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

Michael Berk; Robyn L Woods; Mark R Nelson; Raj C Shah; Christopher M Reid; Elsdon Storey; Sharyn Fitzgerald; Jessica E Lockery; Rory Wolfe; Mohammadreza Mohebbi; Seetal Dodd; Anne M Murray; Nigel Stocks; Paul B Fitzgerald; Catherine Mazza; Bruno Agustini; John J McNeil

doi:10.1001/jamapsychiatry.2020.1214

. 2020 Jun 3;77(10):1–9. doi: 10.1001/jamapsychiatry.2020.1214

Effect of Aspirin vs Placebo on the Prevention of Depression in Older People

A Randomized Clinical Trial

Michael Berk ^1,^2,^3,^4,^✉, Robyn L Woods ², Mark R Nelson ⁵, Raj C Shah ⁶, Christopher M Reid ^2,⁷, Elsdon Storey ², Sharyn Fitzgerald ², Jessica E Lockery ², Rory Wolfe ², Mohammadreza Mohebbi ^1,⁸, Seetal Dodd ¹, Anne M Murray ⁹, Nigel Stocks ¹⁰, Paul B Fitzgerald ^11,¹², Catherine Mazza ¹, Bruno Agustini ¹, John J McNeil ²

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

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.

^✉

Corresponding author.

PMCID: PMC7271558 PMID: 32492080

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.

This substudy of a randomized clinical trial sought to determine whether low-dose aspirin reduces the risk of 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

Figure 1. — CES-D-10 indicates Center for Epidemiologic Studies Depression 10-item scale.

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 categories	Patients, No. (%)
	Aspirin group (n = 9524)^a		Placebo group (n = 9586)^a
	CES-D-10 < 8	CES-D-10 ≥ 8	CES-D-10 < 8	CES-D-10 ≥ 8
Total	8599 (90.3)	925 (9.7)	8632 (90.0)	954 (10.0)
Age, mean (SD), y	75.1 (4.6)	75.3 (4.8)	75.1 (4.5)	75.1 (4.6)
Weight, mean (SD), kg	76.9 (15.0)	77.6 (16.6)	77.1 (14.7)	76.6 (15.8)
BMI, mean (SD)	28.0 (4.7)	28.8 (5.5)	28.0 (4.6)	28.6 (5.3)
Female	4778 (55.6)	595 (64.3)	4753 (55.1)	653 (68.5)
Country
Australia	7526 (87.5)	795 (86.0)	7578 (87.8)	800 (83.9)
United States	1073 (12.5)	130 (14.0)	1054 (12.2)	154 (16.1)
Living status
At home alone	2710 (31.5)	387 (41.8)	2739 (31.7)	414 (43.4)
At home with family, friends, or a spouse	5858 (68.1)	529 (57.2)	5856 (67.8)	534 (56.0)
In a residential home^b	31 (0.4)	9 (1.0)	37 (0.5)	6 (0.6)
Hispanic/Latino ethnicity	215 (2.5)	25 (2.7)	209 (2.4)	39 (4.1)
Race
White	7992 (94.0)	832 (90.6)	8015 (93.8)	855 (90.7)
Black/African American	391 (4.6)	66 (7.2)	387 (4.5)	65 (6.9)
Other	124 (1.4)	20 (2.2)	143 (1.7)	23 (2.4)
English-speaking	8189 (95.2)	885 (95.7)	8274 (95.9)	912 (95.6)
Born overseas	1928 (22.4)	215 (23.2)	1937 (22.4)	195 (20.4)
Education >12 y	4744 (55.2)	473 (51.2)	4737 (54.9)	523 (54.8)
Smoking status
Current	298 (3.5)	54 (5.8)	326 (3.8)	56 (5.9)
Former	3519 (40.9)	389 (42.1)	3522 (40.8)	367 (38.4)
Never	4782 (55.6)	482 (52.1)	4784 (55.4)	531 (55.7)
Alcohol drinking
Current	6644 (77.3)	664 (71.8)	6629 (76.8)	701 (73.5)
Former	488 (5.7)	78 (8.4)	493 (5.7)	77 (8.1)
Never	1467 (17.0)	183 (19.8)	1510 (17.5)	176 (18.4)
Depression history^c
Unsure	48 (1.6)	8 (1.8)	41 (1.4)	12 (2.8)
No	2356 (77.5)	238 (53.1)	2385 (78.2)	216 (49.8)
Yes	635 (20.9)	202 (45.1)	623 (20.4)	206 (47.4)

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Abbreviation: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared).

^{^a}

One CES-D-10 score was missing in the aspirin group, and 3 were missing in the placebo group at baseline.

^{^b}

Supervised care or assisted living.

^{^c}

The question about a history of depression were only asked after June 2013 (n = 6970 participants).

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.

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 Groups^a.

