Tricyclic Antidepressants (TCAs) are so-called because of their molecular structure, which contains three rings of atoms. They act mainly by inhibiting the reuptake of both norepinephrine and serotonin. Other receptors that might also experience a TCA induced inhibition are muscuranic, alpha1 adrenergic, and histaminic receptors.

The TCAs of interest in the treatment of depression include amitriptyline (Elavil, Endep, Tryptanol), amoxapine (Asendin, Asendis, Defanyl, Demolox, Moxadil), clomipramine (Anafranil), imipramine (Tofranil), desipramine (Norpramin, Pertofrane), dothiepin hydrochloride (Thaden, Prothiaden), doxepin (Adapin, Sinequan), Iofepramine (Lomont, Gamanil), triimipramine (Surmontil), nortriptyline (Pamelor, Aventyl), and protriptyline (Vivactil).

Amitriptyline inhibits serotonin and noradrenaline reuptake almost equally. It is approved for the treatment of endogenous depression, involutional melancholia, and reactive depression. Amoxapine mainly inhibits the reuptake of norepinephrine.

Clomipramine is the most serotonergic TCA but exhibits higher risk for seizures. Doxepin is very effective in causing histamine block. Imipramine is converted by the body to desipramine. Desipramine strongly inhibits the reuptake of norepinephrine and induces very little anti-cholinergic side effects. It prevents fluctuations in the mood of depressive patients. Trimipramine induces antidepressant effect by raising the level of norepinephrine to normal. Anti-cholinergic and sedative effect are observed with its use. Nortriptyline is the least hypotensive TCA.

The potential side effects of Tricyclic Antidepressants (TCAs) are allergic reactions, blood cell problems, blurred vision, dry mouth, weakness, fatigue, weight gain, constipation, difficulty with urination, sexual dysfunction, sweating, muscle twitches, rash, dizziness, tremors, ECG abnormalities, seizures, stroke, and Neuroleptic Malignant Syndrome (with amoxapine). The secondary amine TCAs (desipramine and nortriptyline) are generally better tolerated than tertiary amine TCAs.

It should also be noted that an abrupt discontinuation of TCA therapy could cause cholinergic side effects such as diarrhea, nausea, or vomiting. Thus, a gradual reduction in dose before the complete discontinuation of TCA is a preventive step.