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Project properties

Title	Cumulative Exposure to Anticholinergic and Sedative Medications and Cognitive and Physical Function in Patients with Depression: a 9-Year Prospective Cohort Study
Keywords	antidepressants polypharmacy chronic depression
Researchers	dr. K. Taxis dr. H. Burger dr. H. Riese J. Wouters
Nature of the research	Analysis of observational longitudinal data
Fields of study	pharmacology GP medicine psychiatry

Background / introduction

Medications with anticholinergic and sedative properties are known to have adverse effects on cognitive and physical function in older geriatric patients. 1 Younger patients with depression and other psychiatric disorders are another group of patients who are likely to be exposed to anticholinergic and sedative drugs. Many psychotropic medications (i.e. anti-depressants, anti-psychotics and anti-anxiolytics) have anticholinergic or sedative properties. Antidepressants are likely to be overprescribed in patients with depression 2 given that they remain frequently prescribed, despite contradictory findings in the literature about their efficacy. 3-5 Moreover, co-medication for somatic conditions is often present in patients with depression.6 Given that medications from various therapeutic classes, including drugs for the respiratory, alimentary, and urinary tract, have anticholinergic potency, somatic co-medication is likely to add to the cumulative anticholinergic and sedative burden. Taken together, cumulative exposure to anticholinergic and sedative medications is likely in patients with depression and other psychiatric disorders. This may have important adverse consequences. Given that many patients with depression are known to have cognitive impairment, 7 cumulative anticholinergic and sedative exposure may aggravate pre-existent cognitive impairment. In turn, this has likely consequences for patients’ functional independence and quality of life. Something similar can be said about physical impairment.

Research question / problem definition
The objective of the current proposal is to examine longitudinal associations of cumulative anticholinergic and sedative exposure with cognitive and physical function in middle aged men and women with depression and polypharmacy. Findings from this study are likely to demonstrate if de-prescribing and improving prescribing in other respects is required for these vulnerable patients.

Workplan

Data from the NEtherlands Study of Depression and Anxiety (NESDA) will be examined. The NESDA study (N = 2981) is a nationally representative prospective cohort study among patients with depression and anxiety and healthy controls. Longitudinal data have been collected over 9 years in different health care settings. The aims of the NESDA study are to describe the long-term prognosis and consequences, the clinical, psychosocial, biological, and genetic determinants of depression and anxiety, as well as to understand patients’ views on depression and anxiety.
Available data are of high quality. Medication intake has been verified against medication packages and dosages have also been recorded. Cumulative exposure to anticholinergic and sedative medications will be quantified with the Drug Burden Index (DBI). 8 The DBI has been examined extensively in geriatric patients and community-dwelling older people aged > 65 years. 9 Both objective and self-reported clinically relevant outcomes are available in the NESDA study. Outcomes include measures of physical function (grip strength, and physical activity), cognitive function (digit span), social activity and innovative ecological momentary assessment (EMA) measurements of mood. Furthermore, severity of depression and co-morbidities have also been assessed. In (generalized) linear mixed models and related statistical analyses, we will examine associations that will be adjusted for severity of depression and co-morbidity. The intern will be supervised by experienced and passionate clinical researchers. Consultation can be asked from our colleagues including pharmacists, GPs, and psychiatrists. In the project, we will collaborate with national and international experts. Thus, the project is characterized by working in a multidisciplinary team, will offer possibilities to collaborate on an international level, and will enable publishing findings in clinical journals.

References

1. Fox C, Smith T, Maidment I, et al. Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: A systematic review. Age Ageing. 2014;43(5):604-615.
2. Jureidini J, Tonkin A. Overuse of antidepressant drugs for the treatment of depression. CNS Drugs. 2006;20(8):623-632.
3. Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ. Benefits from antidepressants: Synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine. Arch Gen Psychiatry. 2012;69(6):572-579.
4. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: A systematic review. Lancet. 2003;361(9358):653-661.
5. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: A meta-analysis of data submitted to the food and drug administration. PLoS Med. 2008;5(2):e45.
6. Klabbers G, Bosma H, Van der Does AJ, et al. The educational patterning of health-related adversities in individuals with major depression. J Affect Disord. 2010;126(1-2):96-102.
7. Elliott R, Sahakian BJ, McKay AP, Herrod JJ, Robbins TW, Paykel ES. Neuropsychological impairments in unipolar depression: The influence of perceived failure on subsequent performance. Psychol Med. 1996;26(5):975-989.
8. Hilmer SN, Mager DE, Simonsick EM, et al. A drug burden index to define the functional burden of medications in older people. Arch Intern Med. 2007;167(8):781-787.
9. Wouters H, van der Meer H, Taxis K. Quantification of anticholinergic and sedative drug load with the drug burden index: A review of outcomes and methodological quality of studies. Eur J Clin Pharmacol. 2016.

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