Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies.

The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design. Efficacy was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and -10 versus placebo: -1.5, P = 0.018; -1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (-1.8, P = 0.010; -1.8, P = 0.004, respectively). The overall effect size (Hedges' g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a history of inadequate treatment response: a randomized, double-blind study.

BACKGROUND: For many patients with generalized anxiety disorder (GAD), first-line treatment does not lead to remission. This study investigated the efficacy and tolerability of adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with GAD and an inadequate response to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: Patients were randomized to quetiapine XR or placebo adjunctive to SSRI/SNRIs in an 11-week study. The primary endpoint was change from randomization to week 8 in Hamilton Anxiety Rating Scale (HAM-A) total score. Secondary variables were HAM-A psychic/somatic clusters, response, and remission, and Clinical Global Impression­Severity of Illness (CGI-S) score. RESULTS: A total of 409 patients received quetiapine XR (n=209) or placebo (n=200). The week 8 mean change in HAM-A total score was not statistically significant for quetiapine XR (­10.74; P=.079) vs placebo (­9.61). Secondary variables were generally consistent with the primary analysis, except for a significant reduction in HAM-A total score (week 1) and significant improvements in HAM-A psychic cluster and CGI-S total scores (week 8). Adverse events included dry mouth, somnolence, sedation, headache, and dizziness. CONCLUSIONS: In patients with GAD and an inadequate response to SSRI/SNRIs, adjunctive quetiapine XR did not show a statistically significant effect for the primary endpoint at week 8, although some secondary endpoints were statistically significant vs placebo. Quetiapine XR was generally well tolerated.

Challenges and proposed solutions to conducting Alzheimer's disease psychosis trials.

Alzheimer's disease psychosis (ADP) produces a significant burden for patients and their care partners, but at present there are no approved treatments for ADP. The lack of approved treatments may be due to the challenges of conducting clinical trials for this disease. This perspective article discusses distinct challenges and proposed solutions of conducting ADP trials involving seven key areas: (1) methods to reduce the variable and sometimes high rates of placebo response that occur for treatments of neuropsychiatric symptoms; (2) the use of combined or updated criteria that provide a precise, consensus definition of ADP; (3) the use of eligibility criteria to help recruit individuals representative of the larger ADP population and overcome the difficulty of recruiting patients with moderate-to-severe ADP; (4) consideration of multiple perspectives and implementation of technology to reduce the variability in the administration and scoring of neuropsychiatric symptom assessments; (5) the use of clinically appropriate, a priori-defined severity thresholds and responder cutoffs; (6) the use of statistical approaches that address absolute effect sizes and a three-tier approach to address the fluctuation of neuropsychiatric symptoms; and (7) the implementation of feasible diagnostic and target-engagement biomarkers as they become available. The goal of these proposed solutions is to improve the evaluation of potential ADP therapies, within the context of randomized, placebo-controlled trials with clinically meaningful endpoints and sustained treatment responses.

Safety Profile of Pimavanserin Therapy in Elderly Patients with Neurodegenerative Disease-Related Neuropsychiatric Symptoms: A Phase 3B Study.

Background: Pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, is the only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP). Further expanding knowledge of the safety profile of pimavanserin in PDP and neurodegenerative diseases (NDD) such as Alzheimer's disease is of great interest for informing its use in patients with PDP (with or without dementia), given this population is highly sensitive to adverse effects following antipsychotic use. Objective: This trial evaluated the effects of pimavanserin compared to placebo in frail older adults and elderly patients with neuropsychiatric symptoms related to NDD, such as hallucinations and delusions, to better understand the safety of pimavanserin in this population. Methods: This was a phase 3b, 8-week treatment (study duration of up to 16 weeks), multicenter, randomized, double-blind, placebo-controlled, two-arm parallel-group trial (NCT03575052). The primary endpoint was safety and tolerability, measured by treatment-emergent adverse events (TEAEs). Secondary safety endpoints were change from baseline in motor and cognitive function; exploratory endpoints included suicidality, sleep quality, and neuropsychiatric symptoms. Results: Incidences of TEAEs were similar between treatment groups; 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%), and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%). Pimavanserin did not impact motor- or cognitive-related function. Conclusions: Pimavanserin was well tolerated and not associated with motor or cognitive impairment. Together, these findings highlight the manageable and generally favorable safety profile of pimavanserin in patients with NDD, contributing to our knowledge on the safety of pimavanserin as it generalizes to patients with PDP.

