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 D2 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 D2 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. Ulotaront increased subjective drowsiness, but reaction times were impaired by less than 10% and did not correlate with BOLD responses. In the Monetary Incentive Delay task (reward processing), ulotaront significantly modulated striatal responses to incentive cues, induced medial orbitofrontal responses, and prevented insula activation seen in HS subjects. In the N-Back working memory task, ulotaront modulated BOLD signals in brain regions associated with cognitive impairment in schizophrenia. Ulotaront did not show antidepressant-like biases in an emotion processing task. HS had significantly reduced connectivity in default, salience, and executive networks compared to LS participants and both drugs reduced this difference. Although performance impairment may have weakened or contributed to the fMRI findings, the profile of ulotaront on BOLD activations elicited by reward, memory, and resting state is compatible with an indirect modulation of dopaminergic function as indicated by preclinical studies. This phase 1 study supported the subsequent clinical proof of concept trial in people with schizophrenia.Clinical trial registration: Registry# and URL: ClinicalTrials.gov NCT01972711, https://clinicaltrials.gov/ct2/show/NCT01972711.

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

Objective: To assess the effects of lurasidone on anxiety symptoms and sleep disruption, and their moderating and mediating roles on treatment response in bipolar depression.Methods: 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. Functional outcome was assessed by the Sheehan Disability Scale.Results: All subjects (n = 824) had at least 1 psychic anxiety and 729 (88.5%) had at least 1 somatic anxiety symptom at baseline. 594 subjects (72.1%) experienced baseline sleep disturbance. Lurasidone, as monotherapy (20-60 mg/d and 80-120 mg/d pooled dose groups vs placebo) and adjunctive therapy (20 to 120 mg/d flexibly dosed vs placebo) with lithium or valproate, significantly reduced HAM-A psychic anxiety (-4.82 vs -2.97, P < .001, monotherapy; -5.56 vs -4.26, P = .009, adjunctive therapy) and somatic anxiety (-1.89 vs -1.37, P = .048, monotherapy; -2.22 vs -1.47, P = .006, adjunctive therapy) subcomponents. Improvement in anxiety symptoms mediated reduction in depressive symptoms and functional impairment. Decrease in sleep at baseline predicted change in anxiety symptoms with lurasidone treatment at week 6.Conclusions: Lurasidone was superior to placebo in reducing psychic and somatic anxiety in the short-term treatment of bipolar depression. Improvement in depressive symptoms and reduction in functional impairment were associated with reduction in anxiety symptoms moderated by baseline sleep disturbance during lurasidone treatment.Trial Registration: ClinicalTrials.gov identifiers: NCT00868699 and NCT00868452.

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-HT1A 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. METHODS: In a multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, ulotaront was evaluated in 16 adults with narcolepsy-cataplexy. Two oral doses of ulotaront (25 mg and 50 mg) were administered daily for 2 weeks and compared with matching placebo (6-treatment sequence, 3-period, 3-treatment). RESULTS: Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared to placebo. A sustained 2-week administration of both doses of ulotaront reduced the mean number of short-onset REM periods (SOREMPs) during daytime multiple sleep latency test (MSLT) compared to placebo. Although cataplexy events decreased from the overall mean baseline during the 2-week treatment period, neither dose of ulotaront statistically separated from placebo (p = 0.76, 25 mg; p = 0.82, 50 mg), and no significant improvement in patient and clinician measures of sleepiness from baseline to end of the 2-week treatment period occurred in any treatment group. CONCLUSIONS: Acute and sustained treatment with ulotaront reduced nighttime REM duration and daytime SOREMPs, respectively. The effect of ulotaront on suppression of REM did not demonstrate a statistical or clinically meaningful effect in narcolepsy-cataplexy. REGISTRATION: ClinicalTrials.gov identifier: NCT05015673.

