What are the first‑generation antidepressants?

First-Generation Antidepressants

First-generation antidepressants consist of two main classes: tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). 1

Tricyclic Antidepressants (TCAs)

TCAs were among the first antidepressants introduced clinically, with imipramine being the inaugural drug in this family discovered in the 1950s. 2 This class includes:

• Amitriptyline (Elavil, Endep) 3
• Imipramine (Tofranil, Janimine) 3
• Nortriptyline (Aventyl, Pamelor) 3
• Desipramine (Norpramin, Pertofrane) 3
• Protriptyline (Vivactil) 3
• Doxepin (Adapin, Sinequan) 3
• Clomipramine (Anafranil) 3
• Trimipramine (Surmontil) 3

Mechanism and Limitations

• TCAs enhance serotonergic and/or noradrenergic mechanisms but also block histaminic, cholinergic, and alpha-1-adrenergic receptor sites, causing unwanted side effects including weight gain, dry mouth, constipation, drowsiness, and dizziness. 4
• These agents are potentially lethal in overdose, which is a critical safety concern. 1, 5

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs were also discovered in the 1950s, with iproniazid—originally used for tuberculosis treatment—being the first MAOI introduced for depression. 2 This class includes:

• Tranylcypromine (Parnate) 6, 3
• Phenelzine (Nardil) 3
• Isocarboxazid (Marplan) 3
• Furazolidone (Furoxone) 3
• Pargyline (Eutonyl) 3

Critical Safety Concerns

• MAOIs can interact with tyramine-containing foods to cause potentially lethal hypertensive crises. 4
• These drugs present dangerous interactions with numerous medications and over-the-counter products, including sympathomimetics, other antidepressants, and certain CNS depressants. 6, 3
• MAOIs are contraindicated in patients with pheochromocytoma, cerebrovascular disease, cardiovascular disease, hypertension, and liver disease. 6, 3

Clinical Context and Current Role

• First-generation antidepressants have been largely superseded by second-generation agents (SSRIs, SNRIs, SSNRIs) due to the newer drugs having similar efficacy but lower toxicity in overdose. 1, 7
• TCAs should not be used as first-line agents due to higher adverse effect burden, overdose risk, and lack of superiority over second-generation antidepressants. 8
• Despite their limitations, TCAs and particularly MAOIs continue to have a role in treatment-resistant depression when newer agents have failed. 9
• When switching between MAOIs and other antidepressants, medication-free intervals of at least one week (or 4-5 half-lives of the discontinued drug) are required to prevent severe reactions including hypertensive crises and serotonin syndrome. 6, 3

Common Pitfall

• Never combine first-generation antidepressants with second-generation antidepressants or other MAOIs without appropriate washout periods, as this can result in life-threatening hypertensive crises or serotonin syndrome. 6, 3