Individuals with bipolar disorder are commonly correctly diagnosed a decade after symptom onset. Machine learning techniques may aid in early recognition and reduce the disease burden. As both individuals at risk and those with a manifest disease display structural brain markers, structural magnetic resonance imaging may provide relevant classification features.

Following a pre-registered protocol, we trained linear support vector machine (SVM) to classify individuals according to their estimated risk for bipolar disorder using regional cortical thickness of help-seeking individuals from seven study sites (N = 276). We estimated the risk using three state-of-the-art assessment instruments (BPSS-P, BARS, EPIbipolar).

For BPSS-P, SVM achieved a fair performance of Cohen's κ of 0.235 (95% CI 0.11–0.361) and a balanced accuracy of 63.1% (95% CI 55.9–70.3) in the 10-fold cross-validation. In the leave-one-site-out cross-validation, the model performed with a Cohen's κ of 0.128 (95% CI −0.069 to 0.325) and a balanced accuracy of 56.2% (95% CI 44.6–67.8). BARS and EPIbipolar could not be predicted. In post hoc analyses, regional surface area, subcortical volumes as well as hyperparameter optimization did not improve the performance.

Individuals at risk for bipolar disorder, as assessed by BPSS-P, display brain structural alterations that can be detected using machine learning. The achieved performance is comparable to previous studies which attempted to classify patients with manifest disease and healthy controls. Unlike previous studies of bipolar risk, our multicenter design permitted a leave-one-site-out cross-validation. Whole-brain cortical thickness seems to be superior to other structural brain features.

Early-onset psychosis (EOP) refers to the development of a first episode of psychosis before 18 years of age. Individuals at clinical high risk for psychosis (CHR-P) include adolescents and young adults, although most evidence has focused on adults. Negative symptoms are important prognostic indicators in psychosis. However, research focusing on children and adolescents is limited.

To provide meta-analytical evidence and a comprehensive review of the status and advances in the diagnosis, prognosis and treatment of negative symptoms in children and adolescents with EOP and at CHR-P.

PRISMA/MOOSE-compliant systematic review (PROSPERO: CRD42022360925) from inception to 18 August 2022, in any language, to identify individual studies conducted in EOP/CHR-P children and adolescents (mean age <18 years) providing findings on negative symptoms. Findings were systematically appraised. Random-effects meta-analyses were performed on the prevalence of negative symptoms, carrying out sensitivity analyses, heterogeneity analyses, publication bias assessment and quality assessment using the Newcastle–Ottawa Scale.

Of 3289 articles, 133 were included (n = 6776 EOP, mean age 15.3 years (s.d. = 1.6), males = 56.1%; n = 2138 CHR-P, mean age 16.1 years (s.d. = 1.0), males = 48.6%). There were negative symptoms in 60.8% (95% CI 46.4%–75.2%) of the children and adolescents with EOP and 79.6% (95% CI 66.3–92.9%) of those at CHR-P. Prevalence and severity of negative symptoms were associated with poor clinical, functional and intervention outcomes in both groups. Different interventions were piloted, with variable results requiring further replication.

Negative symptoms are common in children and adolescents at early stages of psychosis, particularly in those at CHR-P, and are associated with poor outcomes. Future intervention research is required so that evidence-based treatments will become available.

Patients with a severe mental illness such as bipolar I disorder (BP-I) have a higher prevalence of obesity and related metabolic comorbidities than the general population. This study evaluated the impact of cariprazine on weight and blood pressure in patients with BP-I depression using electronic medical records (EMRs) from a nationally representative database.

Analyses were based on data from EMRs in the Symphony Health’s Integrated Dataverse® from March 2015 to October 2018. Patients ≥18 years of age with ≥2 cariprazine fills (first dispensing=index date) and clinical activity for ≥12 months pre-index (baseline) and ≥1 month post-index were included. Patients also had a diagnosis of BP-I depression at their most recent episode prior to cariprazine initiation. The on-treatment period spanned from the index date to the earliest of cariprazine discontinuation, a switch to another atypical or long-acting injectable antipsychotic, end of clinical activity, or end of data. Metabolic outcomes of interest were weight and blood pressure (systolic and diastolic). For each outcome, patients were required to have ≥1 measurement in both the baseline and on-treatment periods. Linear trajectories during those periods were estimated using mixed-effects models; 95% confidence intervals (CIs) were calculated using non-parametric bootstrap procedures.

