Diagnosing mental health challenges in bereavement is controversial; however, regardless of one’s position on this matter, assessments of bereaved individuals continue to occur in clinical and research contexts. It is critical for evaluations to account for contextual factors that are unique to bereavement. This paper summarizes considerations for diagnosing depression in bereaved individuals, focusing on use of the six-item Hamilton Depression Rating Scale (HAM-D6).

Following a literature review of the Hamilton Depression Rating Scale (HAM-D) and various versions, we summarized decision rules we used in scoring the HAM-D6 in a study of parents bereaved by cancer. We expanded on existing scoring guidelines for each of the HAM-D6 items, including depressed mood, work and activities, general somatic symptoms, guilt, psychic anxiety, and psychomotor retardation, and illustrated clinical distinctions and probes for assessors to consider through case examples from our research with bereaved parents.

Considerations for assessing depressive symptoms and behavior changes in the context of bereavement were summarized. Symptoms that may be diagnostic of depression in some populations may reflect other factors in the bereaved, such as a change in priorities, social expectations surrounding grief, or avoidance of grief activators. Nuanced factors are important for assessors to consider when administering the HAM-D6 to bereaved individuals.

Our sharing of these considerations is not intended to promote diagnosis of depression in bereavement but to highlight the unique contextual factors that distinguish symptoms of depression from common experiences of grievers when applying an assessment tool such as the HAM-D6. While validated measures can be constraining, they can have clinical utility; they may increase standardization in research, help clinicians communicate with each other, advance the field more generally to understand the varying struggles bereaved individuals experience, and systemically facilitate access to services via managed care.

Earlier onset of schizophrenia, which occurs more commonly in males, is characterized by greater illness severity, chronicity, and functional impairment with a less favorable prognosis than later-onset schizophrenia. The aim of this pooled analysis was to evaluate the long-term safety and effectiveness of lurasidone in the treatment of schizophrenia in adolescents (13–17 years) and young adults (18–25 years).

The 2 pooled studies used similar designs and outcome measures. Patients (13–25 years) with schizophrenia completed an initial double-blind 6-week trial of lurasidone (40 and 80 mg/d), and (80 and 160 mg/d) in the young adult trial. In the open-label long-term trials, adolescent patients were treated with 20-80 mg/d of lurasidone, and adults were treated with 40–160 mg/d of lurasidone. Efficacy was evaluated based on the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity Scale (CGI-S).

The safety population consisted of 306 patients (mean age, 16.2 years; 208 patients (68.0%) who completed 12 months of treatment; 8.2% discontinued by 12 months due to an adverse event. Mean (SD) change in the PANSS total score from extension Baseline to Months 6 and 12 was -11.8 (13.9) and -15.3 (15.0), respectively (OC); and mean (SD) change in the CGI-S score was -0.8 (1.0) and -1.0 (1.1), respectively (OC). The most frequent adverse events were headache (17.6%), anxiety (11.4%), schizophrenia (9.8%), and nausea (9.8). No clinically meaningful changes were observed in weight, metabolic parameters, or prolactin.

In adolescents and young adults with schizophrenia, treatment with lurasidone was generally well-tolerated and effective. Long-term treatment was associated with continued reduction in symptoms of schizophrenia. Long-term treatment was associated with minimal effects on weight, metabolic parameters, and prolactin.

Angelini Pharma S.p.A. and Sunovion Pharmaceuticals Inc.

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.

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.

Four medications are FDA approved for bipolar depression: lurasidone (LUR), cariprazine (CAR), quetiapine IR & XR (QUE), and olanzapine-fluoxetine combination (OFC). Indirect comparisons for efficacy using Number Needed to Treat (NNT) and for tolerability using Number Needed to Harm (NNH) can be useful clinical benchmarks to aid treatment decisions. Benefit and risk may also be examined using the Likelihood to be Helped or Harmed (LHH). In this post-hoc analysis, we examined the benefit-risk ratio of the four treatments using LHH.

Individual and pooled monotherapy data from short-term clinical registration trials of patients with bipolar depression were assessed for LUR, CAR, pooled QUE (300 and 600 mg), and pooled OFC (considered as monotherapy for this study at fixed doses of 6/25, 6/50, 12/50 mg) data. NNT estimates were calculated using the proportions of MADRS responders (defined as ≥ 50% improvement at study endpoint) and MADRS remitters (defined as a score of ≤ 10 [for LUR and CAR] and ≤ 12 [for QUE and OFC]) at study endpoint. NNH data were calculated for the proportions of patients who discontinued due to an adverse event (AE) and for individual AEs commonly associated with each treatment. LHH was calculated as the ratio of NNH/NNT to determine the benefit-risk ratio.

