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Chapter 3. Antidepressants

DOI: 10.1176/appi.books.9781585624119.600853

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According to the Centers for Disease Control and Prevention 2007 annual report "Health, United States," antidepressants are the most commonly prescribed agents in all of medicine (National Center for Health Statistics 2007). The wisdom of such a widespread use of this class of medications is debated in the literature and the popular press. However, what is not debatable is that clinicians have felt increasingly comfortable in prescribing these medications. The growing popularity of antidepressants rests on a number of factors, including their efficacy in the treatment of depression, broad spectrum of activity, relative safety, and ease of use. Factors such as marketing also have played a role in the widespread adoption of antidepressants in clinical practice.

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Figure 3–1. Chemical structures of selective serotonin reuptake inhibitors (SSRIs).

Figure 3–2. Chemical structures of the serotonin-norepinephrine reuptake inhibitors (venlafaxine, desvenlafaxine, duloxetine, and milnacipran).

Figure 3–3. Chemical structures of serotonin2 (5-HT2) antagonists.

Figure 3–4. Chemical structure of bupropion.

Figure 3–5. Chemical structure of mirtazapine.

Figure 3–6. Chemical structures of tricyclic and tetracyclic antidepressants.

Figure 3–7. Sigmoidal relationship between clinical response and imipramine plus desipramine plasma levels.

Figure 3–8. Curvilinear relationship between clinical response and nortriptyline plasma levels.

Figure 3–9. Chemical structures of monoamine oxidase inhibitors (MAOIs).
Table Reference Number

Note. FDA = U.S. Food and Drug Administration; GAD = generalized anxiety disorder; GI = gastrointestinal; MAOI = monoamine oxidase inhibitor; MDD = major depressive disorder; OCD = obsessive-compulsive disorder; PD = panic disorder; PMDD = premenstrual dysphoric disorder; PTSD = posttraumatic stress disorder; TCA = tricyclic antidepressant.

Selective serotonin reuptake inhibitors (SSRIs): overview

Efficacy

First-line treatment in

MDD (FDA approved for all except fluvoxamine), dysthymia

PD (FDA approved for fluoxetine, paroxetine, and sertraline)

OCD (FDA approved for all except citalopram and escitalopram)

Social anxiety disorder (FDA approved for sertraline, fluvoxamine, and paroxetine)

PTSD (FDA approved for sertraline and paroxetine)

Bulimia (FDA approved for fluoxetine)

GAD (FDA approved for paroxetine and escitalopram)

PMDD (FDA approved for fluoxetine [Sarafem only], paroxetine [controlled release only], and sertraline)

Side effects

GI side effects (nausea, diarrhea, heartburn)

Sexual dysfunction ( libido, delayed orgasm)

Headache

Insomnia/somnolence

Safety in overdose

Generally safe in overdose to 30–90 days' supply; manage with vital sign support, lavage

Seizures/status epilepticus (rare)

Dosage and administration

Citalopram, paroxetine, fluoxetine: qd dosing, starting at 10–20 mg, increasing to a maximum of 40 mg (citalopram), 50 mg (paroxetine), and 80 mg (fluoxetine).

Escitalopram: qd dosing, starting at 10 mg, increasing to 20 mg after minimum of 1 week.

Sertraline: starts at 25–50 mg and is increased, as needed, to 200 mg maximum.

Full benefits in 4–8 weeks

Discontinuation

Paroxetine, fluvoxamine, sertraline: discontinuation associated with parasthesias, nausea, headaches, flulike symptoms 1–7 days after sudden discontinuation

Drug interactions

MAOI (contraindicated): serotonin syndrome

TCA levels (paroxetine, fluoxetine)

Carbamazepine, phenobarbital, phenytoin levels

Haloperidol, clozapine levels (fluvoxamine)

Theophylline levels (fluvoxamine)

Encainide, flecainide levels (avoid)

Table Reference Number
Table 3–1. Inhibition of cytochrome P450 enzymes by antidepressants
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Table 3–2. Pharmacokinetics of selective serotonin reuptake inhibitors (SSRIs)
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Table 3–3. Adjunctive agents for selective serotonin reuptake inhibitor (SSRI)–induced sexual dysfunction
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Table 3–4. Selective serotonin reuptake inhibitors (SSRIs) and other available antidepressants: names, formulations and strengths, and dosages
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Table 3–5. The serotonin2 (5-HT 2) antagonists
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Table 3–6. Common or troublesome side effects of trazodone and nefazodone
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Note. CNS = central nervous system; ECG = electrocardiogram; FDA = U.S. Food and Drug Administration; GI = gastrointestinal; MAOI = monoamine oxidase inhibitor; MDD = major depressive disorder; OCD = obsessive-compulsive disorder; SSRI = selective serotonin reuptake inhibitor.

