{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T17:34:26Z","timestamp":1784309666384,"version":"3.55.0"},"reference-count":43,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>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.<\/jats:p><\/jats:sec>Objective<\/jats:title>To assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>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<\/jats:italic> (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.<\/jats:p><\/jats:sec>Intervention<\/jats:title>Participants were randomized to receive standard care plus 20 mg\/d of simvastatin or placebo.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The primary outcome was the difference between the 2 groups in change in Montgomery-\u00c5sberg 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.<\/jats:p><\/jats:sec>Results<\/jats:title>A total of 150 participants were randomized to simvastatin (n\u2009=\u200977; median [IQR] age, 40 [30-45] years; 43 [56%] female) or placebo (n\u2009=\u200973; median [IQR] age, 35 [31-41] years; 40 [55%] female). A significant baseline to end point reduction in Montgomery-\u00c5sberg Depression Rating Scale total score was observed in both groups and did not differ significantly between groups (estimated mean difference for simvastatin vs placebo, \u22120.61; 95% CI, \u22123.69 to 2.46; P<\/jats:italic>\u2009=\u2009.70). 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.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>ClinicalTrials.gov Identifier: NCT03435744<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.0147","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T16:10:09Z","timestamp":1676909409000},"page":"e230147","source":"Crossref","is-referenced-by-count":21,"title":["Effect of Adjunctive Simvastatin on Depressive Symptoms Among Adults With Treatment-Resistant Depression"],"prefix":"10.1001","volume":"6","author":[{"given":"M. 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