Adjunct Minocycline Shows No Benefit in Treatment-Resistant Depression

Adjunctive minocycline provided similar outcomes as placebo for people with treatment-resistant depression, the MinoTRD randomized clinical trial showed.

Treatment with minocycline, a tetracycline antibiotic, did not show a significant difference in depression severity scores versus placebo on the Montgomery-Åsberg Depression Rating Scale (MADRS), according to Isabella Heuser, MD, PhD, of Charité – Universitätsmedizin Berlin in Germany, and co-authors.

After 6 weeks, the mean score reduction in the minocycline treatment group was 8.46 points compared with 8.01 points in the placebo group. The difference of the least squares means for the two treatment groups was not statistically significant (1.46 points, 95% CI -1.04 to 3.96, P=0.25), the researchers reported in JAMA Network Open.

Minocycline also showed no significant effect on secondary outcomes. The drug was well tolerated, and the trial was completed by 85.2% of participants in the minocycline group and 86.2% of participants in the placebo group.

Treatment with minocycline has been considered a novel antidepressant approach due to its neuroprotective effects, the authors noted.

“There is profound evidence for antidepressant effects of minocycline in animal models, most likely mediated through beneficial effects on microglial activation,” Heuser and colleagues wrote.

“The failure of minocycline treatment to reduce depressive symptoms in a naturalistic sample of patients with treatment-resistant depression is a setback for anti-inflammatory treatment strategies in this clinical population, given the suggestive evidence for advantageous effects of minocycline from prior, albeit considerably smaller, trials,” they observed.

The MinoTRD (Minocycline in Treatment-Resistant Depression) trial was conducted at nine university hospitals in Germany between 2016 and 2020. It randomized 168 people to either adjunctive minocycline (n=81) or placebo (n=87).

Participants were included based on a current diagnosis of major depressive disorder, severity of depressive symptoms, and previous failure to respond to antidepressant medication. They were on an antidepressant regimen for at least 6 weeks without dose changes in the last 2 weeks before enrollment.

About half (47%) of participants were women and 94.6% were white. Mean age was 46.1 and mean MADRS score at baseline was 26.5. Baseline characteristics of participants were similar between treatment cohorts, but there were more females in the placebo group (55.2%) than in the minocycline group (38.3%).

For 6 weeks, participants took either 200 mg of minocycline daily (two 50 mg capsules in the morning and two in the evening) or placebo.

Despite previous findings that minocycline was effective against inflammation, the trial population was not selected for increased levels of serum C-reactive protein (CRP), Heuser and colleagues noted. A post hoc analysis for baseline CRP did not suggest minocycline would be more effective in participants exhibiting higher-grade baseline inflammation, however.

A possible limitation of MinoTRD may be that the treatment duration of 6 weeks was too short, the authors acknowledged.

“However, one of the goals of novel treatment strategies is a more rapid onset of action suggesting that a treatment period limited to 6 weeks should be considered advantageous compared with longer treatment regimens for any novel treatment strategy in treatment-resistant depression,” they wrote.