Year	Patients, No.	Aspirin group, No. (%)	Placebo group, No. (%)	Odds ratio^b (95% CI)
Baseline	19 110	925 (9.7)	954 (9.9)	NA
1	18 100	1454 (16.1)	1424 (15.7)	1.06 (0.96-1.18)
2	7132	566 (16.0)	539 (15.0)	1.09 (0.94-1.24)
3	15 170	1316 (17.4)	1307 (17.1)	1.06 (0.95-1.17)
4	10 409	868 (16.9)	903 (17.1)	1.04 (0.92-1.17)
5	7257	663 (18.5)	675 (18.4)	1.05 (0.92-1.19)
6	2708	257 (19.0)	245 (18.1)	1.13 (0.94-1.34)

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Abbreviation: NA, not applicable.

^{^a}

P value and (test statistic) for intervention by follow-up (annual visit) interaction test: χ²₆, 2.68; P = .85.

^{^b}

Odds ratio comparing aspirin with placebo at follow-up annual visit, divided by the odds ratio comparing the 2 groups at baseline.

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).

Table 3. Twelve-Item Short-Form Health Survey Mental Component Summary Scores Comparison in Aspirin and Placebo Groups.

Year	Patients, No.	Mental component score
		Mean (SD)		Differential change^a (95% CI)^b	Effect size (Cohen d)
		Aspirin group	Placebo group	Differential change^a (95% CI)^b	Effect size (Cohen d)
Baseline	19 106	55.8 (7.1)	55.6 (7.2)	NA	NA
1	18 088	55.5 (7.4)	55.6 (7.1)	–0.3 (–0.5 to 0.0)	–0.03
2	17 350	55.7 (7.3)	55.6 (7.4)	0.0 (–0.2 to 0.2)	0.00
3	15 112	55.6 (7.5)	55.6 (7.3)	–0.1 (–0.4 to 0.1)	–0.01
4	11 413	55.6 (7.5)	55.7 (7.4)	–0.2 (–0.5 to 0.0)	–0.02
5	7209	55.2 (7.5)	55.4 (7.5)	–0.3 (–0.7 to 0.0)	–0.04
6	7209	55.5 (7.6)	55.4 (7.2)	–0.2 (–0.7 to 0.2)	–0.07

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Abbreviation: NA, not applicable.

^{^a}

Differential change from baseline at follow-ups (aspirin vs placebo) was estimated from a 2-way interaction of intervention allocation and follow-up annual visit from a generalized estimating equation model; the references were the baseline measurement and the placebo group.

^{^b}

P value and test statistic for intervention by follow-up annual visit interaction test: 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).

Figure 2. — 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.

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,^28,29,30 epidemiological,^31,32,33,34 and clinical^35,36 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.^51,52,53 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.

Supplement 1.

Protocol.

Click here for additional data file.^{(867.9KB, pdf)}

Supplement 2.

eTable. Exploratory Outcomes (CESD-10≥10, and ≥12) Comparison in Aspirin and Placebo: Odds Ratios at Follow-Up Annual Visits.

Click here for additional data file.^{(170.4KB, pdf)}

Supplement 3.

Data-Sharing Statement.

