Anticholinergic Burden in Schizophrenia: what fellow doctors need to know

Cognitive impairment is one of the strongest predictors of long-term functioning in schizophrenia—and growing evidence shows that anticholinergic medication burden is one of the most modifiable contributors. A study of more than 1,100 outpatients found that higher cumulative anticholinergic load was independently associated with worse performance across every major cognitive domain, including memory, attention, processing speed, and executive function.

Key Points for Clinicians

• Antipsychotics are the biggest drivers of anticholinergic burden, particularly

  • first-generation agents, and

  • second-generation medications such as clozapine and olanzapine.

• “Add-on” anticholinergics (benztropine, trihexyphenidyl, diphenhydramine) contribute significantly and are often unnecessary beyond the acute EPS period.

• Cumulative load matters: SSRIs, benzodiazepines, tricyclics, mood stabilizers, some antihistamines, and bladder medications all contribute small but meaningful increments.

• High anticholinergic burden is not benign—it is associated with

  • poorer global cognition

  • slower motor speed

  • reduced independence

  • impaired daily functioning and poorer community outcomes.

• Older adults with schizophrenia are especially vulnerable, but cognitive impairment related to anticholinergic load appears across all age groups.

Clinical Implications for PCPs and Psychiatry

1. Regularly review medication lists

Long-term, stable patients often accumulate medications slowly over time. A simple medication reconciliation can identify unnecessary high-burden agents.

2. Deprescribe when appropriate

Chronic benztropine use without current EPS is a common—and reversible—cause of cognitive impairment. Consider tapering when safe.

3. Choose lower-burden antipsychotics when clinically feasible

Agents such as aripiprazole, lurasidone, ziprasidone, and risperidone generally carry lower anticholinergic load.

4. Educate patients and families

Many families assume cognitive decline is “just part of schizophrenia.” In reality, a sizeable portion is medication-related and potentially reversible.

5. Consider anticholinergic burden a confounder in treatment studies

During cognitive remediation, medication trials, or functional rehabilitation, a high ACB score may limit treatment response.6. Address hidden sources of anticholinergics

PCPs and psychiatrists should collaborate to reduce OTC and non-psychiatric contributors:

• diphenhydramine for sleep

• sedating antihistamines

• bladder antispasmodics

• older TCAs prescribed for pain or insomnia

Bottom Line

Anticholinergic burden is common, clinically significant, and highly modifiable. Reducing unnecessary anticholinergic exposure can meaningfully improve cognition—the strongest determinant of long-term recovery, independence, and functional outcomes in schizophrenia.