A Systematic Review of Amnestic and Non-Amnestic Mild Cognitive Impairment Induced by Anticholinergic, Antihistamine, GABAergic and Opioid Drugs
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Mild cognitive deficits are experienced by 18% of community-dwelling older adults, many of whom do not progress to dementia. The effect of commonly used medication on subtle impairments in cognitive function may be under-recognized.
The aim of the review was to examine the evidence attributing amnestic or non-amnestic cognitive impairment to the use of medication with anticholinergic, antihistamine, GABAergic or opioid effects.
MEDLINE and EMBASE were searched for randomized, doubleblind, placebo-controlled trials of adults without underlying central nervous system disorders who underwent detailed neuropsychological testing prior to and after oral administration of drugs affecting cholinergic, histaminergic, GABAergic or opioid receptor pathways. Seventy-eight studies were identified, reporting 162 trials testing medication from the four targeted drug classes. Two investigators independently appraised study quality and extracted relevant data on the occurrence of amnestic, non-amnestic or combined cognitive deficits induced by each drug class. Only trials using validated neuropsychological tests were included. Quality of the evidence for each drug class was assessed based on consistency of results across trials and the presence of a dose-response gradient.
In studies of short-, intermediate- and long-acting benzodiazepine drugs (n = 68 trials), these drugs consistently induced both amnestic and non-amnestic cognitive impairments, with evidence of a dose-response relationship. H1-antihistamine agents (n = 12) and tricyclic antidepressants (n = 15) induced non-amnestic deficits in attention and information processing. Non-benzodiazepine derivatives (n = 29) also produced combined deficits, but less consistently than benzodiazepine drugs. The evidence was inconclusive for the type of cognitive impairment induced by different bladder relaxant antimuscarinics (n = 9) as well as for narcotic agents (n = 5) and antipsychotics (n = 5). Among healthy volunteers >60 years of age, low doses of commonly used medications such as lorazepam 0.5 mg, oxybutynin immediate release 5 mg and oxycodone 10 mg produced combined deficits.
Non-amnestic mild cognitive deficits are consistently induced by first-generation antihistamines and tricyclic antidepressants, while benzodiazepines provoke combined amnestic and non-amnestic impairments. Risk-benefit considerations should be discussed with patients in order to enable an informed choice about drug discontinuation or substitution to potentially reverse cognitive adverse effects.
KeywordsMild Cognitive Impairment Neuropsychological Test Zolpidem Oxybutynin Desloratadine
We gratefully acknowledge the assistance of Audrey Attia, Marion Guillemont, Jean-Francois Cabana, Thomas Jubault and Don Sheppard in the preparation of this manuscript.
This work was sponsored by The Michel Saucier Endowed Chair in Geriatric Pharmacology, Health and Aging, from the Faculty of Pharmacy, Université de Montréal. The sponsors had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review and approval of the manuscript.
The financial disclosures for the authors are as follows: Cara Tannenbaum was supported by The Michel Saucier Endowed Chair in Geriatric Pharmacology, Health and Aging, from the Faculty of Pharmacy, Université de Montréal and by a junior researcher award from the Fondation de Recherche en Santé du Québec. She declares having received honoraria and/or consulting fees from Allergan Inc., Astellas, Ferring and Pfizer during the past 3 years. Amélie Paquette was supported by the Canadian Institutes of Health grant 108262. Ryan Carnahan was supported by an Agency for Healthcare Research and Quality (AHRQ) Centers for Education and Research on Therapeutics cooperative agreement ♯5 U18 HSO16094 (the Iowa Older Adults CERT). He has previously received research support from Eli Lilly and Co., Forest Laboratories, Wyeth and Boehringer Ingelheim. All other authors declare that they have received no support from any organization for the submitted work, have no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and have no other relationships or activities that could appear to have influenced the submitted work.
Contributions: Cara Tannenbaum had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Cara Tannenbaum, Amélie Paquette and Ryan Carnahan contributed to the design of the study. All authors contributed to the data collection, management, analysis and interpretation of the data, and the preparation and review of the manuscript.
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