Pimavanserin for psychosis in Parkinson's disease dementia: Subgroup analysis of the HARMONY Trial.

INTRODUCTION: Pimavanserin is FDA-approved to treat Parkinson's disease (PD) psychosis. We analyzed the effect of pimavanserin on psychosis in the PD dementia (PDD) subgroup from the phase 3 HARMONY trial. METHODS: This subgroup analysis included PDD patients enrolled in an international, multicenter, randomized discontinuation study of pimavanserin for dementia-related psychosis. PDD patients with moderate-to-severe psychosis, age 50-90 years, received pimavanserin 34 mg/day for 12 weeks (open-label period). Those with a sustained psychosis response to pimavanserin at weeks 8 and 12 were randomized during the double-blind period to continue pimavanserin or receive placebo. Primary efficacy endpoint was time to psychosis relapse as measured by the SAPS-H + D and CGI-I. Safety was assessed, as were effects on motor symptoms and cognitive abilities using the ESRS-A and MMSE. RESULTS: 392 patients were enrolled in HARMONY (mean age: 72.6 years; 38.8 % female): 59 had PDD; 49/59 remained on pimavanserin during the open-label period (safety analysis set), and 36/49 were randomized to pimavanserin (n = 16) or placebo (n = 20) in the double-blind phase (intent-to-treat analysis set). Risk of psychosis relapse was lower with pimavanserin 34 mg compared with placebo in the double-blind phase (HR = 0.052; 95 % CI 0.016-0.166; 1-sided nominal p < 0.001). During the open-label period, 46.9 % experienced a treatment-emergent adverse event; event incidence was similar across arms in the double-blind period. Pimavanserin did not adversely affect motor or cognitive function in either treatment phase. CONCLUSIONS: Pimavanserin significantly reduced risk of psychosis relapse in patients with PDD, was well tolerated, and did not worsen motor or cognitive function.

Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a history of inadequate treatment response: a randomized, double-blind study.

BACKGROUND: For many patients with generalized anxiety disorder (GAD), first-line treatment does not lead to remission. This study investigated the efficacy and tolerability of adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with GAD and an inadequate response to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS: Patients were randomized to quetiapine XR or placebo adjunctive to SSRI/SNRIs in an 11-week study. The primary endpoint was change from randomization to week 8 in Hamilton Anxiety Rating Scale (HAM-A) total score. Secondary variables were HAM-A psychic/somatic clusters, response, and remission, and Clinical Global Impression­Severity of Illness (CGI-S) score. RESULTS: A total of 409 patients received quetiapine XR (n = 209) or placebo (n = 200). The week 8 mean change in HAM-A total score was not statistically significant for quetiapine XR (­10.74; P = .079) vs placebo (­9.61). Secondary variables were generally consistent with the primary analysis, except for a significant reduction in HAM-A total score (week 1) and significant improvements in HAM-A psychic cluster and CGI-S total scores (week 8). Adverse events included dry mouth, somnolence, sedation, headache, and dizziness. CONCLUSIONS: In patients with GAD and an inadequate response to SSRI/ SNRIs, adjunctive quetiapine XR did not show a statistically significant effect for the primary endpoint at week 8, although some secondary endpoints were statistically significant vs placebo. Quetiapine XR was generally well tolerated.

Acute haemorrhage from a large renal epithelioid angiomyolipoma: diagnostic and management considerations in a teenage patient with a rare cancer.

Acute renal haemorrhage is a life-threatening condition that is complicated in the context of renal malignancy. Here, we present the case of a teenage male presenting acutely with a large, bleeding renal epithelioid angiomyolipoma (EAML) of the kidney-a rare cancer, which is part of the perivascular epithelioid cell tumour family. The patient was managed acutely with prompt resuscitation, transfer to a centre of expertise and haemorrhagic control using radiologically guided endovascular techniques; this subsequently permitted an oncologically sound procedure (radical nephrectomy, inferior vena cava thrombectomy and lymphadenectomy) to be performed within 24 hours. The description and discussion around this unique case summarises the patient's clinical journey, while exploring the current literature surrounding diagnosis and outcomes of patients with renal EAMLs.

Development and content validity of a patient reported outcomes measure to assess symptoms of major depressive disorder.

