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The cognitive effect of anticholinergics for patients with overactive bladder

Abstract

Overactive bladder (OAB) is often treated with medications that block the cholinergic receptors in the bladder (known as anticholinergics). The effect of this medication class on cognition and risk of dementia has been increasingly studied over the past 40 years after initial studies suggested that the anticholinergic medication class could affect memory. Short-term randomized clinical trials demonstrated that the administration of the anticholinergic oxybutynin leads to impaired memory and attention, and large, population-based studies showed associations between several different anticholinergic medications and dementia. However, trials involving anticholinergics other than oxybutynin have not shown such substantial effects on short-term cognitive function. This discordance in results between short-term cognitive safety of OAB anticholinergics and the long-term increased dementia risk could be explained by the high proportion of patients using oxybutynin in the OAB subgroups of the dementia studies, or a study duration that was too short in the prospective clinical trials on cognition with other OAB anticholinergics. Notably, all studies must be interpreted in the context of potential confounding factors, such as when prodromal urinary symptoms associated with the early stages of dementia lead to an increase in OAB medication use, rather than the use of OAB medication causing dementia. In patients with potential risk factors for cognitive impairment, the cautious use of selected OAB anticholinergic agents with favourable physicochemical and pharmacokinetic properties and clinical trial evidence of cognitive safety might be appropriate.

Key points

  • Short-term randomized clinical trials (most <4 weeks) have not shown substantial cognitive impairment with overactive bladder (OAB) anticholinergics other than oxybutynin.

  • Very few long-term clinical studies (>3 months) on OAB anticholinergics exist, and those studies that are available have conflicting results and are limited by methodological issues.

  • Large, observational studies of OAB anticholinergic use have shown that these medications are associated with an ~20% increased relative risk of dementia, but residual confounding and reverse causality cannot be ruled out.

  • Alternative OAB treatments might be more appropriate for patients >65 years of age and those patients with underlying mild cognitive impairment (or conditions that put them at risk of it); if necessary, careful use of anticholinergics with favourable physicochemical, pharmacokinetic and pharmacodynamic properties and cognitive safety data could be considered.

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Fig. 1: Distribution and general role of the muscarinic acetylcholine receptors in the human body and brain.
Fig. 2: Anatomy of the BBB, and how certain anticholinergics interact with it.

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Acknowledgements

J.N.P. is supported in part by funding from the United Kingdom’s Department of Health NIHR Biomedical Research Centres funding scheme. K.R. is supported by funding from the United Kingdom’s Alzheimer’s Society.

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B.W., K.R. and J.N.P. researched data for the article, made substantial contributions to discussion of its content, and wrote, edited and reviewed the article prior to submission.

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Correspondence to Blayne Welk.

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Nature Reviews Urology thanks D. Robinson; R. Khavari, who co-reviewed with R. High; and L. Cardozo for their contribution to the peer review of this work.

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Glossary

Protopathic bias

Also known as reverse causality. When a medication is initiated to treat the initial symptoms of an undiagnosed disease.

Mini-mental state examination

(MMSE). A standardized and widely used test of cognitive function for adults, which evaluates orientation, attention, memory, language and visual–spatial skills.

Face–name association test

A cross-modal associative memory test, which uses 16 face–name pairs and 16 face–occupation pairs, and the person has to try to remember different pairs during both immediate and delayed (30 min later) tests.

EEG frequency bands

Electroencephalogram (EEG) readings can be decomposed into different component frequencies (delta, theta, alpha, beta and gamma), which are associated with specific functional characteristics.

Selective serotonin reuptake inhibitors

(SSRIs). Medications that inhibit the reabsorption of serotonin into neurons, which can help with psychiatric problems such as depression and anxiety.

Cholinesterase inhibitors

These medications prevent the breakdown of acetylcholine, and can improve intracellular communication and treat symptoms of dementia.

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Welk, B., Richardson, K. & Panicker, J.N. The cognitive effect of anticholinergics for patients with overactive bladder. Nat Rev Urol 18, 686–700 (2021). https://doi.org/10.1038/s41585-021-00504-x

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