Effect of Aspirin vs Placebo on the Prevention of Depression in Older People: A Randomized Clinical Trial | Depressive Disorders | JAMA Psychiatry | JAMA Network
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Figure 1.  Consolidated Standards of Reporting Trials Diagram for the Aspirin for the Prevention of Depression Trial
Consolidated Standards of Reporting Trials Diagram for the Aspirin for the Prevention of Depression Trial

CES-D-10 indicates Center for Epidemiologic Studies Depression 10-item scale.

Figure 2.  Cumulative Incidence of Incident Depression
Cumulative Incidence of Incident Depression

An episode of major depressive disorder was defined as Center for Epidemiologic Studies Depression 10-item scale score of 8 or more. Shown is the cumulative incidence of incident depression (ie, first episodes of depression among those in whom it was not present at baseline) observed during the trial.

Table 1.  Demographic Characteristics of Participants, Stratified by Center for Epidemiologic Studies Depression 10-Item Scale (CES-D-10) Score of 8 or More at Baseline
Demographic Characteristics of Participants, Stratified by Center for Epidemiologic Studies Depression 10-Item Scale (CES-D-10) Score of 8 or More at Baseline
Table 2.  Comparison of Prevalent Scores of 8 or More on the Center for Epidemiologic Studies Depression 10-Item Scale at Follow-up in Aspirin and Placebo Groupsa
Comparison of Prevalent Scores of 8 or More on the Center for Epidemiologic Studies Depression 10-Item Scale at Follow-up  in Aspirin and Placebo Groupsa
Table 3.  Twelve-Item Short-Form Health Survey Mental Component Summary Scores Comparison in Aspirin and Placebo Groups
Twelve-Item Short-Form Health Survey Mental Component Summary Scores Comparison in Aspirin and Placebo Groups
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    3 Comments for this article
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    Clarification of statement in this article's abstract
    Jack Modell, MD | Contract research organization
    The authors note, "There currently appears to be no evidence-based pharmacotherapies for the primary prevention of depression." While this statement is true with regard to prevention of depression in the general population, which indeed may be what is intended by "primary prevention," bupropion extended-release (Wellbutrin XL) was approved in 2006 for the prevention of seasonal depressive episodes in [non-depressed] patients with a diagnosis of seasonal affective disorder (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021515s036lbl.pdf). To my knowledge (please correct me if I am mistaken), this is currently the only approved pharmacotherapy for prevention of depressive episodes prior to their onset.
    CONFLICT OF INTEREST: None Reported
    Lack of pharmacokinetic basis for research.
    Iouri Banakh, MClinPharm | Peninsula Health, Frankston Hospital
    Low dose aspirin has antiplatelet effects, but not anti-inflammatory effects due to the first pass effect by the liver. The results of this study were completely predictable and of little scientific value. A larger dose that gets through to the main circulation would have actually answered the question if aspirin provides a benefit in reducing depression. It is disappointing to see such research published when basic pharmacokinetics of the drug have not been considered or mentioned in the methods or background.
    CONFLICT OF INTEREST: None Reported
    RE: Effect of aspirin vs placebo on the prevention of depression in older people
    Tomoyuki Kawada, MD | Nippon Medical School
    Berk et al. conducted a double-blinded, placebo-controlled randomized clinical trial to evaluate the relationship between low-dose aspirin (100 mg) and risk (benefit) of depression in healthy older adults. The authors defined major depressive disorder as a score of 8 or more on the Center for Epidemiologic Studies Depression 10-item (CES-D-10) scale. There were no significant differences in the proportions of CES-D-10 scores of 8 or more between the aspirin and placebo groups. Namely, hazard ratio (95% confidence interval [CI]) of aspirin use for depression was 1.02 (0.96-1.08), and low-dose aspirin did not prevent depression in healthy older adults. I have some concerns about their study.

    Fundamentally, CES-D-10 scale is not a tool for making diagnosis of major depression. Instead, it reflects depressive symptoms caused by several intrinsic and extrinsic factors. This is not related to the cut-off point, and there is a gap between structured interview and CES-D-10 scale score.

    First, I suspect that the authors speculated the mechanism of the association between aspirin use and (the risk reduction of) depression via prevention of (micro-) infarct and/or early-stage of neuro-degeneration. As many actors are related to depression/depressive symptom, the lack of association cannot be confirmed in this trial. Anyway, structured interview seems to be indispensable to verify the association.

