Schizophrenia is a challenging and complex mental health condition, with traditional therapies typically focusing on dopamine receptor modulation, specifically through D2 receptor antagonism, to help manage symptoms. However, recent advances are reshaping the treatment landscape, offering novel mechanisms of action, unique delivery methods, and enhanced options for patient adherence.

In recent years, a growing number of treatments have emerged that go beyond the usual dopamine-centric focus. One such development is SEP-363856, or ulotaront, a trace amine-associated receptor 1 (TAAR1) agonist that takes a unique approach to managing schizophrenia by interacting with trace amine receptors. Initial studies were encouraging, but recent Phase 3 trials did not demonstrate a significant improvement over placebo, possibly due to an unusually strong placebo response. Nonetheless, the drug's safety profile remained favorable, and ongoing US Food and Drug Administration (FDA) discussions will determine its future direction.1

Another noteworthy avenue for nondopaminergic treatment is xanomeline-trospium chloride, also known by its brand name Cobenfy, a novel combination of xanomeline and trospium that modulates muscarinic receptors M1 and M4 rather than dopamine receptors.2 This mechanism provides an alternative pathway for symptom management while reducing some of the adverse effects commonly associated with dopamine-targeting medications. Approved by the FDA in 2024, xanomeline-trospium chloride represents a promising addition to the schizophrenia treatment arsenal.3

Another option is lumateperone, a treatment initially approved in 2019 under the brand name Caplyta, that has continued to expand its therapeutic reach. Lumateperone offers an approach that combines serotonin 5-HT2A receptor binding with moderate antagonism at D2 receptors, resulting in a distinct pharmacological profile that separates it from traditional antipsychotics. This mechanism, along with a relatively low risk of metabolic and extrapyramidal side effects, makes lumateperone suitable for long-term use in patients with schizophrenia.4 Recent Phase 3 trials have also demonstrated its effectiveness as an adjunctive therapy for major depressive disorder, revealing its potential for broader therapeutic applications.5

Treatment adherence is also being addressed through new delivery options. Long-acting injectables, such as the recently FDA-approved Invega Hafyera, allow for 6-month paliperidone palmitate injections, decreasing the dosing frequency and supporting sustained symptom management.6 Another long-acting option, Uzedy, provides risperidone in a formulation designed for flexible dosing, which may further aid adherence.7

For patients who prefer not to take oral medications, transdermal drug systems are gaining popularity. The asenapine transdermal patch (Secuado) represents a step forward in noninvasive treatment. The patch ensures consistent plasma concentrations, which may simplify adherence management for both patients and clinicians.8

In managing agitation associated with schizophrenia, other treatments have emerged recently as well. Two potential options are BXCL501 and intranasal olanzapine. BXCL501, a sublingual film formulation of dexmedetomidine, has shown promise in treating agitation related to both schizophrenia and Alzheimer’s disease.9 Intranasal olanzapine offers a needle-free method for rapid symptom relief, although it awaits FDA approval.10

The combination of olanzapine and samidorphan, branded as Lybalvi, has also gained FDA approval for schizophrenia and bipolar I disorder. By pairing olanzapine with samidorphan, Lybalvi mitigates the weight gain often associated with olanzapine, presenting a safer metabolic option for long-term treatment.11

In summary, schizophrenia treatment continues to evolve with options that reflect a more patient-centered approach. With the development of new mechanisms of action, innovative delivery methods, and improved adherence strategies, the future of schizophrenia care appears brighter and more promising than ever.

References:

  1. 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  
  2. 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
  3. 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
  4. Edinoff A, Wu N, deBoisblanc C, Feltner CO, et al. Lumateperone for the treatment of schizophrenia. Psychopharmacol Bull. 2020;50(4):32-59.  
  5. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and safety of lumateperone for major depressive episodes associated with bipolar I or bipolar II disorder: a phase 3 randomized placebo-controlled trial. Am J Psychiatry. 2021;178(12):1098-1106. doi:10.1176/appi.ajp.2021.20091339
  6. Peters L, Dyer M, Schroeder E, D’Souza MS. Invega hafyera (Paliperidone palmitate): extended-release injectable suspension for patients with schizophrenia. J Pharm Technol. 2023;39(2):88-94. doi:10.1177/87551225231153541
  7. Markowicz-Piasecka M, Kubisiak M, Asendrych-Wicik K, et al. Long-acting injectable antipsychotics—a review on formulation and in vitro dissolution. Pharmaceutics. 2023;16(1):28. doi:10.3390/pharmaceutics16010028  
  8. Asenapine approved as first transdermal patch for treatment of schizophrenia. Pharmacy Times. October 15, 2019. Accessed November 12, 2024.https://www.pharmacytimes.com/view/asenapine-approved-as-first-and-only-transdermal-patch-for-treatment-of-schizophrenia
  9. Zeller S, Benabou R, Risinger R, Robison H. 72 orally dissolving, thin film dexmedetomidine (BXCL501) demonstrates significant reduction in agitation across a range of agitation severity in patients with schizophrenia and bipolar disorder. Ann Emerg Med. 2021;78(4):S29-S30. doi:10.1016/j.annemergmed.2021.09.081
  10. Citrome L, Correll CU, San L, et al. Alternative approaches for addressing acute agitation in schizophrenia and bipolar disorder. Prim Care Companion CNS Disord. 2024;26(1):23nr03596. doi: 10.4088/PCC.23nr03596
  11. Managing weight, metabolic syndrome, and diabetes in schizophrenia patients. Psychiatrist.com. October 17, 2024. Accessed November 12, 2024. https://www.psychiatrist.com/news/managing-weight-metabolic-syndrome-and-diabetes-in-schizophrenia-patients/