In total, 1702 patients who met study eligibility criteria had ≥1 weight measurement recorded in the baseline and on-treatment periods; of these patients, 178 had bipolar I depression as their most recent episode. Patients gained an average of 2.43 kg/year during the baseline period and 0.60 (95% CI: -1.97, 3.70) kg/year during the on-treatment period. Analyses of blood pressure change (n=179) showed that cariprazine had neutral effects over the on-treatment period. Patients’ systolic blood pressure increased at 1.12 mmHg/year during baseline and decreased at -0.63 (95% CI: -3.59, 2.25) mmHg/year during the on-treatment period. For diastolic blood pressure, increases of 0.25 mmHg/year during baseline and 0.44 (95% CI: -1.65, 2.16) mmHg/year during the on-treatment period were observed.

Although patient weight was increasing prior to cariprazine initiation, a neutral weight trajectory was seen with long-term cariprazine treatment among those with a most recent BP-I depression episode. Cariprazine also had minimal impact on systolic or diastolic blood pressure. Overall, these findings are consistent with prior short- and long-term studies showing that cariprazine has a neutral weight and metabolic profile.

AbbVie

Functional recovery is a treatment goal that goes beyond symptomatic remission and encompasses multiple aspects of schizophrenia patients’ lives, including quality of life, physical, and mental functioning. There is evidence that long-acting injectable (LAI) treatments promote adherence and reduce rehospitalisation and functional decline, which could facilitate patients’ ability to reach functional recovery. Despite this, LAIs are underused in the first-episode (FEP) and early-phase (EP) patient population, due to physician hesitancy and concerns around stigma. A Delphi panel was held to gain expert consensus on an approach to the domains and assessment of functional recovery elements in FEP and EP schizophrenia patients.

A literature review and input from a steering committee of 5 experts in psychiatry informed statements development for a three-round modified Delphi process. Round one was conducted via one-to-one video conference interviews, and the successive rounds were conducted via electronic surveys, which enabled international collaboration. Statements on the different domains and assessment for functional recovery were presented to 17 psychiatrists, practicing in 7 countries (France, Italy, US, Germany, Spain, Denmark, and UK), experienced in the treatment of schizophrenia with LAIs. Several analysis rules determined whether a statement could progress to the next round and specified the level of agreement required to achieve consensus. Measures of central tendency (mode, mean) and variability (interquartile range) were reported back to help panelists look at their previous responses in the context of the overall group.

A consensus was reached (defined a priori as ≥80% agreement) on all 27 statements covering the dimensions, assessment, and level of achieved functional recovery for FEP and EP patients. The following domains are important to consider when assessing functional recovery: depression, aggressive behaviour, social interaction, family functioning, education/employment, sexual functioning, and leisure activities. Additionally, panellists reached consensus that dimensions should be minimally impairing, if present (excluding sexual functioning) and asked about at every encounter with the patient (excluding sexual functioning and leisure activities). In summary, this Delphi panel yielded agreement that functional recovery is multidimensional and should be assessed regularly as part of usual care on an individual patient level in FEP and EP schizophrenia patients.

Lundbeck Otsuka Alliance

Schizophrenia is among the top ten causes of years lost due to disability. Goals of treatment are evolving beyond remission of psychotic symptoms to include physical and mental functioning, quality of life, and long-term functional recovery. Evidence has shown long-acting injectables (LAIs) are beneficial for schizophrenia patients by increasing treatment adherence and decreasing relapse and rehospitalisation. This potentially reduces disease progression and facilitates functional recovery. However, LAIs are underused and often seen as a last resort for first-episode (FEP) and early-phase (EP) patients, due to physicians’ lack of familiarity and stigma.

A three-round modified Delphi panel was held to gain expert consensus on an approach to functional recovery in FEP and EP patients with LAIs. A literature review and input from a steering committee of 5 experts in psychiatry informed the development of statements. Round one was carried out via one-to-one video conference interviews, and the subsequent rounds were conducted via electronic surveys, which enabled international collaboration. Delphi panellists were 17 psychiatrists with schizophrenia treatment experience, practicing in 7 countries (France, Italy, US, Germany, Spain, Denmark, and UK). Several analysis rules determined whether a statement could progress to the next round and specified the level of agreement required to achieve consensus. Measures of central tendencies (mode, mean) and variability (interquartile range) of aggregated responses from the previous round were reported to panelists to understand their response in relation to the group.

