Effects of ulotaront on brain circuits of reward, working memory, and emotion processing in healthy volunteers with high or low schizotypy.

Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptor agonist without antagonist activity at dopamine D or the serotonin 5-HT2A receptors, has demonstrated efficacy in the treatment of schizophrenia. Here we report the phase 1 translational studies that profiled the effect of ulotaront on brain responses to reward, working memory, and resting state connectivity (RSC) in individuals with low or high schizotypy (LS or HS). Participants were randomized to placebo (n = 32), ulotaront (50 mg; n = 30), or the D receptor antagonist amisulpride (400 mg; n = 34) 2 h prior to functional magnetic resonance imaging (fMRI) of blood oxygen level-dependent (BOLD) responses to task performance.

The Effect of Lurasidone on Anxiety Symptoms in Patients With Bipolar Depression: A Post Hoc Analysis.

To assess the effects of lurasidone on anxiety symptoms and sleep disruption, and their moderating and mediating roles on treatment response in bipolar depression. This post hoc analysis included pooled data from 2 previously published 6-week placebo-controlled trials of lurasidone for bipolar I depression conducted between April 2009 and February 2012. Hamilton Anxiety Rating Scale (HAM-A) "psychic anxiety" (items 1-6, 14) and "somatic anxiety" (items 7-13) subscores were calculated.

A multicenter, double-blind, placebo-controlled, randomized, Phase 1b crossover trial comparing two doses of ulotaront with placebo in the treatment of narcolepsy-cataplexy.

Background: Ulotaront (SEP-363856) is a novel agonist at trace amine-associated receptor 1 and serotonin 5-HT receptors in clinical development for the treatment of schizophrenia. Previous studies demonstrated ulotaront suppresses rapid eye movement (REM) sleep in both rodents and healthy volunteers. We assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cataplexy and alertness in subjects with narcolepsy-cataplexy.

Sleep Disturbance, Irritability, and Response to Lurasidone Treatment in Children and Adolescents with Bipolar Depression.

Background: The presence of mixed (subsyndromal hypomanic) symptoms may influence treatment outcomes in pediatric bipolar depression. This post-hoc analysis investigated "bridge" symptoms that have cross-sectional and predictive associations with depressive and manic symptom clusters in youth with bipolar depression.

Methods: The moderating effects of these bridge symptoms on the response to flexibly dosed lurasidone 20-80 mg/d compared to placebo treatment was analyzed in children and adolescents with bipolar I depression in a six-week, placebo-controlled, double-blind study followed by a 2-year, openlabel extension study of lurasidone.

Assessment of Negative Symptoms in Clinical Trials of Acute Schizophrenia: Test of a Novel Enrichment Strategy.

Drug trials for negative symptoms in schizophrenia select patients based on the severity and stability of negative symptoms, using criteria that are not suitable for trials of acute exacerbation of schizophrenia. Here we present a method to prognostically enrich subjects having a predefined factor structure in PANSS and apply it to the measurement of negative symptoms specifically in trials of acute schizophrenia. A vector of 1335 elements based on between- and within-item variances, covariances, and differences of PANSS items was created to calculate an index of heterogeneity and to enrich for a predetermined symptom construct in PANSS.

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.

A Randomized, Double-blind, Placebo-controlled Proof-of-Concept Trial to Evaluate the Efficacy and Safety of Non-racemic Amisulpride (SEP-4199) for the Treatment of Bipolar I Depression.

Background: Non-racemic amisulpride (SEP-4199) is an 85:15 ratio of aramisulpride:esamisulpride with a 5-HT7 and D2 receptor binding profile optimized for the treatment of bipolar depression. The aim of this study was to evaluate the efficacy and safety of SEP-4199 for the treatment of bipolar depression.

Methods: Patients meeting DSM-5 criteria for bipolar I depression were randomized to 6 weeks of double-blind, placebo-controlled treatment with SEP-4199 200 mg/d or 400 mg/d.

Systematic Review and Network Meta-analysis: Efficacy and Safety of Second-Generation Antipsychotics in Youths With Bipolar Depression.

Objective: To assess the relative efficacy and safety of second-generation antipsychotics for treating major depressive episodes in youths with bipolar disorder.

