Large Trials for First-Episode Psychosis: One Debuts, Another Marks 10 Years

May 19, 2015

Progress in identifying and effectively treating first-episode schizophrenia was marked by the simultaneous publication of a report on a 6-year study and on the 10-year follow-up of a large-scale trial.

[[{"type":"media","view_mode":"media_crop","fid":"36607","attributes":{"alt":"Large Trials for First-Episode Psychosis: One Debuts, Another Marks 10 Years","class":"media-image media-image-right","id":"media_crop_8789786514899","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3755","media_crop_rotate":"0","media_crop_scale_h":"150","media_crop_scale_w":"150","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Progress in identifying and effectively treating first-episode schizophrenia was marked this month by the simultaneous publication of a report on a 6-year study being undertaken across Europe, and on the 10-year follow-up of a large-scale trial in Denmark.

The OPTiMiSE study (Optimization of Treatment and Management of Schizophrenia in Europe) will identify 500 participants with first-episode schizophrenia by early 2016 to evaluate a new algorithm of medication treatment, assess potential biological predictors of response, and apply Web-based educational and motivational programs to promote treatment adherence.1 In addition, this European Commission–funded program will include a separate randomized clinical trial to investigate cannabidiol as a possible alternative to antipsychotics.

The OPTiMiSE medication treatment will extend for up to 22 weeks following algorithm options of continuing the initial antipsychotic, switching to an alternative, or using clozapine in nonremitters. The investigators, with lead author Stefan Leucht, Department of Psychiatry and Psychotherapy, Technische Universität München, emphasized the importance of developing optimal treatment in the early phase of illness, “as swift restoration of social and professional functioning improves long-term outcome.”

In an accompanying commentary in the May issue of Schizophrenia Bulletin, Ceslo Arango, Child and Adolescent Psychiatry Department, Universidad Complutense, Madrid, and coauthors anticipate that the OPTiMiSE study will yield information to guide treatment well into the future. The investigation of potential biological markers of illness and treatment response, including MRI images from these first-episode patients with minimal prior exposure to antipsychotic medication, will “prepare the field for personalized medication strategies as drugs with novel mechanisms of action become available.”2

In the same May issue, Rikke Secher, of Copenhagen University Hospital, and colleagues reported on a 10-year follow-up of the Opus Specialized Early Intervention Trial from Denmark. This trial of 547 participants, recruited from 1998 through 2000, compared outcomes from 2 years of treatment. Participants were randomized to treatment with a specialized assertive early intervention program, psychoeducational family intervention, and social skills training, or to treatment as usual (TAU).3

The development and clinical testing of the OPUS treatment and its subsequent implementation throughout Denmark was recently described in Early Intervention in Psychiatry.4 The investigators not-ed that the name OPUS is not an acronym. “It comes from the world of music and signifies a piece of work,” they explained. “Each piece in the treatment plays an important role and the interplay demands planning,” the investigators wrote. “The OPUS program aims to integrate psychiatric and social interventions.”

New algorithm, novel compound

The OPTiMiSE medication treatment algorithm was developed after a review of randomized controlled trials that evaluated switching antipsychotics for participants without adequate improvement, including the large-scale CATIE study (Clinical Antipsychotic Trials for Intervention Effectiveness). Leucht and colleagues1 found 10 studies that met inclusion criteria, but they noted “none of the available studies, including the SWITCH study, was restricted to first-episode patients, making such trials a research priority.”

The treatment regimens will start with 4 weeks of amisulpride in flexible daily doses of 200 to 800 mg. Participants who do not attain remission will be randomized to 6 weeks of double-blind treatment with either a continuation of amisulpride or a switch to olanzapine in a 5- to 20-mg daily dose. If response is inadequate after completing this phase, participants may enter a 12-week open-label trial with 100 to 800 mg of clozapine daily.

Arango and colleagues2 observe in their commentary that starting with amisulpride (an agent not available in the US) may suggest a rationale for the subsequent alternative agent. They note that amisulpride is a specific D2/3 blocker that differs from other atypical antipsychotic drugs that engage with multiple receptors. “Patients included in OPTiMiSE will have minimal prior exposure to antipsychotics, . . . and the issue of risk/benefit of switching from a D2/3 mechanism to a drug with a broader receptor engagement profile will be addressed.”

The separate trial to evaluate cannabidiol in first-episode schizophrenia follows from evidence that this component of cannabis can counter the psychotomimetic effects of tetrahydrocannabinol and may exert antipsychotic effects. It has been compared with amisulpride in a double-blind study in patients with acute schizophrenia and was associated with comparable therapeutic outcomes and fewer adverse effects.5

Outcomes 10 years after OPUS

Secher and colleagues3 recounted that many of the positive outcomes of the OPUS treatment found 1 and 2 years after the intervention had not fully persisted into the 5-year follow-up, 3 years after the experimental treatment concluded. At that time, however, significantly more of the OPUS patients were still able to live independently, compared with the TAU cohort. Now in the 10-year follow-up, with interviews of 68% of the participants still living in Denmark, the investigators found continued positive outcomes in relation to independent living, but no difference between OPUS and TAU in income, work-related outcomes, or marital status.

Since the results still favor OPUS, however, the researchers suggest “it could be prudent to investigate if the positive effects of OPUS can be extended, eg, by lengthening the duration of the intervention from 2 to 5 years.”

In their commentary, Arango and colleagues2 observe, “The real challenge in schizophrenia may not be inducing treatment response or even remission, but maintaining this remission.”


1. Leucht S, Winter-van Rossum I, Heres S, et al. The Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) trial: rationale for its methodology and a review of the effective-ness of switching antipsychotics. Schizophr Bull. 2015;41:549-558.

2. Arango C, Kapur S, Kahn RS. Going beyond “trial-and-error” in psychiatric treatments: OPTiMiSE-ing the treatment of first episode of schizophrenia. Schizophr Bull. 2015;41:546-548.

3. Secher RG, Hjorthøj CR, Austin SF, et al. Ten-year follow-up of the OPUS Specialized Early Intervention Trial for patients with a first episode of psychosis. Schizophr Bull. 2015;41:617-626.

4. Nordentoft M, Melau M, Iverson T, et al. From research to practice: How OPUS treatment was accepted and implemented throughout Denmark. Early Interv Psychiatry. 2015;9:156-162.

5. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94.