Mechanism of Action of SSRIs in Depression
The overall pharmacologic goal of selective serotonin reuptake inhibitors (SSRIs) in treating depression is to increase the amount of serotonin found in the synapses. 1, 2
Core Mechanism
SSRIs selectively inhibit the reuptake of serotonin (5-HT) at presynaptic nerve endings, which prevents the removal of serotonin from the synaptic cleft via the membrane transporter. 1, 3, 4 This blockade results in an increased synaptic concentration of serotonin available to stimulate postsynaptic receptors. 1, 5
Time Course of Effect
Acute administration of SSRIs has little immediate effect on synaptic serotonin levels due to regulatory feedback mechanisms. 3
Prolonged administration (several weeks) causes desensitization of three key feedback systems:
Only after these feedback mechanisms weaken does the pharmacological activity of SSRIs fully express itself through sustained elevation of synaptic serotonin, which explains the 4–6 week latency before clinical antidepressant effects appear. 3
Clinical Application
SSRIs are recommended as first-line pharmacologic treatment for moderate to severe major depressive disorder, with a number needed to treat of 7–8 for achieving remission. 2, 6
The increased synaptic serotonin is necessary for therapeutic effect—tryptophan depletion studies demonstrate that depleting serotonin in patients whose depression is in remission on an SSRI causes recurrence of the disorder. 5
All second-generation antidepressants (including SSRIs) show equivalent efficacy in treatment-naïve patients; medication selection should be guided by adverse-effect profile, cost, and patient preferences rather than presumed efficacy differences. 2, 6