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Cited by 35Dementia and Cognitive Impairment ResearchTreatment of Major DepressionPharmaceutical Practices and Patient Outcomes

The DOI matches its Crossref record; 56 of the 57 references it cites were found in a registry or an index, and 1 are not checked yet; 18 of the 45 sources its claims cite were checked for support.

Risk analysis of use of different classes of antidepressants on subsequent dementia: A nationwide cohort study in Taiwan

Open access
Then, Chee-Kin, Chi, Nai-Fang, Chung, Kuo-Hsuan, Kuo, Lynn, Liu, Kao-Hui, Hu, Chaur-Jong, Shen, Shing-Chuan, Lin, Yen-Kuang·2017·PLOS ONE
DOI 10.1371/journal.pone.0175187PMC PMC5383251
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Abstract

Depression and dementia are common mental health problems and are associated in several ways. Early-life depression is associated with increased risk of later life dementia, and depression can present as a preclinical symptom or consequence of dementia. Despite the plausible relationship between these two clinical entities, the potential association between antidepressant medication and dementia has rarely been investigated. We conducted a 9-year retrospective analysis of Taiwan's National Health Insurance Research Database (NHIRD), enrolling 5819 cases who had received prescriptions of antidepressants between 2003 and 2006, and 23,276 (with ratio of 1:4) age, sex, and index date-matched controls. The hazard ratio (HR) of dementia among antidepressant users with depression was 2.42 (95% confidence interval (CI): 1.15-5.10), for those without depression was 4.05 (95% CI: 3.19-5.15), compared to antidepressant non-users respectively. Among the 6 classes of common antidepressants used in Taiwan, the adjusted HRs were 3.66 (95% CI: 2.62-5.09) for SSRIs, 4.73 (95% CI: 2.54-8.80) for SNRI, 3.26 (95% CI: 2.30-4.63) for TCAs, 6.62 (95% CI: 3.34-13.13) for TeCA, 4.94 (95% CI: 2.17-11.24) for MAOI, and 4.48 (95% CI: 3.13-6.40) for SARI. Furthermore, the multivariate analysis result showed that the adjusted HRs of cumulative defined daily doses (cDDDs) were 3.74 (95% CI: 2.91-4.82), 3.73 (95% CI: 2.39-5.80) and 5.22 (95% CI: 3.35-8.14) for those who had cDDDs of <90, 90-180 and >180 compared to those who had taken no antidepressant medication. This is a retrospective study based on secondary data, hence, we could not claim causality between antidepressant medication and dementia. However, a potential association between antidepressant and occurrence of dementia after controlling for the status of depression was observed. Lack of patients' data about smoking status and body mass index in NHIRD, which are considered related to dementia, was also a limitation in this study. In this study, we concluded that antidepressant medication is a potential risk factor for dementia, independent from any effect of depression itself.

Verified 2026-11-07 · 1 reference not checked yet

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a 9-year retrospective nationwide cohort in Taiwan, antidepressant users had a higher incidence of subsequent dementia than matched non-users, with an adjusted hazard ratio of 3.89 (95% CI 3.08–4.92). The association varied by antidepressant class and cumulative dose, but the authors state causality cannot be claimed from these secondary data.

Key findings

  • Dementia incidence was 2.68 per 100 persons among antidepressant users versus 0.86 per 100 persons among non-users; the adjusted HR for antidepressant use was 3.89 (95% CI 3.08–4.92).
  • Adjusted HRs by class were 6.62 (95% CI 3.34–13.13) for TeCA, 4.94 (95% CI 2.17–11.24) for MAOI, 4.73 (95% CI 2.54–8.80) for SNRI, 4.48 (95% CI 3.13–6.40) for SARI, 3.66 (95% CI 2.62–5.09) for SSRIs, and 3.26 (95% CI 2.30–4.63) for TCAs.
  • Higher cumulative antidepressant exposure was associated with higher dementia risk: adjusted HRs were 3.74 (95% CI 2.91–4.82) for cDDD <90, 3.73 (95% CI 2.39–5.80) for 90–180, and 5.22 (95% CI 3.35–8.14) for >180, with a significant upward trend (p < .001).
  • Antidepressant effects were observed in both depression and non-depression groups: adjusted HR 2.42 (95% CI 1.15–5.10) with depression and 4.05 (95% CI 3.19–5.15) without depression; the interaction was not significant (p = 0.193).

