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CNS Drugs

, Volume 33, Issue 1, pp 17–29 | Cite as

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

  • Rita KhouryEmail author
  • George T. Grossberg
Review Article
  • 85 Downloads

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.

Notes

Compliance with Ethical Standards

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.

References

  1. 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.Google Scholar
  2. 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.Google Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.CrossRefGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefGoogle Scholar
  13. 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.CrossRefGoogle Scholar
  14. 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.CrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.CrossRefGoogle Scholar
  17. 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.CrossRefGoogle Scholar
  18. 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.CrossRefGoogle Scholar
  19. 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.CrossRefGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefGoogle Scholar
  25. 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.CrossRefGoogle Scholar
  26. 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.CrossRefGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 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.CrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.CrossRefGoogle Scholar
  35. 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.CrossRefGoogle Scholar
  36. 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.CrossRefGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.CrossRefGoogle Scholar
  39. 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.CrossRefGoogle Scholar
  40. 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.CrossRefGoogle Scholar
  41. 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.CrossRefGoogle Scholar
  42. 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.CrossRefGoogle Scholar
  43. 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.Google Scholar
  44. 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.CrossRefGoogle Scholar
  45. 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.CrossRefGoogle Scholar
  46. 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.CrossRefGoogle Scholar
  47. 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.CrossRefGoogle Scholar
  48. 48.
    Patten SB. Confounding by severity and indication in observational studies of antidepressant effectiveness. Can J Clin Pharmacol. 2008;15(2):e367–71.Google Scholar
  49. 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.CrossRefGoogle Scholar
  50. 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.CrossRefGoogle Scholar
  51. 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.CrossRefGoogle Scholar
  52. 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.CrossRefGoogle Scholar
  53. 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.CrossRefGoogle Scholar
  54. 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.CrossRefGoogle Scholar
  55. 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.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Division of Geriatric PsychiatrySt. Louis University School of MedicineSt. LouisUSA

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