Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo-Controlled Phase 3 Trial.

OBJECTIVE: This study assessed the efficacy and safety of a 14-day treatment course of once-daily zuranolone 50 mg, an investigational oral positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor, for the treatment of major depressive disorder. METHODS: Patients 18-64 years of age with severe major depressive disorder were enrolled in this randomized, double-blind, placebo-controlled trial. Patients self-administered zuranolone 50 mg or placebo once daily for 14 days. The primary endpoint was change from baseline in total score on the 17-item Hamilton Depression Rating Scale (HAM-D) at day 15. Safety and tolerability were assessed by incidence of adverse events. RESULTS: Of 543 randomized patients, 534 (266 in the zuranolone group, 268 in the placebo group) constituted the full analysis set. Compared with patients in the placebo group, patients in the zuranolone group demonstrated a statistically significant improvement in depressive symptoms at day 15 (least squares mean change from baseline HAM-D score, -14.1 vs. -12.3). Numerically greater improvements in depressive symptoms for zuranolone versus placebo were observed by day 3 (least squares mean change from baseline HAM-D score, -9.8 vs. -6.8), which were sustained at all visits throughout the treatment and follow-up periods of the study (through day 42, with the difference remaining nominally significant through day 12). Two patients in each group experienced a serious adverse event; nine patients in the zuranolone group and four in the placebo group discontinued treatment due to adverse events. CONCLUSIONS: Zuranolone at 50 mg/day elicited a significantly greater improvement in depressive symptoms at day 15, with a rapid time to effect (day 3). Zuranolone was generally well tolerated, with no new safety findings compared with previously studied lower dosages. These findings support the potential of zuranolone in treating adults with major depressive disorder.

Zuranolone in Major Depressive Disorder: Results From MOUNTAIN-A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

Objective: To evaluate the efficacy and safety of zuranolone, an investigational neuroactive steroid and GABAA receptor positive allosteric modulator, in major depressive disorder (MDD).Methods: The phase 3, double-blind, randomized, placebo-controlled MOUNTAIN study enrolled adult outpatients with DSM-5-diagnosed MDD, 17-item Hamilton Depression Rating Scale total score (HDRS-17) ≥ 22, and Montgomery-Asberg Depression Rating Scale total score ≥ 32. Patients were randomized to treatment with zuranolone 20 mg, zuranolone 30 mg, or placebo for 14 days, followed by an observation period (days 15-42) and an extended follow-up (days 43-182). The primary endpoint was change from baseline (CFB) in HDRS-17 at day 15.Results: 581 patients were randomized to receive zuranolone (20 mg, n = 194; 30 mg, n = 194) or placebo (n = 193). Day 15 HDRS-17 least-squares mean (LSM) CFB was -12.5 (zuranolone 30 mg) vs -11.1 (placebo; P = .116). Improvement vs placebo was significant at days 3, 8, and 12 (all P < .05). LSM CFB (zuranolone 20 mg vs placebo) was not significant at any measured time point. Post hoc analyses of zuranolone 30 mg in patients with measurable plasma zuranolone concentration and/or severe disease (baseline HDRS-17 ≥ 24) showed significant improvement vs placebo at days 3, 8, 12, and 15 (all P < .05). Incidence of treatment-emergent adverse events was similar between zuranolone and placebo groups; the most common (≥ 5%) were fatigue, somnolence, headache, dizziness, diarrhea, sedation, and nausea.Conclusions: MOUNTAIN did not meet its primary endpoint. Significant rapid improvements in depressive symptoms were observed with zuranolone 30 mg at days 3, 8, and 12. Zuranolone was generally well tolerated in patients with MDD.Trial Registration: ClinicalTrials.gov identifier: NCT03672175.

