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Regular Research Article| Volume 27, ISSUE 11, P1177-1188, November 2019

Exposure to Antidepressant Medication and the Risk of Incident Dementia

      Highlights

      • This study examined the association between antidepressant use and the risk of dementia.
      • The group exposed to antidepressants had an increased incidence of dementia.
      • Clinicians, caregivers, and patients may wish to consider this potential negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment.

      Abstract

      Objective

      To test competing hypotheses that monotherapeutic antidepressant exposure is associated with an increased versus a decreased risk of dementia.

      Methods

      A prospective national matched cohort study from Israel (N = 71,515) without dementia (2002–2012) aged 60 and over were followed up for incident dementia from May 2013 to October 2017. Exposure to antidepressant monotherapy was classified with Anatomical Therapeutic Chemical Codes (N06A) from January 1, 2013 to December 31, 2016. The association between antidepressant monotherapy and the risk of incident dementia was quantified with hazard ratios (HR) and their 95% confidence intervals (CI) obtained from Cox regression models unadjusted and adjusted for 42 covariates. The robustness of the results was tested with 24 sensitivity analyses: 19 analyses restricted to subsamples with plausible differential dementia risks (e.g., anxiety and depression), and 5 analyses across and within antidepressant drug classes.

      Results

      In the primary analysis, the risk of incident dementia for the group exposed to antidepressant monotherapy compared to the group unexposed to antidepressants was estimated with an unadjusted HR = 4.09 (df = 1, 95% Wald CI = 3.64, 4.60) and an adjusted HR = 3.43 (df = 1, 95% Wald CI = 3.04, 3.88). Across the 24 sensitivity analyses the estimated adjusted HR values ranged from 1.99 to 5.47.

      Conclusion

      In this study, monotherapeutic antidepressant exposure in old age was associated with increased incident dementia. Clinicians, caregivers, and patients may wish to consider this potentially negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment.