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. RESULTS: Sleep disturbances, assessed by "difficulty with sleep" (Children's Depression Rating Scale, Revised [CDRS-R] item 4) and "decreased need for sleep" (Young Mania Rating Scale [YMRS] item 4), and "irritability" (CDRS-R item-8, YMRS item 5) were identified as "bridge" symptoms and found to have replicable causal associations with depressive (CDRS-R total) and manic symptom clusters (YMRS total) at baseline and week-6. A greater improvement in overall depression severity at week 6 with lurasidone (vs. placebo) treatment was observed in the presence (vs. absence) of decreased need for sleep at study baseline, mediated in part by significant reductions from study baseline in decreased need for sleep and manic symptom severity. The absence of sleep disturbance and irritability in patients at open-label extension study baseline was associated with higher rates of sustained recovery (symptomatic and functional remission) over 6 months compared to patients with those symptoms at baseline (68% vs. 50%, Number Needed to Treat=6). CONCLUSION: Our findings suggest that sleep disturbance and irritability are cardinal symptoms that "bridge" between depressive and manic symptom clusters and influence treatment outcomes in youth with bipolar depression.

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. The primary endpoint was change in the Montgomery-Asberg Depression Rating Scale (MADRS) at Week 6. The primary efficacy analysis population consisted of patients in Europe and US (n = 289); the secondary efficacy analysis population (ITT; n = 337) included patients in Japan. RESULTS: Endpoint improvement in MADRS total score was observed on both the primary analysis for SEP-4199 200 mg/d (P = 0.054; effect size [ES], 0.31) and 400 mg/d (P = 0.054; ES, 0.29), and on the secondary (full ITT) analysis for SEP-4199 200 mg/d (P = 0.016; ES, 0.34) and 400 mg/d (P = 0.024; ES, 0.31). Study completion rates were 81% on SEP-4199 200 mg/d, 88% on 400 mg/d, and 86% on placebo. SEP-4199 had low rates of individual adverse events (<8%) and minimal effects on weight and lipids; median increases in prolactin were +83.6 µg/L on 200 mg/d, +95.2 µg/L on 400 mg/d compared with 0.0 µg/L on placebo. LIMITATIONS: The study excluded patients with bipolar II depression and serious psychiatric or medical comorbidity. CONCLUSION: Study results provide preliminary proof of concept, needing confirmation in subsequent randomized trials, for the efficacy of non-racemic amisulpride in bipolar depression.

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. Available safety outcomes included discontinuations (all-cause, lack of efficacy, adverse events), metabolic parameters (weight change, cholesterol, triglycerides, glucose), changes in prolactin, and somnolence. Results from the NMA were reported as mean changes from baseline or odds ratios (OR) with 95% credible intervals (CrIs). RESULTS: Four RCTs comparing placebo to lurasidone, quetiapine (1 each for immediate- and extended-release), and the olanzapine-fluoxetine combination (OFC) met all of the inclusion criteria. Lurasidone and OFC demonstrated similar and statistically significant improvements in CDRS-R, but quetiapine did not (lurasidone: -5.70 [-8.66, -2.76]; OFC: -5.01 [-8.63, -1.38]; quetiapine: -1.85 [-5.99, 2.27]). Lurasidone was associated with smaller changes in weight, cholesterol, and triglycerides from baseline compared to OFC and quetiapine. There were no differences in changes in glucose levels among antipsychotics. In addition, lurasidone was associated with smaller change in prolactin levels compared to OFC but not quetiapine. CONCLUSION: Evidence from 4 studies in this NMA indicated that lurasidone and OFC, but not quetiapine, were efficacious for the treatment of bipolar depression in youths. Lurasidone was associated with less weight gain and smaller impacts on cholesterol and triglycerides compared with quetiapine and OFC.

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.

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. Here, we uncoupled the potential antidepressant activity in amisulpride, driven by 5-HT7 receptor (5-HT7R) antagonism, from the D2R-mediated antipsychotic activity by discovering that each enantiomer favors a different receptor. Aramisulpride was more potent at 5-HT7R relative to esamisulpride (Ki 47 vs. 1,900 nM, respectively), whereas esamisulpride was more potent at D2R (4.0 vs. 140 nM). We hypothesized that a nonracemic ratio might achieve greater 5-HT7R-mediated antidepressant effects at a lower level of D2R blockade. The dose-occupancy relationship of esamisulpride at D2R was determined by positron emission tomography (PET) imaging in human volunteers. Separately the dose-relationship of aramisulpride was established in humans using suppression of rapid eye movement (REM) sleep as a marker of 5-HT7R antagonism. These results led to the discovery of an 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) that maximizes the potential for antidepressant benefit of aramisulpride via 5-HT7R and reduces esamisulpride to minimize D2R-related extrapyramidal side effects while still retaining D2R-mediated effects predicted to provide benefit in bipolar depression. The antidepressant efficacy of SEP-4199 was recently confirmed in a proof-of-concept trial for the treatment of bipolar depression (NCT03543410).

