SERT 12.5 mg am, RIS 0.75 mg HS Synthroid 0.088 mg, glucophage 500 mg Bid. OLZ 5 mg PRN, gabapentin 500 mg Tid RIS 0.75/0.75/0.5 mg RIS 0.25 am0.5 HS, clonidine 0.05 mg Tid RIS 0.5 mg 1/2 am 1/2 6 pm, vasopressin 0.2 mg HS RIS 0.5 mg am ? 0.25 mg pm ? 0.5 mg HS, lorazepam 0.5 mg PRN RIS 0.5 mg am ? 0.75 mg HS, VPA 250-500 mg, ARI 2 mg HS, SERT 50 mg daily

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J Autism Dev Disord Table 3 continued Subject # 49 50 Concomitant med name and dose

ARI 5 mg HS, Loxapine 5/5/10 mg, VPA ER 500/500/1000 mg, utamide 125 mg, LTG 25/50 mg. Melatonin 3 mg HS Mixed amphetamine salts XR 25 mg AM ? 10 mg(i.r.) at 3 pm

OLZ olanzapine; ARI aripiprazole; ATN atomoxetine; DEX dextroamphetamine; FLX uoxetine; MPH methylphenidate; RIS risperidone; SERT sertraline; TPM topiramate; VPA valproic acid; LTG lamotrigine; GFN guanfacine

dystonias, akathisia and withdrawal dyskinesia. We also tried other pharmacological agents with minimal clinical trial evidence, notably enuramine (Campbell 1988), naltrexone (Campbell et al. 1990; Sandman et al. 1990) and propranolol (Akuffo et al. 1986) in milder cases. Biological studies suggested that the serotonin neurotransmitter system was involved with behaviors in autism including social interactions, aggression and compulsive/ ritualistic symptoms (Anderson et al. 1987; Geller et al. 1982; Kuperman et al. 1985). The selective serotonin reuptake inhibitors were not yet marketed in the United States, nor was clomipramine, the most serotonergic tricyclic drug. Fenuramine was of limited use clinically in our experience in this population. Therefore our clinical group tried amitriptlyine as the most potent serotonergic tricyclic agent then available (Richelson and Nelson 1984). Furthermore, tricyclic agents were extensively used to treat ADHD symptoms in children at the time (Biederman and Jellinek 1984). We prescribed AMI as a non-stimulant treatment for ADHD-like symptoms of hyperactivity, impulsivity and inattention in youth with ASD. Aggression and self-injury also improved, with the caveat that other medications including stimulants and antipsychotics, most recently atypical antipsychotics were also used together with AMI. Doses of AMI were employed to achieve signicant clinical improvement based on the principal of start low and go slow, with mean nal AMI dose in this case series of 1.3 mg/kg/day. Low-dose AMI (bearing in mind that dosing guidelines for tricyclics are 13 mg/kg/day) was observed to benet hyperactivity, inattention, impulsive aggression, sleep, appetite, anxiety and enuresis; although proof of concept prospective studies using standardized rating scales are still required. No clinical trials of AMI for the indication of hyperactivity and impulsivity in ASD have yet been published. In addition, prospective studies are needed to determine the role of AMI in improving core symptoms of ASD; although according to our clinical experience, there appears to be a measurable improvement in restricted and repetitive behaviors which are core features associated with ASD in youth. Stimulant monotherapy, in doses tolerable in youth with ASD, often fails to signicantly improve hyperactivity and impulsivity symptoms. Children with ASD may be more

prone to stimulant side effects and often tolerate only low doses (Hellings et al. 2006a, RUPP Autism Network 2005). In addition, stimulants may worsen self-injurious behaviors such as head-banging, self hitting and self-biting according to our clinical experience, although studies of this phenomenon are needed. The Research Units on Pediatric Psychopharmacology (RUPP) Autism Network (2005) conducted a study of methylphenidate (MPH). The groups found that tolerability and treatment response in children with ASD, while signicantly positive in comparison to placebo, were lower than that reported in normally developing individuals, even though subjects were pre-selected for tolerability after a MPH trial dose. Effect sizes were 0.200.54, with variables being dose and rater. Not uncommonly, low doses of stimulants are used in clinical practice in combination with antipsychotics; however residual hyperactivity and impulsivity may lead to trials of other agents. The latter may include the norepinephrine reuptake inhibitor atomoxetine, alone or in combination (Arnold 2006; Posey et al. 2006). However, headaches, tachycardia, elevated blood pressure, behavioral activation, and gastrointestinal side effects in this population with an already elevated incidence of gastrointestinal problems (Horvath and Perman 2002), often limit atomoxetine use in these children with ASD. Difculties in swallowing the large atomoxetine capsule or of nding a pharmacy to compound it to a liquid form, high treatment costs and insurance denials also limit its use. The risks of using a TCA in these patients were weighed against possible benets based on our experience, given that many of these youths parents reported multiple prior treatment trial failures. While TCAs are considered sedating and no side-effect rating scale including sedation as an item was used, sedation was recorded in only 6 subjects in this predominantly high-functioning sample. Anticholinergic adverse effects such as dry mouth, blurred vision and constipation may have been under-elicited. No cases manifesting urinary retention occurred; enuresis improved in many. Readers are cautioned that AMI remains a potentially dangerous drug and outcomes cannot be attributed only to AMI since it was used in combination treatments in all cases but two. However, our ndings suggest possible short and long-term benets when used cautiously in treatment-resistant youth