There was consensus (defined a priori as ≥80% agreement) on the 8 statements relating to long-term treatment goals and LAI links to functional recovery. LAI treatment in FEP and EP patients increases adherence and reduces treatment burden and functional decline compared to the same and other oral medication. Additionally, there was consensus that LAIs lead to better treatment outcome and functional recovery. Other important factors to achieving functional recovery include patient attitude towards treatment and psychoeducation. Furthermore, consensus was reached that functional recovery and quality of life are linked. In summary, this Delphi panel yielded agreement that functional recovery is a reachable goal for FEP and EP patients and can be enhanced using LAIs.

Lundbeck Otsuka Alliance

KarXT combines the M1/M4 preferring muscarinic receptor agonist xanomeline and the peripherally restricted anticholinergic trospium. In the phase 2 EMERGENT-1 study, KarXT met the primary endpoint of a significant reduction in Positive and Negative Syndrome Scale (PANSS) total score through week 5 vs placebo, improved other key secondary efficacy measures, and was generally well tolerated.

EMERGENT-2 was a phase 3, randomized, double-blind, placebo-controlled, 5-week trial of KarXT in acutely psychotic patients with schizophrenia in the inpatient setting. Eligible patients were randomized 1:1 to KarXT or matched placebo. Dosing of KarXT (mg xanomeline/mg trospium) started at 50 mg/20 mg BID and increased to a maximum of 125 mg/30 mg BID. The primary efficacy endpoint was change from baseline to week 5 in PANSS total score. Key secondary endpoints included change from baseline to week 5 in PANSS positive subscale, PANSS negative subscale, and PANSS negative Marder factor scores compared with placebo. Efficacy analyses were performed using the modified intent-to-treat population (patients with ≥1 dose of study medication, a baseline PANSS assessment, and ≥1 postbaseline PANSS assessment). All patients receiving ≥1 dose of study drug were included in safety analyses.

252 US patients were enrolled. KarXT demonstrated a statistically significant and clinically meaningful 9.6-point reduction from baseline to week 5 (effect size=0.61) in PANSS total score vs placebo (p<0.0001); a significant improvement in PANSS total score was demonstrated starting at week 2 (first postbaseline rating) and continued through the study end. KarXT also met key secondary endpoints. Results at week 5 included a 2.9-point reduction in PANSS positive subscale score with KarXT vs placebo (p<0.0001), a 1.8-point reduction in PANSS negative subscale score with KarXT vs placebo (p=0.0055), and a 2.2-point reduction in PANSS negative Marder factor score with KarXT vs placebo (p=0.0022). KarXT was generally well tolerated. Overall discontinuation rates were similar with KarXT (25%) and placebo (21%). The overall treatment-emergent adverse events (TEAEs) rate for KarXT and placebo was 75% and 58%, respectively. Discontinuation rates related to TEAEs were similar between KarXT (7%) and placebo (6%). Rates of serious TEAEs were similar with KarXT and placebo (2%, each group); no serious TEAEs were determined to be drug related. The most common TEAEs (≥5%) with KarXT were all mild to moderate in severity and included constipation, dyspepsia, nausea, vomiting, headache, blood pressure increases, dizziness, gastroesophageal reflux disease, abdominal discomfort, and diarrhea. KarXT was not associated with sedation/somnolence, weight gain, and extrapyramidal symptoms.

KarXT has the potential to be the first in a new class of treatments for patients with schizophrenia and a promising alternative to postsynaptic dopamine D2 receptor antagonists.

Karuna Therapeutics, Inc.

Treatments for bipolar disorder are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides ≥150mg/dL, high density lipoprotein cholesterol <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) ≥130mmHg or diastolic BP ≥85mmHg, fasting glucose ≥100mg/dL.

MetSy elevates the risk of developing type II diabetes, cardiovascular disease, and premature morbidity. Lumateperone (LUMA), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials.

LUMA 42-mg monotherapy was evaluated in 2 randomized, double-blind, placebo (PBO)-controlled studies (Study 401 [NCT02600494]; Study 404 [NCT03249376]) in patients with a major depressive episode (MDE) associated with bipolar I or bipolar II disorder. This post hoc pooled analysis of these studies compares rates of MetSy with LUMA 42 mg and PBO in the treatment of bipolar depression.

