Rationale: Ketamine has rapid antidepressant effects that represent a significant advance in treating depression, but its poor safety and tolerability limit its clinical utility. Accreting evidence suggests that serotonergic neurotransmission participates in the rapid antidepressant effects of ketamine and hallucinogens. Thus, understanding how serotonin contributes to these effects may allow identification of novel rapid antidepressant mechanisms with improved tolerability. Objective: The goal of this paper is to understand how serotonergic mechanisms participate in rapid antidepressant mechanisms. Methods: We review the relevance of serotonergic neurotransmission for rapid antidepressant effects and evaluate the role of 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors in synaptic plasticity, BDNF signaling, and GSK-3β activity. Subsequently, we develop hypotheses on the relationship of these receptor systems to rapid antidepressant effects. Results: We found that 5-HT1A and 5-HT1B receptors may participate in ketamine’s rapid antidepressant mechanisms, while agonists at 5-HT2A and 5-HT4 receptors may independently behave as rapid antidepressants. 5-HT1A, 5-HT2A, and 5-HT4 receptors increase synaptic plasticity in the cortex or hippocampus but do not consistently increase BDNF signaling. We found that 5-HT1A and 5-HT1B receptors may participate in rapid antidepressant mechanisms as a consequence of increased BDNF signaling, rather than a cause. 5-HT2A and 5-HT4 receptor agonists may increase BDNF signaling, but these relationships are tenuous and need more study. Finally, we found that ketamine and several serotonergic receptor systems may mechanistically converge on reduced GSK-3β activity. Conclusions: We find it plausible that serotonergic neurotransmission participates in rapid antidepressant mechanisms by increasing synaptic plasticity, perhaps through GSK-3β inhibition.
|State||Accepted/In press - 2022|