Sex differences in antidepressant efficacy

Abstract

Sex differences have been observed across many psychiatric diseases, especially mood disorders. For major depression, the most prevalent psychiatric disorder, females show a roughly two-fold greater risk as compared to males. Depression is sexually dimorphic with males and females exhibiting differences in clinical presentation, course, and response to antidepressant treatment. In this review, we first discuss sex differences observed in depressed patients, as well as animal models that reveal potential underlying mechanisms. We then discuss antidepressant treatments including their proposed mechanism of action and sex differences observed in treatment response. We include possible mechanisms underlying these sex differences with particular focus on synaptic transmission.

Fig. 1

Antidepressant mechanism of action. Schematic of the proposed mechanisms of action for antidepressants at the synapse level. Serotonin and norepinephrine are represented together for simplicity. Ketamine has two proposed mechanisms, which are both shown. One is block of extrasynaptic NMDA receptors, leading to repression of eEF2 kinase and dephosphorylation of eEF2, thereby disinhibiting translation of BDNF. The second mechanism is block of NMDA receptors on inhibitory neurons, leading to increased excitation, BDNF release, and activation of mTOR through a TrkB-dependent signaling cascade. GABA-NAMs are negative allosteric modulators of alpha5 subunit-containing GABA receptors and thereby increase excitation and promote activity-dependent synaptic strengthening. SSRIs and TCAs act by blocking serotonin reuptake, increasing the synaptic concentration of serotonin, and thus increasing activation of serotonin receptors, thereby promoting activation of CaMK and PKA signaling and leading to increased synaptic strength via transcription and post translational modifications