CoChat
Sign Up
Cited by 12Dementia and Cognitive Impairment ResearchPharmaceutical Practices and Patient OutcomesAlzheimer's disease research and treatments

The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.

Association between CNS-active drugs and risk of Alzheimer’s and age-related neurodegenerative diseases

Open access
Cortes-Flores, Helena, Torrandell-Haro, Georgina, Brinton, Roberta Diaz·2024·Frontiers in Psychiatry
DOI 10.3389/fpsyt.2024.1358568PMC PMC10937406
Open this paper in CoChat — free accountOpen PDF

Abstract

Objective: As neuropsychiatric conditions can increase the risk of age-related neurodegenerative diseases (NDDs), the impact of CNS-active drugs on the risk of developing Alzheimer’s Disease (AD), non-AD dementia, Multiple Sclerosis (MS), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) was investigated. Research design and methods: A retrospective cohort analysis of a medical claims dataset over a 10 year span was conducted in patients aged 60 years or older. Participants were propensity score matched for comorbidity severity and demographic parameters. Relative risk (RR) ratios and 95% confidence intervals (CI) were determined for age-related NDDs. Cumulative hazard ratios and treatment duration were determined to assess the association between CNS-active drugs and NDDs at different ages and treatment duration intervals. Results: In 309,128 patients who met inclusion criteria, exposure to CNS-active drugs was associated with a decreased risk of AD (0.86% vs 1.73%, RR: 0.50; 95% CI: 0.47-0.53; p <.0001) and all NDDs (3.13% vs 5.76%, RR: 0.54; 95% CI: 0.53-0.56; p <.0001). Analysis of impact of drug class on risk of AD indicated that antidepressant, sedative, anticonvulsant, and stimulant medications were associated with significantly reduced risk of AD whereas atypical antipsychotics were associated with increased AD risk. The greatest risk reduction for AD and NDDs occurred in patients aged 70 years or older with a protective effect only in patients with long-term therapy (>3 years). Furthermore, responders to these therapeutics were characterized by diagnosed obesity and higher prescriptions of anti-inflammatory drugs and menopausal hormonal therapy, compared to patients with a diagnosis of AD (non-responders). Addition of a second CNS-active drug was associated with greater reduction in AD risk compared to monotherapy, with the combination of a Z-drug and an SNRI associated with greatest AD risk reduction. Conclusion: Collectively, these findings indicate that CNS-active drugs were associated with reduced risk of developing AD and other age-related NDDs. The exception was atypical antipsychotics, which increased risk. Potential use of combination therapy with atypical antipsychotics could mitigate the risk conferred by these drugs. Evidence from these analyses advance precision prevention strategies to reduce the risk of age-related NDDs in persons with neuropsychiatric disorders.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3389/fpsyt.2024.1358568

