Original Study| Volume 18, ISSUE 12, P1076-1081, December 01, 2017

Download started.


Associations of Neuropsychiatric Symptoms and Antidepressant Prescription with Survival in Alzheimer’s Disease

Published:August 30, 2017DOI:



      Depression is associated with increased mortality in community samples. The use of antidepressant medication may also increase mortality, however, it is still unclear whether taking antidepressants before or after a diagnosis of dementia influences survival.




      A cohort with a diagnosis of Alzheimer disease (AD) from a large mental health and dementia care database in South London, linked to hospitalization and mortality data.


      Mild dementia (Mini-Mental State Examination ≥18/30) at the point of diagnosis.


      We ascertained antidepressant prescription, either in the 6 months before or after dementia diagnosis, and used the HoNOS65+, a standard clinician-rated measure of patient well-being, to determine depression severity and other neuropsychiatric, physical health, and functional difficulties. We conducted a survival analysis, adjusted for potential confounders and addressed possible confounding by indication through adjusting for a propensity score.


      Of 5473 patients with AD, 22.8% were prescribed an antidepressant in a 1-year window around dementia diagnosis. Of these, 2415 (44.1%) died in the follow-up period [mean (standard deviation) 3.5 (2.4) years]. Prescription of an antidepressant, both before and after dementia diagnosis, was significantly associated with higher mortality after adjusting for a broad range of potential confounders including symptom severity, functional status, and physical illness (hazard ratio 1.22; 95% confidence interval 1.08–1.37 for prescription prior to dementia diagnosis; 95% confidence interval 1.04–1.45 for prescription post dementia diagnosis). In stratified analyses, risks remained significant in those without neuropsychiatric symptoms.