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. Multiple tolerability outcomes were examined. Results from random effects models were reported as difference in change from baseline for continuous variables or odds ratios for dichotomous variables. Treatments were ranked using the surface under the curve cumulative ranking probabilities. Number needed to treat (NNT) and harm (NNH) were calculated. RESULTS: Eighteen RCT's met inclusion criteria of the systematic literature review. On change in MADRS, lurasidone (- 4.71 [95% Crl - 6.98, - 2.41]), quetiapine (- 4.80 [- 5.93, - 3.72]), olanzapine (- 4.57 [- 5.92, - 3.20]), and cariprazine (- 2.29 [- 3.47, - 1.09]) were more efficacious than placebo. Lurasidone was associated with a significantly greater odds of response (≥50% improvement in MADRS) compared to cariprazine (1.78 [95% Crl 1.08, 2.77]), aripiprazole (2.38 [1.38, 3.85]), and ziprasidone (2.47 [1.41, 3.98]), but was similar to olanzapine (1.68 [0.99,2.65]) and quetiapine (1.25 [0.78, 1.90]). For change in CGI-BP-S-overall score, lurasidone was significantly better than cariprazine (- 0.38 [95% Crl - 0.66,-0.10]) and ziprasidone (- 0.58 [- 0.91,-0.26]), but similar to quetiapine (- 0.08 [- 0.36, 0.19])and olanzapine (- 0.04 [- 1.41, 1.46]). Lurasidone (0.34 kg [95% Crl - 0.22, 0.89]) and aripiprazole (0.20 kg [- 0.59, 1.00]) had a similar weight change compared to placebo, but olanzapine (2.88 kg [2.40, 3.36]), quetiapine (1.17 kg [0.84, 1.49]), and cariprazine (0.65 kg [0.34, 0.96]) were associated with greater weight gain. The NNT for response was the lowest for lurasidone (NNT = 5) followed by quetiapine (NNT = 6), olanzapine (NNT = 10) and cariprazine (NNT = 12). CONCLUSIONS: In this NMA in adults with bipolar depression, which evaluated change in depressive symptoms (assessed by MADRS) across short-term trials, the largest improvement versus placebo was observed for lurasidone, olanzapine and quetiapine with cariprazine, showing a smaller treatment effect. Aripiprazole and ziprasidone were ineffective for the treatment of bipolar depression. Improvement in CGI-BP-S score for lurasidone was larger than cariprazine and ziprasidone but similar to quetiapine and olanzapine. Based on short term studies lurasidone and aripiprazole had similar weight gain compared to 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. Patients were continuously enrolled 12 months pre- and 24 months post-index date. Each month during the post-index period was categorized as monotherapy with lurasidone, aripiprazole, olanzapine, quetiapine or risperidone, no/minimal treatment, or other. Marginal structural models were performed to estimate hospitalization risk and length of stay (LOS) (all-cause and bipolar I disorder-related) compared to lurasidone. RESULTS: The analysis included 8262 adults. Compared to lurasidone, the adjusted odds ratios (aORs) of all-cause hospitalization were significantly higher for olanzapine (aOR = 1.60, 95% CI = 1.09-2.10) and quetiapine (aOR = 1.54, 95% CI = 1.18-1.89). The risk was significantly higher for bipolar I disorder-related hospitalization for quetiapine (aOR = 1.57, 95% CI = 1.10-2.04) and risperidone (aOR = 1.80, 95% CI = 1.04-2.56) compared to lurasidone. The bipolar I disorder-related LOS per 100 patient-months was more than twice as long for quetiapine (8.42 days) compared to lurasidone (3.97 days, p < .01). CONCLUSIONS: Lurasidone-treated adult Medicaid patients with bipolar I disorder had significantly lower risk of all-cause hospitalization than those treated with olanzapine and quetiapine and lower risk of bipolar I disorder-related hospitalization than quetiapine and risperidone. Bipolar I disorder-related hospital LOS was significantly shorter for patients treated with lurasidone compared to quetiapine.