Cites

11 of 11 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 96

  1. Poletti, 2013, Behavioral and psychological symptoms of dementia: factor analysis and relationship with cognitive impairment, Eur Neurol, 69, 76, 10.1159/000341956 · DOI
  2. Van Der Mussele, 2014, Depression in mild cognitive impairment is associated with progression to Alzheimer's disease: a longitudinal study, J Alzheimers Dis, 42, 10.3233/JAD-140405 · DOI
  3. Kohler, 2016, Neuropsychiatric disturbances in mild cognitive impairment (MCI): A systematic review of population-based studies, Curr Alzheimer Res, 13, 10.2174/1567205013666160502123129 · DOI
  4. Postuma, 2019, Prodromal parkinson's disease: the decade past, the decade to come, Mov Disord, 34, 10.1002/mds.27670 · DOI
  5. Dujardin, 2020, Neuropsychiatric disorders in parkinson's disease: what do we know about the role of dopaminergic and non-dopaminergic systems, Front Neurosci, 14, 10.3389/fnins.2020.00025 · DOI
  6. Makhani, 2021, The multiple sclerosis prodrome, Nat Rev Neurol, 17, 10.1038/s41582-021-00519-3 · DOI
  7. Vienažindytė, 2022, Do prodrome symptoms influence multiple sclerosis disease course and severity, Med Hypotheses, 165, 10.1016/j.mehy.2022.110888 · DOI
  8. Roos, 2016, Depression in amyotrophic lateral sclerosis, Neurology, 86, 10.1212/WNL.0000000000002671 · DOI
  9. Bauer, 2019, Inflammation in psychiatric disorders: what comes first, Ann N Y Acad Sci, 1437, 57, 10.1111/nyas.13712 · DOI · Paper page
  10. Ochneva, 2022, Protein misfolding and aggregation in the brain: common pathogenetic pathways in neurodegenerative and mental disorders, Int J Mol Sci, 23, 10.3390/ijms232214498 · DOI
  11. Irwin, 2016, Sleep disturbance, sleep duration, and inflammation: A systematic review and meta-analysis of cohort studies and experimental sleep deprivation, Biol Psychiatry, 80, 40, 10.1016/j.biopsych.2015.05.014 · DOI · Paper page
  12. Cordone, 2019, Sleep and beta-amyloid deposition in alzheimer disease: insights on mechanisms and possible innovative treatments, Front Pharmacol, 10, 10.3389/fphar.2019.00695 · DOI
  13. Hyung, 2021, Cerebral amyloid accumulation is associated with distinct structural and functional alterations in the brain of depressed elders with mild cognitive impairment, J Affect Disord, 281, 10.1016/j.jad.2020.12.049 · DOI
  14. Wang, 2022, Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression, J Neuroinflamm, 19, 132, 10.1186/s12974-022-02492-0 · DOI
  15. Boskovic, 2011, Oxidative stress in schizophrenia, Curr Neuropharmacol, 9, 10.2174/157015911795596595 · DOI
  16. Gulec, 2012, Oxidative stress in patients with primary insomnia, Prog Neuropsychopharmacol Biol Psychiatry, 37, 10.1016/j.pnpbp.2012.02.011 · DOI
  17. Guo, 2013, Oxidative stress, mitochondrial damage and neurodegenerative diseases, Neural Regener Res, 8, 10.3969/j.issn.1673-5374.2013.21.009 · DOI
  18. Kaufmann, 2019, Common brain disorders are associated with heritable patterns of apparent aging of the brain, Nat Neurosci, 22, 10.1038/s41593-019-0471-7 · DOI
  19. Vico Varela, 2019, Excitatory-inhibitory imbalance in Alzheimer's disease and therapeutic significance, Neurobiol Dis, 127, 10.1016/j.nbd.2019.04.010 · DOI
  20. Gatchel, 2017, Depressive symptoms and tau accumulation in the inferior temporal lobe and entorhinal cortex in cognitively normal older adults: A pilot study, J Alzheimers Dis, 59, 10.3233/JAD-170001 · DOI
  21. Li, 2017, Beta-amyloid deposition in patients with major depressive disorder with differing levels of treatment resistance: a pilot study, EJNMMI Res, 7, 24, 10.1186/s13550-017-0273-4 · DOI
  22. Romoli, 2021, Amyloid-beta: a potential link between epilepsy and cognitive decline, Nat Rev Neurol, 17, 10.1038/s41582-021-00505-9 · DOI
  23. Lv, 2022, Sleep deficiency promotes Alzheimer's disease development and progression, Front Neurol, 13, 10.3389/fneur.2022.1053942 · DOI
  24. Miranda, 2019, Brain-derived neurotrophic factor: A key molecule for memory in the healthy and the pathological brain, Front Cell Neurosci, 13, 10.3389/fncel.2019.00363 · DOI · Paper page
  25. Morgese, 2019, Monoaminergic system modulation in depression and alzheimer's disease: A new standpoint, Front Pharmacol, 10, 10.3389/fphar.2019.00483 · DOI
