Pharmacotherapy of Depression and Bipolar Disorder. Major Depression Pathogenesis/Etiology. Antidepressant Drugs. SSRIs. Tricyclic Antidepressants
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1 3/3/214 Pharmacotherapy of Depression and Bipolar Disorder Daniel Streetman, PharmD, MS Pharmacotherapy Specialist Lexicomp Wolters Kluwer Health Major Depression Diagnostic Criteria Sleep... insomnia or hypersomnia Interest... markedly decreased interest/pleasure in most activities Guilt... excessive or inappropriate feelings of guilt Energy... loss of energy or fatigue Concentration... decreased ability to think or concentrate; indecisiveness Appetite... increase or decrease in appetite Psychomotor... observed psychomotor agitation or retardation Suicide... recurrent suicidal ideation Major Depression Pathogenesis/Etiology Complex... not completely understood Without apparent "trigger" event vs. reaction to particular trigger Monoamine-deficiency hypothesis caused by relative deficiency in monoamine neurotransmitters (i.e., NE, 5-HT) induction of depressive symptoms with reserpine, tyrosine hydroxylase inhibitors resolution with drugs that enhance monoaminemediated neurotransmission Antidepressant Drugs Tricyclic Antidepressants (TCAs) Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Monoamine Oxidase Inhibitors (MAOIs) Others Variable effects on specific neurotransmitters (mostly NE and 5-HT; some DA) Unlikely to fully account for clinical effectiveness Full clinical response requires several weeks Tricyclic Antidepressants Block neuronal reuptake of monoamine neurotransmitters (NE, 5-HT) Also antagonize H 1, ACh, and NE receptors Orthostatic hypotension, Sedation, Anticholinergic effects; Sweating; Cardiac toxicity; Seizures; Suicide risk Many drug interactions MAOIs, anticholinergics, CNS depressants Opposing interactions with direct- vs. indirect-acting sympathomimetics SSRIs Block neuronal reuptake of serotonin Little impact on other transmitters/receptors General CNS excitation (vs. sedation) Pharmacokinetic differences among agents Fluoxetine (& active metabolite) t½ 72 hrs Others, t½ = 24 hrs All with some drug interaction risk CYP-mediated (lowest with escitalopram) Serotonergic 1
2 3/3/214 Half-Life and Duration of Inhibition Agents with longer t½ take longer to reach steady-state Different durations of activity and risk for withdrawal syndrome J Clin Psychopharmacol 22;22: Fluoxetine Paroxetine Sertraline Citalopram Escitalopram Half-life (hrs) SSRI Inhibition Potency Drug 1A2 2C9 2C19 2D6 3A Fluoxetine Fluvoxamine Sertraline Paroxetine Citalopram Escitalopram / / / / = mild inhibitor, = moderate inhibitor, = strong inhibitor / / / Chiba and Kobayashi. Antidepressants. In: Levy et al, eds. Metabolic Drug Interactions. Lippincott Williams & Wilkins, Philadelphia, PA. 2. Lexapro Product Labeling, 22. J Clin Psychiatry 1998;59(suppl 15): Half-Life and Duration of Inhibition Time to Baseline CYP2D6 (days) Fluoxetine (2mg) Paroxetine (2mg) Sertraline (1mg) J Clin Psychopharmacol 22;22: SSRIs Sexual dysfunction impotence, anorgasmia, decreased interest Weight gain Initial weight loss; up to 1/3 of patients gain 2 lbs Serotonin syndrome altered mental status, incoordination, myoclonus, hyperreflexia, excessive sweating, tremor, fever Withdrawal syndrome dizziness, HA, sensory alterations, tremor, anxiety Antiplatelet activity; Osteoporosis High Level of Serotonin Activity Paroxetine Clomipramine Sertraline Fluoxetine Citalopram Imipramine Fluvoxamine Amitriptyline Venlafaxine Desipramine Nortriptyline Doxepin Trazodone Buproprion Low Level of Mirtazapine Serotonin Activity Circulation 23;18:32-6. SNRIs Selective inhibition of both 5-HT and NE Little effect on other transmitters/receptors Adverse effects and drug interactions largely similar to SSRIs Venlafaxine (Effexor) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Milnacipran (Savella) Levomilnacipran (Fetzima) 2