Click here for additional data file.^{(74.4KB, pdf)}

References

1.Cuijpers P, van Straten A, Smit F, Mihalopoulos C, Beekman A. Preventing the onset of depressive disorders: a meta-analytic review of psychological interventions. Am J Psychiatry. 2008;165(10):1272-1280. doi: 10.1176/appi.ajp.2008.07091422 [DOI] [PubMed] [Google Scholar]
2.Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206-215. doi: 10.1016/j.bbi.2015.06.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013;150(3):736-744. doi: 10.1016/j.jad.2013.06.004 [DOI] [PubMed] [Google Scholar]
4.Więdłocha M, Marcinowicz P, Krupa R, et al. . Effect of antidepressant treatment on peripheral inflammation markers: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80(Pt C):217-226. doi: 10.1016/j.pnpbp.2017.04.026 [DOI] [PubMed] [Google Scholar]
5.Pasco JA, Nicholson GC, Williams LJ, et al. . Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010;197(5):372-377. doi: 10.1192/bjp.bp.109.076430 [DOI] [PubMed] [Google Scholar]
6.Berk M, Dean O, Drexhage H, et al. . Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Med. 2013;11(1):74. doi: 10.1186/1741-7015-11-74 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Berk M, Woods RL, Nelson MR, et al. . ASPREE-D: Aspirin for the prevention of depression in the elderly. Int Psychogeriatr. 2016;28(10):1741-1748. doi: 10.1017/S104161021600079X [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Wolfe R, Murray AM, Woods RL, et al. . The aspirin in reducing events in the elderly trial: statistical analysis plan. Int J Stroke. 2018;13(3):335-338. doi: 10.1177/1747493017741383 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.ASPREE Investigator Group Study design of Aspirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials. 2013;36(2):555-564. doi: 10.1016/j.cct.2013.09.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007)—Updated 2015. National Health and Medical Research Council; 2015. [Google Scholar]
11.National Health and Medical Research Council The Australian Code for the Responsible Conduct of Research. National Health and Medical Research Council, the Australian Research Council, and Universities Australia; 2018. [Google Scholar]
12.World Medical Association World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]
13.US Food and Drug Administration Integrated addendum to ICH E6(R1): Guideline for good clinical practice E6(R2); International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Published 2016. Accessed April 20, 2020. https://www.fda.gov/files/drugs/published/E6%28R2%29-Good-Clinical-Practice--Integrated-Addendum-to-ICH-E6%28R1%29.pdf
14.Chan A-W, Tetzlaff JM, Altman DG, et al. . SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-207. doi: 10.7326/0003-4819-158-3-201302050-00583 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Moher D, Schulz KF, Altman DG, CONSORT Group . The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Clin Oral Investig. 2003;7(1):2-7. doi: 10.1007/s00784-002-0188-x [DOI] [PubMed] [Google Scholar]
16.Hopewell S, Clarke M, Moher D, et al. ; CONSORT Group . CONSORT for reporting randomised trials in journal and conference abstracts. Lancet. 2008;371(9609):281-283. doi: 10.1016/S0140-6736(07)61835-2 [DOI] [PubMed] [Google Scholar]
17.Mohebbi M, Dodd S, Dean OM, Berk M. Patient centric measures for a patient centric era: agreement and convergent between ratings on the Patient Global Impression of Improvement (PGI-I) scale and the Clinical Global Impressions-Improvement (CGI-S) scale in bipolar and major depressive disorder. Eur Psychiatry. 2018;53:17-22. doi: 10.1016/j.eurpsy.2018.05.006 [DOI] [PubMed] [Google Scholar]
18.Vilagut G, Forero CG, Barbaglia G, Alonso J. Screening for depression in the general population with the Center for Epidemiologic Studies Depression (CES-D): a systematic review with meta-analysis. PLoS One. 2016;11(5):e0155431. doi: 10.1371/journal.pone.0155431 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for depression in well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am J Prev Med. 1994;10(2):77-84. doi: 10.1016/S0749-3797(18)30622-6 [DOI] [PubMed] [Google Scholar]
20.Irwin M, Artin KH, Oxman MN. Screening for depression in the older adult: criterion validity of the 10-item Center for Epidemiological Studies Depression Scale (CES-D). Arch Intern Med. 1999;159(15):1701-1704. doi: 10.1001/archinte.159.15.1701 [DOI] [PubMed] [Google Scholar]
21.Ghubash R, Daradkeh TK, Al Naseri KS, Al Bloushi NB, Al Daheri AM. The performance of the Center for Epidemiologic Study Depression Scale (CES-D) in an Arab female community. Int J Soc Psychiatry. 2000;46(4):241-249. doi: 10.1177/002076400004600402 [DOI] [PubMed] [Google Scholar]
22.World Health Organization Depression and other common mental disorders: global health estimates. Published 2017. Accessed April 21, 2020. https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf [Google Scholar]
23.Fournier JC, DeRubeis RJ, Hollon SD, et al. . Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47-53. doi: 10.1001/jama.2009.1943 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.McNeil JJ, Woods RL, Nelson MR, et al. ; ASPREE Investigator Group . Baseline characteristics of participants in the ASPREE (Aspirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci. 2017;72(11):1586-1593. doi: 10.1093/gerona/glw342 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.McNeil JJ, Wolfe R, Woods RL, et al. ; ASPREE Investigator Group . Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379(16):1509-1518. doi: 10.1056/NEJMoa1805819 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.McNeil JJ, Woods RL, Nelson MR, et al. ; ASPREE Investigator Group . Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379(16):1499-1508. doi: 10.1056/NEJMoa1800722 [DOI] [PMC free article] [PubMed] [Google Scholar]
27.McNeil JJ, Nelson MR, Woods RL, et al. ; ASPREE Investigator Group . Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018;379(16):1519-1528. doi: 10.1056/NEJMoa1803955 [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Brunello N, Alboni S, Capone G, et al. . Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol. 2006;21(4):219-225. doi: 10.1097/00004850-200607000-00004 [DOI] [PubMed] [Google Scholar]
29.Alboni S, Benatti C, Capone G, Tascedda F, Brunello N. Neither all anti-inflammatory drugs nor all doses are effective in accelerating the antidepressant-like effect of fluoxetine in an animal model of depression. J Affect Disord. 2018;235:124-128. doi: 10.1016/j.jad.2018.04.063 [DOI] [PubMed] [Google Scholar]
