Transcript Psychopharmacology What you should know to survive the LMCC

Psychopharmacology
What you need to know to survive the
LMCC and Internship
Khalid Bazaid, MD, FRCPC
Assistant Professor
Child & Adolescent Psychiatrist
Children’s Hospital of Eastern Ontario
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
for the major classes of psychotropic
medications
To practice applying this knowledge
MCC Objectives for the Qualifying Examination
(with my updates for DSM-5)
• Initiate pharmacologic treatment of
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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)
MCC Objectives for the Qualifying Examination
• Judicious use of pharmacotherapy in
personality disorders
– Attention to risk of abuse, overdose
• Recognize Medication-Induced Movement
disorders
– e.g. dystonia due to antipsychotics
Which of the following is NOT a
common side effect of SSRI’s?
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a.
b.
c.
d.
e.
Nausea
Headache
Rigidity
Anxiety
Sleep disruption
Which of the following receptors does
Mirtazepine/Remeron NOT block?
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a.
b.
c.
d.
e.
Histamine
5HT1
5HT2
5HT3
Alpha 2
At which dose level does Venlafaxine/Effexor XR
typically begin to have a noradrenergic effect?
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a.
b.
c.
d.
75mg
150mg
225mg
300mg
Which is not an indication for the
use of Benzodiazepines?
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a.
b.
c.
d.
e.
Catatonia
Long term hypnotic
Mania
Alcohol withdrawal
Anxiety
How are the novel hypnotics (e.g. Zopiclone,
Zolpidem) different from Benzodiazepines?
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a. Do not cause falls
b. Do not lead to tolerance
c. Used as long term hypnotics
d. More selective for the alpha one subtype
of GABA-A receptor
Which of these is the most prominent side
effect of atypical antipsychotics?
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a.
b.
c.
d.
Rigidity
Dystonia
Dyskinesia
Akathisia
Which of the following is an example of a low
potency typical antipsychotic?
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a.
b.
c.
e.
f.
Haloperidol (Haldol)
Pimozide (Orap)
Olanzapine (Zyprexa)
Clomipramine (Anafranil)
Chlorpromazine (Thorazine)
Which class of cognitive enhancers is indicated
in mild to moderate Alzheimer’s Disease?
• a. Cholinesterase inhibitor
• b. NMDA receptor antagonist
Which mood stabilizer can reduce the risk
of suicide in Bipolar Disorder?
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a.
b.
c.
d.
Valproic Acid/Epival
Lamotrigine/Lamictal
Lithium
Carbamazepine/Tegretol
What is the most common excitatory
neurotransmitter in the brain?
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a.
b.
c.
d.
e.
Serotonin
Glutamate
Norepinephrine
GABA
Dopamine
Antidepressants: Indications
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MDD
Premenstrual Dysphoric Disorder
GAD
Social phobia
PTSD
OCD
Panic Disorder
Pain disorders (DSM-5 Somatic Symptom Disorder with
predominant pain)
• (insomnia)
SSRI: Mechanism of Action
• In depression, the serotonin neuron has a relative deficiency of
serotonin and the autoreceptors and postsynaptic receptors are
increased in number & sensitivity
• When the reuptake pump is blocked, the level of serotonin increases in
the somatodendritic area, sending a message to the nucleus to decrease
production of autoreceptors
• This leads to disinhibition of the serotonin neuron, releasing more
serotonin at the axon terminal
• Increased levels of serotonin in the synapse leads to changes in the
post synaptic neuron gene products such as down regulation
(decreased number and sensitivity) of postsynaptic receptors and