The NNT estimates for response vs. placebo were: 5 for both LUR 20–60 mg and 80–120 mg; 10 for both CAR 1.5 mg and 3.0 mg; 6 for QUE; and 4 for OFC. The NNTs for remission vs placebo were: 7 for LUR 20–60 mg and 9 for LUR 80–120 mg; 10 for CAR 1.5 mg and 13 for CAR 3.0 mg; 6 for QUE; and 5 for OFC. The NNH estimates for discontinuations due to AEs were: 642 for LUR 20–60 mg and −151 for LUR 80–120 mg; 298 for CAR 1.5 mg and 31 for CAR 3.0 mg; 10 for QUE; and −37 for OFC. NNH values that were negative were assigned a value of 1000 to permit LHH to be calculated. The LHHs for response vs discontinuation due to an AE were: 128.4 for LUR 20–60 mg and 200 for LUR 80–120 mg; 29.8 for CAR 1.5 mg and 3.1 for CAR 3.0 mg; 1.7 for QUE; and 250 for OFC. The LHHs for response vs akathisia were: 3.6 for LUR 20–60 mg and 2.4 for LUR 80–120 mg; 3.6 for CAR 1.5 mg and 1.3 for CAR 3.0 mg; 34 for QUE; and not available (NA) for OFC. The LHHs for response vs EPS were: 8 for LUR 20–60 mg and 3.2 for LUR 80–120 mg; 5 for CAR 1.5 mg and 2.5 for CAR 3.0 mg; NA for QUE; and NA for OFC. The LHH for response vs weight gain was 5.8 for LUR 20–60 mg and 1110 for LUR 80–120 mg; 5 for both doses of CAR; 2.7 for QUE; and 1.5 for OFC.

LHH can illustrate the trade-offs regarding potential benefits versus potential harms. Across a variety of measures, the lower-dose groups for both LUR and CAR generally evidenced a better benefit-risk profile than the higher-dose groups. While quetiapine and OFC demonstrated robust efficacy, their reduced tolerability resulted in a more marginal benefit-risk ratio for some of the outcomes.

Sunovion Pharmaceuticals Inc.

Lurasidone is approved for the treatment of bipolar depression both as monotherapy and adjunctive therapy with lithium or valproate (Li/VPA). The aim of these analyses was to evaluate the prevalence of treatment-emergent mania (TEM) and worsening of mania symptom severity in clinical trials of both adult and pediatric patients with bipolar depression treated with lurasidone.

In these post-hoc analyses, TEM and change in manic symptom severity as measured by the Young Mania Rating Scale (YMRS) were evaluated in two double-blind (DB), 6-week studies in adults of lurasidone monotherapy, 20–60 mg/d (n=161) and 80–120 mg/d (n=162) vs. placebo (n=162), and adjunctive therapy of lurasidone 20–120 mg/d + Li/VPA (n=179) vs. placebo + Li/VPA (n=161). Prevalence of TEM was also evaluated in a 6-month, open-label (OL) extension study of adults treated with lurasidone monotherapy (n=316) or adjunctive therapy (n=497). In pediatric patients (ages 10–17) TEM and change in manic symptoms was evaluated in a DB 6-week study of lurasidone monotherapy (n=173) vs. placebo (n=170) and in a 24-month OL extension study. TEM was defined as an adverse event of mania or hypomania and/or having a YMRS score =16 at 2 consecutive post-baseline weekly visits (or the final assessment) in short-term studies or 1 post-baseline monthly visit in long-term studies.

Adult studies: In short-term studies, TEM rates were comparable in patients treated with lurasidone monotherapy 20–60 mg/d (3.7%) and 80–120 mg/d (1.9%) vs. placebo (1.9%). TEM rates were also comparable in patients treated with lurasidone 20–120 mg/d (1.1%) adjunctive to Li/VPA vs. placebo + Li/VPA (1.2%). In the monotherapy study, significant reduction in YMRS score was observed at study endpoint for the 20–60 mg/d group compared to placebo (−1.9 vs. −1.3; p<0.05) with similar improvement relative to placebo in the 80–120 mg/d group. Change for YMRS score was comparable for lurasidone and placebo in the adjunctive study. In long-term studies, 1.3% of adult patients treated with lurasidone monotherapy (n=316) met criteria for mania, and 3.8% of patients on adjunctive lurasidone therapy (n=497) met TEM criteria. Pediatric studies: TEM rates were comparable in patients treated with lurasidone vs. placebo (1.7% vs. 2.3%). LS mean reduction in symptoms of mania from baseline to week 6 was significantly greater for lurasidone vs. placebo on YMRS score (−2.0 vs. −1.1; p<0.05). Pediatric long-term studies: After two years of OL treatment with lurasidone, 5.2% of patients met TEM criteria. Mean change in YMRS total score from DB baseline to Month 24 continued to improve (−2.0).

