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

Lead Research Organisation: University of Manchester

Abstract

One of the major disabilities affecting the quality of life of people with schizophrenia is the development of a set of so-called negative symptoms comprising social withdrawal, self-neglect, loss of motivation and mild impairment of intelligence. Standard drug treatments are effective in reducing psychotic symptoms such as paranoid delusions and hearing voices, but they have little impact on negative symptoms. Two formal clinical trials suggest that a standard antibiotic and anti-inflammatory drug called minocycline commonly used in acne and other infections, reduces negative symptoms. In both studies patients with stable symptoms took either minocycline or exactly matching dummy tablets (placebo) in addition to their routine treatment for 6 or 12 months. Negative symptoms improved twice as much in those taking additional minocycline than in those taking the dummy tablets. It also lessened the weight gain that standard treatments usually cause. Other studies suggest that minocycline may also improve positive symptoms in acute episodes of illness. The aim of this proposal is to investigate whether minocycline is especially effective given early in the course of illness and to understand how it works. The proposal is to compare minocycline with placebo capsules added to each person’s treatment within 3 years of starting it. We will follow the effects on positive and negative symptoms over 12 months. Minocycline might work by protecting brain cells from damage possibly caused by inflammation. Brain imaging will tell us whether subtle changes in the grey matter of the brain in schizophrenia are lessened by minocycline over 12 months and whether this accounts for reduced negative symptoms. Measuring chemicals (cytokines) in the blood will tell us whether minocycline is working by blocking inflammation in the brain. Another possibility is simply that minocycline helps negative symptoms by helping brain cells work better and this can also be studied using modern brain imaging methods and by determining whether improvements are lost when the drug is stopped. This multicentre UK-wide study will be carried out by a group of experienced researchers in early psychosis that have worked together over several years to set up and test a secure UK research network for people in their first episode of psychosis. It is called PsyGrid (www.psygrid.org) and was funded by the Medical Research Council and the Department of Health. Clinical assessments from 960 patients were gathered in two years in 8 centres of the Mental Health Research Network (MHRN) in England. We have also shown that we can reliably combine brain imaging results using different brain scanners in different centres (www.neuropsygrid.org).

Technical Summary

AIMS: to use recently developed PsyGrid infrastructure for UK-wide clinical and imaging research in first episode psychosis to: i) determine whether negative symptoms can be lessened or prevented by minocycline treatment initiated early in the course of schizophrenia and ii) collect biomarker data to test hypotheses about how minocycline improves negative symptoms. PRIMARY EFFICACY PREDICTION AND MECHANISTIC HYPOTHESES: 1) Minocycline minimises later negative symptoms when administered during the acute phase of early psychosis 2) Minocycline reduces or prevents the negative symptoms of schizophrenia by: a) reducing the loss of grey matter associated with early psychosis. b) interfering with inflammatory cytokine production. c) an action on glutamate systems to improve negative symptoms and cognitive function. DESIGN. Multicentre, one year, double-blind randomised placebo-controlled trial of minocycline versus placebo, added to standard antipsychotic drug (APD) treatment, for patients in an early episode of schizophrenia-related psychosis. INTERVENTION. Minocycline or matching placebo 300mg daily for 12 months. OUTCOMES. The primary clinical outcome is negative symdrome subscale score on the Positive and Negative Syndrome Scale (PANSS). The mechanistic biomarker variables are: 1) change in medial prefrontal grey matter volume over 12 months, 2) circulating cytokine concentrations and 3) working memory performance and brain activation. These measures will be related to changes in PANSS negative symptoms at 2, and 12 months and to quality of life assessments. POPULATION AND SAMPLE SIZE. 170 patients with early psychosis recruited over 22 months from 6 established PsyGrid centres. STATISTICAL ANALYSIS. Group differences in outcomes and putative mediators will be evaluated using random effects models for longitudinal data (allowing for treatment centre and other baseline covariates). Tests of the mechanistic hypotheses (i.e. mediation), and their sensitivity of the results to possible hidden confounding, will use instrumental variable methods from PI Dunn’s MRC Methodology Research Programme projects; see Emsley R, Dunn G & White I (2009) modelling mediation and moderation of treatment effects in randomised controlled trials of complex interventions. Statistical Methods in Medical Research published online on 16/07/09. EXPERTISE. The investigators are experienced in the recruitment of early psychosis patients and the confidential collection of clinical assessments and brain imaging through their involvement in PsyGrid and NeuroPsyGrid.

