Acute Exacerbation Of Schizophrenia Research Articles

The specific anti-hostility effect of lurasidone in patients with an acute exacerbation of schizophrenia: results of pooled post hoc analyses in adolescents and adults.

Symptoms of hostility in patients during acute exacerbations of schizophrenia have been associated with aggressive behavior. Data suggest that some second-generation antipsychotics have specific anti-hostility effects, independent of sedation and positive symptom improvement. Two post hoc analyses were performed to examine the efficacy of lurasidone for reducing hostility in patients with schizophrenia. One analysis pooled adults (N = 1168) from 5 placebo-controlled, 6-week trials of lurasidone (40-160 mg). Another analysis pooled younger patients (up to age 25 years, N = 427) from the adult studies and a similarly designed trial of lurasidone (40 or 80 mg) in adolescent patients (13-17 years old). The outcome measure was mean change in the hostility item (P7) of the Positive and Negative Syndrome Scale (PANSS). To address pseudospecificity, results were adjusted for positive symptom change and sedation. In adults with a baseline PANSS hostility score ≥2, significant improvement in hostility was observed for all doses with a dose-related increase in effect size (Cohen's d): lurasidone 40 mg = 0.18, 80 mg = 0.24, 120 mg = 0.36, and 160 mg = 0.53. The same dose-response pattern was observed for the more severe hostility subgroups (P7: ≥3, ≥4), and in the early-onset population. Results suggest that lurasidone has specific, dose-related anti-hostility effects.

Comparing the latent state-trait structure of the PANSS in cariprazine-medicated and placebo-controlled patients with acute schizophrenia.

After over a hundred years of research, the question whether the symptoms of schizophrenia are rather trait-like (being a relatively stable quality of individuals) or state-like (being substance to change) is still unanswered. To assess the trait and the state component in patients with acute schizophrenia, one group receiving antipsychotic treatment, the other not. Data from four phase II/III, 6-week, randomized, double-blind, placebo-controlled trials of similar design that included patients with acute exacerbation of schizophrenia were pooled. In every trial, one treatment group received a third-generation antipsychotic, cariprazine, and the other group placebo. To assess symptoms of schizophrenia, the Positive and Negative Symptom Scale (PANSS) was applied. Further analyses were conducted using the five subscales as proposed by Wallwork and colleagues. A latent state-trait (LST) model was developed to estimate the trait and state components of the total variance of the observed scores. All symptom dimensions behaved more in a trait-like manner. The proportions of all sources of variability changed over the course of the observational period, with a bent around weeks 3 and 4. Visually inspected, no major differences were found between the two treatment groups regarding the LST structure of symptom dimensions. This high proportion of inter-individual stability may represent an inherent part of symptomatology that behaves independently from treatment status.

Antipsychotic dose, dopamine D2 receptor occupancy and extrapyramidal side-effects: a systematic review and dose-response meta-analysis.

Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D2 receptor (D2R) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The D2R occupancy curves showed that the risk increased substantially when D2R occupancy exceeded 75-85%, except for D2R partial agonists that had smaller ORs albeit high D2R occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current D2R therapeutic window for EPS.

Review of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist Ulotaront: Part II—Summary of Initial Clinical Efficacy/Safety Results

AbstractIntroductionUlotaront is a trace amine-associated receptor 1 (TAAR1) agonist with serotonin 5-HT1A agonist activity that has received FDA Breakthrough Therapy Designation for the treatment of schizophrenia. Here we summarize ongoing clinical research characterizing the efficacy and safety of ulotaront as a member of the novel trace amine-associated receptor 1 (TAAR1) agonist class.MethodsSummarized are results from a double-blind, placebo-controlled study to evaluate the efficacy and safety of ulotaront (50 mg or 75 mg) in an acute exacerbation of schizophrenia, and a 6-month, open-label follow-up study. Also summarized are post-hoc analyses evaluating negative symptom efficacy, and key safety and adverse event (AE) outcomes.ResultsIn the short-term study, treatment with ulotaront was associated with significant (p<0.001) endpoint improvement in the PANSS total score (effect size [ES]: 0.45), the CGI-Severity score (ES: 0.52) and the Brief Negative Symptom Scale total score (ES: 0.48). The incidence of any AE was lower on ulotaront versus placebo (45.8% vs. 50.4%), and the number needed to harm (NNH) for individual AEs on ulotaront were all >40. Ulotaront was associated with lower risk for antipsychotic class-related AEs (extrapyramidal symptoms, akathisia, somnolence, nausea/vomiting, increased weight/metabolic labs, prolactinemia). The 6-month study demonstrated further improvement, with a completion rate (67%) that was higher than reported for current dopamine D2 antipsychotics.ConclusionsThe emerging profile of ulotaront is characterized by significant improvement in positive and negative symptoms of schizophrenia. The safety and tolerability profile of ulotaront is markedly different with respect to antipsychotic class-related AEs. The benefit-risk profile of ulotaront, as a member of a novel TAAR1 agonist class, is distinguished from antipsychotics by lack of AEs related to D2 and serotonin 5-HT2A receptor blockade.FundingSunovion Pharmaceuticals, Inc., and Otsuka Pharmaceutical Development & Commercialization, Inc.