Short-term and long-term treatment with lurasidone demonstrated significant improvement in manic symptoms and was not associated with an increased risk of TEM in either adult or pediatric patient populations compared to rates reported in clinical populations of patients.

Sunovion Pharmaceuticals Inc.

Few studies have examined treatment response in adolescents with schizophrenia who are treatment-naive; and there is no placebo-controlled study that we are aware of in first episode treatment-naive patients with schizophrenia. The aim of this analysis was to evaluate the long-term efficacy of lurasidone in antipsychotic-naive adolescents with schizophrenia.

Patients aged 13–17 years with schizophrenia, and a PANSS total score ≥70 and <120, were randomized to 6 weeks of double-blind (DB) treatment with lurasidone (40 or 80 mg/day) or placebo. Six-week completers were eligible to enroll in a 2-year open-label extension phase receiving lurasidone flexibly dosed from 20–80 mg/day. In a post-hoc analysis, efficacy was evaluated for 2 patient groups based on treatment status prior to entering the initial 6-week DB study (treatment naïve [TN] vs. treated previously [TP]). Treatment-naïve was defined as never having received antipsychotic treatment. Efficacy measures included the PANSS total score and the Clinical Global Impression, Severity (CGI-S) score. Level of functioning was assessed using the Children’s Global Assessment Scale (CGAS), with a score of 70 representing normative levels of functioning.

A total of 50 TN and 221 TP patients completed the 6-week DB study and entered the extension study; and 30 (60.0%) TN and 126 (57.0%) TP patients completed 104 weeks. During the initial 6 weeks of DB treatment, mean change in PANSS total score at endpoint was greater for lurasidone vs. 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). During OL extension phase treatment with lurasidone, mean change from DB baseline in the PANSS total score for TN and TP patients, at week 52 was −32.6 (n=38) and −28.1 (n=151), respectively; and at week 104 was −33.6 (n=30) and −29.2 (n=126), respectively. Mean change from DB baseline in CGI-S score at both weeks 52 and 104 was −1.8 for TN patients and −1.5 for TP patients. At DB baseline mean CGAS scores indicated significant functional impairment in both the TN and TP patients (CGAS=48 and 43, respectively). During OL treatment with lurasidone, mean change (from DB baseline) in the CGAS score at Weeks 52 and 104, respectively, was +22.0 and +22.9 in TN patients, and +21.1 and +22.9 in TP patients. During OL treatment with lurasidone, mean observed change from DB baseline in the weight (in kg,) at Weeks 52 and 104, respectively, was +4.2 and +4.8 in TN patients, and +4.0 and +5.0 in TP patients. These weight increases are consistent with expected weight gains in adolescents during a 2-year period (based on CDC growth charts).

In this post-hoc analysis of a 2-year study, adolescents with schizophrenia who had received no previous antipsychotic therapy showed greater improvement compared to previously treated patients during both short- and long-term treatment with lurasidone.

Sunovion Pharmaceuticals Inc.

The aim of this pooled analysis was to evaluate the efficacy and safety of lurasidone in the treatment of an acute exacerbation of schizophrenia in adolescents and young adults.

The six pooled studies in this analysis used similar study designs and outcome measures. Patients (aged 13–25 years) were randomized to 6 weeks of double-blind, placebo-controlled treatment with lurasidone in fixed doses of 40, 80, 120, or 160 mg. The primary efficacy endpoint was Week 6 change in the Positive and Negative Syndrome Scale (PANSS) total score; secondary efficacy endpoints included Week 6 change in the Clinical Global Impression–Severity scale.

The safety population consisted of 537 patients (mean age: 18.1 years); 82.6% of patients completed the studies. Treatment with lurasidone was significantly better than placebo at all doses (p < 0.001) for change in the PANSS total score at Week 6. Placebo-adjusted PANSS scores ranged from −9.4 to −16.1 (effect sizes: 0.53–0.90), with effect sizes increasing at higher doses. For lurasidone (combined doses), three adverse events occurred with a frequency of ≥5% (nausea: 13.5%; somnolence: 12.1%; akathisia: 10.1%). At last observation carried forward (LOCF)-endpoint weight gain of ≥7% was similar for lurasidone versus placebo (3.6 vs. 4.7%). Minimal median changes were observed at endpoint in cholesterol, −2.0 mg/dL; triglycerides, 0.0 mg/dL; and glucose, 0.0 mg/dL.

In adolescents and young adults with schizophrenia, treatment with lurasidone in doses of 40–160 mg/d was a safe, well-tolerated, and effective treatment. Short-term treatment with lurasidone was associated with minimal effects on weight and metabolic parameters.

Minimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia.

Patients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score.

About 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of −15.6 at week 52 and −18.4 at week 104.

In adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.

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).

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).

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.

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.

