An important study led by BBRF grantees has closely examined a commonplace pharmacologic property of many antipsychotic and other medications commonly prescribed to people with chronic schizophrenia and has concluded that this property can "substantially" contribute to the risk of cognitive impairment.

Medications with anticholinergic properties were the focus of the study. Anticholinergic compounds are those which block the action of the neurotransmitter acetylcholine at synapses in both the central nervous system (brain and spinal cord) and the peripheral nervous system (nerves elsewhere in the body). Many antipsychotic medications, both "first generation" agents like chlorpromazine and "second-generation" agents such as clozapine, have anticholinergic properties, although the degree to which antipsychotics (and other psychiatric medications) block acetylcholine varies from medicine to medicine. Many have a small to moderate anticholinergic impact, but some have a comparatively large impact, as assessed by pharmacologists.

Increasingly, the anticholinergic properties of medications are being scrutinized for their impacts on brain health. One recent study of healthy adults aged 55 and over highlighted the negative cumulative impact of anticholinergic medication exposure and suggested "strong and potentially causal associations between increased burden of anticholinergic medicines and both cognitive impairment and risk of dementia."

This is particularly relevant for those living with schizophrenia since cognitive impairment is often a major symptom of the illness. It affects a wide range of functions including attention, learning, memory, executive functioning, and social cognition.

Indeed, cognitive impairments are "directly linked to poor psychosocial outcomes," say authors of the new study. Appearing in the American Journal of Psychiatry, the study was led by Yash B. Joshi, M.D., Ph.D., and Gregory A. Light, Ph.D., both of the University of California, San Diego. Dr. Joshi is a 2018 BBRF Young Investigator; Dr. Light is the 2014 winner of BBRF's Baer (Maltz) Prize for Outstanding Schizophrenia Research, and is a 2013 BBRF Independent Investigator and 2006 and 2003 Young Investigator. Nine other BBRF grantees, prize winners and Scientific Council members were involved in the study.

The study assessed the total burden of anticholinergic medications taken by 1,120 chronic schizophrenia outpatients, 58% of whom lived in board-and-care or transitional living programs. The average age of participants was 46; nearly 70% were male; the average participant had been diagnosed with schizophrenia at age 22, and took a single antipsychotic medicine. One-third of participants also took an antidepressant medicine and/or other medicines, including mood stabilizers or tranquillizing agents such as benzodiazepines.

Guided by previously established research protocols, the researchers assigned each prescribed medicine a numerical score, rating it on a scale from having no anticholinergic effect (0) to having a high effect (3). The study rated participants with a combined medication score of 3 or greater to have a "high" anticholinergic burden. In the prior study of healthy older adults, scores of 3 or greater for 3 years or more were associated with a 50% increase in the odds of developing dementia over that study's 11-year duration.

"We found that many patients [in our study] have medication regimens with high anticholinergic burden, with an average score of 3.8," the researchers reported. Overall, 63% of the 1,120 participants had a score of at least 3, and one-fourth had a score of 6 or greater. The authors noted that participants in their study were not included if they had major medical issues. Since individuals with schizophrenia may be more vulnerable to a variety of health issues, and medications used to treat these health issues may have anticholinergic properties, the team speculated that total anticholinergic burden may be even higher for many individuals in the community living with schizophrenia.

Consistent with findings in the prior study of healthy older adults, the new study found that "anticholinergic burden was significantly associated with generalized impairments in cognitive functioning in schizophrenia patients." Antipsychotic medicines contributed more than half of the total anticholinergic burden, they said, with other medicines accounting for the remainder. The researchers stressed that their results point to the total score—total anticholinergic burden—as being the key factor in contributing to risk for cognitive impairments, as opposed to any particular medication or medications considered individually.

The researchers said it was important that their results be understood in the proper context: working "to optimize outcomes" in chronic schizophrenia patients. "Psychotropic medications, especially antipsychotics, are critically important in schizophrenia, have substantially improved the lives and outcomes for countless patients living with the illness, and represent an essential staple of comprehensive treatment," they stressed.

They suggested that their results, if further validated, might help guide prescribing physicians making medication decisions for their patients. On the one hand, "psychotropic medications are necessary to reduce symptoms [such as psychosis, hallucinations and delusions] and to help patients achieve or maintain functional gains," they said. On the other hand, "the longer-term impact of all medications may contribute to longer-term cognitive disability."

The practical question posed by their findings, they said, was therefore how to weigh the potential added risk of cognitive impairment posed by any given patient's medication regimen, and on that basis, to consider swapping out one or more medications for others to reduce the total anticholinergic burden, and hence, potentially, the risk of cognitive impairment.

The team said that their method of "scoring" anticholinergic burden—additively, medicine-by-medicine—"is easily deployable in routine clinical settings and can readily be incorporated into electronic medication records." Before such use is potentially made of their method, however, they would need to be replicated and studied over the longer-term, which would enable observation of the clinical course of patients and the durability of the relationship noted in the current paper between anticholinergic burden and risk of cognitive impairment.

The team also noted that it may be possible to use "adjuvant treatment" to reduce negative cognitive impact of anticholinergic medication burden. As an example, they cited a prior study also led by Drs. Joshi and Light in which chronic schizophrenia outpatients who followed a computerized cognitive training intervention had reduced "anticholinergic burden-associated cognitive deterioration." They urged further study of such accessory treatments.

The research team also included: Ming T. Tsuang, M.D., Ph.D., BBRF Scientific Council, 2010 BBRF Lieber Prize winner, 1998 Distinguished Investigator; Raquel E. Gur, M.D., Ph.D., BBRF Scientific Council, 2009 BBRF Lieber Prize winner, 1999 Distinguished Investigator; Neal R. Swerdlow, M.D., Ph.D., 2016 BBRF Distinguished Investigator, 1990 Independent Investigator, 1990 Young Investigator; Bruce I. Turetsky, M.D., 2001 BBRF Independent Investigator; Debby W. Tsuang, M.D., Ph.D., 2009 BBRF Independent Investigator, 2001 Young Investigator; Tiffany A. Greenwood, Ph.D., 2008 BBRF Young Investigator; William S. Stone, Ph.D., 2000 and 1997 BBRF Young Investigator; Ruben C. Gur, Ph.D., 2007 BBRF Distinguished Investigator; and David L. Braff, M.D., 2014 BBRF Lieber Prize winner and 2007 Distinguished Investigator.