Factor Analysis Investigating the Efficacy of HP-3070 Transdermal System in Positive and Negative Syndrome Scale Five Adults With Schizophrenia

AbstractIntroductionHP-3070, a once-daily asenapine transdermal system, is FDA-approved for adults with schizophrenia. In a pivotal phase 3 randomized controlled study, patients with schizophrenia who were treated once daily with HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores compared with placebo. The PANSS score’s five-factor structure can also assess treatment efficacy across different domains. This post-hoc analysis of the pivotal study evaluated the efficacy of HP-3070 by examining these domains.MethodsIn the pivotal phase 3 study, adults with acute exacerbations of schizophrenia were randomized to 6 weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. Factor analysis of PANSS scores was performed using five domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates.ResultsThe analysis included 607 patients. Least-squares mean estimates (standard error) of the difference from placebo in change from baseline to Week 6 for each factor were as follows: negative symptoms, 3.8mg/24h, -0.9 (0.43), P=0.045, and 7.6mg/24h, -0.4 (0.43), P=0.41; positive symptoms, 3.8mg/24h, -2.3 (0.57), P<0.001, and 7.6mg/24h, -2.0 (0.57), P<0.001; disorganized thought, 3.8mg/24h, -1.5 (0.38), P<0.001, and 7.6mg/24h, -0.9 (0.38), P=0.03; uncontrolled hostility/excitement: 3.8mg/24h, -1.1 (0.30), P<0.001, and 7.6mg/24h -0.9 (0.30), P=0.002; anxiety/depression, 3.8mg/24h, -0.5 (0.31), P=0.14, and 7.6mg/24h, -0.6 (0.31), P=0.07.ConclusionsHP-3070 demonstrated treatment effects on a PANSS five-factor model, with the results indicating impact on negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression. These findings suggest that HP-3070 may address a broad range of symptoms in schizophrenia.FundingNoven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical, Co.

Does short-term antipsychotic discontinuation of up to 3 weeks worsen symptoms in acute schizophrenia? A pooled analysis of placebo washout data.

This study aimed to examine symptom changes during short-term discontinuation of antipsychotics up to 3 weeks including the placebo washout phase in acute schizophrenia. The data from three double-blind, randomized, controlled trials comparing lurasidone versus placebo in patients with acute exacerbation of schizophrenia were analyzed. Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS) total and the Clinical Global Impression-Severity scale (CGI-S) scores. The scores before and after the antipsychotic discontinuation phase were compared, and factors associated with score changes were explored. Among 2154 patients participating in the trials, 600 who received antipsychotic monotherapy and completed the antipsychotic discontinuation phase were included in the analysis. No patients received clozapine. The mean duration of the discontinuation phase was 5.9 ± 2.5 days. The PANSS total and CGI-S scores significantly changed from 94.0 ± 9.5 to 95.4 ± 10.5 (P < 0.001) and from 4.9 ± 0.6 to 4.9 ± 0.7 (P=0.041), respectively, during this phase; however, the absolute difference was minimal. The score changes were not associated with the type or dose of prior antipsychotics, or the duration or strategy (abrupt vs gradual) of antipsychotic discontinuation. Symptoms may not worsen to a clinically meaningful degree after short-term discontinuation of non-clozapine antipsychotics up to 3 weeks in patients with acute exacerbation of schizophrenia, suggesting that antipsychotic efficacy persists at least several days after discontinuation. This finding supports once-daily dosing regimen of antipsychotics and abrupt antipsychotic discontinuation when switching to another antipsychotic.

Blood Viscosity and Inflammation in First-Episode and Acute Exacerbations of Schizophrenia: A Case-Control Study with Healthy Controls.