30.Wang Y, Yang F, Liu YF, Gao F, Jiang W. Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats. Neurosci Lett. 2011;499(2):74-79. doi: 10.1016/j.neulet.2011.05.035 [DOI] [PubMed] [Google Scholar]
31.Sepehrmanesh Z, Fahimi H, Akasheh G, Davoudi M, Gilasi H, Ghaderi A. The effects of combined sertraline and aspirin therapy on depression severity among patients with major depressive disorder: a randomized clinical trial. Electron Physician. 2017;9(11):5770-5777. doi: 10.19082/5770 [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Almeida OP, Alfonso H, Jamrozik K, Hankey GJ, Flicker L. Aspirin use, depression, and cognitive impairment in later life: the Health in Men study. J Am Geriatr Soc. 2010;58(5):990-992. doi: 10.1111/j.1532-5415.2010.02827.x [DOI] [PubMed] [Google Scholar]
33.Pasco JA, Jacka FN, Williams LJ, et al. . Clinical implications of the cytokine hypothesis of depression: the association between use of statins and aspirin and the risk of major depression. Psychother Psychosom. 2010;79(5):323-325. doi: 10.1159/000319530 [DOI] [PubMed] [Google Scholar]
34.Kessing LV, Rytgaard HC, Gerds TA, Berk M, Ekstrøm CT, Andersen PK. New drug candidates for depressiona nationwide population-based study. Acta Psychiatr Scand. 2019;139(1):68-77. doi: 10.1111/acps.12957 [DOI] [PubMed] [Google Scholar]
35.Müller N. COX-2 inhibitors, aspirin, and other potential anti-inflammatory treatments for psychiatric disorders. Front Psychiatry. 2019;10:375. doi: 10.3389/fpsyt.2019.00375 [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21(4):227-231. doi: 10.1097/00004850-200607000-00005 [DOI] [PubMed] [Google Scholar]
37.Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:79-85. doi: 10.1016/j.pnpbp.2013.09.006 [DOI] [PubMed] [Google Scholar]
38.Bhatt S, Pundarikakshudu K, Patel P, et al. . Beneficial effect of aspirin against interferon-α-2b-induced depressive behavior in Sprague Dawley rats. Clin Exp Pharmacol Physiol. 2016;43(12):1208-1215. doi: 10.1111/1440-1681.12660 [DOI] [PubMed] [Google Scholar]
39.Williams LJ, Pasco JA, Mohebbi M, et al. . Statin and aspirin use and the risk of mood disorders among men. Int J Neuropsychopharmacol. 2016;19(6):pyw008. doi: 10.1093/ijnp/pyw008 [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Almeida OP, Flicker L, Yeap BB, Alfonso H, McCaul K, Hankey GJ. Aspirin decreases the risk of depression in older men with high plasma homocysteine. Transl Psychiatry. 2012;2:e151. doi: 10.1038/tp.2012.79 [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Molero P, Ruiz-Estigarribia L, Lahortiga-Ramos F, et al. . Use of non-steroidal anti-inflammatory drugs, aspirin and the risk of depression: the “Seguimiento Universidad de Navarra (SUN)” cohort. J Affect Disord. 2019;247:161-167. doi: 10.1016/j.jad.2019.01.020 [DOI] [PubMed] [Google Scholar]
42.Glaus J, Vandeleur CL, Lasserre AM, et al. . Aspirin and statin use and the subsequent development of depression in men and women: results from a longitudinal population-based study. J Affect Disord. 2015;182:126-131. doi: 10.1016/j.jad.2015.03.044 [DOI] [PubMed] [Google Scholar]
43.Bauer IE, Green C, Colpo GD, et al. . A double-blind, randomized, placebo-controlled study of aspirin and N-acetylcysteine as adjunctive treatments for bipolar depression. J Clin Psychiatry. 2018;80(1):18m12200. doi: 10.4088/JCP.18m12200 [DOI] [PubMed] [Google Scholar]
44.Savitz JB, Teague TK, Misaki M, et al. . Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry. 2018;8(1):27. doi: 10.1038/s41398-017-0073-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Bhatnagar P, Wickramasinghe K, Wilkins E, Townsend N. Trends in the epidemiology of cardiovascular disease in the UK. Heart. 2016;102(24):1945-1952. doi: 10.1136/heartjnl-2016-309573 [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Jorm AF, Patten SB, Brugha TS, Mojtabai R. Has increased provision of treatment reduced the prevalence of common mental disorders? review of the evidence from four countries. World Psychiatry. 2017;16(1):90-99. doi: 10.1002/wps.20388 [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Morris G, Puri BK, Walker AJ, et al. . Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders. Neurosci Biobehav Rev. 2019;107:862-882. doi: 10.1016/j.neubiorev.2019.09.025 [DOI] [PubMed] [Google Scholar]
48.O’Neil A, Jacka FN, Quirk SE, et al. . A shared framework for the common mental disorders and non-communicable disease: key considerations for disease prevention and control. BMC Psychiatry. 2015;15:15. doi: 10.1186/s12888-015-0394-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Ornelas A, Zacharias-Millward N, Menter DG, et al. . Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev. 2017;36(2):289-303. doi: 10.1007/s10555-017-9675-z [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Stocks NP, González-Chica DA, Woods RL, et al. ; ASPREE Investigator Group . Quality of Life for 19,114 participants in the ASPREE (Aspirin in Reducing Events in the Elderly) study and their association with sociodemographic and modifiable lifestyle risk factors. Qual Life Res. 2019;28(4):935-946. doi: 10.1007/s11136-018-2040-z [DOI] [PMC free article] [PubMed] [Google Scholar]
51.Ikonomidis I, Andreotti F, Economou E, Stefanadis C, Toutouzas P, Nihoyannopoulos P. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation. 1999;100(8):793-798. doi: 10.1161/01.CIR.100.8.793 [DOI] [PubMed] [Google Scholar]
52.Gao XR, Adhikari CM, Peng LY, et al. . Efficacy of different doses of aspirin in decreasing blood levels of inflammatory markers in patients with cardiovascular metabolic syndrome. J Pharm Pharmacol. 2009;61(11):1505-1510. doi: 10.1211/jpp.61.11.0010 [DOI] [PubMed] [Google Scholar]
53.Chen YG, Xu F, Zhang Y, et al. . Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J (Engl). 2006;119(1):32-36. doi: 10.1097/00029330-200601010-00006 [DOI] [PubMed] [Google Scholar]
54.Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010;71(5):520-527. doi: 10.4088/JCP.09m05117yel [DOI] [PubMed] [Google Scholar]
55.Gaziano JM, Brotons C, Coppolecchia R, et al. ; ARRIVE Executive Committee . Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018;392(10152):1036-1046. doi: 10.1016/S0140-6736(18)31924-X [DOI] [PMC free article] [PubMed] [Google Scholar]
56.Bowman L, Mafham M, Stevens W, et al. ; ASCEND Study Collaborative Group . ASCEND: a Study of Cardiovascular Events in Diabetes: characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144. doi: 10.1016/j.ahj.2017.12.006 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Protocol.