SEP-363856 is a novel psychotropic agent that has shown broad efficacy in animal models of schizophrenia and depression. Its antipsychotic effects appear to be mediated by agonist activity at both trace amine-associated receptor 1 (TAAR1) and 5-HT1A receptors. Notably, SEP-363856 does not bind to any dopaminergic, serotonergic (except 5-HT1A), glutamatergic, or other neuroreceptors thought to mediate the effects of currently available antipsychotics. The aim of this study was to evaluate the efficacy and safety of SEP-363856 in acutely symptomatic patients with schizophrenia.

Patients aged 18-40 years meeting DSM-5 criteria for schizophrenia (PANSS total score ≥80) were randomized, double-blind, to 4-weeks of flexible-dose SEP-363856 (50 or 75 mg/d) or placebo. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total score (primary), PANSS subscale scores, and the Clinical Global Impressions-Severity (CGI-S) score. Change from baseline in primary and secondary measures were analyzed using a mixed model for repeated measures (MMRM) analysis.

Study treatment groups were similar at baseline: SEP-363856 (N=120; male, 64.2%; mean age, 30.0 years; PANSS total score, 101.4) and placebo (N=125; male, 63.2%; mean age, 30.6 years; PANSS total score, 99.7). Least-squares (LS) mean reduction from baseline to week 4 was significantly greater for SEP-363856 vs. placebo on the PANSS total score (-17.2 vs. -9.7; P=0.001; effect size, 0.45), PANSS positive subscale score (-5.5 vs. -3.9; P=0.019; effect size, 0.32), PANSS negative subscale score (-3.1 vs. -1.6; P=0.008; effect size, 0.37), PANSS general psychopathology subscale score (-9.0 vs. -4.7; P<0.001; effect size, 0.51), and the CGI-Severity score (-1.0 vs. -0.5; P<0.001; effect size, 0.52). Discontinuation rates for SEP-363856 vs. placebo were similar overall (21.7% vs. 20.8%) and due to an adverse event (8.3% vs. 6.4%). Change in weight, lipids, glucose and prolactin was similar in SEP-363856 and placebo groups. Adverse events occurring with an incidence ≥2% on SEP-363856 or placebo (with SEP-363856 incidence higher than placebo) were: somnolence (6.7% vs. 4.8%), agitation (5.0% vs. 4.8%), nausea (5.0% vs. 3.2%), diarrhea (2.5% vs. 0.8%), and dyspepsia (2.5% vs. 0%). The proportion of patients who reported any extrapyramidal symptom was 3.3% on SEP-363856 and 3.2% on placebo.

In this placebo-controlled study, treatment with SEP-363856, a novel psychotropic agent, was associated with statistically significant and clinically meaningful improvement in schizophrenia symptoms as demonstrated by endpoint change in PANSS total and subscale scores, and CGI-Severity scores. Safety and tolerability findings for SEP-363856 were in general similar to placebo. In particular, SEP-363856 was not associated with extrapyramidal symptoms, akathisia, or hyperprolactinemia, consistent with its non-D2 mechanism of action.

NCT02969382

Supported by funding from Sunovion Pharmaceuticals Inc.

Binge-eating disorder (BED) is associated with obesity (BMI ≥30) in approximately 40-45% of patients. Dasotraline is a long-acting dopamine/norepinephrine reuptake inhibitor with a PK profile characterized by slow absorption and an elimination half-life of 47-77 hours, permitting once-daily dosing. In a recent placebo-controlled, flexible-dose study, dasotraline demonstrated significant efficacy in patients with BED. We now report an analysis from this study of the effect of dasotraline on body weight.

Patients with moderate-to-severe BED, based on DSM-5 criteria, were randomized to 12 weeks of double-blind flexible-dose treatment with dasotraline (4-8 mg/d) vs. placebo. The primary efficacy outcome was number of binge-eating days/week. Mean change in body weight at Week 12 (assessed as a safety outcome) was analyzed by baseline body mass index (BMI, kg/m2) category. Inferential statistics were not performed.

The safety population consisted of 317 patients (female, 84%; mean age, 38.2 years; mean weight, 97.3 kg). At baseline, the proportions of patients in each BMI category were as follows: normal (<25 kg/m2: 5.7%), overweight (25 to <30 kg/m2: 18.3%), obesity class I (30 to <35 kg/m2: 24.9%), class II (35 to <40 kg/m2: 29.3%), and class III (≥40 kg/m2: 21.8%). For the overall patient sample, treatment with dasotraline significantly reduced the number of binge-eating days per week vs. placebo (-3.74 vs. -2.75; P<0.0001; effect size = 0.74). Mean changes at Week 12 in weight (kg) for completers treated with dasotraline vs. placebo, by baseline BMI category, were as follows: normal weight (-4.6 vs. -0.2), overweight (-5.8 vs. +1.3), and combined obesity classes I-III (-6.2 vs. +0.3). Among obese patients (Class I-III, combined) treated with dasotraline, weight reduction (≥5%) was observed in 45.3% of patients (vs. 4.1% on placebo); and weight reduction ≥10% in approximately 13.7% of patients (vs. none on placebo). Weight-related adverse events, for dasotraline vs. placebo, consisted of decreased appetite (19.7% vs. 6.9%), decreased weight (12.1% vs. 0%), and increased weight (0.6% vs. 1.3%).

