The EMERGENT-3 trial, published in the Journal of the American Medical Association Psychiatry, represents a significant advancement in the treatment of schizophrenia, particularly for individuals experiencing acute psychosis. This phase 3 clinical trial evaluated the efficacy and safety of xanomeline-trospium, a novel antipsychotic medication targeting muscarinic receptors, compared to placebo in adults with schizophrenia.
Most antipsychotic medications that are currently approved and marketed act on dopamine receptors by either blocking them or partially activating them. This agonization and antagonization of the dopamine receptors generally helps with the positive symptoms of schizophrenia such as delusions, hallucinations, disorganized speech, and more. Helping the positive symptoms of schizophrenia comes at a cost of a plethora of adverse events, such as developing Parkinson's disease-like symptoms due to the mechanism of action of the medications. Additionally, the current medications do not have much of an effect on negative symptoms such as flat affect, lack of speech, lack of motivation, etc. Current antipsychotic medications out there are insufficient as monotherapy in most patients, as prescribing multiple antipsychotics is common clinical practice. This indicates a need for more effective therapy that can better control symptoms.
The disease etiology of schizophrenia is hypothesized to be derived from imbalances in both dopamine and acetylcholine in the brain. Targeting the muscarinic acetylcholine receptors is not a common effect of many antipsychotic drugs available - and that is where the novel drug xanomeline-trospium comes in. Xanomeline-trospium acts on the muscarinic receptors both centrally and peripherally, as an agonist and antagonist.
The trial enrolled 256 participants who were randomized to receive either xanomeline-trospium or placebo. The primary efficacy endpoint was the change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Xanomeline-trospium demonstrated a statistically significant and clinically meaningful reduction in PANSS total score compared to placebo at week 5. This improvement was evident as early as week 2 and continued through the end of the trial. Xanomeline-trospium also showed significant improvements in PANSS positive symptoms, as well as CGI-S scores. The percentage of PANSS responders (participants with at least a 30% reduction in PANSS total score) was significantly higher in the xanomeline-trospium group compared to placebo. The drug was generally well tolerated, with gastrointestinal effects being the most common adverse events.
The EMERGENT-3 trial provides compelling evidence for the efficacy and safety of xanomeline-trospium in adults with schizophrenia experiencing acute psychosis. The significant reduction in PANSS total score, along with improvements in positive symptoms and CGI-S scores, highlights the potential of xanomeline-trospium as a new treatment option for schizophrenia. Further studies, including longer-term trials and comparisons with existing treatments, will be valuable in fully understanding the role of xanomeline-trospium in the management of schizophrenia.
Sources:: Journal of the American Medical Association Psychiatry, World Psychiatry