BACKGROUND: Although many symptoms of Major Depressive Disorder (MDD) are assessed through patient-report, there are currently no patient-reported outcome (PRO) instruments that incorporate documented evidence of patient input in PRO instrument development. A review of existing PROs used in MDD suggested the need to conduct qualitative research with patients with MDD to better understand their experience of MDD and develop an evaluative instrument with content validity. The aim of this study was to develop a disease-specific questionnaire to assess symptoms important and relevant to adult MDD patients. METHODS: The questionnaire development involved qualitative interviews for concept elicitation, instrument development, and cognitive interviews to support content validity. For concept elicitation, ten MDD severity-specific focus group interviews with thirty-eight patients having clinician-confirmed diagnoses of MDD were conducted in January 2009. A semi-structured discussion guide was used to elicit patients' spontaneous descriptions of MDD symptoms. Verbatim transcripts of focus groups were coded and analyzed to develop a conceptual framework to describe MDD. A PRO instrument was developed by operationalizing concepts elicited in the conceptual framework. Cognitive interviews were carried out in patients (n = 20) to refine and test the content validity of the instrument in terms of item relevance and comprehension, instructions, recall period, and response categories. RESULTS: Concept elicitation focus groups identified thirty-five unique concepts falling into several domains: i) emotional, ii) cognitive, iii) motivation, iv) work, v) sleep, vi) appetite, vii) social, viii) activities of daily living, ix) tired/fatigue, x) body pain, and xi) suicidality. Concept saturation, the point at which no new relevant information emerges in later interviews, was achieved for each of the concepts. Based on the qualitative findings, the PRO instrument developed had 15 daily and 20 weekly items. The cognitive interviews confirmed that the instructions, item content, and response scales were understood by the patients. CONCLUSIONS: Rigorous qualitative research resulted in the development of a PRO measure for MDD with supported content validity. The MDD PRO can assist in understanding and assessing MDD symptoms from patients' perspectives as well as evaluating treatment benefit of new targeted therapies.

Synchronous and metachronous ureteric metastases from adenocarcinoma of the colon.

Primary adenocarcinoma of the ureter occurs in only <1%. Furthermore, metastatic carcinoma to the ureter is very rare and has been described to occur from breast, lung, stomach and prostate cancers. However, metastases to the ureter from colon cancers are extremely rare, and have been largely reported as incidental post-mortem cases. We describe two cases of asymptomatic ureteric metastases secondary to adenocarcinoma of the colon; one is synchronous, whilst the other is a metachronous ureteric metastasis. With the increasing use of radiological imaging modalities such as CT and MRI (Clin Imaging 2001;25:197-202, 2001), together with increasing survival rates of primary cancers, asymptomatic ureteric metastases are more likely to be diagnosed. In summary, metastatic ureteric carcinoma of colonic origin must be considered as a differential diagnosis when there is a radiological abnormality of the ureter in patients with a history of adenocarcinoma of the colon. This should be considered even in patients with colon adenocarcinoma who have previously undergone adjuvant chemotherapy with curative intent.

Course of Psychosis in Schizophrenia With Alcohol Use Disorder: A Post Hoc Analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia Phase 1 Study.

OBJECTIVE: Patients with schizophrenia and comorbid alcohol use disorder remain understudied. This post hoc analysis evaluated data from Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia study (January 2001-December 2004). METHODS: Patients without substance abuse (except marijuana use) in the month before study entry were categorized into those with a history of alcohol use disorder (SZ + AUD) within 5 years before study entry and those without alcohol use disorder (SZ-only) per DSM-IV criteria. Time to first and recurrent exacerbations and hospitalizations were compared between disease states and between olanzapine and perphenazine, quetiapine, risperidone, and ziprasidone. RESULTS: A total of 1,338 patients (SZ + AUD = 22.6%; SZ-only = 77.4%) were included. Time to first exacerbation of SZ was significantly shorter in the SZ + AUD versus SZ-only population (median = 5.4 vs 6.4 months; hazard ratio [HR] = 1.20 [95% CI, 1.01-1.42]; P = .039). Similar findings were observed for first hospitalization (HR = 1.63 [95% CI, 1.20-2.22]; P = .002) and recurrent hospitalizations (HR = 1.60 [95% CI, 1.18-2.15]; P = .002). The most common reasons leading to exacerbation in both groups were an increase in symptom severity and lack of efficacy. In patients with SZ + AUD related or unrelated to marijuana, perphenazine, quetiapine, risperidone, and ziprasidone were associated with significantly shorter time to first exacerbation versus olanzapine. CONCLUSIONS: This post hoc analysis confirmed that patients with SZ + AUD had a worse illness course than patients with SZ-only and suggests that olanzapine may be associated with a longer time to first and recurrent exacerbations versus other antipsychotics in this difficult-to-treat population. Further research is needed to identify effective treatments for this important yet understudied patient population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00014001.

