REVIEW OF: Joshi YB et al, Am J Psychiatry 2021;178(9):838–847

STUDY TYPE: Cross-sectional study

Schizophrenia is associated with impaired cognition. Medications with anticholinergic properties, including antipsychotics, benztropine (Cogentin), and antidepressants, can worsen this problem and may confer increased risk of dementia. What we don’t know is the size of this impact on cognition, which this study aimed to ­characterize.

Researchers examined the magnitude and sources of medications with anticholinergic properties in schizophrenia, as well as their links to global cognition and cognitive subdomains. They conducted a cross-sectional study of 1,120 adult outpatients under age 65 with schizophrenia or schizoaffective disorder who participated in the larger Consortium on the Genetics of Schizophrenia-2 study. Most subjects were young (mean age 24 years), 69% were male, 43% were White, and 40% were Black. Patients had assessments of psychopathology, anticholinergic burden (using the Anticholinergic Cognitive Burden [ACB] scale), and cognition (using the Penn Computerized Neurocognitive Battery). The ACB is a validated expert rating scale that assigns dose-independent, categorical ratings to medications based on anticholinergic properties (with 1 = low/minimal, 2 = moderate, and 3 = strong/definite).

Most of the total anticholinergic burden was attributable to antipsychotics, followed by “traditional” anticholinergics (eg, benztropine, diphenhydramine, hydroxyzine, and trihexyphenidyl), antidepressants, mood stabilizers, and benzodiazepines (see also www.acbcalc.com). Most patients (90%) were taking a second-generation antipsychotic, 18% were taking two antipsychotics, and 20% were taking benztropine or a similar medication.

Greater anticholinergic burden was associated with significantly worse cognition scores, after controlling for potential confounding factors including dose and number of antipsychotics, psychotic symptom severity, illness duration, number of hospitalizations, and smoking. The global cognition of patients with high or very high anticholinergic burden was approximately 0.5 standard deviations worse compared to patients with no anticholinergic burden. This translates to greater cognitive impairment in patients with high anticholinergic burden, a finding that is of potential clinical significance.

Limitations of this study included the cross-sectional design, which precludes any causal inferences, and the exclusion of patients with significant medical conditions (leading to a likely underestimation of the impact of anticholinergic burden). Also, the ACB scale does not account for dose, previous medication exposures, or the effects of medication adherence.

CARLAT TAKE
Anticholinergic medications may impair cognition in schizophrenia, and that burden is raised by high doses of antipsychotics and excessive use of benztropine. Antipsychotics with a lower anticholinergic burden include brexpiprazole, lumateperone, lurasidone, ziprasidone, and the first-generation thiothixene.