KarXT is a safe and effective novel antipsychotic for patients with schizophrenia

1. Patients in the KarXT (xanomeline–trospium) group reported a significant reduction in Positive and Negative Syndrome Scale (PANSS) score compared to those in the placebo group.

2. Majority of adverse events were mild-to-moderate, with no treatment-related fatalities or increase in extrapyramidal motor symptoms.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Current antipsychotic therapies for schizophrenia are associated with adverse side effects and medication resistance, often due to antagonism of the D₂ dopamine receptors. As such, new treatments are needed. Xanomeline, a dual M₁ and M₄ muscarinic receptor agonist, in combination with trospium (KarXT), presents a unique approach without blocking D₂ dopamine receptors. This randomized controlled trial aimed to evaluate the safety and efficacy of KarXT versus placebo in schizophrenia patients with acute psychosis. The primary outcome was a change in Positive and Negative Syndrome Scale (PANSS) score from baseline to week 5, while key secondary outcomes were PANSS positive and negative subscale scores. According to study results, KarXT significantly reduced positive and negative symptoms of schizophrenia. Although this study was well done, it was limited by a relatively short trial duration, thus affecting the validity of the findings.

Click to read the study in The Lancet

Relevant Reading: Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia

In-depth [randomized-controlled trial]: Between Dec 16, 2020, and Apr 13, 2022, 407 patients were screened for eligibility across 22 inpatient sites in the USA. Included were patients aged 18–65 with schizophrenia, an episode of acute psychosis requiring hospitalization, a PANSS score ≥ 80, and Clinical Global Impression-Severity score ≥ 4. Altogether, 252 patients (126 in KarXT and placebo, respectively) were included in the final analysis. The primary outcome of a reduction in PANSS score was significantly greater in the KarXT group (-21.2 points, standard error [SE] 1.7) than in the placebo group (-11.6 points, SE 1.6; p<0.0001). This was also the case for secondary outcomes of PANSS positive-subscale score (-2.9 points, p<0.05) and PANSS negative-subscale score (-1.8 points, p<0.05) in KarXT. Findings from this study suggest that KarXT is effective in reducing positive and negative symptoms of schizophrenia, offering a new class of well-tolerated antipsychotic medications.

Image: PD

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