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with ASD and co-morbid hyperactivity, impulsivity, aggression and self-injury. The authors performed the chart review, rstly to examine safety and efcacy parameters of AMI to inform clinical practice, but also to inform future studies and much-needed drug development. There is a lack of studies of medications useful for sleep, a signicant problem in children and adolescent with ASD, and AMI in low doses may be helpful for this. The prefrontal cortex of the cerebral hemispheres is a key brain neural system controlling executive functions and behavioral inhibition, and is primarily noradrenergic, dopaminergic and cholinergic. In addition, AMI has been reported to increase serum brain derived neurotrophic factor (BDNF) long-term and was associated with neurogenesis and neurotrophic activity as well as cognitive enhancement in aged 3xtg Alzheimers disease mice (Hellweg et al. 2008; Chadwick et al. 2011). Since children with ASD often present with core symptoms of signicant restricted and repetitive behavior, anxiety, insomnia, decreased appetite as well as the ADHD-like symptoms, the serotonin reuptake transporter inhibition effect of AMI may benet these symptoms. Concomitant low-dose risperidone was also used for anxiety, aggression and self-injury in 48 % of cases (see Table 2). The noradrenergic reuptake transporter inhibiting properties of AMI in prefrontal cortex may exert effects on impulse control similar to that occurring with atomoxetine, whereas anticholinergic effects could offer benets for sleep, anxiety and enuresis, although prospective studies including imaging would be needed to conrm or refute this hypothesis. A majority of youth in this study tolerated stimulants in addition to AMI. A recent double-blind, placebo-controlled multisite study of citalopram for repetitive behaviors in youth with ASD was negative (King et al. 2009) however, the serotonin reuptake inhibition by AMI may be benecial for anxiety, sleep and mood in such youth. We suggest that noradrenergic agents acting on the prefrontal cortex together with serotonin reuptake inhibition in the case of AMI are possibly more effective for such children to achieve behavioral inhibition of repetitive behaviors, however further studies are needed. In this study of a tertiary-referred, largely treatmentresistant sample of children and adolescents with ASD and ADHD symptoms, AMI showed promising treatment outcomes when used cautiously in low doses with careful EKG monitoring. Thirty percent of these patients had failed a trial of atomoxetine in the past, and almost half (40 %) had failed 3 or more trials of ADHD medications. All children and adolescents presented to our university clinic outpatient service with problematic hyperactivity, impulsivity and ASD. The mean AMI blood level (sum of AMI and nortriptyline metabolites) of 114.1 50.5 ng/ml in our sample is

near the lower end of the well published therapeutic range of approximately 100250 ng/ml used by laboratories measuring plasma levels for treatment of depression based on efcacy and safety indicators. The therapeutic range for individuals with ASD may be lower than the given range, considering that a signicant number of subjects (22 %), by parent report, received important benet from AMI although their trough serum levels were in the undetectable range (below 50 ng/ml) and they were conrmed to be taking the medication. The anticholinergic action of AMI is signicant at such low doses and could benet gastrointestinal problems. There were no unexpected side effects noted (see Table 2). A signicant increase in QTc was noted when AMI was used in combination with lithium, as occurred in 1 case. Clearly, AMI should not be prescribed together with other medications that cause QTc prolongation. Blockade of voltage-sensitive sodium channels in heart and brain is thought to be responsible for CNS and cardiac adverse effects of AMI (Stahl 2008). No formal drug side effect rating scales were used in these clinic visits however a prospective study would employ such scales. New-onset seizures did not occur apart from equivocal seizures in one subject and AMI was discontinued by the neurologist in that subject. All the subjects who had seizures while receiving AMI, had a history of seizures prior to AMI trial. Weaknesses of the study include that concomitant medications were used in all but two cases. Also, medication dosage adjustment of all medications took place during the period of treatment studied, related to the present study being a retrospective chart review. Other study weaknesses include the lack of standardized measures to diagnose ASDs such as the Autism Diagnostic Inventory- Revised (Lord et al. 1994), lack of standardized rating scales of ADHD symptoms, for example the Aberrant Behavior Checklist (Aman et al. 1985) and the retrospective design. This retrospective chart review study may inform drug choices and dosage for future sequential combination treatment studies in treatment-resistant youth with ASD.

