Skip to main content
SpringerLink
Log in

Impact of Antidepressant Use on the Trajectory of Alzheimer’s Disease: Evidence, Mechanisms, and Therapeutic Implications

  • Review Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

The relationship between antidepressants and Alzheimer’s disease (AD) is very complex, and the literature is mixed regarding the effect of these medications on the trajectory of the disease. This paper reviews findings from relevant clinical studies that have assessed the impact of antidepressants on AD onset and disease progression. To date, these medications seem to attenuate the risk of developing the disease without affecting the rate of progression. However, most evidence stems from observational studies that are subject to methodological bias. Serotonergic antidepressants are thought to affect AD pathophysiology by reducing β-amyloid (Aβ) plaque formation and promoting hippocampal neurogenesis. However, the mechanisms underlying their effect need to be examined further, especially in humans. Moreover, more robust clinical studies in terms of design (randomized controlled trials) and longer duration of follow-up are needed. Variables, including depression timeline/onset and its clinical course, apolipoprotein E4 (APOE4) genotype status, sex, dose/duration of antidepressant treatment, and AD biomarkers need to be incorporated in future trials to better elucidate the effect of antidepressants on AD risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Prince M, Comas-Herrera A, Knapp M, Guerchet M, Karagiannidou M. World Alzheimer Report 2016: improving healthcare for people living with dementia coverage, quality and costs now and in the future; 2016. Accessed 1 July 2018.

  2. Zissimopoulos J, Crimmins E, St. Clair P. The value of delaying Alzheimer’s disease onset. Forum Health Econ Policy. 2014;18(1):25–39. https://doi.org/10.1515/fhep-2014-0013.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, et al. Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimer’s Dementia. 2016;12(3):292–323. https://doi.org/10.1016/j.jalz.2016.02.002.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimer’s Dementia. 2018;14(4):535–62. https://doi.org/10.1016/j.jalz.2018.02.018.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673–734. https://doi.org/10.1016/S0140-6736(17)31363-6.

    Article  PubMed  Google Scholar 

  6. Steenland K, Karnes C, Seals R, Carnevale C, Hermida A, Levey A. Late-life depression as a risk factor for mild cognitive impairment or Alzheimer’s disease in 30 US Alzheimer’s disease centers. J Alzheimer’s Dis. 2012;31(2):265–75. https://doi.org/10.3233/jad-2012-111922.

    Article  CAS  Google Scholar 

  7. Ismail Z, Elbayoumi H, Fischer CE, et al. Prevalence of depression in patients with mild cognitive impairment: a systematic review and meta-analysis. JAMA Psychiatry. 2017;74(1):58–67. https://doi.org/10.1001/jamapsychiatry.2016.3162.

    Article  PubMed  Google Scholar 

  8. Chi S, Wang C, Jiang T, Zhu XC, Yu JT, Tan L. The prevalence of depression in Alzheimer’s disease: a systematic review and meta-analysis. Curr Alzheimer Res. 2015;12(2):189–98.

    Article  CAS  PubMed  Google Scholar 

  9. Brommelhoff JA, Gatz M, Johansson B, McArdle JJ, Fratiglioni L, Pedersen NL. Depression as a risk factor or prodomal feature for dementia? Findings in a population-based sample of Swedish twins. Psychol Aging. 2009;24(2):373–84. https://doi.org/10.1037/a0015713.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Li G, Wang LY, Shofer JB, et al. Temporal relationship between depression and dementia: findings from a large community-based 15-year follow-up study. Arch Gen Psychiatry. 2011;68(9):970–7. https://doi.org/10.1001/archgenpsychiatry.2011.86.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ismail Z, Gatchel J, Bateman DR, Barcelos-Ferreira R, Chantillon M, Jaeger J, et al. Affective and emotional dysregulation as pre-dementia risk markers: exploring the mild behavioral impairment symptoms of depression, anxiety, irritability, and euphoria. Int Psychogeriatr. 2018;30(2):185–96. https://doi.org/10.1017/s1041610217001880.

    Article  PubMed  Google Scholar 

  12. Mirza SS, Wolters FJ, Swanson SA, Koudstaal PJ, Hofman A, Tiemeier H, et al. 10-year trajectories of depressive symptoms and risk of dementia: a population-based study. Lancet Psychiatry. 2016;3(7):628–35. https://doi.org/10.1016/S2215-0366(16)00097-3.