The incidence and shift in MetSy were analyzed in data pooled from 2 studies that recruited patients aged 18–75 years with a confirmed diagnosis of bipolar I or bipolar II disorder who were experiencing an MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score ≥20 and Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score ≥4). Patients in these studies were randomized 1:1 to LUMA or PBO and treated for 6 weeks.

The safety population comprised 746 patients (LUMA, 372; PBO, 374). Rates of MetSy were similar between groups at baseline (LUMA, 20.7%; PBO, 22.2%) and at the end of treatment (EOT, LUMA, 21.8%; PBO, 23.8%). More LUMA patients (36.4%) compared with PBO patients (30.1%) improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. The individual criteria that shifted the most from meeting MetSy criteria at baseline to no longer meeting criteria at EOT was BP for LUMA (46.8%) and glucose for PBO (43.2%). The rate of MetSy developed during treatment was similar for LUMA (10.8%) and PBO (10.7%) with approximately half of these patients (LUMA, 43.8%; PBO, 45.2%) shifting due to a change in ≥2 criteria.

In this post hoc analysis of 2 randomized, PBO-controlled trials in patients with a MDE associated with bipolar I or bipolar II disorder, LUMA 42 mg had similar rates of MetSy compared with PBO. These results suggest that LUMA 42 mg is a promising new treatment for bipolar depression with a favorable metabolic profile.

Intra-Cellular Therapies, Inc.

Valbenazine is a once-daily VMAT2 inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics, antiemetics, and other dopamine receptor blocking agents. The efficacy, safety, and tolerability of valbenazine has been established in several phase 3 trials, including a long-term study (KINECT 4 [NCT02405091]) in which participants received open-label valbenazine (40 or 80 mg) for 48 weeks. Post hoc analyses of KINECT 4 data were conducted to assess patterns of treatment response.

Data from KINECT 4 treatment completers (participants who reached the Week 48 visit and had the longest duration of treatment) were analyzed post hoc. TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7, as rated by the study investigator), the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and the Patient Global Impression of Change (PGIC). Analyses were conducted at Week 8 (first study visit after the valbenazine dose-optimization period) and Week 48 using the following definitions of response: ≥50% and ≥70% improvement from baseline in AIMS total score; rating of “much improved” or “very much improved” (score ≤2) on the CGI-TD and PGIC.

Of the 167 participants who entered KINECT 4, 103 (62%) were treatment completers and included for analysis. Of these 103 participants, 39% and 86% met the ≥50% AIMS response threshold at Weeks 8 and 48, respectively. The percentages of participants who met the highly rigorous AIMS ≥70% response threshold at Weeks 8 and 48 were 17% and 52%, respectively. Of the 40 participants with AIMS ≥50% total score improvement at Week 8, 95% also met this threshold at Week 48 (“sustained response”). Of the 63 participants with <50% AIMS improvement at Week 8, 81% achieved the ≥50% response threshold by end of treatment at Week 48. The proportion of participants meeting the threshold for CGI-TD response also increased over time, from 50% at Week 8 to 92% at Week 48. PGIC results were similar, with response rates of 53% and 88% at Weeks 8 and 48, respectively.

Post hoc analyses of data from a 48-week, open-label study of once-daily valbenazine showed that the proportion of participants meeting rigorous treatment response thresholds increased over time. By the end of treatment at Week 48, >80% of participants demonstrated robust improvements in TD, as assessed using the AIMS (≥50% improvement), CGI-TD (score ≤2), and PGIC (score ≤2).

Neurocrine Biosciences, Inc.

Antipsychotics are widely used in the treatment of major depressive disorder (MDD), but there has been no comprehensive meta-analytic assessment that examined their use as monotherapy and adjunctive therapy.

A systematic review and a meta-analysis were conducted on randomized placebo-controlled trials (RCTs) that reported on the efficacy and safety/tolerability of antipsychotics for the treatment of adults with MDD. Data of both monotherapy and adjunctive antipsychotic use were extracted, but analyzed separately using a random-effects model. Co-primary outcomes were study-defined-treatment response and intolerability-related discontinuation. We also illustrated the risk/benefit balance of antipsychotics for MDD, using two-dimensional graphs representing the primary efficacy and safety/tolerability outcome. Secondary outcomes included psychopathology, remission, all-cause-discontinuation, inefficacy-related discontinuation, and adverse events.