increased production of BDNF
SSRI: Side Effect Profile
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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)
SSRI: Rare but Dangerous Side Effects
• UGI bleeding (platelet dysfunction), esp. in combo with
NSAID’s or other blood-thinning agents
• SIADH
• Osteoporosis and fractures in the elderly
• Serotonin syndrome
SSRI discontinuation syndrome
• Incidence: 20% after 6 weeks of use
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Flu-like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbances
Hyperarousal (agitation/anxiety)
• Prevent with slow taper
Norepinephrine & Dopamine Reuptake
Inhibitor:Mechanism of Action
(Bupropion/Wellbutrin)
• Blockade of norepinephrine and dopamine reuptake
pumps, leads to similar cascade as with SSRI’s
NDRI: Side Effect Profile
• Seizures (not with extended release formulations & following correct
dosing; contraindicated with Bulimia or electrolyte disturbances)
• Headache, Hypertension (SNS activation)
• Agitation (mood and psychomotor circuits) and Anticholinergic*
(relative decrease in parasympathetic tone)
• Rash
• Emesis, decreased appetite and weight loss (SNS activation)
• Sleep disruption, Shaking and Sweating (sleep and psychomotor
circuits and SNS activation)
* (red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a
hare; bowel & bladder lose their tone & the heart goes off alone)
Serotonin & Noradrenergic reuptake
Inhibitors: Mechanism of Action
(Venlafaxine/Effexor, Desvenlafaxine/Pristiq, Duloxetine/Cymbalta)
• Blockade of serotonin reuptake at lower dose range
• Blockade of serotonin and norepinephrine reuptake in mid
dose range
• Blockade of serotonin, norepinephrine and dopamine
reuptake at very high dosages
SNRI: Side Effect Profile
• As with SSRI’s in lower to mid dose range
• As with NDRI in mid to high dose range
SNRI: Rare but Dangerous Side Effects
• As with SSRI’s
NaSSA: Mechanism of Action
• Blocks Alpha 2 autoreceptors on norepinephrine neurons &
heteroreceptors on Serotonin neurons, causing more NE & 5HT to be
released
• NE neurons from the locus coeruleus innervate midbrain raphe 5HT
neurons. Therefore, increased NE causes a further increase in 5HT
release
• Blocks 5HT2 receptors, having an anxiolytic effect & blocking sleep
& sexual side effects
• Blocks 5HT3, blocking GI side effects from peripheral receptors &
from brainstem chemoreceptor trigger zone
• Blocks H1 histamine receptors, causing sedation & weight gain
NaSSA: Side Effect Profile
• Weight gain (H1 blockade)
• Anticholinergic (relative decrease in parasympathetic tone)
– very weak effect
• Drowsiness (H1 blockade)
• Equilibrium
NaSSA: Rare but Dangerous Side Effects
• Neutropenia
• Serotonin syndrome
• Hepatotoxicity
• SIADH
• QT prolongation (Health Canada, 28 March 2014, post-marketing)
SARI: Mechanism of Action
Serotonin 2A antagonists/reuptake inhibitors (Trazodone/Desyrel)
• Primarily blocks 5HT2A, reducing sexual dysfunction & sleep
disruption & increasing effect of 5HT1A stimulation (5HT2A &
5HT1A oppose one another’s actions in several ways)
• Weak 5HT reuptake inhibitor, increasing 5HT stimulation of 5HT1A
(therapeutic effects)
• H1 blockade causes sedation
• Alpha One blockade leads to orthostatic hypotension
SARI: Side Effect Profile
• Orthostatic hypotension
• Sedation
SARI: Rare but Dangerous Side Effects
• Serotonin syndrome
• Priapism
TCA: Mechanism of Action
Tricyclic antidepressants:
3° amines (eg amitriptyline, imipramine, doxepine)
2° amines (eg nortriptyline, desipramine)
• Originally developed as treatment for schizophrenia (similar 3-ringed
chemical structure); found ineffective for psychosis but helpful for
depression.
