Sustained Treatment Response and Global Improvements With Long-term Valbenazine in Patients With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.

Time to onset of cannabidiol treatment effects in Dravet syndrome: Analysis from two randomized controlled trials.

OBJECTIVE: We conducted a post hoc analysis of two randomized controlled trials, GWPCARE1 (NCT02091375) and GWPCARE2 (NCT02224703), to estimate the time to onset of cannabidiol (CBD) treatment effects (seizure reduction and adverse events [AEs]) in patients with Dravet syndrome (DS). METHODS: Patients received either plant-derived highly purified CBD (Epidiolex in the United States; 100 mg/ml oral solution) 10 mg/kg/day (CBD10; GWPCARE2) or 20 mg/kg/day (CBD20; GWPCARE1&2), or matching placebo for 14 weeks. Treatment started at 2.5 mg/kg/day, reached 10 mg/kg/day on Day 7, and went up to 20 mg/kg/day on Day 11 during the 14-day titration period. Percentage change from baseline in convulsive seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were also evaluated. RESULTS: Overall, 124 patients received placebo and 194 received CBD (CBD10, n = 64; CBD20, n = 130). Mean age was 9.5 years (range = 2.2-18.9). Patients had discontinued a median of four antiepileptic drugs (range = 0-26) and were currently taking a median of three (range = 1-5). Differences in convulsive seizure reduction between placebo and CBD emerged during titration and became nominally significant by Day 12 for CBD20 (p = .02) and Day 13 for CBD10 (p = .03). Additionally, differences in the 50% responder rate between placebo and CBD became apparent during titration. Onset of the first reported AE occurred during the titration period in 48.4% of placebo patients and 54.1% of CBD patients. The three most common AEs of somnolence, decreased appetite, and diarrhea resolved within 4 weeks of onset in the majority of CBD-treated patients (56.3%-72.9%). SIGNIFICANCE: The therapeutic effect of CBD in DS may start within 2 weeks of treatment in some patients. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week study period.

Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5. METHODS: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day. RESULTS: Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18-1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3 × upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition. SIGNIFICANCE: We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. METHODS: Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. RESULTS: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.

OBJECTIVES: To assess the efficacy and safety profile of add-on cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials. METHODS: Patients received plant-derived, highly purified CBD medicine (Epidiolex® in the USA; Epidyolex® in Europe; 100 mg/ml oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta-analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period. RESULTS: 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62-0.80]; DS, 0.71 [0.60-0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47-0.67]; DS, 0.63 [0.52-0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure-free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam. CONCLUSIONS: Add-on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.

Cannabidiol efficacy independent of clobazam: Meta-analysis of four randomized controlled trials.

OBJECTIVE: The efficacy of cannabidiol (CBD) with and without concomitant clobazam (CLB) was evaluated in stratified analyses of four large randomized controlled trials, two in Lennox-Gastaut syndrome, and two in Dravet syndrome. METHODS: Each trial of CBD (Epidiolex® in the US; Epidyolex® in the EU; 10 and 20 mg/kg/day) was evaluated by CLB use. The treatment ratio was analyzed using negative binomial regression for changes in seizure frequency and logistic regression for the 50% responder rate, where the principle analysis combined both indications and CBD doses in a stratified meta-analysis. Pharmacokinetic data were examined for an exposure/response relationship based on CLB presence/absence. Safety data were analyzed using descriptive statistics. RESULTS: The meta-analysis favored CBD vs. placebo regardless of CLB use. The treatment ratio (95% CI) of CBD over placebo for the average reduction in seizure frequency was 0.59 (0.52, 0.68; P < .0001) with CLB and 0.85 (0.73, 0.98; P = .0226) without CLB, and the 50% responder rate odds ratio (95% CI) was 2.51 (1.69, 3.71; P < .0001) with CLB and 2.40 (1.38, 4.16; P = .0020) without CLB. Adverse events (AEs) related to somnolence, rash, pneumonia, or aggression were more common in patients with concomitant CLB. There was a significant exposure/response relationship for CBD and its active metabolite. CONCLUSIONS: These results indicate CBD is efficacious with and without CLB, but do not exclude the possibility of a synergistic effect associated with the combination of agents. The safety and tolerability profile of CBD without CLB show a lower rate of certain AEs than with CLB.