Forty-five RCTs with 12 724 patients were included in the analysis. In monotherapy (studies = 13, n = 4375), amisulpride [1.99 (1.55–2.55)], sulpiride [1.50 (1.03–2.17)], and quetiapine [1.48 (1.23–1.78)] were significantly superior to placebo regarding treatment response. However, intolerability-related discontinuations were significantly higher compared to placebo with amisulpride and quetiapine. In adjunctive therapy (studies = 32, n = 8349), ziprasidone [1.80 (1.07–3.04)], risperidone [1.59 (1.19–2.14)], aripiprazole [1.54 (1.35–1.76)], brexpiprazole [1.41 (1.21–1.66)], cariprazine [1.27 (1.07–1.52)], and quetiapine [1.23 (1.08–1.41)] were significantly superior to placebo regarding treatment response. However, of these antipsychotics that were superior to placebo, only risperidone was equivalent to placebo regarding discontinuation due to intolerability, while the other antipsychotics were inferior.

Results suggest that there are significant differences regarding the risk/benefit ratio among antipsychotics for MDD, which should inform clinical care.

To evaluate the efficacy of short-term lurasidone in antipsychotic treatment-naïve (TN) adolescents with schizophrenia versus those treated previously (TP) with antipsychotics.

Patients aged 13–17 with schizophrenia, and a Positive and Negative Symptom Scale (PANSS) score ≥ 70 and < 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.

Altogether, 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 < 0.02; effect size = 0.75), and in the TP group (−17.3 vs. -10.0; p < 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.

In 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.

Evidence on risk factors for postpartum depression (PPD) are fragmented and inconsistent.

To assess the strength and credibility of evidence on risk factors of PPD, ranking them based on the umbrella review methodology.

Databases were searched until 1 December 2020, for systematic reviews and meta-analyses of observational studies. Two reviewers assessed quality, credibility of associations according to umbrella review criteria (URC) and evidence certainty according to Grading of Recommendations-Assessment-Development-Evaluations criteria.

Including 185 observational studies (n = 3 272 093) from 11 systematic reviews, the association between premenstrual syndrome and PPD was the strongest (highly suggestive: odds ratio 2.20, 95%CI 1.81–2.68), followed by violent experiences (highly suggestive: odds ratio (OR) = 2.07, 95%CI 1.70–2.50) and unintended pregnancy (highly suggestive: OR=1.53, 95%CI 1.35–1.75). Following URC, the association was suggestive for Caesarean section (OR = 1.29, 95%CI 1.17–1.43), gestational diabetes (OR = 1.60, 95%CI 1.25–2.06) and 5-HTTPRL polymorphism (OR = 0.70, 95%CI 0.57–0.86); and weak for preterm delivery (OR = 2.12, 95%CI 1.43–3.14), anaemia during pregnancy (OR = 1.47, 95%CI 1.17–1.84), vitamin D deficiency (OR = 3.67, 95%CI 1.72–7.85) and postpartum anaemia (OR = 1.75, 95%CI 1.18–2.60). No significant associations were found for medically assisted conception and intra-labour epidural analgesia. No association was rated as ‘convincing evidence’. According to GRADE, the certainty of the evidence was low for Caesarean section, preterm delivery, 5-HTTLPR polymorphism and anaemia during pregnancy, and ‘very low’ for remaining factors.

The most robust risk factors of PDD were premenstrual syndrome, violent experiences and unintended pregnancy. These results should be integrated in clinical algorithms to assess the risk of PPD.

The Positive and Negative Syndrome Scale (PANSS) is widely used in schizophrenia and has been divided into distinct factors (5-factor models) and subfactors. Network analyses are newer in psychiatry and can help to better understand the relationships and interactions between the symptoms of a psychiatric disorder. The aim of this study was threefold: (a) to evaluate connections between schizophrenia symptoms in two populations of patients (patients in the acutely exacerbated phase of schizophrenia and patients with predominant negative symptoms [PNS]), (b) to test whether network analyses support the Mohr 5 factor model of the PANSS and the Kahn 2 factor model of negative symptoms, and finally (c) to identify the most central symptoms in the two populations.

Using pooled baseline data from four cariprazine clinical trials in patients with acute exacerbation of schizophrenia (n = 2193) and the cariprazine–risperidone study in patients with PNS (n = 460), separate network analyses were performed. Network structures were estimated for all 30 items of the PANSS.

