Gepirone (brand name Travivo) is an investigational azapirone antidepressant and anxiolytic drug in development for the treatment of major depressive disorder but has yet to be marketed. Like other azapirones, it acts as a selective partial agonist of the 5-HT1A receptor. Gepirone has been under development in the U.S. in an extended release form (referred to as Gepirone ER). It has been rejected multiple times by the FDA during the drug approval process and Phase III studies evaluating its use in the treatment of MDD were prematurely terminated. These were the initial Phase III studies of gepirone ER in MDD, and the effective dose range had not been determined. In March 2016, the FDA reversed its decision and gave gepirone ER a positive review, clearing the way for the drug to finally gain market approval in the U.S. In addition to its antidepressant and anxiolytic properties, gepirone has been found to improve symptoms of sexual dysfunction in men and women, similarly to the marketed 5-HT1A receptor agonist flibanserin. The pro-sexual effects appear to be independent of its antidepressant and anxiolytic effects. Mechanism of action studies have demonstrated that gepirone possesses a much greater selectivity for 5-HT1A receptors over dopamine D2 receptors. Long-term studies have shown that gepirone has a differential action at presynaptic (agonist) and post-synaptic (partial agonist) 5-HT1A receptors. Treatment with gepirone ER desensitizes presynaptic 5-HT1A receptors, which decreases serotonin autoregulatory inhibition and enhances activation of postsynaptic 5-HT1A receptors. As a partial agonist gepirone ER acts as an agonist when endogenous serotonin is not present and as an antagonist when endogenous serotonin is present. Overall, gepirone ER increases serotonin production when insufficient amounts are present, and decreases serotonin production when excess amounts are present. Gepirone has been tested in Phase II clinical trial as antidepressant medication for pharmacotherapy for cocaine dependent subjects.

Buspirone is the first of a new class of anxioselective agents, the azaspirodecanediones. Animal studies have suggested antianxiety activity and the absence of abuse potential. Behavioural, electrophysiological and receptor binding experiments gradually led to the idea that buspirone owes much of its anxiolytic activity to its ability to attenuate central 5-hydroxytryptamine neurotransmission. In vitro preclinical studies have shown that buspirone has a high affinity for serotonin (5-HT1A) receptors. Some studies do suggest that buspirone may have indirect effects on other neurotransmitter systems. Buspirone differs from typical benzodiazepine anxiolytics in that it does not exert anticonvulsant or muscle relaxant effects. It also lacks the prominent sedative effect that is associated with more typical anxiolytics. The drug was approved by FDA for the treatment of anxiety.