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Anticholinergic Activity of Psychotropic Drugs and Cognitive Impairment Among Participants Aged 45 and Over: The CONSTANCES Study

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Abstract

Introduction

Psychotropic drugs such as anxiolytics, antidepressants and antipsychotics may have anticholinergic properties that could directly affect patients’ cognition.

Objectives

Our objective was to assess the relationship between exposure to anticholinergic-positive (AC+) psychotropic drugs and cognitive impairment compared with psychotropic drugs without anticholinergic activity (AC−).

Methods

This analysis included participants (aged 45–70 years) enrolled between January 2012 and October 2017 in the CONSTANCES cohort treated with psychotropic drugs (antidepressants n = 2602, anxiolytics n = 1195, antipsychotics n = 197) in the 3 years preceding cognitive assessment. Within each drug class, the Anticholinergic Cognitive Burden scale was used to classify drugs as either AC+ or AC−. Cognitive impairment was defined as a score below − 1 standard deviation from the standardized mean of the neuropsychological score. We used multiple logistic regression models and matching on propensity score to estimate the relationship between anticholinergic activity and cognitive impairment.

Results

Our analyses did not show any increased risk of cognitive impairment for AC+ antidepressants and anxiolytics, with the exception of a slight increase for AC+ antidepressants in episodic memory (odds ratio [OR] 1.19; 95% confidence interval [CI] 1.05–1.36). Conversely, we found a more marked increase in risk with AC+ antipsychotics on executive function (Trail Making Test-A [TMT-A], OR 4.49 [95% CI 2.59–7.97] and TMT-B, OR 3.62 [95% CI 2.25–5.89]).

Conclusion

Our results suggest there is no clinically relevant association between the anticholinergic activity of antidepressant and anxiolytic drugs and cognitive impairment in middle-aged adults. An association could exist between AC+ antipsychotics and executive function.

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References

  1. Campbell NL, Perkins AJ, Bradt P, Perk S, Wielage RC, Boustani MA, et al. Association of anticholinergic burden with cognitive impairment and health care utilization among a diverse ambulatory older adult population. Pharmacotherapy. 2016;36:1123–31.

    Article  CAS  Google Scholar 

  2. Montastruc F, Retailleau E, Rousseau V, Bagheri H, Montastruc J-L. Atropinic burden of prescription forms in France: a study in community pharmacies in 2013. Eur J Clin Pharmacol. 2014;70:1147–8.

    Article  Google Scholar 

  3. Richardson K, Fox C, Maidment I, Steel N, Loke YK, Arthur A, et al. Anticholinergic drugs and risk of dementia: case–control study. BMJ. 2018;361:k1315.

    Article  Google Scholar 

  4. Ziad A, Olekhnovitch R, Ruiz F, Berr C, Bégaud B, Goldberg M, et al. Anticholinergic drug use and cognitive performances in middle age: findings from the CONSTANCES cohort. J Neurol Neurosurg Psychiatry. 2018;89:1107–15.

    Article  Google Scholar 

  5. Lagnaoui R, Depont F, Fourrier A, Abouelfath A, Bégaud B, Verdoux H, et al. Patterns and correlates of benzodiazepine use in the French general population. Eur J Clin Pharmacol. 2004;60:523–9.

    Article  CAS  Google Scholar 

  6. médicale (Inserm) I national de la santé et de la recherche. Médicaments psychotropes : Consommations et pharmacodépendances [Internet]. Les éditions Inserm; 2012. http://www.ipubli.inserm.fr/handle/10608/2072. Accessed 29 Oct 2018.

  7. Campbell N, Boustani M, Limbil T, Ott C, Fox C, Maidment I, et al. The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging. 2009;4:225–33.

    PubMed  PubMed Central  Google Scholar 

  8. Mura T, Proust-Lima C, Akbaraly T, Amieva H, Tzourio C, Chevassus H, et al. Chronic use of benzodiazepines and latent cognitive decline in the elderly: results from the three-city study. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol. 2013;23:212–23.

    Article  CAS  Google Scholar 

  9. Trivedi MH, Greer TL. Cognitive dysfunction in unipolar depression: implications for treatment. J Affect Disord. 2014;152:19–27.

    Article  Google Scholar 

  10. Hori H, Noguchi H, Hashimoto R, Nakabayashi T, Omori M, Takahashi S, et al. Antipsychotic medication and cognitive function in schizophrenia. Schizophr Res. 2006;86:138–46.

    Article  Google Scholar 

  11. Vulser H, Wiernik E, Hoertel N, et al. Depression, cognitive functions, and impaired functioning in middle-aged adults from the CONSTANCES cohort. JClin. Psychiatry. 2018;79(6):17m12003.

