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Chapter 32 Antidepressants Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Antidepressants Primarily used to relieve symptoms of depression Can also help patients with anxiety disorders Not indicated for uncomplicated bereavement Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 2 Antidepressant Groups Tricyclic antidepressants Selective serotonin reuptake inhibitors (SSRIs) Serotonin/norepinephrine reuptake inhibitors (SNRIs) Monoamine oxidase inhibitors (MAOIs) Atypical antidepressants Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 3 Depression Most common psychiatric disorder 30% of the U.S. population will experience some form during their lifetime Approximately 5% of adult population is depressed Incidence in women twice as high as in men Risk of suicide is high in depression Often untreated Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 4 Clinical Features Depressed mood Loss of pleasure or interest Insomnia (or sometimes hypersomnia) Anorexia (or sometimes hyperphagia) Mental slowing and loss of concentration Feelings of guilt, worthlessness, helplessness Thoughts of death and suicide Overt suicidal behavior Symptoms must be present most of the day, nearly every day, for at least 2 weeks Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 5 Pathogenesis Complex and incomplete Possible contributing factors Genetic heritage Difficult childhood Chronic low self-esteem Monoamine hypothesis of depression Depression is caused by functional insufficiency of monoamine neurotransmitters Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 6 Treatment Modalities Pharmacotherapy Depression-specific psychotherapy (eg, cognitive behavioral therapy) Electroconvulsive therapy (ECT) Primary therapy When drugs and psychotherapy have not worked When a rapid response is needed For severely depressed patients For suicidal patients Elderly patients at risk of starving Vagus nerve stimulation Only after treatment with at least four drugs has failed Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 7 Suicide Risk with Antidepressants May increase suicidal tendency early in the treatment Patients should be observed closely for: Suicidality Worsening mood Changes in behavior Precautions Prescriptions should be written for the smallest number of doses consistent with good patient management Dosing of inpatients should be directly observed Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 8 Selective Serotonin Reuptake Inhibitors (SSRIs) Introduced in 1987 Most commonly prescribed antidepressants As effective as TCAs, but do not cause hypotension, sedation, or anticholinergic effects Overdose does not cause cardiac toxicity Death by overdose is extremely rare Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 9 Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine (Prozac, Sarafem) Most widely prescribed SSRI in the United States Other SSRIs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 10 Mechanism of Action Produce selective inhibition of serotonin reuptake Produce CNS excitation Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 11 Therapeutic Uses Primarily used to treat major depression Other uses Obsessive-compulsive disorder Bulimia nervosa Premenstrual dysphoric disorder Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 12 Adverse Effects Serotonin syndrome 2–72 hours after treatment Withdrawal syndrome Neonatal effects when used in pregnancy Teratogenesis Extrapyramidal side effects Bruxism Bleeding disorders Sexual dysfunction Weight gain Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 13 Drug Interactions Monoamine oxidase inhibitors Risk of serotonin syndrome Warfarin Tricyclic antidepressants and lithium Can elevate levels of these drugs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 14 Other SSRIs Sertraline (Zoloft) Blocks uptake of serotonin and dopamine CNS stimulation Minimal effects on seizure threshold Therapeutic uses • Major depression • Panic disorder • Obsessive-compulsive disorder • Post-traumatic stress disorder • Premenstrual dysphoric disorder • Social anxiety disorder Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 15 Other SSRIs Sertraline (Zoloft) (cont’d) Side effects • • • • • • • • • Headache Nausea Tremor Diarrhea Insomnia Weight gain Agitation Sexual dysfunction Neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension of the newborn (PPHN ) when used late in pregnancy • Nervousness Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 16 Other SSRIs Sertraline (Zoloft) (cont’d) Drug interactions • MAOIs • Pimozide Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 17 Other SSRIs Fluvoxamine (Luvox) Inhibition of serotonin reuptake Used for obsessive-compulsive disorder Rapidly absorbed from the GI tract Half-life: about 15 hours Interacts adversely with MAOIs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 18 Other SSRIs Fluvoxamine (Luvox) (cont’d) Side effects • Nausea • Vomiting • Constipation • Weight gain • Dry mouth • Headache • Sexual dysfunction • Abnormal liver function • Sedative effects Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 19 Other SSRIs Paroxetine (Paxil, Paxil CR, Pexeva) Inhibition of serotonin uptake Indications • Major depression • Obsessive-compulsive disorder • Social phobia • Panic disorder • Generalized anxiety disorder • Post-traumatic stress disorder • Premenstrual dysphoric disorder Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 20 Other SSRIs Citalopram (Celexa) Does not block receptors for serotonin, acetylcholine, norepinephrine (NE), or histamine Used for major depression Half-life: about 35 hours Side effects (most common) • Nausea • Somnolence • Dry mouth • Sexual dysfunction Can cause neonatal abstinence syndrome Interacts with MAOIs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 21 Other SSRIs Escitalopram (Lexapro) S-isomer of citalopram Better tolerated than citalopram Side effects • Nausea • Insomnia • Somnolence • Sweating • Fatigue Interacts with MAOIs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 22 Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine (Effexor) Duloxetine (Cymbalta) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 23 Venlafaxine (Effexor) Indications Major depression Generalized anxiety disorder Social anxiety disorder (social phobia) Blocks NE and serotonin uptake Does not block cholinergic, histaminergic, or alpha1-adrenergic receptors Serious reactions if combined with MAOIs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 24 Venlafaxine (Effexor) Side effects Nausea Headache Anorexia Nervousness Sweating Somnolence Insomnia Weight loss/anorexia Diastolic hypertension Sexual dysfunction Hyponatremia (in older adult patients) Neonatal withdrawal syndrome Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 25 Desvenlafaxine (Pristiq) Mechanism of action Strong inhibitor of 5-HT and NE reuptake Does not block cholinergic, histaminergic, or alpha1-adrenergic receptors Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 26 Desvenlafaxine (Pristiq) Side effects Nausea Headache Dizziness Insomnia Diarrhea Dry mouth Sweating Constipation Sexual effects, including erectile dysfunction Decreased libido Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 27 Duloxetine (Cymbalta) Mechanism of action and therapeutic use Inhibits serotonin and NE reuptake Weakly inhibits dopamine reuptake Does not inhibit monoamine oxidase (MAO) Relieves depression Relieves pain of diabetic peripheral neuropathy Pharmacokinetics Well absorbed following oral administration Food reduces rate of absorption Highly bound to albumin in the blood Half-life: 12 hours Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 28 Duloxetine (Cymbalta) Adverse effects Effects in pregnancy and lactation Drug interactions Nausea Somnolence Dry mouth Sweating Insomnia Blurred vision Alcohol MAOIs Drugs that inhibit CYP1A2 or CYP2D6 Preparations, dosage, and administration Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 29 Tricyclic Antidepressants Drugs of first choice for many patients with major depression Most common adverse effects: sedation, orthostatic hypotension, and anticholinergic effects Most dangerous adverse effect: cardiac toxicity May increase risk of suicide early in treatment Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 30 Tricyclic Antidepressants Chemistry Mechanism of action Pharmacokinetics Therapeutic uses Adverse effects Drug interactions Dosage and routes of administration Preparations and drug selection Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 31 Chemistry Nucleus of the tricyclic antidepressants has three rings Similar to phenothiazine antipsychotics Produce varying degrees of: Sedation Orthostatic hypotension Anticholinergic effects Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 32 Fig. 32–1. Structural similarities between tricyclic antidepressants and phenothiazine antipsychotics. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 33 Mechanism of Action Block neuronal reuptake of two monoamine transmitters Norepinephrine (NE) Serotonin Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 34 Pharmacokinetics Long and variable half-lives Usually single daily dose Requires individualization of dosage Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 35 Fig. 32–2. Mechanism of action of tricyclic antidepressants. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 36 Therapeutic Uses Depression Bipolar disorder Other uses Neuropathic pain Chronic insomnia Attention-deficit/hyperactivity disorder Panic disorder Obsessive-compulsive disorder Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 37 Adverse Effects Orthostatic hypotension Anticholinergic effects Diaphoresis Sedation Cardiac toxicity Seizures Hypomania “Yawngasm” Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 38 Drug Interactions Monoamine oxidase inhibitors Direct-acting sympathomimetic drugs Indirect-acting sympathomimetic drugs Anticholinergic agents CNS depressants Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 39 Toxicity Clinical manifestations Primarily from anticholinergic and cardiotoxic actions • Dysrhythmias • Tachycardia • Intraventricular blocks • Complete atrioventricular block • Ventricular tachycardia • Ventricular fibrillation Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 40 Toxicity Treatment Gastric lavage Ingestion of activated charcoal Physostigmine Propranolol, lidocaine, or phenytoin Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 41 Dosage and Routes of Administration Dosage Initial doses should