Conclusions Cautious use of low dose AMI shows promising results in treatment-resistant youth with ASD accompanied by hyperactivity, impulsivity, aggression and self injury. Further prospective studies, using standardized rating scales are warranted. AMI is already known to increase nerve growth factor and BDNF long-term, with associated neurotrophic activity and neurogenesis; this may be of additional benet in this challenging patient population.

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J Autism Dev Disord Acknowledgments This work was supported by a grant from the Kansas Center for Autism Research and Training (K-CART). Conict of interest Dr. Hellings has non-reimbursed collaboration with Roche. She has received prior study drug funding from Abbott Laboratories Inc, Janssen Pharmaceuticals, NIMH and NICHD. Dr. Gaffney has grants/contracts with Merck, NIDA, NHTSA and the Department of Defense. The authors wish to thank Ms. Carla J. Meister for her technical assistance in preparation and submission of this manuscript. No other authors have conicts of interest. Frye, R. E., & Rossignol, D. A. (2011). Mitochondrial dysfunction can connect the diverse medical symptoms associated with autism spectrum disorders. Pediatric Research, 69, 41R47R. Ganz, M. L. (2007). The lifetime distribution of the incremental societal costs of autism. Archives of Pediatrics and Adolescent Medicine, 161, 343349. Geller, E., Ritvo, E. R., Freeman, B. J., & Yuwiler, A. (1982). Preliminary observations on the effect of fenuramine on blood serotonin and symptoms in three autistic boys. New England Journal of Medicine, 307, 165169. Gordon, C. T., State, R. C., Nelson, J. E., Hamburger, S. D., & Rapoport, J. L. (1993). A double-blind comparison of clomipramine, desipramine, and placebo in the treatment of autistic disorder. Archives of General Psychiatry, 50, 441447. Guy, W. (1976). ECDEU Assessment Manual for Psychopharmacology (MNIH Publication NO. 76338). Washington, DC: US DHEW NIMH. Hellings, J. A., Zarcone, J. R., Crandall, K., Wallace, D., & Schroeder, S. R. (2001). Weight gain in a controlled study of risperidone in children, adolescents and adults with mental retardation and autism. Journal of Child and Adolescent Psychopharmacology, 11, 229238. Hellings, J. A., Zarcone, J. R., Valdovinos, M. G., Reese, R. M., Gaughan, E., & Schroeder, S. R. (2005). Risperidone-induced prolactin elevation in a prospective study of children, adolescents, and adults with mental retardation and pervasive developmental disorders. Journal of Child and Adolescent Psychopharmacology, 15, 885892. Hellings, J. A., Zarcone, J. R., Reese, R. M., Valdovinos, M. G., Marquis, J. G., Fleming, K. K., et al. (2006a). A crossover study of risperidone in children, adolescents and adults with mental retardation. Journal of Autism and Developmental Disorders, 36, 401411. Hellings, J.A., Tanjim, S., Saranga, V., Thome, A. (2006a). Comorbidity and combination treatments with dextroamphetamine in youth with autism spectrum disorders (ASD) and attention decit hyperactivity disorder (ADHD). [Poster] 50th Annual Meeting (NCDEU) Boca Raton, FL. Hellings, J. A., Cardona, A., & Schroeder, S. R. (2010). Long-term safety and adverse events of risperidone in children, adolescents and adults with pervasive developmental disorders. Journal of Mental Health Research in Intellectual Disabilities, 3, 132144. Hellings, J. A., Boehm, D., Yeh, H., & Schroeder, S. R. (2011). Longterm clinical aripiprazole efcacy and weight changes in youth with developmental disabilities including autism spectrum disorders. Journal of Mental Health Research in Intellectual Disabilities, 4, 114. Hellweg, R., Ziegenhorn, A., Heuser, I., & Deuschle, M. (2008). Serum concentrations of nerve growth factor and brain-derived neurotrophic factor in depressed patients before and after antidepressant treatment. Pharmacopsychiatry, 41, 6671. Horvath, K., & Perman, J. A. (2002). Autistic disorder and gastrointestinal disease. Current Opinion in Pediatrics, 14, 583587. Jackson, J. (2010). Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ, 341, c5222. Kim, Y. S., Leventhal, B. L., Koh, Y., Fombonne, E., Laska, E., Lim, E., et al. (2011). Prevalence of autism spectrum disorder in a population sample. American Journal of Psychiatry,. doi:10.1176/appi.ajp.2011.10101532,2011. King, B. H., Hollander, E., Sikich, L., McCracken, J. T., Scahill, L., Bregman, J. D., et al. (2009). STAART psychopharmacology network: Lack of efcacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: Citalopram ineffective in children with autism. Archives of General Psychiatry, 66, 583590.

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