  26. Martinowich, 2008, Interaction between BDNF and serotonin: role in mood disorders, Neuropsychopharmacology, 33, 73, 10.1038/sj.npp.1301571 · DOI · Paper page
  27. Svob Strac, 2016, The serotonergic system and cognitive function, Transl Neurosci, 7, 35, 10.1515/tnsci-2016-0007 · DOI
  28. Chen, 2022, Locus coeruleus in the pathogenesis of Alzheimer's disease: A systematic review, Alzheimers Dement (N Y), 8, 10.1002/trc2.12257 · DOI
  29. Hurtado-Alvarado, 2016, Blood-brain barrier disruption induced by chronic sleep loss: low-grade inflammation may be the link, J Immunol Res, 2016, 4576012, 10.1155/2016/4576012 · DOI
  30. Sweeney, 2018, Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders, Nat Rev Neurol, 14, 10.1038/nrneurol.2017.188 · DOI · Paper page
  31. Giese, 2014, BDNF: an indicator of insomnia, Mol Psychiatry, 19, 10.1038/mp.2013.10 · DOI
  32. Barker-Haliski, 2015, Glutamatergic mechanisms associated with seizures and epilepsy, Cold Spring Harb Perspect Med, 5, a022863, 10.1101/cshperspect.a022863 · DOI
  33. Busche, 2016, Impairments of neural circuit function in Alzheimer's disease, Philos Trans R Soc Lond B Biol Sci, 371, 10.1098/rstb.2015.0429 · DOI · Paper page
  34. Cai, 2018, Schizophrenia and risk of dementia: a meta-analysis study, Neuropsychiatr Dis Treat, 14, 10.2147/NDT.S172933 · DOI
  35. Kochunov, 2021, A white matter connection of schizophrenia and alzheimer's disease, Schizophr Bull, 47, 197, 10.1093/schbul/sbaa078 · DOI
  36. Zhang, 2022, Attention-deficit/hyperactivity disorder and Alzheimer's disease and any dementia: A multi-generation cohort study in Sweden, Alzheimers Dement, 18, 10.1002/alz.12462 · DOI
  37. Leffa, 2023, Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults, Mol Psychiatry, 28, 10.1038/s41380-022-01867-2 · DOI
  38. Malberg, 2000, Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus, J Neurosci, 20, 10.1523/JNEUROSCI.20-24-09104.2000 · DOI · Paper page
  39. Minzenberg, 2004, Association of anticholinergic load with impairment of complex attention and memory in schizophrenia, Am J Psychiatry, 161, 10.1176/appi.ajp.161.1.116 · DOI
  40. Hashioka, 2009, Anti-inflammatory effects of antidepressants: possibilities for preventives against alzheimers disease, Cent Nervous System Agents Medicinal Chem, 9, 10.2174/187152409787601897 · DOI
  41. Long, 2013, Valproic acid attenuates neuronal loss in the brain of APP/PS1 double transgenic Alzheimer's disease mice model, Curr Alzheimer Res, 10, 10.2174/1567205011310030005 · DOI
  42. Yao, 2014, Valproate improves memory deficits in an Alzheimer's disease mouse model: investigation of possible mechanisms of action, Cell Mol Neurobiol, 34, 10.1007/s10571-013-0012-y · DOI
  43. Baptista, 2016, Long-term treatment with low doses of methamphetamine promotes neuronal differentiation and strengthens long-term potentiation of glutamatergic synapses onto dentate granule neurons, eNeuro, 3, 10.1523/ENEURO.0141-16.2016 · DOI
  44. Holth, 2017, Sleep in alzheimer's disease - beyond amyloid, Neurobiol Sleep Circadian Rhythms, 2, 4, 10.1016/j.nbscr.2016.08.002 · DOI
  45. Shukla, 2019, Methamphetamine regulates betaAPP processing in human neuroblastoma cells, Neurosci Lett, 701, 10.1016/j.neulet.2019.02.023 · DOI
  46. Amieva, 2008, Prodromal Alzheimer's disease: successive emergence of the clinical symptoms, Ann Neurol, 64, 10.1002/ana.21509 · DOI · Paper page
  47. 2021, Basics of Alzheimer’s Disease and Dementia
  48. 2022, Alzheimer’s disease facts and figures
  49. Budd Haeberlein, 2022, Two randomized phase 3 studies of aducanumab in early alzheimer's disease, J Prev Alzheimers Dis, 9, 197, 10.14283/jpad.2022.30 · DOI · Paper page
  50. Van Dyck, 2023, Lecanemab in early alzheimer's disease, N Engl J Med, 388, 9, 10.1056/NEJMoa2212948 · DOI · Paper page
  51. USA PearlDiver Mariner Patient Claims Database
  52. Branigan, 2020, Association between hormone-modulating breast cancer therapies and incidence of neurodegenerative outcomes for women with breast cancer, JAMA Netw Open, 3, 10.1001/jamanetworkopen.2020.1541 · DOI
