PsychopharmacologyWhat you should know to survive the

LMCC and Internship

Kate Huntington, MD

April 2008

Objectives

To review:• indications for• mechanism of action • side effects (remember not everyone gets

these)• monitoring parameters

for the major classes of psychotropic medications

SSRI’s: Indications

• MDD• GAD• Social phobia• PTSD• OCD• Augmentation in BD• Premenstrual Dysphoric Disorder• Panic Disorder

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, causing autoreceptors (the brakes) to decrease in number & sensitivity

• This turns off the brake on the serotonin neuron and electrical impulses flow down the axon, releasing more serotonin at the axon terminal

• Increased levels of serotonin in the synapse leads to down regulation (decreased number and sensitivity) of postsynaptic receptors & other downstream changes

SSRI: Side Effect Profile

• Headache

• Anxiety (limbic projections) and Agitation (basal ganglia projections)

• Nausea (chemoreceptor trigger zone)

• Diarrhea (peripheral GI 5HT3 & 5HT4 receptors)

• Sexual dysfunction (spinal projections) and Sleep disruption or Somnolence (Brainstem sleep centre)

SSRI: Rare but Dangerous Side Effects

• UGI bleeding (platelet dysfunction)

• SIADH

• SSRI discontinuation syndrome (slow taper)

• Serotonin syndrome

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 SR formulation & following correct dosing; contraindicated with Bulimia or electrolyte disturbances)

• Headache• Agitation (limbic cortex)• Rash• Emesis• Sleep disruption (limbic cortex) and Shaking (cerebellum)

Serotonin & Noradrenergic reuptake Inhibitors: Mechanism of Action

(Venlafaxine/Effexor)

• Blockade of serotonin reuptake up to about 150 mg

• Blockade of serotonin and norepinephrine reuptake from about 150-225mg

• Blockade of serotonin, norepinephrine and dopamine reuptake above 225 mg

SNRI: Side Effect Profile

• Same as SSRI up to 150 mg

• >150 mg, may also see sustained increase in diastolic BP & other noradrenergic-type side effects (see NDRI)

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 (puts the brakes on the brakes)

• 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: constipation, urinary retention, dry mouth, blurred vision, drowsiness, sinus tachycardia, confusion/delirium, fever (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)

• Drowsiness (H1 blockade)

• Equilibrium

NaSSA: Rare but Dangerous Side Effects

• Neutropenia

• Serotonin syndrome

• Hepatotoxicity

• Possibly SIADH

SARI: Mechanism of ActionSerotonin 2A antagonists/reuptake inhibitors (Trazadone/Desyrel)

• Primarily blocks 5HT2A, reducing sexual dysfunction & sleep disruption & increasing effect of 5HT1A stimulation (5HT2A & 5HT1A oppose one another)

• 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)

• 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 & sodium channels in the heart & brain

TCA: Side Effect Profile

• Antihistamine – weight gain & sedation

• Anticholinergic – (remember toxidrome from NaSSA)

• Anti-alpha adrenergic – dizziness, orthostatic hypotension

• Blockade of fast sodium channels – prolongation of QTc (risk of Torsades)

TCA: Rare but Dangerous Side Effects

• Torsades de Pointes

• 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)

• 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 norepinepherine & dopamine (see SSRI’s & NDRI’s)

• Orthostatic hypotension

MAOI: Rare but Dangerous Side Effects

• Blood dyscrasias• Hepatotoxicity• Teratogenicity• Serotonin Syndrome - (even more susceptable than with other

serotenergic antidepressants)• 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

cheese and wine)

Serotonin Syndrome

Major Criteria Minor Criteria

Mental Symptoms

impaired consciousness,

elevated mood,

coma/semicoma

restlessness,

insomnia

Autonomic

Symptoms

fever, sweating Tachycardia, dyspnea,

diarrhea

Neurological

Symptoms

myoclonus, tremor, shivering, rigidity, hyperreflexia

uncoordination, dilated pupils, akathisia

Co-incidence with the addition or increase of a serotenergic agentDevelopment of at least 4 major or 3 major plus 2 minor criteria

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

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

Stimulants: Indications

• ADHD

• Narcolepsy

• (treatment resistant depression)

Stimulants: Mechanism of action

• Increases dopamine and NE actions by blocking their reuptake and facilitating their release

• Action in DL prefrontal cortex improves attention, concentration, executive function and wakefulness

• Action in Basal Ganglia may improve hyperactivity

• 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

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, malnutritian, catatonia, severe psychosis or agitation)

• When other treatments are more risky (elderly, pregnant)

• Patient preference

• Psychotic depression (gold standard – 95% response)

ECT: Relative Contraindications(weigh pros & cons)

• Space occupying cerebral lesions

• Increased ICP

• Recent MI

• Recent CVA

• Aneurysm

• Retinal detachment

• Pheochomocytoma

ECT: Mechanism of Action

• Neurotransmitter theory

• Enhances DA, 5HT & NE neurotransmissiom

• Neuroendocrine theory

• Increased release of neurohormones including prolactin, TSH, ACTH & endorphins

• 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 1/10,000-0.2 / 100 000

• Cardiovascular

• 2° initial vagal stimulation

• Bradycardia / asystole / ectopic activity

• 2° sympathetic stimulation

• Increased HR & increased BP

• Prolonged apnea

• Pseudocholinesterase deficiency

• Prolonged seizure

• Treat with IV benzo

Mood Stabilizers: Indications

• Bipolar Affective Disorder (BD)

• Migraine or cluster headaches

• Chronic aggression or impulsivity

• Lithium reduces suicidal risk in BD and augments antidepressants in MDD and OCD

