Anticholinergic burden promotes poor cognition in psychosis patients

Anticholinergic burden appears to worsen cognitive functioning among patients with psychosis, but reducing the use of anticholinergic medication helps improve cognition, suggests a study.

“From a clinical perspective, tapering off anticholinergic medication may be beneficial,” the investigators said. “However, further randomized clinical trials are needed for an unbiased quantification of benefit.”

In this systematic review and meta-analysis, investigators searched the databases of Medline, Embase, and PsychINFO from inception to October 2023. Studies on the cognitive assessment and quantification of anticholinergic burden via clinical scales, serological anticholinergic activity, or tapering of anticholinergic medications were identified.

The investigators performed analyses in R using the metafor package. They employed random-effects meta-analysis models, along with assessment of heterogeneity, study quality, and meta-regressions (age, sex, and antipsychotic dosage in chlorpromazine equivalents).

A total of 1,337 citations were retrieved, of which 40 met the eligibility criteria. The included citations involved 25 anticholinergic burden studies (4,620 patients), six serological anticholinergic activity studies (382 patients), and nine tapering studies (186 patients).

Anticholinergic burden showed a negative association with global cognition (r, –0.37, 95 percent confidence interval [CI], –0.48 to –0.25), verbal learning (r, –0.28, 95 percent CI, –0.36 to –0.21), visual learning (r, –0.17, 95 percent CI, –0.28 to –0.06), working memory (r, –0.22, 95 percent CI, –0.29 to –0.14), processing speed (r, –0.24, 95 percent CI, –0.35 to –0.13), attention (r, –0.19, 95 percent CI, –0.29 to –0.08), executive functions (r, –0.17, 95 percent CI, –0.27 to –0.06), and social cognition (r, –0.12, 95 percent CI, –0.19 to –0.05). [Am J Psychiatry 2025;doi:10.1176/appi.ajp.2024026]

Likewise, serological anticholinergic activity negatively correlated with verbal learning (r, –0.26, 95 percent CI, –0.38 to –0.14), working memory (r, –0.19, 95 percent CI, –0.35 to –0.03), and executive functions (r, –0.16, 95 percent CI, –0.27 to –0.04).

However, tapering off anticholinergic medications resulted in improved scores in verbal learning (d, 0.77, 95 percent CI, 0.44–1.1), working memory (d, 0.94, 95 percent CI, 0.63–1.26), and executive functions (d, 0.44, 95 percent CI, 0.26–0.62).

“These findings highlight the negative impact of routinely used pharmacological interventions on cognitive function in individuals with psychosis,” the investigators said.

Contributing factors

“While our findings demonstrate that anticholinergic burden may contribute to the cognitive impairments seen in psychosis regardless of the stage of psychosis, there is a wide range of additional contributing factors,” they noted. [Mol Psychiatry 2023;28:1902-1918]

A psychotic illness may similarly be driven by genetic, neurodevelopmental, environmental, and neurodegenerative factors. [Am J Psychiatry 2020;177:298-307; JAMA Psychiatry 2021;78:632-641; JAMA Psychiatry 2020;77:387-396]

“Therefore, the observed effect sizes likely reflect the complexity of cognitive impairment in psychosis, with anticholinergic burden accounting for a significant but not large proportion of the overall deficits,” the investigators said.

The World Health Organization does not recommend the prophylactic and long-term use of anticholinergic drugs in people with psychosis. However, anticholinergics are still prescribed for these patients to treat the extrapyramidal side effects of antipsychotics. [Br J Psychiatry 1990;156:412]

“The present findings provide support for the hypothesis that reducing anticholinergic burden has procognitive effects,” according to the investigators.