  53. Torrandell-Haro, 2020, Statin therapy and risk of Alzheimer's and age-related neurodegenerative diseases, Alzheimers Dement (N Y), 6, 10.1002/trc2.12108 · DOI
  54. Kim, 2021, Association between menopausal hormone therapy and risk of neurodegenerative diseases: Implications for precision hormone therapy, Alzheimers Dement (N Y), 7, 10.1002/trc2.12174 · DOI
  55. Fan, 2017, Increased dementia risk predominantly in diabetes mellitus rather than in hypertension or hyperlipidemia: a population-based cohort study, Alzheimers Res Ther, 9, 7, 10.1186/s13195-017-0236-z · DOI
  56. Tini, 2020, Alzheimer's disease and cardiovascular disease: A particular association, Cardiol Res Pract, 2020, 2617970, 10.1155/2020/2617970 · DOI
  57. Wang, 2022, Risk of dementia or cognitive impairment in COPD patients: A meta-analysis of cohort studies, Front Aging Neurosci, 14, 10.3389/fnagi.2022.962562 · DOI
  58. Stocker, 2023, Association of kidney function with development of alzheimer disease and other dementias and dementia-related blood biomarkers, JAMA Netw Open, 6, 10.1001/jamanetworkopen.2022.52387 · DOI
  59. Broe, 2000, Anti-inflammatory drugs protect against Alzheimer disease at low doses, Arch Neurol, 57, 10.1001/archneur.57.11.1586 · DOI
  60. Yasar, 2013, Antihypertensive drugs decrease risk of Alzheimer disease: Ginkgo Evaluation of Memory Study, Neurology, 81, 896, 10.1212/WNL.0b013e3182a35228 · DOI
  61. Jayadevappa, 2019, Association between androgen deprivation therapy use and diagnosis of dementia in men with prostate cancer, JAMA Netw Open, 2, 10.1001/jamanetworkopen.2019.6562 · DOI
  62. Torrandell-Haro, 2022, Association between specific type 2 diabetes therapies and risk of alzheimer's disease and related dementias in propensity-score matched type 2 diabetic patients, Front Aging Neurosci, 14, 10.3389/fnagi.2022.878304 · DOI
  63. Li, 2014, Behavioral and psychological symptoms in Alzheimer's disease, BioMed Res Int, 2014, 927804, 10.1155/2014/927804 · DOI
  64. Bartels, 2020, To be continued? Long-term treatment effects of antidepressant drug classes and individual antidepressants on the risk of developing dementia: A german case-control study, J Clin Psychiatry, 81, 19, 10.4088/JCP.19m13205 · DOI
  65. Bietry, 2017, Benzodiazepine use and risk of developing alzheimer's disease: A case-control study based on swiss claims data, CNS Drugs, 31, 10.1007/s40263-016-0404-x · DOI
  66. Guo, 2021, Association between Z drugs use and risk of cognitive impairment in middle-aged and older patients with chronic insomnia, Front Hum Neurosci, 15, 10.3389/fnhum.2021.775144 · DOI
  67. Goveas, 2012, Depressive symptoms, antidepressant use, and future cognitive health in postmenopausal women: the Women's Health Initiative Memory Study, Int Psychogeriatr, 24, 10.1017/S1041610211002778 · DOI · Paper page
  68. Tapiainen, 2018, The risk of Alzheimer's disease associated with benzodiazepines and related drugs: a nested case-control study, Acta Psychiatr Scand, 138, 91, 10.1111/acps.12909 · DOI
  69. Lee, 2018, Use of sedative-hypnotics and the risk of Alzheimer's dementia: A retrospective cohort study, PloS One, 13, 10.1371/journal.pone.0204413 · DOI
  70. Cheng, 2017, The association between the use of zolpidem and the risk of alzheimer's disease among older people, J Am Geriatr Soc, 65, 10.1111/jgs.15018 · DOI
  71. Vollmar, 2008, Venlafaxine exhibits an anti-inflammatory effect in an inflammatory co-culture model, Int J Neuropsychopharmacol, 11, 10.1017/S1461145707007729 · DOI
  72. Lee, 2010, The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment, Psychiatry Investig, 7, 10.4306/pi.2010.7.4.231 · DOI
  73. Quesseveur, 2013, BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities, Transl Psychiatry, 3, 10.1038/tp.2013.30 · DOI · Paper page
  74. Walker, 2013, A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression, Neuropharmacology, 67, 10.1016/j.neuropharm.2012.10.002 · DOI · Paper page
  75. Patricio, 2015, Differential and converging molecular mechanisms of antidepressants' action in the hippocampal dentate gyrus, Neuropsychopharmacology, 40, 10.1038/npp.2014.176 · DOI · Paper page
  76. Kim, 2013, Antidepressants for neuro-regeneration: from depression to Alzheimer's disease, Arch Pharm Res, 36, 10.1007/s12272-013-0238-8 · DOI
