The Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) Trial: Rationale for its Methodology and a Review of the Effectiveness of Switching Antipsychotics

Leucht, Stefan; Rossum, Inge Winter-van; Heres, Stephan; Arango, Celso; Fleischhacker, W. Wolfgang; Glenthøj, Birte; Leboyer, Marion; Leweke, F. Markus; Lewis, Shôn; McGuire, Philip; Meyer‐Lindenberg, Andreas; Rujescu, Dan; Kapur, Shitij; Kahn, René S.; Sommer, Iris E.

doi:10.1093/schbul/sbv019

Cited by 47 publications

(25 citation statements)

References 54 publications

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“…This may be the reason for which only a few studies have investigated the association between baseline levels of peripheral biomarkers and remission in FEP patients. To identify biological predictors of remission in FEP patients, we have analyzed clinical data and biological samples from the multinational, multi-centered, randomized, double-blind “Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE)” study in which FEP patients were clinically assessed before and after 4 weeks of treatment with the second-generation antipsychotic amisulpride 24 . Our results demonstrate that serum levels of immune-related proteins before treatment combined with a few clinical variables could predict remission in at least a subtype of FEP patients.…”

Section: Introductionmentioning

confidence: 99%

Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study

Martinuzzi¹,

Barbosa²,

Daoudlarian³

et al. 2019

Transl Psychiatry

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Early response to first-line antipsychotic treatments is strongly associated with positive long-term symptomatic and functional outcome in psychosis. Unfortunately, attempts to identify reliable predictors of treatment response in first-episode psychosis (FEP) patients have not yet been successful. One reason for this could be that FEP patients are highly heterogeneous in terms of symptom expression and underlying disease biological mechanisms, thereby impeding the identification of one-size-fits-all predictors of treatment response. We have used a clustering approach to stratify 325 FEP patients into four clinical subtypes, termed C1A, C1B, C2A and C2B, based on their symptoms assessed using the Positive and Negative Syndrome Scale (PANSS) scale. Compared to C1B, C2A and C2B patients, those from the C1A subtype exhibited the most severe symptoms and were the most at risk of being non-remitters when treated with the second-generation antipsychotic drug amisulpride. Before treatment, C1A patients exhibited higher serum levels of several pro-inflammatory cytokines and inflammation-associated biomarkers therefore validating our stratification approach on external biological measures. Most importantly, in the C1A subtype, but not others, lower serum levels of interleukin (IL)-15, higher serum levels of C-X-C motif chemokine 12 (CXCL12), previous exposure to cytomegalovirus (CMV), use of recreational drugs and being younger were all associated with higher odds of being non-remitters 4 weeks after treatment. The predictive value of this model was good (mean area under the curve (AUC) = 0.73 ± 0.10), and its specificity and sensitivity were 45 ± 0.09% and 83 ± 0.03%, respectively. Further validation and replication of these results in clinical trials would pave the way for the development of a blood-based assisted clinical decision support system in psychosis.

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Section: Introductionmentioning

confidence: 99%

Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study

Martinuzzi¹,

Barbosa²,

Daoudlarian³

et al. 2019

Transl Psychiatry

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“…Exclusion criteria for all subjects were: history of significant head trauma, dependence on illicit substances [19], medical co-morbidity (other than minor illnesses), lifetime use of antipsychotic drugs for longer than two weeks [20], contra-indications to PET and MRI scanning (such as pregnancy), or prescription of mood stabilizer medication.…”

Section: Methodsmentioning

confidence: 99%

Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study

et al. 2018

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Psychotic illnesses show variable responses to treatment. Determining the neurobiology underlying this is important for precision medicine and the development of better treatments. It has been proposed that dopaminergic differences underlie variation in response, with striatal dopamine synthesis capacity (DSC) elevated in responders and unaltered in nonresponders. We therefore aimed to test this in a prospective cohort, with a nested case-control comparison. 40 volunteers (26 patients with first-episode psychosis and 14 controls) received an 18 F-DOPA Positron Emission Tomography scan to measure DSC (Ki cer ) prior to antipsychotic treatment. Clinical assessments (Positive and Negative Syndrome Scale, PANSS, and Global Assessment of Functioning, GAF) occurred at baseline and following antipsychotic treatment for a minimum of 4 weeks. Response was defined using improvement in PANSS Total score of >50%. Patients were followed up for at least 6 months, and remission criteria applied. There was a significant effect of group on Ki cer in associative striatum (F (2, 37) = 7.9, p = 0.001). Ki cer was significantly higher in responders compared with non-responders (Cohen's d = 1.55, p = 0.01) and controls (Cohen's d = 1.31, p = 0.02). Ki cer showed significant positive correlations with improvements in PANSS-positive (r = 0.64, p < 0.01), PANSS negative (rho = 0.51, p = 0.01), and PANSS total (rho = 0.63, p < 0.01) ratings and a negative relationship with change in GAF (r = −0.55, p < 0.01). Clinical response is related to baseline striatal dopaminergic function. Differences in dopaminergic function between responders and non-responders are present at first episode of psychosis, consistent with dopaminergic and non-dopaminergic sub-types in psychosis, and potentially indicating a neurochemical basis to stratify psychosis.