Elevated proinflammatory status and alterations in blood flow, both of which are associated with the pathophysiology of schizophrenia, may be linked with an increased risk of cardiovascular diseases. However, such a relationship at different acute stages of schizophrenia has not been evaluated. We aimed to examine whether blood viscosity and systemic inflammatory status varied between first-episode schizophrenia (FES) and acute exacerbations of schizophrenia. Fifty-two patients with FES, 69 schizophrenia patients with acute exacerbation (S-AE) and 56 healthy controls (HC) were included in the study. Whole blood viscosity (WBV) was calculated according to de Simone's formula at low and high shear rates (LSR and HSR). Systemic immune-inflammation index (SII) and systemic inflammatory response index (SIRI) were calculated from hemogram screening data at admission. When adjusted for age, WBV at both LSR and HSR were significantly decreased in both FES and S-AE groups compared to HCs. Systemic inflammatory response index was significantly higher in FES patients than in the S-AE and HC groups. Total cholesterol (TC) and WBV at HSR were correlated in patients. Total cholesterol predicted WBV at LSR in patients with FES whereas other independent variables including age and SIRI did not. Both first and subsequent episodes of schizophrenia are associated with reduced blood viscosity. Increased inflammatory status may not fully explain such a relationship. Extrapolation of hemorheological characteristics in schizophrenia may help to stratify cardiovascular risk and reflect the pathophysiological process in the early and later stages of schizophrenia.

Effects of lurasidone on hostility in patients with an acute exacerbation of schizophrenia: a pooled analysis of short-term studies

Effects of lurasidone on hostility in patients with an acute exacerbation of schizophrenia: a pooled analysis of short-term studies

Effectiveness of Lurasidone 80 mg in Patients with Schizophrenia: Results of an Open-Label, 12-Week Extension Study.

To evaluate the effectiveness and safety of lurasidone 80 mg/day (versus the 40 mg/day dose) during a 12-week, open-label extension study in patients with an acute exacerbation of schizophrenia who had completed a 6-week double-blind study of lurasidone. A total of 289 adult patients with schizophrenia completed the double-blind study and enrolled in the 12-week extension study. Lurasidone was flexibly dosed at 40 or 80 mg/day. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) subscale scores, Clinical Global Impression-Severity Scale (CGI-S), and Calgary Depression Scale for Schizophrenia (CDSS), analyzed based on last observation carried forward (LOCF-endpoint). Safety/tolerability assessments included adverse events, body weight, laboratory tests, and discontinuation due to adverse events. Mean endpoint change was greater for lurasidone in modal doses of 80 mg/d (N=136) vs 40 mg/d (N=153) on the PANSS positive subscale (-3.0 vs -2.3), PANSS negative subscale (-1.9 vs -1.7), PANSS General Psychopathology subscale (-5.1 vs -3.8), the CGI-S score (-0.5 vs -0.4), and the CDSS score (-0.7 vs -0.1). Discontinuation rates due to adverse events on lurasidone modal 80 mg/d vs 40 mg/d were 4.4% vs 7.2%; and the most common adverse events in the modal 80 mg/d group were nasopharyngitis, 7.4% (vs 4.6% on modal 40 mg/d), constipation, 5.9% (vs 2.0%), and headache, 5.9% (vs 2.0%). In patients with acute schizophrenia treated with lurasidone 40 mg/d, increasing the dose to 80 mg/d was well tolerated, and was associated with greater improvement in PANSS subscale scores compared to continued treatment with a dose of 40 mg/d.

Clinical Effectiveness of Lurasidone Monotherapy in Patients with Acute Episodes of Schizophrenia and Associated Symptoms of Depression.

