Optimization of Treatment and Management of Schizophrenia in Europe (OPTIMISE)

The purpose of the study is optimising current treatments in schizophrenia and explore novel therapeutic options for schizophrenia. The study intends to both address basic, but so far unanswered, questions in the treatment of schizophrenia and develop new interventions. It is expected that the project will lead to evidence that is directly applicable to treatment guidelines, and will identify potential mechanisms for new drug development.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder
• Intervention / Treatment: Drug: Amisulpride open label; Drug: 6-week amisulpride double blind treatment; Drug: 6-week olanzapine double blind treatment; Drug: 12-week clozapine open-label treatment; Behavioral: Psychosocial intervention

Detailed Description

Despite nearly fifty years of pharmacological and psychosocial research, the overall prognosis of schizophrenia has improved only marginally. While the efficacy of most antipsychotic medication is generally uncontested, their overall functional impact has been modest. In order to improve this unsatisfactory result, this study aims to optimize current treatments in schizophrenia and explore novel therapeutic options for schizophrenia. The study comprises a medication intervention component, a psychosocial intervention component, a biological predictor component and an MRI component. MRI assessments are performed at baseline, and used to determine whether potential organic causes for psychotic symptoms are present, and to test prospective value of these assessments for subsequent treatment response. MRI assessments of healthy volunteers will be included to test for deviations in patients' assessments; these volunteers will not participate in any other protocol procedure. The medication intervention component comprises a first 4-week phase of amisulpride treatment. Non-responders will subsequently be randomised to a 6-week double blind phase on either amisulpride or olanzapine. Patients who classify as non-responders at the end of this phase, a 12-week open label treatment with clozapine is initiated. Patients who classify as a responder in phase I, II or III, are drop outs or who are non-responders at the end of phase III flow to the psychosocial intervention component of the study. During this part, several interventions are tested, aimed to increase treatment compliance and keep patients on the medication to which they've responded well. Through the biological predictor component, it is determined whether glutamatergic markers predict response to first and second line treatments, and if an empirical combination of pharmacogenetic, proteomics- and metabolomic markers can provide clinical valuable predictive value.

• Study Type: Interventional
• Enrollment (Actual): 479
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia, 3053
    • Melbourne Neuropsychiatry Centre
• Austria
  • Innsbruck, Austria, A-6020
    • Department of Biological Psychiatry, Innsbruck University Clinics
• Belgium
  • Leuven, Belgium, B - 3070
    • Katholieke Universiteit Leuven (KU Leuven)
• Bulgaria
  • Sofia, Bulgaria, 1113
    • University Specialised Hospital for Active Treatment in Neurology and Psychiatry "St. Naum"
• Czechia
  • Hradec Králové, Czechia, CZ - 500 05
    • Psychiatrická klinika LF UK, Fakultní nemocnice
  • Ustavni 91
    • Prague, Ustavni 91, Czechia, 181 03 Praha 8-Bohnice
      • Psychiatricke Centrum Praha
• Denmark
  • Glostrup, Denmark, DK-2600
    • Center for Neuropsychiatric Research
• France
  • Créteil Cedex, France, 94010
    • Institut National de la Santé et de la Reserche Médicale (INSERM)
• Germany
  • Halle, Germany, 06097
    • Martin-Luther-University (MLU) of Halle-Wittenberg
  • Mannheim, Germany, J 5, D-68159
    • Deprtment of Psychiatry, University of Heidelberg
  • München, Germany, 80336
    • Ludwig-Maximilians University München
  • München, Germany, 81675
    • Technische Universität München (TUM)
• Israel
  • Tel Hashomer, Israel, 52621
    • Sheba Medical Centre Department of Psychiatry
• Italy
  • Naples, Italy, 80138
    • Department of Psychiatry University of Naples
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
• Poland
  • Poznan, Poland, 60-572
    • Department of Adult Psychiatry, University of Medical Sciences
• Romania
  • Bucuresti, Romania, 7000
    • Obregia Psychiatric Hospital
• Spain
  • Barcelona, Spain, 08036 Barcelona
    • Hospital Clinic i Provincial
  • Madrid, Spain, 28007
    • Servicio Madrileño de Salud (SERMAS)
  • Madrid, Spain, 28040 Madrid
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28041 Madrid
    • Instituto de Investigación Hospital 12 de Octubre
  • Oviedo, Spain, 33011 Oviedo
    • Universidad de Oviedo
• Switzerland
  • Oetwil am See, Switzerland, CH-8618
    • Clienia Schlössli AG, Privatklinik für Psychiatrie und Psychotherapie
• United Kingdom
  • London, United Kingdom, SE5 8AF
    • King's College London, Departments of Psychological Medicine, Psychiatry & Cognitive Neuroscience
  • London, United Kingdom, W12 0NN
    • West london Mental Health Trust
  • Manchester, United Kingdom, M13 9PL
    • University of Manchester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of schizophrenia as defined by DSM-IV-R as determined by the M.I.N.I.plus
2. Age 18 or older.
3. The first psychosis occurred at least one year and no more than 7 years ago.*
4. If patients are using an antipsychotic drug, a medication switch is currently under consideration.
5. Capable of providing written informed consent.