The dysfunctional attitudes scale: psychometric properties in depressed adolescents.

The psychometric properties and factor structure of the Dysfunctional Attitudes Scale were examined in a sample of 422 male and female adolescents (ages 12-17) with current major depressive disorder. The scale demonstrated high internal consistency (alpha = .93) and correlated significantly with self-report and interview-based measures of depression. Confirmatory factor analysis indicated that a correlated 2-factor model, with scales corresponding to perfectionism and need for social approval, provided a satisfactory fit to the data. The goodness-of-fit was equivalent across sexes and age groups. The findings support the use of the Dysfunctional Attitudes Scale and its subscales in the assessment of clinically depressed adolescents.

An exploratory analysis of the impact of family functioning on treatment for depression in adolescents.

This article explores aspects of family environment and parent-child conflict that may predict or moderate response to acute treatments among depressed adolescents (N = 439) randomly assigned to fluoxetine, cognitive behavioral therapy, their combination, or placebo. Outcomes were Week 12 scores on measures of depression and global impairment. Of 20 candidate variables, one predictor emerged: Across treatments, adolescents with mothers who reported less parent-child conflict were more likely to benefit than their counterparts. When family functioning moderated outcome, adolescents who endorsed more negative environments were more likely to benefit from fluoxetine. Similarly, when moderating effects were seen on cognitive behavioral therapy conditions, they were in the direction of being less effective among teens reporting poorer family environments.

Buprenorphine/samidorphan combination for the adjunctive treatment of major depressive disorder: results of a phase III clinical trial (FORWARD-3).

BACKGROUND: The endogenous opioid system is a fundamental regulator of mood in humans. Previously reported clinical trials have demonstrated the efficacy of the investigational agent buprenorphine/samidorphan (BUP/SAM) combination, an opioid-system modulator, for the adjunctive treatment of major depressive disorder. We present here a third phase III study of different design. METHODS: Adult patients with major depressive disorder and inadequate response to antidepressant therapy were enrolled in this double-blind, placebo-controlled, placebo run-in study to evaluate the efficacy, safety, and tolerability of adjunctive BUP/SAM 2 mg/2 mg. Patients with baseline Hamilton Depression Rating Scale score $20 received double-blind placebo in addition to background antidepressant therapy for 4 weeks. Nonresponders were randomized to receive adjunctive BUP/SAM 2 mg/2 mg or placebo for 6 weeks. The primary end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS)-10 total score from randomization at baseline to the end of the 6-week treatment period. RESULTS: Least-squares mean change in MADRS-10 score at end of treatment was -4.8 (SE 0.67) in the BUP/SAM 2 mg/2 mg group and -4.6 (SE 0.66) in the placebo group (mean difference -0.3 [SE 0.95], P=0.782). There were no differences in MADRS-based response or remission rates. Overall, 42.9% of the BUP/SAM 2 mg/2 mg group and 34.5% of the placebo group experienced at least one treatment-emergent adverse event during the 6-week treatment period, most of which were mild or moderate in severity. There were no clinically important changes in laboratory parameters, weight, or vital signs and no evidence of abuse potential during treatment or opiate-withdrawal symptoms post treatment. CONCLUSION: Efficacy results in FORWARD-3 measured by change in MADRS-10 score did not meet the primary end point, but postbaseline improvement in MADRS-10 in the BUP/SAM 2 mg/2 mg group was consistent with that seen in previously reported trials. BUP/SAM 2 mg/2 mg was well tolerated.

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial.

Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as adjunctive treatment for major depressive disorder. BUP/SAM is a fixed-dose combination of buprenorphine, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and samidorphan, a µ-opioid receptor antagonist added to address the abuse and dependence potential of buprenorphine. In this study, we assessed the effect of samidorphan on the abuse potential of buprenorphine in the BUP/SAM combination in nondependent, recreational, adult opioid users (ClinicalTrials.gov ID: NCT02413281). Participants were randomized to 6 treatments in a blinded, Williams crossover design: placebo, BUP/SAM at the intended therapeutic dose (2 mg/2 mg), at 4-fold (8 mg/8 mg) and 8-fold (16 mg/16 mg) the therapeutic dose, and buprenorphine alone (8 mg and 16 mg). The primary end point was maximum effect (Emax ) on the visual analog scale for "at the moment" Drug Liking. Emax of Drug Liking for the BUP/SAM 2 mg/2 mg dose was similar to that for placebo (median within-subject difference [90% confidence interval]: 2.5 [0.0-9.0]). The supratherapeutic doses of BUP/SAM showed differences of small magnitude on Drug Liking Emax compared to placebo. Drug Liking Emax for all BUP/SAM doses were significantly lower than those observed for either buprenorphine dose alone. Fewer participants reported adverse events associated with abuse potential with BUP/SAM than with buprenorphine alone, and the overall safety profile of BUP/SAM was consistent with prior reports in healthy volunteers. These findings indicate that samidorphan substantially reduces the abuse potential of buprenorphine in the BUP/SAM combination.

Integration of sugarcane production technologies for enhanced cane and sugar productivity targeting to increase farmers' income: strategies and prospects.

The idea of doubling the farmers' income in next 5 years has been slated by the Government of India. The specific target of increasing sugarcane farmers' income could be achieved by developing cost-effective technologies, transferring them from laboratory to land, educating the farmers and creating a linkage between all stakeholders. Consistent efforts shall be required to harness all possible sources for increasing farmer's income in and outside the agriculture sector with respect to improvement in sugarcane and sugar productivity, enhancement in resource use efficiency and adopting various other ways and means including intercropping, management of pests and diseases, use of biotechnological tools and minimizing post-harvest deterioration. The advances in sugarcane biotechnology could become remarkable in the coming years, both in terms of improving productivity as well as increasing the value and utility of this crop substantially. In future, genetically modified sugarcane varieties with increased resistance to different biotic and abiotic stresses would serve more towards sugarcane crop improvement. Any possibility of enhancement in the income of sugarcane farmers shall also be dependent upon the profitability and sustainability of the sugar industry. Integration of sugarcane production technologies for improvement in farm productivity, diversified sugarcane production system, reduced cost of cultivation along with increased processing plant efficiency and diversification to produce value added products shall ensure smooth and higher payment to the farmers. Development of low-cost technologies to convert "waste to resource" on a smaller scale shall also help the farmers to increase their income further. This paper focuses on possible measures to be taken up in each aspects of sugarcane cultivation including biotechnological approaches to achieve the goal of enhancing the income of sugarcane farmers substantially, particularly in the sub-tropical region of India.

Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia.

OBJECTIVE: Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia. METHODS: This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan. RESULTS: Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group. CONCLUSIONS: The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.

Abuse Potential of Samidorphan: A Phase I, Oxycodone-, Pentazocine-, Naltrexone-, and Placebo-Controlled Study.

Samidorphan is a µ-opioid receptor antagonist in development for the treatment of schizophrenia, in combination with olanzapine, and major depressive disorder, in combination with buprenorphine, at proposed therapeutic doses of samidorphan 10 mg and 2 mg, respectively. A double-blind, double-dummy, active- and placebo-controlled, crossover study evaluated the abuse potential of samidorphan in healthy, nondependent, recreational opioid users. Following a qualification phase, participants were randomized to 1 of 6 treatment sequences of study drugs: placebo, samidorphan (10 or 30 mg), oxycodone (40 mg), pentazocine (30 mg), and naltrexone (100 mg) in a 6 × 6 Williams design. The primary end point was maximum effect (Emax ) for "at-the-moment" Drug Liking visual analog scale scores. Secondary end points included Emax visual analog scale scores for Take Drug Again and Overall Drug Liking and safety assessments. Among 47 participants, at-the-moment Emax Drug Liking scores for positive study controls oxycodone and pentazocine were significantly higher than placebo (P < .001) and samidorphan (both doses; P < .001). Both samidorphan doses had Emax Drug Liking scores similar to placebo and naltrexone (median within-subject differences of 0.0). Emax Take Drug Again scores for samidorphan (both doses) were higher than placebo, but similar to naltrexone, an unscheduled µ-opioid receptor antagonist. Adverse events to evaluate abuse potential occurred less frequently with samidorphan, naltrexone, and placebo than with oxycodone and pentazocine. Findings from this study support a lack of abuse potential with samidorphan at doses up to 30 mg and a safety profile consistent with previous samidorphan clinical studies.