Among patients completing 12 weeks of treatment with dasotraline, weight reduction ≥5% was observed in 45% of obese patients with a BMI ≥30. The most frequent weight-related adverse event was decreased appetite, reported in approximately one in five patients treated with dasotraline.

Clinicaltrials.gov number: NCT02564588

Supported by funding from Sunovion Pharmaceuticals Inc.

Bipolar I disorder frequently has an early onset, with an estimated prevalence rate of 1.8% in pediatric populations. Early onset is associated with a high degree of chronicity; however, limited data are available on the long-term efficacy of drug therapies in pediatric populations. The aim of the current study was to evaluate the long-term safety and efficacy of lurasidone in children and adolescents with bipolar depression.

Patients 10-17 years with bipolar I depression were randomized to 6 weeks of double-blind (DB) treatment with lurasidone or placebo. Patients who completed the study were eligible to enroll in a 2-year, open-label (OL) extension study in which patients were continued on flexibly-dosed lurasidone (20-80 mg/d; LUR-LUR) or switched from placebo to lurasidone (PBO-LUR). The primary efficacy measure was the Children’s Depression Rating Scale, Revised (CDRS-R); response was defined as ≥50% reduction from DB baseline in the CDRS-R total score.

A total of 306 patients completed the 6-week DB study and entered the extension study; 195 (63.7%) completed 52 weeks, and 168 (54.9%) completed 104 weeks of treatment. Mean CDRS-R total score at DB baseline was 59.4 in patients treated with lurasidone, and 58.7 in patients treated with placebo; and mean CDRS-R total score at OL baseline (after 6 weeks of DB treatment) was 36.6 in the LUR-LUR group and 41.9 in the PBO-LUR group. For the total sample of patients in the OL study, mean change (from OL baseline) in the CDRS-R score was -13.4 at week 52 and -16.4 at week 104; and responder rates were 51.0% at OL baseline (64.5% for LUR-LUR; 36.9% for PBO-LUR), 88.4% at week 52, and 91.1% at week 104. During OL treatment with lurasidone, 31 patients (10.1%) discontinued due to an adverse event. The most commonly reported events were headache (23.9%), nausea (16.4%), and somnolence (9.8%). OL treatment with lurasidone was associated with few effects on metabolic parameters or prolactin. Mean change from DB baseline in weight was +4.25 kg at week 52 (vs. an expected weight gain of 3.76 kg based on CDC normative data), and +6.75 kg at week 104 (vs. CDC expected weight gain of 6.67 kg).

Two years of treatment with lurasidone in children and adolescents with bipolar depression was generally well-tolerated, with relatively low rates of study discontinuation. Lurasidone treatment was associated with few effects on weight, metabolic parameters, and prolactin. Patients also continued to experience improvement in depressive symptoms during long-term treatment with lurasidone.

Clinicaltrials.gov identifier: NCT01914393

Supported by funding from Sunovion Pharmaceuticals Inc.

Early-onset schizophrenia is characterized by greater severity and more functional impairment than adult-onset schizophrenia. Few studies have prospectively evaluated short- or long-term antipsychotic efficacy in treatment-naïve (vs. previously treated) first-episode schizophrenia. The aim of this post-hoc analysis was to evaluate the long-term efficacy of lurasidone in antipsychotic-naïve adolescents with schizophrenia.

Patients aged 13-17 years with schizophrenia were randomized to 6 weeks of double-blind (DB), fixed-dose treatment with lurasidone (40 mg/day or 80 mg/day) or placebo. Six-week completers were eligible to enroll in an open-label (OL), flexible dose 2-year lurasidone treatment study. Efficacy over 104 weeks of OL treatment with lurasidone was evaluated for 2 patient groups based on treatment status prior to entering the initial DB study (treatment-naïve [TN] vs. treated previously [TP]). Treatment-naïve was defined as never having received antipsychotic treatment prior to randomization. Efficacy measures included the PANSS total score and the Clinical Global Impressions-Severity (CGI-S) score. Treatment response was defined as ≥20% reduction from baseline in PANSS total score.

