Richard J Drake1, Nusrat Husain2, Max Marshall3, Shôn W Lewis4, Barbara Tomenson5, Imran B Chaudhry6, Linda Everard7, Swaran Singh8, Nick Freemantle9, David Fowler10, Peter B Jones11, Tim Amos12, Vimal Sharma13, Chloe D Green14, Helen Fisher15, Robin M Murray16, Til Wykes16, Iain Buchan17, Max Birchwood8. 1. Division of Psychology & Mental Health, University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Prestwich, Manchester, UK. Electronic address: richard.drake@manchester.ac.uk. 2. Division of Psychology & Mental Health, University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK; Lancashire Care & South Cumbria NHS Foundation Trust, Preston, Lancashire, UK. 3. Lancashire Care & South Cumbria NHS Foundation Trust, Preston, Lancashire, UK. 4. Division of Psychology & Mental Health, University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Prestwich, Manchester, UK. 5. Division of Population Health, Health Services Research & Primary Care, University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK. 6. Division of Neuroscience & Experimental Psychology, University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK; Department of Psychiatry, Ziauddin University, Karachi, Pakistan. 7. Birmingham and Solihull NHS, Mental Health Foundation, Trust, Birmingham, UK. 8. Department of Mental Health & Wellbeing, University of Warwick, Warwick, UK. 9. Institute for Clinical Trials, University College London, London, UK. 10. School of Psychology, University of Sussex, Brighton, UK; Sussex Partnership NHS Foundation Trust, Worthing, UK. 11. Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, UK; NIHR Collaboration for Leadership in Applied Health Research & Care East of England, Cambridge, UK. 12. School of Clinical Sciences, University of Bristol, Bristol, UK; Avon & Wiltshire Mental Health Partnership NHS Trust, Chippenham, UK. 13. Chester Medical School, University of Chester, Chester, UK; Cheshire & Wirral Partnership NHS Foundation Trust, Chester, UK. 14. Manchester Academic Health Science Centre, Manchester, UK; Greater Manchester Mental Health NHS Foundation Trust, Prestwich, Manchester, UK. 15. MRC Centre for Social, Genetic & Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 16. Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; NIHR Maudsley Biomedical Research Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 17. Division of Informatics, Imaging & Data Sciences, University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; Salford Royal NHS Foundation Trust, Salford, UK; Institute of Population Health Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.
Abstract
BACKGROUND: Delayed treatment for first episodes of psychosis predicts worse outcomes. We hypothesised that delaying treatment makes all symptoms more refractory, with harm worsening first quickly, then more slowly. We also hypothesised that although delay impairs treatment response, worse symptoms hasten treatment, which at presentation mitigates the detrimental effect of treatment delay on symptoms. METHODS: In this longitudinal analysis and modelling study, we included two longitudinal cohorts of patients with first-episode psychosis presenting to English early intervention services from defined catchments: NEDEN (recruiting 1003 patients aged 14-35 years from 14 services between Aug 1, 2005, and April 1, 2009) and Outlook (recruiting 399 patients aged 16-35 years from 11 services between April 1, 2006, and Feb 28, 2009). Patients were assessed at baseline, 6 months, and 12 months with the Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale for Schizophrenia, Mania Rating Scale, Insight Scale, and Social and Occupational Functioning Assessment Scale. Regression was used to compare different models of the relationship between duration of untreated psychosis (DUP) and total symptoms at 6 months. Growth curve models of symptom subscales tested predictions arising from our hypotheses. FINDINGS: We included 948 patients from the NEDEN study and 332 patients from the Outlook study who completed baseline assessments and were prescribed dopamine antagonist antipsychotics. For both cohorts, the best-fitting models were logarithmic, describing a curvilinear relationship of DUP to symptom severity: longer DUP predicted reduced treatment response, but response worsened more slowly as DUP lengthened. Increasing DUP by ten times predicted reduced improvement in total symptoms (ie, PANSS total) by 7·339 (95% CI 5·762 to 8·916; p<0·0001) in NEDEN data and 3·846 (1·689 to 6·003; p=0·0005) in Outlook data. This was true of treatment response for all symptom types. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN (coefficients 0·099 [95% CI 0·033 to 0·164]; p=0·0028 in NEDEN and 0·007 [-0·081 to 0·095]; p=0·88 in Outlook). INTERPRETATION: Long DUP was associated with reduced treatment response across subscales, consistent with a harmful process upstream of individual symptoms' mechanisms; response appeared to worsen quickly at first, then more slowly. These associations underscore the importance of rapid access to a comprehensive range of treatments, especially in the first weeks after psychosis onset. FUNDING: UK Department of Health, National Institute of Health Research, and Medical Research Council.
BACKGROUND: Delayed treatment for first episodes of psychosis predicts worse outcomes. We hypothesised that delaying treatment makes all symptoms more refractory, with harm worsening first quickly, then more slowly. We also hypothesised that although delay impairs treatment response, worse symptoms hasten treatment, which at presentation mitigates the detrimental effect of treatment delay on symptoms. METHODS: In this longitudinal analysis and modelling study, we included two longitudinal cohorts of patients with first-episode psychosis presenting to English early intervention services from defined catchments: NEDEN (recruiting 1003 patients aged 14-35 years from 14 services between Aug 1, 2005, and April 1, 2009) and Outlook (recruiting 399 patients aged 16-35 years from 11 services between April 1, 2006, and Feb 28, 2009). Patients were assessed at baseline, 6 months, and 12 months with the Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale for Schizophrenia, Mania Rating Scale, Insight Scale, and Social and Occupational Functioning Assessment Scale. Regression was used to compare different models of the relationship between duration of untreated psychosis (DUP) and total symptoms at 6 months. Growth curve models of symptom subscales tested predictions arising from our hypotheses. FINDINGS: We included 948 patients from the NEDEN study and 332 patients from the Outlook study who completed baseline assessments and were prescribed dopamine antagonist antipsychotics. For both cohorts, the best-fitting models were logarithmic, describing a curvilinear relationship of DUP to symptom severity: longer DUP predicted reduced treatment response, but response worsened more slowly as DUP lengthened. Increasing DUP by ten times predicted reduced improvement in total symptoms (ie, PANSS total) by 7·339 (95% CI 5·762 to 8·916; p<0·0001) in NEDEN data and 3·846 (1·689 to 6·003; p=0·0005) in Outlook data. This was true of treatment response for all symptom types. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN (coefficients 0·099 [95% CI 0·033 to 0·164]; p=0·0028 in NEDEN and 0·007 [-0·081 to 0·095]; p=0·88 in Outlook). INTERPRETATION: Long DUP was associated with reduced treatment response across subscales, consistent with a harmful process upstream of individual symptoms' mechanisms; response appeared to worsen quickly at first, then more slowly. These associations underscore the importance of rapid access to a comprehensive range of treatments, especially in the first weeks after psychosis onset. FUNDING: UK Department of Health, National Institute of Health Research, and Medical Research Council.
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