The Journal of clinical psychiatryAug 14, 1999

Are antidepressants selective or do they affect multiple brain targets?

Psychedelic Science Weekly Brief ↗PubMed ↗

Updated Feb 14, 2026

Abstract

The introduction of mirtazapine represents a significant development in antidepressant therapy by enhancing both norepinephrine and serotonin neurotransmission.

Tricyclic antidepressants (TCAs) demonstrate strong antidepressant activity through the roles of norepinephrine and serotonin.
Selective serotonin reuptake inhibitors (SSRIs) further emphasize the importance of serotonin in treating depression.
Selective norepinephrine reuptake inhibitors (SNRIs) highlight the relevance of norepinephrine in the antidepressant response.
SNRIs, such as venlafaxine and milnacipran, inhibit norepinephrine and serotonin reuptake without the adverse effects seen in TCAs.
Mirtazapine enhances both norepinephrine and serotonin activity by blocking specific receptors, potentially improving anxiety and sleep without typical side effects of SSRIs.

Simplified

The understanding of mechanisms of antidepressant action has evolved over time. The strong antidepressant activity of the tricyclic antidepressants (TCAs) has supported the role of both norepinephrine and serotonin (5-HT) in depression and the mechanism involved in antidepressant action. The next generation of antidepressants included the selective serotonin reuptake inhibitors (SSRIs), further supporting the role of serotonin, while the selective norepinephrine reuptake inhibitors such as maprotiline and reboxetine underlined the relevance of norepinephrine. These developments suggest that either facilitation of serotonin or norepinephrine or both may lead to an antidepressant response. The next step was the development of mixed serotonin-norepinephrine reuptake inhibitors (SNRIs), exemplified by venlafaxine and milnacipran. As with the TCAs, the antidepressant activity of SNRIs is based on inhibition of norepinephrine and serotonin reuptake, but unlike TCAs they do not have anticholinergic, antihistaminergic, and cardiotoxic effects. Although norepinephrine is known to stimulate serotonin cell firing rate via the alpha1-adrenoceptors, norepinephrine and serotonin have independent antidepressant actions. The latest development has been the introduction of the noradrenergic and specific serotonergic antidepressant mirtazapine. Its antidepressant effect appears to be related to dual enhancement of central noradrenergic and serotonergic neurotransmission by blockade of alpha2-adrenoceptors. In addition, mirtazapine directly blocks 5-HT2 and 5-HT3 receptors, which may account for its anxiolytic and sleep-improving properties as well as its lack of adverse events that are typical of SSRIs.

Are antidepressants selective or do they affect multiple brain targets?

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