Emerging drugs for the treatment of major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) continues to be one of the highest contributors to disease burden and years lived with disability in the world. Current existing treatments have been associated with intolerable side effects, long onset of action and suboptimal remission rates. Newer agents are being developed that will be reviewed here, such as glutamate and gamma-aminobutyric acid (GABA) and the reinvigorated testing of psychedelic drugs. This review will summarize the target mechanisms of the newer ADTs currently in development and available on the market. AREAS COVERED: It briefly covers the existing agents for MDD and treatment-resistant depression (TRD) and the need for new agents with higher efficacy. Therapeutic agents currently in Phase II or later clinical trials are listed and discussed, based on a thorough review of the US National Institutes of Health clinicaltrials.gov index and a search of the Informa Pharmaprojects database. Compounds of interest are grouped into scientific rationale and include atypical antipsychotics, GABA positive allosteric modulators, glutamatergic agents, opioids, orexin 2 receptor antagonists, and psychedelics. EXPERT OPINION: New therapeutic agents currently in development are promising, with a more rapid onset of action and the ability to augment and treat TRD.

Efficacy and Safety of a 2-Month Formulation of Aripiprazole Lauroxil With 1-Day Initiation in Patients Hospitalized for Acute Schizophrenia Transitioned to Outpatient Care: Phase 3, Randomized, Double-Blind, Active-Control ALPINE Study.

OBJECTIVE: Evaluate efficacy and safety of a 2-month formulation of aripiprazole lauroxil (AL) with 1-day initiation during hospitalization for acute exacerbation of schizophrenia followed by transition to outpatient care. METHODS: The phase 3b double-blind Aripiprazole Lauroxil and Paliperidone palmitate: INitiation Effectiveness (ALPINE) study was conducted from November 2017 to March 2019. Adults with acute schizophrenia according to DSM-5 criteria were randomized (1:1) to AL (AL NanoCrystal Dispersion + oral aripiprazole 30 mg, day 1; AL 1,064 mg, day 8 and every 8 weeks [q8wk]) or paliperidone palmitate (PP 234 mg, day 1; PP 156 mg, day 8 and then q4wk) for 25 weeks. Patients remained hospitalized ≥ 2 weeks after randomization per protocol. Primary endpoint was within-group change in Positive and Negative Syndrome Scale total score (PANSST) from baseline to week 4. Secondary analyses included within- and between-group changes from baseline at various time points. Adverse events (AEs) and laboratory data were monitored. RESULTS: A total of 200 patients were randomized (AL, n = 99; PP, n = 101); 56.6% and 42.6%, respectively, completed the study. For AL, the mean baseline PANSST was 94.1; scores were significantly reduced from baseline at week 4 (-17.4; P < .001) and were also reduced at weeks 9 (-19.8) and 25 (-23.3). With PP, PANSST also improved significantly from baseline (94.6) at week 4 (-20.1; P < .001) and also improved at weeks 9 (-22.5) and 25 (-21.7). The 3 most common AEs over 25 weeks in the AL group were injection site pain (17.2%), increased weight (9.1%), and akathisia (9.1%). The same AEs were the most common in the PP group (injection site pain [24.8%], increased weight [16.8%], and akathisia [10.9%]). CONCLUSIONS: AL and PP were efficacious and well-tolerated for initiating treatment of schizophrenia in the hospital and continuing outpatient treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03345979.

Efficacy and Safety of a Combination of Olanzapine and Samidorphan in Adult Patients With an Acute Exacerbation of Schizophrenia: Outcomes From the Randomized, Phase 3 ENLIGHTEN-1 Study.