• Therapeutic effects and side effects from blocking Serotonin,
Norepinephrine & Dopamine Reuptake
• Some also have 5HT2 blocking ability (blocks sex & sleep side
effects)
• Side effects from blocking H1 histamine receptors, muscarinic
receptors, alpha one adrenergic receptors
• Overdose can lead to seizures and arrhythmias due to blockade of ion
channels
TCA: Side Effect Profile
• Antihistamine – weight gain & sedation
• Anticholinergic – (remember toxidrome from NDRI)
• Anti-alpha adrenergic – dizziness, orthostatic
hypotension
TCA: Rare but Dangerous Side Effects
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Torsades de Pointes (due to blockade of fast sodium channels)
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EKG – rule out bradycardia and prolonged QTc
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Lytes – rule out electrolyte imbalance
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Make sure not on type 1 or 3 antiarrythmic drugs
SIADH
Serotonin Syndrome
MAOI: Mechanism of Action
Monoamine oxidase inhibitors:
“the classics” (phenylzine/nardil, tranylcypromine/parnate)
Reversible inhibitor: (moclobemide/mannerix)
HISTORY:
• The first clinically effective antidepressants
• Originally, an anti-tuberculosis drug, found to decrease
comorbid depression
• Irreversibly bind MAO (2 wks) & destroy its function,
therefore decrease monoamine breakdown, increasing
5HT, NE & DA
MAOI: Side Effect Profile
• Side effects related to increase in serotonin norepinephrine
& dopamine (see SSRI’s & NDRI’s)
• Orthostatic hypotension
MAOI: Rare but Dangerous Side Effects
• Hyperthermia i.e.Serotonin Syndrome
• even more susceptible than with other serotonergic
antidepressants; need to avoid anything that has serotonergic
effects such as antidepressants and opioids)
• When you see an MAOI, get a pharmacy consult, the patient
should consult their pharmacist about any over - the – counter
medications
• Hypertensive crisis
• Consult the dietician Re: MAOI diet
• Patients need to avoid all foods with tyramine (aged foods such as
aged cheeses and wines or tap beer) and any medications with
noradrenergic effects (cold remedies, stimulants etc)
• Hepatotoxicity
• Blood dyscrasias
Serotonin Syndrome: HARMED
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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
Starting Antidepressants: General Guidelines
• Start with a reuptake inhibitor or mirtazapine (not a TCA or MAOI)
• Start at lowest possible dose (half of this with anxiety and in the
elderly and medically frail)
• Increase by this increment about every five half lives (or about once a
week) until one of the following endpoints:
• Intolerable side effects
• Full response
• Maximum dose
• Continue to monitor for therapeutic effects, side effects and safety
• How you use them is more important than which one you choose
Choice of Initial Antidepressant in Adults
• There is comparable efficacy between and within classes of
medication, therefore, initial selection is based on:
• Symptom profile
• Side effect profile in relation to the individual patient
• Patient preference
• Cost
• History of previous response of the patient or family members
• Comorbid psychiatric or medical illnesses
• Potential drug-drug interaction
• The BEST antidepressant is the one that a patient will
actually take acutely and for the long haul…and one that
you know well
Treatment choices in children
• Concerns were raised about the safety of
antidepressants (Paroxetine and Venlafaxine) in
children and youth in 2004
• Further metaanalyses and epidemiologic studies now
confirm that antidepressants in children and youth are
safe with close (weekly) monitoring.
• Problems with Venlafaxine and Paroxetine may have
been related to poor adherence and discontinuation
symptoms
Choice of Initial Treatment in children/youth
• Mild to moderate depression:
– Start with psychotherapy or non-medication interventions
as first line
– Second line is to add medication; best evidence is for
Fluoxetine; other SSRI’s could be considered next
• Moderate to severe depression:
– First line is to consider medication but depending on
patient/family preference, may also start with
psychotherapy or monitoring
• Note that the clinical presentation in children and youth can
change quickly; they may appear severely depressed one week
then by the next week be in a new relationship and everything
is better…
Course of Recovery From
Depression
Response
2-3 weeks:
3-4 weeks:
6-8 weeks:
Improved
sleep,
appetite,
vegetative
shifts
objective
improvement
energy
suicidal
ideation may 
subjective
improvement
Goals of antidepressant therapy
• REMISSION of symptoms and maintaining that level of
improvement in order to prevent relapse and recurrence
• Rate of relapse is significantly less for patients who
achieve full remission of symptoms
• Patients who have been ill longer tend to be more
treatment resistant; there is also evidence of hippocampal
atrophy with prolonged illness, leading to the concept of
disease progression and the hope that this can be modified
by treating all mood episodes to the point of remission
Stimulants: Indications
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ADHD
Narcolepsy
(treatment resistant depression)
(apathy in elderly)
Stimulants: Mechanism of action
(1)
• Increases dopamine and NE actions by blocking
their reuptake and facilitating their release
• Improves the efficiency of information processing
in the frontal subcortical circuits, relieving
frontally mediated symptoms of inattention,
hyperactivity and impulsivity.