Click here for additional data file.^{(867.9KB, pdf)}

Supplement 2.

eTable. Exploratory Outcomes (CESD-10≥10, and ≥12) Comparison in Aspirin and Placebo: Odds Ratios at Follow-Up Annual Visits.

Click here for additional data file.^{(170.4KB, pdf)}

Supplement 3.

Data-Sharing Statement.

Click here for additional data file.^{(74.4KB, pdf)}

[yoi200029r1] 1.Cuijpers P, van Straten A, Smit F, Mihalopoulos C, Beekman A. Preventing the onset of depressive disorders: a meta-analytic review of psychological interventions. Am J Psychiatry. 2008;165(10):1272-1280. doi: 10.1176/appi.ajp.2008.07091422 [DOI] [PubMed] [Google Scholar]

[yoi200029r2] 2.Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206-215. doi: 10.1016/j.bbi.2015.06.001 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r3] 3.Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord. 2013;150(3):736-744. doi: 10.1016/j.jad.2013.06.004 [DOI] [PubMed] [Google Scholar]

[yoi200029r4] 4.Więdłocha M, Marcinowicz P, Krupa R, et al. . Effect of antidepressant treatment on peripheral inflammation markers: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2018;80(Pt C):217-226. doi: 10.1016/j.pnpbp.2017.04.026 [DOI] [PubMed] [Google Scholar]

[yoi200029r5] 5.Pasco JA, Nicholson GC, Williams LJ, et al. . Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry. 2010;197(5):372-377. doi: 10.1192/bjp.bp.109.076430 [DOI] [PubMed] [Google Scholar]

[yoi200029r6] 6.Berk M, Dean O, Drexhage H, et al. . Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Med. 2013;11(1):74. doi: 10.1186/1741-7015-11-74 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r7] 7.Berk M, Woods RL, Nelson MR, et al. . ASPREE-D: Aspirin for the prevention of depression in the elderly. Int Psychogeriatr. 2016;28(10):1741-1748. doi: 10.1017/S104161021600079X [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r8] 8.Wolfe R, Murray AM, Woods RL, et al. . The aspirin in reducing events in the elderly trial: statistical analysis plan. Int J Stroke. 2018;13(3):335-338. doi: 10.1177/1747493017741383 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r9] 9.ASPREE Investigator Group Study design of Aspirin in Reducing Events in the Elderly (ASPREE): a randomized, controlled trial. Contemp Clin Trials. 2013;36(2):555-564. doi: 10.1016/j.cct.2013.09.014 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r10] 10.National Health and Medical Research Council National Statement on Ethical Conduct in Human Research (2007)—Updated 2015. National Health and Medical Research Council; 2015. [Google Scholar]

