Schizophrenia: anticholinergic drugs are linked to greater cognitive impairment

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Writing in the May 14, 2021 issue of The American Journal of Psychiatry , a multi-institution team of scientists led by researchers at University of California San Diego School of Medicine report that medications commonly prescribed to reduce the severity of physical and mental health symptoms associated with schizophrenia may have a cumulative effect of worsening cognitive function in patients.

Psychotropic medications are often necessary and beneficial, but they possess other secondary properties that are not directly related to reducing symptoms, including anticholinergic properties.

That is, apart from their actual intended effects, they also inhibit acetylcholine, a neurotransmitter that is important in brain signaling and in a number of other body functions.

Apart from schizophrenia, which is estimated to affect roughly 1.5 million Americans, drugs with anticholinergic properties are used to treat a wide variety of conditions, including urinary incontinence, chronic obstructive pulmonary disorder and some muscle disorders.

“Many medications have anticholinergic effects, and we are becoming increasingly aware about their potential long-term risks,” said lead study author Yash Joshi, MD, assistant professor in the Department of Psychiatry at UC San Diego School of Medicine.

In fact, anticholinergic drugs have been linked to cognitive impairment and increased dementia risk in healthy adults. For example, a 2020 study by UC San Diego School of Medicine researchers found an association between anticholinergic medications and increased risk of Alzheimer’s disease.

Another study cited by authors reported that taking just one strong anticholinergic medication for three years was associated with a 50 percent increase in the odds of developing dementia over the 11-year study period.

Persons living with schizophrenia commonly experience significant difficulties with attention, learning, memory, executive function (such as reasoning and planning) and social cognition. Since these mental processes are critical for many daily activities, cognitive impairment in schizophrenia can lead to significant disability.

In the latest study, Joshi and colleagues sought to comprehensively characterize how the cumulative anticholinergic burden from different classes of medications impact cognition in patients with schizophrenia.

“We wanted to better understand how anticholinergic medication burden impacted cognitive functioning in individuals who may have already some cognitive difficulties due to schizophrenia,” he said.

Researchers assessed medical records, including prescribed medications, of 1,120 study participants with schizophrenia. They found that 63 percent of participants had an anticholinergic cognitive burden (ACB) score of at least 3.

“This is striking because previous studies have shown that an ACB score of 3 in a healthy, older adult is associated with cognitive dysfunction and a 50 percent increased risk for developing dementia,” said Joshi.

Notably, roughly one-quarter of the schizophrenia patients in the study had ACB scores of 6 or more.

The authors wrote that while such numbers may be high for persons living without any psychiatric illness, they are not difficult to achieve in patients receiving routine psychiatric care, which often includes medications with anticholinergic properties. For example, a patient prescribed daily olanzapine for symptoms of psychosis already starts with an ACB score of 3; add hydroxyzine for anxiety and insomnia in the same patient and their ACB score doubles.

Many patients with schizophrenia are treated with multiple psychotropic drugs – other medications for other health conditions could increase this burden further.

“It is easy even for well-meaning clinicians to inadvertently contribute to anticholinergic medication burden through routine and appropriate care,” said Gregory Light, Ph.D., professor of psychiatry and senior author. “The unique finding here is that this burden comes from medications we don’t usually think of as typical anticholinergic agents.”

The authors said ACB should be considered when physicians prescribe medications for patients with schizophrenia, noting that emerging data suggests reducing anticholinergic burden is associated not only with cognitive benefit, but an improved quality of life.

“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,” said Joshi.

“Everyone caring for those living with schizophrenia – mental health providers, primary care providers, specialists, and loved ones – should be vigilant in trying to reduce anticholinergic burden in a holistic way so that we can be good stewards of our patients’ long-term cognitive health.

If clinically feasible and safe, this could include reducing the number of psychotropic medications, changing some psychotropic medications to others with lower anticholinergic properties, or using complementary approaches to enhance cognitive functioning.”


