PsychopharmacologyWhat you should know to survive the

LMCC and Internship

Dr. Kate Huntington

khuntington@toh.on.ca

April 2013

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

Which of the following is not a common side effect of SSRI’s?

• a. Nausea

• b. Headache

• c. Rigidity

• d. Anxiety

• e. Sleep disruption

Which of the following receptors does Mirtazepine/Remeron not block?

• a. Histamine

• b. 5HT1

• c. 5HT2

• d. 5HT3

• e. Alpha 2

At which dose level does Venlafaxine/Effexor XR typically

begin to have a noradrenergic effect?

• a. 75mg

• b. 150mg

• c. 225mg

• d. 300mg

Which is not an indication for the use of Benzodiazepines?

• a. Catatonia

• b. Long term hypnotic

• c. Mania

• d. Alcohol withdrawal

• e. Anxiety

How are the novel hypnotics different from Benzodiazepines?

• 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?

• a. Rigidity

• b. Dystonia

• c. Dyskinesia

• d. Akathisia

Which of the following is an example of a low potency typical

antipsychotic?

• a. Haloperidol/Haldol

• b. Pimozide/Orap

• c. Olanzapine/Zyprexa

• e. Clomipramine/Anafranil

• f. 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?

• a. Valproic Acid/Epival

• b. Lamotrigene/Lamictal

• c. Lithium

• d. Carbamazepine/Tegretol

What is the most common excitatory neurotransmitter in the brain?

• a. Serotonin

• b. Glutamate

• c. Norepinephrine

• d. GABA

• e. Dopamine

Antidepressants: Indications

• MDD

• Premenstrual Dysphoric Disorder

• GAD

• Social phobia

• PTSD

• OCD

• Panic Disorder

• Pain disorders

• (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

• 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 (slow taper)• Flu-like symptoms• Insomnia• Nausea• Imbalance• Sensory disturbances• Hyperarousal (agitation/anxiety)

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)

• Drowsiness (H1 blockade)

• Equilibrium

NaSSA: Rare but Dangerous Side Effects

• Neutropenia

• Serotonin syndrome

• Hepatotoxicity

• SIADH

SARI: Mechanism of ActionSerotonin 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

TCA: Mechanism of ActionTricyclic 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

• Torsades de Pointes (due to blockade of fast sodium channels)

• EKG – rule out bradycardia and prolonged QTc

• Lytes – rule out electrolyte imbalance

• Make sure not on type 1 or 3 antiarrythmic drugs

• SIADH

• Serotonin Syndrome

MAOI: Mechanism of ActionMonoamine 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• Teratogenicity• Blood dyscrasias

Serotonin Syndrome: HARMED

• Hyperthermia

• Agitation/Autonomic instability

• Rigidity/Reflexes increased

• MyoClonus/tremors

• Encephalopathy

• Diaphoresis

For reference only

Hypertensive Crisis

• Norepinephrine is the amine most closely linked with control of blood pressure

• MAO normally inactivates norepinepherine

• Tyramine, an amine present in aged foods, causes release of norepinepherine

• 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 mirtazepine (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

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

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 Course of Recovery From DepressionDepression

Response

2-3 weeks:

Improved sleep,

appetite, vegetative

shifts

3-4 weeks:

objective improvement

energysuicidal

ideation may

6-8 weeks:

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

• ADHD

• Narcolepsy

• (treatment resistant depression)

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

• 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 – 95% 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)

• No longterm deficits

ECT: Side Effect Profile

• Rare:• Mortality 2 / 1 000 000• 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)

• Space occupying cerebral lesions

• Increased ICP

• Recent MI

• Recent CVA

• Aneurysm

• Retinal detachment

• Pheochomocytoma

Mood Stabilizers: Indications

• Bipolar Affective Disorder (BPAD)• Migraine or cluster headaches• Chronic aggression or impulsivity• Seizure disorders• Pain conditions (TGN, migraine)• Lithium reduces suicidal risk in BPAD and

augments antidepressants in MDD and OCD

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 BPAD (Bipolar Affective Disorder)

• First line for acute mania: • Lithium, • Valproic Acid • atypical antipsychotics (olanzapine, risperidone, quetiapine, ziprasidone,

aripiprazole) • taper and discontinue antidepressants

• First line for acute bipolar depression: • Lithium• lamotrigine • quetiapine

• do not use antidepressant monotherapy

• First line for maintenance therapy: • Lithium• Valproic acid• Lamotrigine• Atypical antipsychotics quetiapine, risperidone LAI and Olanzapine

Goals of treatment in BPAD

• Again, the goal is to treat to complete remission of all mood symptoms

• 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:

• 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• Tremor/Teratogen (increased risk Ebstein’s anomaly