Method: A systematic literature review using PRISMA guidelines and network meta-analysis (NMA) of randomized controlled trials (RCTs) of second-generation antipsychotics for bipolar depression in youths 10 to 18 years of age was conducted. Efficacy measures included Children's Depression Rating Scale, Revised (CDRS-R) and Clinical Global Impressions-Bipolar Disorder-Severity Depression (CGI-BP-S-depression) and Overall (CGI-BP-S-overall) scores.

Efficacy and tolerability of atypical antipsychotics for acute bipolar depression: a network meta-analysis.

Background: While clinical trial evidence has firmly established the efficacy of several atypical antipsychotics (AAPs) for treating bipolar depression, no randomized controlled trials (RCT's) comparing AAPs have been conducted. This Bayesian network meta-analysis (NMA) compared the relative efficacy and tolerability of AAP monotherapy in adults with bipolar depression.

Methods: Efficacy measures included change in Montgomery Åsberg Depression Rating Scale (MADRS), Clinical Global Improvement - Bipolar Disorder (CGI-BP), response, and remission.

Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5-HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders.

In contrast to the dose-occupancy relationship in the treatment of schizophrenia, the minimal effective level of dopamine receptor 2 (D2R) blockade for antipsychotics in the treatment of bipolar depression is unknown. Lower doses aimed at reducing extrapyramidal side effects must be balanced against the need to retain the therapeutic benefit of D2R blockade on emergent cycling, mixed, manic, anxiety, and/or psychotic symptoms. Dose-reductions intended to lower D2R blockade, however, could also decrease concomitant serotonin receptor antagonism and its potential benefit on depressive symptoms.

Dasotraline in adults with attention deficit hyperactivity disorder: a placebo-controlled, fixed-dose trial.

In a previous study, dasotraline demonstrated efficacy at a dose of 8 mg/day in adults with attention deficit hyperactivity disorder (ADHD). The aim of the current study was to evaluate the efficacy and safety of dasotraline in doses of 4 and 6 mg/day. Adults meeting Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria for ADHD were randomized to 8 weeks of double-blind, once-daily, fixed-dose treatment with dasotraline 4 mg/day, 6 mg/day, or placebo.

Hospitalization risk among adults with bipolar I disorder treated with lurasidone versus other oral atypical antipsychotics: a retrospective analysis of Medicaid claims data.

Objective: To compare the risk of hospitalization for adult Medicaid beneficiaries with bipolar I disorder treated with lurasidone vs. other oral atypical antipsychotics (AAPs) as monotherapy.

Methods: A retrospective cohort study of the IBM MarketScan Multi-State Medicaid Claims database identified adults with bipolar I disorder who initiated an AAP (index date) between 1 January 2014 and 30 June 2019.

Healthcare resource utilization, costs and treatment patterns in patients with bipolar disorder treated with lurasidone or cariprazine.

Objective: To compare healthcare resource utilization (HCRU), costs, and treatment adherence and persistence for patients with bipolar disorder treated with lurasidone or cariprazine.

Methods: Adult patients with bipolar disorder who initiated lurasidone or cariprazine as monotherapy or adjunctive therapy between 1 January 2016 and 30 June 2019 were identified from the IBM MarketScan Commercial and Medicare Supplemental Database. The date of the first claim for lurasidone or cariprazine was defined as the index date.

Characterization of specific and distinct patient types in clinical trials of acute schizophrenia using an uncorrelated PANSS score matrix transform (UPSM).

Understanding the specificity of symptom change in schizophrenia can facilitate the evaluation antipsychotic efficacy for different symptom domains. Previous work identified a transform of PANSS using an uncorrelated PANSS score matrix (UPSM) to reduce pseudospecificity among symptom domains during clinical trials of schizophrenia. Here we used UPSM-transformed factor scores to identify 5 distinct patient types, each having elevated and specific severity among each of 5 symptom domains.

Major depressive disorder with mixed features and treatment response to lurasidone: A symptom network model.

Background: To investigate the symptom network structure of major depressive disorder (MDD) with mixed features and implications for treatment.

Methods: In this post-hoc analysis of a previously reported randomized trial, patients meeting DSM-IV-TR criteria for MDD presenting with two or three manic symptoms (DSM-5 mixed features specifier) were randomized to 6 weeks of double-blind treatment with lurasidone 20-60 mg/d (N = 109) or placebo (N = 100). The network structure of symptoms at baseline and their treatment moderating effects were investigated.

