Current understanding of the mechanism of action of classic and newer antidepressant drugs

Until 1980, the two major classes of antidepressant drugs were the tricyclics (TCAs) and the monoamine oxidase inhibitors (MAOIs). During the 1980s several additional classes of drugs appeared. Among these, selective serotonin reuptake inhibitors (SSRIs) have a distinct and well‐characterized mechanism of action, and have become among the most widely prescribed antidepressant drugs. A common factor in the action of antidepressants with different chemical structures is the ability to increase the synaptic availability of one or more neurotransmitters, as a result either of blockade of the reuptake process or inhibition of metabolic degradation. However, the delay in clinical response to antidepressants suggests that, even if the acute pharmacologic effects of antidepressants may be essential for efficacy, symptom resolution requires some adaptive changes in neurotransmission. More recent studies, therefore, have focused on the signal transduction process beyond the receptor level, and on the regulation of gene expression of specific proteins. The side‐effect profiles of antidepressants are related to their acute mechanisms of action. TCAs lack specificity of their pharmacological action, and are associated with antimuscarinic, antihistaminic, and alpha‐adrenergic blocking actions, that account for many unwanted side effects but do not contribute to their therapeutic profile. The SSRIs, as a result of their selective action to inhibit serotonin reuptake, appear to have more tolerable side effects than TCAs and are less likely to be lethal when taken in overdose. SSRIs have little or no affinity for neurotransmitter receptors. The most common side effect is gastrointestinal discomfort. Depression 2:119–126 (1994/1995).