3 3/3/214 Other Antidepressants Bupropion (Wellbutrin) Effects primarily limited to dopamine No weight gain or sexual dysfunction Can cause seizures; agitation, headache, dizziness Mirtazapine (Remeron) Blocks presynaptic 2 receptors; 5-HT & NE release Inhibits H 1 and M receptors; Sedation and weight gain Reboxetine Selective norepinephrine reuptake inhibitor Dry mouth, hypotension, constipation, decreased libido Limited sedation or weight gain Other Antidepressants Nefazodone (Serzone) Blocks 5-HT 2 & 1 receptors, and 5-HT & NE reuptake Sedation, headache, dry mouth Significant drug interaction risks Trazodone (Desyrel, Oleptro, others) Moderate inhibition of 5-HT reuptake Pronounced sedation, mildly anticholinergic, priapism Vilazodone (Viibryd) Selective inhibitor of 5-HT reuptake, also acts as partial agonist of 5-HT 1A receptors Slow titration (14 days); Take with food MAOIs Inhibit neuronal metabolism of monoamine transmitters (NE, 5-HT, DA) More transmitter available for release and receptor binding Irreversible inhibition; ~2 weeks for reversal CNS stimulation, orthostasis Many CRITICAL dietary and drug interactions Risks of Dietary Tyramine with MAO Inhibitors Tyramine Content: > 25 mg 1-25 mg 6-8 mg Hypertensive Crisis: severe headache, blurred vision, difficulty thinking, seizure, chest pain, nausea/vomiting Hypertensive Crisis Headache (severe), Stroke Elevated BP, increased HR, nausea, vomiting MAOIs and Dietary Tyramine Physiologic Consequences of Specific Foods Tyramine Content (mg) Risk generally highest for fermented, cured/aged, processed, or pickled products (e.g., aged hard cheeses, sauerkraut, fermented soy sauce, overripe avocado/fruits) Cheddar Swiss Blue Tap Beer Salami Soy sauce Btl Beer Pepperoni Am. Chs. So which class/drug to pick? No clear advantage of any one drug 6-8% response rate Algorithms or guidelines Comorbidities, Age Other medications 3
4 3/3/214 What dose? For how long? Which dose to use? Starting dose is often usual dose SSRIs, desvenlafaxine, duloxetine, mirtazepine Start low and increase slowly TCAs How long to treat? acute phase = 6-12 weeks continuation phase = additional 4-9 months maintenance phase = years, if needed and Other Drugs to Augment Therapy Buspirone, T 3, Lamotrigine, Lithium Mostly added to improve partial response Second generation antipsychotics Olanzapine Risperidone Aripiprazole Quetiapine First Generation (Typical) Main effects believed to be via D 2 antagonist actions Higher risk of EPS Few adverse metabolic effects Second Generation (Atypical) D 2 antagonist (weak) and 5-HT 2 antagonist (strong) Lower risk of EPS, but significant risk of adverse metabolic effects Both groups also act as histamine (H 1 ), cholinergic (M), and adrenergic ( 1 ) receptor antagonists Differences Among Drug EPS Sedation Weight Gain BP Anticholinergic Thioridazine Chlorpromazine Perphenazine Thiothixene Pimozide Haloperidol Clozapine Risperidone Paliperidone Aripiprazole Quetiapine Ziprasidone Olanzapine Extrapyramidal Symptoms Acute dystonia: sustained muscle contractions causing twisting, abnormal, and/or repetitive movement Parkinsonism: limb muscle rigidity, tremor, bradykinesia Akathisia: profound restlessness Tardive dyskinesia: involuntary movements of face and tongue (twisting, writhing, etc.) Extrapyramidal Symptoms Time-Course of Onset Acute Dystonia Start of Therapy hrs-days Parkinsonism 5-3 days 5-6 days Akathisia Tardive Dyskinesia months-years 4