    Second, Kim et al. conducted a meta-analysis to evaluate the association between aspirin use and depression. Pooled odds ratio/relative risk (RR) (95% CI) of aspirin use for depression was 1.10 (1.05-1.16) without heterogeneity. In cases of prospective studies, pooled RR (95% CI) of aspirin use for depression was 1.11 (1.08-1.14). Furthermore, a duration of aspirin use ≥5 years and a dosage ≥500 mg daily was significantly associated with depression. In this review, aspirin use had an adverse effect on depression, and there is no benefit of aspirin use for depression incidence. I recommended to conduct a meta-analysis of a randomized clinical trials to verify the association.


    References
    1. Berk M, Woods RL, Nelson MR, et al. Effect of aspirin vs placebo on the prevention of depression in older people: A randomized clinical trial. JAMA Psychiatry. 2020 doi:10.1001/jamapsychiatry.2020.1214
    2. Kim HB, Kim JS, Jung JG. The association between aspirin use and depression: a systematic review and meta-analysis of observational studies. Pharmacoepidemiol Drug Saf. 2020;29(6):613-622. doi:10.1002/pds.5011
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    June 3, 2020

    Effect of Aspirin vs Placebo on the Prevention of Depression in Older People: A Randomized Clinical Trial

    Author Affiliations
    • 1The Institute for Mental and Physical Health and Clinical Translation Strategy Research Centre, Deakin University School of Medicine, Geelong, Australia
    • 2School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
    • 3Department of Psychiatry, University of Melbourne, Parkville, Australia
    • 4Orygen Youth Health Research Centre, Parkville, Australia
    • 5Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
    • 6Rush Alzheimer’s Disease Center, Department of Family Medicine, Rush University Medical Center, Chicago, Illinois
    • 7School of Public Health, Curtin University, Perth, Australia
    • 8Biostatistics Unit, Faculty of Health, Deakin University, Geelong, Australia
    • 9Berman Center for Outcomes and Clinical Research, Hennepin Healthcare Research Institute, Minneapolis, Minnesota
    • 10Discipline of General Practice, Adelaide Medical School, University of Adelaide, Australia
    • 11Epworth Centre for Innovation in Mental Health, the Epworth Clinic, Epworth Healthcare, Camberwell, Australia
    • 12Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University, Melbourne, Australia
    JAMA Psychiatry. 2020;77(10):1012-1020. doi:10.1001/jamapsychiatry.2020.1214
    Key Points

    Question  Does low-dose aspirin reduce the risk of depression in healthy older adults?

    Findings  In this randomized clinical trial of 19 114 older adults in Australia and the United States, those taking low-dose aspirin (100 mg daily) did not have a lower rate of prevalent depression compared with those taking a placebo, per measurements taken at any of the postrandomization annual visits.

    Meaning  In this study, low-dose aspirin did not prevent depression in healthy older adults.

    Abstract

    Importance  Depression is associated with increased inflammation, which may precede its onset, especially in older people. Some preclinical data suggest potential antidepressant effects of aspirin, supported by limited observational data suggesting lower rates of depression in individuals treated with aspirin. There currently appears to be no evidence-based pharmacotherapies for the primary prevention of depression.

    Objective  To determine whether low-dose aspirin (100 mg) reduces the risk of depression in healthy older adults.

    Design, Setting, and Participants  This double-blinded, placebo-controlled randomized clinical trial was a substudy of the Aspirin in Reducing Events in the Elderly (ASPREE) trial, which examined if aspirin increased healthy life span, defined as survival free of dementia and disability. The prespecified secondary outcome was depression. Individuals of all races/ethnicities older than 70 years in Australia, as well as white individuals older than 70 years and black and Hispanic individuals older than 65 years in the United States, were included.

    Interventions  Participants were randomized to aspirin (100 mg daily) or placebo, with a median (interquartile range) follow-up of 4.7 (3.5-5.6) years.

    Main Outcomes and Measures  The primary outcome was a proxy measure of major depressive disorder defined as a score of 8 or more on the Center for Epidemiologic Studies Depression 10-item (CES-D-10) scale.