A total of 50 TN and 221 TP patients completed the 6-week DB study and entered the extension study; and 30 (60.0%) TN and 126 (57.0%) TP patients completed 104 weeks. In the ITT population of the initial DB study, treatment with lurasidone (vs. placebo) yielded larger effects at DB endpoint on the PANSS total score in the TN group (-25.0 vs. -14.4; P<0.02; effect size [ES]=0.75) compared to the TP group (-17.3 vs. -10.0; P<0.001; ES=0.45); and in the CGI-S score in the TN group (-1.07 vs. -0.28; P=0.002; ES=0.97) compared to the TP group (-0.91 vs. -0.55; P=0.005; ES=0.38). During OL treatment with lurasidone, the magnitude of improvement from DB baseline continued to be somewhat larger in the PANSS total score for TN patients (n=38) vs. TP patients (151) at week 52 (-32.6 vs. -28.1) and week 104 (-33.6 vs. -29.2); and in the CGI-S score for TN vs. TP patients at week 52 (-2.1 vs. -1.5) and week 104 (-2.1 vs. -1.6). Responder rates during treatment with lurasidone were 72.0% (TN group) and 61.1% (TP group) at OL baseline (number-needed-to-treat [NNT]=10), 100% and 90.1% at week 52 [NNT=11], and 100% and 88.9% at week 104 [NNT=11]. During OL treatment, the most common adverse events for TN vs. TP patients were headache (26.0% vs. 23.5%), nasopharyngitis (24.0% vs. 5.4%), nausea (16.0% vs. 11.8%), and dizziness (16.0% vs. 4.1%).

In this post-hoc analysis of a 2-year OL extension study, antipsychotic-naïve adolescents with schizophrenia responded well to treatment with lurasidone at doses of 40 mg/day or 80 mg/day. TN patients achieved greater improvement than TP patients during acute treatment; and these greater treatment effects were largely maintained during 2 years of continued treatment with lurasidone.

Supported by funding from Sunovion Pharmaceuticals Inc

Dasotraline is a long-acting dopamine/norepinephrine reuptake inhibitor with a PK profile characterized by slow absorption and a t½ of 47-77 hours, permitting once-daily dosing. In a previous flexible dose study, dasotraline demonstrated significant efficacy in the treatment of binge-eating disorder (BED). The aim of this confirmatory fixed-dose study was to evaluate efficacy and safety of dasotraline in the treatment of patients with BED.

Patients meeting DSM-5 criteria for BED were randomized to 12 weeks of double-blind treatment with dasotraline (4 mg/d or 6 mg/d), or placebo. The primary efficacy endpoint was change in number of binge-eating days per week at week 12. Secondary efficacy endpoints included changes at Week 12 on the Binge Eating Clinical Global Impression of Severity Scale (BE-CGI-S), the Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating (Y-BOCS-BE), and the proportion of patients with 100% cessation of binge-eating episodes during the final 4 weeks of treatment. Efficacy was assessed using an MMRM analysis (and a logistic regression model for cessation) with a pre-specified sequential testing procedure used to control overall type I error rate.

A total of 486 were in the ITT population (dasotraline 6 mg/d (N=162), 4 mg/d (N=161), or placebo (N=163). At week 12, treatment with dasotraline was associated with significant reduction in number of binge-eating days per week in the 6 mg/d group vs. placebo (-3.5 vs. -2.9; P=0.0045), but non-significant improvement in the 4 mg/d group vs. placebo (-3.2; P=0.12). Greater improvement was observed vs. placebo for dasotraline 6 mg/d and 4 mg/d, respectively, on the BE-CGI-S (P<0.01 and P<0.03) and the Y-BOC-BE (P<0.001 and P<0.02; all P-values were nominal, not adjusted for multiplicity). The proportion of patients who achieved 4-week cessation of binge-eating episodes was only significant for the dasotraline 6 mg in the completer population (P<0.05; post-hoc analysis) but was not significant for either dose of dasotraline vs. placebo when drop-outs were included in the analysis. The most common adverse events on dasotraline 6 mg/d and 4 mg/d were combined insomnia (early, middle, late), dry mouth, headache, decreased appetite, nausea, and anxiety. Changes in systolic and diastolic blood pressure were minimal. Mean baseline to endpoint changes in supine pulse rate on dasotraline 6 mg/d and 4 mg/d vs. placebo was +6.2 bpm and +4.8 vs. +0.2 bpm.

In this 12-week, placebo-controlled, fixed-dose study, treatment with dasotraline 6 mg/d was associated with a significant reduction in frequency of binge-eating days per week; efficacy was not demonstrated for the 4 mg dose. Treatment with both doses of dasotraline resulted in improvement in the Y-BOCS-BE and the BE-CGI-S. Dasotraline was safe and generally well-tolerated at both doses; most common adverse events were insomnia, dry mouth and headache.

Clinicaltrials.gov: NCT03107026

Supported by funding from Sunovion Pharmaceuticals Inc.

