T205. LUMATEPERONE IN THE TREATMENT OF SCHIZOPHRENIA: EVALUATION OF EXTRAPYRAMIDAL AND MOTOR SYMPTOMS IN 4 LATE-PHASE CLINICAL TRIALS

Abstract

Background: Evidence for the management of inadequate clinical response to clozapine in treatment-resistant schizophrenia is sparse. Accordingly, an international initiative aimed to develop consensus recommendations for treatment strategies for clozapine-refractory patients with schizophrenia. Methods: We conducted an online survey among members of the Treatment Response and Resistance in Psychosis (TRRIP) working group. An agreement threshold of ≥75% (responses "agree"+"strongly agree") was set to define a first-round consensus. Questions achieving agreement or disagreement proportions of >50% in the first round, were represented to develop second-round final consensus recommendations. Results: From a total of 61 TRRIP members 44 (first round) and 49 (second round) participated in the consensus-process. Expert recommendations included raising clozapine plasma levels to ≥350 ng/mL for refractory positive, negative and mixed symptoms. In case of ineffective plasma level-guided dose escalation waiting for a delayed response was recommended for persistent positive symptoms. For ongoing clozapine-refractory positive symptoms, combination with a second antipsychotic, (amisulpride and oral aripiprazole) and augmentation with ECT achieved consensus. For clozapine-refractory negative symptoms, waiting for a delayed response was recommended, and as an intervention, clozapine augmentation with an antidepressant reached consensus. For clozapine-refractory suicidality, augmentation with antidepressants or mood-stabilisers, and ECT met consensus criteria. For aggression, augmentation with a mood-stabiliser or combination with antipsychotic medication achieved consensus. Generally, cognitive-behavioural therapy (CBT) and psychosocial interventions reached consensus. Discussion: This consensus-based series of recommendations provides a framework for decision-making to manage the challenging clinical situation of CRS, where the evidence from randomised-controlled trials remains sparse. Background: Standard of care (SOC) antipsychotics exhibit efficacy at high dopamine D2 receptor occupancy (60%-80%), which is associated with increased risk of extrapyramidal symptoms (EPS). Lumateperone (lumateperone tosylate, ITI-007) is a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neuro-transmission. Efficacy of lumateperone 42 mg (ITI-007 60 mg) has been established in randomized placebo-controlled trials and, in contrast to other antipsychotics, occurs at low D2 receptor occupancy (40%). In controlled trials, lumateperone 42 mg was well tolerated with a favorable safety profile. An open-label long-term study of patients with stable symptoms of schizo-phrenia switched from SOC antipsychotics to lumateperone 42 mg further supported the safety and effectiveness of lumateperone treatment. This post hoc analysis evaluated the incidence of EPS across short-and long-term studies of lumateperone in patients with schizophrenia. Methods: EPS data were pooled from 3 short-term placebo-controlled studies of lumateperone 42 mg in patients with an acute exacerbation of schizophrenia (Studies 005, 301, and 302); 2 of the studies (Studies 005 and 302) had risperidone 4 mg as an active control. Data from the open-label 1-year trial (Study 303) in patients who were switched from SOC antipsychotics to lumateperone 42 mg were utilized to evaluate EPS risk with long-term treatment. EPS assessments included incidence and time to onset of EPS-related treatment-emergent adverse events (TEAEs). EPS assessment scales included the clinician-rated Abnormal Involuntary