Methods

  • Retrospective population-based cohort using Taiwan’s National Health Insurance Research Database (NHIRD), a 1-million-beneficiary subset; 5,819 antidepressant users from 2003–2006 and 23,276 controls matched 1:4 by age, sex, and index date.
  • Cases had ambulatory antidepressant prescriptions with continuous visits <30 days apart, first-to-last prescription >30 days apart, and only one antidepressant type; exclusions were age >80 in 2015, prior dementia, and undetermined sex.
  • Outcomes were dementia diagnoses (ICD-9-CM 290, 294.1, 331.0) confirmed by two repeated diagnoses; analyses used Kaplan-Meier/log-rank tests and Cox proportional hazards models adjusted for stroke, diabetes, hypertension, hyperlipidemia, depression, insomnia, anxiety, and Charlson comorbidity index, plus cDDD and subgroup/sensitivity analyses.

Limitations

  • The paper states it is retrospective and based on secondary data, so causality between antidepressant medication and dementia cannot be claimed; NHIRD also lacks smoking status and body mass index.
  • The paper notes potential inaccuracies in clinical diagnosis and ICD-9 coding during 2001–2011, and that patients over 80 were excluded due to confounding and limited follow-up.
  • Evident from the design: observational cohort findings may be affected by residual confounding and detection bias, and restricting cases to one antidepressant type limits generalizability to patients using multiple antidepressants.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0175187

Cites

56 of 57 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

18 of 45 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation
    § Introduction · p. 2

    Early-life depression is a risk factor for later-life dementia.

    “Overall, there is accumulating evidence indicating two consensuses that early-life depression is a risk factor for later life dementia, and depression can be a symptom or consequence of dementia [5-8].”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [5] J da Silva, 2013, Affective disorders and risk of developing dementia: systematic review, The British journal of psychiatry: the journal of mental science source

      The section on depression characteristics reports studies finding increased dementia risk after early-onset depression, including onset 25 years before dementia. But it also says findings are contradictory, and the Sources discussion explicitly says the review does not completely support the view that early-life depression is a consistent risk factor. The unqualified claim overstates the review's conclusion. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [6] AL Byers, 2011, Depression and risk of developing dementia, Nature reviews Neurology source
    • cites [7] KP Muliyala, 2010, The complex relationship between depression and dementia, Ann Indian Acad Neur source

      The “Mechanisms Underlying the Relationship” section reports that a past history of depression is associated with increased dementia risk, even when depression occurred more than 10 years before dementia onset. It does not specifically establish early-life depression as a risk factor, and it describes the risk-factor explanation as a possibility. The Abstract says the relationship remains far from conclusive, rather than a consensus. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [8] S Bennett, 2014, Depression and dementia: cause, consequence or coincidence?, Maturitas source
  • Premisecitation
    § Discussion · p. 12

    Antidepressants damage normal cells, including osteoblasts, osteoclasts, hepatocytes, etc.

    “(c) antidepressants damage normal cells, including osteoblasts, osteoclasts, hepatocytes, etc [25, 28].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [25] JM Hodge, 2013, Selective serotonin reuptake inhibitors inhibit human osteoclast and osteoblast formation and function, Biological psychiatry source
    • cites [28] S Chen, 2014, Sertraline, an antidepressant, induces apoptosis in hepatic cells through the mitogen-activated protein kinase pathway, Toxicological sciences: an official journal of the Society of Toxicology source

      The Abstract reports that sertraline caused cytotoxicity in rat primary hepatocytes, and the Results show cell damage in human HepG2 liver cells. This supports the hepatocyte example, but the paper does not establish damage to normal osteoblasts or osteoclasts, which are also included in the cited sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data
    § Results · p. 5

    There was no significant interaction between depression and antidepressant medication in the Cox model (p = 0.193).

    “Our results show no significant interaction was observed between these two entities (p = 0.193).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results · p. 7

    The TCAs group and SSRIs group had the lowest incidence of dementia among antidepressant classes.

    “The TeCA group had the greatest hazard ratio for dementia, while the TCAs group and SSRIs group are the two groups which had the lowest incidence of dementia (Table 3).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The ICD-9-CM codes used to identify dementia and Alzheimer's disease accurately identify these conditions.
    • Rests on an assumption: The control group is comparable to the antidepressant group except for the measured covariates; no unmeasured confounding is present.
    • Rests on an assumption: The proportional hazards assumption holds for the Cox regression models.
  • Findingown data
    § Abstract · p. 1

    Among the 6 classes of common antidepressants used in Taiwan, the adjusted hazard ratio of dementia was 4.73 (95% CI 2.54-8.80) for SNRI.