    Results  Of the 19 114 participants enrolled in the trial, 9525 received aspirin and 9589 received a placebo. The mean (SD) age was 75.2 (4.0) years in the aspirin group and 75.1 (4.5) years in the placebo group; 9531 (56.4%) were women. Participants' demographics and clinical characteristics at baseline were similar between groups. A total of 79 886 annual CES-D-10 measurements were taken, with a mean of 4.2 measurements per participant. There were no significant differences at annual visits in the proportions of CES-D-10 scores of 8 or more between the aspirin and placebo groups. The incidence rate of new CES-D-10 scores of 8 or more was 70.4 events per 1000 person-years in the aspirin group and 69.1 in the placebo group (hazard ratio, 1.02 [95% CI, 0.96-1.08]; P = .54).

    Conclusions and Relevance  Low-dose aspirin did not prevent depression in this large-scale study of otherwise healthy older adults.

    Trial Registration  ClinicalTrials.gov Identifier: NCT01038583

    Introduction

    Preventive approaches for many noncommunicable disorders from cancer to cardiovascular disease have had major influence on incidence, morbidity, and mortality. Psychiatry, in contrast, lacks an evidence base for population-wide prevention strategies. Existing effective preventive strategies for depression largely use psychotherapeutic, cognitive behavioral–type therapies for people with early-stage or emerging symptoms.1 There are no evidence-based primary preventive pharmacotherapies for depression.

    Support for a possible role of inflammation in depression include the association between inflammatory disorders and higher rates of depression, the propensity of proinflammatory cytokines and interferon administered to volunteers to induce depressive symptoms, and higher levels of the inflammatory blood biomarkers tumor necrosis factor α, interleukin-6 (IL-6), and C-reactive protein in depression, including in late-life depression.2,3 After antidepressant treatment for depression, IL-4, IL-6, and IL-10 cytokine levels were reduced when symptoms were reduced.4 Higher levels of cytokines and acute-phase markers, such as C-reactive protein, appear to precede the onset of de novo depression.5 These associations raise the question as to whether depression could be prevented by suppressing inflammation. Indeed, preclinical, pharmacoepidemiologic, and pilot clinical trial data suggest that aspirin, with its anti-inflammatory properties, may have clinical potential.6

    The Aspirin for the Prevention of Depression (ASPREE-D) trial7 is a substudy of the Aspirin in Reducing Events in the Elderly (ASPREE) trial. The parent study was a 5-year randomized clinical trial jointly supported by the National Institute on Aging and the Australian National Health and Medical Research Council comparing the effects of aspirin (100 mg daily) and placebo in 19 114 healthy older adults on survival free of dementia or physical disability.8,9 The primary aim of ASPREE-D was to determine if the use of low-dose aspirin reduces the risk of depression in healthy individuals 70 years or older (or 65 years or older among racial/ethnic minorities in the US), as assessed using the Center for Epidemiologic Studies Depression Scale 10-item (CES-D-10) scores.9 The secondary aims were to determine its effect on mental health quality of life, as indexed by the 12-item Short Form Health Survey (SF-12) mental component summary scores, and assess the time to a first CES-D-10 score of 8 or more, as well as incidence of hospitalization for depression. The primary hypothesis was that low-dose aspirin would reduce the risk of depression, defined as a CES-D-10 score of 8 or more, at any postrandomization point.

    Methods

    The ASPREE trial was a multicenter, double-blinded, placebo-controlled, primary-prevention randomized clinical trial of daily usage of 100 mg of enteric-coated aspirin among older adults who were relatively healthy and community dwelling in Australia and the US and were 70 years and older (or 65 years or older, if African American or Hispanic and dwelling in the US). The trial was conducted according to the Australian National Statement on Ethical Conduct in Human Research,10 the Australian Code for the Responsible Conduct of Research,11 the 2008 Declaration of Helsinki,12 and the International Conference on Harmonization of Good Clinical Practice E613 and was approved by institutional review boards at all sites. The protocol was developed in accordance with Standard Protocol Items Recommendations for Intervention Trials (SPIRIT) 2013 guidelines,14 reported using the Consolidated Standards of Reporting Trials (CONSORT) guidelines and according to the International Conference on Harmonization E9 Statistical Principles for Clinical Trials,15,16 and registered on ClinicalTrials.gov (identifier NCT01038583).

