Statins And Depression: Science Says This Combination Doesn't Work

Researchers tested whether simvastatin, a cholesterol-lowering medication, could help treat depression in obese people. All participants took the antidepressant escitalopram, and half also received simvastatin. After 12 weeks, there was no significant improvement in depression symptoms for those taking simvastatin, but the medication reduced cholesterol and inflammation, improving cardiovascular health.

Depression, also called major depressive disorder, is one of the illnesses that most impacts quality of life worldwide. Approximately one in six people will experience depression at some point in their lives. Obesity is also a major public health problem: currently, about one in eight people on the planet meets the criteria for this diagnosis. These two conditions often co-occur.

When a person has only one of them, the risk of developing the other increases by about 50% to 60%. Both depression and obesity are linked to chronic diseases, such as heart disease and diabetes, and also to a higher risk of premature death. Therefore, it is urgent to find more effective treatments when both occur at the same time.

Statins are medications typically used to lower blood cholesterol. They work by blocking an enzyme important for cholesterol production in the liver. However, beyond this effect, research has shown that statins can influence processes in the body that are also linked to depression, such as inflammation, the production of new neurons, the regulation of stress hormones, and the functioning of certain neurotransmitters.

Some studies have suggested that people who use statins have a lower risk of developing depression, but others have not confirmed this link.

Clinical trials, which are controlled studies designed to reliably test a treatment, have already evaluated the use of statins alongside antidepressants. Some smaller studies have found positive results, indicating that the combination could reduce symptoms of depression. However, more recent, larger, and better-conducted studies have not shown clear advantages.

Until now, no study of this type had been conducted specifically with people who suffer from depression and obesity simultaneously. This group is considered more difficult to treat, as they tend to have longer-lasting symptoms and greater resistance to conventional medications.

To investigate this, researchers conducted a study comparing two groups of patients with severe depression and obesity. All received the antidepressant escitalopram, but half also received simvastatin, while the other half received a placebo pill, which has no active effect. The goal was to determine whether simvastatin would help improve depression more than treatment with escitalopram alone.

The study was conducted at nine medical centers in Germany and included 161 adult patients. Participants were followed for 12 weeks. For the first two weeks, everyone took 10 milligrams of escitalopram per day, increasing to 20 milligrams by the end of the study. Those in the simvastatin group also received 40 milligrams of this medication per day.

The main outcome the scientists analyzed was the change in scores on a questionnaire that measures depression severity, called the Montgomery-Åsberg Depression Rating Scale, from the beginning to the end of treatment. The researchers also assessed other aspects of mental health and blood tests related to cardiovascular risk.

At the end of the study, there was no significant difference between the groups regarding improvement in depression symptoms. Simvastatin did not provide additional benefits over the effect of escitalopram in treating depression, nor in other mental health indicators assessed.

On the other hand, simvastatin clearly reduced bad cholesterol (low-density lipoprotein), total cholesterol, and C-reactive protein, which is a marker of inflammation in the body.

In summary, this study showed that, for patients with severe depression and obesity, adding simvastatin to escitalopram treatment did not help improve depression. However, the drug did provide benefits for cardiovascular health, which may be important for reducing future risk of heart disease.

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Simvastatin as Add-On Treatment to Escitalopram in Patients With Major Depression and Obesity: A Randomized Clinical Trial

Christian Otte, Woo Ri Chae, Deniz Yildirim Dogan, Dominique Piber, Stefan Roepke, An Bin Cho, Samuel Trumm, Michael Kaczmarczyk, Jelena Brasanac, Katja Wingenfeld, Stefanie Koglin, Johannes Wieditz, Klaus Junghanns, Michael Lucht, David Prvulovic, Tillmann H. C. Krüger, Jan Terock, Moritz Haaf, Tobias Hofmann, Nicole Mauche, Jan Philipp Klein, Hans Jörgen Grabe, Andreas Reif, Kai G. Kahl, Deborah Janowitz, Gregor Leicht, Kim Hinkelmann, Maria Strauß, Tim Friede, and Stefan M. Gold

JAMA Psychiatry. 2025;82;(8):759-767.

DOI: 10.1001/jamapsychiatry.2025.0801

Abstract: 

Major depressive disorder (MDD) and obesity are common noncommunicable disorders associated with substantial disease burden, which frequently occur comorbidly. Intriguingly, converging lines of evidence from animal models and genetic and observational studies have suggested a biological link between obesity, metabolic syndrome, and depression. Several small randomized clinical trials (RCTs) have suggested the antidepressive potential of statins. To examine whether simvastatin added to escitalopram is efficacious in improving depressive symptoms compared with add-on placebo. This was a confirmatory, double-blind, placebo-controlled, multicenter RCT. Adults with MDD and comorbid obesity from 9 tertiary care settings in Germany were enrolled in this analysis. Data were analyzed from July to October 2024. Simvastatin (40 mg per day) or placebo as add-on to escitalopram (10 mg for the first 2 weeks, then increased to 20 mg until the end of study) in a double-blind fashion for 12 weeks. The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline (week 0) to week 12. From August 21, 2020, to June 06, 2024, a total of 161 patients were enrolled at 9 sites in Germany, of which 160 patients were included in the intention-to-treat analysis (placebo: n = 79, simvastatin: n = 81; mean [SD] age, 39.0 [11.0] years; 126 female [79%]). Retention in the trial was excellent (95.6%), and blinding was effectively maintained. There were 4 serious adverse events with no difference between the groups. Primary end point analysis in the intention-to-treat sample showed no significant treatment effect of add-on simvastatin in MADRS scores (mixed models for repeated measures least squares mean difference, 0.47 points; 95% CI, −2.08 to 3.02; P = .71). No effects of simvastatin treatment were observed in any of the mental health–related secondary end points. However, simvastatin treatment significantly reduced low-density lipoprotein cholesterol (simvastatin, −40.37 mg/dL; 95% CI, −47.41 to −33.33 mg/dL; placebo, −3.78 mg/dL; 95% CI, −11.18 to 3.62 mg/dL; P < .001), total cholesterol (simvastatin, −39.07 mg/dL; 95% CI, −49.42 to −28.73 mg/dL; placebo, −4.89 mg/dL; 95% CI, −15.64 to 5.87 mg/dL; P < .001), and C-reactive protein (simvastatin, −1.04 mg/L; 95% CI, −1.89 to −0.20 mg/L; placebo, 0.57 mg/L; 95% CI, −0.28 to 1.42 mg/L; P = .003) compared with placebo. The study failed to meet its primary end point. This demonstrates that simvastatin did not exert additional antidepressive effects when added to escitalopram in patients with comorbid MDD and obesity, despite improving the cardiovascular risk profile. Trial Registration; ClinicalTrials.gov Identifier: NCT04301271