      Key Words

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      References

        • Livingston G
        • Sommerlad A
        • Orgeta V
        • et al.
        Dementia prevention, intervention, and care.
        Lancet. 2017; 390: 2673-2734
        • Prince M
        • Bryce R
        • Albanese E
        • et al.
        The global prevalence of dementia: a systematic review and meta-analysis.
        Alzheimers Dement. 2013; 9 (e62): 63-75
        • Kodesh A
        Prevalence and comorbidities of dementia in Israel: a nationally representative cohort study.
        Int Psychogeriatr. 2018; : 1-5https://doi.org/10.1017/S1041610218001461
        • Alzheimer's Association Report
        2018 Alzheimer's disease facts and figures.
        Alzheimer's Dement. 2018; 14: 367-429
        • Reitz C
        • Brayne C
        • Mayeux R
        Epidemiology of Alzheimer disease.
        Nat Rev Neurol. 2011; 7: 137-152
        • Yaffe K
        Modifiable risk factors and prevention of dementia: what is the latest evidence?.
        JAMA Intern Med. 2018; 178: 281-282
        • Baumgart M
        • Snyder HM
        • Carrillo MC
        • et al.
        Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective.
        Alzheimers Dement. 2015; 11: 718-726
        • Beekman AT
        • Copeland JR
        • Prince MJ
        Review of community prevalence of depression in later life.
        Br J Psychiatry. 1999; 174: 307-311
        • da Silva J
        • Goncalves-Pereira M
        • Xavier M
        • et al.
        Affective disorders and risk of developing dementia: systematic review.
        Br J Psychiatry. 2013; 202: 177-186
        • Ownby RL
        • Crocco E
        • Acevedo A
        • et al.
        Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis.
        Arch Gen Psychiatry. 2006; 63: 530-538
        • Tham A
        • Jonsson U
        • Andersson G
        • et al.
        Efficacy and tolerability of antidepressants in people aged 65 years or older with major depressive disorder—a systematic review and a meta-analysis.
        J Affect Disord. 2016; 205: 1-12
        • Tedeschini E
        • Levkovitz Y
        • Iovieno N
        • et al.
        Efficacy of antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-controlled randomized trials.
        J Clin Psychiatry. 2011; 72: 1660-1668
        • Kok RM
        • Reynolds 3rd, CF
        Management of depression in older adults: a review.
        JAMA. 2017; 317: 2114-2122
        • Newman SC
        • Schopflocher D
        Trends in antidepressant prescriptions among the elderly in Alberta during 1997 to 2004.
        Can J Psychiatry. 2008; 53: 704-707
        • Mamdani MM
        • Parikh SV
        • Austin PC
        • et al.
        Use of antidepressants among elderly subjects: trends and contributing factors.
        Am J Psychiatry. 2000; 157: 360-367
        • Curkovic M
        • Dodig-Curkovic K
        • Eric AP
        • et al.
        Psychotropic medications in older adults: a review.
        Psychiatr Danub. 2016; 28: 13-24
        • Jackson SH
        • Jansen PA
        • Mangoni AA
        Off-label prescribing in older patients.
        Drugs Aging. 2012; 29: 427-434
        • Jessen F
        • Kaduszkiewicz H
        • Daerr M
        • et al.
        Anticholinergic drug use and risk for dementia: target for dementia prevention.
        Eur Arch Psychiatry Clin Neurosci. 2010; 260: S111-S115
        • Bali V
        • Holmes HM
        • Johnson ML
        • et al.
        Comparative effectiveness of second-generation antidepressants in reducing the risk of dementia in elderly nursing home residents with depression.
        Pharmacotherapy. 2016; 36: 38-48
        • Hashioka S
        • McGeer PL
        • Monji A
        • et al.
        Anti-inflammatory effects of antidepressants: possibilities for preventives against Alzheimer's disease.
        Cent Nerv Syst Agents Med Chem. 2009; 9: 12-19
        • Leonard BE
        Changes in the immune system in depression and dementia: causal or co-incidental effects?.
        Int J Dev Neurosci. 2001; 19: 305-312
        • Dranovsky A
        • Hen R
        Hippocampal neurogenesis: regulation by stress and antidepressants.
        Biol Psychiatry. 2006; 59: 1136-1143
        • Hwang J
        • Zheng LT
        • Ock J
        • et al.
        Inhibition of glial inflammatory activation and neurotoxicity by tricyclic antidepressants.
        Neuropharmacology. 2008; 55: 826-834
        • Fuhrer R
        • Dufouil C
        • Dartigues JF
        • et al.
        Exploring sex differences in the relationship between depressive symptoms and dementia incidence: prospective results from the Paquid Study.
        J Am Geriatr Soc. 2003; 51: 1055-1063
        • Kessing LV
        • Sondergard L
        • Forman JL
        • et al.
        Antidepressants and dementia.
        J Affect Disord. 2009; 117: 24-29
        • Heser K
        • Luck T
        • Rohr S
        • et al.
        Potentially inappropriate medication: association between the use of antidepressant drugs and the subsequent risk for dementia.
        J Affect Disord. 2018; 226: 28-35
        • Saczynski JS
        • Rosen AB
        • McCammon RJ
        • et al.
        Antidepressant use and cognitive decline: the health and retirement study.
        Am J Med. 2015; 128: 739-746
        • Lee CW
        • Lin CL
        • Sung FC
        • et al.
        Antidepressant treatment and risk of dementia: a population-based, retrospective case-control study.
        J Clin Psychiatry. 2016; 77 (quiz 122): 117-122
        • Wang C
        • Gao S
        • Hendrie HC
        • et al.
        Antidepressant use in the elderly is associated with an increased risk of dementia.
        Alzheimer Dis Assoc Disord. 2016; 30: 99-104
        • Bature F
        • Guinn BA
        • Pang D
        • et al.
        Signs and symptoms preceding the diagnosis of Alzheimer's disease: a systematic scoping review of literature from 1937 to 2016.
        BMJ Open. 2017; 7e015746
        • Chinitz D
        • Shalev C
        • Galai N
        • et al.
        The second phase of priority setting. israel's basic basket of health services: the importance of being explicitly implicit.
        Br Med J. 1998; 317: 1005-1007
        • Maust DT
        • Kim HM
        • Seyfried LS
        • et al.
        Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm.
        JAMA Psychiatry. 2015; 72: 438-445
        • Therneau TM
        • Grambsch PM
        Modeling Survival Data: Extending the Cox Model.
        Springer, London2000
        • Richardson K
        • Fox C
        • Maidment I
        • et al.
        Anticholinergic drugs and risk of dementia: case-control study.
        BMJ. 2018; 361: k1315
        • Then CK
        • Chi NF
        • Chung KH
        • et al.
        Risk analysis of use of different classes of antidepressants on subsequent dementia: a nationwide cohort study in taiwan.
        PLoS One. 2017; 12e0175187
        • Anstey KJ
        • von Sanden C
        • Salim A
        • et al.
        Smoking as a risk factor for dementia and cognitive decline: a meta-analysis of prospective studies.
        Am J Epidemiol. 2007; 166: 367-378
        • Kivimaki M
        • Luukkonen R
        • Batty GD
        • et al.
        Body mass index and risk of dementia: analysis of individual-level data from 1.3 million individuals.
        Alzheimers Dement. 2018; 14: 601-609
        • Wong J
        • Motulsky A
        • Abrahamowicz M
        • et al.
        Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system.
        BMJ. 2017; 356: j603
        • Lang L
        • Clifford A
        • Wei L
        • et al.
        Prevalence and determinants of undetected dementia in the community: a systematic literature review and a meta-analysis.
        BMJ Open. 2017; 7e011146
        • Djernes JK
        • Gulmann NC
        • Foldager L
        • et al.
        13 year follow up of morbidity, mortality and use of health services among elderly depressed patients and general elderly populations.
        Aust N Z J Psychiatry. 2011; 45: 654-662