Schizophrenia and Disorders With Psychotic Features
Conditions
Keywords
psychosis, schizophrenia, negative symptoms, minocycline
Brief summary
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.
Detailed description
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.
Interventions
DRUGMinocycline
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.
DRUGPlacebo
Matching placebo with appearance of over - encapsulated minocycline
Sponsors
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
University of Manchester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to 35 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Severity of negative symptoms of psychosis | twelve months | Measured by Negative symptoms scale in the Positive and Negative Syndrome Scale |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in body weight | Twelve months | Measuring weight gain in kilograms, a side effect of standard anti-psychotic medication therapy |
| Positive symptoms of psychosis | twelve months | Measured by the Positive symptoms scale in the Positive and Negative Syndrome Scales |
| General social and psychological functioning | twelve months | Measured by Global Assessment of Functioning from DSM-IV |
| Intelligence | twelve months | Measured by Wechsler Adult Intelligence Scale for patients with schizophrenia |
| Anti-psychotic medication dose | twelve months | Measured in chlorpromazine equivalent units |
| Verbal learning | 12 months | Auditory-Verbal Learning Task |
| Social and Occupational functioning | 12 months | Score on Social Functioning Scale |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in medial prefrontal grey matter volume (primary biomarker outcome) | twelve months | Change Measured by T1-weighted magnetic resonance imaging (MRI) |
| Circulating interleukin (IL-6) concentration (primary biomarker outcome) | twelve months | Measured by blood cytokine screen test |
| Dorsolateral-prefrontal cortex blood oxygen level dependent response during working memory task (primary biomarker outcome) | twelve months | Measured by functional magnetic resonance imaging during N-back task |
| Pattern of total and regional grey matter volumes (secondary biomarker outcome) | twelve months | Measured by T1-weighted magnetic resonance imaging |
| Multivariate pattern of circulating cytokine concentrations (secondary biomarker outcome) | twelve months | Measured by blood cytokine screen test |
| Distribution of Hurst exponent (brain functional connectivity measure; secondary biomarker outcome) | twelve months | Measured by functional magnetic resonance imaging during resting state |
| Verbal fluency | 12 months | Verbal fluency, words per minute beginning with F, A and S |
| Working memory | 12 months | Performance on the N-back task during scanning |
Outcome results
None listed