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The broad-spectrum antibiotic minocycline (multiple brands) is not effective when added to standard antidepressant therapy, the largest randomized controlled trial of minocycline in treatment-resistant depression (TRD) shows.

In the MinoTRD trial, lorazepam leg cramps 6 weeks of minocycline 200 mg daily added to stable antidepressant therapy did not show a statistically significant advantage over placebo on the overall course of depressive symptoms.

“The failure of minocycline treatment to reduce depressive symptoms in a naturalistic sample of patients with TRD is a setback for anti-inflammatory treatment strategies in this clinical population,” Julian Hellmann-Regen, MD, Department of Psychiatry and Neurosciences, Charité – Universitätsmedizin Berlin, Germany, and colleagues write.  

The findings were published online September 14 in JAMA Network Open.

No Additional Benefit

The “inflammatory hypothesis” of depression maintains that depression arises from increased immune activation and neurotrophic mechanisms.

This view is supported by observations that depression is accompanied by increased levels of pro-inflammatory cytokines. In addition, low-grade inflammatory processes may interfere with response to typical antidepressant medications. 

Minocycline has been put forth as a novel antidepressant, and a few small trials have hinted at a benefit, as reported by Medscape Medical News.

In the MinoTRD trial, 168 patients (mean age, 46 years; 53% men) with TRD were randomly allocated minocycline 200 mg/day or matching placebo in addition to usual antidepressant treatment for 6 weeks.

Results showed minocycline was well tolerated but was not superior to placebo in reducing depressive symptoms, the researchers report.

Overall, the mean Montgomery-Åsberg Depression Rating Scale (MADRS) score at baseline was 26.5. There was no significant between-group difference in mean change in MADRS score from baseline to 6 weeks, the primary outcome.

After 6 weeks of treatment, the mean reduction in MADRS score was 8.46 points in the minocycline group versus 8.01 points in the placebo group, and the difference of 1.46 points was not significant (P = .25).

Six weeks of minocycline treatment did not alter the course of depression severity compared with placebo, the investigators note.

Minocycline treatment also showed no statistically significant effect on secondary outcomes of response, remission, and various other clinical rating scales.

Caveats and Cautionary Notes

The researchers note that one explanation for the null result of the MinoTRD trial could be that the 6-week treatment duration was not long enough to reveal detectable differences. They point to a small study that showed a strong effect of minocycline compared with placebo by and after 8 weeks of treatment.

However, a closer look at that study suggests the overall effect in the minocycline group was due to an almost complete lack of improvement in the placebo group, “which is very unusual,” the investigators write.

In the MinoTRD trial, the magnitude of improvement for placebo was as expected from similar trials in TRD, they point out.

They also note that, unlike some other trials, the MinoTRD trial purposely recruited a naturalistic population of TRD, assuming (but not confirming) elevated baseline inflammation as a potential underlying cause in at least a subgroup of the patients.

Post-hoc stratification by baseline CRP levels in MinoTRD participants did not yield any results supporting the hypothesis of minocycline treatment possibly being more effective in participants with higher-grade baseline inflammation, the researchers report.

“Our results from this large randomized controlled trial of a pleiotropic anti-inflammatory drug in this difficult-to-treat patient population are of great clinical importance, robustly demonstrating that minocycline add-on treatment does not outperform placebo, not even in those participants with elevated levels of CRP prior to treatment initiation,” they write.

The trial was funded by a grant from the German Federal Ministry of Education and Research within the Consortium Optimizing Treatment of Depression, as part of the Research Network for Psychiatric Disorders. Hellmann-Regen has reported no relevant financial relationship. Disclosures for the other investigators are listed in the article.

JAMA Netw Open. Published online September 14, 2022. Full article

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