Stimulants: Mechanism of action
(2)
• Action in DL prefrontal cortex improves attention,
concentration, executive function and wakefulness
• Action in cortical and subcortical motor areas may
improve hyperactivity
• Action in the orbital frontal cortex may improve
impulsivity
• Action in medial prefrontal cortex may improve
depression, fatigue and sleepiness
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
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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
• Parkinson’s Disease
ECT: Indications (cont.)
• Indications for First Line Use:
• Need for rapid improvement (suicide, malnutrition, catatonia,
severe psychosis or agitation)
• When other treatments are more risky (elderly)
• Patient preference
• Psychotic depression (gold standard – 80-90% response)
ECT: Mechanism of Action
• 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
ECT: Side Effect Profile
• Common
• Headache
• Muscle ache
• Nausea
• Memory impairment
• Delirium
• Amnesia (anterograde & retrograde)
• Few longterm deficits
ECT: Side Effect Profile
• Rare:
• Mortality 1/10 000 per course of ECT (6-12 treatments)
• Cardiovascular
• initial vagal stimulation
• Bradycardia / asystole / ectopic activity
• sympathetic stimulation during tonic clonic phase of seizure
• Increased HR & increased BP
• Sometimes parasympathetic rebound with second phase of
bradycardia
• Prolonged apnea
• Pseudocholinesterase deficiency
• Prolonged seizure
• Treat with IV benzo
ECT: Relative Contraindications
(weigh pros & cons)
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Space occupying cerebral lesions
Increased ICP
Recent MI
Recent CVA
Aneurysm
Retinal detachment
Pheochomocytoma
Mood Stabilizers: Indications
• A heterogeneous group of medications
• Used to treat diverse conditions, including
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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
What is a “mood stabilizer”?
• These medications can be thought of as
treating one or more of the following
phases:
– Acute bipolar depression
– Acute bipolar mania
– Maintenance
Choice of Treatment in BD
(Bipolar Disorder)
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First line for acute mania:
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First line for acute bipolar depression:
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• 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
First line for maintenance therapy:
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Lithium
Valproic acid
Lamotrigine
Atypical antipsychotics quetiapine, risperidone LAI and Olanzapine
Goals of treatment in BPAD
• Treat to complete remission
• It has been theorized that under-treated discrete
depressive and manic episodes may progress to
mixed and dysphoric episodes, rapid cycling and
treatment resistance
• The hope is that recognition and full treatment of
mood episodes may prevent progression to more
difficult mood states
Lithium: Mechanism of Action
• MOA is unclear
• Thought to be involved in:
• Modulating second messenger systems (ie G protein-coupled
receptors, through which most hormones and neurotransmitters
mediate their effects) which leads to:
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Increasing GABA activity
Reducing glutamate activity
Stabilizing catecholamine receptors
Blocking the effects of some hormones (eg. ADH and TSH) on end
organs
• Works in acute bipolar mania, depression and maintenance
phases
• Decreases suicide, deliberate self harm and death from all
causes in patients with mood disorders
Lithium: Side Effect Profile
• Lethargy
• Insipidis (diabetes insipidis)
• Tremor/Teratogen (increased risk Ebstein’s
anomaly (0.1% vs 0.005%) in first trimester)
• Hypothyroid
• Increased weight
• Vomiting, nausea, GI
• Miscellaneous: EKG changes (T wave flattening
or inversion, sick sinus syndrome), acne, hair loss,
hypercalcemia
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
• There is delayed distribution and elimination in the brain relative to serum
therefore early signs are peripheral and later signs are central unless high
level is chronic, in which case peripheral and central symptoms will occur
simultaneously
• Peripheral symptoms: nausea, vomitting, cramping, diarrhea
• Central symptoms: tremulousness, hyperreflexia, ataxia, mental status
changes, coma, seizures
• Can lead to irreversible neurotoxicity including cognitive impairment,
peripheral neuropathy and cerebellar dysfunction
• Hospitalize for levels >2.0 or based on clinical symptoms
Lithium: Initial Work-up
