Gepirone for Major Depressive Disorder: From Pharmacokinetics to Clinical Evidence: A Narrative Review

Gepirone, a selective 5-hydroxytryptamine (serotonin) 1A (5-HT_1A) receptor agonist, offers a promising strategy for treating mood and anxiety disorders. The therapeutic importance of 5-HT_1A modulation is well established, as these receptors regulate serotonergic neurotransmission both presynaptically, in the somatodendritic regions of raphe neurons, and postsynaptically, in structures including the hippocampus, neocortex, septum, amygdala, and hypothalamus. Gepirone exhibits a distinctive pharmacological profile, acting as a full agonist at presynaptic autoreceptors and a partial agonist at postsynaptic receptors, with high affinity for 5-HT_1A and much lower affinity for 5-HT_2A receptors. Its effects on serotonergic signaling are time-dependent. Acute administration suppresses serotonergic firing through autoreceptor activation, while chronic treatment induces autoreceptor desensitization, leading to enhanced 5-HT release in projection areas. This process is complemented by partial agonism at postsynaptic 5-HT_1A receptors, which further supports long-term neuromodulation. This article provides an integrated overview of gepirone's mechanism of action, bridging receptor pharmacology, neurophysiological adaptations, and therapeutic implications. Particular emphasis is placed on the compound's unique dual role in regulating serotonergic tone over time, a feature that differentiates it from other 5-HT_1A-targeting agents. By linking molecular mechanisms to clinical outcomes, we highlight gepirone's potential advantages in efficacy, safety, and tolerability compared with conventional antidepressants. This comprehensive perspective underscores gepirone as a paradigmatic example of selective 5-HT_1A modulation and offers novel insights into the development of targeted treatments for depression and anxiety.