BACKGROUND: Evidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis.
METHODS: We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14-18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433.
FINDINGS: Of 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial.
INTERPRETATION: This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence.
FUNDING: National Institute for Health Research.
Bibliographical noteFunding Information:
MAPS was funded by the UK National Institute for Health Research under its Health Technology Assessment Programme following a commissioned call (project number 15/31/04). The call specified the interventions, population, setting, study design, and main outcomes. The funder of the study had no role in data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
APM reports personal fees from training workshops in cognitive behavioural therapy (CBT) for psychosis and royalties from books on the topic, outside of the submitted work. MP reports personal fees and fees paid to the Psychosis Research Unit of Greater Manchester Mental Health NHS Foundation Trust for CBT training outside of the submitted work. LJ reports personal fees from New Harbinger Publications, outside of the submitted work. DFr reports grants from the National Institute for Health Research (NIHR) and the UK Medical Research Council outside of the submitted work. MRB reports royalties from Oxford University Press and personal fees from the UK Medical Defence Union, outside of the submitted work. NH is the chair of the board of trustees of the Manchester Global Foundation, a Charitable Incorporated Organisation registered in England and Wales; is a past trustee of Lancashire Mind, the Pakistan Institute of Living and Learning, and the Abaseen Foundation; established an independent general hospital (Remedial Centre) in Karachi, Pakistan, which is now owned and operated by his sibling with a pharmacy attached; and received honoraria and travel grants from Eli Lilly, Bristol Myers Squibb, Lundbeck, AstraZeneca, and Janssen Pharmaceuticals outside of the submitted work. GM reports grants from the NIHR Health Technology Assessment (HTA) Programme during the conduct of the study. JN reports membership in the NIHR boards: Efficacy and Mechanisms Evaluation Board (2019–present), Commissioning Priority Review Decision-Making Committee (2015), HTA Commissioning Board (2010–16), HTA Commissioning Sub-Board (Expression of Interest; 2014), HTA Funding Boards Policy Group (2016–19), HTA General Board (2016–19), HTA Post-Board Funding Teleconference (2016–19), NIHR Clinical Trials Unit Standing Advisory Committee (2018–present), NIHR HTA and Efficacy and Mechanism Evaluation Editorial Board (2014–19), and Pre-exposure Prophylaxis Impact Review Panel (2017); outside of the submitted work. DS reports personal fees from the National Clinical Audit of Psychosis of the Royal College of Psychiatrists, royalties from Wiley Blackwell publication for the book Promoting Recovery in Early Psychosis , membership in the current National Institute for Health and Care Excellence (NICE) guideline development group for rehabilitation in adults with complex psychosis and related severe mental health conditions, and current board membership at the UK National Collaborating Centre for Mental Health, outside of the submitted work. CH was chair of the NICE guideline development group for schizophrenia in children and young people (2011–13) and was chair of the NICE psychosis and schizophrenia in children evidence update (2014–15), outside of the submitted work. All other authors declare no competing interests.
We would like to thank all participants who agreed to take part in the trial. We are grateful to the Psychosis Research Unit Service User Reference Group for their consultation regarding the design of the study and contribution to the development of study materials. We are also grateful to our independent trial steering committee (Graham Murray, Carl Bateson, Susanna Dodd, Rebecca Walwyn, and Alison Brabban) and independent data monitoring committee (Emmanuelle Peters, Thomas R E Barnes, Zak Howarth, and Rod Taylor) for providing oversight of the trial. We also wish to thank the many researchers, network staff, and trial therapists who supported the study (Felicity Waite, Jessica Bird, Sarah Reeve, Peter Cairns, Roger Collin, Leanne Groves, Jon Wilson, Sarah Maxwell, Xavier Coll, Samantha Hartley, Laura Hancox, Robyn Queenan, and Samantha Fraser). This project was funded by the NIHR under its HTA Programme (project number 15/31/04) and will be published in full in the NIHR library HTA journal. Max Birchwood of the MAPS group is funded by the NIHR Applied Research Collaboration West Midlands. The views expressed are those of the author(s) and not necessarily those of the NIHR or the UK Government Department of Health and Social Care.
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