Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 32 Antidepressants

2 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

3 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Antidepressant Groups  Tricyclic antidepressants  Selective serotonin reuptake inhibitors (SSRIs)  Serotonin/norepinephrine reuptake inhibitors (SNRIs)  Monoamine oxidase inhibitors (MAOIs)  Atypical antidepressants

4 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

5 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

6 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

7 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Treatment Modalities  Pharmacotherapy  Primary therapy  Depression-specific psychotherapy (eg, cognitive behavioral therapy)  Electroconvulsive therapy (ECT)  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

8 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

9 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

10 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Selective Serotonin Reuptake Inhibitors (SSRIs)  Fluoxetine (Prozac, Sarafem)  Most widely prescribed SSRI in the United States  Other SSRIs

11 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Mechanism of Action  Produce selective inhibition of serotonin reuptake  Produce CNS excitation

12 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Therapeutic Uses   Primarily used to treat major depression   Other uses   Obsessive-compulsive disorder   Bulimia nervosa   Premenstrual dysphoric disorder

13 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

14 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Interactions  Monoamine oxidase inhibitors  Risk of serotonin syndrome  Warfarin  Tricyclic antidepressants and lithium  Can elevate levels of these drugs

15 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs  Sertraline (Zoloft)  Blocks uptake of serotonin and dopamine  CNS stimulation  Minimal effects on seizure threshold  Therapeutic uses Major depression Major depression Panic disorder Panic disorder Obsessive-compulsive disorder Obsessive-compulsive disorder Post-traumatic stress disorder Post-traumatic stress disorder Premenstrual dysphoric disorder Premenstrual dysphoric disorder Social anxiety disorder Social anxiety disorder

16 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs  Sertraline (Zoloft) (cont’d)  Side effects Headache Headache Nausea Nausea Tremor Tremor Diarrhea Diarrhea Insomnia Insomnia Weight gain Weight gain Agitation Agitation Sexual dysfunction Sexual dysfunction Neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension of the newborn (PPHN ) when used lateregnancy Neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension of the newborn (PPHN ) when used late in pregnancy Nervousness Nervousness

17 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs  Sertraline (Zoloft) (cont’d)  Drug interactions MAOIs MAOIs Pimozide Pimozide

18 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

19 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs  Fluvoxamine (Luvox) (cont’d)  Side effects Nausea Nausea Vomiting Vomiting Constipation Constipation Weight gain Weight gain Dry mouth Dry mouth Headache Headache Sexual dysfunction Sexual dysfunction Abnormal liver function Abnormal liver function Sedative effects Sedative effects

20 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs  Paroxetine (Paxil, Paxil CR, Pexeva)  Inhibition of serotonin uptake  Indications Major depression Major depression Obsessive-compulsive disorder Obsessive-compulsive disorder Social phobia Social phobia Panic disorder Panic disorder Generalized anxiety disorder Generalized anxiety disorder Post-traumatic stress disorder Post-traumatic stress disorder Premenstrual dysphoric disorder Premenstrual dysphoric disorder

21 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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 Nausea Somnolence Somnolence Dry mouth Dry mouth Sexual dysfunction Sexual dysfunction  Can cause neonatal abstinence syndrome  Interacts with MAOIs

22 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs  Escitalopram (Lexapro)  S-isomer of citalopram  Better tolerated than citalopram  Side effects Nausea Nausea Insomnia Insomnia Somnolence Somnolence Sweating Sweating Fatigue Fatigue  Interacts with MAOIs

23 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)  Venlafaxine (Effexor)  Duloxetine (Cymbalta)

24 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Venlafaxine (Effexor)  Indications  Major depression  Generalized anxiety disorder  Social anxiety disorder (social phobia)  Blocks NE and serotonin uptake  Does not block cholinergic, histaminergic, or alpha 1 -adrenergic receptors  Serious reactions if combined with MAOIs

25 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

26 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Desvenlafaxine (Pristiq)  Mechanism of action  Strong inhibitor of 5-HT and NE reuptake  Does not block cholinergic, histaminergic, or alpha 1 -adrenergic receptors

27 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Desvenlafaxine (Pristiq)  Side effects  Nausea  Headache  Dizziness  Insomnia  Diarrhea  Dry mouth  Sweating  Constipation  Sexual effects, including erectile dysfunction  Decreased libido

28 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

29 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Duloxetine (Cymbalta)  Adverse effects  Nausea  Somnolence  Dry mouth  Sweating  Insomnia  Blurred vision  Effects in pregnancy and lactation  Drug interactions  Alcohol  MAOIs  Drugs that inhibit CYP1A2 or CYP2D6  Preparations, dosage, and administration

30 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

31 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Tricyclic Antidepressants  Chemistry  Mechanism of action  Pharmacokinetics  Therapeutic uses  Adverse effects  Drug interactions  Dosage and routes of administration  Preparations and drug selection

32 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chemistry  Nucleus of the tricyclic antidepressants has three rings  Similar to phenothiazine antipsychotics  Produce varying degrees of:  Sedation  Orthostatic hypotension  Anticholinergic effects

33 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 32–1. Structural similarities between tricyclic antidepressants and phenothiazine antipsychotics.

