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Randomized Controlled Trial
. 2023 Feb 1;6(2):e230147.
doi: 10.1001/jamanetworkopen.2023.0147.

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

M Ishrat Husain  1   2 , Imran B Chaudhry  3   4   5 , Ameer B Khoso  5 , Tayyeba Kiran  5 , Nawaz Khan  5 , Farooq Ahmad  5 , John Hodsoll  6 , M Omair Husain  1   2 , Haider A Naqvi  7 , Asad T Nizami  8 , Nasim Chaudhry  5 , Hazrat A Khan  9 , Fareed Minhas  8 , Jeffrey H Meyer  1   2 , Moin A Ansari  10 , Benoit H Mulsant  1   2 , Nusrat Husain  4 , Allan H Young  6
Affiliations
Randomized Controlled Trial

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

M Ishrat Husain et al. JAMA Netw Open. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr M. I. Husain reported receiving grants from Compass Pathways, having stock options in Mindset, and consulting for Psyched Therapeutics and Wake Network outside the submitted work and previously serving as a member of the Board of Trustees of the Pakistan Institute of Living and Learning. Dr I. Chaudhry reported receiving support to attend and present scientific papers for national and international educational meetings and conferences from various pharmaceutical companies outside the submitted work. Dr Meyer reported receiving grants from Sanofi and Exceltis outside the submitted work and having a patent pending for inflammatory markers in depression and an issued patent for a dietary supplement for postpartum depression. Dr Mulsant reported receiving personal fees from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto during the conduct of the study and nonfinancial support from Capital Solution Design LLC (software used in a study founded by the CAMH Foundation) and HAPPYneuron (software used in a study founded by Brain Canada) outside the submitted work. Dr N. Husain reported receiving grants from the National Institute of Health Research, Wellcome Trust, Medical Research Council, and Grand Challenges Canada outside the submitted work and serving as the president of the Manchester Medical Society and as a National Institute for Health and Care Research (NIHR) senior investigator. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram
HamD-24 indicates 24-item of the Hamilton Rating Scale for Depression; LDL-C, low-density lipoprotein cholesterol (to convert to mmol/L, multiply by 0.0259).
Figure 2.
Figure 2.. Trajectory of Montgomery-Åsberg Depression Rating Scale Scores
Whiskers indicate 95% CIs.
See this image and copyright information in PMC

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