    Both ASPREE and ASPREE-D study methods are published in detail elsewhere (protocol in Supplement 1).7,9 In Australia, recruitment largely took place in primary care settings. General practitioners provided a list of participants who were potentially eligible, and they were sent letters of invitation. When participants contacted the ASPREE Coordinating Center, screening questions were asked, and further screening was conducted at 2 baseline study visits. In between the study visits, the general practitioners assessed participants’ health and those considered sufficiently healthy for a primary prevention trial of low-dose aspirin were deemed eligible for the study. Researchers in the US identified participants using clinic-based mailing lists, electronic medical records, and advertisements. Men and women were included in the study if they were willing and able to give informed consent and were eligible for randomization. Key exclusion criteria were a history of a diagnosed cardiovascular event or established cardiovascular disease (including stroke, transient ischemic attack, myocardial infarction, unstable angina, coronary artery reperfusion procedures and bypass grafting, abdominal aortic aneurysm, and cardiac failure); atrial fibrillation; dementia or a score of less than 78 on the Modified Mini-Mental State Examination; substantial physical disability, defined by severe difficulty or inability to perform any of the 6 Katz activities of daily living at baseline; a condition with a high current or recurrent risk of bleeding; anemia; a condition likely to cause death within 5 years; current use of other antiplatelet or antithrombotic medication; current use of aspirin for secondary prevention; or uncontrolled hypertension (systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥105 mm Hg).

    Randomization of the study drug followed a block randomization procedure and was stratified by site and age (65-79 vs >80 years). Participants were randomized to receive either 100 mg of enteric-coated aspirin or an enteric-coated placebo, which were identical in appearance, in a ratio of 1:1. Study participants, investigators, and general practitioner coinvestigators were blinded to treatment allocation.

    The ASPREE study began in March 2010, completed recruitment in December 2014, and was concluded in June 2017 because of a National Institutes of Health determination of futility regarding the primary end point. The primary ASPREE end point was a composite of death or dementia (adjudicated according to the DSM-IV criteria) or persistent loss of the same Katz basic activity of daily living. All clinical and safety end points were adjudicated by independent end point adjudication committees who were provided with deidentified clinical information about the event.

    The principal outcome variable of ASPREE-D was a proxy measure of major depressive disorder, defined as a CES-D-10 score of 8 or more. Because some participants may have had a CES-D-10 score of 8 or more at baseline or a history of depression, this primary outcome pooled both incident and recurrent depression. The CES-D-10 is a validated self-rated questionnaire with a single factor structure17 that indexes depressive symptom severity in community populations.18,19 When compared with a formal psychiatric diagnosis of late-life depression, the scale has been shown to have a sensitivity of 97% and a specificity of 84%.20 Against a formal DSM-IV diagnosis, the sensitivity and specificity of the CES-D-10 were 82% and 83%, respectively.21

    The CES-D-10 was initially administered at baseline and at years 1, 3, 5, and 7. On receipt of further funding (National Health and Medical Research Council identifier GNT1081901), we added CES-D-10 assessments to years 2, 4, and 6. Participants were thus assessed for depression annually until the end of their participation in the study. The number of participants who reached the CES-D-10 threshold at any annual follow-up was a secondary outcome measure of ASPREE and a primary outcome of ASPREE-D. The SF-12 was administered annually. The mental component summary score was a secondary outcome measure of ASPREE-D.

    The target ASPREE sample size was 19 000. To assess power for the ASPREE-D primary hypothesis, we extrapolated from the extant literature22 that the risk of prevalent depression at any time in the placebo group would be 10%. We anticipated a 5% annual dropout rate and a within-participant correlation of 0.60 between baseline and follow-up measurements of depression, using a compound symmetry matrix. Based on these assumptions, we had 90% power to detect the specified difference in depression risk (ie, an odds ratio [OR] of 0.90 at annual follow-up) between the aspirin and placebo group at a 5% significance level.7

    Statistical Analyses

    Primary analyses were undertaken by 3 authors (M.M., J.E.L., and R.W.) on an intent-to-treat basis, including all participants as randomized regardless of treatment received. Details of the predefined statistical analyses plan for ASPREE have been published elsewhere.8 The primary effectiveness analysis compared the aspirin and the placebo groups with regard to changes in the prevalence ratio of CES-D-10 scores of 8 or more from baseline to annual follow-up visits. Treatment effects for the repeated binary CES-D-10 outcomes were determined via a population mean model using the generalized estimating equation (GEE) approach with logit link function. The GEE model accounted for within-individual repeated measures using an exchangeable working correlation matrix, and a robust sandwich variance estimator was used. The model contained the fixed effect of intervention allocation and nominal values of measurement points (annual visits) as the main effects, and a 2-way interaction between intervention allocation and annual visit. The 2-way interaction estimates the effect of aspirin across the annual visits in this setting. Ratios of ORs and 95% CIs from the 2-way interaction parameters were reported to compare the aspirin group with placebo at each annual visit follow-up with respect to baseline. The global test of the interaction term was then used to test the primary hypothesis of differential between-group (ie, aspirin vs placebo) change in the proportions of CES-D-10 scores of 8 or more. Similar analytical approaches were used for exploratory analyses based on higher cutoffs of CES-D-10 scores at 10 or more and 12 or more, given data that biological therapies, such as antidepressants, may have greater efficacy in individuals with more severe depression.23

