Antibiotic Fails to Cut Negative Symptoms of Schizophrenia

Megan Brooks

October 17, 2018

In patients with recent-onset psychosis, adding the antibiotic minocycline to standard therapy has no effect on negative or other symptoms, in what is believed to be the largest double-blind, placebo-controlled trial of the drug in psychosis to date.

The BeneMin study results are "decisively negative, with no evidence of deterioration in negative symptoms or indices of inflammation or grey-matter loss, and no evidence that minocycline prevents or ameliorates negative symptoms or inflammatory or neuropathic processes," the authors led by Bill Deakin, MD, PhD, University of Manchester, United Kingdom, report.

The study was published online October 12 in Lancet Psychiatry.

Further Trials Unwarranted

The BeneMin study probed the therapeutic potential of minocycline in recent-onset schizophrenia and also its potential neuroprotective and anti-inflammatory mechanism of action.

The study included 207 patients with schizophrenia and schizoaffective disorder in their early illness phase (≤ 5 years), with 104 randomly allocated to minocycline (200 mg/day for 2 weeks, then 300 mg/day for the remainder of the 12-month study period) and 103 to matching placebo, on top of standard antipsychotic therapy and routine clinical care.

Compared with placebo, the addition of minocycline had no effect on ratings of negative symptoms on the Positive and Negative Syndrome Scale (PANSS), the primary clinical outcome (treatment effect difference, –0.19, 95% CI, –1.23 to 0.85; P = .73).

The primary biomarker outcomes — medial prefrontal grey-matter volume, dorsolateral prefrontal cortex activation during a working memory task, and plasma concentration of interleukin 6 — did not change over time and were not affected by minocycline.

Minocycline should not be used in the early adjunctive treatment of schizophrenia

"Minocycline should not be used in the early adjunctive treatment of schizophrenia," the researchers conclude. They note that 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."

"The notion that there are inflammatory underpinnings for some cases with psychosis is becoming well supported," Dolores Malaspina, MD, director of the psychosis program at the Icahn School of Medicine at Mount Sinai in New York City, who wasn't involved in the study, told Medscape Medical News.

"However studies done at the group level, which do not include biomarkers for probable inflammatory etiology in individual cases, are unlikely to show benefits of such interventions," she noted.

"As we move towards precision psychiatry there may be future person-specific trials of medications with such mechanism."

Noteworthy Study

Christoph U. Correll, MD, professor of psychiatry and molecular medicine, Hofstra Northwell School of Medicine, Hempstead, New York, said this is a noteworthy study.

"It is a very well-designed and well-conducted study in a sufficiently large sample, with a sufficiently long duration, testing potential biological target engagement in addition to the clinical outcome, and attempts to guard against biases, such as rater imprecision and nonadherence," he told Medscape Medical News.

Correll noted that the BeneMin results differ from prior studies and a prior meta-analysis that found significant advantages of augmentation with minocycline for PANSS total, negative, and general symptoms scores, clinical global impressions, and executive functioning in schizophrenia patients with a mean illness duration of 17.8 years.

He noted that the results can only be generalized to patients with schizophrenia or schizoaffective disorder in their early illness phase (≤ 5 years) treated with second-generation antipsychotics with only mild to moderate illness severity.

"Importantly, the study neither selected patients for severity of negative symptoms (rather at least mild positive symptoms was the inclusion criterion), nor for proinflammatory status," said Correll, who is medical director, Recognition and Prevention (RAP) Program, Zucker Hillside Hospital, Glen Oaks, New York.

"Prior studies in which minocycline was found to be beneficial were small, making a type I error possible, but patients were generally more chronically ill (illness duration, 17.8 years) and had higher PANSS total and PANSS negative symptom scores. Therefore, it is possible that the study by Deakin and colleagues could have had a floor effect, in that patients were too stable to improve significantly," said Correll.

"While prevention of worsening of negative symptoms was an added aim of the study, at a group level, patients improved and did not worsen on negative symptoms, even in the placebo arm, again making it impossible to separate from placebo on preventing the emergence and/or worsening of negative symptoms, as this did not occur," he added.

"Based on these important findings," said Correll said, "future studies with minocycline should be as large and well designed and conducted as the current study, but enrich the sample for the outcome and potential biological markers in order to test if, in fact, minocycline is also not more effective than placebo in patients with more than mild to moderate illness severity, illness chronicity, and marked or predominant and persistent negative symptoms."

Funding for the study was provided by the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) program, a partnership of the Medical Research Council (MRC) and NIHR. Deakin has received grants from P1vital and grants and personal fees from Autifony. A complete list of author disclosures is listed with the original article. Correll has been a consultant and/or advisor to or has received honoraria from Alkermes, Allergan, Angelini, Boehringer Ingelheim, Gerson Lehrman Group, Indivior, Intra-Cellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, ROVI, Servier, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a data safety monitoring board for Boehringer Ingelheim, Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a shareholder of LB Pharma. Malaspina has reported no relevant financial relationships.

Lancet Psych. Published online October 12, 2018. Abstract

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