The acetylcholinesterase inhibitors (ChEIs) and the NMDA receptor antagonist memantine are hitherto the only specific pharmacologic treatments approved for Alzheimer dementia, the most common type of dementia.1 Although their benefit appears to be modest,2,3 a significant body of evidence supports their effectiveness for improving cognition and their cost-effectiveness.4,-,12

Degeneration of basal forebrain cholinergic neurons is one of the earliest findings in Alzheimer dementia and precedes dementia development.13,14 Progression of Alzheimer dementia is better correlated with cholinergic system dysfunction than amyloid plaque load.15 Reduction of the volume of the basal forebrain precedes changes of hippocampal volume and predicts the cortical spread of Alzheimer pathology.16

ChEIs work by maximizing the availability of endogenous acetylcholine in the brain.17 However, few randomized clinical trials (RCTs) have examined the effectiveness of ChEIs in Alzheimer dementia after 1 year of treatment18,-,22 or followed up patients beyond this point.20 Studies of long-term cognitive decline are difficult due to high attrition and loss to follow-up.20 Although not RCTs, follow-up of ChEI-treated Alzheimer dementia cohorts has shown small cognitive benefits at 2, 3, and >10 years.23,-,25 Moreover, a positive short-term response to ChEIs can delay nursing home placement.26 Other studies have shown associations between ChEI use and decreased risk of myocardial infarction, stroke, and death in patients with dementia.27,-,30

We conducted a longitudinal cohort study on the Swedish Dementia Registry (SveDem) to investigate whether the cognitive benefit of ChEIs in routine settings persists over the long term and whether ChEI use is associated with decreased risk of severe dementia and death.

Discussion
In this large longitudinal national dementia cohort, ChEI use was associated with a reduction in cognitive decline over time, and this effect was modest but persisted over the long term. ChEI use also was associated with reduced risk for mortality, which is in line with previous results from our group.27,28 A dose-response effect was observed for both of these outcomes. Only galantamine demonstrated a reduction in the risk for severe dementia (MMSE score <10).

Little is known about the long-term effects of ChEI on cognitive decline in Alzheimer dementia. In a 2018 Cochrane systematic review, which included 30 studies on donepezil for Alzheimer dementia, only 3 studies18,-,20 had a follow-up of 1 year, and only 1 study18 could be included in the meta-analysis. A recent meta-analysis (n = 16,576 patients with Alzheimer dementia; 63 RCTs) with an average duration of 8 months showed that although ChEIs had a benefit for cognition, the effect did not reach significant improvement.38

In the British Alzheimer’s Disease 2000 study, patients with Alzheimer dementia were randomized to donepezil or placebo for 2 years. Donepezil users had 0.8 points higher MMSE scores at 2 years, but the study was underpowered and hard to interpret.20 In another study was performed in 5 Northern European countries, a significant advantage of donepezil treatment over placebo was observed at 52 weeks in cognition, activities of daily living, and the Progressive Deterioration Scale.18

The findings of our study showing significantly slower cognitive decline in patients with ChEI use are in line with results from other clinical trials. However, the magnitude of the effect appears to be somewhat smaller in our study, which is probably related to the characteristics of our cohort, the particular design, and limitations.

First, we defined medication exposure within the 3 months after the dementia diagnosis, a conservative design that intended to mimic the intention-to-treat design of clinical trials and to avoid reverse causation in which the rate of cognitive decline would cause changes in medication status. Patients who were defined as treated could have stopped taking ChEIs and would still be analyzed within the treatment group, which could naturally attenuate the difference in effect. This could not be the case for nonusers; patients who were initially nonusers who started treatment after 3 months were excluded from analyses and did not contribute follow-up time in either group.

In general, patients are registered in SveDem early in the disease process.31 In our study, patients with a baseline MMSE score >20 declined faster than patients who started with lower MMSE scores. Second, ours is a cohort study using patients from the SveDem and naturalistic follow-ups. Attrition to follow-up was high, at ≈50%. Third, we defined study inclusion at the date of dementia diagnosis or the date when the patient started ChEI (whichever came first); for this reason, a small proportion of patients (6.6% in our study) were already treated when the MMSE was performed, which would contribute to reduce the magnitude of the difference between users and nonusers.

Patients with faster cognitive decline may have higher likelihood of dropout because institutionalization, mortality, and management of the social aspects of advanced dementia probably dominate the care efforts and disrupt follow-up. Missing follow-ups would then be more frequent among severely impaired patients. This creates a situation in which patients who are followed up are more likely to start with better cognition and to decline less over time.