    Google Scholar 

  12. Kaup AR, Byers AL, Falvey C, Simonsick EM, Satterfield S, Ayonayon HN, et al. Trajectories of depressive symptoms in older adults and risk of dementia. JAMA Psychiatry. 2016;73:525–31.

    Article  Google Scholar 

  13. Greenblatt HK, Greenblatt DJ. Use of antipsychotics for the treatment of behavioral symptoms of dementia. J Clin Pharmacol. 2016;56:1048–57.

    Article  CAS  Google Scholar 

  14. Ruiz F, Goldberg M, Lemonnier S, Ozguler A, Boos E, Brigand A, et al. High quality standards for a large-scale prospective population-based observational cohort: constances. BMC Public Health. 2016;16:877.

    Article  Google Scholar 

  15. Zins M, Goldberg M, CONSTANCES Team. The French CONSTANCES population-based cohort: design, inclusion and follow-up. Eur J Epidemiol. 2015;30:1317–28.

    Article  Google Scholar 

  16. Bilan de santé et questionnaires | L’espace scientifique | Cohorte Constances [Internet]. [cited 2020 Dec 12]. https://www.constances.fr/questionnaires.php. Accessed 20 June 2019.

  17. Bezin J, Duong M, Lassalle R, Droz C, Pariente A, Blin P, et al. The national healthcare system claims databases in France, SNIIRAM and EGB: powerful tools for pharmacoepidemiology. Pharmacoepidemiol Drug Saf. 2017;26:954–62.

    Article  Google Scholar 

  18. Campbell NL, Maidment I, Fox C, Khan B, Boustani M. The 2012 update to the anticholinergic cognitive burden scale. J Am Geriatr Soc [Internet]. Wiley-Blackwell; 2013. p. S142–3. https://www.research.aston.ac.uk/en/publications/the-2012-update-to-the-anticholinergic-cognitive-burden-scale. Accessed 05 Oct 2020.

  19. Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175:401–7.

    Article  Google Scholar 

  20. WHOCC - ATC/DDD Index [Internet]. https://www.whocc.no/atc_ddd_index/. Accessed 19 Sept 2019.

  21. Grober E, Buschke H, Crystal H, Bang S, Dresner R. Screening for dementia by memory testing. Neurology. 1988;38:900–3.

    Article  CAS  Google Scholar 

  22. Borkowski JG, Benton AL, Spreen O. Word fluency and brain damage. Neuropsychologia. 1967;5:135–40.

    Article  Google Scholar 

  23. Cardebat D, Doyon B, Puel M, Goulet P, Joanette Y. Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level. Acta Neurol Belg. 1990;90:207–17.

    CAS  PubMed  Google Scholar 

  24. Wechsler D. WAIS-R, Wechsler Adult Intelligence Scale- Revised, Manual. New York, NY: Psychological Corporation; 1981.

    Google Scholar 

  25. The Fundamentals of Clinical Neuropsychiatry [Internet]. https://www.global.oup.com/academic/product/the-fundamentals-of-clinical-neuropsychiatry-9780195130379.

  26. Boll TJ, Reitan RM. Effect of age on performance of the Trail Making Test. Percept Mot Skills. 1973;36:691–4.

    Article  CAS  Google Scholar 

  27. Miner T, Ferraro FR. The role of speed of processing, inhibitory mechanisms, and presentation order in trail-making test performance. Brain Cogn. 1998;38:246–53.

    Article  CAS  Google Scholar 

  28. Dion M, Potvin O, Belleville S, Ferland G, Renaud M, Bherer L, et al. Normative data for the Rappel libre/Rappel indicé à 16 items (16-item Free and Cued Recall) in the elderly Quebec-French population. Clin Neuropsychol. 2015;28(Suppl 1):S1-19.

    PubMed  Google Scholar 

  29. Busse A, Hensel A, Gühne U, Angermeyer MC, Riedel-Heller SG. Mild cognitive impairment: long-term course of four clinical subtypes. Neurology. 2006;67:2176–85.

    Article  CAS  Google Scholar 

  30. Morin AJS, Moullec G, Maïano C, Layet L, Just J-L, Ninot G. Psychometric properties of the Center for Epidemiologic Studies Depression Scale (CES-D) in French clinical and nonclinical adults. Rev Epidemiol Sante Publique. 2011;59:327–40.

    Article  CAS  Google Scholar 

  31. Tammenmaa-Aho I, Asher R, Soares-Weiser K, Bergman H. Cholinergic medication for antipsychotic-induced tardive dyskinesia. Cochrane Schizophrenia Group, editor. Cochrane Database Syst Rev [Internet]. 2018. https://doi.org/10.1002/14651858.CD000207.pub2

  32. Rosenbaum PR, Rubin DB. The central role of the propensity score in observational studies for causal effects. 1983. https://dash.harvard.edu/handle/1/3382855. Accessed 03 July 2018.

