Novel Therapy Linked to Cognitive Benefit in Schizophrenia

TOPLINE:

Xanomeline/trospium chloride, a novel M1/M4 muscarinic receptor agonist, is linked to significant cognitive improvement in patients with acute schizophrenia and cognitive impairment in pooled data from two phase 3 trials.

METHODOLOGY:

• Combined data from two 5-week inpatient phase 3 trials were used to evaluate the efficacy of xanomeline/trospium monotherapy vs placebo in 357 adult patients with acute schizophrenia.
• Computerized assessments of the four key cognitive domains of executive function, visual memory, sustained attention, and verbal recall/recognition were completed at screening, baseline, and weeks 3 and 5.
• Treatment involved flexible dosing, starting with 50 mg/20 mg twice daily for 2 days and then increasing to 100 mg/20 mg twice daily for days 3-7, with an optional increase to a maximum of 125 mg/30 mg twice daily from day 8.
• Participants were classified as cognitively impaired if they performed one or more SDs below healthy normative standards on baseline tests.

TAKEAWAY:

• Xanomeline/trospium vs placebo showed no significant effect on cognitive scores in the full sample.
• In the cognitively impaired subgroup, patients receiving xanomeline/trospium (n = 71) had a significantly greater cognitive improvement at 5 weeks than those receiving placebo (n = 66; effect size, 0.54; P = .004).
• Those in the treatment group also showed the largest improvement in verbal recognition memory, with additional benefits observed for sustained attention and executive functioning.
• The treatment effect increased with a more stringent baseline impairment threshold of at least 1.5 SD below healthy normative standards (effect size, 0.8).
• Cognitive improvements showed minimal correlation with changes in total, positive, and negative symptoms in both treatment groups, suggesting independent mechanisms of action.

IN PRACTICE:

“Collectively, the xanomeline/trospium clinical studies reflect the first time a monotherapy for the treatment of schizophrenia has shown a replicable cognitive benefit,” the lead author said in a press release.

SOURCE:

The study, led by William P. Horan, PhD, Bristol Myers Squibb, Boston, was published online on December 11 in theAmerican Journal of Psychiatry.

LIMITATIONS:

The study design focused on acutely symptomatic inpatients, limiting the ability to isolate cognitive function changes from symptom changes. Additional limitations included the deviations from MATRICS trial guidelines, the relatively short 5-week treatment duration, the brief cognitive battery, and the lack of a functional co-primary measure.

DISCLOSURES:

This study was funded by Karuna Therapeutics, a Bristol Myers Squibb company. Four authors reported being employees of Bristol Myers Squibb. Full disclosures for all investigators are listed in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.