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April 2015
Based on the 2014 lecture by Dr. Lisa McMurray
Objectives
To review:
indications for
mechanism of action
side effects (remember not everyone gets
these)
monitoring parameters
ADHD
Agitation in Delirium
Dementia/Major Neurocognitive Disorder
Major Depressive Disorder
Manic Episode
Anxiety Disorders
Obsessive-Compulsive Disorder (formerly an anxiety
disorder)
Substance withdrawal
Substance Use disorders (e.g. nicotine replacement)
a.
b.
c.
d.
e.
Nausea
Headache
Rigidity
Anxiety
Sleep disruption
a.
b.
c.
d.
e.
Histamine
5HT1
5HT2
5HT3
Alpha 2
a.
b.
c.
d.
75mg
150mg
225mg
300mg
a.
b.
c.
d.
e.
Catatonia
Long term hypnotic
Mania
Alcohol withdrawal
Anxiety
a.
b.
c.
d.
Rigidity
Dystonia
Dyskinesia
Akathisia
a.
b.
c.
e.
f.
Haloperidol (Haldol)
Pimozide (Orap)
Olanzapine (Zyprexa)
Clomipramine (Anafranil)
Chlorpromazine (Thorazine)
a.
b.
c.
d.
Valproic Acid/Epival
Lamotrigine/Lamictal
Lithium
Carbamazepine/Tegretol
a.
b.
c.
d.
e.
Serotonin
Glutamate
Norepinephrine
GABA
Dopamine
Antidepressants: Indications
MDD
Premenstrual Dysphoric Disorder
GAD
Social phobia
PTSD
OCD
Panic Disorder
Pain disorders (DSM-5 Somatic Symptom Disorder with
predominant pain)
(insomnia)
Headache
Anxiety and Agitation (mood and psychomotor circuits)
Nausea (weight/appetite circuit and GI receptors)
Diarrhea (peripheral GI 5HT3 & 5HT4 receptors)
Sexual dysfunction (spinal projections) and Sleep disruption or
Somnolence (sleep circuit)
Flu-like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbances
Hyperarousal (agitation/anxiety)
As with SSRIs
Neutropenia
Serotonin syndrome
Hepatotoxicity
SIADH
Orthostatic hypotension
Sedation
Serotonin syndrome
Priapism
HISTORY:
The first clinically effective antidepressants
Originally, an anti-tuberculosis drug, found to decrease
comorbid depression
Hyperthermia
Agitation/Autonomic instability
Rigidity/Reflexes increased
MyoClonus/tremors
Encephalopathy
Diaphoresis
Hypertensive Crisis
Norepinephrine (NE) is the amine most closely linked with
control of blood pressure
MAO normally inactivates norepinephrine (NE)
Tyramine, an amine present in aged foods, causes release of
norepinephrine (NE)
In the presence of MAOI, this increased NE cannot be
broken down, resulting in a hypertensive crisis
2-3 weeks:
3-4 weeks:
6-8 weeks:
Improved
sleep,
appetite,
vegetative
shifts
objective
improvement
energy
suicidal
ideation may
subjective
improvement
Stimulants: Indications
ADHD
Narcolepsy
(treatment resistant depression)
(apathy in elderly)
Stimulants:
Common Side Effects
Headaches and Heart concerns (palpitations,
tachycardia and hypertension)
Insomnia, Irritibility and Increased stimulation
Dizziness
Exacerbation of tics, tremor
Stomach: anorexia, nausea, abdo pain, weight
loss, possibly slowing of normal growth in
children
Stimulants:
Rare Side Effects
Psychosis
Leukopenia
Anemia
Seizures
Stimulants:
Ongoing Monitoring
Blood pressure at baseline and with dose
increases
In children, ongoing monitoring of height
and weight
ECT: Indications
Common
MDE
Mania
Mixed state
Catatonia
Schizophenia with
prominent affective
symptoms
Schizoaffective disorder
Uncommon
Delirium
NMS
Parkinsons Disease
Neurotransmitter theory
Enhances DA, 5HT & NE neurotransmissiom
Neuroendocrine theory
Increased release of neurohormones including prolactin, TSH,
ACTH & endorphins
Neurogenesis theory
Increased neuroplasticity
Release of BDNF
Anticonvulsant theory
Increase in seizure threshold during course of ECT; CSF of animals
receiving ECS is anticonvulsant when given IV to recipient animals
Common
Headache
Muscle ache
Nausea
Memory impairment
Delirium
Amnesia (anterograde & retrograde)
Few longterm deficits
Bipolar Disorder
Migraine or cluster headaches
Chronic aggression or impulsivity
Seizure disorders
Pain conditions (TGN, migraine)
Lithium reduces suicidal risk in Bipolars and
augments antidepressants in MDD
Choice of Treatment in BD
(Bipolar Disorder)
Lithium,
Valproic Acid
atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole
lurasidone)
taper and discontinue antidepressants
Lithium
lamotrigine
quetiapine
Lurasidone (July 2013)
do not use antidepressant monotherapy
Lithium
Valproic acid
Lamotrigine
Atypical antipsychotics quetiapine, risperidone LAI and Olanzapine
Lithium: Toxicity
Narrow therapeutic index!!!