be low Routes of administration All can be administered by mouth Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 42 Preparation and Drug Selection Nine equally effective tricyclic antidepressants (TCAs) Selection based on side effects Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 43 Monoamine Oxidase Inhibitors 2nd- or 3rd-choice antidepressants for most patients As effective as TCAs or SSRIs, but more dangerous Risk of triggering hypertensive crisis if patient eats foods rich in tyramine Drug of choice for atypical depression Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 44 Monoamine Oxidase Inhibitors Mechanism of action Convert monoamine neurotransmitters (NE, serotonin, and dopamine) into inactive products Inactivate tyramine and other biogenic amines Two forms of MAO in the body • MAO-A and MAO-B Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 45 Monoamine Oxidase Inhibitors Mechanism of action (cont’d) Affected by antidepressants Act on MAO in two ways: reversible and irreversible • Reversible: lasts 3 to 5 days • Irreversible: lasts about 2 weeks All of the MAOIs in current use cause irreversible inhibition Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 46 Fig. 32–3. Mechanism of action of monoamine oxidase inhibitors. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 47 Monoamine Oxidase Inhibitors Therapeutic uses Depression Other uses • Bulimia nervosa • Obsessive-compulsive disorder • Panic attacks Adverse effects CNS stimulation Orthostatic hypotension Hypertensive crisis from dietary tyramine Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 48 Monoamine Oxidase Inhibitors Drug interactions Indirect-acting sympathomimetic agents Interactions secondary to inhibition of hepatic MAO Antidepressants: TCAs and SSRIs Antihypertensive drugs Meperidine Preparations, dosage, and administration All MAOIs administered orally Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 49 Fig. 32–4. Interaction between dietary tyramine and MAOIs. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 50 Transdermal MAOI: Selegiline Selegiline (Emsam) First transdermal treatment for depression Much lower risk of hypertensive crisis with transdermal route vs. oral route Enters the system without going through GI tract Adverse effects still occur when used with sympathomimetic drugs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 51 Atypical Antidepressants Bupropion (Wellbutrin) Actions and uses • Acts as stimulant and suppresses appetite • Antidepressant effects begin in 1–3 weeks • Does not affect serotonergic, cholinergic, or histaminergic transmission • Does not cause weight gain • Increases sexual desire and pleasure Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 52 Atypical Antidepressants Bupropion (Wellbutrin) (cont’d) Adverse effects • Can cause seizures • Agitation • Tremor • Tachycardia • Blurred vision • Dizziness • Headache • Insomnia Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 53 Atypical Antidepressants Bupropion (Wellbutrin) (cont’d) Adverse effects (cont’d) • Dry mouth • GI upset • Constipation • Weight loss Drug interactions • MAOIs can increase the risk of bupropion toxicity Preparations, dosage, and administration • Immediate-release, sustained-release, or extendedrelease tablets Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 54 Other Atypical Antidepressants Mirtazapine (Remeron) Nefazodone (Serzone) Trazodone (Oleptro) Vilazodone (Vibryd) Amoxapine (Asendin) Reboxetine (Vestra) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 55 Nonconventional Drugs for Depression Ketamine St. John’s wort (Hypericum perforatum) S-Adenosylmethionine Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 56 Electroconvulsive Therapy Outside the realm of pharmacology Valuable treatment for depression Two desirable characteristics Two primary types of patients Effectiveness Rapid onset (relative to antidepressant drugs) Those who have failed to respond to drugs Severely depressed, suicidal patients Can terminate ongoing depressive episode Adverse effect Some loss of memory for events immediately surrounding treatment Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 57 Transcranial Magnetic Therapy Outside the realm of pharmacology Reserved for major depression Employs an insulated magnetic coil, placed against the scalp, to deliver pulsed magnetic fields to the left dorsolateral prefrontal cortex Daily 40-minute sessions for 6 weeks Adverse effects Transient headaches and scalp discomfort. Patients may also experience eye pain, toothache, muscle twitching, and seizures. Cognitive changes have not been reported Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 58 Vagus Nerve Stimulation For long-term therapy of treatment-resistant depression (TRD) Mechanism of action When at least four antidepressant drugs have failed An implanted device Delivers electrical pulses to the vagus nerve Side effects Hoarseness Voice alteration Cough Dyspnea Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 59 Light Therapy Exposure to bright light Effective treatment of seasonal affective disorder (SAD) and for nonseasonal major depression May enhance serotonergic neurotransmission The more intense the light, the greater the response Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 60