5 3/3/214 Adverse Effects Neuroleptic malignant syndrome "Lead pipe" rigidity, high fever, sweating, autonomic instability (dysrhythmias, altered blood pressure), and altered consciousness Supportive treatments... possibly dantrolene and/or bromocriptine Anticholinergic effects Orthostatic hypotension -- 1 inhibition Sedation -- antihistamine effects Adverse Effects Increased prolactin Via anti-dopamine effects gynecomastia, galactorrhea, menstrual cycle irregularities, sexual dysfunction Seizures -- reduced seizure threshold Sexual dysfunction Decreased libido, anorgasmia, erectile dysfunction Adverse Effects QT prolongation Increased risk of potentially fatal form of ventricular fibrillation (Torsades de Pointes) Avoid use in high-risk patients, other QTprolonging drugs, drug interactions Risk highest with chlorpromazine, thioridazine, haloperidol (& paliperidone?), iloperidone, asenapine, and pimozide Select Atypical Olanzapine (Zyprexa )... tablet, ODT, IM injection (immediate and extended-release) Risperidone (Risperdal )... tablet, ODT, solution, extended-release injection Paliperidone (Invega )... ER tablet, extendedrelease injection (IM) Quetiapine (Seroquel )... tablet, XR tablet Iloperidone (Fanapt )... tablet Asenapine (Saphris )... sublingual tablet NPO x 1 min post-dose - AUC 19% with water at 2min; 1% at 5min Select Atypical Ziprasidone (Geodon )... PO (cap), injection Take with food Aripiprazole (Abilify )... tablet, ODT Lurasidone (Latuda )... tablet Take with food ( 35 calories) Bipolar Disorder Mood disorder with one or more episodes or mania or hypomania Chronic illness Many relapses and improvements Depression typically predominates 32-5% of weeks with depression symptoms 1-9% of weeks with mania or hypomania Particularly high suicide risk 1/3 with prior attempt; more often fatal 5
6 3/3/214 Bipolar Disorder Treatment Overview FGAs/SGAs Treatment of acute mania Bipolar depression Antidepressants Adjunct therapy with mood-stabilizing agents Mood-stabilizing agents Lithium Valproic acid, Carbamazepine, Lamotrigine Lithium Standard mood-stabilizing drug Very effective: acute mania, maintenance Strong effect on suicidal behavior (7% risk) Modestly effective: acute bipolar depression Genetic role in response Family history Uncertain but complex mechanism of action Lithium Goal serum concentration: meq/l Usual dose = 6-9 mg/day Narrow therapeutic index Nausea, dyspepsia, diarrhea Tremor Polyuria, polydipsia Drug interactions Thiazide diuretics, ACE inhibitors, ARBs Valproic Acid Particularly useful for rapid cycling, mixed mood features, concurrent substance abuse Not FDA-approved for maintenance Goal serum concentration: mcg/ml Anorexia, nausea, dyspepsia, diarrhea Tremor Drowsiness Weight gain Carbamazepine Less desirable due to ADEs, interactions Goal serum concentration: 4-12 mcg/ml Drowsiness, ataxia, lethargy, confusion, diplopia, dysarthria Hyponatremia Leukopenia, other rare blood dyscrasias Major drug interaction risks Strong inducer of metabolism Lamotrigine Primarily for maintenance (not acute) Long, deliberate dose titration required start at 25 mg/d and double every 1-2 weeks goal = 2-4 mg/day Maculopapular rash Approximately 1% of patients Risk for severe progression tied to dosing Drowsiness, dizziness, headache 6
7 3/3/214 7
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