We endeavored to evaluate the efficacy of Lurasidone at doses of 40-160 mg per day on symptoms of schizophrenia associated with symptoms of depression in real clinical practice in a Russian patient population. One hundred sixty eight patients aged 18-65 years old, who at the time of the start of the observation were being treated in a hospital or day hospital due to an exacerbation of paranoid schizophrenia accompanied by symptoms of depression, were prescribed lurasidone. Treatment with lurasidone and other concomitant drugs, their prescription, withdrawal, selection, and dose modifications were determined based on the indications for the use of those drugs and the recommended doses in the instructions, clinical need, and patient interests, rather than by the goals of the study. During the observation period, the severity of depressive symptoms according to the Calgary Depression Scale (CDSS) and that of psychotic symptoms according to the Positive and Negative Syndrome Scale (PANSS) were assessed six times (before the start of treatment and then on the 4th, 7th, 14th, 28th, and 42nd days). A statistically significant reduction in the severity of the symptoms was observed with the use of lurasidone in doses ranging from 40 mg to 160 mg per day. The fastest and most significant (p <0.001) reductions in the total PANSS and CDSS scores were observed with lurasidone 120 mg. A somewhat lower efficacy of lurasidone was observed at a dose of 160 mg. The largest reductions in the total PANSS and CDSS scores with lurasidone 120 mg were associated with the highest survival rate and the longest median time from treatment initiation to discontinuation or follow-up. The most commonly reported side effects with lurasidone in this study (nausea, akathisia, tremor and drowsiness) were consistent with the known safety profile of the drug. Adverse events in most cases were assessed as mild, or occasionally moderate. A six-week prospective observational study of the real-world clinical effectiveness of lurasidone in doses ranging from 40 mg to 160 mg per day established statistically and clinically significant improvements in both psychotic and depressive symptoms in patients with acute exacerbation of schizophrenia and associated symptoms of depression.

Trace Amine-Associated Receptor 1 Agonists for Schizophrenia

TAAR1 agonists are an emerging drug class in the treatment of schizophrenia as they may offer a novel mechanism of action for symptom management without blocking dopamine D2 receptors, unlike currently available antipsychotic medications that act primarily via D2 binding. Two TAAR1 agonists are currently in clinical development for schizophrenia. The first is ulotaront, a TAAR1 full agonist with 5-hydroxytryptamine 1A agonist activity that is administered orally once daily, and the other is ralmitaront, a TAAR1 partial agonist that is also administered orally once daily. The published clinical trial evidence on TAAR1 agonists currently only pertains to ulotaront, which includes a 4-week, phase II, placebo-controlled randomized trial on patients with acute exacerbation of schizophrenia and a 26-week, open-label extension study of this same trial. These studies demonstrated improvements across disease-specific and global impression scales following treatment with ulotaront, with statistically significant differences compared to placebo, and no increased risk of the side effects (extrapyramidal symptoms and metabolic changes) associated with traditional D2-binding antipsychotic therapies. There is currently no cost information available for TAAR1 agonists. Ulotaront is currently undergoing phase III trials and, though it is not currently approved in any country and the date of Health Canada licensing and marketing in Canada is not yet known, it is expected to be the first TAAR1 agonist for schizophrenia in the Canadian market. Ulotaront received Breakthrough Therapy designation from the FDA in 2019 to expedite its development and the drug’s manufacturer is planning to file a New Drug Application with the FDA in 2023. Ralmitaront is currently in phase II trials, which are expected to be completed in 2023.

The efficacy of cariprazine in chronic schizophrenia – post hoc analyses of phase II/III clinical trials

IntroductionChronic schizophrenia patients are experiencing persistent and severe illness for more than 15-20 years and are usually suffering from long-term negative symptoms. Cariprazine, a novel D3-D2 partial agonist has been proven to be effective in the treatment of acute schizophrenia, however its ability to treat chronic patients has not been assessed yet.ObjectivesThe primary aim of the present post-hoc analysis is to assess the efficacy of cariprazine in treating patients with chronic schizophrenia (late-stage and residual schizophrenia patients).MethodsData from 3 phase II/III 6-week, randomized, double-blind, placebo-controlled trials with similar design in patients with acute exacerbation of schizophrenia were pooled and patients with more than 15 years of schizophrenia were analysed (late-stage patients). Furthermore, schizophrenia patients experiencing predominantly negative symptoms from a 26-week, randomized, double-blind, active-controlled, fixed-flexible-dose trial with an ICD-10 code of F20.5 were analysed post-hoc (residual patients).ResultsAltogether, 414 late stage (286 cariprazine and 128 placebo) and 35 residual (23 cariprazine and 12 risperidone) patients were identified. The pooled analysis evaluating mean change from baseline to week 6 in the PANSS total score indicated statistically significant difference in favour of cariprazine in the late stage (LSMD -6.7, p&lt;0.01) subpopulation compared to placebo. The mean change from baseline in patients with residual schizophrenia in the cariprazine arm was -9.6 on the PANSS-FSNS scale, while -7.9 in the risperidone arm.ConclusionsBased on the results, it seems that cariprazine might be a good treatment option for patients with chronic schizophrenia. Nonetheless, further studies are needed to confirm this.DisclosureI am an employee of Gedeon Richter Plc.

Emerging Treatments in Schizophrenia.