Psychiatric adverse events and effects on mood with prolonged-release naltrexone/bupropion combination therapy: a pooled analysis.

BACKGROUND/OBJECTIVES: Prolonged-release (PR) naltrexone 32 mg/bupropion 360 mg (NB) is approved for chronic weight management as an adjunct to reduced-calorie diet and increased physical activity. Central nervous system-active medications have the potential to affect mood; therefore, post hoc analysis of clinical trial data was conducted to evaluate psychiatric adverse events (PAEs) and effects on mood of NB therapy versus placebo. SUBJECTS/METHODS: Data were pooled from 5 prospective, double-blind, randomized, placebo-controlled clinical trials (duration range, 24-56 weeks) of NB in subjects with overweight or obesity. PAEs were collected via AE preferred terms, organized into major subtopics (e.g., anxiety, depression, sleep disorders), and divided into category terms (e.g., anxiety, potential anxiety symptoms). Additionally, the Inventory of Depressive Symptomatology Self Report (IDS-SR; score range 0-84) and the Columbia Classification Algorithm of Suicide Assessment (C-CASA) evaluated treatment-emergent depressive/anxiety symptoms and suicidal behavior/ideation, respectively. RESULTS: Baseline characteristics and comorbidities were comparable for placebo (n = 1515) and NB (n = 2545). Most common PAEs in the NB group (using category grouping; NB vs placebo) were sleep disorders (12.7 vs 7.9%, P < 0.001), anxiety (5.4 vs 3.3%, P = 0.029), and depression (1.8 vs 2.7%, P = 0.014); PAEs were more frequent during dose escalation and generally mild or moderate. Mean (SD) changes in IDS-SR total score from baseline to endpoint were small in both groups: 0.13 (5.83) for NB and -0.45 (5.65) for placebo. Retrospective AE categorization via C-CASA confirmed no completed suicides, suicide attempts, or preparatory acts toward imminent suicidal behavior. CONCLUSIONS: This large pooled analysis of 5 clinical trials provides additional safety information about the NB PAE profile. Anxiety and sleep disorder-related PAEs were more frequent with NB versus placebo but were mostly mild to moderate and generally occurred early. Depression-related PAEs were less common with NB than placebo, and NB was not associated with suicidal ideation or behavior in this patient population.

INTERACT: a randomized phase 2 study of the DAAO inhibitor luvadaxistat in adults with schizophrenia.

Deficits in N-methyl-d-aspartate receptor (NMDAR) signaling are implicated in the pathogenesis of schizophrenia. Luvadaxistat (TAK-831/NBI-1065844) is an investigational d-amino acid oxidase (DAAO) inhibitor that increases d-serine levels at NMDAR coagonist sites. INTERACT is a phase 2 randomized, placebo-controlled study that evaluated the efficacy and safety of three doses of luvadaxistat, covering a range of DAAO occupancy and d-serine levels, in patients with schizophrenia with persistent negative symptoms. The study included a 14-day, single-blinded placebo run-in period and a 12-week, double-blinded treatment period. The primary efficacy endpoint was the 12-week change from baseline in Positive and Negative Syndrome Scale-Negative Symptom Factor Score (PANSS NSFS). Secondary efficacy endpoints included the 12-week changes from baseline in Brief Assessment of Cognition in Schizophrenia (BACS) score and Schizophrenia Cognition Rating Scale (SCoRS) score. Safety endpoints included adverse event assessments. The full analysis set included all randomized patients (N = 256 [placebo, n = 87; luvadaxistat 50 mg, n = 58; 125 mg, n = 56; 500 mg, n = 55]); 228 patients completed the study. No significant improvements in PANSS NSFS were observed at any dose versus placebo at week 12. Improvements were observed with luvadaxistat 50 mg versus placebo in cognitive endpoints: BACS composite score (nominal one-sided p = 0.031) and SCoRS interviewer total score (nominal one-sided p = 0.011). Luvadaxistat did not significantly improve negative symptoms of schizophrenia. However, luvadaxistat 50 mg met the prespecified secondary endpoints for cognitive performance (BACS) and function (SCoRS), warranting further investigation in patients with cognitive impairment associated with schizophrenia. Luvadaxistat was well-tolerated in INTERACT, with no new safety signals observed. ClinicalTrials.gov: NCT03382639.