    “Among the 6 classes of common antidepressants used in Taiwan, the adjusted HRs were 3.66 (95% CI: 2.62-5.09) for SSRIs, 4.73 (95% CI: 2.54-8.80) for SNRI, 3.26 (95% CI: 2.30-4.63) for TCAs, 6.62 (95% CI: 3.34-13.13) for TeCA, 4.94 (95% CI: 2.17-11.24) for MAOI, and 4.48 (95% CI: 3.13-6.40) for SARI.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 33
  • It may state two separate claims as one. 15
  • The quote only partly states this claim. 1

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation
    § Discussion · p. 10

    Depression as a risk factor for dementia and depression as a prodromal symptom remain controversial, the causal relation between depression and dementia is difficult to clarify, and previous literature findings are inconsistent.

    “In the pathogenesis of dementia, both ideas that mention depression as a risk factor for dementia and depression as a prodromal symptom remain controversial. It is difficult to clarify the causal relation between depression and dementia, and findings in the previous literature are inconsistent on these issues [10, 38, 39].”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [10] JS Saczynski, 2010, Depressive symptoms and risk of dementia: the Framingham Heart Study, Neurology source
    • cites [38] AK Berger, 1999, The occurrence of depressive symptoms in the preclinical phase of AD: a population-based study, Neurology source
    • cites [39] PJ Chen, 1999, The temporal relationship between depressive symptoms and dementia—A community-based prospective study, Archives of general psychiatry source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation
    § Discussion · p. 10

    The finding that depression is associated with dementia is consistent with previous studies that identified depression as one of the risk factors of dementia.

    “This finding is consistent with previous studies that identified depression as one of the risk factors of dementia [9, 10].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [9] AL Byers, 2011, Depression and risk of developing dementia, Nature Reviews Neurology source

      The sections on earlier- and late-life depression report that depression is associated with an increased risk of subsequent dementia. But the late-life section says those studies cannot determine whether depression is a risk factor, an early symptom, or a consequence of dementia, so calling it an established risk factor overstates the evidence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [10] JS Saczynski, 2010, Depressive symptoms and risk of dementia: the Framingham Heart Study, Neurology source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 11

    The 30-day criterion for antidepressant users is widely accepted in other studies.

    “and this criterion is widely accepted in other studies [40-42].”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [40] CM Chung, 2016, Antidepressants in association with reducing risk of oral cancer occurrence: a nationwide population-based cohort and nested case-control studies, Oncotarget source

      In Materials and Methods > Study patients (page unavailable), the paper defines antidepressant exposure as a prescription for at least one month, supporting its use of a roughly 30-day criterion. It does not say that this criterion is widely accepted or used in other studies. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [41] BH Cheng, 2016, Effects of depression and antidepressant medications on hip fracture: A population-based cohort study in Taiwan, Medicine source

      The Drug evaluation section (page unavailable) defines antidepressant exposure using defined daily doses and includes only patients treated for more than 180 days. The Discussion (page unavailable) mentions a 1–30-day window for dopaminergic drugs in another study, but does not say that a 30-day criterion for antidepressant users is widely accepted. Searches for that criterion and its use in other studies found no supporting passage. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [42] YH Hsieh, 2015, Antidepressants and Gastric Cancer: A Nationwide Population-Based Nested Case-Control Study, PloS one source

      The Materials and Methods section (Antidepressants’ exposure; page not provided) uses a threshold of at least 28 defined daily doses, which is close to—but not the same as—a 30-day criterion. It does not say that a 30-day criterion for antidepressant users is widely accepted in other studies. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 13

    Sheline et al. proposed that Citalopram, an SSRI, decreased cerebrospinal fluid (CSF) amyloid beta protein production in a dose-dependent manner in both animal and human studies.

    “Sheline et al. proposed that Citalopram, an SSRI, decreased cerebrospinal fluid (CSF) amyloid beta protein production in a dose-dependent manner in both animal and human studies”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [56] YI Sheline, 2014, An antidepressant decreases CSF Abeta production in healthy individuals and in transgenic AD mice, Sci Transl Med source

      The Study Design and human Results report that citalopram reduced CSF Aβ production in healthy volunteers, while the Introduction and Discussion describe a dose-response effect on brain Aβ concentrations in mice. The claim extends dose dependence to the human findings, which used a single citalopram dose, and describes the mouse measurement as CSF production rather than brain interstitial-fluid Aβ concentrations. (LLM, conf=0.91)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 12

    Gray et al. revealed that the cumulative use of tricyclic antidepressants was related to a higher hazard ratio for dementia.