Tricyclic antidepressants (TCAs): overview

Efficacy

Second- or third-line agents for MDD (FDA approved for all)

Panic disorder

OCD (FDA approved for clomipramine)

Pain syndromes

Migraine prophylaxis

Enuresis (FDA approved for imipramine)

Side effects

Dry mouth, constipation, urinary retention, blurred vision, confusion

Weight gain

Sedation

Sexual dysfunction

Orthostasis

Tachycardia

Cardiac conduction abnormalities

Dosage and administration

Individualize with low hs dosing (25–50 mg) for imipramine and amitriptyline. Increase by 25–50 mg every 3–7 days to target dosage of 150–300 mg/day. (Nortriptyline should be started at 10–25 mg and increased, as needed, to a maximum dosage of 150 mg/day.) Monitor levels and ECGs after dose stabilized.

Safety in overdose

Lethal in overdose (induces arrhythmias).

Lavage and monitor on a cardiac bed for QRS widening.

Discontinuation

Flulike and GI symptoms from cholinergic rebound. Reduce by 25–50 mg every 3 days.

Drug interactions

CNS depressants: sedation, ataxia

Anticoagulants: warfarin levels

Antipsychotics: TCA and antipsychotic levels

Cimetidine: TCA levels

Clonidine: hypertensive crisis (avoid)

l-Dopa: TCAs absorption

MAOIs: serotonin syndrome (avoid clomipramine; imipramine and amitriptyline may be used with close monitoring)

Stimulants: TCA levels

Oral contraceptives: TCA levels

Quinidine: arrhythmias (avoid)

SSRIs: TCA levels

Sympathomimetics: arrhythmias, hypertension, tachycardia

Table Reference Number
Table 3–7. Norepinephrine (NE) and serotonin (5-HT) reuptake–blocking effects of the non-MAOI antidepressants
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Table 3–8. Relative receptor-blocking effects of antidepressants
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Table 3–9. Common or troublesome side effects of tricyclic and tetracyclic drugs
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Table 3–10. Tricyclic and tetracyclic antidepressants: names, formulations and strengths, and dosages
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Table 3–11. Approximate therapeutic serum level ranges for tricyclic and tetracyclic drugs
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Table 3–12. Monoamine oxidase inhibitors (MAOIs): names, formulations and strengths, and dosages
Table Reference Number

Note. FDA = U.S. Food and Drug Administration; MDD = major depressive disorder; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Monoamine oxidase inhibitors (MAOIs): overview

Efficacy

Third-line agents for

 MDD (FDA approved for resistant depression)

 Social anxiety

 Panic disorder

Second-line agents for Parkinson's disease (selegiline has FDA approval)

Side effects

Weight gain

Orthostasis

Sexual dysfunction

Dry mouth

Insomnia/somnolence

Headache

Safety in overdose

Can be lethal in overdose. Hypertensive crisis, stroke, and myocardial infarction have been reported. Manage with lavage, emesis induction, and close management of blood pressure and airway.

Dosage and administration

Phenelzine: start at 15 mg bid or tid and increase by 15 mg per week to target dosage of 60–90 mg/day.

Tranylcypromine: start at 10 mg bid or tid and increase by 10 mg per week to target dosage of 40–60 mg/day.

Isocarboxazid: start at 10 mg bid and increase dosage, if the drug is tolerated, by 10 mg every 2–4 days to 40 mg/day by end of first week. Maximum recommended dosage is 60 mg/day, administered in divided doses.

Selegiline transdermal system (Emsam): start with 6-mg patch daily for 4 weeks and then increase to 9-mg patch for 2 weeks, and then 12-mg patch as needed. No dietary restrictions at 6 mg/day.

Discontinuation

Flulike symptoms, hallucinations, hypomania, and dysphoria reported with sudden discontinuation. Taper dose by 25% per week.

Drug interactions

Foods containing high levels of tyramine (contraindicated) (see Table 3–14Table 3–14): hypertensive crisis

-Blockers: hypotension, bradycardia

Oral hypoglycemics: hypoglycemic effects

Bupropion (contraindicated): hypertensive crisis, seizure

Carbamazepine (contraindicated): hypertensive crisis

Meperidine (contraindicated): serotonin syndrome

Nefazodone: possible serotonin syndrome

Sympathomimetics: hypertensive crisis

SSRIs (contraindicated): serotonin syndrome

TCAs: clomipramine contraindicated

Mirtazapine (contraindicated): hypertensive crisis

SNRIs (contraindicated): serotonin syndrome

Table Reference Number
Table 3–13. Common or troublesome side effects of monoamine oxidase inhibitors (MAOIs)
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Table 3–14. Foods to be avoided with monoamine oxidase inhibitors (MAOIs)

References

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