The D-amino acid oxidase inhibitor luvadaxistat improves mismatch negativity in patients with schizophrenia in a randomized trial.

Several attempts have been made to enhance N-methyl-D-aspartate (NMDA) receptor function in schizophrenia, but they have yielded mixed results. Luvadaxistat, a D-amino acid oxidase (DAAO) inhibitor that increases the glutamate co-agonist D-serine levels, is being developed for the treatment of cognitive impairment associated with schizophrenia. We conducted a biomarker study in patients, assessing several endpoints related to physiological outcomes of NMDA receptor modulation to determine whether luvadaxistat affects neural circuitry biomarkers relevant to NMDA receptor function and schizophrenia. This was a randomized, placebo-controlled, double-blind, two-period crossover phase 2a study assessing luvadaxistat 50 mg and 500 mg for 8 days in 31 patients with schizophrenia. There were no treatment effects of luvadaxistat at either dose in eyeblink conditioning, a cerebellar-dependent learning measure, compared with placebo. We observed a nominally significant improvement in mismatch negativity (MMN) and a statistical trend to improvement for auditory steady-state response at 40 Hz, in both cases with 50 mg, but not with 500 mg, compared with placebo. Although the data should be interpreted cautiously owing to the small sample size, they suggest that luvadaxistat can improve an illness-related circuitry biomarker at doses associated with partial DAAO inhibition. These results are consistent with 50 mg, but not higher doses, showing a signal of efficacy in cognitive endpoints in a larger phase 2, 12-week study conducted in parallel. Thus, MMN responses after a short treatment period may predict cognitive function improvement. MMN and ASSR should be considered as biomarkers in early trials addressing NMDA receptor hypofunction.

Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. METHODS: Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT00532779. FINDINGS: 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was -1.3% (SE 0.3) in the placebo group, -6.1% (0.3) in the naltrexone 32 mg plus bupropion group (p<0.0001 vs placebo) and -5.0% (0.3) in the naltrexone 16 mg plus bupropion group (p<0.0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p<0.0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p<0.0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 1.5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups. Combination treatment was not associated with increased depression or suicidality events compared with placebo. INTERPRETATION: A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity. FUNDING: Orexigen Therapeutics.

Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial.

Importance: Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose. Objective: To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. Interventions: Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment. Main Outcomes and Measures: The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. Results: Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium. Conclusions and Relevance: Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02224703.

Bayesian adaptive non-inferiority with safety assessment: retrospective case study to highlight potential benefits and limitations of the approach.

Adaptive trial design applied to randomized clinical trials of psychiatric medicines offers the potential to make clinical trials more efficient. In the current analysis, we retrospectively applied Bayesian adaptive allocation methods to a case study in agitated patients with schizophrenia and related diseases. The original study used a randomized, double-blind, parallel design. The objective of this analysis was to demonstrate the potential benefits of Bayesian adaptive designs by shortening the study duration and therefore limiting patient exposure to ineffective placebo or an active comparator with a known side effect. Bayesian methods allowed us to fully leverage historical data along with data observed as the study was ongoing to calculate predictive probabilities of patient response to treatment without experiencing a specified side effect. Using the Bayesian adaptive approach would have required less than half the number of patients as the original study to draw the same conclusion. Sample size was reduced from 311 to 156 patients, thereby decreasing the number of patients exposed to placebo from 54 to 30 and the number exposed to the active control with a known side effect from 126 to 60.

Nonresponse, partial response, and failure to achieve remission: humanistic and cost burden in major depressive disorder.

