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The main objective of this study is to test the antidepressant (AD) efficacy of the pleiotropic and anti-inflammatory
tetracycline minocycline as an adjunct to an antidepressant standard treatment in patients suffering from treatment-resistant major depressive disorder (TRD). It has widely been demonstrated that patients with TRD exhibit an altered inflammatory status with increased peripheral cytokine levels that may eventually result in chronic, sub-threshold pro-inflammatory activation of microglia in the CNS. The latter may represent one specific neurobiological correlate of depressive symptoms in TRD. Evidence from animal models suggests this process to be targetable by anti-inflammatory minocycline. In the MINO-TRD trial, which is conduced as a nationwide, multi-center randomized placebo-controlled trial, 200 mg of oral minocycline daily are administered as add-on to AD standard treatment for a total period of 6 weeks with a 6 month follow-up period to a total number of n = 128 patients suffering from TRD. Eligibility to participate in the trial will explicitly not be based on a priori peripheral inflammatory markers. Instead, a large panel of putative predictive and therapeutic biomarkers will be assessed throughout the trial, including a patient-specific cell model system based on monocyte-derived macrophages that provides an ex vivo model for patient-specific microglia-like cells. These cells will be used in parallel to the clinical intervention and provide a precision medicine approach for the targeted discovery of cell-based biomarkers.