Exclusion Criteria:

1. Intolerance / hypersensitivity to one of the drugs (including active substances, metabolites and excipients) in this study including oral risperidone, paliperidone and aripiprazole and/or hypersensitivity to risperidone.
2. Pregnancy or lactation.
3. Patients who are currently using clozapine.
4. Patients who do not fully comprehend the purpose or are not competent to make a rational decision whether or not to participate.
5. Patients with a documented history of non-response and/or intolerance to any of the study medications and/or a documented history of non-response to a treatment with one of the study drugs of at least 6 weeks within the registered dose range.
6. Forensic patients.
7. Patients who have been treated with an investigational drug within 30 days prior to screening.
8. Simultaneous participation in another intervention study (neither medication or psychosocial intervention).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Phase I: 1 arm 'amisulpride open label'; For 4 weeks, all patients will be treated with amisulpride open label.	Drug: Amisulpride open label; 4-week open label amisulpride treatment
Active Comparator: Phase II: 'amisulpride double blind'; Patients who do not meet remission criteria during phase I (4 weeks open label amisulpride), flow to phase II where they are randomised to 1 of 2 6-week double blind treatment arms, one of which is 'amisulpride double blind'	Drug: 6-week amisulpride double blind treatment; 6-week amisulpride double blind treatment
Active Comparator: Phase II 'olanzapine double blind'; Patients who do not meet remission criteria during phase I (4 weeks open label amisulpride), flow to phase II where they are randomised to 1 of 2 6-week double blind treatment arms, one of which is 'olanzapine double blind'	Drug: 6-week olanzapine double blind treatment; 6-week olanzapine double blind treatment
Other: Phase III: 1 arm 'clozapine open label'; Patients who do not meet remission criteria during phase II (6-week double blind amisulpride vs olanzapine), flow to phase III, where only 1 arm is available: 'clozapine open label'	Drug: 12-week clozapine open-label treatment; 12-week clozapine open-label treatment
Experimental: Psychosocial intervention; Patients who meet remission criteria during any of the phases of the medication component, patients who drop out of the medication component and patients who did not meet remission criteria at the end of the medication component, will flow to the psychosocial intervention component, where they are randomised to 1 of 2 arms, one of which is the 'Psychosocial Intervention' arm.	Behavioral: Psychosocial intervention; Psychosocial intervention
No Intervention: Psychosocial Intervention phase: 'TAU'; Patients who meet remission criteria during any of the phases of the medication component, patients who drop out of the medication component and patients who did not meet remission criteria at the end of the medication component, will flow to the psychosocial intervention component, where they are randomised to 1 of 2 arms, one of which is the 'Treatment as usual' arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PANSS	Study consists of multiple components, each with their own objectives. For this (medication) component: number of patients in remission, based on PANSS scores (criteria of Andreasen et al.; 2005) after 4 weeks open label amisulpride, after 6 weeks double blind amisulpride or olanzapine and after 12 weeks of open label clozapine.	Jan 2016
Sellwood rating scale	Psychosocial intervention component, objective A: drug adherence rates as a function of (standardized self report and) Sellwood rating scales after 12 and 52 weeks.	Jan 2016
Biological profile	Biological predictors component, objective A: drug response (remission vs non-remission) as a function of biological profile, after 4 weeks, 10 weeks and 22 weeks (after each medication phase).	jan 2016
MRS measures	Biological predictors component, objective B: using MRS scans, differences between responders and non-responders in regional glutamate levels a) at baseline and b) between baseline and after one month of treatment with amisulpiride.	jan 2016
SOFAS global functioning	Psychosocial intervention component, objective B: drug adherence rates as a function of standardized global functioning (SOFAS score after 1 year) following psychosocial intervention vs treatment as usual.	jan 2016
MRI assessments	MRI component objective: the percentage of first episode patients that show radiological abnormalities suggestive of neurological disorders which may explain the occurrence of psychotic symptoms - measurement at baseline only.	jan 2016