Anything that affects water and electrolyte imbalance can
contribute to Lithium toxicity (CAUTION with flu, dehydation,
meds)
Levels are increased by NSAIDS, diuretics, ACE inhibitors,
tetracycline, anticonvulsants
Levels are decreased by caffeine and salt
Lithium: Toxicity
Lithium : Rx
Adult
Acute mania about 1800mg/day (bid-tid dosing)
Acute mania level 1.0 1.5
Maintenance usually about 900-1200 mg/d; give at hs for renal
protection
Maintenance level 0.6-1.0
Geriatric
Dosing 150 600 mg/d (bid dosing)
Level 0.4 0.8
For maintenance, give at hs for renal protection
Sedation (31%)
Tremor (10-29%)
Unsteadiness (dizziness)
Nausea (20%) /GI
Valproic Acid:
longer term side effects
On the surface:
Acne , hair loss
Systemic:
thrombocytopenia
liver dysfunction +/- elevated ammonia levels
reproductive changes incl menstrual irregularities (up to 45%),
PCOS, teratogenicity (5-15%)
Valproic Acid: Rx
Reference only
Starting dose:
250 qhs (geriatrics)
250 bid-tid (adults)
15-30 mg/kg/day in bid dosing for acute mania in
adults
Levels: 350 800 umol/l
Lamotrigene: Rx
Start with 25 mg/d
Double the dose every 2 weeks
Usual maintenance dose is 200 mg in 2 divided doses
(reached by week six)
Atypical Antipsychotics:
Olanzapine and Quetiapine
All atypical antipsychotics are indicated to
treat bipolar mania
Quetiapine is first line monotherapy for
bipolar depression; so is Lurasidone
Olanzapine, Quetiapine, Aripiprazole, and
Risperidone LAI are first line maintenance
treatments
Anxiolytics: Indications
eg. Benzodiazepines (lorazapam)
Short term hypnotic (But decrease REM,
Stages 3 & 4 sleep)
Anxiolytic
Acute mania
Alcohol withdrawal
Catatonia
Anxiolytics:
Mechanism of action
Affinity of GABA-A receptor for GABA
(a positive allosteric modulator)
GABA-A receptors with alpha one subunits
most important for sleep
GABA-A receptors with alpha two or three
subunits are most important for anxiety (but
all available at this time are non-selective
and therefore also sedating)
Memory decline
Addiction(dependency &withdrawal)
Ataxia/Falls
Drowsiness/dizziness/disinhibition
Anxiolytics:Contraindications
With COPD or sleep apnea
Avoid in the elderly; with long term use
taper by 25 % q-monthly after treating the
underlying anxiety disorder with an SSRI as
indicated
Novel hypnotics
(e.g. Zopiclone/Imovane)
Indications: short term hypnotic agents
Mechanism of action:
Some are selective for the alpha 1 subtype of
GABA-A receptor (sedating effects) and not
the alpha 2 (anxiolytic, muscle relaxant and
alcohol potentiating) or alpha 5 (linked to
memory)
Side Effects:
Similar to benzodiazepines
Antipsychotics: Indications
Psychotic illness
Delirium
Mood disorder with psychosis
Severe agitation or aggression
Typical Antipsychotics:
Mechanism of action
D2 blockade
Produces antipsychotic effect in the mesolimbic pathway
Causes worsening of negative and cognitive symptoms in the
mesocortical pathway, where a dopamine deficit is thought to
cause these symptoms
Causes
EPS
(dystonia,
dyskinesia,
akathesia,
parkinsonism)in the nigrostriatal pathway
Causes increased prolactin in the tuberoinfundibular pathway
(gynecomastia, galactorrhea and sexual dysfunction)
High potency
EPS
Haldol
Loxapine
Perphenazine
Chlorpromazine
Low potency
Antihistamine
AntiAlphaAdrenergic
Anticholinergic
Atypical Antipsychotics:
Indications
Same as typicals
Agitation/aggression in dementia NOT
responding
to
adequate
nonpharmacological interventions
Bipolar Disorder
Augmentation in MDD