    The GEE models, assuming Gaussian distribution with identity link function, were used for analyzing the SF-12 mental component. The GEE models accounted for within-individual repeated measures using an unstructured working correlation matrix. The SF-12 models used the same fixed-effect parameter structure as the CES-D-10 binary outcome models, and for SF-12, the 2-way interaction of intervention allocation and follow-up time estimated the intervention effect as between-group differential change from baseline scores at each annual visit follow-up. The coefficients from the 2-way interactions were reported as aspirin effects at each follow-up annual visit, with 95% CIs. In addition, the Cohen d effect size for between-group differential change was reported. Cox proportional-hazards models were used in participants with CES-D-10 scores less than 8 at baseline to compare incidence rate of CES-D-10 scores of 8 or more at annual follow-ups between the aspirin and placebo groups. Hazard ratios and 95% CIs were reported.

    Logistic regression was used for comparing overall proportion of hospitalization at follow-up periods attributable to depression in the aspirin and placebo groups. All tests of treatment effects were conducted using an α level of .05. For the primary outcome, P values were not presented for the annual follow-up comparisons, and only the overall χ2 test for the interaction was reported. Confidence intervals and P values were not adjusted for multiple comparisons in secondary outcomes. All analyses were performed using Stata version 15 (StataCorp).

    Results

    A total of 19 114 participants (16 703 in Australia and 2411 in the US) were recruited from March 2010 to December 2014 and randomized to receive aspirin or placebo (9525 participants to the aspirin group and 9589 to the placebo group) (Figure 1). The demographic and clinical characteristics of the participants at baseline according to the CES-D-10 cutoff in both groups were similar (Table 1). The mean (SD) age of the participants was 75.2 (4.60) years in the aspirin group and 75.1 (4.5) years in the placebo group, and 9531 (56.4%) of the participants were women. Regarding background, 16 007 participants (93.5%) were white, and 16 463 (95.6%) spoke English at home. Details of the baseline characteristics of the cohort are published elsewhere.24

    The mean (SD) CES-D-10 score at baseline was 3.2 (3.3) in both groups. There were 1879 participants with a baseline CES-D-10 score of 8 or more, with 925 (9.7%) in the aspirin group and 954 (9.9%) in the placebo group. A total of 1666 participants (50.2% in the aspirin group) reported a history of depression (ie, having ever been diagnosed or treated by a physician for depression), of whom 202 (24.1%) had CES-D-10 scores of 8 or more at baseline taking aspirin and 206 (24.9%) taking placebo. Subgroup analysis of these participants showed no significant difference in the prevalence of depressive symptoms at annual follow-ups (follow-up year by treatment group interaction: χ26, 3.75; P = .71). Further exploration showed no specific pattern in baseline adjusted depressive symptoms ratios at annual follow-ups (OR range, 0.92-1.67). Antidepressant use was not statistically different between treatment groups at baseline or across annual follow-ups.

    Adherence to treatment was measured, and 11 281 of 17 868 participants (63.1%) were still taking study medication after the median 4.7 years of follow-up. The participants in each group taking the study medication in the final year numbered 5512 of 8869 (62.1%) for aspirin and 5769 of 8999 (64.1%) for placebo. When calculated as a proportion of time in the study, participants in the aspirin arm took the study medication for a mean (SD) of 73% (35%) of their time in the study; this was a mean (SD) of 75% (34%) in the placebo arm. These rates are consistent with other pragmatic primary prevention trials.

    Principal End Point of ASPREE-D (CES-D)

    Of 19 114 randomized participants, 1 participant had no CES-D-10 measurement and 19 113 participants had a baseline and at least 1 valid follow-up CES-D-10 measurement. In total, 79 886 CES-D-10 participant measurements were reported across the study period, with a mean of 4.2 measurements per participant.

