Researchers have found that the investigational combination of xanomeline-trospium (KarXT) is effective and well-tolerated in individuals with schizophrenia who are experiencing acute psychosis. The randomized controlled phase III EMERGENT-3 trial demonstrated that the combination therapy significantly reduced Positive and Negative Syndrome Scale (PANSS) total scores over five weeks compared to placebo, indicating its potential as an alternative treatment option. This study was published in the journal JAMA Psychiatry by Kaul and colleagues.
Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. Traditional antipsychotic medications often target dopamine receptors, but the combination therapy of xanomeline-trospium represents a new approach that does not involve D2 dopamine receptor blocking activity.
The EMERGENT-3 trial was a randomized, double-blind, multicenter, placebo-controlled trial involving 256 participants aged 18 to 65 with a diagnosis of schizophrenia. Participants were assigned to either the xanomeline-trospium group (n=125) or the placebo group (n=131). The xanomeline-trospium group received varying doses of the combination therapy over the five-week treatment period, while the placebo group received a placebo.
The primary outcome was a change in PANSS total scores from baseline to week 5. Secondary endpoints included changes in PANSS positive and negative subscale scores.
The key findings of the study were:
• Participants receiving xanomeline-trospium experienced a greater reduction in PANSS total scores compared to those on placebo (−20.6 vs −12.2).
• The least squares mean difference was −8.4 (95% CI −12.4 to −4.3, P<0.001).
• The Cohen d effect size was 0.60, indicating a moderate effect of the combination therapy.
• The xanomeline-trospium group showed significant reduction in PANSS positive subscale score (−7.1 vs −3.6) at week 5 compared to placebo.
• The combination therapy was well tolerated, with few serious treatment-emergent adverse events.
• Discontinuation rates were similar between the therapy and placebo groups (6.4% vs 5.5%).
The findings suggest that the novel combination therapy xanomeline-trospium may offer a new treatment option for individuals with schizophrenia experiencing acute psychosis. The results are consistent with previous trials and support the potential for xanomeline-trospium to be the first non-dopamine medication with proven efficacy in treating acute episodes of schizophrenia.
Xanomeline-trospium demonstrates promise as a novel combination therapy for treating acute psychosis in individuals with schizophrenia. The therapy's efficacy and tolerability make it a potential alternative to traditional antipsychotics. Further research is needed to evaluate the long-term durability of the therapy's effect and safety.
Reference:
Kaul, I., Sawchak, S., Walling, D. P., Tamminga, C. A., Breier, A., Zhu, H., Miller, A. C., Paul, S. M., & Brannan, S. K. (2024). Efficacy and safety of xanomeline-trospium chloride in schizophrenia: A randomized clinical trial. JAMA Psychiatry (Chicago, Ill.). https://doi.org/10.1001/jamapsychiatry.2024.0785
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