Features of
Atypical Antipsychotics
Block both D2 and 5HT2A
Cause less EPS than typical antipsychotics
Improve positive symptoms as well as
typical antipsychotics
Atypical Antipsychotics:
Mechanism of action
5HT2A, when stimulated, normally stops
dopamine release; when this is blocked, it
causes dopamine release
The different dopamine pathways have
varying amounts of D2 and 5HT2A
receptors
Atypical Antipsychotics:
Mechanism of action cont
In pathways with more 5HT2A receptors to block, SDAs lead
to dopamine release(i.e. the mesocortical pathway, reducing
negative and cognitive symptoms)
In pathways with more D2 receptors to block, SDAs cause
dopamine blockade (i.e.the mesolimbic pathway, with
antipsychotic effects)
In pathways where receptor numbers are relatively equal,
there is no change in the amount of dopamine (i.e. in the
tuberoinfundibular pathway, preventing increased prolactin)
In the nigrostriatal pathway, there are just enough 5HT2
receptors to bring the D2 blockade down below 80%, the
critical number to prevent EPS.
Atypical Antipsychotics:
Side Effects
Less effects on:
EPS, negative symptoms and cognition
A
Atypical Antipsychotics:
Monitoring
Baseline personal and family history of vascular
risk factors
Obtain baseline weight and calculate BMI; BMI
monthly for three months and then 3x per year
Baseline waist circumference at the umbilicus, BP,
fasting glucose and lipid profile; repeat at 3
months and then annually
Neuroleptic Malignant
Syndrome
Antipsychotic use (+) fever (+) rigidity (+) 2
others of:
Fever
Encephalopathy (neuro s/s or change in mental status)
Vital signs unstable
Elevated CPK/ WBC
Rigidity
Cognitive Enhancers
Cholinergic Agents
Donepezil/Aricept
- Rivastigmine/Exelon
- Galantamine/Reminyl
-
NMDA Antagonist
- Memantine/Ebixa
Cognitive Enhancers:
Indications
AChEI: early to moderate Alzheimers
severe Alzheimers
Some evidence for:
Lewy Body Dementia
Galantamine in Mixed Dementia
Donepezil in Vascular Dementia
Cholinesterase Inhibitors
Mechanism of Action
Inhibits centrally-acting
acetylcholinesterase, making more
acetylcholine available
This compensates in part for degenerating
cholinergic neurons that regulate memory
Diarrhea
Urination
Miosis/muscle weakness
Bronchorrhea
Bradycardia
Emesis
Lacrimation
Salivation/sweating
Cholinesterase Inhibitors:
use caution or consultation with:
History of seizures
History of bradycardia, sinus node
dysfunction or other serious conduction
abnormality
History of PUD or other risk factors for GI
bleeding
History of COPD or asthma
Memantine: Effects
Socialization
Household tasks
ADL
Persecutory ideation
Excessive activity (agitation)
Memantine:
Mechanism of action
A dysfunction of glutamatergic neurotransmission,
manifested as neuronal excitotoxicity, is hypothesized to be
involved in the etiology of Alzheimers disease
Memantine binds the NMDA receptor with a higher affinity
than Mg2+ (which are normally there), inhibiting a
prolonged influx of Ca2+ (thereby preventing excitotoxicity)
The receptor can still be activated by the relatively high
concentrations of glutamate released following
depolarization of the presynaptic neuron
Cognitive enhancers:
monitoring
Response may be seen 1 month, typically 3
months
Realistic expectation is to maintain
PRACTICE CASES
CDMQ 1
A 25 year old man (who was previously a PhD candidate at McGill but
has been unemployed and not seeking work for the last two years) is
brought in to the emergency by police.
