Schizophrenia Meds a Key Contributor to Cognitive Impairment

Megan Brooks

June 03, 2021

Dr Yash Joshi

Anticholinergic medication burden from antipsychotics, antidepressants, and other psychotropics has a cumulative effect of worsening cognitive function in patients with schizophrenia, new research indicates.

"The link between long-term use of anticholinergic medications and cognitive impairment is well-known and growing," lead researcher Yash Joshi, MD, Department of Psychiatry, University of California San Diego School of Medicine, told Medscape Medical News.

"While this association is relevant for everyone, it is particularly important for those living with schizophrenia, who often struggle with cognitive difficulties conferred by the illness itself," said Joshi.

"Brain health in schizophrenia is a game of inches, and even small negative effects on cognitive functioning through anticholinergic medication burden may have large impacts on patients' lives," he added.

The study was published online May 14 in the American Journal of Psychiatry.

"Striking" Results

Joshi and colleagues set out to comprehensively characterize how the cumulative anticholinergic burden from different classes of medications affect cognition in patients with schizophrenia.

They assessed medical records, including all prescribed medications, for 1120 adults with a diagnosis of schizophrenia or schizoaffective disorder.

For each participant, prescribed medications were rated and summed using a modified anticholinergic cognitive burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB).

The investigators found that 63% of participants had an ACB score of at least 3, which is "striking," said Joshi, given that previous studies have shown that an ACB score of 3 in a healthy, older adult is associated with cognitive dysfunction and a 50% increased risk of developing dementia.

About one quarter of participants had an ACB score of 6 or higher.

Yet, these high ACB scores are not hard to achieve in routine psychiatric care, the researchers note.

For example, a patient taking olanzapine daily to ease symptoms of psychosis would have an ACB score of 3; if hydroxyzine was added for anxiety or insomnia, the patient's ACB score would rise to 6, they point out.

Lightening the Load

Antipsychotics contributed more than half of the anticholinergic burden, while traditional anticholinergics, antidepressants, mood stabilizers, and benzodiazepines accounted for the remainder.

"It is easy even for well-meaning clinicians to inadvertently contribute to anticholinergic medication burden through routine and appropriate care. The unique finding here is that this burden comes from medications we don't usually think of as typical anticholinergic agents," senior author Gregory Light, PhD, with UC San Diego School of Medicine, said in a news release. 

Anticholinergic medication burden was significantly associated with generalized impairments in cognitive functioning across all cognitive domains on the PCNB with comparable magnitude and after controlling for multiple proxies of functioning or disease severity.

Higher anticholinergic medication burden was associated with worse cognitive performance. The PCNB global cognitive averages for none, low, average, high, and very high anticholinergic burdens were, respectively (in z values), –0.51, –0.70, –0.85, –0.96, and –1.15.

The results suggest "total cumulative anticholinergic burden — rather than anticholinergic burden attributable to a specific antipsychotic or psychotropic medication class — is a key contributor to cognitive impairment in schizophrenia," the researchers write.

"The results imply that clinicians who treat patients with schizophrenia may be able to improve cognitive health by reducing cumulative anticholinergic medication burden if it is clinically safe and practical," said Joshi.

"This may be accomplished by reducing overall polypharmacy or transitioning to equivalent medications with lower overall anticholinergic burden. While 'traditional' anticholinergic medications should always be scrutinized, all medications should be carefully evaluated to understand whether they contribute to cumulative anticholinergic medication burden," he added.

Confirmatory Findings

Commenting on the study for Medscape Medical News, Jessica Gannon, MD, assistant professor of psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, said the author's findings "aren't surprising but the work that they did was pretty comprehensive and I think further fleshed out some of our concerns about the impact of anticholinergics on cognitive function in patients with schizophrenia."

"We certainly have to use some of these medications for patients, like antipsychotics that do have some anticholinergic burden associated with them. We don't really have other options," Gannon said.

"But certainly I think this calls us to be better stewards of medication in general. And when we prescribe for comorbid conditions, like depression and anxiety, we should be careful in our prescribing practices, try not to prescribe an anticholinergic medication and, if they have been prescribed, to deprescribe them," Gannon added.

The study was supported by grants from the National Institute of Mental Health; the Sidney R. Baer, Jr. Foundation; the Brain and Behavior Research Foundation; the VISN-22 Mental Illness Research, Education, and Clinical Center; and the Department of Veterans Affairs. Joshi and Gannon have reported no relevant financial relationships.

Am J Psychiatry. Published online May 14, 2021. Abstract

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