The magnitude of the yearly decline observed in our study was −1.62 points per year, which is in line with previous clinical trials. In the National Alzheimer’s Coordinating Center study, the average decline was 1.9 points in the first year and 1.5 in the second year of follow-up.39 In the 1-year, randomized, placebo-controlled study of patients with mild to moderate AD18 the placebo group declined ≈2 points per year compared to a decline of ≈0.5 points per year for the donepezil users. Meanwhile, in our study, the benefit observed with ChEIs was smaller although our conservative definition of medication exposure makes it hard to directly compare these results.

ChEIs have been proven to have symptomatic effects in Alzheimer dementia beyond those detected by standard measures of cognition. As previously shown by our group, ChEIs have been associated with reductions in myocardial infarction,28 stroke27 and mortality,27 while anticholinergic medications have been associated with increases in stroke and mortality risk.40 Better cognition may in itself be protective for mortality, but ChEIs also may have beneficial systemic effects.27,28 Stroke and mortality prevention in mild to moderate dementia stages is desirable, and stroke prevention could theoretically prolong independent functioning in dementia.41,-,44

Meanwhile, a recent study showed that initiation of antipsychotic treatment was reduced in those treated with ChEIs.45 In our study, the benefit of ChEI was similar in those diagnosed with MMSE scores <20 and those with higher MMSE scores, and the cognitive benefits persisted over time. In the Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO-AD) clinical trial, withdrawal of donepezil in patients with moderate to severe Alzheimer dementia increased the risk of nursing home placement during 12 months after treatment.46

Continuation was associated with better cognition.47 In addition, galantamine use was associated with reduced risk for severe dementia and mortality and had the largest effect size for the association with cognitive decline in our study. Galantamine is a rapidly reversible ChEI and the only ChEI that acts as an allosteric nicotinic modulator.48,49 This dual effect as an acetylcholinesterase inhibitor and nicotinic receptors modulator may explain its enhanced effects.

The strengths of our study are the large sample size and long cognitive follow-up. In addition, data were obtained through standard patient registration and thus reflect real-world data. We acknowledge some limitations.

First, regarding the observational study design, we cannot infer causality, and we acknowledge the possibility of residual and unknown confounding. However, we controlled for the unbalanced confounders in our propensity score–matching cohort.

Second, patients were considered exposed throughout the whole follow-up period according to treatment status at study entry. We attempted to mimic the intention-to-treat design of clinical trials to ensure a conservative estimate of the effects of ChEI on cognition and because of the fear of reverse causality, in which the speed of cognitive decline could influence decisions to start or withdraw treatment.

Third, we acknowledge that the vascular pathology in the group with mixed Alzheimer dementia may have affected the response to ChEI on the cognition trajectories. If anything, this may have contributed to an underestimation of the effects of the ChEI presented in this study. In addition, individual patient information on reasons for prescription or side effects of ChEI and information on the dispensation form of the ChEI were not available.

Fourth, the national coverage of SveDem is not absolute, and there is no clear count of how many patients develop dementia each year in Sweden. On the basis of different approximations of dementia incidence and prevalence, the coverage of SveDem for new dementia cases is estimated to be between 30% and 43%, depending on different estimations of incident cases regardless of whether they receive a diagnosis.50 The dementia diagnostic workup follows standard clinical practice, and few patients have a changed dementia diagnosis at follow-up,31 which suggests adequate diagnostic accuracy.

Fifth, although the majority of patients are diagnosed early in the dementia disease process, some patients are diagnosed in a later stage, resulting in a variation of cognitive functioning at the time of the initiation of ChEI treatment. Finally, because our data were collected in real-world clinical practice, there were differences in the number of MMSE measurements performed between individuals, and these MMSE measurements were not missing at random; however, we attempted to address the potential concern of dropout by adjusting the estimates using inverse probability of censoring weighting. Results with and without adjusted weighting were similar and robust.

ChEIs are associated with cognitive benefits that are modest but persist over the long term. ChEIs are associated with reduced mortality risk, which may be partly explained by the modest cognitive effects. Galantamine was the only ChEI that demonstrated a significant reduction in the risk of developing severe dementia, in addition to presenting the strongest effect on cognition.

reference link: https://n.neurology.org/content/96/17/e2220


More information: Yash B. Joshi et al. Anticholinergic Medication Burden–Associated Cognitive Impairment in Schizophrenia, American Journal of Psychiatry (2021). DOI: 10.1176/appi.ajp.2020.20081212

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