The Journal of clinical psychiatryMar 23, 1999

How antidepressant medications work

Psychedelic Science Weekly Brief ↗PubMed ↗

Updated Feb 14, 2026

Abstract

The evolution of antidepressant medications spans nearly 50 years, shifting from early first-generation drugs to more targeted newer options.

First-generation antidepressants, such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), were effective by enhancing serotonergic and noradrenergic activity.
TCAs are associated with significant side effects, including weight gain, dry mouth, and drowsiness, due to their action on multiple receptor sites.
MAOIs can lead to dangerous hypertension when interacting with tyramine and pose risks with various medications.
Newer antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs) and others like venlafaxine and bupropion, aim to minimize unwanted side effects by targeting specific brain receptors.
The paper examines the mechanisms of action of these newer antidepressants and discusses potential future developments in depression treatment.

Simplified

The psychopharmacology of depression is a field that has evolved rapidly in just under 5 decades. Early antidepressant medications--tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs)--were discovered through astute clinical observations. These first-generation medications were effective because they enhanced serotonergic or noradrenergic mechanisms or both. Unfortunately, the TCAs also blocked histaminic, cholinergic, and alpha1-adrenergic receptor sites, and this action brought about unwanted side effects such as weight gain, dry mouth, constipation, drowsiness, and dizziness. MAOIs can interact with tyramine to cause potentially lethal hypertension and present potentially dangerous interactions with a number of medications and over-the-counter drugs. The newest generation of antidepressants, including the single-receptor selective serotonin reuptake inhibitors (SSRIs) and multiple-receptor antidepressants venlafaxine, mirtazapine, bupropion, trazodone, and nefazodone, target one or more specific brain receptor sites without, in most cases, activating unwanted sites such as histamine and acetylcholine. This paper discusses the new antidepressants, particularly with regard to mechanism of action, and looks at future developments in the treatment of depression.

How antidepressant medications work

Abstract

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