While negative symptoms in patients with an acute exacerbation of schizophrenia are correlated with other PANSS symptoms, these negative symptoms are not correlated with other PANSS symptoms in patients with PNS. The Mohr factors were partially reflected in the network analyses. The two most central symptoms (largest node strength) were delusions and uncooperativeness in acute phase patients and hostility and delusions in patients with PNS.

This network analysis suggests that symptoms of schizophrenia are differently structured in acute and PNS patients. While in the former, negative symptoms are mainly secondary, in patients with PNS, they are mainly primary. Further, primary negative symptoms are better conceptualized as distinct negative symptom dimensions of the PANSS.

SEP-363856 is a novel psychotropic agent without dopamine D2 receptor occupancy. Although its mechanism of action has not been fully elucidated, preclinical data suggest that agonism at trace amine receptor 1 (TAAR1) and the serotonin 5-H1A receptor contributes to its efficacy. In a double-blind (DB), placebo-controlled study, SEP−363856 demonstrated significant efficacy in the treatment of an exacerbation of schizophrenia (Koblan et al, NEJM 2020; 82:1497–1506). We present results of a 6-month extension study whose aim was to evaluate the safety and effectiveness of longer-term treatment with SEP−363856.

Patients with an acute exacerbation of schizophrenia who completed a 4-week, DB, placebo-controlled, flexible-dose (50 or 75 mg) study of SEP−363856 were given the option to enroll in an extension study in which they were treated, open-label (OL), with flexible doses (25/50/75 mg/d) of SEP−363856 for 26-weeks. The primary outcomes were safety measures; effectiveness outcomes were secondary and included the PANSS total score and the Brief Negative Symptom Scale (BNSS) total score.

A total of 193 patients completed the 4-week DB study, and 156 (80.8%) were dosed in the OL extension study and received at least one dose of SEP−363856 (safety population). Study completer rate was 66.9%; reasons for discontinuation consisted of adverse event (11.5%), withdrawal of consent (10.2%), lack of efficacy (5.1%), and other (6.4%). 15 patients experienced an SAE: schizophrenia (n=11); acute psychosis (N=1); uterine hemorrhage and suicidal ideation (N=1 each); there were no deaths in the study. Individual AEs with an incidence =2% were schizophrenia (12.2%), headache (11.5%), insomnia (8.3%), anxiety (5.1%), somnolence (4.5%), nasopharyngitis (4.5%), nausea (3.8%), irritability (3.2%), influenza (3.2%), weight decreased (3.2%), and prolactin increased (2.6%). On movement scales, minimal mean change from OL-baseline to Week 26 occurred on the Barnes total score (−0.1), AIMS total score (0.0) and SAS score (−0.1). Mean month 6 change from DB baseline in weight was −0.3 kg. No clinically meaningful median changes were observed at week 26 in metabolic laboratory parameters (total and LDL cholesterol, triglycerides, hemoglobin A1c) or in prolactin levels. During 6 months of OL treatment, one patient had an increase in QTcF =60 msec; no patients had a QTcF interval =480 msec. Treatment with SEP−363856 was associated with significant improvement from OL baseline to week 26 in PANSS total score (−22.6) and BNSS total score (−11.3).

Treatment with SEP−363856 was associated with continued improvement from open-label baseline in the PANSS total (−22.6) and BNSS total (−11.3) scores. The most frequently reported adverse events (= 5%) were schizophrenia, headache, insomnia and anxiety. SEP−363856 had minimal effects on weight, lipids, glycemic indices, prolactin, and was associated with minimal risk of extrapyramidal symptom.

Sunovion Pharmaceuticals Inc.

Current treatments for schizophrenia are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides =150mg/dL, high density lipoprotein cholesterol (HDL) <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) =130mmHg or diastolic BP =85mmHg, fasting glucose =100mg/dL. Patients with MetSy have an elevated risk of developing type II diabetes and increased mortality due to cardiovascular disease. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA approved for the treatment of schizophrenia. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials. This post hoc analysis of 2 randomized, double-blind, placebo-controlled studies of patients with an acute exacerbation of schizophrenia compared rates of MetSy with lumateperone and risperidone. Data from an open-label long-term trial of lumateperone were also evaluated.

The incidence and shift in MetSy were analyzed in data pooled from 2 short-term (4 or 6 week) placebo- and active-controlled (risperidone 4mg) studies of lumateperone 42mg (Studies 005 and 302). The pooled lumateperone data were compared with data for risperidone. Data from an open-label 1-year trial (Study 303) evaluated MetSy in patients with stable schizophrenia switched from prior antipsychotic (PA) treatment to lumateperone 42mg.