    “In addition, Gray et al. revealed that the cumulative use of tricyclic antidepressants, was related to a higher hazard ratio for dementia, and this finding was consistent with our results [52].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [52] SL Gray, 2015, Cumulative Use of Strong Anticholinergics and Incident Dementia A Prospective Cohort Study, Jama Intern Med source

      The Abstract Results identify tricyclic antidepressants as a common anticholinergic class and report higher dementia hazard at the highest level of cumulative anticholinergic use. The Results also find elevated risk in a sensitivity analysis of antidepressants, but do not report a hazard ratio specifically for tricyclic antidepressants. The claim is therefore more specific than the reported finding. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation
    § Discussion · p. 12

    Antidepressant medication causes severe neurological side effects, which reflect antidepressants interfering with brain function, possibly via altering neurotransmitter systems.

    “(b) antidepressant medication causes severe neurological side effects, which reflect antidepressants interfering with brain function, possibly via altering neurotransmitter systems [29-31]”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [29] S Banerjee, 2011, Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial, Lancet source
    • cites [30] PB Rosenberg, 2010, Sertraline for the treatment of depression in Alzheimer disease, The American journal of geriatric psychiatry: official journal of the American Association for Geriatric Psychiatry source

      In Results > Adverse Events (page unavailable), dizziness and tremor were more common with sertraline than placebo in patients with Alzheimer disease. But serious neurological adverse events did not differ significantly (4 versus 3), and the paper does not attribute these effects to interference with brain function or altered neurotransmitter systems. The claim overstates the severity, extends a sertraline finding to antidepressants generally, and adds an unsupported mechanism. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [31] S Madhusoodanan, 2010, Extrapyramidal symptoms associated with antidepressants—a review of the literature and an analysis of spontaneous reports, Annals of clinical psychiatry: official journal of the American Academy of Clinical Psychiatrists source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Introduction · p. 2

    Depression can be a symptom or consequence of dementia.

    “Overall, there is accumulating evidence indicating two consensuses that early-life depression is a risk factor for later life dementia, and depression can be a symptom or consequence of dementia [5-8].”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [5] J da Silva, 2013, Affective disorders and risk of developing dementia: systematic review, The British journal of psychiatry: the journal of mental science source
    • cites [6] AL Byers, 2011, Depression and risk of developing dementia, Nature reviews Neurology source
    • cites [7] KP Muliyala, 2010, The complex relationship between depression and dementia, Ann Indian Acad Neur source
    • cites [8] S Bennett, 2014, Depression and dementia: cause, consequence or coincidence?, Maturitas source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 12

    Amitriptyline, one of the tricyclic antidepressants, is the most common treatment strategy for neurologic pain and fibromyalgia in many guidelines.

    “For instance, amitriptyline, one of the tricyclic antidepressants, is the most common treatment strategy for neurologic pain and fibromyalgia in many guidelines [49, 50].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [49] RA Moore, 2012, Amitriptyline for neuropathic pain and fibromyalgia in adults, Cochrane Db Syst Rev source
    • cites [50] C Moret, 2006, Antidepressants in the treatment of fibromyalgia, Neuropsychiatric disease and treatment source

      The Abstract (page not available) describes tricyclic antidepressants, particularly amitriptyline, as among the most common treatment strategies for fibromyalgia; the Conclusion also identifies amitriptyline as the most studied TCA for that condition. Our copy does not establish that it is the single most common strategy, or that many guidelines recommend it for neurologic pain and fibromyalgia. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The authors may not put it forward as true. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Interpretationcitation
    § Discussion · p. 13

    This ability may be a potential preventive strategy for AD.

    “and this ability may be a potential preventive strategy for AD [56].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [56] YI Sheline, 2014, An antidepressant decreases CSF Abeta production in healthy individuals and in transgenic AD mice, Sci Transl Med source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingcitation
    § Discussion · p. 12

    The ratio of depression among antidepressant users in this study is slightly lower than the result presented by Chi-Shin Wu et al. in 2012.

    “which is slightly lower than result presented by Chi-Shin Wu et al. in 2012 [17].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] CS Wu, 2012, Utilization of antidepressants in Taiwan: a nationwide population-based survey from 2000 to 2009, Pharmacoepidemiology and drug safety source

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one. The quote only partly states this claim.

    Findingown data
    § Results · p. 5

    The prevalence of stroke, depression, diabetes mellitus, hypertension, hyperlipidemia, insomnia, and anxiety was significantly higher in antidepressant users than in controls.

