Minocycline as adjunctive treatment for treatment-resistant depression: study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2)

Abstract

Background: Available evidence suggests that adjunctive treatment with immunomodulatory medications may be effective in the treatment of major depressive disorder (MDD). A pilot trial of the tetracycline minocycline as adjunctive treatment in treatment-resistant depression (TRD), produced promising results, however, a larger scale trial is needed to confirm the antidepressant actions of this drug. Methods: This is a 12-week double blind, placebo-controlled, randomized trial of minocycline as an add-on to standard antidepressants for adults (age > 18) with DSM-5 major depressive episode, who have failed to respond to at least two adequate trials of antidepressant treatment. It is a parallel-arm study with 50 participants in each group. The primary outcome measure is change in 17-item Hamilton Depression Rating Scale (HRSD-17) total scores from baseline to week 12. Secondary measures include the Clinical Global Impression (CGI) scale, World Health Organization Quality of Life Short Version (WHOQOL-BREF) and the Generalized Anxiety Disorder scale (GAD-7). Peripheral inflammatory biomarkers will be collected at baseline, week 6 and 12.Discussion: If minocycline is well tolerated and effective in reducing depressive symptoms in patients with TRD, it would warrant genuine consideration as a treatment option for TRD. Additionally, if results demonstrate that minocycline has antidepressant properties, and that changes in inflammatory status are associated with its antidepressant action, it will inform the development of individualized treatment for a subset of patients with MDD. Trial registration: Clinicaltrials.gov identifier: NCT03947827. Registered 13th May, 2019.

Updated Review and Meta-Analysis of Probiotics for the Treatment of Clinical Depression: Adjunctive vs. Stand-Alone Treatment

“…Studies have now established that antidepressants from most classes (including SSRIs, SNRIs, tricyclic antidepressants (TCA), monoamine oxidase inhibitors (MAOI), atypical and NMDA receptor antagonists) exhibit antimicrobial activity; however, the nature of this activity may differ between classes [38]. Conversely, some antibiotics also present antidepressant properties, and their efficacy for treatmentresistant depression is currently under investigation (e.g., minocycline [39,40]). It is yet unclear how the compositional gut microbiota abnormalities identified in depression [7,8] are impacted by these treatments.…”

Inflammation increases the development of depression behaviors in male rats after spinal cord injury

“…Notably, however, others have reported null effects with minocycline treatment in both rats and mice ( Deak et al., 2005 ; Vogt et al., 2016 ). Further, the largest randomized, placebo-controlled trial of anti-inflammatory treatments for depression has been recently completed and found no evidence that minocycline was superior to placebo, and no effects of minocycline treatment on serum C-reactive protein, a marker of inflammation ( Husain et al., 2020 ). Many variables including the route of administration, length of treatment, and etiology of depression may significantly affect the efficacy of anti-inflammatory strategies.…”

“…Minocycline, a tetracycline antibiotic known for its anti-inflammatory properties and ability to cross the blood-brain barrier, has been the focus of a number of recent clinical trials. It has proven to be significantly better than placebo for the treatment of unipolar depression ( Rosenblat and McIntyre 2018 ), although its efficacy has been called into question with a more recent clinical trial ( Husain et al., 2020 ). Minocycline has also been shown to attenuate depression-like behavior in numerous animal models of depression, including the olfactory bulbectomised (OB) rat and in rats with depression induced with lipopolysaccharide (LPS) ( Henry et al., 2008 ; O’Connor et al., 2009 ), restraint stress ( Hinwood et al., 2013 ) and inescapable shock ( Arakawa et al., 2012 ).…”

Neuroinflammatory alterations in trait anxiety: modulatory effects of minocycline

“…Along these lines, investigation of the effectiveness of minocycline in the treatment of chemotherapy-induced anxiety and depression in breast cancer patients is currently registered (NCT02203552). Also recently, another clinical trial has been initiated to assess the effect of minocycline as an adjunctive treatment (to standard antidepressants) for treatment-resistant depression and comorbid GAD 69 .…”