The chemical structures of TCAs and related compounds are remarkably similar (Figure 3–6). Desipramine and nortriptyline are demethylated metabolites of imipramine and amitriptyline, respectively. Amoxapine is a derivative of the antipsychotic loxapine and has an additional fourth ring off a side chain. Maprotiline is a four-ring compound, with the fourth ring arising perpendicular to the traditional three rings. Its side chain is identical to that of desipramine.

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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.
Table Reference Number

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


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


Sexual dysfunction



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.


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
Table Reference Number
Table 3–8. Relative receptor-blocking effects of antidepressants
Table Reference Number
Table 3–9. Common or troublesome side effects of tricyclic and tetracyclic drugs
Table Reference Number
Table 3–10. Tricyclic and tetracyclic antidepressants: names, formulations and strengths, and dosages
Table Reference Number
Table 3–11. Approximate therapeutic serum level ranges for tricyclic and tetracyclic drugs


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