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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 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. 3 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 (patient with plan or serious intent should be hospitalized for therapy) 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. 4 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. 5 Treatment Modalities Pharmacotherapy Primary therapy Depression-specific psychotherapy (eg, cognitive behavioral therapy) The two together are better than either one alone, consider psychotherapy/counseling while waiting for antidepressants to work, which may be 4-8 weeks Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 6 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. 7 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. 8 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. 9 Mechanism of Action Produce selective inhibition of serotonin reuptake Produce CNS excitation Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 10 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. 11 Adverse Effects Serotonin syndrome (agitation, sweating, hyperreflexia) 2–72 hours after treatment Withdrawal syndrome – therapy is generally continued for a 912 months, but withdraw from meds gradually) Neonatal effects when used in pregnancy Teratogenesis Extrapyramidal side effects Bruxism Bleeding disorders Sexual dysfunction- drug holiday Friday/Saturday may be prescribed Weight gain Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 12 Drug Interactions Monoamine oxidase inhibitors Risk of serotonin syndrome- discontinue MAOI 2 weeks prior to starting SSRI Warfarin Tricyclic antidepressants and lithium Can elevate levels of these drugs Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 13 Other SSRIs Sertraline (Zoloft) Paroxetine (Paxil) Citalopram (Celexa) Escitalopram (Lexapro) Fluvoxamine (Luvox) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 14 Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine (Effexor) Duloxetine (Cymbalta) Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 15 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. 16 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. 17 Tricyclic Antidepressants (Imipramine, amitriptyline) 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. 18 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. 19 Mechanism of Action Block neuronal reuptake of two monoamine transmitters Norepinephrine (NE) Serotonin Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 20 Fig. 32–2. Mechanism of action of tricyclic antidepressants. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 21 Adverse Effects Orthostatic hypotension Anticholinergic effects Diaphoresis Sedation Cardiac toxicity Seizures Hypomania “Yawngasm” Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 22 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. 23 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. 24 Toxicity Treatment Gastric lavage Ingestion of activated charcoal Physostigmine Propranolol, lidocaine, or phenytoin Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 25 Monoamine Oxidase Inhibitors (phenelzine, isocarboxacid) 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 (see page 32-6) Drug of choice for atypical depression Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 26 Monoamine Oxidase Inhibitors Mechanism of action Block MOA, the enzyme that converts monoamine neurotransmitters (NE, serotonin, and dopamine) into inactive products Inactivate tyramine and other biogenic amines Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 27 Fig. 32–3. Mechanism of action of monoamine oxidase inhibitors. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 28 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. 29 Monoamine Oxidase Inhibitors Drug interactions Sympathomimetic agents Interactions secondary to inhibition of hepatic MAO Antidepressants: TCAs (risk of hypertensive episodes) and SSRIs (increased risk of serotonin syndrome) Meperidine- hyperpyrexia Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 30 Fig. 32–4. Interaction between dietary tyramine and MAOIs. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 31