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Psychopharmacology What 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 150225mg • 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 Action Serotonin 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 Action Tricyclic 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 Action Monoamine 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 agent Development 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 Depression Response 2-3 weeks: 3-4 weeks: 6-8 weeks: Improved sleep, appetite, vegetative shifts objective improvement energy suicidal ideation may subjective improvement Stimulants: Indications • ADHD • Narcolepsy • (treatment resistant depression) 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 MD-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 Ataxia Stupor Coma myoclonic 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: 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) • 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 effects Side 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 effects High potency EPS Haldol Pimozide Loxapine Perphenazine Low potency Mellaril Antihistamine Chlorpromazine AntiAlphaAdrenergic Anticholinergic QT prolongation with pimozide, CPZ Atypical Antipsychotics: Indications • Same as typicals • Agitation/aggression in dementia responding to adequate pharmacological interventions NOT non- 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 • 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 Enhancers Cholinergic Agents - Donepezil - Rivastigmine - Galantamine NMDA Antagonist - Memantine Cognitive Enhancers: Indications AChEI: early to moderate AD Lewy Body Dementia Mixed Dementia Memantine: Moderate to severe AD Cholinesterase Inhibitors: Indications • 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 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 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 Cognitive enhancers: monitoring • Response may be seen 1 month, typically 3 months • Realistic expectation is to “maintain”