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. The primary efficacy endpoint was changed in the ADHD Rating Scale, Version IV (ADHD RS-IV) total score. Secondary efficacy endpoints included the Clinical Global Impression, Severity (CGI-S) Scale. Least squares mean reduction at week 8 in the ADHD RS-IV HV total score was not significantly greater (vs. placebo) in the dasotraline 4 mg/day group (-15.0 vs. -13.9; n.s.; or in the dasotraline 6 mg/day group (-16.5 vs. -13.9; P = 0.074; Hochberg correction). Treatment with dasotraline 6 mg/day was significant at week 8 (uncorrected) on the ADHD RS-IV total score (P = 0.037) and the CGI-S score (P = 0.011). Treatment with the 4 mg/day dose of dasotraline was NS. Treatment with dasotraline was generally well tolerated. The results provide additional evidence that supports the potential efficacy of dasotraline, in doses of 6 mg/day, in adults with ADHD.

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. A difference-in-difference (DID) analysis, which mitigated bias by using each cohort as its own control, compared the changes in HCRU and costs from 6-months pre-treatment (baseline) to 6-months post-treatment (follow-up) between the two cohorts. Treatment adherence (medication possession ratio and proportion of days covered) and persistence (time to discontinuation) were assessed during the 6-month post-treatment period. Adjusted analyses were conducted using inverse probability of treatment weighting on HCRU, costs, and time to discontinuation. RESULTS: A total of 16,683 patients treated with lurasidone and 4,128 patients treated with cariprazine were identified. Average age (39-40) and proportion female (68-71%) were similar between cohorts. Both cohorts had reductions in hospitalizations from baseline to follow-up, and the decrease was significantly greater for the lurasidone cohort compared to the cariprazine cohort (change in the proportions of patients with all-cause hospitalizations: -5.3% vs. -2.5%, DID = -2.8%, p<.001). The total healthcare costs increased from baseline to follow-up in both cohorts, and the increase was significantly lower for the lurasidone cohort (change in total all-cause healthcare cost per person: $3,413 vs. $4,642, DID=-$1,228, p = .022). The lurasidone cohort had significantly lower risk of discontinuing treatment (hazard ratio = 0.86, p<.001) than the cariprazine cohort. CONCLUSIONS: Patients with bipolar disorder treated with lurasidone had greater reductions in hospitalizations from 6-months pre-treatment to 6-months post-treatment and had a lower increase in total costs compared to patients treated with cariprazine.

Efficacy and safety of dasotraline in adults with binge-eating disorder: a randomized, placebo-controlled, fixed-dose clinical trial.

OBJECTIVE: The aim of this fixed-dose study was to evaluate the efficacy and safety of dasotraline in the treatment of patients with binge-eating disorder (BED). METHODS: Patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for BED were randomized to 12 weeks of double-blind treatment with fixed doses of dasotraline (4 and 6 mg/d), or placebo. The primary efficacy endpoint was change in number of binge-eating (BE) days per week at week 12. Secondary efficacy endpoints included week 12 change on the BE CGI-Severity Scale (BE-CGI-S) and the Yale-Brown Obsessive-Compulsive Scale Modified for BE (YBOCS-BE). RESULTS: At week 12, treatment with dasotraline was associated with significant improvement in number of BE days per week on the dose of 6 mg/d (N = 162) vs placebo (N = 162; -3.47 vs -2.92; P = .0045), but not 4 mg/d (N = 161; -3.21). Improvement vs placebo was observed for dasotraline 6 and 4 mg/d, respectively, on the BE-CGI-S (effect size [ES]: 0.37 and 0.27) and on the YBOCS-BE total score (ES: 0.43 and 0.29). The most common adverse events on dasotraline were insomnia, dry mouth, headache, decreased appetite, nausea, and anxiety. Changes in blood pressure and pulse were minimal. CONCLUSION: Treatment with dasotraline 6 mg/d (but not 4 mg/d) was associated with significantly greater reduction in BE days per week. Both doses of dasotraline were generally safe and well-tolerated and resulted in global improvement on the BE-CGI-S, as well as improvement in BE related obsessional thoughts and compulsive behaviors on the YBOCS-BE. These results confirm the findings of a previous flexible dose study.

