CLEAR - clozapine in early psychosis: study protocol for a multi-centre, randomised controlled trial of clozapine vs other antipsychotics for young people with treatment resistant schizophrenia in real world settings.

BACKGROUND: Clozapine is an antipsychotic drug with unique efficacy, and it is the only recommended treatment for treatment-resistant schizophrenia (TRS: failure to respond to at least two different antipsychotics). However, clozapine is also associated with a range of adverse effects which restrict its use, including blood dyscrasias, for which haematological monitoring is required. As treatment resistance is recognised earlier in the illness, the question of whether clozapine should be prescribed in children and young people is increasingly important. However, most research to date has been in older, chronic patients, and evidence regarding the efficacy and safety of clozapine in people under age 25 is lacking. The CLEAR (CLozapine in EARly psychosis) trial will assess whether clozapine is more effective than treatment as usual (TAU), at the level of clinical symptoms, patient rated outcomes, quality of life and cost-effectiveness in people below 25 years of age. Additionally, a nested biomarker study will investigate the mechanisms of action of clozapine compared to TAU. METHODS AND DESIGN: This is the protocol of a multi-centre, open label, blind-rated, randomised controlled effectiveness trial of clozapine vs TAU (any other oral antipsychotic monotherapy licenced in the British National Formulary) for 12 weeks in 260 children and young people with TRS (12-24 years old). AIM AND OBJECTIVES: The primary outcome is the change in blind-rated Positive and Negative Syndrome Scale scores at 12 weeks from baseline. Secondary outcomes include blind-rated Clinical Global Impression, patient-rated outcomes, quality of life, adverse effects, and treatment adherence. Patients will be followed up for 12 months and will be invited to give consent for longer term follow-up using clinical records and potential re-contact for further research. For mechanism of action, change in brain magnetic resonance imaging (MRI) biomarkers and peripheral inflammatory markers will be measured over 12 weeks. DISCUSSION: The CLEAR trial will contribute knowledge on clozapine effectiveness, safety and cost-effectiveness compared to standard antipsychotics in young people with TRS, and the results may guide future clinical treatment recommendation for early psychosis. TRIAL REGISTRATION: ISRCTN Number: 37176025, IRAS Number: 1004947. TRIAL STATUS: In set-up. Protocol version 4.0 01/08/23. Current up to date protocol available here: https://fundingawards.nihr.ac.uk/award/NIHR131175# /.

The nature and efficacy of culturally-adapted psychosocial interventions for schizophrenia: a systematic review and meta-analysis.

BACKGROUND: Evidence-based psychosocial treatments for schizophrenia founded on Western belief systems and values may not be efficacious in different cultures without adaptation. This systematic review analyses the nature and outcomes of culturally-adapted psychosocial interventions in schizophrenia, examining how interventions have been adapted, their efficacy and what features drive heterogeneity in outcome. METHOD: Articles identified by searching electronic databases from inception to 3 March 2016, reference lists and previous reviews were independently screened by two authors for eligible controlled trials. Data on the nature of adaptations was analysed inductively using thematic analyses. Meta-analyses were conducted using random effects models to calculate effect sizes (Hedges' g) for symptoms. RESULTS: Forty-six studies with 7828 participants were included, seven adapted for minority populations. Cultural adaptations were grouped into nine themes: language, concepts and illness models, family, communication, content, cultural norms and practices, context and delivery, therapeutic alliance, and treatment goals. Meta-analyses showed significant post-treatment effects in favour of adapted interventions for total symptom severity (n = 2345, g: -0.23, 95% confidence interval (CI) -0.36 to -0.09), positive (n = 1152, g: -0.56, 95% CI -0.86 to -0.26), negative (n = 855, g: -0.39, 95% CI -0.63 to -0.15), and general (n = 525, g: -0.75, CI -1.21 to -0.29) symptoms. CONCLUSIONS: The adaptation process can be described within a framework that serves as a benchmark for development or assessment of future adaptations. Culturally adapted interventions were more efficacious than usual treatment in proportion to the degree of adaptation. There is insufficient evidence to show that adapted interventions are better than non-adapted interventions. Features of context, intervention and design influenced efficacy. Investigating whether adaptation improves efficacy, most importantly amongst ethnic minorities, requires better designed trials with comparisons against unadapted interventions.

Modafinil and cognitive enhancement in schizophrenia and healthy volunteers: the effects of test battery in a randomised controlled trial.

BACKGROUND: Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better. METHODS: A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models. RESULTS: In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning. CONCLUSIONS: As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.

In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study.

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.

A naturalistic, randomized, controlled trial combining cognitive remediation with cognitive-behavioural therapy after first-episode non-affective psychosis.

BACKGROUND: Cognitive remediation (CR) preceding cognitive-behavioural therapy for psychosis (CBTp) was trialled within routine clinical services, with the hypothesis that following first-episode non-affective psychosis CR would enhance CBTp efficacy by improving neuropsychological performance. METHOD: A total of 61 patients with DSM-IV non-affective psychoses waiting for routine CBTp were randomized to computerized CR over 12 weeks, supported by a trained support worker, or time-matched social contact (SC). Primary outcome was the blind-rated Psychotic Symptoms Rating Scale (PSYRATS). Secondary outcomes included measures of CBTp progress, cognition, symptoms, insight and self-esteem: all at baseline, after CR (12 weeks) and after CBTp (42 weeks). PSYRATS and global neuropsychological efficacy were tested using mixed-effects models with a group × time interaction term. Measures of CBTp progress and some neuropsychological measures were modelled by regression. RESULTS: There was no significant difference between the CR and SC groups in PSYRATS (group × time coefficient 0.3, 95% confidence interval -0.4 to 1.1, p = 0.39). However, after CR CBTp was shorter [median 7 sessions, interquartile range (IQR) 2-12 after CR; median 13, IQR 4-18 after SC; model p = 0.011] and linked to better insight (p = 0.02). Global cognition did not improve significantly more after CR (p = 0.20) but executive function did (Wisconsin Card Sort, p = 0.012). CONCLUSIONS: CBTp courses preceded by CR were far shorter but achieved the same outcome as CBTp preceded by an active control, consistent with neuropsychological improvement enhancing CBTp. CR was delivered by staff with minimal training, offering the potential to reduce the costs of CBTp considerably.