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Lytes, BUN, Cr (renally excreted)
Calcium
TSH (5% hypothyroidism)
EKG with rhythm strip (contraindicated with sick sinus
syndrome)
• B-hcg
• Metabolic baseline including baseline weight and BMI;
consider checking for diabetes/pre-diabetes and
hypercholesterolemia in those who are overweight (BMI
25-30) or obese (BMI>30)
Lithium: Ongoing Monitoring
• Lithium level every five days until steady state is reached
then at 3-6 months, with signs of dehydration or toxicity
or with change in medications or salt intake
• Repeat kidney functions, TSH and EKG every 6-12
months, Calcium
• Monitor weight and BMI during treatment and re-check for
diabetes/pre-diabetes and hypercholesterolemia if >5%
weight gain
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
Valproic Acid: treatment effects
• Treats bipolar mania
• First line for bipolar depression in
combination with lithium or
SSRI/bupropion
• Second line monotherapy for bipolar
depression
• Indicated for maintenance phase
Valproic Acid: Acute Side Effect Profile
STUN
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Sedation (31%)
Tremor (10-29%)
Unsteadiness (dizziness)
Nausea (20%) /GI
Valproic Acid:
longer term side effects
• On the surface:
– Acne , hair loss
• Under the surface:
– weight gain, edema
• Systemic:
– thrombocytopenia
– liver dysfunction +/- elevated ammonia levels
– reproductive changes incl menstrual irregularities (up to
45%), PCOS, teratogenicity (5-15%)
• Avoid use in women of childbearing age
Valproic Acid: Initial Work-up & Ongoing
Monitoring
Initial
• CBC + LFT’s
• Epival level every 3-4 days until steady state reached
• Metabolic baseline including baseline weight and BMI; consider
checking for diabetes/pre-diabetes and hypercholesterolemia in those
who are overweight (BMI 25-30) or obese (BMI>30)
Ongoing
• Repeat tests monthly x 6 months then Q6mos or if symptoms develop
• Monitor weight and BMI during treatment and re-check for
diabetes/pre-diabetes and hypercholesterolemia if >5% weight gain
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
Lamotrigine: Treatment effects
• Treats bipolar depression (modest effect)
• First line maintenance treatment
Lamotrigine: Side Effect Profile
• Rash – 0.3% adults / 1% in children. With slow titration
risk was
reduced to 0.01% comparable to other
anticonvulsants. Can develop into Stevens-Johnson
Syndrome (increased risk with Valproate)
• Activation (3-8%), Ataxia
• Spaced out (cognitive slowing), Sedation, Sleep
disturbances
• H/A, Hypersensitivity reactions
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)
Anxiolytics: Side effects
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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
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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)
Typical Antipsychotics: Side effects
High potency
EPS
Haldol
Loxapine
Perphenazine
Low potency
Chlorpromazine
QT prolongation with pimozide, CPZ
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, SDA’s
lead to dopamine release(i.e. the mesocortical pathway,
reducing negative and cognitive symptoms)
• In pathways with more D2 receptors to block, SDA’s 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 different set of concerns:
• Weight gain (get baseline weight)
• Akathisia
• Sedation
• Hyperglycemia/Hyperlipidemia(baseline fasting lipids
and glucose)
• Dizziness (orthostatic hypotension; check BP)
• In dementia increase mortality and risk of
cardiovascular events
• Risk of agranulocytosis and seizure (dose dependent)
with Clozapine
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 Alzheimer’s
severe Alzheimer’s
Some evidence for:
Lewy Body Dementia
Galantamine in Mixed Dementia
Donepezil in Vascular Dementia
Memantine: Moderate to severe AD
Cholinesterase Inhibitors: Effects
• Abilities
• Behaviour
• Cognition
• Decrease in caregiver time
• Entry into Nursing Home
Cholinesterase Inhibitors
Mechanism of Action
• Inhibits centrally-acting
acetylcholinesterase, making more
acetylcholine available
• This compensates in part for degenerating
cholinergic neurons that regulate memory
AChEI: Common Side Effects
Muscle Cramps
Insomnia/
incontinence
Nausea
Diarrhea
•
•
•
•
•
•
•
•
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 Alzheimer’s 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
Memantine: Common Side Effects
Confusion
Headache
Equilibrium (dizziness)
Constipation
Kidney function
(But in large studies had a similar rate of
treatment emergent side effects as placebo)
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”.
