1 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Antidepressants

2 Elsevier Inc. items and derived items © 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 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Antidepressant Groups Tricyclic antidepressants Selective serotonin reuptake inhibitors (SSRIs) Serotonin/norepinephrine reuptake inhibitors (S/NRIs) Monoamine oxidase inhibitors (MAOIs) Atypical antidepressants

4 Elsevier Inc. items and derived items © 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 Incidence in women 2x as high as in men Risk of suicide is high in depression Often untreated

5 Elsevier Inc. items and derived items © 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 Elsevier Inc. items and derived items © 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 a functional insufficiency of monoamine neurotransmitters

7 Elsevier Inc. items and derived items © 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 Elsevier Inc. items and derived items © 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 Elsevier Inc. items and derived items © 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

10 Elsevier Inc. items and derived items © 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

11 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Chemistry Nucleus of the tricyclic antidepressants have three rings Similar to phenothiazine antipsychotics Produce varying degrees of: Sedation Orthostatic hypotension Anticholinergic effects

12 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Mechanism of Action Block neuronal reuptake of two monoamine transmitters Norepinephrine (NE) Serotonin

13 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Pharmacokinetics Long and variable half-lives Usually single daily dose Requires individualization of dosage

14 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Fig Mechanism of action of tricyclic antidepressants. A, Under drug-free conditions, the actions of norepinephrine and serotonin are terminated by active uptake of these transmitters back into the nerve terminals from which they were released. B, By inhibiting the uptake pumps for norepinephrine and serotonin, tricyclic antidepressants cause these transmitters to accumulate in the synaptic space, thereby intensifying transmission. (P = uptake pump, T = transmitter [norepinephrine or serotonin], TCA = tricyclic antidepressant, P = uptake pump.)

15 Elsevier Inc. items and derived items © 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

16 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Adverse Effects Orthostatic hypotension Anticholinergic effects Diaphoresis Sedation Cardiac toxicity Seizures Hypomania Yawngasm

17 Elsevier Inc. items and derived items © 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

18 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Toxicity Clinical manifestations Primarily from anticholinergic and cardiotoxic actions Dysrhythmias Tachycardia Intraventricular blocks Complete atrioventricular block Ventricular tachycardia Ventricular fibrillation

19 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Toxicity Treatment Gastric lavage Ingestion of activated charcoal Physostigmine Propranolol, lidocaine, or phenytoin

20 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Dosage and Routes of Administration Dosage Initial doses should be low See Table 32-2 Routes of administration All can be administered by mouth

21 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Preparation and Drug Selection Nine equally effective tricyclic antidepressants (TCAs) Selection based on side effects

22 Elsevier Inc. items and derived items © 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

23 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine (Prozac) Most widely prescribed SSRI in the U.S. Other SSRIs

24 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Mechanism of Action Produces selective inhibition of serotonin reuptake Produces CNS excitation

25 Elsevier Inc. items and derived items © 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

26 Elsevier Inc. items and derived items © 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

27 Elsevier Inc. items and derived items © 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

28 Elsevier Inc. items and derived items © 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 Panic disorder Obsessive-compulsive disorder Post-traumatic stress disorder Premenstrual dysphoric disorder Social anxiety disorder

29 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs Sertraline (Zoloft) (cont’d) Side effects Headache Nausea Tremor Diarrhea Insomnia Weight gain Agitation Sexual dysfunction NAS and PPHN when used late in pregnancy Nervousness

30 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs Sertraline (Zoloft) (cont’d) Drug interactions MAOIs Pimozide

31 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs Paroxetine (Paxil) Inhibition of serotonin uptake Indications Major depression Obsessive-compulsive disorder Social phobia Panic disorder Generalized anxiety disorder Post-traumatic stress disorder Premenstrual dysphoric disorder

32 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs Citalopram (Celexa) Does not block receptors for serotonin, acetylcholine, 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

33 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Other SSRIs Escitalopram (Lexapro) S-isomer of citalopram Better tolerated than citalopram Side effects Nausea Insomnia Somnolence Sweating Fatigue Interacts with MAOIs

34 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Serotonin/Norepinephrine Reuptake Inhibitors (S/NRIs) Venlafaxine (Effexor) Duloxetine (Cymbalta)

35 Elsevier Inc. items and derived items © 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

36 Elsevier Inc. items and derived items © 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 elderly patients) Neonatal withdrawal syndrome

37 Elsevier Inc. items and derived items © 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

38 Elsevier Inc. items and derived items © 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 MAO inhibitors Drugs that inhibit CYP1A2 or CYP2D6 Preparations, dosage, and administration

39 Elsevier Inc. items and derived items © 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

40 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Monoamine Oxidase Inhibitors Mechanism of action Converts monoamine neurotransmitters (NE, serotonin, and dopamine) into inactive products Inactivates tyramine and other biogenic amines Two forms of MAO in the body MAO-A and MAO-B

41 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Monoamine Oxidase Inhibitors Mechanism of action (cont’d) Affected by antidepressants Acts 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

42 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Fig Mechanism of action of monoamine oxidase inhibitors. A, Under drug-free conditions, much of the norepinephrine or serotonin that undergoes reuptake into nerve terminals becomes inactivated by MAO. Inactivation helps maintain an appropriate concentration of transmitter within the terminal. B, MAO inhibitors prevent inactivation of norepinephrine and serotonin, thereby increasing the amount of transmitter available for release. Release of supranormal amounts of transmitter intensifies transmission. (MAO = monoamine oxidase, P = uptake pump, T = transmitter [norepinephrine or serotonin].)

43 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Monoamine Oxidase Inhibitors Therapeutic uses Depression Other uses Bulimia nervosa Obsessive-compulsive disorders Panic attacks Adverse effects CNS stimulation Orthostatic hypotension Hypertensive crisis from dietary tyramine

44 Elsevier Inc. items and derived items © 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

45 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Fig Interaction between dietary tyramine and MAOIs. A, In the absence of MAOIs, much of ingested tyramine is inactivated by MAO in the intestinal wall (not shown in the figure). Any dietary tyramine that is not metabolized in the intestinal wall is transported directly to the liver, where it undergoes immediate inactivation by hepatic MAO. No tyramine reaches the general circulation. B, Three events occur in the presence of MAOIs: (1) Inhibition of neuronal MAO raises levels of norepinephrine in sympathetic nerve terminals. (2) Inhibition of intestinal and hepatic MAO allows dietary tyramine to pass through the intestinal wall and liver to enter the systemic circulation intact. (3) Upon reaching peripheral sympathetic nerve terminals, tyramine promotes the release of accumulated norepinephrine stores, thereby causing massive vasoconstriction and excessive stimulation of the heart. (MAO = monoamine oxidase, NE = norepinephrine, R = receptor for norepinephrine.)

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

47 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Atypical Antidepressants Bupropion (Wellbutrin) (cont’d) Adverse effects Can cause seizures Agitation Tremor Tachycardia Blurred vision Dizziness Headache Insomnia

48 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. 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 extended-release tablets

49 Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Other Atypical Antidepressants Nefazodone (Serzone) Mirtazapine (Remeron) Trazodone (Desyrel)

50 Elsevier Inc. items and derived items © 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

51 Elsevier Inc. items and derived items © 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