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“…Efficacy in the switch arm was higher in those who were at least moderately ill at the time of the switch. The SWITCH 41 and OPTiMiSE (Optimization of Treatment and Management of Schizophrenia in Europe) 42 studies are two large-scale RCTs that have been undertaken to investigate switching strategies in patients who have not shown an early response to antipsychotic treatment. At the time of writing the results were not available.…”

Section: Acute Efficacy Of Pharmacological Strategies Following Antipmentioning

confidence: 99%

The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses

Haddad

Correll

2018

Therapeutic Advances in Psychopharmacology

168

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Schizophrenia is the eighth leading cause of disability worldwide in people aged 15-44 years. Before antidopaminergic antipsychotics were introduced in the 1950s, no effective medications existed for the treatment of schizophrenia. This review summarizes key metaanalytic findings regarding antipsychotic efficacy in the acute treatment of schizophrenia, including clozapine in treatment-resistant patients. In the most comprehensive meta-analysis of randomized controlled trials conducted in multi-episode schizophrenia, antipsychotics outperformed placebo regarding total symptoms, positive symptoms, negative symptoms, depressive symptoms, quality of life and social functioning. Amongst these outcomes, the standardized mean difference for overall symptoms was largest, that is, 0.47 (95% credible interval = 0.42-0.51), approaching a medium effect size, being reduced to 0.38 when publication bias and small-trial effects were accounted for. A comparison of two meta-analyses indicated that firstepisode patients, compared with multi-episode patients, were more likely to have at least minimal treatment response [⩾20% Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) score reduction: 81% versus 51%] and good response (⩾50% PANSS/BPRS score reduction: 52% versus 23%). In multi-episode schizophrenia, no response or worsening after 2 weeks of a therapeutic antipsychotic dose was highly predictive of not achieving a good response at endpoint (median treatment = 6 weeks: specificity = 86%; positive predictive value = 90%), suggesting a change in treatment should be considered in such cases. In first-episode psychosis, adequately dosed antipsychotic treatment trials for more than 2 weeks are recommended before using no response or worsening as a decision point for aborting a given antipsychotic. In clearly defined treatment-resistant schizophrenia, clozapine generally outperformed other antipsychotics, especially when dosed appropriately (target = 3-6 months' duration; trough clozapine level ⩾350-400 μg/L) with a response rate (⩾20% PANSS/BPRS) of 33% by 3 months of treatment. High antipsychotic doses and psychotropic combinations are unlikely to be superior to standard doses of antipsychotic monotherapy. Acute antipsychotic efficacy in schizophrenia depends on the targeted symptom domain (greater efficacy: total and positive symptoms, lesser efficacy: negative symptoms, depressive symptoms, social functioning and quality of life). Greater antipsychotic efficacy is associated with higher total baseline symptom severity, treatment-naïveté/first-episode status, shorter illness duration, and trials that are nonindustry sponsored and that have a lower placebo effect. The heterogeneity of antipsychotic response across individuals and key symptom domains, the considerable degree of nonresponse/treatment resistance in multi-episode patients, and the adverse effect potential of antipsychotics are major limitations, underscoring the need to develop new medications for the treatment of schizophrenia. Drug de...

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The Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) Trial: Rationale for its Methodology and a Review of the Effectiveness of Switching Antipsychotics

Abstract: Current literature fails to provide basic guidance for the pharmacological treatment of schizophrenia. The OPTiMiSE trial is expected to provide a basis for clinical guidelines to treat patients with a first episode of schizophrenia.

Cited by 47 publications

References 54 publications

Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study

Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study

Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study

The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses

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