34 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Mechanism of Action  Block neuronal reuptake of two monoamine transmitters  Norepinephrine (NE)  Serotonin

35 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Pharmacokinetics   Long and variable half-lives   Usually single daily dose   Requires individualization of dosage

36 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 32–2. Mechanism of action of tricyclic antidepressants.

37 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Therapeutic Uses  Depression  Bipolar disorder  Other uses  Neuropathic pain  Chronic insomnia  Attention-deficit/hyperactivity disorder  Panic disorder  Obsessive-compulsive disorder

38 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adverse Effects  Orthostatic hypotension  Anticholinergic effects  Diaphoresis  Sedation  Cardiac toxicity  Seizures  Hypomania  “Yawngasm”

39 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Drug Interactions  Monoamine oxidase inhibitors  Direct-acting sympathomimetic drugs  Indirect-acting sympathomimetic drugs  Anticholinergic agents  CNS depressants

40 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Toxicity  Clinical manifestations  Primarily from anticholinergic and cardiotoxic actions Dysrhythmias Dysrhythmias Tachycardia Tachycardia Intraventricular blocks Intraventricular blocks Complete atrioventricular block Complete atrioventricular block Ventricular tachycardia Ventricular tachycardia Ventricular fibrillation Ventricular fibrillation

41 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Toxicity  Treatment  Gastric lavage  Ingestion of activated charcoal  Physostigmine  Propranolol, lidocaine, or phenytoin

42 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Dosage and Routes of Administration  Dosage  Initial doses should be low  Routes of administration  All can be administered by mouth

43 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Preparation and Drug Selection  Nine equally effective tricyclic antidepressants (TCAs)  Selection based on side effects

44 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

45 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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 MAO-A and MAO-B

46 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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 Reversible: lasts 3 to 5 days Irreversible: lasts about 2 weeks Irreversible: lasts about 2 weeks  All of the MAOIs in current use cause irreversible inhibition

47 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 32–3. Mechanism of action of monoamine oxidase inhibitors.

48 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Monoamine Oxidase Inhibitors  Therapeutic uses  Depression  Other uses Bulimia nervosa Bulimia nervosa Obsessive-compulsive disorder Obsessive-compulsive disorder Panic attacks Panic attacks  Adverse effects  CNS stimulation  Orthostatic hypotension  Hypertensive crisis from dietary tyramine

49 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

50 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 32–4. Interaction between dietary tyramine and MAOIs.

51 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

52 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Atypical Antidepressants  Bupropion (Wellbutrin)  Actions and uses Acts as stimulant and suppresses appetite Acts as stimulant and suppresses appetite Antidepressant effects begin in 1–3 weeks Antidepressant effects begin in 1–3 weeks Does not affect serotonergic, cholinergic, or histaminergic transmission Does not affect serotonergic, cholinergic, or histaminergic transmission Does not cause weight gain Does not cause weight gain Increases sexual desire and pleasure Increases sexual desire and pleasure

53 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Atypical Antidepressants  Bupropion (Wellbutrin) (cont’d)  Adverse effects Can cause seizures Can cause seizures Agitation Agitation Tremor Tremor Tachycardia Tachycardia Blurred vision Blurred vision Dizziness Dizziness Headache Headache Insomnia Insomnia

54 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Atypical Antidepressants  Bupropion (Wellbutrin) (cont’d)  Adverse effects (cont’d) Dry mouth Dry mouth GI upset GI upset Constipation Constipation Weight loss Weight loss  Drug interactions MAOIs can increase the risk of bupropion toxicity MAOIs can increase the risk of bupropion toxicity  Preparations, dosage, and administration Immediate-release, sustained-release, or extended- release tablets Immediate-release, sustained-release, or extended- release tablets

55 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Atypical Antidepressants  Mirtazapine (Remeron)  Nefazodone (Serzone)  Trazodone (Oleptro)  Vilazodone (Vibryd)  Amoxapine (Asendin)  Reboxetine (Vestra)

56 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nonconventional Drugs for Depression  Ketamine  St. John’s wort (Hypericum perforatum)  S-Adenosylmethionine

57 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Electroconvulsive Therapy  Outside the realm of pharmacology  Valuable treatment for depression  Two desirable characteristics  Effectiveness  Rapid onset (relative to antidepressant drugs)  Two primary types of patients  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

58 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

59 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Vagus Nerve Stimulation  For long-term therapy of treatment-resistant depression (TRD)  When at least four antidepressant drugs have failed  Mechanism of action  An implanted device  Delivers electrical pulses to the vagus nerve  Side effects  Hoarseness  Voice alteration  Cough  Dyspnea

60 Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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