Patient-reported health-related quality of life from a randomized, placebo-controlled phase 2 trial of zuranolone in adults with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD), a disabling, potentially life-threatening condition, negatively affects health-related quality of life (HRQoL). This secondary analysis aimed to understand the impact of the neuroactive steroid zuranolone on HRQoL using the Short Form-36v2 Health Survey (SF-36v2). METHODS: Adult patients with MDD and 17-item Hamilton Rating Scale for Depression total score ≥22 were randomized 1:1 to receive zuranolone 30 mg or placebo for 2 weeks, with 4 weeks follow-up. SF-36v2 scores were assessed at Day 15 across 8 domains (Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health) and 2 summary scores (Physical and Mental Component), using a mixed-effects model for repeated measures. Correlations between SF-36v2 scores and clinician-reported efficacy endpoints were assessed using Pearson's correlation. RESULTS: Eighty-nine patients were treated with zuranolone 30 mg (n = 45) or placebo (n = 44). In zuranolone-treated patients, HRQoL improved across all SF-36v2 domains and summary scores at Day 15. Improvements exceeding established minimally important difference thresholds were observed in Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional, and Mental Health scores. Improvements in General Health, Vitality, Mental Health, and Mental Component Summary were statistically significant versus placebo (p ≤ 0.025). Clinician-rated endpoints negatively correlated with SF-36v2 scores. LIMITATIONS: The small unipolar depression sample may not be representative of all US MDD patients. HRQoL measures could be impacted by factors unrelated to depression. CONCLUSIONS: Zuranolone-treated patients reported rapid and significant improvements in HRQoL versus placebo at Day 15. HRQoL improvements correlated with improvements in clinician-rated assessments. TRIAL REGISTRATION: clinicaltrials.gov:NCT03000530; https://clinicaltrials.gov/ct2/show/NCT03000530.

A phase 1 double-blind, placebo-controlled study of zuranolone (SAGE-217) in a phase advance model of insomnia in healthy adults.

OBJECTIVE: To evaluate single zuranolone (SAGE-217) 30 or 45 mg doses in a 5-h phase advance insomnia model. METHODS: In this double-blind, three-way crossover study, healthy adults received placebo (n = 41), zuranolone 30 mg (n = 44), and zuranolone 45 mg (n = 42) across three treatment periods. Sleep was assessed by polysomnography and a postsleep questionnaire. Next-day residual effects and safety/tolerability were evaluated. RESULTS: Compared with placebo, zuranolone resulted in significant improvements in median sleep efficiency (30 mg, 84.6%; 45 mg, 87.6%; placebo, 72.9%; p < 0.001 for both doses), wake after sleep onset (WASO; 30 mg, 55.0 min; 45 mg, 42.5 min; placebo, 113.0 min; p < 0.001 for both doses), duration of awakenings (30 mg, 4.2 min, p < 0.001; 45 mg, 3.7 min, p = 0.001; placebo, 7.4 min), and total sleep time (TST; 30 mg, 406.3 min; 45 mg, 420.3 min; placebo, 350.0 min; p < 0.001 for both doses). Subjective endpoints (WASO, TST, sleep latency, sleep quality) also improved relative to placebo. Zuranolone was generally well tolerated, and the most common adverse events (≥2 participants, any period) were headache and fatigue. CONCLUSION: Zuranolone improved sleep measures versus placebo in a phase advance model of insomnia in healthy adults, supporting future studies in patients with insomnia disorder.

Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial.

Importance: Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child. Objective: To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD. Design, Setting, and Participants: This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019. Interventions: Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks. Main Outcomes and Measures: Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments. Results: Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo. Conclusions and Relevance: In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD. Trial Registration: ClinicalTrials.gov Identifier: NCT02978326.

Number Needed to Treat and Number Needed to Harm analysis of the zuranolone phase 2 clinical trial results in major depressive disorder.

BACKGROUND: Zuranolone (SAGE-217) is a novel, investigational positive allosteric modulator of GABAA receptors being investigated in major depressive disorder (MDD). This analysis of phase 2 data quantified the benefit and risk of zuranolone (30mg) versus placebo and antidepressants in terms of number needed to treat (NNT) and number needed to harm (NNH). METHODS: Rates of response, remission, and all-cause discontinuation for zuranolone and 11 antidepressant comparators were obtained from the zuranolone phase 2 clinical study (N=89) and a published network meta-analysis, respectively. An indirect treatment comparison was conducted using the Bucher method to compare zuranolone to standard-of-care. RESULTS: Zuranolone demonstrated greater benefit compared to placebo on Day 3 (NNT range for response=4-5, NNT for remission=10) and at Day 15 (NNT=3 for response and remission). Compared to SSRIs and SNRIs, zuranolone at Day 15 showed improved treatment response (NNT=4 [95% CI = 3; 16] and 5 [95% CI = 3; 25], respectively) and remission (NNT=4 [95% CI = 2; 13] and 4 [95% CI = 2; 18], respectively). This was accompanied by a reduction in all-cause discontinuation, with negative NNH values (-57 and -28), respectively. LIMITATIONS: Variations in study design across the included trials may limit the generalizability of results. CONCLUSIONS: With a small positive NNT as early as Day 3 indicating robust benefit and a negative NNH indicating reduced harm, this analysis based on a phase 2 study suggests that patients with MDD may benefit from the benefit-to-risk profile of zuranolone.

