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Table 1 Summary of key observational studies investigating the association between aspirin use and mental illness.

From: Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness

Author, year; study Hypotheses Study design Agent and dosage Sample Psychiatric measure Presentation of results Key finding
Sturmer, 1996; EBSHP ASA use affected decline of cognitive function Cohort study ASA: <1, 1 to 2 and, >2 tablets/day ASA effect hypothesized to be more dependent on frequency than on dose, mean daily dose was not used 3,631 NII >65 years old; 2,773 at 3-year follow-up, and 2,023 at 6-year follow-up SPMSQ, EBMT OR No significant effect seen. Modest benefit of ASA, especially with intermittent use, on decline of cognitive function
Henderson, 1997 ASA prevented dementia or cognitive impairment Community survey. Two-wave: cross-sectional at 2 wave; longitudinal from 1to 2 wave ASA yes/no (unknown dose) 1,045 participants 70 years old at baseline; 588 people with cognitive assessment at both waves CIE = MMSE, SLMT, NART Mean and SD Cross-sectional: no significant difference in cognitive tests. Longitudinal: no differences in cognitive decline or incidence of dementia
Stewart, 1997; BLSA Reduced risk of AD in ASA users Longitudinal ASA yes/no; NSAIDs yes/no; acetaminophen yes/no 1,686 participants in baseline study BIMCT, MMES, Immediate and Delayed Cued Recall, BNT, CVF, TMT A and B, Clock Drawing and other constructions, CESDS, PFAQ, NART RR Non-significant AD risk ratio for ASA users. Duration of ASA use and the risk of AD were not significantly associated
Peacock, 1999; ARIC study Association of regular use of NSAIDs or ASA with cognitive function Cross-sectional cohort study NSAIDs yes/no; ASA yes/no 13,153 participants, 48 to 67 years old Delayed word recall test, WAIS-R digit symbol subtest, WFT Mean Weak negative association (<0.1) between current ASA and word fluency & recall. No association of lifetime ASA and cognitive index scores. ASA treatment for 8 years weakly associated with better word fluency
Landi, 2003 Relationship between NSAIDs and AD Cross-sectional ASA yes/no; NSAIDs yes/no 2,708 participants admitted to home care programs CPS Mean and SD NSAID users had a nearly 50% lower risk of cognitive impairment. For subjects using ASA, the risk estimated was similar; 67% decreased risk of cognitive impairment associated with non-ASA NSAID use
Nilsson, 2003; OCTO-Twin ASA protective for AD Cross-sectional and longitudinal Low-dose ASA (75 mg/day + 3500 mg/week) 250, 500 mg 702 participants >80 years old, 91 with dementia at baseline; 88 developed dementia during observational period; 315 people at follow-up DSM-III-R criteria for dementia, NINCDS/ARDRA criteria for AD, NINDS/AIREN criteria for vascular dementia, MMSE β At 9-year follow-up, significant association between ASA and lower frequency of AD and all dementia; significantly more likely that intact cognitive function was maintained in those taking ASA. Use of low-dose ASA alone did not affect the risk ratio
Cornelius, 2004; Kungsholmen Project Association between ASA and NSAIDs with AD and overall dementia, and influence of apoE ε4 Longitudinal cohort study ASA 75 to 500 mg/day yes/no; NSAIDs yes/no. Differences in dosages not considered 1,301 subjects >75 years old dementia-free at baseline; 987 at 1*follow-up (314 died); 650 at 2*follow-up (281 died) DSM III-R criteria for dementia, Hachinski scale for differential diagnoses AD versus VaD versus Mixed dementia, MMSE, neurological and psychiatric examinations, neuropsychological assessment Incidence 6-year increased AD risk in the ASA/apoE ε4 negative group
Jonker, 2004; LASA Protective effect of ASA on cognitive decline in older people Community-based study; ?case-control NSAIDs yes/no; ASA <100 mg yes/no 612 participants, 62 to 85 years old MMSE, AVLT, coding task OR 3-year follow-up of decline in episodic memory (immediate recall) for ASA users was reduced by more than three times. Effect of ASA was significant only in >75-year-olds
Shepherd, 2004; SOP Study ASA protective against AD   ASA yes/no 151 NII, >75 years old, dementia-free MMSE, Logical Memory and Similarities subtest from WAIS-R, BNT, visuo-perceptual abilities from the JLOT, COWAT Mean and SD ASA use was a significant positive predictor of performance on the Logical Memory test
Arvanitakis, 2008; ROS Relation between NSAIDs/AD, change in cognition, and AD pathology Longitudinal ASA yes/no; non-ASA NSAIDs yes/no 1,019 Catholic clergy, mean age 75 years old, dementia-free As reported previously [12] HR At 1 year-no apparent relation of ASA to incident AD, change in cognition, or AD pathology
Szekely, 2008; CHCS Association between NSAIDs, ASA, and acetaminophen with dementia and AD Prospective ASA yes/no; NSAIDs yes/no; acetaminophen yes/no. No dosage reported 3229 participants >65 years old, dementia-free 1228 ASA users NINCDS/ARDRA criteria for AD, ADDTC criteria for VaD, Mixed dementia diagnosis, 3MSE, MRI OR At 10 years, risk of AD, VaD, and all-cause dementia was not associated with use of ASA
Almeida, 2010 ASA decreased prevalence of depression and cognitive impairment Retrospective Not reported 5,556 men 69 to 87 years old GDS, MMSE OR ASA not associated with lower OR of depression or cognitive impairment in >75-year-old men. Discontinuation of ASA between the two assessments related to greater OR of depression than non-users