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. Subjects from placebo-controlled clinical trials of acute schizophrenia were clustered (baseline) and classified (post-baseline) by a machine-learning algorithm. At baseline, all 5 patient types were similar in PANSS total score. Post-baseline, subjects' memberships among the 5 UPSM patient types were relatively stable over treatment duration and were relatively insensitive to overall improvements in symptoms, in contrast to other methods based on untransformed PANSS items. Using UPSM-transformed PANSS, drug treatment effect sizes versus placebo were doubly-dissociated for specificity across symptom domains and within specific patient types. This approach illustrates how broader clinical trial populations can nevertheless be utilized to characterize the specificity of new mechanisms across the dimensions of schizophrenia psychopathology.

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. RESULTS: Network analyses showed that both ``elevated mood'' (YMRS item 1) and ``increased motor activity-energy'' (YMRS item 2) were associated with ``sleep disturbance'' ("bridge" symptom) and the depressive symptom cluster. Presence of both "elevated mood" and "increased motor activity-energy" at baseline predicted significantly less improvement in MADRS and CGI-S score at week 6 with lurasidone (vs. placebo) compared to patients without these manic symptoms at baseline. The network model also showed "rapid/pressured speech" (YMRS item 6) at baseline predicted improvement in both manic and depressive symptoms with lurasidone vs. placebo treatment. LIMITATIONS: This was a post-hoc analysis where findings need to be confirmed by prospective controlled studies. CONCLUSIONS: This post-hoc analysis describes the symptom network structure of MDD with mixed features in a patient sample at study baseline. Specific manic symptoms were found to be linked to sleep disturbance (characterized as a "bridge" symptom), which in turn linked the manic and depressive symptom clusters. The presence (vs. absence) of the specific manic symptoms we identified moderated the antidepressant and antimanic effects of lurasidone in the treatment of MDD with mixed (subthreshold hypomanic) features.

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. In short-term studies, the odds of meeting criteria for MetS at week 6 LOCF (adjusted for baseline metabolic syndrome status) was similar for the lurasidone and placebo groups (OR = 1.18; [95% CI, 0.81-1.71]; P = .39), but the odds (vs placebo) were significantly greater for olanzapine (OR = 2.81; [95% CI, 1.53-5.15]; P < .001) and quetiapine (OR = 3.49; [95% CI, 1.93-6.29]; P < .0001). No dose effect was observed for lurasidone across the dose range of 40-160 mg/d. In long-term studies, the odds of MetS after 12 months of treatment was significantly higher for risperidone compared with lurasidone (OR = 2.12; 95% CI, 1.15-3.90; P = .016) and for quetiapine XR compared with lurasidone (OR = 3.92; 95% CI, 1.15-13.40; P = .029). In open-label extension studies, the rate of MetS decreased in patients switched to lurasidone after 6 weeks of treatment with olanzapine or 12 months of treatment with risperidone. CONCLUSION: In this analysis of lurasidone clinical trials, the odds of developing metabolic syndrome were minimal during short- and long-term treatment with lurasidone (40-160 mg/d).

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. Primary endpoint was change in diary-based assessment of number of binge-eating days per week at week 12. Key secondary endpoints included changes from baseline in Clinical Global Impressions-Severity of Illness scale (CGI-S) and Yale-Brown Obsessive Compulsive Scale Modified for Binge-Eating (YBOCS-BE) and percentage of subjects with cessation of binge eating in the final 4 weeks. RESULTS: Treatment with dasotraline was associated with a significantly greater reduction in binge-eating days per week at study endpoint (vs placebo; least squares mean [SE] difference score, -0.99 [0.17]; P < .0001; effect size [ES], 0.74). Significant endpoint improvement was observed for the 3 key secondary measures, CGI-S (P < .0001; ES, 0.95), YBOCS-BE (P < .0001; ES, 0.96), and 4-week cessation of binge eating (46.5% vs 20.6%; P < .0001). The most common adverse events in the dasotraline vs placebo groups were insomnia (44.6% vs 8.1%), dry mouth (27.4% vs 5.0%), decreased appetite (19.7% vs 6.9%), and anxiety (17.8% vs 2.5%). Discontinuation due to adverse events occurred in 11.3% of patients on dasotraline vs 2.5% on placebo. CONCLUSIONS: The results of this placebo-controlled, double-blind study found dasotraline to be an efficacious, safe, and generally well-tolerated treatment for BED. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02564588.