Choice of Treatment in BD (Bipolar Disorder)

• For first onset acute manic or mixed episodes, start lithium, epival or an atypical antipsychotic; taper and discontinue antidepressants if possible

• For acute bipolar depression, initiate either lithium or lamotrigene

• For rapid cycling (more than four episodes per year), initiate either lithium, epival or lamotrigene; taper and discontinue antidepressants

• For maintenance therapy, lithium and epival are most supported. Alternatives include lamotrigene, carbamazepine, oxcarbazepine and M-ECT

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

• Effective in treating classic, euphoric mania & BD with M-D-E pattern

Lithium: Side Effect Profile(THE MAGIC WAND)

• Tremor

• Hypothyroid (5%)

• EKG changes (bradycardia, reversible T-wave flattening or inversion; contraindicated in sick sinus syndrome, can lead to sinus node dysfunction)

• Muscle weakness

• Alopecia

• GI upset

• Increased WBC (transient)

• Cardiac abnormality: increased risk Ebstein’s anomaly

(0.1% vs 0.005%) in first trimester

Lithium: Side Effect Profile (cont.)(THE MAGIC WAND)

• Weight gain (50%)• Acne (rashes in general)• Neurological (in toxicity)• Diabetes insipidus/Drinking more

• Early Toxicity GI distress, hand tremor, fatigue, thirst, headache, decreased concentration

• Late Toxicity AtaxiaStupor Comamyoclonic jerking increase DTR’s seizure

Lithium: Initial Work-up

• CBC ( can increase WBC)

• Lytes, BUN, Cr (renally excreted)

• TSH (5% hypothyroidism)

• EKG with rhythm strip(contraindicated with sick sinus syndrome)

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

• Levels are increased by NSAIDS, thiazide diuretics, ACEI, tetracycline, anticonvulsants

• Levels are decreased by osmotic diuretics (mannitol), carbonic anhydrase inhibitors, caffeine, increased salt

• Repeat kidney functions, Li level, TSH and EKG every 6-12 months

• Target Li level is 0.5-1.2 in adults and 0.4-0.8 in the elderly

Why Use an Anticonvulsant as a Mood Stabilizer: The Kindling Hypothesis

• Underlying pathophysiologic mechanisms in BD are poorly understood

• Mania and epilepsy may share the underlying mechanism of kindling (repeated subthreshold stimuli generating an action potential leading to seizure in epilepsy or mood states in BD)

• It is hypothesized that both disorders may be caused by dysfunctional cation (Na &Ca) pumps, which leads to an imbalance between excitatory (glutamate) & inhibitory (GABA) neurotransmitters

• Anticonvulsants are thought to prolong inactivation of cation channels during activity such as seizure(or mood episode), preventing spread & leading to downstream changes in GABA & glutamate

Epival: Side Effect Profile(TURN SO BALD & FAT)

• Tremor (10-29%)

• Unsteadiness

• Rashes (incl. S-J-S)

• Nausea (20%) / GI upset

• Sedation (31%)

• Oligomenorrhea/PCO (menstral irregularity in 45%)

Epival: Side Effect Profile (cont.)(TURN SO BALD & FAT)

• Blood dyscrasia • thrombocytopenia (always ask about bruising and bleeding)• Anemia (macrocytic)• Agranlocytosis(ask about symptoms of infection)• Coagulopathies

• Alopecia (treat with Zn & selenium)• LFT elevation (up to 44%) (always ask re.: nausea, vomiting, edema,

malaise)• Dysarthria• Fat (weight gain) / insulin resistance• Ammonia levels can rise (can cause confusion, stupor, coma)• Teratogen (5-15%)

Epival: Initial Work-up & Ongoing Monitoring

• Initial

• CBC + LFT’s

• Epival level weekly until steady state reached

• Ongoing

• Repeat tests monthly x 6 months then Q6mos or if symptoms (bruising/bleeding/infection/general malaise) develop

• Target range 350-800 umol

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 25-50 mg/d

• Increase every 2 weeks by 25-50 mg

• Usual maintenance dose is 100-500 mg in 2 divided doses

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)

• Two main receptor types• BZ1 – Located mostly in the cerebellum

– Anxiolytic and sedative-hypnotic actions• BZ2 – Located mostly in the spinal cord,

striatum and limbic system– Muscle relaxant actions

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. Imovane)

Indications: short term hypnotic agents Mechanism of action:• Higher affinity for BZ1 than BZ2 therefore

less side effects• More specific to CNS vs. peripheral

receptors therefore less side effectsSide Effects: Same as benzodiazepines but

reported to be less

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

HaldolPimozide

MellarilChlorpromazine

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

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

• Obtain baseline weight and calculate BMI; BMI monthly for three months and then q4mths

• Baseline personal and family history of obesity, dyslipidemia, hypertension and cardiovascular disease

• 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 of: • ↑ WBC • Lab evidence muscle injury (CK or myoglobinuria)• Diaphoresis• ↑ HR • ↑ or labile BP• Dysphagia• Tremor• Incontinence• Change in MS• Mutism

Cognitive EnhancersCognitive Enhancers

Cholinergic Agents- Donepezil

- Rivastigmine

- Galantamine

NMDA Antagonist- Memantine

Cognitive Enhancers: Cognitive Enhancers: IndicationsIndications

AChEI: early to moderate AD

Lewy Body Dementia

Mixed 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

Cholinesterase Inhibitors: Common Side Effects

Muscle Cramps Insomnia Nausea Diarrhea

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

Cognitive enhancers: Cognitive enhancers: monitoringmonitoring

• Response may be seen 1 month, typically 3 months

• Realistic expectation is to “maintain”