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

Lone Baandrup (Member of study group), OPTiMiSE study group, Rene Kahn, Iris Sommer, Inge Winter-van Rossum, Metten Somers, Paula C Ywema, Shitisj Kapur, Philip McGuire, Marion Leboyer, Andres Meyer-Lindenberg, Shon W Lewis, Stefan Leucht, Celso Arango, Wolfgang W Fleischhacker, Anne Lotte Meijering, Jocelyn Petter, Resy Van de Brug, Joost Schotsman, Jildou ZwerverJos Peuskens, Marc De Hert, Erik Thys, Lucho G Hranov, Valentin Hranov, Jan Libiger, Richard Köhler, Pavel Mohr, Birte Glenthøj, Brian Broberg, Signe Düring, Lone Baandrup, Stephane Jamain, Stephan Heres, Dan Rujescu, Ina Giegling, Mark Weiser, Mor Bar Heim, Michael Davidson, Silvana Galderisi, Paola Bucci, Armida Mucci, Janusz Rybakowski, Agnieszka Remlinger-Molenda, Ilan Gonen, Paull Radu, Marina Díaz-Marsá, Alberto Rodriguez-Jiminez, Tomas Palomo, Roberto Rodriguez-Jiminez, Paz García-Portilla, Miquel Bernado, Julio Bobes, Christina Vilares Oliveira, Gregor Berger, Claudia Wildt, Paola Dazzan, Roccio Perez-Iglesias, Richard Drake, Sarah Gregory, Danielle Wilson, Covadonga M Díaz-Caneja, Marius J C Eijkemans

133 Citations (Scopus)


BACKGROUND: 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.

METHODS: 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.

FINDINGS: 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.

INTERPRETATION: 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.

FUNDING: European Commission Seventh Framework Program.

Original languageEnglish
Article number5
JournalThe Lancet. Psychiatry
Issue number10
Pages (from-to)797-807
Number of pages11
Publication statusPublished - Oct 2018


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