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ImportanceEarly identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms.ObjectivesTo assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia.Design, setting, and participantsA randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity.InterventionsOral avagacestat or placebo daily.Main outcomes and measureSafety and tolerability of avagacestat.ResultsOf the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures.Conclusions and relevanceAvagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD.Trial registrationclinicaltrials.gov Identifier: NCT00890890.

Major depressive disorder (MDD) is a disabling psychiatric condition for which effective treatment remains an outstanding need. Antidepressants are currently the mainstay of treatment for depression; however, almost two-thirds of patients will fail to achieve remission with initial treatment. As a result, a range of augmentation and combination strategies have been used in order to improve outcomes for patients. Despite the popularity of these approaches, limited data from double-blind, randomized, placebo-controlled studies are available to allow clinicians to determine which are the most effective augmentation options or which patients are most likely to respond to which options. Recently, evidence has shown that adjunctive therapy with atypical antipsychotics has the potential for beneficial antidepressant effects in the absence of psychotic symptoms. In particular, aripiprazole has shown efficacy as an augmentation option with standard antidepressant therapy in two, large, randomized, double-blind studies. Based on these efficacy and safety data, aripiprazole was recently approved by the FDA as adjunctive therapy for MDD. The availability of this new treatment option should allow more patients with MDD to achieve remission and, ultimately, long-term, successful outcomes.

Patients who have a return of their depressive symptoms after treatment may have abnormal brain function in the orbitofrontal cortex, the dorsolateral prefrontal cortex, and the thalamus. This was the conclusion of researchers who used PET imaging to measure the metabolic activity in the brains of 18 patients who were successfully treated for depression. They were given a substance that reduces the amount of several neurotransmitters involved in depression.

Bulimia nervosa and alcohol use disorders frequently co-occur. A review of the literature, however, reveals a paucity of information on treatment of patients with these comorbid conditions. We present a case report of a 34-year-old Caucasian female with a 20-year history of bulimia nervosa with co-occurring alcohol dependence, who participated in a randomized placebo-controlled medication augmentation trial for bulimia nervosa. The patient served as a pilot subject who met the exclusionary criterion of alcohol dependence, but received all the assessment and intervention procedures of the clinical trial for bulimia nervosa. Despite double-blind random assignment to a placebo condition, the patient's symptoms of bulimia nervosa substantially improved over the course of the 5-week efficacy trial. We hypothesize that this improvement was due to concurrent abstinence from alcohol rather than a placebo effect. Keywords - bulimia nervosa; alcohol dependence; clinical trial; abstinence.

Orally administered riluzole extends survival in patients with amyotrophic lateral sclerosis, although it has significant shortcomings (eg, adverse events, dysphagic patients) that limit its utility. BHV‐0223 is a Zydis‐based orally disintegrating formulation of riluzole designed for sublingual administration that addresses the limitations of conventional tablets. This study assessed the bioequivalence between 40‐mg BHV‐0223 and standard 50‐mg oral riluzole tablets, and the food effect on BHV‐0223 pharmacokinetics in healthy volunteers. Overall, 133 healthy subjects received BHV‐0223 and riluzole tablets under fasted conditions. Geometric mean ratios for the area under the plasma concentration–time curve (AUC) from time zero to time of last nonzero concentration (AUC0‐t) (89.9%; confidence interval [CI], 87.3%–92.5%), AUC from time zero to infinity (AUC0‐∞) (89.8%; CI, 87.3%–92.4%), and maximum observed concentration (112.7%; CI, 105.5%–120.4%) all met bioequivalence criteria (80%–125%). Subsequently, 67 subjects received BHV‐0223 under fed conditions. The geometric mean ratios of AUC0‐t (91.2%; CI, 88.1–94.3%), and AUC0‐∞ (92.0%; CI, 89.0–95.1%) were similar, but maximum observed concentration ratios were not within bioequivalence criteria. BHV‐0223 was well tolerated. This study demonstrated that 40‐mg sublingual BHV‐0223 is bioequivalent to 50‐mg oral riluzole tablets. [ABSTRACT FROM AUTHOR]