Efficacy and Safety of Dasotraline in Adults With Binge-Eating Disorder: A Randomized, Placebo-Controlled, Flexible-Dose Clinical Trial.

Objective: Binge-eating disorder (BED) is the most prevalent eating disorder; however, few evidence-based treatments are available. The aim of this study was to evaluate the efficacy and safety of dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, in adults with BED.

Methods: Patients with a DSM-5 diagnosis of BED (intent-to-treat sample, N = 315) were randomized to 12 weeks of double-blind treatment with once-daily, flexible doses (4, 6, or 8 mg/d) of dasotraline or placebo.

Lurasidone and risk for metabolic syndrome: results from short- and long-term clinical studies in patients with schizophrenia.

Objective: To assess the effects of treatment with lurasidone on risk for metabolic syndrome (MetS) in patients with schizophrenia.

Methods: Rates of metabolic syndrome during treatment with lurasidone (40-160 mg/d) were analyzed using pooled, short-term data from three randomized, double-blind, placebo-controlled studies (vs olanzapine and quetiapine XR); long-term data from two active-comparator-controlled studies (vs risperidone and quetiapine XR); and data from two open-label studies in which patients were switched from olanzapine or risperidone to lurasidone.

Results: MetS was defined based on the National Cholesterol Education Program criteria.

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.

Dysregulated Prefrontal Cortex Inhibition in Prepubescent and Adolescent Fragile X Mouse Model.

Changes in excitation and inhibition are associated with the pathobiology of neurodevelopmental disorders of intellectual disability and autism and are widely described in Fragile X syndrome (FXS). In the prefrontal cortex (PFC), essential for cognitive processing, excitatory connectivity and plasticity are found altered in the FXS mouse model, however, little is known about the state of inhibition. To that end, we investigated GABAergic signaling in the Fragile X Mental Retardation 1 (FMR1) knock out (Fmr1-KO) mouse medial PFC (mPFC).

Lurasidone in Children and Adolescents with Bipolar Depression Presenting with Mixed (Subsyndromal Hypomanic) Features: Analysis of a Randomized Placebo-Controlled Trial.

To evaluate the efficacy and safety of lurasidone in the treatment of children and adolescents with bipolar depression presenting with mixed (subsyndromal hypomanic) features. Patients, 10-17 years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5), diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with once-daily flexible doses of lurasidone 20-80 mg or placebo.

Switching to Lurasidone following 12 months of treatment with Risperidone: results of a 6-month, open-label study.

Background: Patients with a diagnosis of schizophrenia are at an increased risk for developing metabolic syndrome, which is associated with greater cardiovascular morbidity and mortality. Treatment with some commonly used antipsychotic medications may increase the risk of developing metabolic syndrome. The aim of the study was to evaluate the safety of lurasidone in patients who continued lurasidone or switched from risperidone to lurasidone.

A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia.

Background: An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT) receptors, may represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia.

Methods: We performed a randomized, controlled trial to evaluate the efficacy and safety of SEP-363856 in adults with an acute exacerbation of schizophrenia. The patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with SEP-363856 (50 mg or 75 mg) or placebo for 4 weeks.

C-reactive protein and response to lurasidone treatment in children and adolescents with bipolar I depression: Results from a placebo-controlled trial.

This study sought to investigate associations between levels of high-sensitivity c-reactive protein (hsCRP) prior to treatment and change in depressive symptoms and cognition in a short-term, double-blind, placebo-controlled study of lurasidone in children and adolescents with bipolar I depression. Patients 10-17 years of age with a DSM-5 diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with flexibly dosed lurasidone (20-80 mg/day) (n = 173) or placebo (n = 170). The primary efficacy measure was change from baseline to week 6 in the Children's Depression Rating Scale, Revised (CDRS-R).

Lurasidone compared to other atypical antipsychotic monotherapies for adolescent schizophrenia: a systematic literature review and network meta-analysis.

This network meta-analysis assessed the efficacy and tolerability of lurasidone versus other oral atypical antipsychotic monotherapies in adolescent schizophrenia. A systematic literature review identified 13 randomized controlled trials of antipsychotics in adolescents with schizophrenia-spectrum disorders. A Bayesian network meta-analysis compared lurasidone to aripiprazole, asenapine, clozapine, olanzapine, paliperidone extended-release (ER), quetiapine, risperidone, and ziprasidone.