New Schizophrenia Drug Shows Marked Effect on Cognitive Deficits

Individuals with schizophrenia and cognitive deficits who were treated with the combination of xanomeline and trospium chloride showed clinically significant improvements in cognition compared with those receiving placebo, according to a report today in the American Journal of Psychiatry. The results, pooled from two Phase 3 clinical trials, replicate cognitive benefits seen in smaller studies.

Xanomeline/trospium chloride was approved for use by the U.S. Food and Drug Administration (with the brand name Cobenfy) in September 2024 for the treatment of schizophrenia in adults. Cognitive deficits are a stubborn feature in many cases of schizophrenia that significantly affect long-term trajectory and daily functioning.

“Collectively, the xanomeline/trospium clinical studies reflect the first time a monotherapy for the treatment of schizophrenia has shown a replicable cognitive benefit,” wrote lead author William Horan, Ph.D., executive director of clinical development at Bristol Myers, and colleagues. This study was sponsored by Karuna Therapeutics, a Bristol Myers Squibb company.

Across the two trials, 357 patients with acute schizophrenia were randomly assigned to receive oral xanomeline/trospium or placebo twice daily for five weeks. Most participants assigned to xanomeline/trospium were taking the maximum dosage of 125 mg/30 mg twice daily at week 5, with the remainder taking an intermediate dosage of 100 mg/20 mg.

Participants completed a computerized assessment of four key cognitive domains (executive function, visual memory, sustained attention, and verbal recall and recognition) at baseline, week 3, and week 5. Overall, 137 participants had significant cognitive deficits at baseline.

Among patients with cognitive impairment, those receiving xanomeline/trospium showed a significantly larger improvement in their cognitive scores from baseline to week 5 than the placebo group, with a calculated effect size of 0.54 (indicating a moderate level of improvement). The largest difference in performance between the xanomeline/trospium and placebo groups observed at week 5 was for verbal recall and recognition.

The effect remained significant after accounting for changes in positive and negative symptoms—suggesting that the effect on cognition is independent of improvement in psychotic symptoms. As with previous studies, there was no evidence of cognitive benefit for xanomeline/trospium when analyzing the full sample of 357 participants.

Cobenfy is the first drug approved for schizophrenia that does not act on dopamine (D2) receptors in the brain; rather it targets muscarinic acetylcholine receptors in areas of the brain more central to the cognitive and behavioral symptoms of schizophrenia.

For related information, see the Psychiatric News article “Questions and Excitement About New Schizophrenia Drug.”

(Image: Getty Images/iStock/BeritK)

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Anxiety Linked to Cognitive Decline in Older Adults, Study Shows

Symptoms of anxiety in women appear to be associated with a decline over time in executive function—the ability to plan ahead and organize one’s thoughts, according to a report in The American Journal of Geriatric Psychiatry.

Among both men and women 65 years and older, anxiety appears to predict a decline in verbal memory, which refers to the ability to remember words.

“Adequate treatment of anxiety symptoms could potentially beneficially influence the risk for developing neurodegenerative disease,” wrote Sebastian Köhler, Ph.D., an associate professor of psychiatry at Maastricht University, and colleagues.

Köhler and colleagues analyzed data on 918 participants who were 50 years of age or older in the Maastricht Aging Study, a longitudinal population-based study of factors associated with cognitive aging in the Netherlands.

The researchers measured the anxiety symptoms of the participants at baseline, using the anxiety subscale of the Symptom Check List-90 (SCL-90). The researchers recorded anxiety scores along a continuous scale of severity; they classified patients in the highest quartile as having “high anxiety.” The participants also underwent neuropsychological testing, which measured executive function, memory, speed of information processing, and verbal fluency. During a 12-year follow-up, the cohort was tested every three years.

Overall, being in the highest quartile on anxiety symptoms (“high anxiety”) did not predict a faster decline in executive functioning over time. However, among women, increasing severity of anxiety was associated with a worse cognitive trajectory. A similar sex-specific effect was found for processing speed and verbal fluency.

In contrast, faster decline in verbal memory was associated with “high anxiety” irrespective of sex but was more pronounced in those 65 years and older.

“Further longitudinal research is needed to fully understand the relationship between anxiety and cognition including potentially mediating mechanisms,” the researchers wrote.

For more information, see the Psychiatric News article “Worsening Anxiety in Older Adults May Precede Alzheimer's.”

(Image: iStock/SolStock)

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