Binge-eating disorder (BED), the most common eating disorder in the US, is frequently associated with impairment in quality of life and functioning. Dasotraline, a long-acting dopamine/norepinephrine reuptake inhibitor, has a PK profile characterized by slow absorption and an elimination half-life of 47-77 hours, and is dosed once-daily. In a recent placebo-controlled, flexible-dose study, dasotraline demonstrated significant efficacy in patients with BED. We now report an analysis from this study of the effect of dasotraline on binge-related obsessions and compulsions.

Patients with moderate-to-severe BED, based on DSM-5 criteria, were randomized to 12 weeks of double-blind, placebo controlled, treatment with flexible doses of dasotraline (4, 6, and 8 mg/d). The primary efficacy measure was number of binge-eating days/week; secondary measures included the Binge Eating Clinical Global Impression of Severity (BE-CGI-S) score and the Yale-Brown Obsessive-Compulsive Scale Modified for Binge-Eating (Y-BOCS-BE), a validated, 10-item interviewer-administered measure designed to assess the severity of obsessional thoughts and compulsive behaviors related to binge eating. Change from baseline in efficacy measures in the Intent-to-treat (ITT) population were analyzed using a mixed model for repeated measures (MMRM) analysis.

The ITT population consisted of 317 patients (female, 84%; mean age, 38.2 years). LS mean reduction from baseline in number of Binge Eating (BE) days per week was significantly greater for dasotraline vs. placebo at week 12 (-3.74 vs. -2.75; P<0.0001; effect size [ES] = 0.74; primary endpoint); week 12 change was significantly greater for dasotraline vs. placebo on the Y-BOCS-BE total score (-17.05 vs. -9.88; P<0.0001; ES, 0.96), the obsession subscale score (-8.32 vs. -4.58; P<0.0001; ES, 0.95), and the compulsion subscale score (-8.69 vs. -5.35; P<0.0001; ES, 0.87). All 10 YBOCS-BE items were significantly improved on dasotraline vs. placebo at week 12 (P<0.001 for all comparisons; with effect sizes ranging from 0.54 to 0.90). At Week 12 (LOCF), for dasotraline and placebo, 52.3% and 18.4% of patients, respectively, had a BE-CGI-S score of 1 (“normal; not at all ill”; NNT=3). At endpoint, for patients with a global illness severity score of 1, the corresponding mean Y-BOCS-BE total scores were 0.5 and 0.7 for dasotraline and placebo, respectively, indicating that when BED illness severity approaches “normal, not at all ill”, binge-related obsessions and compulsions demonstrate comparably low levels of severity.

In this placebo-controlled, 12-week study of patients with moderate-to-severe binge eating disorder, treatment with dasotraline (4-8 mg/d) was associated with significant and clinically meaningful reduction in binge-related obsessional thoughts and compulsive behaviors.

Clinicaltrials.gov number: NCT02564588

Supported by funding from Sunovion Pharmaceuticals Inc.

Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours. This phase 3 study evaluated the efficacy and safety of dasotraline in children with attention deficithyperactivity disorder (ADHD) throughout the day, in a laboratory classroom setting (NCT02734693).

Children (6–12 years) meeting DSM-5 criteria for ADHD were randomized to 2 weeks of dasotraline or placebo (dosed daily at home at approximately 8 PM). Following an abbreviated practice day, laboratory classroom evaluations took place at baseline and on Day 15. The primary endpoint was mean change from baseline at Day 15 in ADHD symptoms, as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Combined Score (SKAMP-CS), obtained from the average of 7 assessments collected across the 12-hour laboratory classroom day (12–24 hours post-dose). Secondary endpoints included SKAMP scores obtained throughout the day at individual timepoints from 8 AM through 8 PM (12–24 hours post-dose), and measures of safety and tolerability.

The ITT population comprised 112 patients. Mean age was 9.5 years, 68.8% were male; 92% completed the study. Dasotraline 4 mg/day significantly improved mean SKAMP-CS versus placebo (p<0.0001, effect size 0.85) with significant effects persisting throughout the day. Mean SKAMP subscores improved significantly versus placebo (Attention p<0.0001, effect size 0.81; Deportment p<0.001, effect size 0.70). Treatment-emergent adverse events were generally mild or moderate in severity; most frequent (with dasotraline 4 mg/day; placebo) included: insomnia (19.6%; 3.6%, all terms combined), decreased appetite (10.7%; 3.6%), headache (10.7%; 8.9%), affect lability (8.9%; 7.1%), irritability (5.4%; 3.6%), postural orthostatic tachycardia syndrome (5.4%; 0%), and perceptual disturbances (5.4%; 0%).

In this 2-week, randomized, double-blind, laboratory classroom study in children with ADHD, once-daily dasotraline significantly improved ADHD symptoms (including deportment and attention), compared with placebo, and demonstrated sustained efficacyup to 24 hours post-dose. The most common adverse events were insomnia, decreased appetite, and headache.

Study sponsored by Sunovion Pharmaceuticals Inc.

