The Serotonin 1A (5-HT 1A ) Receptor as a Pharmacological Target in Depression

Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin 1A (5-HT 1A ) receptor in the pathophysiology of depression. Stimulation of the 5-HT 1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT 1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT 1A receptor, the evidence implicating it in depression and in the effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT 1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT 1A ‘biased agonism’, using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT 1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effects of 5-HT 1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT 1A biased agonists.