Improved quality of life over one year is associated with improved adherence in patients with schizophrenia.

AIM: Quality of life (QoL) is increasingly considered an important outcome in health research. We wished to explore the determinants of change in QoL in patients with schizophrenia over the course of a one-year RCT. METHODS: Predictors of change in observer-rated QoL (Quality of Life Scale: QLS) were assessed in 363 patients with schizophrenia during the CUtLASS clinical trial. RESULTS: Change in QLS score over the course of a year correlated with change in psychotic and depressive symptoms and treatment adherence. Linear regression showed that improvement in QoL was predicted by reduction in negative and depressive symptoms and improvement in adherence rating. These three change scores together explained 38% of the variance in QLS change. Exploration of the direction of any possible causal effect, using TETRAD, indicated that improved adherence leads to improved QoL, and that change in depression also leads to QoL change. The relationship between QoL and negative symptoms suggests that greater social activity (reflected as better QoL scores) improves negative symptoms. Such a direct relationship between treatment adherence and QoL has not been reported before. CONCLUSION: Improving adherence to medication would appear to be a key approach to improving measured quality of life in people with schizophrenia.

Patient factors associated with receipt of combination antipsychotic drug therapy in the treatment of schizophrenia.

Although discouraged in available treatment guidelines, combination antipsychotic prescribing (CAP) is a common practice in the treatment of schizophrenia. Patient characteristics may be associated with this type of treatment. A dataset (N = 363) derived from parallel randomised controlled trials was interrogated to identify factors associated with the receipt of CAP, and a logistic regression analysis was used to predict the occurrence of CAP. Significant predictors of CAP were longer illness, low global functioning score and high treatment adherence rating. Co-prescribed patients received a higher combined dose.

The evolution of insight, paranoia and depression during early schizophrenia.

BACKGROUND: How insight, paranoia and depression evolve in relation to each other during and after the first episode of schizophrenia is poorly understood but of clinical importance. METHOD: Serial assessments over 18 months were made using multiple instruments in a consecutive sample of 257 patients with first episode DSM-IV non-affective psychosis. Repeated measures of paranoia, insight, depression and self-esteem were analysed using structural equation modelling, to examine the direction of relationships over time after controlling for confounds. RESULTS: Depression was predicted directly by greater insight, particularly at baseline, and by greater paranoia at every stage of follow-up. Neither relationship was mediated by self-esteem, although there was a weak association of lower self-esteem with greater depression and better insight. Paranoia was not strongly associated with insight. Duration of untreated psychosis and substance use at baseline predicted depression at 18 months. CONCLUSIONS: In first-episode psychosis, good insight predicts depression. Subsequently, paranoia is the strongest predictor. Neither effect is mediated by low self-esteem. Effective treatment of positive symptoms is important in preventing and treating low mood in early schizophrenia.

Health beliefs link to duration of untreated psychosis and attitudes to later treatment in early psychosis.

BACKGROUND: Health beliefs influence health behaviours and have been shown to influence outcomes in a variety of illnesses, treatments and preventative interventions. AIMS: We aimed to measure health beliefs in first episode psychosis with the hypotheses that their structure would resemble that in physical illness (diabetes) and would correlate with prior duration of untreated psychosis and later attitudes to treatment. METHOD: The Multidimensional Health Locus of Control scale was used in a sample of 50 people with schizophrenia during the first episode and at 18-month follow-up, 51 diabetic controls and 51 normal controls. RESULTS: Schizophrenia patients, both at first episode and 18 months later, had a pattern of health beliefs that was similar to those of the patients with diabetes and significantly different to the normal controls. There were significant associations between internal locus of control score and short DUP, and between external locus of control score and a positive attitude to medication as measured by the Drug Attitudes Inventory. CONCLUSIONS: Health beliefs in first episode schizophrenia correlate with determinants of outcome.

Causes and consequences of duration of untreated psychosis in schizophrenia.

BACKGROUND: It is unclear what determines duration of untreated psychosis (DUP) in schizophrenia and why long DUP predicts poor outcome. AIMS: First, to test the hypothesis that specific patterns of symptoms and social functioning acting before treatment prolong DUP. Second, to clarify the mechanisms linking DUP with recovery after treatment. METHOD: Two hundred and forty-eight consecutive first admissions with schizophrenia were interviewed to assess DUP, symptoms and social functioning at admission, and symptoms were re-assessed after 6-12 weeks. RESULTS: Median DUP was 12 weeks. Long DUP was predicted by poor insight, social isolation and preserved coping skills, but not by demographic factors. Even allowing for all these variables, long DUP predicted poor outcome. CONCLUSIONS: Longer DUP results partly from a pattern of symptoms and social functioning which reduces concern by the sufferer and relevant others. DUP's relationship to outcome is strongest in the initial months of psychosis. This has implications for targeting early intervention.