Trial of SAGE-217 in Patients with Major Depressive Disorder.

BACKGROUND: Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. METHODS: In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). RESULTS: A total of 89 patients underwent randomization: 45 patients were assigned to the SAGE-217 group, and 44 to the placebo group. The mean baseline HAM-D score was 25.2 in the SAGE-217 group and 25.7 in the placebo group. The least-squares mean (±SE) change in the HAM-D score from baseline to day 15 was -17.4±1.3 points in the SAGE-217 group and -10.3±1.3 points in the placebo group (least-squares mean difference in change, -7.0 points; 95% confidence interval, -10.2 to -3.9; P<0.001). The differences in secondary end points were generally in the same direction as those of the primary end point. There were no serious adverse events. The most common adverse events in the SAGE-217 group were headache, dizziness, nausea, and somnolence. CONCLUSIONS: Administration of SAGE-217 daily for 14 days resulted in a reduction in depressive symptoms at day 15. Adverse events were more common in the SAGE-217 group than in the placebo group. Further trials are needed to determine the durability and safety of SAGE-217 in major depressive disorder and to compare SAGE-217 with available treatments. (Funded by Sage Therapeutics; ClinicalTrials.gov number, NCT03000530.).

Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials.

BACKGROUND: Post-partum depression is associated with substantial morbidity, and improved pharmacological treatment options are urgently needed. We assessed brexanolone injection (formerly SAGE-547 injection), a positive allosteric modulator of γ-aminobutyric-acid type A (GABAA) receptors, for the treatment of moderate to severe post-partum depression. METHODS: We did two double-blind, randomised, placebo-controlled, phase 3 trials, at 30 clinical research centres and specialised psychiatric units in the USA. Eligible women were aged 18-45 years, 6 months post partum or less at screening, with post-partum depression and a qualifying 17-item Hamilton Rating Scale for Depression (HAM-D) score (≥26 for study 1; 20-25 for study 2). Women with renal failure requiring dialysis, anaemia, known allergy to allopregnanolone or to progesterone, or medical history of schizophrenia, bipolar disorder, or schizoaffective disorder were excluded. Patients were randomly assigned (1:1:1) to receive a single intravenous injection of either brexanolone 90 µg/kg per h (BRX90), brexanolone 60 µg/kg per h (BRX60), or matching placebo for 60 h in study 1, or (1:1) BRX90 or matching placebo for 60 h in study 2. Patients, the study team, site staff, and the principal investigator were masked to treatment allocation. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all patients who started infusion of study drug or placebo, had a valid HAM-D baseline assessment, and had at least one post-baseline HAM-D assessment. The safety population included all randomised patients who started infusion of study drug or placebo. Patients were followed up until day 30. The trials have been completed and are registered with ClinicalTrials.gov, numbers NCT02942004 (study 1) and NCT02942017 (study 2). FINDINGS: Participants were enrolled between Aug 1, 2016, and Oct 19, 2017, in study 1, and between July 25, 2016, and Oct 11, 2017, in study 2. We screened 375 women simultaneously across both studies, of whom 138 were randomly assigned to receive either BRX90 (n=45), BRX60 (n=47), or placebo (n=46) in study 1, and 108 were randomly assigned to receive BRX90 (n=54) or placebo (n=54) in study 2. In study 1, at 60 h, the least-squares (LS) mean reduction in HAM-D total score from baseline was 19·5 points (SE 1·2) in the BRX60 group and 17·7 points (1·2) in the BRX90 group compared with 14·0 points (1·1) in the placebo group (difference -5·5 [95% CI -8·8 to -2·2], p=0·0013 for the BRX60 group; -3·7 [95% CI -6·9 to -0·5], p=0·0252 for the BRX90 group). In study 2, at 60 h, the LS mean reduction in HAM-D total score from baseline was 14·6 points (SE 0·8) in the BRX90 group compared with 12·1 points (SE 0·8) for the placebo group (difference -2·5 [95% CI -4·5 to -0·5], p=0·0160). In study 1, 19 patients in the BRX60 group and 22 patients in the BRX90 group had adverse events compared with 22 patients in the placebo group. In study 2, 25 patients in the BRX90 group had adverse events compared with 24 patients in the placebo group. The most common treatment-emergent adverse events in the brexanolone groups were headache (n=7 BRX60 group and n=6 BRX90 group vs n=7 placebo group for study 1; n=9 BRX90 group vs n=6 placebo group for study 2), dizziness (n=6 BRX60 group and n=6 BRX90 group vs n=1 placebo group for study 1; n=5 BRX90 group vs n=4 placebo group for study 2), and somnolence (n=7 BRX60 group and n=2 BRX90 group vs n=3 placebo group for study 1; n=4 BRX90 group vs n=2 placebo group for study 2). In study 1, one patient in the BRX60 group had two serious adverse events (suicidal ideation and intentional overdose attempt during follow-up). In study 2, one patient in the BRX90 group had two serious adverse events (altered state of consciousness and syncope), which were considered to be treatment related. INTERPRETATION: Administration of brexanolone injection for post-partum depression resulted in significant and clinically meaningful reductions in HAM-D total score at 60 h compared with placebo, with rapid onset of action and durable treatment response during the study period. Our results suggest that brexanolone injection is a novel therapeutic drug for post-partum depression that has the potential to improve treatment options for women with this disorder. FUNDING: Sage Therapeutics, Inc.

Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial.

BACKGROUND: Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of γ-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. METHODS: For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (≤6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ≥26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. FINDINGS: This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21·0 points (SE 2·9) in the brexanolone group compared with 8·8 points (SE 2·8) in the placebo group (difference -12·2, 95% CI -20·77 to -3·67; p=0·0075; effect size 1·2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). INTERPRETATION: In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress. FUNDING: Sage Therapeutics, Inc.

The tropical rain belts with an annual cycle and a continent model intercomparison project: TRACMIP.

This paper introduces the Tropical Rain belts with an Annual cycle and a Continent Model Inter-comparison Project (TRACMIP). TRACMIP studies the dynamics of tropical rain belts and their response to past and future radiative forcings through simulations with 13 comprehensive and one simplified atmosphere models coupled to a slab ocean and driven by seasonally varying insolation. Five idealized experiments, two with an aquaplanet setup and three with a setup with an idealized tropical continent, fill the space between prescribed-SST aquaplanet simulations and realistic simulations provided by CMIP5/6. The simulations reproduce key features of present-day climate and expected future climate change, including an annual-mean intertropical convergence zone (ITCZ) that is located north of the equator and Hadley cells and eddy-driven jets that are similar to present-day climate. Quadrupling CO2 leads to a northward ITCZ shift and preferential warming in Northern high latitudes. The simulations show interesting CO2-induced changes in the seasonal excursion of the ITCZ and indicate a possible state dependence of climate sensitivity. The inclusion of an idealized continent modulates both the control climate and the response to increased CO2; for example, it reduces the northward ITCZ shift associated with warming and, in some models, climate sensitivity. In response to eccentricity-driven seasonal insolation changes, seasonal changes in oceanic rainfall are best characterized as a meridional dipole, while seasonal continental rainfall changes tend to be symmetric about the equator. This survey illustrates TRACMIP's potential to engender a deeper understanding of global and regional climate and to address questions on past and future climate change.

Efficacy and safety of lisdexamfetamine for treatment of adults with moderate to severe binge-eating disorder: a randomized clinical trial.