OBJECTIVE: To characterize the spectrum of clinical outcomes achieved with depression treatment and the associated impact on quality of life (QOL), functional status, overall well-being, health-care costs, and productivity. SOURCES: Electronic databases including Medline were searched for English language sources between 1995 and 2007 using key words of depression, nonresponse, partial response, and remission and QOL, functional status, utility, cost, and productivity. STUDY SELECTION: Relevant abstracts were obtained for 488 references and full-text articles were reviewed that included primary data and compared outcomes by treatment response. Data were abstracted from 26 full-text articles. DATA ABSTRACTION: Detailed evidence tables were prepared with the relevant data as well as information on the study design. All data abstracted were checked for accuracy. synthesis: Treatment remitters and partial responders reported clinically and statistically significant improvements in QOL, functional status, and overall well-being compared to nonresponders. Annual health-care costs and productivity losses were significantly lower for remitters and partial responders compared to nonresponders. CONCLUSIONS: The reduced disease burden for remitters and partial responders compared to nonresponders indicates that new treatment strategies that improve the rates of response/remission with initial treatment might have value to patients and to society.

Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder.

LY354740, a potent and selective mGlu (metabotropic glutamate receptor)2/3 agonist, has shown efficacy in the treatment of generalized anxiety disorder (GAD). LY544344 is a LY354740 prodrug that increases LY354740 bioavailability. This 8-week study was designed to evaluate the efficacy, safety, and tolerability of LY544344 in the treatment of GAD. Participants had a diagnoses of GAD, baseline Hospital Anxiety and Depression Scale anxiety subscale scores > or = 10, and moderate illness severity. Patients were randomized to double-blind treatment with LY544344 16 mg b.i.d. (n = 28), LY544344 8 mg b.i.d. (n = 36), or placebo (n = 44). LY544344 16 mg b.i.d.-treated patients showed significantly greater improvement from baseline in Hamilton Anxiety and Clinical Global Impression-Improvement scores, as well as response and remission rates compared with placebo-treated patients. LY544344 was well tolerated and there were no significant differences in the incidence of treatment-emergent adverse events among the three treatment groups. However, the trial was discontinued early based on findings of convulsions in preclinical studies. In conclusion, the findings of this study support the potential efficacy of mGlu2/3 receptor agonist agents in the treatment of GAD. Additional studies will be needed to further assess the toxicological and clinical profile of LY354740/LY544344.

Duloxetine as an SNRI treatment for generalized anxiety disorder: results from a placebo and active-controlled trial.

This study examined the efficacy and tolerability of duloxetine 60-120 mg/day for the treatment of patients with generalized anxiety disorder. This was a multicenter, randomized, double-blind, flexible-dose, placebo and active-controlled (venlafaxine extended-release 75-225 mg/day) trial designed to assess duloxetine 60-120 mg/day during 10 weeks of treatment in adults with Diagnostic and statistical manual of mental disorders-IV-defined generalized anxiety disorder. The primary efficacy outcome measure was mean change from baseline to endpoint in the Hamilton Anxiety Rating Scale total score assessed using analysis of covariance. A total of 487 patients were randomly assigned to duloxetine (n=162), venlafaxine XR (n=164), or placebo (n=161). Significantly greater improvement on the Hamilton Anxiety Rating Scale total score occurred in the duloxetine (P=0.007) and venlafaxine XR (P<0.001) groups compared with the placebo group. Overall discontinuation rates did not differ among the three groups, but adverse event-related discontinuation was significantly higher in the duloxetine (14.2%, P<0.001) and venlafaxine XR (11.0%, P=0.001) groups than in the placebo group (1.9%). During the 2-week drug-tapering phase, discontinuation-emergent adverse events were significantly greater in the venlafaxine XR group (26.9%, P=0.04), but not in the duloxetine group (19.4%, P=0.448) compared with placebo (15.8%). Duloxetine 60-120 mg/day and venlafaxine XR 75-225 mg/day were each efficacious treatments for patients with generalized anxiety disorder.

Efficacy of duloxetine for the treatment of generalized anxiety disorder: implications for primary care physicians.