Publications

10 25 50
 
Description Clinical trials of novel treatments for bipolar dsepression Minocycline/celecoxib
Amount $295,000 (USD)
Organisation Stanley Medical Research Institute (SMRI) 
Sector Charity/Non Profit
Country Global
Start  
 
Description Clinical trials of novel treatments for schizophrenia (omega 3/Minocycline for ARMS
Amount $298,240 (USD)
Organisation Stanley Medical Research Institute (SMRI) 
Sector Charity/Non Profit
Country Global
Start  
 
Description MRC Confidence in Concepts
Amount £78,000 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 09/2018
 
Description MRC challenge scheme
Amount £3,422,098 (GBP)
Funding ID MR/K020803/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 06/2018
 
Description Stratified Medicine
Amount £3,920,095 (GBP)
Funding ID MR/L011794/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2014 
End 06/2018
 
Description Sunovion commercial
Amount £455,071 (GBP)
Organisation P1vital Consortium 
Sector Private
Country United Kingdom
Start 03/2013 
End 08/2015
 
Description BeneMin 
Organisation King's College London
Department Clinical Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We lead the BeneMin clinic trial of minocycline in early psychosis. EME/NIHR grant
Collaborator Contribution Recruitment of patients
Impact in pregress
Start Year 2011
 
Description BeneMin 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We lead the BeneMin clinic trial of minocycline in early psychosis. EME/NIHR grant
Collaborator Contribution Recruitment of patients
Impact in pregress
Start Year 2011
 
Description BeneMin 
Organisation Queen Elizabeth Hospital Birmingham
Country United Kingdom 
Sector Hospitals 
PI Contribution We lead the BeneMin clinic trial of minocycline in early psychosis. EME/NIHR grant
Collaborator Contribution Recruitment of patients
Impact in pregress
Start Year 2011
 
Description BeneMin 
Organisation University of Cambridge
Department Department of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution We lead the BeneMin clinic trial of minocycline in early psychosis. EME/NIHR grant
Collaborator Contribution Recruitment of patients
Impact in pregress
Start Year 2011
 
Description BeneMin 
Organisation University of Edinburgh
Department Division of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution We lead the BeneMin clinic trial of minocycline in early psychosis. EME/NIHR grant
Collaborator Contribution Recruitment of patients
Impact in pregress
Start Year 2011
 
Description MRC Spring study (MR/K020803/1) 
Organisation Cardiff University
Department Brain Research Imaging Centre (CUBRIC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Cubric: magneto ecncepahalography (MEG) & magnetic resonance spectroscopy (MRS) Nottingham: MEG and c13 MRS
Collaborator Contribution 3 centre collaboration to recruit patients with early and established psychosis for biomarkers of glutamate, GABA neurochemistry and function in early psychosis
Impact Just starting. See outpiuts of MR/K020803/1
Start Year 2013
 
Description MRC Spring study (MR/K020803/1) 
Organisation University of Nottingham
Department Sir Peter Mansfield Magnetic Resonance Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Cubric: magneto ecncepahalography (MEG) & magnetic resonance spectroscopy (MRS) Nottingham: MEG and c13 MRS
Collaborator Contribution 3 centre collaboration to recruit patients with early and established psychosis for biomarkers of glutamate, GABA neurochemistry and function in early psychosis
Impact Just starting. See outpiuts of MR/K020803/1
Start Year 2013
 
Description Proteomics 
Organisation University of Manchester
Department Stoller Biomarker Discovery Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution The MRC Stoller centre can measure serum protein profiles - about 600 proteins. This stimulated us to successfully apply for Confidence in Concepts award to profile proteins in collections of serum gathered as part of 3 MRC grants - STRATA; Defining the disturbance in glutamate; and Benemin. A total of about 450 samples are being analysed. The profiles will be related to symptom and neurochemical (MRS) measures. This will provide pilot data for planned MRC proposals.
Collaborator Contribution Expertise in proteomic analysis including biostatistical expertise in identifying subtypes of clinical populations based proteomics
Impact CinC funding
Start Year 2017
 
Title Minocycline 
Description Clinical trial of minocycline added to treatment as usual for early schizophrenia primary efficacy end point - improvement of negative symptoms over 12 months; primary mechanistic end point - prevention of grey matter loss using imaging in early psychosis. 207 patients recruited within 24 months to target and on time 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2016
Development Status Closed
Clinical Trial? Yes
Impact The results are being analysed 
 
Description "Reassembling the Self" Psychosis, Schizophrenia and Art. I month exhibition + Co-organiser and Opening speaker at 1-day symposium for 150 service users and relatives. Waterside Gallery 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Co-organiser and Opening speaker at 1-day symposium for 150 service users and relatives. Waterside Gallery
Year(s) Of Engagement Activity 2015
URL https://www.watersideartscentre.co.uk/whats-on/?category=reassembling-the-self
 
Description Article in Independent newspaper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Cheap Acne Drug Helps Mental Illness
Front Page news 2/3/2012


Many enquiries from patients and carers about joining the BeneMin study.
Year(s) Of Engagement Activity 2012
 
Description European College of Neuropsychopharmacology Talk of the Month 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Neuroinflammation and the possibility of preventing schizophrenia



313 hits on youtube. Unknown number on ECNP website
Year(s) Of Engagement Activity 2013
URL http://www.youtube.com/watch?v=WzM8IG-avpM
 
Description Work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact hosted student for 2 weeks.

university course applied for in related area
Got into Nottingham Medical school
Year(s) Of Engagement Activity 2009