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 < .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.

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

Objectives: To evaluate the efficacy and safety of lurasidone in the treatment of children and adolescents with bipolar depression presenting with mixed (subsyndromal hypomanic) features. Methods: 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. The presence of mixed (subsyndromal hypomanic) features in this pediatric bipolar depression trial was defined as a Young Mania Rating Scale score of 5 or greater at study baseline. Key efficacy measures included change from baseline to week 6 in the Children's Depression Rating Scale-Revised (CDRS-R) score (primary endpoint) and Clinical Global Impressions-Bipolar Severity (CGI-BP-S) score, using a mixed model for repeated measures analysis. Results: At baseline, subsyndromal hypomanic features were present in 54.2% of patients. Treatment with lurasidone (vs. placebo) was associated with significantly greater reductions in CDRS-R scores at week 6, independent of the presence (-21.5 vs. -15.9, p < 0.01; effect size d = 0.43) or absence (-20.5 vs. -14.9, p < 0.01; d = 0.44) of subsyndromal hypomanic features. Likewise, lurasidone (vs. placebo) was associated with significantly greater reductions in CGI-BP-S scores at week 6, independent of the presence (-1.6 vs. -1.1, p < 0.001, d = 0.51) or absence (-1.3 vs. -1.0, p = 0.05; d = 0.31) of these subsyndromal hypomanic features. Rates of protocol-defined treatment-emergent hypomania or mania were similar for lurasidone and placebo in patients with (lurasidone 8.2% vs. placebo 9.0%) or without subsyndromal hypomanic features (lurasidone 1.3% vs. placebo 3.7%). Conclusions: In this post hoc analysis of a randomized placebo-controlled trial, lurasidone was found to be efficacious in the treatment of child and adolescent patients with bipolar depression who presented with mixed (subsyndromal hypomanic) features. No differences in safety profile, including the risk of treatment-emergent mania, were observed in patients with or without subsyndromal hypomanic features in this study.

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 secondary aim was assessment of the effect of long-term lurasidone on the Positive and Negative Syndrome Scale (PANSS). METHODS: The treatment sample in the current study consisted of clinically stable patients with schizophrenia (N = 223) who had completed a 12-month, double-blind study of lurasidone vs. risperidone. In the current extension study, all patients received 6 months of open-label treatment with lurasidone, either continuing lurasidone assigned during the preceding double-blind trial, or switching from double-blind risperidone to lurasidone. Safety and tolerability parameters included body weight, prolactin, and metabolic laboratory tests. RESULTS: Six months of OL treatment with lurasidone was generally well-tolerated, with a low incidence of parkinsonism (4.5%) and akathisia (3.1%). Overall, few adverse events were rated as severe (4.9%), and discontinuation due to an adverse event was low in the lurasidone continuation vs. risperidone switch groups (3.7% vs. 6.9%). In the lurasidone continuation versus risperidone switch groups, change from OL baseline to 6-month endpoint (observed case) was observed in mean body weight (- 0.6 vs. -2.6 kg), median total cholesterol (- 4.0 vs. + 4.5 mg/dL), triglycerides (- 4.5 vs. -5.5 mg/dL), glucose (0.0 vs. -3.0 mg/dL) and prolactin (males, + 0.15 vs. -11.2 ng/mL; females, + 1.3 vs. -30.8 ng/mL). Improvement in PANSS total score was maintained, from OL baseline to endpoint in the continuation vs. switch groups (+ 1.0 vs. -1.0; OC). CONCLUSIONS: In this 6-month extension study, lurasidone treatment was generally well-tolerated and associated with minimal effects on weight, metabolic parameters, and prolactin levels. Patients who switched from risperidone to lurasidone experienced reductions in weight, metabolic parameters and prolactin levels commensurate with increases in these safety parameters experienced during the previous 12 months of treatment with risperidone. TRIAL REGISTRATION: ClinicalTrials.gov NCT00641745 (Date of Registration: March 24, 2008).