Results from a long-term open-label extension study of adjunctive buprenorphine/samidorphan combination in patients with major depressive disorder.

Buprenorphine/samidorphan (BUP/SAM; ALKS 5461) is an investigational opioid system modulator for the adjunctive treatment of patients with major depressive disorder (MDD), who did not respond adequately to prior antidepressant therapy (ADT). FORWARD-2, an open-label extension study, assessed long-term safety and tolerability of adjunctive BUP/SAM treatment in these patients. Patients from four short-term trials and de novo patients were enrolled; all had confirmed MDD and a current major depressive episode lasting 2-24 months. Patients were treated with an established ADT for ≥8 weeks before receiving sublingual, adjunctive BUP/SAM 2 mg/2 mg for up to 52 weeks. Safety (primary objective) was assessed via adverse events (AEs), the Columbia-Suicide Severity Rating Scale, and the Clinical Opiate Withdrawal Scale (COWS). Exploratory evaluation of efficacy was done using the Montgomery-Åsberg Depression Rating Scale (MADRS). Of 1485 patients, 50% completed the study and 11% discontinued due to AEs. AEs of nausea, headache, constipation, dizziness, and somnolence, each occurred in ≥10% of patients. There was no evidence of increased suicidal ideation or behavior. Euphoria-related AEs were uncommon (1.2%). Following abrupt BUP/SAM discontinuation, "drug withdrawal" AEs were infrequent (0.4%), and the incidence of COWS categorical worsening after abrupt drug discontinuation was low (6.5%). Improvements in mean MADRS scores were maintained until study end, suggesting durability of antidepressant effect in patients continuing treatment. BUP/SAM was generally well tolerated, with a low risk of abuse and an AE profile consistent with those seen in placebo-controlled studies. Withdrawal reports were uncommon and of limited clinical impact.

Androgen manipulation alters oxidative DNA adduct levels in androgen-sensitive prostate cancer cells grown in vitro and in vivo.

Intracellular reactive oxygen species (ROS) may cause oxidative DNA damage, resulting in the formation of adducts such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and the cyclic pyrimidopurinone N-1, N(2) malondialdehyde-2'-deoxyguanosine (M(1)dG). These adducts have been associated with carcinogenesis, genomic instability and clonal evolution. We tested two hypotheses in human prostate cancer cells grown in vitro and in a xenograft model: (1) treatment of androgen-sensitive cells with DHT increases levels of oxidative DNA adduct levels; (2) flutamide, a competitive androgen receptor antagonist, prevents DHT-induced changes. Levels of M(1)dG and 8-oxo-dG adducts were determined by immunoslot blot and liquid chromatography-tandem mass spectrometry. M(1)dG and 8-oxo-dG levels were significantly higher than control levels in LNCaP cells exposed to supra-physiological concentrations (25-100 nM) of DHT (both P<0.05 by ANOVA). Flutamide pre-treatment completely prevented this increase. In the xenograft model, tumour levels of M(1)dG were decreased by 46% (P=0.001 by Mann-Whitney Test) in flutamide-treated animals compared to controls. The changes demonstrated suggest that oxidative DNA adducts may serve as biomarkers of the efficacy of androgen manipulation in chemoprevention trials.

SET-C versus fluoxetine in the treatment of childhood social phobia.

OBJECTIVE: To determine the efficacy of fluoxetine, pill placebo, and Social Effectiveness Therapy for Children (SET-C) for children and adolescents with social phobia. METHOD: Youths ages 7 to 17 were randomly assigned to one of the treatment conditions. Outcome was evaluated using self-reports, parent ratings, independent evaluator ratings, and behavioral assessment. RESULTS: Both fluoxetine and SET-C were more efficacious than placebo in reducing social distress and behavioral avoidance and increasing general functioning. SET-C was superior to fluoxetine on each of these measures and was the only treatment superior to placebo in terms of improving social skills, decreasing anxiety in specific social interactions, and enhancing ratings of social competence. Furthermore, whereas fluoxetine appears to exert maximum effect by 8 weeks, SET-C provides continued improvement through week 12. CONCLUSIONS: Both fluoxetine and SET-C are efficacious for social phobia, although SET-C appears to provide added benefit by enhancing social skills.