Relapse of anti-inflammatory therapy in depression

Broad spectrum antibiotic minocycline (many brands) Not effective when added to standard antidepressant therapy Largest randomized controlled trial of minocycline in treatment resistance depression (TRD) Presentations.

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

Julian Hellmann-Regen, MD, Department of Psychiatry and Neurosciences, Charité – Universitätsmedizin Berlin, Germany and writing colleagues.

The results were Posted online September 14 in JAMA Network is open.

No additional benefit

The ‘inflammatory hypothesis’ of depression asserts 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 usual antidepressant medications.

Minocycline has been introduced as a new antidepressant, and some small trials have hinted at a benefit. As mentioned by Medscape Medical News.

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

The researchers reported that the results showed that minocycline was well tolerated but was not superior to placebo in reducing depressive symptoms.

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

After 6 weeks of treatment, the mean reduction in the 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 (s = .25).

The researchers noted that six weeks of minocycline treatment did not change the course of depression severity compared to placebo.

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

Warnings and cautionary notes

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

However, a closer look at that study suggested that 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 researchers wrote.

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

They also note that, in contrast to some other trials, the MinoTRD trial recruited a group of normal TRD populations, assuming (but without confirming) elevated primary inflammation as a possible underlying cause in at least a subset of patients.

The researchers reported that subsequent stratification by baseline CRP levels in MinoTRD participants yielded no results supporting the hypothesis of minocycline treatment that may be more effective in participants with high-grade underlying inflammation.

“Our results from this large, randomized, controlled trial of a multidirectional anti-inflammatory drug in this hard-to-treat patient group are of great clinical significance, strongly demonstrating that minocycline add-on therapy is not superior to placebo, not even in those participants with elevated levels of the lipoprotein. C-interactive before starting treatment,” they wrote.

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

Gamma Netto is open. Posted online September 14, 2022. full article

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