    Table 2 shows the number of participants with CES-D-10 scores of 8 or more in aspirin and placebo groups at baseline and follow-up annual visits. The prevalence of depressive symptoms was higher at annual visits than baseline in both groups (Table 2), with the proportion of participants with CES-D-10 scores of 8 or more increasing to almost double at the end of follow-up. However, the changes from baseline were not significantly different between aspirin and placebo groups.

    Secondary End Points of ASPREE-D
    SF-12 Mental Scores

    A total of 90 980 SF-12 measurements from 19 111 participants were taken over the study period (Table 3). The mean (SD) mental component summary scores at baseline were 55.8 (7.1) and 55.6 (7.2) in the aspirin and placebo groups, respectively. Between-group differential changes (aspirin vs placebo) from baseline ranged from 0.0 to 0.3 points in favor of the placebo group; however, the differences were very small (Cohen d ≤0.10). No significant differences were observed between aspirin and placebo groups in differential changes from baseline of the SF-12 mental component summary score (χ26, 9.61; P = .14).

    Hospitalization Attributable to Depression

    A total of 58 participants were hospitalized for depression during the study period, of whom 33 (0.35%) were in the aspirin group and 25 (0.26%) were in the placebo group. There was no statistically significant difference in the between-group comparison of hospitalization proportions (OR, 1.33 [95% CI, 0.79-2.24]).

    Incidence Rate of CES-D-10 Scores of 8 or More

    A total of 2350 participants in the aspirin group (70.4 events per 1000 person-years) and 2314 in the placebo group (69.1 events per 1000 person-years) reached the end point of a CES-D-10 score of 8 or more for the first time at an annual follow-up. The between-group difference was not significant (hazard ratio, 1.02 [95% CI, 0.96-1.08]; P = .54) (Figure 2).

    Exploratory End Point of ASPREE-D
    CES-D-10 Scores of 10 or More and 12 or More

    In a sensitivity analysis, a similar pattern of only small differences between the aspirin and placebo groups was observed for those with more severe depression using both CES-D-10 score cutoffs of 10 or more and 12 or more, as was seen for the cutoff score of 8 or more (eTable in Supplement 2). None of these were statistically significant.

    Discussion

    The results of ASPREE-D failed to support the primary hypothesis of this study that individuals taking low-dose aspirin would have a lower rate of prevalent depression compared with those taking placebo, with depression defined in this large pragmatic trial as a CES-D-10 score of 8 or more at any postrandomization annual visit. Given the large sample size, the prolonged observation window, and the rigor of the primary ASPREE study in ascertaining end points and maintaining follow-up, this suggests that low-dose aspirin is unlikely to be effective in preventing depression in a healthy older cohort. It also adds to the null findings for aspirin in cardiovascular events,25 disability-free survival,26 and all-cause mortality27 in the ASPREE parent study.

    The association of depression with elevated markers of inflammation has spurred the initiation of multiple preclinical,28-30 epidemiological,31-34 and clinical35,36 studies of aspirin and other anti-inflammatory therapies, such as celecoxib. A meta-analysis of observational data supports the efficacy of celecoxib in depression.37 Aspirin is a nonsteroidal anti-inflammatory agent that acts as an irreversible inhibitor of both cyclooxygenase-1 and cyclooxygenase-2. It promotes production of anti-inflammatory moieties, such as lipoxins, which may lower levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor α, and IL-6, and reduce biomarkers of oxidative damage.6

    Aspirin was associated with increased sucrose preference and reduced immobility in the forced swim test, as well as decreased cortisol levels and increased brain serotonin levels in an interferon model of depression in Sprague Dawley rats, suggesting both clinical model efficacy and influences on salient pathways.38 Several pharmacoepidemiology studies suggest that people taking aspirin may have a lower risk for depression,33,34,39,40 notwithstanding some conflicting data that have failed to show a benefit of aspirin.41,42 Early clinical trials of aspirin in mood disorders have also generated promising but preliminary signals of efficacy. Adjunctive aspirin together with sertraline was superior to sertraline alone in participants with major depressive disorder. Additionally, in two 2 × 2 designs of minocycline and aspirin and N-acetylcysteine and aspirin, both combination strategies seemed more effective than the placebo combinations.31,43,44 However, treatment and prevention studies of definitive methodological quality are necessary to confirm these preliminary findings.