[yoi200029r11] 11.National Health and Medical Research Council The Australian Code for the Responsible Conduct of Research. National Health and Medical Research Council, the Australian Research Council, and Universities Australia; 2018. [Google Scholar]

[yoi200029r12] 12.World Medical Association World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]

[yoi200029r13] 13.US Food and Drug Administration Integrated addendum to ICH E6(R1): Guideline for good clinical practice E6(R2); International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Published 2016. Accessed April 20, 2020. https://www.fda.gov/files/drugs/published/E6%28R2%29-Good-Clinical-Practice--Integrated-Addendum-to-ICH-E6%28R1%29.pdf

[yoi200029r14] 14.Chan A-W, Tetzlaff JM, Altman DG, et al. . SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200-207. doi: 10.7326/0003-4819-158-3-201302050-00583 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r15] 15.Moher D, Schulz KF, Altman DG, CONSORT Group . The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Clin Oral Investig. 2003;7(1):2-7. doi: 10.1007/s00784-002-0188-x [DOI] [PubMed] [Google Scholar]

[yoi200029r16] 16.Hopewell S, Clarke M, Moher D, et al. ; CONSORT Group . CONSORT for reporting randomised trials in journal and conference abstracts. Lancet. 2008;371(9609):281-283. doi: 10.1016/S0140-6736(07)61835-2 [DOI] [PubMed] [Google Scholar]

[yoi200029r17] 17.Mohebbi M, Dodd S, Dean OM, Berk M. Patient centric measures for a patient centric era: agreement and convergent between ratings on the Patient Global Impression of Improvement (PGI-I) scale and the Clinical Global Impressions-Improvement (CGI-S) scale in bipolar and major depressive disorder. Eur Psychiatry. 2018;53:17-22. doi: 10.1016/j.eurpsy.2018.05.006 [DOI] [PubMed] [Google Scholar]

[yoi200029r18] 18.Vilagut G, Forero CG, Barbaglia G, Alonso J. Screening for depression in the general population with the Center for Epidemiologic Studies Depression (CES-D): a systematic review with meta-analysis. PLoS One. 2016;11(5):e0155431. doi: 10.1371/journal.pone.0155431 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r19] 19.Andresen EM, Malmgren JA, Carter WB, Patrick DL. Screening for depression in well older adults: evaluation of a short form of the CES-D (Center for Epidemiologic Studies Depression Scale). Am J Prev Med. 1994;10(2):77-84. doi: 10.1016/S0749-3797(18)30622-6 [DOI] [PubMed] [Google Scholar]

[yoi200029r20] 20.Irwin M, Artin KH, Oxman MN. Screening for depression in the older adult: criterion validity of the 10-item Center for Epidemiological Studies Depression Scale (CES-D). Arch Intern Med. 1999;159(15):1701-1704. doi: 10.1001/archinte.159.15.1701 [DOI] [PubMed] [Google Scholar]

[yoi200029r21] 21.Ghubash R, Daradkeh TK, Al Naseri KS, Al Bloushi NB, Al Daheri AM. The performance of the Center for Epidemiologic Study Depression Scale (CES-D) in an Arab female community. Int J Soc Psychiatry. 2000;46(4):241-249. doi: 10.1177/002076400004600402 [DOI] [PubMed] [Google Scholar]

[yoi200029r22] 22.World Health Organization Depression and other common mental disorders: global health estimates. Published 2017. Accessed April 21, 2020. https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf [Google Scholar]

[yoi200029r23] 23.Fournier JC, DeRubeis RJ, Hollon SD, et al. . Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47-53. doi: 10.1001/jama.2009.1943 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r24] 24.McNeil JJ, Woods RL, Nelson MR, et al. ; ASPREE Investigator Group . Baseline characteristics of participants in the ASPREE (Aspirin in Reducing Events in the Elderly) study. J Gerontol A Biol Sci Med Sci. 2017;72(11):1586-1593. doi: 10.1093/gerona/glw342 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r25] 25.McNeil JJ, Wolfe R, Woods RL, et al. ; ASPREE Investigator Group . Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379(16):1509-1518. doi: 10.1056/NEJMoa1805819 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r26] 26.McNeil JJ, Woods RL, Nelson MR, et al. ; ASPREE Investigator Group . Effect of aspirin on disability-free survival in the healthy elderly. N Engl J Med. 2018;379(16):1499-1508. doi: 10.1056/NEJMoa1800722 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r27] 27.McNeil JJ, Nelson MR, Woods RL, et al. ; ASPREE Investigator Group . Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med. 2018;379(16):1519-1528. doi: 10.1056/NEJMoa1803955 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r28] 28.Brunello N, Alboni S, Capone G, et al. . Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression. Int Clin Psychopharmacol. 2006;21(4):219-225. doi: 10.1097/00004850-200607000-00004 [DOI] [PubMed] [Google Scholar]

