title: The benefit of minocycline on negative symptoms in early-phase psychosis in addition to standard care - extent and mechanism (BeneMin): study protocol for a randomised controlled trial.
abstract: 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. We present a protocol 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 UK and 15 National Health Service Trusts and Health Boards will be involved in recruiting participants, performing the study and analysing the data.
  
  
  CONCLUSIONS
  The BeneMin trial can inform as to whether in minocycline we have found a new and effective therapy against negative symptoms of psychosis. The European Union Clinical Trial Register: EudraCT 2010-022463-35 with the registration finalised in July 2011. The recruitment in the trial started in January 2013 with the first patient recruited in March 2013.
authors.affiliation: Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. dml45@cam.ac.uk.|Department of Psychiatry, Brain Mapping Unit, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Robinson Way, Cambridge, CB2 0SZ, UK. dml45@cam.ac.uk.
authors.forename: Danuta M
authors.initials: DM
authors.lastname: Lisiecka
authors.affiliation: Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK. js369@cam.ac.uk.|Department of Psychiatry, Brain Mapping Unit, University of Cambridge, Herchel Smith Building for Brain and Mind Sciences, Robinson Way, Cambridge, CB2 0SZ, UK. js369@cam.ac.uk.|Cambridge and Peterborough NHS Foundation Trust, Cambridge, UK. js369@cam.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Suckling
authors.affiliation: Department of Medicine, Centre for Mental Health, Faculty of Medicine, Imperial College, London, UK. t.r.barnes@imperial.ac.uk.|West London Mental Health NHS Trust, London, UK. t.r.barnes@imperial.ac.uk.
authors.forename: Thomas R E
authors.initials: TR
authors.lastname: Barnes
authors.affiliation: Institute of Brain, Behaviour and Mental Health, Clinical and Cognitive Neurosciences, University of Manchester, Manchester, UK. imran.chaudhry@manchester.ac.uk.|Lancashire Care Early Intervention Service, Accrington, UK. imran.chaudhry@manchester.ac.uk.
authors.forename: Imran B
authors.initials: IB
authors.lastname: Chaudhry
authors.affiliation: Department of Psychosis Studies, Institute of Psychiatry, King's College, London, UK. paola.dazzan@kcl.ac.uk.
authors.forename: Paola
authors.initials: P
authors.lastname: Dazzan
authors.affiliation: Institute of Brain, Behaviour and Mental Health, Clinical and Cognitive Neurosciences, University of Manchester, Manchester, UK. nusrat.husain@manchester.ac.uk.
authors.forename: Nusrat
authors.initials: N
authors.lastname: Husain
authors.affiliation: Cambridge and Peterborough NHS Foundation Trust, Cambridge, UK. pbj21@cam.ac.uk.|Department of Psychiatry, University of Cambridge, Cambridge, UK. pbj21@cam.ac.uk.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Jones
authors.affiliation: Institute of Neurology, University College London, London, UK. e.joyce@ucl.ac.uk.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Joyce
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK. S.Lawrie@ed.ac.uk.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lawrie
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK. r.upthegrove@bham.ac.uk.|Early Intervention Service, Birmingham and Solihull Mental Health NHS Foundation Trust, Birmingham, UK. r.upthegrove@bham.ac.uk.
authors.forename: Rachel
authors.initials: R
authors.lastname: Upthegrove
authors.affiliation: Institute of Brain, Behaviour and Mental Health, Clinical and Cognitive Neurosciences, University of Manchester, Manchester, UK. bill.deakin@manchester.ac.uk.|Manchester Mental Health and Social Care Trust, Manchester, UK. bill.deakin@manchester.ac.uk.
authors.forename: Bill
authors.initials: B
authors.lastname: Deakin
mesh_terms: D002985:Clinical Protocols; D004311:Double-Blind Method; D006801:Humans; D008279:Magnetic Resonance Imaging; D008911:Minocycline / Q000009:adverse effects / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017063:Outcome Assessment, Health Care; D011618:Psychotic Disorders / Q000188:drug therapy*
chemical_list: D018696:Neuroprotective Agents; D008911:Minocycline