      The prescription of antidepressants around the time of dementia diagnosis may be a risk factor for mortality.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the American Medical Directors Association
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Lyketsos C.G.
        • Carrillo M.C.
        • Ryan J.M.
        • et al.
        Neuropsychiatric symptoms in Alzheimer's disease.
        Alzheimer Dement. 2011; 7: 532-539
        • Modrego P.J.
        Depression in Alzheimer's disease. Pathophysiology, diagnosis, and treatment.
        J Alzheimer Dis JAD. 2010; 21: 1077-1087
        • Ownby R.L.
        • 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
        • Lyketsos C.G.
        • Lee H.B.
        Diagnosis and treatment of depression in Alzheimer's disease. A practical update for the clinician.
        Dement Geriatr Cognit Disord. 2004; 17: 55-64
        • Chi S.
        • Wang C.
        • Jiang T.
        • et al.
        The prevalence of depression in Alzheimer's disease: A systematic review and meta-analysis.
        Curr Alzheimer Res. 2015; 12: 189-198
        • Lara E.
        • Haro J.M.
        • Tang M.X.
        • et al.
        Exploring the excess mortality due to depressive symptoms in a community-based sample: The role of Alzheimer's Disease.
        J Affect Disord. 2016; 202: 163-170
        • Gomez-Gallego M.
        • Gomez-Garcia J.
        • Ato-Lozano E.
        The mediating role of depression in the association between disability and quality of life in Alzheimer's disease.
        Aging Mental Health. 2017; 21: 163-172
        • Taylor W.D.
        Depression in the elderly.
        N Engl J Med. 2014; 371: 1228-1236
        • Zhu C.W.
        • Livote E.E.
        • Kahle-Wrobleski K.
        • et al.
        Utilization of antihypertensives, antidepressants, antipsychotics, and hormones in Alzheimer disease.
        Alzheimer Dis Assoc Disord. 2011; 25: 144-148
        • Petracca G.
        • Teson A.
        • Chemerinski E.
        • et al.
        A double-blind placebo-controlled study of clomipramine in depressed patients with Alzheimer's disease.
        J Neuropsychiatry Clini Neurosci. 1996; 8: 270-275
        • Nyth A.L.
        • Gottfries C.G.
        The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study.
        Br J Psychiatry. 1990; 157: 894-901
        • Lyketsos C.G.
        • DelCampo L.
        • Steinberg M.
        • et al.
        Treating depression in Alzheimer disease: Efficacy and safety of sertraline therapy, and the benefits of depression reduction: The DIADS.
        Arch Gen Psychiatry. 2003; 60: 737-746
        • de Vasconcelos Cunha U.G.
        • Lopes Rocha F.
        • Avila de Melo R.
        • et al.
        A placebo-controlled double-blind randomized study of venlafaxine in the treatment of depression in dementia.
        Dement Geriatr Cogn Disord. 2007; 24: 36-41
        • Petracca G.M.
        • Chemerinski E.
        • Starkstein S.E.
        A double-blind, placebo-controlled study of fluoxetine in depressed patients with Alzheimer's disease.
        Int Psychogeriatr. 2001; 13: 233-240
        • Bains J.
        • Birks J.
        • Dening T.
        Antidepressants for treating depression in dementia.
        Cochrane Database Syst Rev. 2002; 4: CD003944
        • Krivoy A.
        • Balicer R.D.
        • Feldman B.
        • et al.
        Adherence to antidepressant therapy and mortality rates in ischaemic heart disease: Cohort study.
        Br J Psychiatry. 2015; 206: 297-301
        • Zivin K.
        • Kim H.M.
        • Yosef M.
        • et al.
        Antidepressant medication treatment and risk of death.
        J Clini Psychopharmacol. 2016; 36: 445-452
        • Hansen R.A.
        • Khodneva Y.
        • Glasser S.P.
        • et al.
        Antidepressant medication use and its association with cardiovascular disease and all-cause mortality in the reasons for geographic and racial differences in stroke (REGARDS) study.
        Ann Pharmacother. 2016; 50: 253-261
        • Jennum P.
        • Baandrup L.
        • Ibsen R.
        • Kjellberg J.
        Increased all-cause mortality with use of psychotropic medication in dementia patients and controls: A population-based register study.
        Eur Neuropsychopharmacol. 2015; 25: 1906-1913
        • Enache D.
        • Fereshtehnejad S.M.
        • Kareholt I.
        • et al.
        Antidepressants and mortality risk in a dementia cohort: Data from SveDem, the Swedish Dementia Registry.
        Acta Psychiatrica Scandinavica. 2016; 134: 430-440
        • Perera G.
        • Broadbent M.
        • Callard F.
        • et al.
        Cohort profile of the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Case Register: Current status and recent enhancement of an Electronic Mental Health Record-derived data resource.
        BMJ Open. 2016; 6: e008721
        • Fernandes A.C.
        • Cloete D.
        • Broadbent M.T.
        • et al.
        Development and evaluation of a de-identification procedure for a case register sourced from mental health electronic records.
        BMC Med Inform Decision Making. 2013; 13: 71
        • Cunningham H.
        GATE, a general architecture for text engineering.
        Comput Hum. 2002; 36: 223-254
        • World Health Organization
        International statistical classification of diseases and related health problems.
        • Folstein M.F.
        • Folstein S.E.
        • McHugh P.R.
        “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician.
        J Psychiatr Res. 1975; 12: 189-198
        • Noble M.
        • McLennan D.
        • Wilkinson K.
        • et al.
        The English indices of deprivation 2007.
        Communities and Local Government, London, United Kingdom2008
        • Burns A.
        • Beevor A.
        • Lelliott P.
        • et al.
        Health of the Nation Outcome Scales for elderly people (HoNOS 65+).
        Br J Psychiatry. 1999; 174: 424-427
        • Pirkis J.E.
        • Burgess P.M.
        • Kirk P.K.
        • et al.
        A review of the psychometric properties of the Health of the Nation Outcome Scales (HoNOS) family of measures.
        Health Qual Life Outcomes. 2005; 3: 76
        • Austin P.C.
        An introduction to propensity score methods for reducing the effects of confounding in observational studies.
        Multivariate Behav Res. 2011; 46: 399-424
        • Martinez-Ramirez D.
        • Giugni J.C.
        • Almeida L.
        • et al.
        Association between antidepressants and falls in Parkinson's disease.
        J Neurol. 2016; 263: 76-82
        • Stubbs B.
        • Stubbs J.
        • Gnanaraj S.D.
        • Soundy A.
        Falls in older adults with major depressive disorder (MDD): A systematic review and exploratory meta-analysis of prospective studies.
        Int Psychogeriatr. 2016; 28: 23-29
        • Stubbs B.
        • Brefka S.
        • Dallmeier D.
        • et al.
        Depression and reduced bone mineral density at the hip and lumbar spine: A comparative meta-analysis of studies in adults 60 years and older.
        Psychosom Med. 2016; 78: 492-500
        • Rabenda V.
        • Nicolet D.
        • Beaudart C.
        • et al.
        Relationship between use of antidepressants and risk of fractures: A meta-analysis.
        Osteoporos Int. 2013; 24: 121-137
        • Nezafati M.H.
        • Vojdanparast M.
        • Nezafati P.
        Antidepressants and cardiovascular adverse events: A narrative review.
        ARYA Atheroscler. 2015; 11: 295-304
        • Heist E.K.
        • Ruskin J.N.
        Drug-induced arrhythmia.
        Circulation. 2010; 122: 1426-1435
        • Kemp A.H.
        • Quintana D.S.
        • Gray M.A.
        • et al.
        Impact of depression and antidepressant treatment on heart rate variability: A review and meta-analysis.
        Biol Psychiatry. 2010; 67: 1067-1074
        • Zhang G.Q.
        • Zhang W.
        Heart rate, lifespan, and mortality risk.
        Ageing Res Rev. 2009; 8: 52-60
        • Masters M.C.
        • Morris J.C.
        • Roe C.M.
        “Noncognitive” symptoms of early Alzheimer disease: A longitudinal analysis.
        Neurology. 2015; 84: 617-622
        • Rountree S.D.
        • Chan W.
        • Pavlik V.N.
        • et al.
        Factors that influence survival in a probable Alzheimer disease cohort.
        Alzheimer Res Ther. 2012; 4: 16
        • Coupland C.
        • Dhiman P.
        • Morriss R.
        • et al.
        Antidepressant use and risk of adverse outcomes in older people: Population-based cohort study.
        BMJ. 2011; 343: d4551