OBJECTIVE: This study examined the efficacy and tolerability of duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, for the treatment of patients with generalized anxiety disorder (GAD). METHOD: Patients were ≥ 18 years old and recruited from 5 European countries, the United States, and South Africa. The study had a 9-week, multicenter, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group design. A total of 513 patients (mean age = 43.8 years; 67.8% female) with a DSM-IV-defined GAD diagnosis received treatment with duloxetine 60 mg/day (N = 168), duloxetine 120 mg/day (N = 170), or placebo (N = 175). The primary efficacy measure was the Hamilton Rating Scale for Anxiety (HAM-A) total score. Secondary measures included the Sheehan Disability Scale, HAM-A psychic and somatic anxiety factor scores, and HAM-A response, remission, and sustained improvement rates. The study was conducted from July 2004 to September 2005. RESULTS: Both groups of duloxetine-treated patients demonstrated significantly greater improvements in anxiety symptom severity compared with placebo-treated patients as measured by HAM-A total score and HAM-A psychic and somatic anxiety factor scores (p values ranged from ≤ .01 to ≤ .001). Duloxetine-treated patients had greater functional improvements in Sheehan Disability Scale global and specific domain scores (p ≤ .001) than placebo-treated patients. Both duloxetine doses also resulted in significantly greater HAM-A response, remission, and sustained improvement rates compared with placebo (p values ranged from ≤ .01 to ≤ .001). The rate of study discontinuation due to adverse events was 11.3% for duloxetine 60 mg and 15.3% for duloxetine 120 mg versus 2.3% for placebo (p ≤ .001). CONCLUSION: The results of this study demonstrate that duloxetine 60 mg/day and 120 mg/day were efficacious and well tolerated and thus may provide primary care physicians with a useful pharmacologic intervention for GAD. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00122824.

Concurrent Improvement in Both Binge Eating and Depressive Symptoms with Naltrexone/Bupropion Therapy in Overweight or Obese Subjects with Major Depressive Disorder in an Open-Label, Uncontrolled Study.

INTRODUCTION: Binge eating disorder (BED) is associated with obesity and major depressive disorder (MDD). Naltrexone extended-release (ER)/bupropion ER (NB) is approved as an adjunct to diet and physical activity for chronic weight management. In a prospectively designed 24-week open-label, single-arm, single-site trial of 25 women with MDD and overweight/obesity, NB reduced weight and depressive symptoms. METHODS: This post hoc analysis investigated the relationship between change in self-reported binge eating behavior (evaluated with the Binge Eating Scale [BES]) and changes in weight, control of eating, and depressive symptoms. RESULTS: At baseline, 91% of subjects had moderate or severe BES scores, suggesting BED. BES scores were significantly improved from week 4, and by week 24, 83% reported "little or no problem." Improvement in BES scores correlated with improvement in depressive symptoms and control of eating. CONCLUSION: NB may be effective in reducing binge eating symptoms associated with MDD and overweight/obesity. Evaluation of NB in BED appears warranted. FUNDING: Orexigen Therapeutics, Inc.

Efficacy and safety of the glycine transporter type-1 inhibitor AMG 747 for the treatment of negative symptoms associated with schizophrenia.

OBJECTIVE: To determine the safety and efficacy of AMG 747, an oral inhibitor of glycine transporter type-1 (GlyT1), as an add-on to antipsychotic therapy in clinically stable people with schizophrenia with enduring negative symptoms. METHOD: Analysis of pooled data from two phase 2 studies. Adults diagnosed with schizophrenia stabilized on antipsychotic medication randomized (2:2:2:3) to orally receive daily AMG 747 (5mg, 15mg, or 40mg) or placebo. Primary endpoint was Negative Symptom Assessment (NSA)-16 total score change from baseline to week 12. RESULTS: Studies were terminated early after a report of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in one participant (40-mg AMG 747). At termination, 232 participants had enrolled and 153 completed 12weeks of treatment. At week 12, change from baseline NSA-16 total score showed no differences between groups. Mean decrease in Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS) and NSA-16 global score were greater with 15-mg AMG 747 than placebo (p<0.05). Changes in PANSS-Positive Symptom Factor Scale were not significantly different for any group. Changes in patient-reported outcomes (Sheehan Disability Scale and Quality of Life Enjoyment and Satisfaction Questionnaire) showed trends consistent with greater efficacy of 15-mg AMG 747 compared with placebo (p≤0.1). Adverse event rates were similar among all groups, with no clear differences observed. CONCLUSIONS: Significant treatment effects of 15-mg AMG 747, but not higher or lower doses, were observed on secondary endpoints but not on the primary outcome. These results replicate previous reports of an inverted-U dose response curve and suggest further evaluation of GlyT1 inhibitors in schizophrenia negative symptoms is warranted. TRIAL REGISTRATION: Clinicaltrials.govNCT01568216 (https://clinicaltrials.gov/ct2/show/NCT01568216) and NCT01568229 (https://clinicaltrials.gov/ct2/show/NCT01568229?term=NCT01568229&rank=1); EudraCT number 2011-004844-23 and 2011-004845-42.

