The field of schizophrenia treatment is witnessing a transformative shift with new approaches that address the condition without relying on conventional dopamine receptor blocking. Traditionally, antipsychotics have targeted dopamine D2 receptors, particularly in the brain’s ventral striatum, to alleviate symptoms like hallucinations and delusions. However, this approach often affects other areas of the brain, resulting in side effects such as motor dysfunction and elevated prolactin levels.

Recent developments focus on alternative mechanisms to regulate dopamine and other neurotransmitters without directly blocking D2 receptors. Among these emerging therapies is ulotaront (SEP-363856), which functions as a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A agonist.1,2 Despite challenges in Phase 3 clinical trials, ulotaront’s tolerability profile stood out. Although statistical significance over placebo was not achieved, likely due to high placebo responses during the trials, ulotaront was generally well-received, showing fewer metabolic and movement-related side effects than traditional antipsychotics.2  

Another promising treatment option recently approved by the US Food and Drug Administration (FDA) is xanomeline-trospium, marketed as Cobenfy (formerly KarXT).3 This first-in-class muscarinic agonist works by modulating M1 and M4 receptors, managing dopamine and glutamate activity in the brain.4 Xanomeline-trospium has shown notable success in the Phase 3 EMERGENT trials. These studies demonstrated substantial improvements on the Positive and Negative Syndrome Scale (PANSS) with a safety profile favorable for long-term use, offering a novel mechanism that reduces the risk of dopamine-related side effects such as movement and metabolic issues.5

Another approach involves iclepertin (BI 425809), a glycine transporter-1 (GlyT1) inhibitor currently being tested in Phase 3 trials. This investigational treatment, part of the CONNEX clinical trial program, specifically targets cognitive impairment associated with schizophrenia.6,7 Through N-methyl-D-aspartate (NMDA) receptor modulation, iclepertin aims to enhance cognition—an area of high unmet need for those with schizophrenia. Early trial data from the CONNEX series indicate cognitive improvements, with studies evaluating both safety and long-term efficacy.8

Together, these advances underscore a significant evolution in schizophrenia treatment. By reducing side effects and targeting specific symptoms with new mechanisms, these therapies offer hope for patients and healthcare providers alike, potentially redefining management strategies in the years ahead.

References:

  1. Reynolds de Sousa T, Ribeiro M, Novais F. Assessment of innovative pharmacological targets in schizophrenia. Curr Treat Options Psych. 2024;11(3):203-217. doi:10.1007/s40501-024-00324-x
  2. Achtyes ED, Hopkins SC, Dedic N, Dworak H, Zeni C, Koblan K. Ulotaront: review of preliminary evidence for the efficacy and safety of a TAAR1 agonist in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2023;273(7):1543-1556. doi:10.1007/s00406-023-01580-3  
  3. FDA approves drug with new mechanism of action for treatment of schizophrenia. US Food and Drug Administration. September 26, 2024. Accessed November 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia  
  4. Kantrowitz JT, Correll CU, Jain R, Cutler AJ. New developments in the treatment of schizophrenia: an expert roundtable. Int J Neuropsychopharmacol. 2023;26(5):322-330. doi:10.1093/ijnp/pyad011 
  5. Kaul I, Sawchak S, Walling DP, et al. Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial. JAMA Psychiatry. 2024;81(8):749-756. doi:10.1001/jamapsychiatry.2024.0785  
  6. O’Brien E. New baseline data on iclepertin for schizophrenia. June 18, 2024. Accessed November 18, 2024. https://www.psychiatrictimes.com/view/new-baseline-data-on-iclepertin-for-schizophrenia
  7. Reuteman-Fowler C, Marder SR, Falkai P, Blahova Z, Ikezawa S. CONNEX-X: an extension trial examining the long-term safety of iclepertin in patients with schizophrenia who completed phase III CONNEX trials. Poster presented at: American Psychiatric Association Annual Meeting; May 6, 2024; New York City, NY.  
  8. Rosenbrock H, Desch M, Wunderlich G. Development of the novel GlyT1 inhibitor, iclepertin (BI 425809), for the treatment of cognitive impairment associated with schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2023;273(7):1557-1566. doi:10.1007/s00406-023-01576-z