  33. Mitra R, Reiter JP. A comparison of two methods of estimating propensity scores after multiple imputation. Stat Methods Med Res. 2016;25:188–204.

    Article  Google Scholar 

  34. Pasina L, Colzani L, Cortesi L, Tettamanti M, Zambon A, Nobili A, et al. Relation between delirium and anticholinergic drug burden in a cohort of hospitalized older patients: an observational study. Drugs Aging. 2019;36:85–91.

    Article  CAS  Google Scholar 

  35. Mori K, Yamashita H, Nagao M, Horiguchi J, Yamawaki S. Effects of anticholinergic drug withdrawal on memory, regional cerebral blood flow and extrapyramidal side effects in schizophrenic patients. Pharmacopsychiatry. 2002;35:6–11.

    Article  CAS  Google Scholar 

  36. Rémillard S, Pourcher E, Cohen H. Long-term effects of risperidone versus haloperidol on verbal memory, attention, and symptomatology in schizophrenia. J Int Neuropsychol Soc. 2008;14:110–8.

    Article  Google Scholar 

  37. Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008;168:508–13.

    Article  Google Scholar 

  38. Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol. 2006;46:1481–6.

    Article  CAS  Google Scholar 

  39. Mebarki S, Trivalle C. Évaluation de la charge anticholinergique en gériatrie à l’aide de 3 échelles. NPG Neurol - Psychiatr - Gériatrie. 2014;14:81–7.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank the National Health Insurance Fund (‘Caisse Nationale d’Assurance Maladie’ [CNAM] and its health screening centres (‘Centres d’examens de santé’), where a large part of the data was collected, and ClinSearch, which was in charge of the data quality control.

Author information

Authors and Affiliations

  1. ClinSearch-110, Avenue Pierre Brossolette, Malakoff, France

    Abdelkrim Ziad & Fabrice Ruiz

  2. Population-based Epidemiological Cohorts Unit, US 011 Inserm, Villejuif, France

    Abdelkrim Ziad, Marcel Goldberg & Marie Zins

  3. INSERM, University of Montpellier, U1061, Neuropsychiatry: Epidemiological and Clinical Research, 34093, Montpellier, France

    Claudine Berr & Thibault Mura

  4. Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique Innovation et Méthodologie (BESPIM), Groupe hospitalier Caremeau, CHU de Nîmes, Nîmes University Hospital, Place du Pr Debré, 30029, Nîmes Cedex 9, France

    Thibault Mura

  5. INSERM, U1219-Pharmacoepidemiology, Bordeaux University, 33000, Bordeaux, France

    Bernard Bégaud

  6. Université de Paris, Faculté de Santé, UFR de Médecine, Paris, France

    Cédric Lemogne

  7. Université de Paris, AP-HP, Hôpital Hôtel-Dieu, DMU Psychiatrie et Addictologie, Service de Psychiatrie de l’adulte, INSERM, Institut de Psychiatrie et Neurosciences de Paris (IPNP), UMR_S1266, Paris, France

    Cédric Lemogne & Marie Zins

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  1. Abdelkrim Ziad
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  2. Claudine Berr
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  7. Marie Zins
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Corresponding author

Correspondence to Thibault Mura.

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Funding

The CONSTANCES Cohort Study is supported by the Caisse nationale d’assurance maladie (CNAM), benefits from a grant from ANR (ANR-11-INBS-0002) and is partly funded by MSD, AstraZeneca and Lundbeck.

Conflicts of interest

Abdelkrim Ziad, Claudine Berr, Fabrice Ruiz, Bernard Bégaud, Cédric Lemogne, Marcel Goldberg, Marie Zins, Thibault Mura have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

The study protocol was approved by the appropriate ethics committee. According to French regulations, the CONSTANCES cohort was approved by the Data Protection Authority (Commission Nationale de l’Informatique et des Libertés) and by the INSERM institutional review board.

Consent to participate

All participants signed a written informed consent before inclusion in the present study.

Consent for publication

Not applicable.

Code availability

Not applicable

Availability of data and material

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because they contain information that could compromise the privacy of the study participants.

Authors’ contributions

AZ and TM co-managed the literature searches and undertook the statistical analysis. AZ wrote the first draft of the manuscript. TM, BB and CL made substantial modifications to the manuscript and approved the final version. CB and FR co-managed the literature searches, made substantial modifications to the manuscript and approved the final version. MZ and MG co-designed the cohort study CONSTANCES and wrote the protocol, made substantial modifications to the manuscript and approved the final version. All authors read and approved the manuscript.

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Ziad, A., Berr, C., Ruiz, F. et al. Anticholinergic Activity of Psychotropic Drugs and Cognitive Impairment Among Participants Aged 45 and Over: The CONSTANCES Study. Drug Saf 44, 565–579 (2021). https://doi.org/10.1007/s40264-021-01043-5

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