Data Show Simvastatin Does Not Enhance Escitalopram Response in Comorbid Depression and Obesity

Results from an extensive study (NCT04301271) published in JAMA Psychiatry demonstrate that adding simvastatin (Zocor; Merck & Co.) to escitalopram (Lexapro; Forest Laboratories) did not elicit additional antidepressive effects in patients with comorbid major depressive disorder (MDD) and obesity despite improving cardiovascular risk, affirming that statins should not be relied on to help manage depression.^1-3

Statins, while effective at reducing cardiovascular risk, are unproven in reducing depression symptoms. | Image Credit: © roger ashford - stock.adobe.com

Possible Associations Between Statins and Antidepressive Effects

Previous small, experimental studies have described potential benefits of statins in MDD. One study group determined through an online observational study in 2021 that statins could influence an individual’s emotional biases, which are a marker for depression risk. Recent meta-analyses of cohort studies investigating the association have yielded differing results but suggested possible benefits of statins in lowering depression risk.³

Randomized clinical trials are necessary to truly elucidate the effectiveness of statins in combination with standard antidepressants. Though some small, randomized trials have reported benefits, others have failed to demonstrate any positive effects. Furthermore, no randomized trial has investigated these effects in patients with MDD and comorbid obesity, a difficult-to-treat population that often exhibits chronic MDD and is more difficult to treat with standard methods. Determining the association using a large, randomized population could have major implications for the treatment of both MDD and obesity.¹

“If statins really did have this antidepressive effect, we could kill 2 birds with 1 stone,” Professor Christian Otte, MD, the trial’s lead author, said in a news release accompanying the results. “Depression and adiposity, or obesity, are among the most common medical conditions globally. And they actually often appear together: those who are obese are at a higher risk of depression. In turn, those with depression are at a higher risk of obesity.”²

Despite Improving Metabolic Factors, Statins Have No Impact on Depression

For this 2-arm, double-blind, placebo-controlled, multicenter trial, the study authors randomized 160 patients (placebo: n = 79; simvastatin: n = 81) to receive either simvastatin 40 mg per day or placebo as an add-on to escitalopram. Patients received escitalopram at 10 mg for the first 2 weeks, with doses then increased to 20 mg until the study concluded. The primary outcome measured by the authors was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 12.¹

In both patient groups, MADRS scores from baseline to week 12 decreased substantially (simvastatin: –13.97 points [95% CI, –15.88 to –12.06]; placebo: –13.50 points [95% CI, –15.41 to –11.58]). Patients in the intent-to-treat sample demonstrated no major treatment effects of add-on simvastatin compared with add-on placebo in MADRS scores (MMRM least squares mean difference: 0.47 points [95% CI, –2.08 to 3.02]; P = .71), with preplanned sensitivity analyses confirming the result, according to the investigators.¹

Key secondary end points were also investigated. Patient-reported depression severity, as measured by the Beck Depression Inventory II (BDI-II) score, was reduced in both treatment cohorts, but there was no significant treatment effect for simvastatin. Notably, there were no meaningful group differences in any of the exploratory end points for quality of life, social functioning, or global impression of change from the participants’ or clinicians’ point of view, reaffirming the lack of simvastatin effects on mental health outcomes.¹

Despite the lack of effect on mental health end points, treatment with simvastatin had robust positive effects on metabolic health. Simvastatin helped reduce low-density lipoprotein and total cholesterol levels compared with placebo, suggesting strong adherence to the regimen among participants and the beneficial role statins can still play in this comorbid population.¹

Statins Should Still Be Prescribed in Comorbid MDD and Obesity

Based on currently available evidence, including these results, the investigators believe that it is unlikely that statins have clinically meaningful acute antidepressant effects. However, they counsel pharmacists and other treatment providers to continue prescribing statins in the case of comorbid MDD and obesity. MDD and obesity are each associated with heightened cardiovascular risk, necessitating statin administration in accordance with established guidelines.¹

Importantly, the authors note that patients with mental disorders are less likely to receive medication for cardiovascular indications compared with those without such disorders despite their increased cardiovascular risk. Pharmacists should remain motivated to educate patients with MDD and obesity on the possible physical and mental health benefits of statin use.^1,4

“When it comes to treating depression, statins therefore have no additional benefit,” Otte concluded. “To our present knowledge, traditional antidepressants remain the gold standard.”²

REFERENCES

1. Otte C, Chae WR, Dogan DY, et al. Simvastatin as add-on treatment to escitalopram in patients with major depression and obesity. JAMA Psychiatry. 2025. doi:10.1001/jamapsychiatry.2025.0801

2. Charité – Universitätsmedizin Berlin. Cholesterol-lowering drugs have no antidepressive effect. EurekAlert! News Release. Released June 4, 2025. Accessed July 16, 2025. https://www.eurekalert.org/news-releases/1086367

3. Simvastatin add-on Treatment to Standard Antidepressant Therapy in Patients With Comorbid Obesity and Major Depression (SIMCODE). National Library of Medicine. ClinicalTrials.gov Identifier: NCT04301271. Last Updated December 9, 2024. Accessed July 16, 2025. https://clinicaltrials.gov/study/NCT04301271

4. Mitchaell AJ, Lord O, Malone D, et al. Differences in the prescribing of medication for physical disorders in individuals with v. without mental illness: meta-analysis. British Journal of Psychiatry. 2012;201(6):435-443. doi:10.1192/bjp.bp.111.094532