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Adding the statin simvastatin into the mix was no help for patients with treatment-resistant depression, according to a randomized clinical trial.

Compared with placebo, patients who added 20 mg/day of simvastatin on top of standard of care didn't see a significant difference in Montgomery-Åsberg Depression Rating Scale (MADRS) total score after 12 weeks, missing the trial's primary endpoint (estimated mean difference -0.61, 95% CI -3.69 to 2.46, P=0.70), M. Ishrat Husain, MBBS, MD, of the Centre for Addiction and Mental Health in Toronto, and colleagues found.

At week 12 of treatment, simvastatin patients had a mean 24-item Hamilton Rating Scale for Depression (HamD-24) score of 15.5, while placebo patients had an average score of 17.2, the group reported in .

There also wasn't a significant between-group difference seen in regards to 7-item Generalized Anxiety Disorder Scale (GAD-7) score and 4-item Morisky Medication Adherence Scale score at the end of the trial.

Overall treatment effects weren't moderated by baseline, body mass index, MADRS score, C-reactive protein level, nor lipid levels except for LDL cholesterol, the researchers noted. Interestingly, those with higher baseline LDL cholesterol did see a significantly lower MADRS score by week 12 in the placebo group but not the simvastatin group (b -4.82, 95% CI -7.77 to -1.87, P=0.001).

"[I]n the short-term treatment of [treatment-resistant depression], adjunctive simvastatin provided no therapeutic benefit compared with placebo added to standard care," Husain and co-authors wrote. Some lipid-lowering agents have previously suggested a benefit in treating depression, likely due to their "anti-inflammatory, antioxidant, and glutamatergic effects that are neuroprotective," the team added.

Husain's group referenced a 2021 that included four small randomized trials of adjunctive statins for depression, one of which tested simvastatin, that linked them with a medium antidepressant effect size. None of these, however, were tested in patients with treatment-resistant depression.

For the current trial, the researchers explained that they selected -- which was first approved by the FDA in 1991 -- as their statin of choice because it's the most lipophilic and would therefore have the greatest chance to cross the blood-brain barrier.

The Pakistan-based trial was conducted across several outpatient psychiatric clinics in five urban centers. The 150 participants recruited (77 randomized to simvastatin and 73 to placebo) were between the ages of 18 and 75 and had a DSM-5 confirmed major depressive disorder diagnosis and were currently in a major depressive episode. In addition, at least two antidepressants taken for at least 6 weeks had to have failed, and participants had to have a HamD-24 score of 14 or higher.

Median baseline MADRS, HamD-24, and GAD-7 scores were 28, 31, and 14, respectively. Most participants were taking two psychotropic medications at baseline and had been in their current depressive episode for 5 months.

All were instructed to continue their stable antidepressant dose and not initiate a new one or take up a new psychosocial intervention, but those who were already engaged could continue to do so.

"Further research is needed to identify immune-metabolic phenotypes of depression that may be more responsive to, or preventable with, targeted statins or other immunomodulatory treatments," the researchers concluded.

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