IMPORTANCE: Binge-eating disorder (BED), a public health problem associated with psychopathological symptoms and obesity and possibly with metabolic syndrome, lacks approved pharmacotherapies. OBJECTIVE: To examine the efficacy and safety of lisdexamfetamine dimesylate, a dextroamphetamine prodrug, to treat moderate to severe BED. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, parallel-group, forced dose titration, placebo-controlled clinical trial at 30 sites from May 10, 2011, through January 30, 2012. Safety and intention-to-treat analyses included 259 and 255 adults with BED, respectively. INTERVENTIONS: Lisdexamfetamine dimesylate at dosages of 30, 50, or 70 mg/d or placebo were provided to study participants (1:1:1:1). Dosages were titrated across 3 weeks and maintained for 8 weeks. We followed up participants for a mean (SD) of 7 (2) days after the last dose. MAIN OUTCOMES AND MEASURES: We assessed the change in binge-eating (BE) behaviors measured as days per week (baseline to week 11) with a mixed-effects model using transformed log (BE days per week) + 1. Secondary measures included BE cessation for 4 weeks. Safety assessments included treatment-emergent adverse events, vital signs, and change in weight. RESULTS: At week 11, log-transformed BE days per week decreased with the 50-mg/d (least squares [LS] mean [SE] change, -1.49 [0.066]; P = .008) and 70-mg/d (LS mean [SE] change, -1.57 [0.067]; P < .001) treatment groups but not the 30-mg/d treatment group (LS mean [SE] change, -1.24 [0.067]; P = .88) compared with the placebo group. Nontransformed mean (SD) days per week decreased for placebo and the 30-, 50-, and 70-mg/d treatment groups by -3.3 (2.04), -3.5 (1.95), -4.1 (1.52), and -4.1 (1.57), respectively. The percentage of participants achieving 4-week BE cessation was lower with the placebo group (21.3%) compared with the 50-mg/d (42.2% [P = .01]) and 70-mg/d (50.0% [P < .001]) treatment groups. The incidence of any treatment-emergent adverse events was 58.7% for the placebo group and 84.7% for the combined treatment group. In the treatment groups, 1.5% of participants had serious treatment-emergent adverse effects. Events with a frequency of at least 5% and changes in heart rate were generally consistent with the known safety profile. The mean (SD) change in body weight was -0.1 (3.09), -3.1 (3.64), -4.9 (4.43), -4.9 (3.93), and -4.3 (4.09) kg for the placebo group, the 30-, 50-, and 70-mg/d treatment groups, and the combined treatment groups, respectively (P < .001 for each dose vs placebo group comparison in post hoc analysis). CONCLUSIONS AND RELEVANCE: The 50- and 70-mg/d treatment groups demonstrated efficacy compared with the placebo group in decreased BE days, BE cessation, and global improvement. The safety profile was generally consistent with previous findings in adults with attention-deficit/hyperactivity disorder. Further investigation of lisdexamfetamine in BED is ongoing. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01291173.

Memantine in the treatment of binge eating disorder: an open-label, prospective trial.

OBJECTIVE: To assess preliminarily the efficacy of memantine in binge eating disorder. METHOD: This was an open-label, 12-week, flexible-dose (5-20 mg/day) trial of memantine in binge eating disorder. The primary outcome was frequency of binge days. Secondary outcomes included frequency of binge episodes, body-mass index (BMI), weight, Clinical Global Impressions Severity (CGI-S), Three Factor Eating Questionnaire (TFEQ), Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), and Sheehan Disability Scale (SDS). Longitudinal random regression analysis was performed for frequency of binge days and episodes, BMI, weight, and CGI-S; analysis of baseline to endpoint change was performed for all outcomes. RESULTS: Sixteen individuals received memantine; 15 completed at least one postbaseline evaluation, 9 completed the study. Mean dose at endpoint was 18.3 mg/day. Memantine was associated with significant reductions in frequency of binge days and episodes, severity of illness (p < .001 for both analyses), disinhibition on the TFEQ (p = .015), and disability on the SDS (p < .05 for three subscales). There was no significant change in BMI, weight, MADRS, HAM-A, and TFEQ cognitive restraint and hunger. CONCLUSION: In this open-label trial, memantine was well tolerated and effective in reducing binge eating, severity of illness, and disability, but had little effect on BMI and weight.

A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of pediatric depression.

OBJECTIVE: Escitalopram is a selective serotonin reuptake inhibitor antidepressant indicated for use in adults. This trial examined the efficacy and safety of escitalopram in pediatric depression. METHOD: Patients (6-17 years old) with major depressive disorder were randomized to receive 8 weeks of double-blind flexibly dosed treatment with escitalopram (10-20 mg/day; n = 131) or placebo (n = 133). Randomization was not stratified by age. The primary efficacy measure was the mean change from baseline to endpoint in Children's Depression Rating Scale-Revised (CDRS-R) scores, using the last observation carried forward approach. RESULTS: A total of 82% of patients completed treatment. Escitalopram did not significantly improve CDRS-R scores compared to placebo at endpoint (least squares mean difference = -1.7, p = .31; last observation carried forward). In a post hoc analysis of adolescent (ages 12-17 years) completers, escitalopram significantly improved CDRS-R scores compared with placebo (least squares mean difference = -4.6, p = .047). Headache and abdominal pain were the only adverse events in >10% of patients in the escitalopram group. Discontinuation rates caused by adverse events were 1.5% for both groups. Potential suicide-related events were observed in one escitalopram- and two placebo-treated patients. There were no completed suicides. CONCLUSIONS: Although there were no significant differences between escitalopram and placebo in the total population, the data suggest that escitalopram may have beneficial effects in adolescent patients. Escitalopram appeared to be well tolerated.