The Benefit of Minocycline on Negative Symptoms in Schizophrenia: Extent and Mechanisms (BeneMin)

University of Edinburgh, University of Cambridge, University College, London, University of Birmingham, King's College London, Manchester Mental Health & Social Care Trust, Greater Manchester Mental Health NHS Foundation Trust, Northern Care Alliance NHS Foundation Trust, Lancashire Care NHS Foundation Trust, Cambridgeshire and Peterborough NHS Foundation Trust, West London Mental Health NHS Trust, North East London Foundation Trust, Central and North West London NHS Foundation Trust, Camden and Islington NHS Foundation Trust, South London and Maudsley NHS Foundation Trust, NHS Lothian, NHS Fife, NHS Borders, University Hospital Birmingham NHS Foundation Trust

The purpose of this study is to investigate if minocycline limits the development of negative symptoms in early psychosis and to test via what mechanism of action this change occurs.

Background Negative symptoms of psychosis do not respond to the traditional therapy with first- or second-generation antipsychotics and are among main causes of a decrease in quality of life observed in individuals suffering from the disorder. Minocycline, a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties has been suggested as a new potential therapy for negative symptoms. In the two previous clinical trials comparing minocycline and placebo, both added to the standard care, patients receiving minocycline showed increased reduction in negative symptoms. Three routes to neuroprotection by minocycline have been identified: neuroprotection against grey matter loss, anti-inflammatory action and stabilisation of glutamate receptors. However, it is not yet certain what the extent of the benefit of minocycline in psychosis is and what its mechanism is. This proposal is for a multi-centre double-blind randomised placebo-controlled clinical trial entitled The Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin). Methods After providing informed consent, 226 participants in the early phase of psychosis will be randomised to receive either 100 mg modified-release capsules of minocycline or similar capsules with placebo for 12 months in addition to standard care. The participants will be tested for outcome variables before and after the intervention period. The extent of benefit will be tested via clinical outcome measures, namely the Positive and Negative Syndrome Scale score, social and cognitive functioning scores, antipsychotic medication dose equivalent and level of weight gain. The mechanism of action of minocycline will be tested via blood screening for circulating cytokines and magnetic resonance imaging with three-dimensional T1-weighted rapid gradient-echo, proton density T2-weighted dual echo and T2*-weighted gradient echo planar imaging with N-back task and resting state. Eight research centres in the United Kingdom (UK) and 15 National Health Service Trusts and Health Boards will be involved in recruiting participants, performing the study and analysing the data.

Participants will receive capsules containing 100mg of minocycline (modified release), two per day for the first two weeks of the trial and then three per day for the remainder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.

Participants will receive placebo capsules entirely matching minocycline, two per day for the first two weeks of the trial and then three per day for the reminder of the 12 month treatment period in addition to antipsychotic drug treatment and other interventions by the responsibel medical officer.

Capsules containing 100mg minocycline (modified release), administered orally by the patient, two per day for the first two weeks and then three per day for the reminder of the 12 month treatment period in addition to standard therapy.

Dorsolateral-prefrontal cortex blood oxygen level dependent response during working memory task (primary biomarker outcome)

Inclusion Criteria: Meeting DSM-IV criteria for schizophrenia, schizophreniform or schizo-affective psychosis as assessed by the research team In an episode as defined by the presence of positive symptoms measured by Positive and Negative Syndrome Scale with a score higher than two in items 1,2,3 or 6 in the Positive scale In contact with early intervention community or in-patient service Within 5 years of first diagnosis Intelligence quotient (IQ) greater than 70 Participants and their partners must be willing to use effective birth control throughout the study and seven days after stopping trial medication. Females should have a negative pregnancy test Able to understand and willing to give written informed consent Fluent in English Exclusion Criteria: Current substance misuse diagnosis that in the opinion of the investigator may interfere with the study Patients who, in the investigator's judgement pose a current serious suicidal or violence risk Use of tetracycline antibiotics within 2 months of the randomisation visit or history of sensitivity or intolerance for this type of antibiotics History of Systemic Lupus Erythematosis (SLE) or a history of SLE in a first-degree relative Use of any investigational drug within a month of randomisation visit Relevant current or past hematologic, hepatic, renal, neurological or other medical disorder in the opinion of the principal investigator (PI) or the responsible medical officer (RMO) may interfere with the trial Taking medical treatments that could seriously interact with minocycline as described in the summary of product characteristics (SPC) and judged by the PI or the RMO Clinically significant deviation from the reference range in clinical laboratory test results as judged by the investigator Previous randomisation in the present study Pregnant or breastfeeding Meeting MRI exclusion criteria as defined by local scanning centres

Fully anonymised database will be made available in 2018. Basic demographics, Primary clinical and mechanistic outcome measures. Treatment allocation code