Effect of Adjunctive Simvastatin on Depressive Symptoms Among Adults With Treatment-Resistant Depression: A Randomized Clinical Trial

Importance: Immune-metabolic disturbances have been implicated in the pathophysiology of major depressive disorder and may be more prominent in individuals with treatment-resistant depression (TRD). Preliminary trials suggest that lipid-lowering agents, including statins, may be useful adjunctive treatments for major depressive disorder. However, no adequately powered clinical trials have assessed the antidepressant efficacy of these agents in TRD. Objective: To assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD. Design, Setting, and Participants: This 12-week, double-blind, placebo-controlled randomized clinical trial was conducted in 5 centers in Pakistan. The study involved adults (aged 18-75 years) with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) major depressive episode that had failed to respond to at least 2 adequate trials of antidepressants. Participants were enrolled between March 1, 2019, and February 28, 2021; statistical analysis was performed from February 1 to June 15, 2022, using mixed models. Intervention: Participants were randomized to receive standard care plus 20 mg/d of simvastatin or placebo. Main Outcomes and Measures: The primary outcome was the difference between the 2 groups in change in Montgomery-Åsberg Depression Rating Scale total scores at week 12. Secondary outcomes included changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, and the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. C-reactive protein and plasma lipids were measured at baseline and week 12. Results: A total of 150 participants were randomized to simvastatin (n = 77; median [IQR] age, 40 [30-45] years; 43 [56%] female) or placebo (n = 73; median [IQR] age, 35 [31-41] years; 40 [55%] female). A significant baseline to end point reduction in Montgomery-Åsberg Depression Rating Scale total score was observed in both groups and did not differ significantly between groups (estimated mean difference for simvastatin vs placebo, -0.61; 95% CI, -3.69 to 2.46; P = .70). Similarly, there were no significant group differences in any of the secondary outcomes or evidence for differences in adverse effects between groups. A planned secondary analysis indicated that changes in plasma C-reactive protein and lipids from baseline to end point did not mediate response to simvastatin. Conclusions and Relevance: In this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care. Trial Registration: ClinicalTrials.gov Identifier: NCT03435744.