Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study

Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptors agonist, has demonstrated efficacy in the treatment of patients with an acute exacerbation of schizophrenia in a 4-week, double-blind, placebo-controlled study. The aim of this 26-week open-label extension study was to evaluate the safety and effectiveness of ulotaront (25/50/75 mg/d) in patients who completed the initial 4-week study. Of the 193 4-week completers, 157 patients (81.3%) continued into the open-label extension study; 66.9% were completers. Among all extension phase patients, treatment with ulotaront was associated with minimal changes in body weight (mean [SD] change from double-blind baseline: -0.3 [3.7] kg), cholesterol (median change, -2.0 mg/dL), triglycerides (median, -5.0 mg/dL), and prolactin (female, median, -3.4 ng/mL; male, median, -2.7 ng/mL). Movement disorder scales showed no extrapyramidal effects. Twenty-six weeks of extension phase treatment was associated with a mean (95% CI) observed change from open-label baseline in the PANSS total score of -22.6 (-25.6, -19.6; effect size, 1.46), and a mean (95% CI) change in the CGI-Severity score of -1.0 (-1.2, -0.8; effect size, 1.07). Long-term treatment with the TAAR1 agonist ulotaront, in the daily dose range of 25-75 mg, was characterized by a relatively high completion rate, an adverse event profile notable for the absence of extrapyramidal-related adverse effects, a low liability for adverse weight and metabolic effects, and no effect on prolactin levels. Additional studies are needed to further confirm the long-term efficacy and safety of ulotaront

Association of C-reactive protein and metabolic risk with cognitive effects of lurasidone in patients with schizophrenia

BACKGROUND: Accumulating evidence has implicated insulin resistance and inflammation in the pathophysiology of cognitive impairments associated with neuropsychiatric disorders. This post-hoc analysis based on a placebo-controlled trial investigated the effect of inflammation (indexed by CRP) and metabolic risk factors on cognitive performance in patients with schizophrenia treated with lurasidone. METHODS: Acutely exacerbated patients with schizophrenia were randomized to lurasidone (80 or 160 mg/day), quetiapine XR 600 mg/day, or placebo. A wide range CRP test and a cognitive assessment using the CogState computerized battery were performed at baseline and week 6 study endpoint. Associations between log-transformed CRP, high density lipoprotein (HDL), homeostatic model assessment of insulin resistance (HOMA-IR) and treatment response were evaluated. RESULTS: CRP combined with HDL, triglyceride-to-HDL (TG/HDL) ratio, or HOMA-IR at study baseline were significant moderators of the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment (p \u3c .05). Greater placebo-corrected treatment effect size on the CogState composite score was observed for patients in the lurasidone 160 mg/day treatment group who had either low CRP and high HDL (d = 0.43), or low CRP and low HOMA-IR (d = 0.46). Interactive relationships between CRP, HDL, TG/HDL, HOMA-IR and the antipsychotic efficacy of lurasidone or quetiapine XR were not significant. There were no significant associations between antipsychotic treatment and changes in CRP level at study endpoint. CONCLUSIONS: Findings of this post-hoc analysis based on a placebo-controlled trial in patients with schizophrenia suggest that baseline CRP level combined with measures of metabolic risk significantly moderated the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment. Our findings underscore the importance of maintaining a low metabolic risk profile in patients with schizophrenia

A 6 Week Randomized Double-Blind Placebo-Controlled Trial of Ziprasidone for the Acute Depressive Mixed State

OBJECTIVE: To examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD). METHODS: 73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery-Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo. RESULTS: The primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms. CONCLUSIONS: There was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state. TRIAL REGISTRATION: Clinicaltrials.gov NCT00490542

Neuropsychological normalization with long-term atypical antipsychotic treatment: results of a six-month randomized, double-blind comparison of ziprasidone vs. olanzapine

The authors examined cognitive changes associated with treatment with ziprasidone and olanzapine over a 6-month double-blind clinical trial, using normative standards for the cognitive measures. Sixty-two schizophrenia patients entered the study on ziprasidone treatment (39 completers), and 71 patients entered while receiving treatment with olanzapine (33 completers). From a larger set of cognitive domains assessed in the acute treatment study, we selected verbal learning, executive functioning, and verbal fluency for further analysis due to their functional relevance and extensive normative data. Standard scores were developed based on previously published age- and education-corrected norms. Baseline performance was impaired across all tests on average. The proportion of patients impaired on each of the tests at baseline ranged from 36% (letter fluency) to 89%. Performance was significantly improved by ziprasidone and olanzapine treatment for all cognitive variables and for the composite measure. A number of subjects met the a priori criteria for normalization in performance, ranging from 10% for Trail Making Test Part B to 37% for Word List Total Learning. There were no significant differences across medications in extent of change or likelihood of inducing normalization. Statistically significant improvements in cognitive performance over 6 months of treatment with atypical antipsychotic medications are associated with performance increasing into the normal range of cognitive functioning in a proportion of previously impaired patients