    Article  PubMed  Google Scholar 

  13. Caraci F, Copani A, Nicoletti F, Drago F. Depression and Alzheimer’s disease: neurobiological links and common pharmacological targets. Eur J Pharmacol. 2010;626(1):64–71. https://doi.org/10.1016/j.ejphar.2009.10.022.

    Article  CAS  PubMed  Google Scholar 

  14. Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, et al. Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans. Proc Natl Acad Sci USA. 2011;108(36):14968–73.

    Article  PubMed  Google Scholar 

  15. Sheline YI, West T, Yarasheski K, Swarm R, Jasielec MS, Fisher JR, et al. An antidepressant decreases CSF Abeta production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014;6(236):236re4. https://doi.org/10.1126/scitranslmed.3008169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20(24):9104–10.

    Article  CAS  PubMed  Google Scholar 

  17. Moraros J, Nwankwo C, Patten SB, Mousseau DD. The association of antidepressant drug usage with cognitive impairment or dementia, including Alzheimer disease: a systematic review and meta-analysis. Depress Anxiety. 2017;34(3):217–26. https://doi.org/10.1002/da.22584.

    Article  PubMed  Google Scholar 

  18. Then CK, Chi NF, Chung KH, Kuo L, Liu KH, Hu CJ, et al. Risk analysis of use of different classes of antidepressants on subsequent dementia: a nationwide cohort study in Taiwan. PLoS One. 2017;12(4):e0175187. https://doi.org/10.1371/journal.pone.0175187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Csukly G, Sirály E, Fodor Z, Horváth A, Salacz P, Hidasi Z, et al. The differentiation of amnestic type MCI from the non-amnestic types by structural MRI. Front Aging Neurosci. 2016;8:52. https://doi.org/10.3389/fnagi.2016.00052.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia—meta-analysis of 41 robust inception cohort studies. Acta Psychiatr Scand. 2009;119(4):252–65. https://doi.org/10.1111/j.1600-0447.2008.01326.x.

    Article  CAS  PubMed  Google Scholar 

  21. Tifratene K, Robert P, Metelkina A, Pradier C, Dartigues JF. Progression of mild cognitive impairment to dementia due to AD in clinical settings. Neurology. 2015;85(4):331–8. https://doi.org/10.1212/wnl.0000000000001788.

    Article  PubMed  Google Scholar 

  22. Tsiouris JA, Patti PJ, Flory MJ. Effects of antidepressants on longevity and dementia onset among adults with Down syndrome: a retrospective study. J Clin Psychiatry. 2014;75(7):731–7. https://doi.org/10.4088/JCP.13m08562.

    Article  PubMed  Google Scholar 

  23. Wiseman FK, Al-Janabi T, Hardy J, Karmiloff-Smith A, Nizetic D, Tybulewicz VL, et al. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci. 2015;16(9):564–74. https://doi.org/10.1038/nrn3983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bartels C, Wagner M, Wolfsgruber S, Ehrenreich H, Schneider A. Impact of SSRI therapy on risk of conversion from mild cognitive impairment to Alzheimer’s dementia in individuals with previous depression. Am J Psychiatry. 2018;175(3):232–41. https://doi.org/10.1176/appi.ajp.2017.17040404.

    Article  PubMed  Google Scholar 

  25. Burke SL, Maramaldi P, Cadet T, Kukull W. Decreasing hazards of Alzheimer’s disease with the use of antidepressants: mitigating the risk of depression and apolipoprotein E. Int J Geriatr Psychiatry. 2018;33(1):200–11. https://doi.org/10.1002/gps.4709.

    Article  PubMed  Google Scholar 

  26. Kessing LV, Søndergård L, Forman JL, Andersen PK. Antidepressants and dementia. J Affect Disord. 2009;117(1):24–9. https://doi.org/10.1016/j.jad.2008.11.020.

    Article  CAS  PubMed  Google Scholar 

  27. Caballero J, Hitchcock M, Beversdorf D, Scharre D, Nahata M. Long-term effects of antidepressants on cognition in patients with Alzheimer’s disease. J Clin Pharm Ther. 2006;31(6):593–8.

    Article  CAS  PubMed  Google Scholar 

  28. Dutcher SK, Rattinger GB, Langenberg P, Chhabra PT, Liu X, Rosenberg PB, et al. Effect of medications on physical function and cognition in nursing home residents with dementia. J Am Geriatr Soc. 2014;62(6):1046–55. https://doi.org/10.1111/jgs.12838.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mossello E, Boncinelli M, Caleri V, Cavallini MC, Palermo E, Di Bari M, et al. Is antidepressant treatment associated with reduced cognitive decline in Alzheimer’s disease? Dementia Geriatr Cogn Disord. 2008;25(4):372–9. https://doi.org/10.1159/000121334.