Pasco, 2010; GOS ASA reduced the risk for depression; ASA + statin reduced risk of de novo depression Case-control study, retrospective cohort analysis ASA yes/no 386 women >50 - years old. 1* MDD >50 years old versus no MDD. No prior MDD, followed up from baseline or time of exposure to ASA, until 1* MDD or 10-year follow-up SCID I RV-NP OR and HR OR for MDD in the ASA group was 0.18, P = 0.1 The prevalence of exposure to statins + ASA was lower for women with MDD; OR for MDD was 0.15 (95% CI 0.03 to 0.65, P = 0.01). Exposure to statins + ASA was associated with a reduced risk for MDD
Waldstein, 2010; BLSA Relation between ASA and NSAIDs and age-related change in cognitive functions Cross-sectional and longitudinal ASA yes/no; NSAIDs yes/no 2300 dementia-free Digits Forward and Backward portions of WAIS-R, CVLT, BVRT, TMT, Letter & Category Fluency, BNT, MMSE, BIMCT SE Cross-sectional: use of ASA related to better average performance across testing sessions on measures of verbal and visual learning, and memory and global mental status. Longitudinal: ASA related to greater prospective decline on BIMCT and the BVRT. Significant effects of ASA use were noted for the BVRT, the CVLT learning slope and short free recall, and the MMSE, and indicated better average levels of function for ASA users
Clinical population
Ketterer, 1996; Coronary angiography Regular ASA prophylactic therapy for IHD associated with emotional distress   ASA 80 to 325 mg 174 men CMS, Framingham Type A Scale, KSSFC   ASA associated with less depression and anxiety or worry on the KSSFC
Stanford, 1999; HF or previouS OHT or CB    Usual schedule of drug therapy maintained 135 participants Profile of Mood States Mean and SEM More positive mood in ASA groups due to less fatigue. Tension and TMD in ASA patients just failed to reach criterion for statistical significance
Broe; 2000; SOP Study dementia   Case-control 80% on ASA 175 mg; no high dose 163 NII >75 years old with different dementias categories, and 373 control subjects NINCDS-ADRDA criteria for AD   Inverse association between ASA and AD, but not other dementia, not dosage-related
Mendlewicz, 2006; treatment-resistant DP Accelerating effect of ASA in combination with fluoxetine Open-label, uncontrolled Treated openly during 4 weeks with ASA 160 mg/day in addition to their current antidepressant treatment 21 participants underwent >4 weeks SSRI HDRS Mean and SD SSRI + ASA showed a global response rate of 52%. Remission was achieved in 43% of the total sample and 82% of the responder sample. In the responder group, a significant improvement was seen within week 1, which was sustained until day 28
Stolk, 2010; bipolar disorder NSAIDs and glucocorticoids ameliorate bipolar symptoms   ASA 30 or 80 mg/day or ASA >80 mg/kg or non-selective NSAIDs or COX-2i or GCs + lithium 5145 participants receiving lithium Incidence density of medication events (change in medication or increase of >30% of the current dose) Incidence density ratio Subjects receiving ASA 30 or 80 mg/day were 17% less likely to have a medication event; with >80 mg/kg ASA, non-selective NSAIDs, COX-2i, and GCs were not significant, but non- selective NSAIDs and GCs significantly increased medication events
  1. 3MSE, Modified Mini-Mental State Examination; AD, Alzheimer's disease; ADDTC, Alzheimer Disease Diagnostic and Treatment Centers; apoE, apolipoprotein E; ASA, acetylsalicylic acid (aspirin); AVLT, Auditory-Verbal Learning Test; BIMCT, Blessed Information-Memory-Concentration Test; BNT, Boston Naming Test; BVRT, Benton Visual Retention Test; CESDS, Center for Epidemiologic Studies Depression Scale; CIE, Canberra Interview for the Elderly; CMS, Cook-Medley Scale; COWAT, Controlled Oral Word Association Test; COX-2i, cyclooxygenase-2 inhibitor; CVF, Competing Values Framework; CVLT, California Verbal Learning Test; DSM-III-R, Diagnostic and Statistical Manual of Mental Disorders, 3rd revision; EBMT, East Boston Memory Test; F-U, follow-up; GC, Glucocorticoids; GDS, Geriatric Depression Scale; HDRS, Hamilton Depression Rating Scale; HR, hazard ratio; IHD, ischemic heart disease; JLOT, Judgment of Line Orientation; KSSFC, Ketterer Stress Symptom Frequency Checklist; MDD, Major Depressive Disorder; MMSE, Mini-Mental State Examination; MRI, magnetic resonance imaging; NART, National Adult Reading Test; NII, Non-institutionalized individuals; NINCDS-ADRDA, National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association; NINDS/AIREN, National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences; NSAID non-steroidal anti-inflammatory drug; OR, odds ratio; PFAQ, Pfeffer Activities Questionnaire; PMS, Profile of Mood States; SCID I RV-NP, Structured Clinical Interview for DSM-IV Axis I Disorders, Research Version, Non-patient; SD, standard deviation; SE, standard error; SEM, standard error of the mean; SLMT, Symbol Letter Modalities Test; SPMSQ, Short Portable Mental Status Questionnaire; SSRI, selective serotonin reuptake inhibitor; TMD, Total Mood Disturbance Score; TMT, Trail Making Test; VaD, vascular dementia; vs, versus; WAIS-R, (Wechsler Adult Intelligence Scale - Revised; WFT, Word Fluency Test.