[yoi200029r29] 29.Alboni S, Benatti C, Capone G, Tascedda F, Brunello N. Neither all anti-inflammatory drugs nor all doses are effective in accelerating the antidepressant-like effect of fluoxetine in an animal model of depression. J Affect Disord. 2018;235:124-128. doi: 10.1016/j.jad.2018.04.063 [DOI] [PubMed] [Google Scholar]

[yoi200029r30] 30.Wang Y, Yang F, Liu YF, Gao F, Jiang W. Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats. Neurosci Lett. 2011;499(2):74-79. doi: 10.1016/j.neulet.2011.05.035 [DOI] [PubMed] [Google Scholar]

[yoi200029r31] 31.Sepehrmanesh Z, Fahimi H, Akasheh G, Davoudi M, Gilasi H, Ghaderi A. The effects of combined sertraline and aspirin therapy on depression severity among patients with major depressive disorder: a randomized clinical trial. Electron Physician. 2017;9(11):5770-5777. doi: 10.19082/5770 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r32] 32.Almeida OP, Alfonso H, Jamrozik K, Hankey GJ, Flicker L. Aspirin use, depression, and cognitive impairment in later life: the Health in Men study. J Am Geriatr Soc. 2010;58(5):990-992. doi: 10.1111/j.1532-5415.2010.02827.x [DOI] [PubMed] [Google Scholar]

[yoi200029r33] 33.Pasco JA, Jacka FN, Williams LJ, et al. . Clinical implications of the cytokine hypothesis of depression: the association between use of statins and aspirin and the risk of major depression. Psychother Psychosom. 2010;79(5):323-325. doi: 10.1159/000319530 [DOI] [PubMed] [Google Scholar]

[yoi200029r34] 34.Kessing LV, Rytgaard HC, Gerds TA, Berk M, Ekstrøm CT, Andersen PK. New drug candidates for depressiona nationwide population-based study. Acta Psychiatr Scand. 2019;139(1):68-77. doi: 10.1111/acps.12957 [DOI] [PubMed] [Google Scholar]

[yoi200029r35] 35.Müller N. COX-2 inhibitors, aspirin, and other potential anti-inflammatory treatments for psychiatric disorders. Front Psychiatry. 2019;10:375. doi: 10.3389/fpsyt.2019.00375 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r36] 36.Mendlewicz J, Kriwin P, Oswald P, Souery D, Alboni S, Brunello N. Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study. Int Clin Psychopharmacol. 2006;21(4):227-231. doi: 10.1097/00004850-200607000-00005 [DOI] [PubMed] [Google Scholar]

[yoi200029r37] 37.Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:79-85. doi: 10.1016/j.pnpbp.2013.09.006 [DOI] [PubMed] [Google Scholar]

[yoi200029r38] 38.Bhatt S, Pundarikakshudu K, Patel P, et al. . Beneficial effect of aspirin against interferon-α-2b-induced depressive behavior in Sprague Dawley rats. Clin Exp Pharmacol Physiol. 2016;43(12):1208-1215. doi: 10.1111/1440-1681.12660 [DOI] [PubMed] [Google Scholar]

[yoi200029r39] 39.Williams LJ, Pasco JA, Mohebbi M, et al. . Statin and aspirin use and the risk of mood disorders among men. Int J Neuropsychopharmacol. 2016;19(6):pyw008. doi: 10.1093/ijnp/pyw008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r40] 40.Almeida OP, Flicker L, Yeap BB, Alfonso H, McCaul K, Hankey GJ. Aspirin decreases the risk of depression in older men with high plasma homocysteine. Transl Psychiatry. 2012;2:e151. doi: 10.1038/tp.2012.79 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r41] 41.Molero P, Ruiz-Estigarribia L, Lahortiga-Ramos F, et al. . Use of non-steroidal anti-inflammatory drugs, aspirin and the risk of depression: the “Seguimiento Universidad de Navarra (SUN)” cohort. J Affect Disord. 2019;247:161-167. doi: 10.1016/j.jad.2019.01.020 [DOI] [PubMed] [Google Scholar]

[yoi200029r42] 42.Glaus J, Vandeleur CL, Lasserre AM, et al. . Aspirin and statin use and the subsequent development of depression in men and women: results from a longitudinal population-based study. J Affect Disord. 2015;182:126-131. doi: 10.1016/j.jad.2015.03.044 [DOI] [PubMed] [Google Scholar]

[yoi200029r43] 43.Bauer IE, Green C, Colpo GD, et al. . A double-blind, randomized, placebo-controlled study of aspirin and N-acetylcysteine as adjunctive treatments for bipolar depression. J Clin Psychiatry. 2018;80(1):18m12200. doi: 10.4088/JCP.18m12200 [DOI] [PubMed] [Google Scholar]