Psychometric characteristics of the MATRICS Consensus Cognitive Battery in a large pooled cohort of stable schizophrenia patients.

The MATRICS Consensus Cognitive Battery (MCCB) was developed to assess cognitive treatment effects in schizophrenia clinical trials, and is considered the FDA gold standard outcome measure for that purpose. The aim of the present study was to establish pre-treatment psychometric characteristics of the MCCB in a large pooled sample. The dataset included 2616 stable schizophrenia patients enrolled in 15 different clinical trials between 2007 and 2016 within the United States (94%) and Canada (6%). The MCCB was administered twice prior to the initiation of treatment in 1908 patients. Test-retest reliability and practice effects of the cognitive composite score, the neurocognitive composite score, which excludes the domain Social Cognition, and the subtests/domains were examined using Intra-Class Correlations (ICC) and Cohen's d. Simulated regression models explored which domains explained the greatest portion of variance in composite scores. Test-retest reliability was high (ICC=0.88) for both composite scores. Practice effects were small for the cognitive (d=0.15) and neurocognitive (d=0.17) composites. Simulated bootstrap regression analyses revealed that 3 of the 7 domains explained 86% of the variance for both composite scores. The domains that entered most frequently in the top 3 positions of the regression models were Speed of Processing, Working Memory, and Visual Learning. Findings provide definitive psychometric characteristics and a benchmark comparison for clinical trials using the MCCB. The test-retest reliability of the MCCB composite scores is considered excellent and the learning effects are small, fulfilling two of the key criteria for outcome measures in cognition clinical trials.

Characteristics of two alternative schizophrenia remission definitions: relationship to clinical and quality of life outcomes.

BACKGROUND: The goal of these secondary analyses of clinical trial data was to characterize clinical outcomes in patients with schizophrenia who met symptom severity or duration thresholds for two alternative definitions of remission, and to explore their relationships to improvement duration and quality of life outcomes. METHODS: Definition 1 used threshold criteria for selected PANSS items sustained over at least 6-months Definition 2 used Brief Psychiatric Rating Scale (BPRS) % change, a threshold score for the Clinical Global Improvement-Severity (CGI-S) maintained for at least 8 weeks, and threshold scores for selected BPRS items. Positive and Negative Symptom Scale (PANSS) and Quality of Life scale (QLS) total scores were pooled from 6 clinical trials. The extent to which the alternative severity thresholds from these two definitions and duration of clinical improvement were associated with different clinical and QLS outcomes was explored. Regression analysis also assessed the relative contribution of each of the components of the two definition severity thresholds to improvements in QLS Total score. RESULTS: Increases in QLS scores were greater for those patients who met either threshold criteria relative to those who met neither (p<.0001). Significantly greater improvements in QLS scores were observed for patients who met either threshold criteria at the 8-, 16- and 24-week visits relative to those who met criteria at weeks 16 and 24, or at week 24 only (p<0.001), as well as for the subset of patients who met threshold criteria at both 24 and 52 weeks relative to those who met criteria at only one of these 2 time points. Only 31% to 47% of patients meeting threshold criteria for either definition at the 8-, 16- or 24-week visits remained in remission at the 52-week visit. Among the severity threshold components analyzed, BPRS total % change from baseline was the strongest predictor of improvement in QLS scores. CONCLUSIONS: Quality of life improved most for patients who achieved severity thresholds associated with either remission criteria and who stayed improved for longer periods. Total BPRS change scores accounted for the greatest percentage of the QLS scores variance. Only a fraction of patients who meet severity criteria for either remission definition early in treatment will remain at that level of improvement within the subsequent 9-12 months.