Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression

Abstract

IMPORTANCEInsufficient treatment response and resulting chronicity constitute a major problem in depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, represents a promising repurposing candidate in the treatment of TRD. OBJECTIVE To determine whether 6 weeks of minocycline as add-on to antidepressant treatment as usual can significantly reduce depressive symptoms in patients with TRD. DESIGN, SETTING, AND PARTICIPANTS The study was conducted in Germany and designed as a multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18 to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately respond to an initial antidepressant standard medication as per Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total of 258 patients were screened, of whom 173 were randomized and 168 were included into the intention-to-treat population. Statistical analysis was performed from April to November 2020. INTERVENTIONS Participants were randomized (1:1) to receive adjunct minocycline (200 mg/d) or placebo for 6 weeks. MAIN OUTCOMES AND MEASURES Primary outcome measure was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-totreat mixed model repeated measures. Secondary outcome measures were response, remission, and various other clinical rating scales. RESULTS Of 173 eligible and randomized participants (84 randomized to minocycline and 89 randomized to placebo), 168 formed the intention-to-treat sample (79 [47.0%] were women, 89 [53.0%] were men, 159 [94.6%] were White, 9 [6.4%] were of other race and ethnicity, including Asian and unknown ethnicity), with 81 in the minocycline group and 87 in the placebo group. The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0). There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the (continued) Key Points Question Does 6 weeks of minocycline treatment as add-on to standard antidepressant treatment reduce depressive symptoms in patients with treatment-resistant depression? Findings In this randomized clinical trial of 168 patients with treatmentresistant depression, 6 weeks of minocycline treatment did no...

New antidepressants: monoamines and beyond

“…Minocycline crosses the bloodbrain barrier, inhibits proinflammatory activation of microglial cells and is neuroprotective. 8 But in a recent study of 173 people who failed to respond adequately to an initial antidepressant, six weeks add-on treatment with minocycline did not reduce depressive symptoms any more than placebo. 8 "Specialists are prescribing antiinflammatories off-label in combination with other treatments for people with severe depression that doesn't respond well to other inter ventions," says Professor Pariante.…”

“…8 But in a recent study of 173 people who failed to respond adequately to an initial antidepressant, six weeks add-on treatment with minocycline did not reduce depressive symptoms any more than placebo. 8 "Specialists are prescribing antiinflammatories off-label in combination with other treatments for people with severe depression that doesn't respond well to other inter ventions," says Professor Pariante. "Current anti-inflammatories carry a risk of side-effects, such as gastrointestinal bleeding with NSAIDs.…”

“…For instance, several animal and small clinical studies found that the antibiotic minocycline may be an effective antidepressant, which seems plausible. Minocycline crosses the blood‐brain barrier, inhibits proinflammatory activation of microglial cells and is neuroprotective 8 . But in a recent study of 173 people who failed to respond adequately to an initial antidepressant, six weeks add‐on treatment with minocycline did not reduce depressive symptoms any more than placebo 8 …”

“…Meanwhile, increasing evidence suggests that inflammation contributes to some cases of depression and may impair antidepressant efficacy. 8,9 People with major depression often show, for example, increases in several acute phase proteins and proinflammatory cytokines in blood and cerebrospinal fluid. Several proinflammatory cytokines -including tumour necrosis factor, interleukin (IL)-6 and IL-1 beta -modulate synaptic plasticity.…”

Sex differences in a double-blind randomized clinical trial with minocycline in treatment-resistant depressed patients: CRP and IL-6 as sex-specific predictors of treatment response

“…These results highlight possible sex differences in the neuroprotective and anti-depressant effects of minocycline, with male-sex being possibly associated a better outcome than female-sex. A recent, large clinical trials by Hellmann-Regen et al (2022) found no effects of minocycline on depressive symptoms; although they stratified their sample for median CRP values, these were indicative of very low inflammation, with median values equivalent to approximately 1.2 mg/L in the minocycline arm and 0.6 mg/L in the placebo arm; moreover, they stratified the sample by sex but did not look at sex by CRP groups interaction ( Hellmann-Regen et al, 2022 ).…”