The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial

Abstract

SummaryBackgroundThe antibiotic minocycline has neuroprotective and anti-inflammatory properties that could prevent or reverse progressive neuropathic changes implicated in recent-onset schizophrenia. In the BeneMin study, we aimed to replicate the benefit of minocycline on negative symptoms reported in previous pilot studies, and to understand the mechanisms involved.MethodsIn this randomised, double-blind, placebo-controlled trial, we recruited people with a schizophrenia-spectrum disorder that had begun within the past 5 years with continuing positive symptoms from 12 National Health Service (NHS) trusts. Participants were randomly assigned according to an automated permuted blocks algorithm, stratified by pharmacy, to receive minocycline (200 mg per day for 2 weeks, then 300 mg per day for the remainder of the 12-month study period) or matching placebo, which were added to their continuing treatment. The primary clinical outcome was the negative symptom subscale score of the Positive and Negative Syndrome Scales (PANSS) across follow-ups at months 2, 6, 9, and 12. The primary biomarker outcomes were medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN49141214, and the EU Clinical Trials register (EudraCT) number is 2010-022463-35I.FindingsBetween April 16, 2013, and April 30, 2015, we recruited 207 people and randomly assigned them to receive minocycline (n=104) or placebo (n=103). Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms (treatment effect difference −0·19, 95% CI −1·23 to 0·85; p=0·73). The primary biomarker outcomes did not change over time and were not affected by minocycline. The groups did not differ in the rate of serious adverse events (n=11 in placebo group and n=18 in the minocycline group), which were mostly due to admissions for worsening psychiatric state (n=10 in the placebo group and n=15 in the minocycline group). The most common adverse events were gastrointestinal (n=12 in the placebo group, n=19 in the minocycline group), psychiatric (n=16 in placebo group, n=8 in minocycline group), nervous system (n=8 in the placebo group, n=12 in the minocycline group), and dermatological (n=10 in the placebo group, n=8 in the minocycline group).InterpretationMinocycline does not benefit negative or other symptoms of schizophrenia over and above adherence to routine clinical care in first-episode psychosis. There was no evidence of a persistent progressive neuropathic or inflammatory process underpinning negative symptoms. Further trials of minocycline in early psychosis are not warranted until there is clear evidence of an inflammatory process, such as microgliosis, against which minocycline has known efficacy.FundingNational Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.

Inflammation and Negative Symptoms of Schizophrenia: Implications for Reward Processing and Motivational Deficits

“…Minocycline, a tetracycline antibiotic that has been shown to purportedly be neuroprotective via it's anti-inflammatory and antiapoptotic properties (106), has also been investigated in patients with schizophrenia. A recent meta-analysis demonstrated benefit for minocycline across eight randomized controlled trials (107), although the largest study to date showed no benefit for minocycline for negative symptoms, which was the primary outcome for the study (108). The heterogeneity in results across studies (both individual and meta-analyses) for NSAIDs and minocycline may suggest that there are some individuals who would benefit from anti-inflammatory medications.…”

Adjunctive minocycline in schizophrenia: what one well-conducted study can tell us (and what it can’t)

“…The BeneMin trial3 informs clinical practice in that it should likely not be used to prevent emergence of negative symptoms in early phase patients. However, based on other trials,1 2 it is possible that minocycline is effective in patients with schizophrenia and prominent negative symptoms and/or notable inflammation.…”

“…Generalisation of the BeneMin3 trial results are limited by a selection of patients within their first psychotic episode, with mild to moderate illness severity, prominent positive symptoms and low baseline negative symptoms.…”

Catatonia and the immune system: a review

“…However, a 2018 double blinded, randomised study which specifically aimed to examine the effect of this drug on negative symptoms did not find any benefit. 62 No studies of which we are aware have investigated minocycline specifically for catatonia, but reports exist of two patients with schizophrenia and prominent catatonic features who responded well to minocycline in the absence of infection. 63,64 The evidence for innate immunity…”