The factor structure of clinical symptoms in mixed and manic episodes prior to and after antipsychotic treatment

While the factor structure of clinical symptoms in schizophrenia has been examined and provided crucial information about the illness, there is much less information available in bipolar disorder. This study examined the structure of symptoms of bipolar disorder at an unmedicated baseline assessment and after double-blind treatment with ziprasidone, haloperidol, or placebo. We hypothesized, consistent with recent studies of schizophrenia, that the factor structure after treatment would be similar to the structure of untreated symptoms at study baseline. Hospitalized patients with manic (n = 363) or mixed (n = 71) bipolar episodes were rated with the Hamilton Depression Rating Scale (HAM-D) and the Mania Rating Scale [(MRS); derived from the Schedule for Affective Disorders and Schizophrenia - Change Bipolar Scale]. After 21 days of double-blind treatment, all patients were again rated with the MRS and HAM-D. Exploratory orthogonal factor analysis (varimax rotation) including both HAM-D total scores and the MRS items found different five-factor solutions for mixed and manic patients at the unmedicated baseline assessment. Confirmatory modeling indicated that these models, with some modifications, fit the data well. At the endpoint, however, a single-factor solution was found for mixed and manic groups. Symptomatology in bipolar disorder is multifactorial in an acute and unmedicated state, with slightly different factor structures for mixed and manic episodes. Following treatment, a single severity dimension is detected. These results suggest that symptom dimensions in mania may be different from those seen in schizophrenia, where different elements of symptoms have been proven to have different functional correlates and treatment response

Change in daytime sleepiness and cognitive function in a 6-month, double-blind study of lurasidone and quetiapine XR in patients with schizophrenia

Daytime sleepiness is a commonly reported adverse effect associated with psychotropic agents that may impair cognitive performance and functioning. The objective of this post-hoc analysis was to evaluate the long-term effects of lurasidone and quetiapine XR on daytime sleepiness and neurocognitive performance during a 6-month, double-blind continuation study, in subjects who completed an initial 6-week, randomized, placebo-controlled trial comparing these agents. Daytime sleepiness, cognitive performance, and health-related quality of life were assessed with the Epworth Sleepiness Scale (ESS), CogState computerized battery, and the Quality of Well-Being (QWB-SA) Scale, respectively. Treatment with flexible-dose lurasidone 40–160mg/d, administered once daily in the evening, was associated with significantly reduced daytime sleepiness compared with flexibly dosed quetiapine XR 200–800mg/d (p=0.03, effect size=0.36) at week 32 (month 6 of the continuation study endpoint). Incidence of markedly high sleepiness (ESS >10) was significantly higher in the quetiapine XR (200–800mg/d) group compared with the lurasidone (40–160mg/day) group at both months 3 and 6 visits (p<0.05). Lurasidone (40–160mg/d) significantly improved neurocognitive performance compared to quetiapine XR (200–800mg/d) before (effect size=0.49) and after adjustment (effect size=0.45) for sleepiness effect (p=0.008 and 0.010, respectively). Increased daytime sleepiness was significantly associated with reduced neurocognitive performance (p=0.019) and quality of well-being (p=0.05). Our findings suggest that clinicians should actively monitor patients for the presence of daytime sleepiness due in part to its potential impact on neurocognitive performance and well-being

Insight and Treatment Outcomes in Schizophrenia: Post-hoc Analysis of a Long-term, Double-blind Study Comparing Lurasidone and Quetiapine XR

The objective of this analysis was to evaluate the effect of lurasidone and quetiapine extended-release (XR) on insight and judgment and assess the longitudinal relationships between improvement in insight and cognitive performance, functional capacity, quality of well-being, and depressive symptoms in patients with schizophrenia. Clinically unstable patients with schizophrenia (N=488) were randomized to once-daily, fixed-dose treatment with lurasidone 80mg, lurasidone 160mg, quetiapine XR 600mg, or placebo, followed by a long-term, double-blind, flexible-dose continuation study involving these agents. Significantly greater improvement in insight and judgment (assessed by the Positive and Negative Syndrome Scale G12 item) for the lurasidone and quetiapine XR groups, compared to the placebo group, was observed at Week 6. Over a subsequent six-month continuation period, the flexible dose lurasidone group showed significantly greater improvement in insight from acute phase baseline compared to the flexible-dose quetiapine XR group (QXR-QXR) (p=0.032). Improvement in insight was significantly correlated with improvement in cognition ( =0.014), functional capacity (p=0.006, UPSA-B), quality of well-being ( =0.033, QWB), and depressive symptoms ( =0.05, Montgomery-Åsberg Depression Rating Scale [MADRS] score) across treatment groups and study periods. In this analysis, flexibly dosed lurasidone 40 to 160mg/d was found to be associated with significantly greater improvement in insight compared to flexibly dosed quetiapine XR 200 to 800mg/d over long-term treatment in patients with schizophrenia. Across treatment groups, improvement in insight and judgment was significantly associated with improvement in cognition, functional capacity, quality of well-being, and depressive symptoms over time