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause treatment discontinuation	The different components of the study have their own secondary objectives: Medication component has multiple secondary objectives, most important one is all-cause treatment discontinuation after 4 weeks, 10 weeks and 22 weeks. Number and reason for premature discontinuations (treatment discontinuation) of the amisulpride and the olanzapine group will be compared (after 10 weeks).	jan 2016
All cause discontinuation	Psychosocial intervention component has multiple secondary objectives, most important one is all-cause treatment discontinuation between treatment groups after 12 and 52 weeks.	jan 2016
Biological markers	Biological predictors component has multiple secondary objectives, most important one is the ability of biological markers to predict response to antipsychotic and treatment tolerability in schizophrenia, after 4, 10 and 22 weeks.	jan 2016
MRI assessments	The ability of MRI to predict response to antipsychotic treatment in schizophrenia, after 4, 10 and 22 weeks.	jan 2016

Collaborators and Investigators

• Sponsor: Rene Kahn
• Collaborators: King's College London; Ludwig-Maximilians - University of Munich; Technical University of Munich; University of Manchester
• Investigators: Principal Investigator: René Kahn, MD, PhD, University Medical Center Utrecht, the Netherlands

Publications and helpful links

General Publications

• Fraguas D, Diaz-Caneja CM, Pina-Camacho L, Winter van Rossum I, Baandrup L, Sommer IE, Glenthoj B, Kahn RS, Leucht S, Arango C. The role of depression in the prediction of a "late" remission in first-episode psychosis: An analysis of the OPTiMiSE study. Schizophr Res. 2021 May;231:100-107. doi: 10.1016/j.schres.2021.03.010. Epub 2021 Apr 7.
• Pollak TA, Vincent A, Iyegbe C, Coutinho E, Jacobson L, Rujescu D, Stone J, Jezequel J, Rogemond V, Jamain S, Groc L, David A, Egerton A, Kahn RS, Honnorat J, Dazzan P, Leboyer M, McGuire P. Relationship Between Serum NMDA Receptor Antibodies and Response to Antipsychotic Treatment in First-Episode Psychosis. Biol Psychiatry. 2021 Jul 1;90(1):9-15. doi: 10.1016/j.biopsych.2020.11.014. Epub 2020 Nov 24. Erratum In: Biol Psychiatry. 2021 Jul 1;90(1):69.
• Kahn RS, Winter van Rossum I, Leucht S, McGuire P, Lewis SW, Leboyer M, Arango C, Dazzan P, Drake R, Heres S, Diaz-Caneja CM, Rujescu D, Weiser M, Galderisi S, Glenthoj B, Eijkemans MJC, Fleischhacker WW, Kapur S, Sommer IE; OPTiMiSE study group. Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching study. Lancet Psychiatry. 2018 Oct;5(10):797-807. doi: 10.1016/S2215-0366(18)30252-9. Epub 2018 Aug 13.

Helpful Links

• Study website

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: October 20, 2010
• First Submitted That Met QC Criteria: November 24, 2010
• First Posted (Estimate): November 25, 2010

Study Record Updates

• Last Update Posted (Actual): May 15, 2018
• Last Update Submitted That Met QC Criteria: May 14, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Schizophrenia; Prognosis; Imaging; Pharmacogenetics; Schizoaffective disorder; Schizophreniform disorder; Treatment guidelines
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Disease; Psychotic Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; GABA Agents; Antidepressive Agents, Second-Generation; GABA Antagonists; Olanzapine; Amisulpride; Clozapine
• Other Study ID Numbers: KP7242114; 2010-020185-19 (EudraCT Number)