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.

Emerging Treatments in Schizophrenia.

Although antipsychotics have been available for almost 70 years and greatly improved outcomes for individuals with schizophrenia, all currently available options derive their efficacy from blockade of dopaminergic receptors. However, this mechanism of action leaves many symptoms unresolved and is associated with a significant side effect burden. The mechanisms underlying schizophrenia, which were initially thought to be related to excessive presynaptic dopamine in specific areas of the brain, are now understood to be much more complex and involve structural and molecular changes throughout brain circuits. Consequently, drug discovery efforts have sought new targets in the search for safer and more effective medications that can improve symptoms of schizophrenia and psychosis, including trace amine-associated receptors (TAARs), muscarinic receptors, and serotonergic receptors. Positive phase 2 trial results indicating efficacy and safety of the TAAR1 agonist ulotaront (SEP-363856) and of the muscarinic M1/M4 agonist KarXT (xanomeline plus trospium) for total, positive, and negative symptoms in patients with acute exacerbation of schizophrenia, and of the serotonin 5-HT2A agonist/antagonist pimavanserin in patients with schizophrenia and predominant negative symptoms for negative symptom control are encouraging. Taken together, these data indicate in the context of ongoing phase 3 trial programs that patients with schizophrenia may soon have access to the first non-D2 blocking medication, which could drastically change the treatment landscape and improve outcomes for many of the individuals with schizophrenia who do not fully respond to or cannot tolerate currently available antipsychotic agents that currently all act via postsynaptic dopamine D2 receptor blockade.

Antipsychotic-Induced Weight Gain: Dose-Response Meta-Analysis of Randomized Controlled Trials.

Weight gain is among the most important side-effects of antipsychotics. It is, however, unclear whether it is associated with antipsychotic doses. We aimed to fill this gap with a dose-response meta-analysis. We searched multiple electronic databases (last update search June 2021) for all fixed-dose studies that investigated 16 second-generation antipsychotics and haloperidol in adults with acute exacerbation of schizophrenia or with negative symptoms. We estimated the dose-response curves by conducting random-effects dose-response meta-analyses. We used the restricted cubic spline to model the dose-response relationship. The primary outcome was mean weight gain in kg from baseline to endpoint, the secondary outcome was the number of patients with clinically important weight gain. Ninety-seven studies with 333 dose arms (36 326 participants) provided data for meta-analyses. Most studies were short-term with median duration of 6 weeks (range 4 to 26 weeks). In patients with acute exacerbation, amisulpride, aripiprazole, brexpiprazole, cariprazine, haloperidol, lumateperone, and lurasidone produced mild weight gain in comparison to placebo (mean difference at any dose≤1 kg), while more significant weight gain was observed by all other drugs. For most drugs, dose-response curves showed an initial dose-related increase in weight which plateaued at higher doses, while for others there was no plateau and some even had bell-shaped curves, meaning less weight gain to be associated with higher doses. Second-generation antipsychotics do not only differ in their propensity to produce weight gain, but also in the shapes of their dose-response curves. This information is important for dosing decisions in clinical practice.

Short-term Efficacy and Safety of Lurasidone Versus Placebo in Antipsychotic-Naïve vs. Previously Treated Adolescents with an Acute Exacerbation of Schizophrenia.

AbstractBackgroundTo evaluate the efficacy of short-term lurasidone in antipsychotic treatment-naïve (TN) adolescents with schizophrenia versus those treated previously (TP) with antipsychotics.MethodsPatients aged 13–17 with schizophrenia, and a Positive and Negative Symptom Scale (PANSS) score ≥ 70 and &lt; 120, were randomized to 6 weeks of double-blind treatment with lurasidone (40 or 80 mg/day) or placebo. In a post-hoc, pooled-dose analysis, efficacy was evaluated for TN (criteria: never received antipsychotic treatment) versus TP at the time of the study. Treatment response criteria: ≥20% reduction in PANSS total score.ResultsAltogether, 57 TN and 269 TP patients enrolled in the 6-week DB study. Mean endpoint change in PANSS total score was significantly greater for lurasidone versus placebo in both the TN group (−25.0 vs. -14.4; p &lt; 0.02; effect size = 0.75), and in the TP group (−17.3 vs. -10.0; p &lt; 0.001; effect size = 0.45); and responder rates were higher for lurasidone versus placebo in both the TN group 84.6% versus 38.9%; number needed to treat [NNT] = 3 and in the TP group (60% vs. 42%; NNT = 6). Rates of treatment-emergent adverse events, and mean changes in body weight and metabolic parameters were similar for the TN and TP groups.ConclusionsIn a 6-week, placebo-controlled trial, lurasidone demonstrated significant efficacy in adolescents with schizophrenia regardless of previous antipsychotic therapy status; however, the effect size was notably larger in the TN patient group. In both the TN and TP groups, minimal effects were noted on weight, metabolic parameters, or prolactin.