    “The prevalence of previous medical conditions that are considered to be possible risk factors for dementia, among cases were 6.14% for stroke, 16.65% for depression, 12.39% for DM, 19.38% for hypertension, 13.32% for hyperlipidemia, 19.68% for insomnia, and 23.68% for anxiety. All of the incidences of risk factors were significantly higher in cases than controls.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data
    § Results · p. 5

    The incidence of dementia was 2.68 per 100 persons (95% CI 2.28-3.13) among antidepressant users and 0.86 per 100 persons (95% CI 0.74-0.99) among non-users.

    “The incidence of dementia for antidepressant users was 2.68 per 100 persons, and the CI was 2.28-3.13 per 100 persons, while the incidence of dementia for non-antidepressant users was 0.86 per 100 persons, and the CI was 0.74-0.99 per 100 persons.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data
    § Results · p. 5

    In the Cox model, age, insurance amount, urbanicity, Charlson comorbidity index score, depression, and antidepressant usage were significantly associated with dementia (p < .05).

    “We note that age (p &lt; .001), insurance amount (p &lt; .001), urbanicity (p = .017), CCI score (p = .033), depression (p = .011), and antidepressant usage (p &lt; .001) are significant (Table 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Findingown data
    § Discussion · p. 10

    Antidepressants with higher sedative properties and anticholinergic properties have a higher hazard ratio of dementia in this study.

    “Antidepressants with higher sedative properties (e.g., mirtazapine) and anticholinergic properties (e.g., TCAs) have a higher hazard ratio of dementia in this study.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The ICD-9-CM codes used to identify dementia and Alzheimer's disease accurately identify these conditions.
    • Rests on an assumption: The control group is comparable to the antidepressant group except for the measured covariates; no unmeasured confounding is present.
    • Rests on an assumption: The proportional hazards assumption holds for the Cox regression models.

  • It may state two separate claims as one.

    Findingown data
    § Discussion · p. 13

    Both depression and non-depression case groups with antidepressant use had higher incidences of dementia.

    “(a) Both depression and non-depression case groups with antidepressants use had higher incidences of dementia”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 13

    Mossello et al. mentioned that antidepressant treatment would protect cognitive function in depressed older patients with AD.

    “Mossello et al. mentioned that antidepressant treatment would protect cognitive function in depressed older patients with AD [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] E Mossello, 2008, Is antidepressant treatment associated with reduced cognitive decline in Alzheimer's disease?, Dement Geriatr Cogn source

  • Probably not a substantial claim.

    Premisecitation
    § Discussion · p. 12

    Hsiao et al. reported that a higher ratio of dementia cases had a history of taking antidepressants (11.41%) compared to control (4.88%) (p < .001).

    “Consistent with our results, Hsiao et al. reported that a higher ratio of dementia cases had a history of taking antidepressants (11.41%) compared to control (4.88%) ( p &lt; .001) [51].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] FY Hsiao, 2014, Dose-responsive effect of psychotropic drug use and subsequent dementia: a nationwide propensity score matched case-control study in Taiwan, Journal of the American Medical Directors Association source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 12

    Antidepressants are widely prescribed for other clinically accepted off-label uses including migraine, back pain, and insomnia.

    “Furthermore, antidepressants are widely prescribed for the other clinical accepted off-label uses include migraine [46], back pain [47], insomnia [48], etc.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] S Evers, 2009, EFNS guideline on the drug treatment of migraine—revised report of an EFNS task force, Eur J Neurol source
    • cites [47] R Chou, 2007, Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline, Annals of internal medicine source
    • cites [48] R Chou, 2007, Medications for acute and chronic low back pain: a review of the evidence for an American pain Society/American college of physicians clinical practice guideline, Annals of internal medicine source

  • It may state two separate claims as one.

    Study design and conductown data
    § Results · p. 5

    There were no significant differences between the case and control groups in age or sex distributions.

    “There were no significant differences between the case and control groups in terms of their age (M = 54.56 and 54.55 years, respectively) or sex distributions (males: 43.10% and 43.10%, respectively).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data
    § Main outcome measures · p. 4

    The main outcome of dementia was confirmed by two repeated diagnoses (ICD-9-CM: 290, 294.1, and 331.0), with diagnoses given by neurologists or psychiatrists based on DSM-IV or NINCDS-ADRDA criteria.

    “In Taiwan, diagnoses of dementia are given by neurologists or psychiatrists, and are evaluated based on guidelines in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or NINCDS-ADRDA Alzheimer's Criteria. The main outcome was confirmed by two repeated diagnoses of dementia (ICD-9-CM: 290, 294.1, and 331.0).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductown data
    § Discussion · p. 11

    The adjusted hazard ratios were calculated after controlling for stroke, diabetes mellitus, hypertension, hyperlipidemia, depression, insomnia, anxiety, and Charlson comorbidity index score, except for the targeted risk factor itself.