    The major successes in morbidity of other noncommunicable disorders have arguably been in prevention, not treatment. Unlike the declining rates of disability resulting from, for example, cardiovascular disease,45 the burden of disability from depression has not declined and may even be increasing.46 The identification of inflammatory biomarkers associated with depression risk suggests that strategies targeting these may be a plausible therapeutic and preventive approach. Because these inflammatory markers are shared between a myriad of common noncommunicable medical disorders, treatment affecting these pathways may provide compound benefits across several common mental and medical conditions.47 This argues for a shared approach to tackle noncommunicable disorders,48 a key philosophical premise of ASPREE. However, the many off-target outcomes of aspirin use,49 particularly those associated with bleeding,25 might challenge the widespread indication of aspirin for primary prevention in an older population that is otherwise healthy. Accordingly, the significant increased risk of bleeding events documented in the ASPREE study was not matched by benefit in terms of reduced depression risk.

    Strengths of the study include its large sample size, extensive characterization of the participants, the extensive length of the follow-up period, the participation of healthy older people across 2 continents, and the simplicity of the design. In this complex multi–end point study, structured diagnostic interviews were not feasible. The CES-D-10 score, despite being designed as a screening tool, is validated for use in such studies, correlates well with structured interview, and obviates interrater variability issues in multisite studies.

    Limitations

    The fact that the ASPREE cohort had higher baseline quality of life than is noted in other population-based studies of older adults probably suggests biased recruitment in favor of individuals who are healthy, a reflection of this primary prevention study’s exclusion criteria. Therefore, some demographic features may have differed from the broader population (such as lower rates of smoking), which may compromise assay sensitivity and the generalizability of our findings.50 Nevertheless, there were high CES-D-10 scores at baseline across the cohort, despite the selection of an older population that was relatively healthy. These data are thus not necessarily translatable to people with substantial medical comorbidities or younger populations. Annual assessments may miss intercurrent changes in mood.

    The dosage of aspirin is an area of uncertainty. The literature is unclear on the question of whether low-dose aspirin is able to lower inflammatory cytokines to a meaningful extent.51-53 A successful treatment study of aspirin in schizophrenia used a dose of 1 g daily.54 This negative trial therefore should not necessarily inhibit future studies that, for example, include younger cohorts at earlier illness stages, use higher doses, stratify for baseline biomarkers, or examine groups at high risk and explore indicated or secondary prevention. Stratification according to baseline biomarkers might clarify groups that could benefit from such therapies; future studies in this regard are planned. Future studies should also consider the balance between potential benefits vs harms of low-dose aspirin for primary prevention—especially in light of the significant increased bleeding risk described in ASPREE and other cohorts, including in younger individuals.55,56

    Conclusions

    In summary, this study failed to confirm any potential benefit of low-dose aspirin in reducing the risk of depression in this relatively healthy older population. This lack of efficacy is compounded by a clear increase in the risk of bleeding events documented in previous reports from this study.24 The findings do not support the hypothesis that low-dose aspirin can prevent late-life depression.

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    Article Information

    Accepted for Publication: March 28, 2020.

    Corresponding Author: Michael Berk, MBBCh, PhD, Deakin University School of Medicine, the Institute for Mental and Physical Health and Clinical Translation Strategic Research Centre, PO Box 281, Geelong, Victoria 3220, Australia (michael.berk@barwonhealth.org.au).

    Published Online: June 3, 2020. doi:10.1001/jamapsychiatry.2020.1214

    Author Contributions: Dr Berk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Berk, Woods, Nelson, Shah, Reid, Storey, Lockery, Mohebbi, Dodd, Stocks, P. Fitzgerald, McNeil.

    Acquisition, analysis, or interpretation of data: Berk, Woods, Nelson, Shah, Storey, S. Fitzgerald, Lockery, Wolfe, Mohebbi, Murray, Stocks, P. Fitzgerald, Mazza, Agustini.

    Drafting of the manuscript: Berk, Nelson, Mohebbi, Mazza, Agustini.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Berk, Mohebbi.

    Obtained funding: Woods, Nelson, Reid, Storey, Wolfe, Mohebbi, Murray, McNeil.

    Administrative, technical, or material support: Berk, Shah, Reid, S. Fitzgerald, Lockery, Stocks, P. Fitzgerald, Mazza, Agustini.

    Supervision: Berk, Dodd.