[yoi200029r44] 44.Savitz JB, Teague TK, Misaki M, et al. . Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial. Transl Psychiatry. 2018;8(1):27. doi: 10.1038/s41398-017-0073-7 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r45] 45.Bhatnagar P, Wickramasinghe K, Wilkins E, Townsend N. Trends in the epidemiology of cardiovascular disease in the UK. Heart. 2016;102(24):1945-1952. doi: 10.1136/heartjnl-2016-309573 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r46] 46.Jorm AF, Patten SB, Brugha TS, Mojtabai R. Has increased provision of treatment reduced the prevalence of common mental disorders? review of the evidence from four countries. World Psychiatry. 2017;16(1):90-99. doi: 10.1002/wps.20388 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r47] 47.Morris G, Puri BK, Walker AJ, et al. . Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders. Neurosci Biobehav Rev. 2019;107:862-882. doi: 10.1016/j.neubiorev.2019.09.025 [DOI] [PubMed] [Google Scholar]

[yoi200029r48] 48.O’Neil A, Jacka FN, Quirk SE, et al. . A shared framework for the common mental disorders and non-communicable disease: key considerations for disease prevention and control. BMC Psychiatry. 2015;15:15. doi: 10.1186/s12888-015-0394-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r49] 49.Ornelas A, Zacharias-Millward N, Menter DG, et al. . Beyond COX-1: the effects of aspirin on platelet biology and potential mechanisms of chemoprevention. Cancer Metastasis Rev. 2017;36(2):289-303. doi: 10.1007/s10555-017-9675-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r50] 50.Stocks NP, González-Chica DA, Woods RL, et al. ; ASPREE Investigator Group . Quality of Life for 19,114 participants in the ASPREE (Aspirin in Reducing Events in the Elderly) study and their association with sociodemographic and modifiable lifestyle risk factors. Qual Life Res. 2019;28(4):935-946. doi: 10.1007/s11136-018-2040-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r51] 51.Ikonomidis I, Andreotti F, Economou E, Stefanadis C, Toutouzas P, Nihoyannopoulos P. Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation. 1999;100(8):793-798. doi: 10.1161/01.CIR.100.8.793 [DOI] [PubMed] [Google Scholar]

[yoi200029r52] 52.Gao XR, Adhikari CM, Peng LY, et al. . Efficacy of different doses of aspirin in decreasing blood levels of inflammatory markers in patients with cardiovascular metabolic syndrome. J Pharm Pharmacol. 2009;61(11):1505-1510. doi: 10.1211/jpp.61.11.0010 [DOI] [PubMed] [Google Scholar]

[yoi200029r53] 53.Chen YG, Xu F, Zhang Y, et al. . Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J (Engl). 2006;119(1):32-36. doi: 10.1097/00029330-200601010-00006 [DOI] [PubMed] [Google Scholar]

[yoi200029r54] 54.Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010;71(5):520-527. doi: 10.4088/JCP.09m05117yel [DOI] [PubMed] [Google Scholar]

[yoi200029r55] 55.Gaziano JM, Brotons C, Coppolecchia R, et al. ; ARRIVE Executive Committee . Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. Lancet. 2018;392(10152):1036-1046. doi: 10.1016/S0140-6736(18)31924-X [DOI] [PMC free article] [PubMed] [Google Scholar]

[yoi200029r56] 56.Bowman L, Mafham M, Stevens W, et al. ; ASCEND Study Collaborative Group . ASCEND: a Study of Cardiovascular Events in Diabetes: characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144. doi: 10.1016/j.ahj.2017.12.006 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Effect of Aspirin vs Placebo on the Prevention of Depression in Older People

Michael Berk, MBBCh, PhD

Robyn L Woods, PhD

Mark R Nelson, MBBS, PhD

Raj C Shah, MD

Christopher M Reid, PhD

Elsdon Storey, MBBS, PhD

Sharyn Fitzgerald, PhD

Jessica E Lockery, MBBS

Rory Wolfe, PhD

Mohammadreza Mohebbi, PhD

Seetal Dodd, PhD

Anne M Murray, MD

Nigel Stocks, MBBS, MD

Paul B Fitzgerald, MD, PhD

Catherine Mazza, BA

Bruno Agustini, MD

John J McNeil, MBBS, PhD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Statistical Analyses

Results

Figure 1. Consolidated Standards of Reporting Trials Diagram for the Aspirin for the Prevention of Depression 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.

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

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.

Secondary End Points of ASPREE-D

SF-12 Mental Scores

Table 3. Twelve-Item Short-Form Health Survey Mental Component Summary Scores Comparison in Aspirin and Placebo Groups.

Hospitalization Attributable to Depression

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

Figure 2. Cumulative Incidence of Incident Depression.

Exploratory End Point of ASPREE-D

CES-D-10 Scores of 10 or More and 12 or More

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

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 Groups^a.