    “The adjusted HRs were calculated after controlling for stroke, diabetes mellitus, hypertension, hyperlipidemia, depression, insomnia, anxiety, and Charlson comorbidity index score, except for the targeted risk factor itself.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 13

    Mossello et al. suggested that cognitive protection was possibly via a reduction in depressive symptoms after taking antidepressants.

    “They further suggested that cognitive protection was possibly via a reduction in depressive symptoms after taking antidepressants”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] E Mossello, 2008, Is antidepressant treatment associated with reduced cognitive decline in Alzheimer's disease?, Dement Geriatr Cogn source

  • Probably not a substantial claim.

    Interpretationcitation
    § Discussion · p. 12

    Hsiao et al. established a solid association between the use of antidepressants and dementia.

    “That is, they established a solid association between the use of antidepressants and dementia.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 13

    Another study using a nationwide database in Denmark revealed that continued long-term antidepressant treatment was associated with a reduced rate of dementia.

    “Another study using a nationwide database in Denmark revealed that continued long-term antidepressant treatment was associated with a reduced rate of dementia [55].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] LV Kessing, 2009, Antidepressants and dementia, Journal of affective disorders source

  • It may state two separate claims as one.

    Study design and conductown data
    § Results · p. 5

    Both groups had comparable distributions of Charlson comorbidity index score, and the majority of subjects had scores less than or equal to 1.

    “However, both of the groups had comparable distributions of CCI score and the majority of subjects had the scores of less than or equal to 1.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data
    § Study design and matching · p. 3

    Controls were matched to cases according to age (±10 years), sex, and index date (±10 days) with a 1:4 case-to-control ratio.

    “With a 1:4 case-to-control matched schema in which controls were matched to cases according to age (±10 years), sex, and index date (±10 days), 23,276 patients were enrolled in the control group.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductcitation
    § Data source · p. 3

    The NHIRD is one of the largest and most comprehensive population-based databases in the world, and its completeness and accuracy are ensured by the Department of Health and the NHI Association of Taiwan.

    “The NHIRD was established in March 1995, and is one of the largest and most comprehensive population-based databases in the world; its completeness and accuracy are ensured by the Department of Health and the NHI Association of Taiwan.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] National Health Research Institute. National Health Insurance Research Database(NHIRD). Available at: http://nhird.nhri.org.tw/en/index.html. Accessed December 19, 2015.

  • Probably not a substantial claim.

    Study design and conductcitation
    § Baseline confounding factors · p. 4

    The analysis adjusted for baseline confounding factors using Charlson comorbidity index scores weighted according to mortality risk.

    “Scores of the Charlson comorbidity index (CCI) were applied to adjust baseline confounding factors weighted according to the mortality risk [37].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] M Charlson, 1994, Validation of a combined comorbidity index, Journal of clinical epidemiology source

  • It may state two separate claims as one.

    Interpretationown data
    § Discussion · p. 11

    Antidepressant medication is a potential risk factor for dementia and is independent of depression and other well-known risk factors, such as age, CCI score, stroke, diabetes, hypertension, hyperlipidemia, insomnia, and anxiety.

    “which indicated that antidepressant medication is a potential risk factor for dementia and is independent of depression and other well-known risk factors, such as age, CCI score, stroke, diabetes, hypertension, hyperlipidemia, insomnia, and anxiety (Fig 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig 3

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given
    § Discussion · p. 10

    Medication-induced dementia, a reversible dementia, would be ruled out during making diagnosis of dementia.

    “One of the reasons is that medication-induced dementia, a reversible dementia, would be ruled out during making diagnosis of dementia.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Medication-induced dementia is reversible and would be ruled out during diagnosis of dementia.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given
    § Statistical analysis · p. 5

    The proportional hazards assumption was examined by plotting the log(-log(survival function)) versus log of survival time.

    “Proportional hazards assumption was examined by plotting the log(-log(survival function)) versus log of survival time.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Discussion · p. 11

    Fluoxetine can rescue the effect after exposure to inescapable shock (IS), which results in a state of behavioral despair and reduction of hippocampal cell proliferation.

    “Malberg et al. demonstrated that Fluoxetine can rescue the effect after exposure to inescapable shock (IS), which results in a state of behavioral despair and reduction of hippocampal cell proliferation [43].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] JE Malberg, 2003, Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment, Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology source

  • It may state two separate claims as one.