Which of the following is the
most likely diagnosis?
A. Major depressive disorder
B. Schizophrenia
C. Delirium
D. ADHD
E. Dissociative identity disorder
Which of the following medications would be most
appropriate to discuss starting with the patient?
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
Which of the following side effects
would you counsel the patient about?
A. Headaches, agitation, nausea, diarrhea
B. Tremor, increased blood pressure, increased
sweating
C. Insomnia, decreased appetite, elevated blood
pressure, tics
D. Weight gain, akathisia, sedation, increased lipids
and sugars
E. Sedation, increased thirst, tremor,
hypothyroidism, nausea, hair loss
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.
Which of the following is the
most accurate diagnosis?
A. Hyperthyroidism
B. Generalized anxiety disorder
C. Panic disorder without agoraphobia
D. Panic disorder with agoraphobia
E. Major depressive disorder
In the emergency, this lady received some lorazepam/ativan
which she found quite helpful. She would like a prescription
for this medication. How would you respond to this request?
A. Describe to her that although benzodiazepines can help
reduce anxiety symptoms acutely that they are not in fact
first line treatment. They can best be used as an adjunct
to the first line SSRI while waiting for these to become
effective
B. Give her a prescription for ativan 0.5 mg bid for one
month and follow up at that time to reassess
C. Reinforce with her that benzodiazepines are the best way
of dealing with panic attacks and give her a prescription
of ativan 1 mg bid prn to be used as soon as she
experiences symptoms so that she never needs to
experience the trauma of a full blown panic attack again.
You give her a prescription for escitalopram 10 mg daily and
lorazepam 0.5 mg bid for one week at which point you will
follow up with her. Which of the following side effects
should you discuss with her in regards to the lorazepam?
A. This medication can cause drowsiness and
incoordination. Longer term use will lead to dependence.
B. The most common side effects are weight gain and
sedation
C. The most common side effects are drowsiness and
orthostatic hypotension
D. The most common side effects are restlessness, nausea,
diarrhea and sexual dysfunction
E. This medication can rarely cause a serious rash and must
be adjusted upwards slowly
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 mother’s 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.
Which of the following is the most accurate
description of her current episode?
A. Major depressive episode
B. Bipolar affective disorder, current episode
depressed
C. Bipolar affective disorder, current episode
manic
D. Bipolar affective disorder, current episode
mixed
E. Borderline personality disorder
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
You decide to start Quetiapine as well as standard admission
prn medication, given her significant agitation and recent
threats of violence. You are called by nursing staff in the
middle of the night to inform you that the patient is acutely
distressed, with her head arched back and her tongue
protruding. What is the best treatment for this condition?
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.
Which of the following would be the
best treatment for this condition?
A. Start Citalopram/Celexa 20 mg daily
B. Start Seroquel XR/Quetiapine 100 mg qhs
C. Start both A&B simultaneously
D. ECT/electroconvulsive therapy
E. Start Donepezil/Aricept 5 mg qhs
You continue to follow up with this patient after he is in
complete remission from his depression. Which of the
following conditions will he be at increased risk for in follow
up given his late presentation with depression?
A. Delirium
B. Schizophrenia
C. Dementia
D. Panic disorder
E. Borderline personality disorder
Over the next few years, he gradually begins to complain of
memory deficits, shows evidence of word finding problems
and now requires assistance with grocery shopping and
paying his bills. His MMSE score has dropped from 30 to 23
during this time period. Which of the following treatments
would be most appropriate?
A. Start Citalopram/Celexa 20 mg daily
B. Start Seroquel XR/Quetiapine 100 mg qhs
C. Start both A&B simultaneously
D. ECT/electroconvulsive therapy
E. Start Donepezil/Aricept 5 mg qhs
THANK YOU!
GOOD LUCK