    Article  CAS  Google Scholar 

  30. Rozzini L, Chilovi BV, Conti M, Bertoletti E, Zanetti M, Trabucchi M, et al. Efficacy of SSRIs on cognition of Alzheimer’s disease patients treated with cholinesterase inhibitors. Int Psychogeriatr. 2010;22(1):114–9. https://doi.org/10.1017/s1041610209990184.

    Article  PubMed  Google Scholar 

  31. Rosenberg PB, Mielke MM, Han D, Leoutsakos JS, Lyketsos CG, Rabins PV, et al. The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer’s disease. Int J Geriatr Psychiatry. 2012;27(12):1248–57.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Reifler BV, Teri L, Raskind M, Veith R, Barnes R, White E, et al. Double-blind trial of imipramine in Alzheimer’s disease patients with and without depression. Am J Psychiatry. 1989;146(1):45–9. https://doi.org/10.1176/ajp.146.1.45.

    Article  CAS  PubMed  Google Scholar 

  33. Choe YM, Kim KW, Jhoo JH, Ryu SH, Seo EH, Sohn BK, et al. Multicenter, randomized, placebo-controlled, double-blind clinical trial of escitalopram on the progression-delaying effects in Alzheimer’s disease. Int J Geriatr Psychiatry. 2016;31(7):731–9. https://doi.org/10.1002/gps.4384.

    Article  PubMed  Google Scholar 

  34. Finkel SI, Mintzer JE, Dysken M, Krishnan KR, Burt T, McRae T. A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer’s disease in outpatients treated with donepezil. Int J Geriatr Psychiatry. 2004;19(1):9–18. https://doi.org/10.1002/gps.998.

    Article  PubMed  Google Scholar 

  35. Mowla A, Mosavinasab M, Haghshenas H, Borhani Haghighi A. Does serotonin augmentation have any effect on cognition and activities of daily living in Alzheimer’s dementia? A double-blind, placebo-controlled clinical trial. J Clin Psychopharmacol. 2007;27(5):484–7. https://doi.org/10.1097/jcp.0b013e31814b98c1.

    Article  CAS  PubMed  Google Scholar 

  36. Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682–91. https://doi.org/10.1001/jama.2014.93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Petracca GM, Chemerinski E, Starkstein SE. A double-blind, placebo-controlled study of fluoxetine in depressed patients with Alzheimer’s disease. Int Psychogeriatr. 2001;13(2):233–40.

    Article  CAS  PubMed  Google Scholar 

  38. Lyketsos CG, DelCampo L, Steinberg M, Miles Q, Steele CD, Munro C, 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(7):737–46. https://doi.org/10.1001/archpsyc.60.7.737.

    Article  CAS  PubMed  Google Scholar 

  39. Munro CA, Brandt J, Sheppard J-ME, Steele CD, Samus QM, Steinberg M, et al. Cognitive response to pharmacological treatment for depression in alzheimer disease: secondary outcomes from the Depression in Alzheimer’s Disease Study (DIADS). Am J Geriatr Psychiatry. 2004;12(5):491–8. https://doi.org/10.1097/00019442-200409000-00007.

    Article  PubMed  Google Scholar 

  40. Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, et al. Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry. 2002;10(2):125–8. https://doi.org/10.1097/00019442-200203000-00003.

    Article  PubMed  Google Scholar 

  41. Munro CA, Longmire CF, Drye LT, Martin BK, Frangakis CE, Meinert CL, et al. Cognitive outcomes after sertaline treatment in patients with depression of Alzheimer disease. Am J Geriatr Psychiatry. 2012;20(12):1036–44. https://doi.org/10.1097/JGP.0b013e31826ce4c5.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Banerjee S, Hellier J, Dewey M, Romeo R, Ballard C, Baldwin R, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet (London, England). 2011;378(9789):403–11. https://doi.org/10.1016/s0140-6736(11)60830-1.

    Article  CAS  Google Scholar 

  43. Mokhber N, Abdollahian E, Soltanifar A, Samadi R, Saghebi A, Haghighi MB, et al. Comparison of sertraline, venlafaxine and desipramine effects on depression, cognition and the daily living activities in Alzheimer patients. Pharmacopsychiatry. 2014;47(4–5):131–40. https://doi.org/10.1055/s-0034-1377041.

