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Psychosis is a major mental illness with first onset in young adults. The prognosis is poor in around half of the people affected, and difficult to predict. The few tools available to predict prognosis have major weaknesses which limit their use in clinical practice. We aimed to develop and validate a risk prediction model of symptom nonremission in first-episode psychosis. Our development cohort consisted of 1027 patients with first-episode psychosis recruited between 2005 and 2010 from 14 early intervention services across the National Health Service in England. Our validation cohort consisted of 399 patients with first-episode psychosis recruited between 2006 and 2009 from a further 11 English early intervention services. The one-year nonremission rate was 52% and 54% in the development and validation cohorts, respectively. Multivariable logistic regression was used to develop a risk prediction model for nonremission, which was externally validated. The prediction model showed good discrimination C-statistic of 0.73 (0.71, 0.75) and adequate calibration with intercept alpha of 0.12 (0.02, 0.22) and slope beta of 0.98 (0.85, 1.11). Our model improved the net-benefit by 15% at a risk threshold of 50% compared to the strategy of treating all, equivalent to 15 more detected nonremitted first-episode psychosis individuals per 100 without incorrectly classifying remitted cases. Once prospectively validated, our first episode psychosis prediction model could help identify patients at increased risk of nonremission at initial clinical contact.

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AimsPsychosis is a major mental illness with first onset in young adults. The prognosis is poor in around half of the people affected, and difficult to predict. The few tools available to predict prognosis have major weaknesses which limit their use in clinical practice. We aimed to develop and validate a risk prediction model of symptom non-remission in first-episode psychosis.MethodOur development cohort consisted of 1027 patients with first-episode psychosis recruited between 2005 to 2010 from 14 early intervention services across the National Health Service in England. Our validation cohort consisted of 399 patients with first-episode psychosis recruited between 2006 to 2009 from a further 11 English early intervention services. The one-year non-remission rate was 52% and 54% in the development and validation cohorts, respectively. Multivariable logistic regression was used to develop a risk prediction model for non-remission, which was externally validated.ResultThe prediction model showed good discrimination (C-statistic of 0.74 (0.72, 0.76) and adequate calibration with intercept alpha of 0.13 (0.03, 0.23) and slope beta of 0.99 (0.87, 1.12). Our model improved the net-benefit by 16% at a risk threshold of 50%, equivalent to 16 more detected non-remitted first-episode psychosis individuals per 100 without incorrectly classifying remitted cases.ConclusionOnce prospectively validated, our first episode psychosis prediction model could help identify patients at increased risk of non-remission at initial clinical contact.

BackgroundIn a previous trial we reported that the neuroprotective, anti-inflammatory antibiotic minocycline lessened the negative symptoms of schizophrenia compared with placebo over 1 year. The BeneMin study aimed to replicate this benefit and to determine whether or not there was associated preservation of grey matter, reduction in circulating inflammatory cytokines and enhancement of cognition.ObjectivesTo determine the efficacy of minocycline on the negative symptoms of schizophrenia and the mechanistic role of neuroprotective, anti-inflammatory and cognitive enhancing actions.MethodsTwo hundred and seven patients with a current research diagnosis of schizophrenia within 5 years of onset were randomised by a permuted blocks algorithm to minocycline (300 mg/day) or matching placebo as an adjunct to their continuing treatment. The primary efficacy outcome variable was the negative symptom subscale score from the Positive and Negative Syndrome Scales at 2, 6, 9 and 12 months. The primary mechanistic (biomarker) variables were (1) medial prefrontal grey matter volume (GMV), (2) circulating cytokine interleukin (IL) 6 concentration and (3) dorsolateral prefrontal cortex functional magnetic resonance imaging (fMRI) activations during performance of the N-back task. Movement disorder, side effects and treatment adherence were monitored throughout the study.ResultsCompared with placebo, the addition of minocycline had no effect on the severity of negative symptoms [treatment effect difference –0.186, 95% confidence interval (CI) –1.225 to 0.854] across the 2-, 6-, 9- and 12-month follow-up visits. None of the mechanistic biomarkers was influenced by minocycline: left GMV –91.2 (95% CI –303.8 to 121.4), IL-6 0.072 (95% CI –0.118 to 0.262) and N-back fMRI 0.66 (95% CI –1.53 to 0.20). There were no statistically significant treatment effects on any of the secondary outcomes and no group differences at baseline. Most measures were stable over the 12 months. Twenty-five out of the 29 serious adverse events were hospital admission for worsening psychiatric state, which affected 10 minocycline-treated participants and six placebo-treated participants.Main outcome measuresThe addition of minocycline to standard treatment had no benefit on the symptoms of schizophrenia in this early phase sample. There was no evidence of a progressive neuropathic or inflammatory process affecting GMV.LimitationsAlthough recruitment to target was achieved on time, only 43% (n = 89) of the 207 randomised patients completed 12 months of the study. However, 83% of those who started treatment remained on it and were assessed over 6 months. By contrast, no follow-up data were available for the cognitive and imaging markers in those who dropped out before the final 12-month assessments, and this reduced the power to detect treatment effects on these mechanistic variables. Patients were not selected for the presence of negative symptoms, and their initial overall psychopathology was, at most, moderate and, therefore, less likely to show treatment effects.ConclusionsThe results of the study do not support the use of adjunctive minocycline for the treatment of negative or other symptoms of schizophrenia within 2–5 years of onset. More secure evidence of central inflammation is needed before further trials are conducted at other stages of psychosis.Trial registrationCurrent Controlled Trials ISRCTN49141214.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research partnership. The study was sponsored by Greater Manchester Mental Health NHS Foundation Trust and supported by the UK Clinical Research Network.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO) has been used to investigate whether microglial activation, an indication of neuroinflammation, is evident in the brain of adults with schizophrenia. Interpretation of these studies is confounded by potential modulatory effects of antipsychotic medication on microglial activity. In the first such study in antipsychotic-free schizophrenia, we have used [11C](R)-PK11195 PET to compare TSPO availability in a predominantly antipsychotic-naive group of moderate-to-severely symptomatic unmedicated patients (n=8), similarly symptomatic medicated patients with schizophrenia taking risperidone or paliperidone by regular intramuscular injection (n=8), and healthy comparison subjects (n=16). We found no evidence for increased TSPO availability in antipsychotic-free patients compared with healthy controls (mean difference 4%, P=0.981). However, TSPO availability was significantly elevated in medicated patients (mean increase 88%, P=0.032) across prefrontal (dorsolateral, ventrolateral, orbital), anterior cingulate and parietal cortical regions. In the patients, TSPO availability was also strongly correlated with negative symptoms measured using the Positive and Negative Syndrome Scale across all the brain regions investigated (r=0.651-0.741). We conclude that the pathophysiology of schizophrenia is not associated with microglial activation in the 2-6 year period following diagnosis. The elevation in the medicated patients may be a direct effect of the antipsychotic, although this study cannot exclude treatment resistance and/or longer illness duration as potential explanations. It also remains to be determined whether it is present only in a subset of patients, represents a pro- or anti-inflammatory state, its association with primary negative symptoms, and whether there are significant differences between antipsychotics.