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.
Organisations
- University of Manchester, Manchester, United Kingdom (Collaboration, Lead Research Organisation)
- University of Edinburgh, United Kingdom (Collaboration)
- University of Cambridge (Collaboration)
- Cardiff University, United Kingdom (Collaboration)
- University of Nottingham (Collaboration)
- Queen Elizabeth Hospital Birmingham (Collaboration)
- King's College London, United Kingdom (Collaboration)
Publications

Ajnakina O
(2020)
Predicting onset of early- and late-treatment resistance in first-episode schizophrenia patients using advanced shrinkage statistical methods in a small sample.
in Psychiatry research

Baandrup L
(2020)
Rasch analysis of the PANSS negative subscale and exploration of negative symptom trajectories in first-episode schizophrenia - data from the OPTiMiSE trial.
in Psychiatry research

Barnes TR
(2020)
Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology.
in Journal of psychopharmacology (Oxford, England)

Bucci P
(2020)
Persistent negative symptoms in recent-onset psychosis: Relationship to treatment response and psychosocial functioning.
in European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology

Chand GB
(2020)
Two distinct neuroanatomical subtypes of schizophrenia revealed using machine learning.
in Brain : a journal of neurology



Dazzan P
(2020)
Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study
in Schizophrenia Bulletin

Deakin B
(2019)
Minocycline for negative symptoms of schizophrenia and possible mechanistic actions: the BeneMin RCT
in Efficacy and Mechanism Evaluation
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 | Public |
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 | Public |
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 |
URL | http://www.isrctn.com/ISRCTN49141214 |
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 |