    Article  CAS  PubMed  Google Scholar 

  44. Cherbuin N, Reglade-Meslin C, Kumar R, Jacomb P, Easteal S, Christensen H, et al. Risk factors of transition from normal cognition to mild cognitive disorder: the PATH through Life Study. Dementia Geriatr Cogn Disord. 2009;28(1):47–55. https://doi.org/10.1159/000229025.

    Article  Google Scholar 

  45. Goveas JS, Hogan PE, Kotchen JM, Smoller JW, Denburg NL, Manson JE, et al. Depressive symptoms, antidepressant use, and future cognitive health in postmenopausal women: the Women’s Health Initiative Memory Study. Int Psychogeriatr. 2012;24(8):1252–64.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Sachdev PS, Lipnicki DM, Crawford J, Reppermund S, Kochan NA, Trollor JN, et al. Risk profiles of subtypes of mild cognitive impairment: the Sydney memory and ageing study. J Am Geriatr Soc. 2012;60(1):24–33. https://doi.org/10.1111/j.1532-5415.2011.03774.x.

    Article  PubMed  Google Scholar 

  47. Angst J, Gamma A, Gerber-Werder R, Zarate CA Jr, Manji HK. Does long-term medication with lithium, clozapine or antidepressants prevent or attenuate dementia in bipolar and depressed patients? Int J Psychiatry Clin Pract. 2007;11(1):2–8. https://doi.org/10.1080/13651500600810133.

    Article  CAS  PubMed  Google Scholar 

  48. Patten SB. Confounding by severity and indication in observational studies of antidepressant effectiveness. Can J Clin Pharmacol. 2008;15(2):e367–71.

    PubMed  Google Scholar 

  49. Salas M, Hofman A, Stricker BH. Confounding by indication: an example of variation in the use of epidemiologic terminology. Am J Epidemiol. 1999;149(11):981–3.

    Article  CAS  PubMed  Google Scholar 

  50. Mowla A, Mosavinasab M, Pani A. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double-blind, placebo-controlled, clinical trial. J Clin Psychopharmacol. 2007;27(1):67–70. https://doi.org/10.1097/JCP.0b013e31802e0002.

    Article  CAS  PubMed  Google Scholar 

  51. Ismail Z, Agüera-Ortiz L, Brodaty H, Cieslak A, Cummings J, Fischer CE, et al. The Mild Behavioral Impairment Checklist (MBI-C): a rating scale for neuropsychiatric symptoms in pre-dementia populations. J Alzheimer’s Dis. 2017;56(3):929–38. https://doi.org/10.3233/JAD-160979.

    Article  Google Scholar 

  52. Fisher JR, Wallace CE, Tripoli DL, Sheline YI, Cirrito JR. Redundant G(s)-coupled serotonin receptors regulate amyloid-β metabolism in vivo. Mol Neurodegener. 2016;11:45. https://doi.org/10.1186/s13024-016-0112-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sanchez C, Asin KE, Artigas F. Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther. 2015;145:43–57. https://doi.org/10.1016/j.pharmthera.2014.07.001.

    Article  CAS  PubMed  Google Scholar 

  54. Quinn R. Comparing rat’s to human’s age: how old is my rat in people years? Nutrition (Burbank, Los Angeles County, Calif). 2005;21(6):775–7. https://doi.org/10.1016/j.nut.2005.04.002.

    Article  Google Scholar 

  55. Li YS, Meyer JS, Thornby J. Longitudinal follow-up of depressive symptoms among normal versus cognitively impaired elderly. Int J Geriatr Psychiatry. 2001;16(7):718–27.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Geriatric Psychiatry, St. Louis University School of Medicine, 1438 S Grand Blvd, St. Louis, MO, 63104, USA

    Rita Khoury & George T. Grossberg

Authors
  1. Rita Khoury
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George T. Grossberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rita Khoury.

Ethics declarations

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

RK has no conflicts of interest. GTG is a consultant for Acadia, Alkahest, Allergan, Avanir, Axovant, BioXcel, GE, Genentech, Lundbeck, Novartis, Otsuka, Roche, and Takeda; has received research support from Janssen, Roche, and the National Institutes of Health (NIH); and has served on a speaker’s bureau for Acadia and on safety monitoring committees for EryDel, Merck, and Newron.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khoury, R., Grossberg, G.T. Impact of Antidepressant Use on the Trajectory of Alzheimer’s Disease: Evidence, Mechanisms, and Therapeutic Implications. CNS Drugs 33, 17–29 (2019). https://doi.org/10.1007/s40263-018-0590-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-018-0590-9

Search

Navigation