Recent developments in psychiatric treatment have created more management options for patients with conditions such as schizophrenia and major depressive disorder (MDD). Traditional approaches in these areas have predominantly targeted serotonin, dopamine, and norepinephrine, but many patients continue to experience limited relief from persistent symptoms. New treatment options promise faster symptom relief, fewer side effects, and improved outcomes. 

The recent US Food and Drug Administration (FDA) approval of xanomeline-trospium, sold under the brand name Cobenfy, is the first antipsychotic with a novel mechanism of action to enter clinical practice in the last several decades. This therapy works by targeting M1 and M4 muscarinic receptors, bypassing dopamine pathways entirely and thus avoiding common antipsychotic side effects. In the Phase 3 EMERGENT trials, xanomeline-trospium demonstrated meaningful symptom reductions, providing a new option for patients seeking alternatives to standard therapies.1,2

Another promising development in psychiatric treatment involves trace amine-associated receptor 1 (TAAR1) agonists, which regulate dopamine indirectly rather than blocking dopamine receptors directly. TAAR1 agonists act within cells to influence dopamine, aiming to minimize side effects often seen with conventional antipsychotics. Phase 3 trials were recently completed for the TAAR1 agonist ulotaront in patients with schizophrenia, but the trials did not meet primary endpoints, likely due to significant placebo effects amplified by pandemic-related challenges. However, the developers will continue analyzing data and conducting additional trials. Ulotaront is now being studied for its potential in MDD and generalized anxiety disorder.3,4 

For MDD, focusing on the brain’s extensive gamma-aminobutyric acid (GABA) and glutamate systems—responsible for most neural communication—has opened new treatment possibilities. Zuranolone, known by its brand name Zurzuvae, is a recently FDA-approved GABA-A receptor modulator that offers rapid symptom relief. This medication is currently being explored for broader applications beyond postpartum depression, its initial indication.5 Similarly, esketamine, known commercially as Spravato, targets N-methyl-D-aspartate (NMDA) receptors within the glutamate system, proving effective in alleviating symptoms for those with treatment-resistant depression. The ESCAPE-TRD trial, which compared esketamine with quetiapine, highlights esketamine’s potential in helping patients achieve remission when other therapies fall short.6,7

Orexin modulation is also gaining traction in addressing MDD, particularly for patients experiencing insomnia alongside depressive symptoms. Seltorexant, an orexin-2 receptor antagonist, has shown meaningful improvements in both mood and sleep quality in Phase 3 trials, suggesting its potential as a specialized treatment. With insomnia often exacerbating depressive symptoms, seltorexant could address a critical need for patients requiring both sleep support and mood regulation, marking a step forward in precision psychiatry and signaling the potential for tailored treatment approaches in the field.8 

Together, these new treatment mechanisms—muscarinic cholinergic agonists, TAAR1 agonists, and modulators of GABA, glutamate, and orexin—represent a paradigm shift in psychiatric care. With promising ongoing trials and recent FDA approvals, these treatments may provide patients with more effective options to manage their mental health.

References:

  1. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384(8):717-726. doi:10.1056/NEJMoa2017015 
  2. FDA approves drug with new mechanism of action for schizophrenia treatment. US Food and Drug Administration. September 26, 2024. Accessed November 12, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia
  3. Correll CU, Koblan KS, Hopkins SC, et al. Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study. NPJ Schizophr. 2021;7(1):1-9. doi:10.1038/s41537-021-00190-z
  4. Kuvarzin SR, Sukhanov I, Onokhin K, Zakharov K, Gainetdinov RR. Unlocking the therapeutic potential of ulotaront as a trace amine-associated receptor 1 agonist for neuropsychiatric disorders. Biomedicines. 2023;11(7):1977. doi:10.3390/biomedicines11071977
  5. Alva G, Chepke C, Mattingly G, Crown E. Examining new agents for MDD treatment (zuranolone). Psychiatric Times. December 1, 2023. Accessed November 18, 2024. https://www.psychiatrictimes.com/view/examining-new-agents-for-mdd-treatment-zuranolone-
  6. Bahr R, Lopez A, Rey JA. Intranasal esketamine (Spravatotm) for use in treatment-resistant depression in conjunction with an oral antidepressant. Pharm Ther. 2019;44(6):340.
  7. Young PA, Cubała PW, Nielsen PR, et al. Esketamine nasal spray improves rate and time to remission versus quetiapine extended release in subgroups of patients with treatment resistant depression and two or three plus prior treatment failures: results from ESCAPE-TRD, a randomised phase IIIb trial. BJPsych Open. 2023;9(Suppl 1):S75. doi:10.1192/bjo.2023.245
  8. Thase ME, Krystal AD, Wajs E, et al. Seltorexant, adjunctive to antidepressants, in adults with MDD with insomnia symptoms: results of a double-blind, randomized, placebo-controlled study. Poster presented at: American Society of Clinical Psychopharmacology (ASCP) Annual Meeting; May 28-31, 2024; Miami Beach, FL.