    Interpretationown data
    § Discussion · p. 11

    Dementia may be an iatrogenic result of taking antidepressant medication, besides the pathogenic consequence of depression.

    “Again, this result suggested that dementia may be an iatrogenic result of taking antidepressant medication, besides the pathogenic consequence of depression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductown data
    § Results · p. 5

    The appropriateness of the Cox proportional hazards model is supported by the plot in S1 Fig.

    “The appropriateness of the Cox proportional hazards model is supported by the plot in S1 Fig”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data
    § Results · p. 7

    The study performed sensitivity analysis using Cox proportional hazards regression models on each risk factor as subgroups to assess robustness of the results.

    “In addition, to assess the robustness of our results, we performed sensitivity analysis and conducted the Cox proportional hazards regression models on each risk factor as subgroups.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning
    § Discussion · p. 13

    This study's result should provide more generalized results and could be more widely applied to populations regardless of depression status.

    “Hence, our result should provide more generalized results and could be more widely applied to population regardless of the depression status [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] CW Lee, 2016, Antidepressant treatment and risk of dementia: a population-based, retrospective case-control study, The Journal of clinical psychiatry source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationreasoning
    § Discussion · p. 13

    In Lee et al.'s study, higher odds of antidepressant usage in the case group were predictable.

    “Therefore, higher odds of antidepressant usage in case group were predictable.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given
    § Discussion · p. 13

    We proposed that antidepressant medication might increase the risk of dementia independent of depression.

    “while we proposed that antidepressant medication might increase the risk of dementia independent of depression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationreasoning
    § Discussion · p. 13

    Antidepressant medication deteriorates the pathogenesis of dementia and further causes dementia symptoms to present earlier.

    “Thus, these reliable results indirectly suggest two possible pathways; (a) antidepressant medication increases the risk of dementia; and (b) it deteriorates the pathogenesis of dementia and further causes dementia symptoms to present earlier.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductnone given
    § Discussion · p. 13

    Our conclusions being based on secondary data is the major limitation of this study.

    “Our conclusions being based on secondary data is the major limitation of this study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductnone given
    § Discussion · p. 13

    Taiwan's NHIRD is well-characterized with patients' basic information, medical expenditures, and details of prescription records.

    “Taiwan's NHIRD is well-characterized with patients' basic information, medical expenditures, and details of prescription records, so we could control for a number of potentially confounding factors, to provide more-accurate results.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning
    § Discussion · p. 13

    We could control for a number of potentially confounding factors, to provide more-accurate results.

    “so we could control for a number of potentially confounding factors, to provide more-accurate results.”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    Depression is a confounder rather than a mediator of the relationship between antidepressant use and dementia.

    “In order to examine whether the depression could be a potential confounder in evaluating the risk of antidepressant on dementia, we further added the interaction between depression and antidepressant medication to this regression model.”

  • The paper relies on this without support.

    The association between antidepressant use and dementia is not confounded by the other indications for which antidepressants are prescribed.

    “Antidepressant medication is commonly used for treatment of depressive disorders, and it may also be prescribed for many other indications, including anxiety disorders, neuropathic pain, fatigue, sleep disorders, back pain, and headaches [16].”

  • The paper relies on this without support.

    The ICD-9-CM codes used to identify dementia and Alzheimer's disease accurately identify these conditions.

    “The main outcome was diagnosis of dementia (ICD-9-CM: 290, 294.1), or Alzheimer's disease (ICD-9-CM: 331.0).”

  • The paper relies on this without support.

    The control group is comparable to the antidepressant group except for the measured covariates; no unmeasured confounding is present.

    “The adjusted HRs were calculated after controlling for stroke, diabetes mellitus, hypertension, hyperlipidemia, depression, insomnia, anxiety, and Charlson comorbidity index score.”

  • The paper relies on this without support.

    The proportional hazards assumption holds for the Cox regression models.

    “log(-log(survival function)) versus log(survival time) are plotted for case and control groups separately.”

  • The paper relies on this without support.

    The 5-year exclusion period is sufficient to eliminate prodromal dementia effects.

    “we conducted a sensitivity analysis which excludes patients diagnosed with dementia within the first 5 years following the data of registration of antidepressant treatment.”

  • The paper relies on this without support.

    Medication-induced dementia is reversible and would be ruled out during diagnosis of dementia.

    “One of the reasons is that medication-induced dementia, a reversible dementia, would be ruled out during making diagnosis of dementia.”

  • The paper relies on this without support.

    Subjects who are over 80 years old had a higher proportion of risk factors.

