Adjunctive Aspirin vs Placebo in Patients With Schizophrenia: Results of Two Randomized Controlled Trials

Abstract

Two previous randomized controlled trials (RCTs) suggested that adjunctive aspirin is efficacious in treating schizophrenia. We conducted two 16-week double-blind randomized placebo-controlled RCTs of adjunctive 1000 mg aspirin vs placebo in schizophrenia. Study 1 included 200 patients, with Positive and Negative Syndrome Scale (PANSS) total score as the primary outcome. Study 2 included 160 patients with C-reactive protein (CRP) >1 mg/L at baseline; the primary outcome was PANSS-positive score. Dropout rates for aspirin/placebo were 12% in study 1 and 20% in study 2. Differences in outcome between aspirin and placebo were calculated with linear regression, adjusting for the baseline value of the outcome. No statistically significant between-group differences were found in primary or secondary outcomes in either study. Study 1: mean difference in PANSS at 16 weeks was −3.9 (95% CI: −8.4 to 0.5, P = .10, effect size (ES) = −0.25) and at 8 weeks was −3.5 (95% CI: −7.5 to 0.5, P = .11, ES = −0.22). Study 2: mean difference in PANSS at 16 weeks was 0.3 (95% CI: −4.1 to 4.7, P = .90, ES = 0.02) and in positive PANSS was 0.5 (95% CI: −1.0 to 2.1, P = .50, ES = 0.11). A meta-analysis of these data with the existing studies, excluding one with large baseline differences in total PANSS, found that the overall estimate of the effect of adjunctive aspirin on the PANSS total score comparing group means at the end of the study was −2.9 (95% CI: −6.6 to 0.7; P = .21), favoring aspirin. Our studies and meta-analysis failed to find a statistically significant improvement in the symptoms of schizophrenia from adjunctive aspirin therapy in comparison to placebo in schizophrenia. Trial registration: study 1: Clinicaltrials.gov: NCT01320982; study 2 (high CRP): EudraCT Number: 2014-000757-36.

Anti-inflammatory medications for the treatment of mental disorders: A scoping review

“…One study showed a significant reduction in total PANSS score and positive PANSS subscale compared with placebo at 12 weeks ( Laan et al, 2010 ); one also showed reduction in negative and general PANSS subscales at 6 weeks ( Attari et al, 2017 ). Two studies (reported in the same paper) did not show any benefit of Aspirin on PANSS by 16 weeks ( Weiser et al, 2021 ).…”

Inflammatory monocyte gene signature predicts beneficial within group effect of simvastatin in patients with schizophrenia spectrum disorders in a secondary analysis of a randomized controlled trial

“…Precision medicine aims to identify target groups based on clinical and/or biological factors, who may benefit from specific treatments. This approach has been successfully used in the past for other psychiatric conditions ( Raison et al, 2013 ; Huet et al, 2021 ; Cussotto et al, 2022 ), but has only rarely been used for outcomes of RCTs with schizophrenia patients: Martinuzzi et al (2019) successfully stratified a large number of first episode psychosis patients using the PANSS score in a clinical trial with amisulpride and Weiser pre-selected patients using a cut-off value of CRP in a trial with aspirin ( Weiser et al, 2021 ). Interestingly, post-hoc associations in the first episode psychosis patients did reveal an association of one cluster with higher levels of inflammatory markers ( Martinuzzi et al, 2019 ), but the study of Weiser and colleagues failed to show a significant effect of aspirin in the pre-selected patients.…”

“…Indeed, results of the OPTIMISE study, the so-far largest trial investigating clinical subtypes, found an association of specific clinical subtypes and inflammation, which were also relevant for clinical outcomes 4 weeks later ( Martinuzzi et al, 2019 ). Recently, the acute phase protein C-Reactive Protein (CRP) has been used as a single, prospective stratification marker for treatment with aspiring in SCZ ( Weiser et al, 2021 ), but failed to find an effect. We are not aware of research using stratification of patients based on their inflammatory gene-expression profile in SSD to predict response to anti-inflammatory treatment trials.…”

Candidates for Drug Repurposing to Address the Cognitive Symptoms in Schizophrenia

“…Results from clinical trials investigating effects of adding aspirin to standard antipsychotic treatment in schizophrenia are inconclusive [51,52]. Although some improvements of positive and negative symptoms have been reported, cognitive measures were not included in these studies [51,52]. This suggests the need for future studies investigating cognitive effects of aspirin in schizophrenia.…”

“…For the prevention of dementia, evidence is insufficient to fully evaluate the effect of aspirin on cognitive decline and risk of dementia [49,50]. Results from clinical trials investigating effects of adding aspirin to standard antipsychotic treatment in schizophrenia are inconclusive [51,52]. Although some improvements of positive and negative symptoms have been reported, cognitive measures were not included in these studies [51,52].…”