    Conflict of Interest Disclosures: Dr Berk has received grant/research support from the National Institutes of Health, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, Medical Benefits Fund, National Health and Medical Research Council, Medical Research Futures Fund, Beyond Blue, Rotary Health, A2 Milk Company, Meat and Livestock Board, Woolworths, Avant, and the Harry Windsor Foundation, as well as a National Health and Medical Research Council senior principal research fellowship during the conduct of the study; has been a speaker for AstraZeneca, Lundbeck, Merck, and Pfizer; has served as a consultant to Allergan, Astra Zeneca, Bioadvantex, Bionomics, Collaborative Medicinal Development, Lundbeck Merck, Pfizer and Servier; has received personal fees from Grunbiotics, Livanova, Norwegian Psychiatry Association, Janssen Cilag, Otsuka, Medisquire, HealthEd, Medplan Communications, and Royal Australian and New Zealand College of Psychiatrists outside the submitted work; and has a patent to modulation of physiological processes and agents useful for the same pending, a patent to modulation of diseases of the central nervous system and related disorders pending, and a patent to xanthone-rich plant extracts or compounds therefrom for modulating diseases of the central nervous system and related disorders, issued. Dr Shah receives research support from Eli Lilly and Co Inc, Genentech Inc, Merck and Co Inc, H. Lundbeck A/S, Navidea Biopharmaceuticals, Takeda Development Center Americas Inc, and Toyama Chemical Co, Ltd, as a site principal investigator or a site subinvestigator. Dr Nelson has participated in trials that have received funding from SmithKline Beecham, AstraZeneca, Bayer, Sanofi-Aventis, Merck Sharp & Dohme, Pfizer, Servier Laboratories, and Bristol-Myers Squibb; has served on advisory boards for Sanofi-Aventis, Novartis, Schering-Plough Solvay Pharmaceuticals, and Amgen; has prepared educational material for Servier Laboratories, AstraZeneca, Bristol-Myers Squibb, and MediMark; and has received conference and travel support from Bayer HealthCare AG, Merck Sharpe and Dohme, Novartis, and Sanofi-Aventis. Dr Fitzgerald is supported by a National Health and Medical Research Council practitioner fellowship (1078567); has received equipment for research from MagVenture A/S, Medtronic Ltd, Neuronetics, and Brainsway Ltd, and funding for research from Neuronetics; is on scientific advisory boards for Bionomics Ltd and LivaNova; and is a founder of TMS Clinics Australia. Dr Woods reported grants from the National Institutes of Health, National Health and Medical Research Council, and Victorian Cancer Agency and nonfinancial support from Monash University during the conduct of the study. Dr Nelson reported personal fees from Bayer Healthcare outside the submitted work. Dr Shah reported grants from National Institutes of Health during the conduct of the study. Dr Reid reported grants from National Health and Medical Research Council and the National Institute on Aging during the conduct of the study. Dr Storey reported grants from the National Institutes of Health and National Health and Medical Research Council during the conduct of the study. Dr Wolfe reported grants from the National Institutes on Aging and National Health and Medical Research Council during the conduct of the study. Dr Dodd reported grants from Harry Windsor Foundation and grants from National Health and Medical Research Council outside the submitted work. No other disclosures were reported.

    Funding/Support: The ASPREE-D study is funded by a project grant from the National Health and Medical Research Council (1081901). The ASPREE parent study, which recruited participants and was responsible for all follow-up measurements including clinical end points and other data capture, was funded primarily by a grant from the US National Institute on Aging (1R01AG029824-01A2), with additional support from Australia’s National Health and Medical Research Council (ID334047), the Victorian Cancer Agency, and Monash University. Bayer Pharma AG provided matching aspirin and placebo tablets. Additional funding was received via a National Health and Medical Research Council Senior Principal Research Fellowship (grants APP1059660 and APP1156072 [Dr Berk] and 1045862 [Dr Reid]) and program grant (1092642 [Dr Reid]), the National Institutes of Health (Dr Murray), and the Heart Foundation (Dr Reid).

    Role of the Funder/Sponsor: The funders and sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Data Sharing Statement: See Supplement 3.

    Additional Information: The Aspirin in Reducing Events in the Elderly (ASPREE) trial is registered on the International Standard Randomized Controlled Trial Number Register (ISRCTN83772183). The ASPREE trial had multiple institutional review board approvals in the US and Australia.

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