  77. Wu, 2016, Neuronal activity enhances tau propagation and tau pathology in vivo, Nat Neurosci, 19, 10.1038/nn.4328 · DOI · Paper page
  78. Roehrs, 2010, Drug-related sleep stage changes: functional significance and clinical relevance, Sleep Med Clin, 5, 10.1016/j.jsmc.2010.08.002 · DOI
  79. Ciccone, 1999, Drugs and sex differences: a review of drugs relating to anaesthesia, Br J Anaesth, 82, 10.1093/bja/82.2.255 · DOI
  80. Meador, 2002, Cognitive outcomes and predictive factors in epilepsy, Neurology, 58, 10.1212/WNL.58.8_suppl_5.S21 · DOI
  81. Beghi, 2020, Epilepsy, antiepileptic drugs and dementia, Curr Opin Neurol, 33, 10.1097/WCO.0000000000000802 · DOI
  82. Vossel, 2021, Effect of levetiracetam on cognition in patients with alzheimer disease with and without epileptiform activity: A randomized clinical trial, JAMA Neurol, 78, 10.1001/jamaneurol.2021.3310 · DOI
  83. Huang, 2023, The association between Gabapentin or Pregabalin use and the risk of dementia: an analysis of the National Health Insurance Research Database in Taiwan, Front Pharmacol, 14, 10.3389/fphar.2023.1128601 · DOI
  84. Targa Dias Anastacio, 2022, Neuronal hyperexcitability in Alzheimer's disease: what are the drivers behind this aberrant phenotype, Transl Psychiatry, 12, 257, 10.1038/s41398-022-02024-7 · DOI · Paper page
  85. Hill, 2010, Effect of second-generation antipsychotics on cognition: current issues and future challenges, Expert Rev Neurother, 10, 43, 10.1586/ern.09.143 · DOI
  86. Dong, 2020, Differential effects of different antipsychotic drugs on cognitive function in patients with chronic schizophrenia, Hum Psychopharmacol, 35, 1, 10.1002/hup.2754 · DOI
  87. Albert, 2019, Cognitive functioning following discontinuation of antipsychotic medication. A naturalistic sub-group analysis from the OPUS II trial, Psychol Med, 49, 10.1017/S0033291718001836 · DOI
  88. Clissold, 2019, Comparing the effect of the subcategories of atypical antipsychotic medications on cognition in schizophrenia using a meta-analytic approach, J Clin Exp Neuropsychol, 41, 26, 10.1080/13803395.2018.1488952 · DOI
  89. Meneses, 2012, Serotonin and emotion, learning and memory, Rev Neurosci, 23, 10.1515/revneuro-2012-0060 · DOI
  90. Hoekstra, 2021, Sex differences in antipsychotic efficacy and side effects in schizophrenia spectrum disorder: results from the BeSt InTro study, NPJ Schizophr, 7, 39, 10.1038/s41537-021-00170-3 · DOI
  91. Seeman, 2021, The pharmacodynamics of antipsychotic drugs in women and men, Front Psychiatry, 12, 10.3389/fpsyt.2021.650904 · DOI
  92. Qizilbash, 2015, BMI and risk of dementia in two million people over two decades: a retrospective cohort study, Lancet Diabetes Endocrinol, 3, 10.1016/S2213-8587(15)00033-9 · DOI
  93. Sun, 2020, Late-life obesity is a protective factor for prodromal Alzheimer's disease: a longitudinal study, Aging (Albany NY), 12, 10.18632/aging.102738 · DOI
  94. Kang, 2021, Body mass index trajectories and the risk for Alzheimer's disease among older adults, Sci Rep, 11, 3087, 10.1038/s41598-021-82593-7 · DOI
  95. Zandi, 2002, Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study, JAMA, 288, 10.1001/jama.288.17.2123 · DOI
  96. Kim, 2018, Medication adherence: the elephant in the room, US Pharm, 43

Cited by

Sorted by citations

Metadata

Authors
Cortes-Flores, H., Torrandell-Haro, G., & Brinton, R. D.
Venue
Frontiers in Psychiatry
Publisher
Frontiers Media SA
Published
2024-02-29
Volume
15
Pages
1358568-1358568
ISSN
1664-0640 (ISSN-L)
DOI
10.3389/fpsyt.2024.1358568
PMC
PMC10937406
OpenAlex
W4392292474
Cited by
12
References
11
Citations by year
2026: 3 · 2025: 7 · 2024: 2
FWCI
2.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Institute on Aging (P01-AG026572)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, age-related neurodegenerative diseases, CNS-active drugs, antidepressants, sedatives, antiepileptic drugs, stimulants, atypical antipsychotics, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, dementia, drug repurposing, combination therapy, obesity, anti-inflammatory agents, older adults, treatment duration

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review