(0.1% vs 0.005%) in first trimester)• Hypothyroid• Increased weight• Vomitting, nausea, GI• Miscellaneous: EKG changes (T wave flattening or

inversion), acne, hair loss

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, thiazide diuretics, ACEI, 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• Lytes, BUN, Cr (renally excreted)

• 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

• Monitor weight and BMI during treatment and re-check for diabetes/pre-diabetes and hypercholesterolemia if >5% weight gain

Lithium : Rx

• Adult

• Acute mania about1800mg/d (bid-tid dosing)

• Acute mania level 1.0 – 1.5

• Maintenance usually about 900-1200 mg/d

• Maintenance level 0.6-1.0

• Geriatric

• Dosing 150 – 600 mg/d (bid dosing)

• Level 0.4 – 0.8

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 ProfileSTUN

• Sedation (31%)

• Tremor (10-29%)

• Unsteadiness (dizziness)

• Nausea (20%) /GI

Valproic Acid:longer term side effect

monitoring• On the surface:

– Acne , hair loss

• Under the surface: – weight gain, edema

• Systemic: – blood dyscrasias (esp plt dysfn) – liver dysfunction +/- elevated ammonia levels– reproductive changes incl menstrual irregularities (up to

45%), PCOS, teratogenicity (5-15%)

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: RxReference 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

• First line maintenance treatment

Lamotrigene: Side Effect Profile

• Rash – 0.3% adults / 1% in children. With slow titration risk was reduced to 0.01% comparable to other anticonvulsants.

• 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

• Both Olanzapine, Quetiapine and Risperidone LAI are first line maintenance treatments

Anxiolytics: Indicationseg. 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

• 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 one 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: Reported to be less tolerance, dependence and

withdrawal on discontinuation than BZD

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)

Typical Antipsychotics: Side effectsTypical Antipsychotics: Side effects

High potencyHigh potencyEPSEPS

Haldol

Chlorpromazine

Loxapine

Perphenazine

QT prolongation with pimozide, CPZ

Low potencyLow potencyAntihistamineAntihistamineAntiAlpha-AntiAlpha-AdrenergicAdrenergicAnticholinergicAnticholinergic

Atypical Antipsychotics: Indications

• Same as typicals

• Agitation/aggression in dementia NOT responding to adequate non-pharmacological interventions

• BPAD

• 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:Atypical Antipsychotics:Side EffectsSide 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 EnhancersCognitive Enhancers

Cholinergic Agents- Donepezil/Aricept

- Rivastigmine/Exelon

- Galantamine/Reminyl

NMDA Antagonist- Memantine/Ebixa

Cognitive Enhancers: Cognitive Enhancers: IndicationsIndications

AChEI: early to moderate AD

Lewy Body Dementia

Galantamine in Mixed Dementia

Donepezil in Vascular Dementia

Memantine: Moderate to severe AD

Cholinesterase Inhibitors: Indications

• AAbilities

• BBehaviour

• CCognition

• DDecrease in caregiver time

• EEntry into Nursing Home

Cholinesterase InhibitorsMechanism 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: Indications

SocializationHousehold tasksADLPersecutory ideationExcessive 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: Cognitive enhancers: monitoringmonitoring

• 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, akathesia, 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. Lamotrigene/Lamictal

B. Valproic acid/Epival

C. Quetiapine/Seroquel

D. Risperidone/Risperdal

E. Lithium

You decide to start Seroquel as well as standard admission prn’s 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 and

seems to be having a great deal of difficulty breathing. 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

PRE-TEST REVIEW

Which of the following is not a common side effect of SSRI’s?

• a. Nausea

• b. Headache

• c. Rigidity

• d. Anxiety

• e. Sleep disruption

Which of the following receptors does Mirtazepine not block?

• a. Histamine

• b. 5HT1

• c. 5HT2

• d. 5HT3

• e. Alpha 2

At which dose level does Venlafaxine typically begin to have

a noradrenergic effect?

• a. 75mg

• b. 150mg

• c. 225mg

• d. 300mg

Which is not an indication for the use of Benzodiazepines?

• a. Catatonia

• b. Long term hypnotic

• c. Mania

• d. Alcohol withdrawal

• e. Anxiety

•  

How are the novel hypnotics different from Benzodiazepines?

• 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?

• a. Rigidity

• b. Dystonia

• c. Dyskinesia

• d. Akathisia

Which of the following is an example of a low potency typical

antipsychotic?

• a. Haldol/Haloperidol

• b. Pimozide/Orap

• c. Olanzapine/Zyprexa

• e. Clomipramine/Anafranil

• f. 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?

• a. Valproic Acid/Epival

• b. Lamotrigene/Lamictal

• c. Lithium

• d. Carbamazepine/Tegretol

What is the most common excitatory neurotransmitter in the brain?

• a. Serotonin

• b. Glutamate

• c. Norepinephrine

• d. GABA

• e. Dopamine

THANK YOU!GOOD LUCK