Handwriting Kinematics in Patients with Schizophrenia Treated with Long-Acting Injectable Atypical Antipsychotics: Results From the ALPINE Study

AbstractHandwriting kinematics (HWKs) were assessed in the randomized controlled ALPINE study of 2 long-acting injectable antipsychotics started during an acute exacerbation of schizophrenia. This exploratory analysis examined the relationship between baseline HWKs and response to acute antipsychotic treatment. Adults with acute schizophrenia were assigned to aripiprazole lauroxil or paliperidone palmitate (groups combined for this analysis). Treatment response was defined as ≥20% reduction from baseline in Positive and Negative Syndrome Scale (PANSS) total score at week 4. Two HWK measures, peak velocity (decreases with greater dysfunction) and percentage of nonballistic movements (%NBM; increases with greater dysfunction), were captured in 4 handwriting tasks (complex loops, maximum speed circles, overlay circles, and left-right loops). Peak velocity and %NBM at baseline were compared between responders and nonresponders. The analysis included 143 patients (mean baseline PANSS total score, 94.5). PANSS responders (n = 67 [46.9%]) had a lower mean peak velocity (i.e., slower pen movements) on all HWK tasks at baseline compared with nonresponders (n = 76): complex loops, 8.8 versus 12.1 cm/s; maximum speed circles, 18.0 versus 23.7 cm/s; overlay circles, 12.6 versus 17.2 cm/s; and left-right loops, 11.2 versus 14.6 cm/s. PANSS responders had a greater %NBM on 3 tasks compared with nonresponders: complex loops, 57.1% versus 47.4%; overlay circles, 30.6% versus 24.3%; and left-right loops, 58.7% versus 47.0%. In this exploratory analysis, PANSS responders to aripiprazole lauroxil or paliperidone palmitate treatment at week 4 had lower baseline HWK movement velocities and greater baseline %NBM versus nonresponders, suggesting that baseline HWKs might predict response to these antipsychotic drugs.

Efficacy of Risperidone ISM in patients with an acute exacerbation of schizophrenia: a post-hoc analysis on the PANSS-6 score

Efficacy of Risperidone ISM in patients with an acute exacerbation of schizophrenia: a post-hoc analysis on the PANSS-6 score

Ulotaront, a novel TAAR1 agonist with 5-HT1A agonist activity, lacks abuse liability and attenuates cocaine cue-induced relapse in rats

BackgroundUlotaront (SEP-363856) is a trace amine-associated receptor 1 (TAAR1) agonist with 5-hydroxytryptamine type 1A (5-HT1A) agonist activity that is currently in Phase 3 clinical development for the treatment of schizophrenia. Unlike available antipsychotics, the efficacy of ulotaront is not mediated by blockade of dopamine D2 or serotonin 5-HT2A receptors. In a short-term randomized clinical trial, ulotaront has demonstrated significant efficacy in the treatment of adults with an acute exacerbation of schizophrenia. Given ulotaront’s novel mechanism of action a series of preclinical studies were performed to evaluate its potential abuse liability. MethodsA battery of studies were conducted in male and female rats to evaluate whether ulotaront produces behavioral changes suggestive of human abuse potential. In addition, studies were undertaken to probe the potential for ulotaront to block reinstatement of cocaine-seeking behavior in male rats. ResultsUlotaront was not self-administered by rats trained to self-administer amphetamine, cocaine, or heroin. The subjective qualities of ulotaront were distinct from those produced by amphetamine in a drug discrimination procedure. Ulotaront, and buspirone, a non-scheduled anxiolytic with 5-HT1A agonism, partially generalized to the interoceptive cue elicited by 3, 4-methylenedioxymethamphetamine (MDMA). In addition, ulotaront demonstrated a trend to reduce cocaine-primed induced reinstatement, and dose-dependently reduced cue-reinstated responding. ConclusionThe current results suggest that the TAAR1/5-HT1A agonist ulotaront is not likely to pose a risk for recreational abuse in humans and may have potential therapeutic utility as a treatment of substance use disorders.

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.