    “Subjects who are over 80 years old had higher proportion of risk factors”

  • The paper relies on this without support.

    In Taiwan, patients would only be coded for major depressive disorder (ICD-9-CM: 296.2, 296.3), dysthymic disorder (300.4), or depressive disorder, not otherwise specified (311.0) by psychiatrists if their symptoms meet the DSM-IV criteria.

    “In Taiwan, patients would only be coded for major depressive disorder (ICD-9-CM: 296.2, 296.3), dysthymic disorder (300.4), or depressive disorder, not otherwise specified (311.0) by psychiatrists if their symptoms meet the DSM-IV criteria.”

  • The paper relies on this without support.

    Antidepressants are tightly related to depression.

    “antidepressants are tightly related to depression”

  • The paper relies on this without support.

    Depression is a well-known risk factor for dementia.

    “depression is a well-known risk factor for dementia”

  • The paper relies on this without support.

    The effect between antidepressant medication or depression on increasing the risk of dementia is still unclear.

    “but the effect between antidepressant medication or depression on increasing the risk of dementia is still unclear.”

  • The paper relies on this without support.

    In Taiwan, diagnoses of dementia were made by neurologists or psychiatrists based on guidelines in DSM-IV or NINCDS-ADRDA Alzheimer's Criteria.

    “It is important to note that in Taiwan, diagnoses of dementia were made by neurologists or psychiatrists based on guidelines in DSM-IV or NINCDS-ADRDA Alzheimer's Criteria.”

  • The paper relies on this without support.

    Life expectancy in Taiwan is 80 years old.

    “life expectancy in Taiwan is 80 years old”

  • The paper relies on this without support.

    The subgroup over 80 years old may not have sufficient duration time for follow-up.

    “this subgroup may not have sufficient duration time for follow-up.”

  • The paper relies on this without support.

    This may worsen the confounding of these baseline factors to our analysis in the study.

    “this may worsen the confounding of these baseline factors to our analysis in the study.”
16 of 16

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.

Each contradiction between two passages listed here was confirmed by an independent check.

  • CCI category sizes differ between Tables 1 and 2

    Major

    Table 1 gives 5,191 study participants and 21,666 controls with CCI ≤1, totaling 26,857. Table 2 instead uses 28,770 people for that category.

  • TeCA percentage does not match its count

    Minor

    Table 3 lists 223 TeCA users among 5,819 antidepressant users. That is 3.83%, not the reported 4.00%.

    Reported 4 · recomputed 3.832274

2 of 2

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. AL Byers, 2011, Depression and risk of developing dementia, Nature Reviews Neurology, 7, 323, 10.1038/nrneurol.2011.60 · DOI · Paper page

Cited by

Sorted by citations

Related

Metadata

Authors
Then, C.-K., Chi, N.-F., Chung, K.-H., Kuo, L., Liu, K.-H., Hu, C.-J., Shen, S.-C., & Lin, Y.-K.
Affiliations
  • Taipei Medical University (TW)
  • Taipei Medical University-Shuang Ho Hospital (TW)
  • Taipei Medical University Hospital (TW)
  • University of Connecticut (US)
  • National Taiwan University (TW)
Corresponding author
  • Shen, Shing-Chuan
  • Lin, Yen-Kuang
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2017-04-06
Volume
12
Issue
4
Pages
e0175187
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0175187
PMC
PMC5383251
OpenAlex
W2605242528
Semantic Scholar
6394f85f483bdb35990e53e737a3a4e20c93c7a9
Cited by
35
References
54
Citations by year
2026: 2 · 2024: 6 · 2022: 3 · 2021: 1 · 2020: 9 · 2019: 5 · 2018: 5 · 2017: 4
FWCI
4.75
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Science Council (TW) (NSC 102-2314-B-038-042, NSC 101-2314-B-038-013)
  • Taipei Medical University (TMU104-F-004, TMU104-AE1-B09)
  • Ministry of Science and Technology, Taiwan (TW) (MOST 103-2320-B-038-024)
  • Ministry of Science and Technology, Taiwan (MOST 105-2314-B-038-013-MY3)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
  • Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
Keywords
antidepressants, dementia, depression, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase inhibitors, atypical antipsychotics, dementia risk, Taiwan, National Health Insurance Research Database, cohort studies
MeSH terms
Adult, Antidepressive Agents, Dementia, Female, Humans, Male, Middle Aged, Taiwan, Case-Control Studies, Risk Assessment

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.

A language model drew the claims from the paper on 2026-11-07, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-07 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

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.

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