Police were called as he had been breaking into the homes of strangers
saying that he was looking for Amour. They were concerned by his
disorganized speech and brought him into hospital for assessment.
When seen in the emergency, he is not concerned about being in hospital.
He says that he has been possessed by the goddess of love, Amour,
and is looking for others like himself. When introduced to the
assessing psychiatrist, he tells her that he heard her say the number 17
which alerted him to the fact that there is a special connection between
his circumstance and the television show House.
A. Olanzapine/Zyprexa 5 mg at bedtime
B. Haldoperidol/Haldol 10 mg twice daily
C. Chlorpromazine/Thorazine 100 mg at
bedtime
D. Risperidone/Risperdal Consta 50 mg IM
q2wks
E. Quetiapine/Seroquel XR 900 mg at bedtime
CDMQ 2
A 30 year old woman presents to your family
medicine clinic after several visits to the local
emergency department for episodes of racing heart,
shortness of breath, nausea and a sense that she was
dying. Cardiograms and bloodwork (CBC, TSH)
were normal. As a result of these episodes, she has
become reluctant to leave the house as she is afraid
this will happen when she is driving or when in a
situation where she will not be able to access help.
CDMQ 3
A forty five year old woman with a history of multiple previous
psychiatric hospitalizations is brought in to hospital by police
They were called by her mother who says she has been calling at all hours
of the day and night, very upset and talking really quickly. She has been
borrowing large sums of money which her mother later found out she used
to gamble, which is out of character for her. Tonight she showed up at her
mothers home and was yelling in the street that her father was a menace
to society and she would save everyone by killing him.
In the emergency room, she is irritible, crying and cannot sit still. She is
speaking so quickly that it is difficult to follow what she is saying. She
describes her mood as depressed. She admits she has not been eating
well in a few weeks and feels so worthless that she has been thinking
about killing herself.
You decide to start a mood stabilizer; she tells you that she
has had a bad reaction with one of these medications in the
past where she had to pee a lot and her sodium level was
really high. Which of the following most likely caused this?
A. Lamotrigine/Lamictal
B. Valproic acid/Epival
C. Quetiapine/Seroquel
D. Risperidone/Risperdal
E. Lithium
A. Haloperidol/Haldol 10 mg IM STAT
B. Lorazepam/Ativan 2 mg IM STAT
C. Propranolol 20 mg PO tid
D. Benztropine/Cogentin 2 mg PO bid
E. Benztropine/Cogentin 2 mg IM STAT
CDMQ 4
A 70 y.o. man reluctantly attends your family medicine clinic
with his daughter. She is concerned as he has not been getting
out for the last few months and has lost a lot of weight, about 20
lbs. She continues to invite him to spend time with her and her
family but he has recently been declining, preferring to stay
home and do nothing. He seems tired and sad all of the time.
When you see him, you note that he moves and speaks more
slowly than he did in the past .
When you ask him if he feels that he may be ill, he responds
that he knows that he is being punished for having shoplifted
once when he was a teenager and that he deserves to feel this
way.
A. Delirium
B. Schizophrenia
C. Dementia
D. Panic disorder
E. Borderline personality disorder
THANK YOU!
GOOD LUCK