Use of multiple medications with anticholinergic properties may boost the risk for dementia in patients with schizophrenia, new research suggests.
Researchers found that a higher anticholinergic burden in schizophrenia patients is associated with poor performance on tests of memory, learning, and visuospatial ability.
“We need to be mindful of the anticholinergic properties of the medications we’re using and their potential negative impact on cognition. This is especially true as our patients are getting older and more susceptible to the anticholinergic properties of these medications,” lead investigator Tarek K. Rajji, MD, chief of adult neurodevelopment, the Division of Geriatric Psychiatry, and deputy physician-in-chief of research, the Center for Addiction and Mental Health, and associate professor of psychiatry, University of Toronto, Canada, told Medscape Medical News.
The study was published online November 28 in the Journal of Clinical Psychiatry.
Anticholinergic Burden
Medications with anticholinergic properties block cholinergic receptors in the body. The term “anticholinergic burden” refers to the cumulative effect of the use of multiple medications that have these properties.
Several medications used to treat schizophrenia, including antipsychotics, such as clozapine and olanzapine, antidepressants, and mood stabilizers, have central anticholinergic activity.
Dr Rajji noted that psychiatric medications are not the only drugs that have anticholinergic effects. Analgesics, antihistamines, antiemetics, antiarrhythmics, bronchodilators, and medications used for urinary incontinence also have anticholinergic properties.
Many older patients with schizophrenia have other medical conditions and are taking multiple medications and therefore may have a high anticholinergic burden. They also may be especially sensitive to anticholinergic side effects.
To examine the impact of anticholinergic burden on cognition, the investigators studied 60 schizophrenia patients aged 50 to 79 years (mean age, 63.6 years) whose Mini–Mental State Examination score was 18 or higher and who did not have major depression or a substance use disorder involving alcohol or other agents.
The researchers administered two cognitive batteries that are commonly used to detect cognitive deficits associated with Alzheimer’s disease (AD) dementia ― the Cambridge Neuropsychological Test Automated Battery–Alzheimer’s Disease (CANTAB-AD), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
What was “unique” about the study, said Dr Rajji, was that “it differentiated between what is typically observed as impairment in early Alzheimer’s disease vs the general impairment we see in patients with schizophrenia.”
The researchers used the Anticholinergic Cognitive Burden (ACB) scale, a validated list of medications, both prescription and over-the-counter, that may have anticholinergic effects.
Each medication was rated on a 4-point Likert-type scale (with 0 indicating no anticholinergic activity; 1, possible anticholinergic activity; and 2 or 3, definite anticholinergic activity).
Higher Dementia Risk Explained?
Results showed that patients had poorer performances on measures of delayed memory, episodic memory, immediate memory, spatial working memory, and visuospatial-construction, but not on tests of attention, executive function, language, or reaction time.
For example, for the CANTAB tests, the ACB total score was associated with spatial working memory (P = .04), trended with paired associates learning (as assessed by the PAL: P = .06), and was not associated with reaction time (P = .13).
For the five RBANS domains, the ACB total score was associated with immediate memory (P = .004), visuospatial construction ( P = .02), and delayed memory (P = .002), but not language (P=.09) or attention (P = .86).
The authors note that impairments in episodic memory and in visuospatial ability occur early in the course of AD dementia, whereas deficits in attention and language are typically later manifestations.
The receiver operating characteristic curve sloped off at an ACB total score cutoff of 1.5. At this cutoff, the sensitivity of the ACB total score was 90.3%, and the specificity was 48.3%.
“Taken together, these results suggest that high anticholinergic burden may give rise to cognitive deficits in schizophrenia that are phenotypic of preclinical Alzheimer’s dementia,” the investigators write.
Compared to the general population, patients with schizophrenia have a twofold higher risk of developing dementia before the age of 80 years. The new results suggest that high anticholinergic burden may account for some of this increased risk.
Clinicians should be aware that high anticholinergic burden in older patients with schizophrenia may contribute to a pattern of cognitive deficits characteristic of early AD dementia, said Dr Rajji.
These deficits may be mistakenly attributed to progression of schizophrenia or to the onset of dementia rather than to a secondary treatable cause of anticholinergic burden.
To decrease this burden, said Dr Rajji, clinicians might consider reducing the doses of certain medications or switching to ones that are less anticholinergic.
Reducing the dose should not compromise safety, he said. Previous research by his team shows that in most older patients (50 years or older) with schizophrenia, the dose of an antipsychotic can be reduced without relapse.
Although the ACB scale is available, Dr Rajji said he is not ready to recommend its routine use in the clinic.
What he does suggest is that clinicians discuss with patients and their families the benefits of trying to reduce medication doses.
“Many times, patients come to our clinics with years and years of being on the same medications. This new study provides another reason why we should consider a trial of reducing the dose, taking into account any risks.”
Possible limitations of the study were that the researchers did not collect data on medication adherence and that the ACB does not take into account drug dosages, drug interactions, or metabolism and so yields an imprecise estimation of anticholinergic activity. As well, because of the cross-sectional design and limited sample size, the researchers were unable to infer true causality between anticholinergic burden and cognitive impairment.
Less May Be More
Commenting on the findings for Medscape Medical News, Robert Roca, MD, chair, Council on Geriatric Psychiatry, American Psychiatric Association, and vice president and chief medical officer, Sheppard Pratt Health System, Baltimore, Maryland, said the study contains information of interest for clinicians caring for older patients with schizophrenia who are showing signs of dementia.
“This study highlights evidence that long-term exposure to high levels of anticholinergic activity may increase the risk of developing an enduring pattern of cognitive deficits resembling those seen in Alzheimer disease among patients already burdened with schizophrenia,” he said.
“While these signs may be attributable to the disease itself, they may also be in part a side effect of our treatment.”
Dr Roca noted that in addition to the many antipsychotic medications that are strongly anticholinergic, other medications also have such effects. Some medications ― for example, those that treat the parkinsonian side effects of antipsychotics ― are prescribed precisely because they have such properties, “thus compounding the anticholinergic load.”
Clinicians, said Dr Roca, “need to be alert” to the possibility that current impairment may be reduced or future worsening prevented by lowering doses of drugs with anticholinergic properties, or even eliminating them altogether.
“This resonates with a general principle of pharmacology in older adults ― oftentimes, less is more.”
The authors and Dr Roca have disclosed no relevant financial conflicts of interest.
J Clin Psychiatry. Published online November 28, 2017. Abstract
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