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Lancet Psychiatry. 2018 Oct;5(10):797-807. doi: 10.1016/S2215-0366(18)30252-9. Epub 2018 Aug 13.

Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study.

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Department of Psychiatry, Brain Center Rudolf Magnus, Utrecht, Netherlands; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:
Department of Psychiatry, Brain Center Rudolf Magnus, Utrecht, Netherlands.
Department of Psychiatry and Psychotherapy, Technical University Munich, Munich, Germany.
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, London, UK.
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Greater Manchester Mental Health Foundation Trust, Manchester, UK.
Institut National de la Santé et de la Recherche Médicale U 955, Psychiatrie Génétique et Psychopathologie, Créteil University Paris Est Créteil, Paris, France.
Servicio de Psiquiatría del Niño y del Adolescente, Hospital General Universitario Gregorio Marañon, Universidad Complutense Madrid, Spain; Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain.
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Division of Psychology and Mental Health, School of Health Sciences, University of Manchester, Manchester, UK.
Department of Psychiatry, University Hospital Halle, Halle, Germany.
Department of Psychiatry, Sheba Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Department of Psychiatry, Campania University Luigi Vanvitelli, Naples, Italy.
Center for Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, Mental Health Services, Capital Region of Denmark, Glostrup, Denmark.
Department of Biostatistics and Research Support, University Medical Center Utrecht, Utrecht, Netherlands.
Medical University of Innsbruck, Department of Psychiatry and Psychosomatics, Division of Psychiatry, Innsbruck, Austria.
Institute of Psychiatry, Psychology and Neuroscience, King's Health Partners, London, UK.
Department of Psychiatry, Brain Center Rudolf Magnus, Utrecht, Netherlands; Department of Neuroscience, University Medical Center, Groningen, Netherlands.



No established treatment algorithm exists for patients with schizophrenia. Whether switching antipsychotics or early use of clozapine improves outcome in (first-episode) schizophrenia is unknown.


This three-phase study was done in 27 centres, consisting of general hospitals and psychiatric specialty clinics, in 14 European countries and Israel. Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1). Patients who did not meet symptomatic remission criteria at 4 weeks were randomly assigned to continue amisulpride or switch to olanzapine (≤20 mg/day) during a 6-week double-blind phase, with patients and staff masked to treatment allocation (phase 2). Randomisation was done online by a randomisation website; the application implemented stratification by site and sex, and applied the minimisation method for randomisation. Patients who were not in remission at 10 weeks were given clozapine (≤900 mg/day) for an additional 12 weeks in an open-label design (phase 3). The primary outcome was the number of patients who achieved symptomatic remission at the final visits of phases 1, 2, and 3, measured by intention-to-treat analysis. Data were analysed with a generalised linear mixed model, with a logistic link and binomial error distribution. This trial is registered with, number NCT01248195, and closed to accrual.


Between May 26, 2011, and May 15, 2016, we recruited 481 participants who signed informed consent. Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1. 93 patients who were not in remission continued to the 6-week double-blind switching trial, with 72 (77%) patients completing the trial (39 on olanzapine and 33 on amisulpride); 15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87). Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission. The number of serious adverse events did not differ between the treatment arms in phase 2: one patient on olanzapine was admitted to hospital because of an epileptic seizure, and one patient on amisulpride was admitted to hospital twice because of exacerbations of psychotic symptoms. Over the course of the trial, two serious suicide attempts were reported.


For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation.


European Commission Seventh Framework Program.

[Indexed for MEDLINE]

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