Novel Combination Therapy Xanomeline-Trospium Promising for Treatment of Schizophrenia: JAMA

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