In the acute studies (n=256 lumateperone 42mg, n=255 risperidone 4mg), rates of MetSy were similar between groups at baseline (16% lumateperone, 19% risperidone). At the end of treatment (EOT), MetSy was less common with lumateperone than with risperidone (13% vs 25%). More lumateperone patients (46%) compared with risperidone (25%) patients improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. Conversely, more patients on risperidone than on lumateperone developed MetSy during treatment (13% vs 5%). Differences in MetSy conversion rates were driven by changes in triglycerides and glucose. In the long-term study (n=602 lumateperone 42mg), 33% of patients had MetSy at PA baseline. Thirty-six percent of patients (36%) with MetSy at PA baseline improved to no longer meeting criteria at EOT. Fewer than half that percentage shifted from not meeting MetSy criteria to having MetSy (15%).

In this post hoc analysis, lumateperone 42mg patients had reduced rates of MetSy compared with risperidone patients. In the long-term study, patients with MetSy on PA switched to lumateperone 42mg had a reduction in the risk of MetSy. These results suggest that lumateperone 42mg is a promising new treatment for schizophrenia with a favorable metabolic profile.

Intra-Cellular Therapies, Inc.

Adults with attention-deficit/hyperactivity disorder (ADHD) often face delays in diagnosis and remain untreated, despite significant negative impacts. To evaluate the safety and efficacy of transdermal treatment options in children, adolescents, and adults, a systematic literature review was conducted, with a focus on the implications of transdermal therapies for ADHD in adults.

A MEDLINE/Embase/BIOSIS/SCOPUS database search was conducted December 4, 2019, for English-language articles of interventional clinical trials using transdermal formulations for the treatment of ADHD without publication date limit. Assessed outcomes included efficacy, safety, adherence, abuse potential, cost efficacy, and health-related quality of life.

Of 23 eligible publications, 18 were in children or adolescents (n = 1699; range 23-305), and 5 in adults (n = 274; range 14-90); all included methylphenidate transdermal system (MTS). All seven pediatric publications reporting change in ADHD symptomology from baseline reported a significant improvement with MTS treatment. Similarly, in three adult publications, ADHD symptoms improved significantly with MTS treatment. Safety findings in pediatric and adult studies were comparable; the most frequently reported treatment-emergent adverse events (TEAEs), namely, headache, decreased appetite, and insomnia, were reported in 13/16 (81%) of publications reporting specific TEAEs. MTS-related dermal reactions were mostly mild and transient. Discontinuation due to dermal reactions was reported in 10 studies (range 0%-7.1% [1 of 14 patients]). MTS compliance was high when assessed (97%-99%).

Transdermal therapies provide a useful treatment formulation for ADHD. Studies of MTS and other transdermal formulations, such as amphetamine, in adult patients are needed in this underserved population.

During the COVID-19 pandemic, the use of telemedicine as a way to reduce COVID-19 infections was noted and consequently deregulated. However, the degree of telemedicine regulation varies from country to country, which may alter the widespread use of telemedicine. This study aimed to clarify the telepsychiatry regulations for each collaborating country/region before and during the COVID-19 pandemic.

We used snowball sampling within a global network of international telepsychiatry experts. Thirty collaborators from 17 different countries/regions responded to a questionnaire on barriers to the use and implementation of telepsychiatric care, including policy factors such as regulations and reimbursement at the end of 2019 and as of May 2020.

Thirteen of 17 regions reported a relaxation of regulations due to the pandemic; consequently, all regions surveyed stated that telepsychiatry was now possible within their public healthcare systems. In some regions, restrictions on prescription medications allowed via telepsychiatry were eased, but in 11 of the 17 regions, there were still restrictions on prescribing medications via telepsychiatry. Lower insurance reimbursement amounts for telepsychiatry consultations v. in-person consultations were reevaluated in four regions, and consequently, in 15 regions telepsychiatry services were reimbursed at the same rate (or higher) than in-person consultations during the COVID-19 pandemic.

Our results confirm that, due to COVID-19, the majority of countries surveyed are altering telemedicine regulations that had previously restricted the spread of telemedicine. These findings provide information that could guide future policy and regulatory decisions, which facilitate greater scale and spread of telepsychiatry globally.