Binge eating disorder (BED) is the most common eating disorder in the US, with a lifetime prevalence of 2.8%. Disturbances in reward circuitry have been implicated in its pathogenesis. Dasotraline is a novel and potent dopamine and norepinephrine reuptake inhibitor with slow absorption and a long half-life resulting in stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated the efficacy and safety of flexibly-dosed dasotraline (4, 6, and 8 mg/day) vs placebo in adults with moderate to severe BED over a 12-week period (NCT02564588).

Key inclusion criteria included moderate to severe BED based on a history of ≥2 binge eating days/week for ≥6 months prior to screening, and ≥3 binge eating days for each of2 weeks prior to randomization, as documented in participant’s binge eating diary. Patients were randomized 1:1 to flexibly-dosed dasotraline (4, 6, 8 mg/day) or placebo. Theprimary endpoint was change from baseline (CFB) in the number of binge eating days per week at Week 12. Key secondary endpoints were: CFB in Clinical Global Impression–Severity (CGI-S) Scale at Week 12; CFB in Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (YBOCS-BE) at Week 12; and the percentage ofsubjects with a 4-week cessation from binge eating prior to Week 12 or end of treatment (EOT). Except for 4-week cessation, the other three variables were analyzed using amixed model for repeated measures (MMRM).

317 subjects (84% female) received ≥1 dose of study medication (mean age was 38.2 years; mean number of binge eating days per week, 4.25; mean CGI-S score, 4.5; mean BMI, 34.7). The MMRM analysis of CFB at Week 12 in the number of binge days/week yielded a significant mean difference of –0.99 (95% CI: –0.65 to –1.33; p<0.001) infavour of dasotraline (–3.74 in the dasotraline group vs –2.75 in the placebo group). All three key secondary endpoints were met at Week 12 or EOT: 46.5% of subjects in thedasotraline group achieved at least 4 consecutive weeks’ cessation from binge eating vs 20.6% in the placebo group (p<0.001); CFB in CGI-S and YBOCS-BE scores were also statistically significant in favour of dasotraline (p<0.001). The treatment-emergent adverse events (TEAEs) that occurred more frequently with dasotraline vs placebo at >2% incidence included: insomnia (44.6% vs 8.1%), dry mouth (27.4% vs 5.0%), decreased appetite (19.7% vs 6.9%), anxiety (17.8% vs 2.5%), nausea (12.7% vs 6.9%) and decreased body weight (12.1% vs 0%). Discontinuation due to AEs occurred in 11.5% of patients taking dasotraline vs 2.5% taking placebo.

In adults with moderate to severe BED, there were highly significant and clinically meaningful reductions with dasotraline vs placebo in the frequency of binge eating, global severity of illness, and obsessive-compulsive symptoms related to binge eating. These results suggest dasotraline may offer a novel, well-tolerated and efficacious treatmentfor BED.

Study sponsored by Sunovion Pharmaceuticals Inc.

Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated dasotraline in children aged 6–12 years (NCT02428088).

Patients were randomized 1:1:1 to 6 weeks of once-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo. The primary efficacy endpoint was change from baseline (CFB) at Week 6 in ADHD Rating Scale Version IV – Home Version (ADHD RS-IV HV) total score, using a mixed model for repeated measures (MMRM) in the intent-to-treat (ITT) population. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score and safety endpoints.

The mean age of 342 randomized patients was 9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% of patients completed the study. In the ITT population (N=336), ADHD RS-IV HV total score improved significantly with dasotraline 4 mg/day vs placebo(least squares [LS] mean [SE] CFB at Week 6: –17.53 [±1.31] vs –11.36 [±1.29], respectively, p<0.001; effect size [ES]: 0.48). Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/day vs placebo at Week 6 (p=0.001, p=0.003, respectively). Improvement in CGI-S score was statistically significant with dasotraline 4 mg/day vs placebo(LS mean [SE] CFB at Week 6: –1.39 [±0.12] vs –1.04 [±0.12], respectively, p=0.040; ES: 0.29). No significant improvement was observed on the ADHD RS-IV HV total score and the CGI-S score for dasotraline 2 mg/day vs placebo. The most frequent treatment-emergent AEs (≥5% and higher than placebo) were (2 mg/day; 4 mg/day; placebo): insomnia (15.3%; 21.7%; 4.3%, all terms combined), decreased appetite (12.6%; 21.7%; 5.2%), weight loss (5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%), nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%; 5.2%; 2.6%).

Compared with placebo, dasotraline 4 mg/day significantly improved ADHD symptoms in children, as assessed by ADHD RS-IV HV total score and inattentiveness and hyperactivity/impulsivity subscale scores. Dasotraline was generally well tolerated; most common AEs were insomnia, decreased appetite, weight loss and irritability.

Study sponsored by Sunovion Pharmaceuticals Inc.