OBJECTIVE: To assess the antipsychotic efficacy and safety of a combination of olanzapine and samidorphan (OLZ/SAM). METHODS: This 4-week, phase 3, randomized, double-blind, placebo- and olanzapine-controlled study was conducted from December 2015 to June 2017 in adults with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who were experiencing an acute exacerbation. Patients were randomized 1:1:1 to OLZ/SAM, olanzapine monotherapy, or placebo. The primary and key secondary efficacy endpoint assessed was the change in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness Scale (CGI-S) score between baseline and week 4, respectively, for OLZ/SAM versus placebo. Safety monitoring occurred throughout. RESULTS: 401 patients received ≥ 1 dose of study drug; 352 completed treatment. Treatment with OLZ/SAM resulted in significant improvements versus placebo in PANSS total and CGI-S scores from baseline to week 4 (least squares [LS] mean ± SE: -6.4 ± 1.8 [P < .001] and -0.38 ± 0.12 [P = .002], respectively). Olanzapine treatment resulted in similar improvements (PANSS and CGI-S LS mean ± SE of -5.3 ± 1.84 [P = .004] and -0.44 ± 0.12 [P < .001], respectively). Adverse events (AEs) occurred in 54.5%, 54.9%, and 44.8% of patients on OLZ/SAM, olanzapine, and placebo, respectively. Weight gain, somnolence, dry mouth, anxiety, and headache were the most common AEs (ie, ≥ 5%) with active treatment. CONCLUSIONS: OLZ/SAM treatment resulted in statistically and clinically significant efficacy improvements over 4 weeks versus placebo in adults with acutely exacerbated schizophrenia. Improvements were similar to those observed with olanzapine. OLZ/SAM was well tolerated, with a safety profile similar to that of olanzapine. TRIAL REGISTRATIONS: ClinicalTrials.gov identifier: NCT02634346; EudraCT number: 2015-003373-15​​.

Recognizing Binge-Eating Disorder in the Clinical Setting: A Review of the Literature.

OBJECTIVE: Review the clinical skills needed to recognize, diagnose, and manage binge-eating disorder (BED) in a primary care setting. DATA SOURCES: A PubMed search of English-language publications (January 1, 2008-December 11, 2014) was conducted using the term binge-eating disorder. Relevant articles known to the authors were also included. STUDY SELECTION/DATA EXTRACTION: Publications focusing on preclinical topics (eg, characterization of receptors and neurotransmitter systems) without discussing clinical relevance were excluded. A total of 101 publications were included in this review. RESULTS: Although BED is the most prevalent eating disorder, it is underdiagnosed and undertreated. BED can be associated with medical (eg, type 2 diabetes and metabolic syndrome) and psychiatric (eg, depression and anxiety) comorbidities that, if left untreated, can impair quality of life and functionality. Primary care physicians may find diagnosing and treating BED challenging because of insufficient knowledge of its new diagnostic criteria and available treatment options. Furthermore, individuals with BED may be reluctant to seek treatment because of shame, embarrassment, and a lack of awareness of the disorder. Several short assessment tools are available to screen for BED in primary care settings. Pharmacotherapy and psychotherapy should focus on reducing binge-eating behavior, thereby reducing medical and psychiatric complications. CONCLUSIONS: Overcoming primary care physician- and patient-related barriers is critical to accurately diagnose and appropriately treat BED. Primary care physicians should take an active role in the initial recognition and assessment of suspected BED based on case-finding indicators (eg, eating habits and being overweight), the initial treatment selection, and the long-term follow-up of patients who meet DSM-5 BED diagnostic criteria.

Psychometric evaluation of the Work Readiness Questionnaire in schizophrenia.

OBJECTIVE/INTRODUCTION: Unemployment can negatively impact quality of life among patients with schizophrenia. Employment status depends on ability, opportunity, education, and cultural influences. A clinician-rated scale of work readiness, independent of current work status, can be a valuable assessment tool. A series of studies were conducted to create and validate a Work Readiness Questionnaire (WoRQ) for clinicians to assess patient ability to engage in socially useful activity, independent of work availability. METHODS: Content validity, test-retest and inter-rater reliability, and construct validity were evaluated in three separate studies. RESULTS: Content validity was supported. Cronbach's α was 0.91, in the excellent range. Clinicians endorsed WoRQ concepts, including treatment adherence, physical appearance, social competence, and symptom control. The final readiness decision showed good test-retest reliability and moderate inter-rater reliability. Work readiness was associated with higher function and lower levels of negative symptoms. Low positive and high negative predictive values confirmed the concept validity. DISCUSSION: The WoRQ has suitable psychometric properties for use in a clinical trial for patients with a broad range of symptom severity. The scale may be applicable to assess therapeutic interventions. It is not intended to assess eligibility for supported work interventions. CONCLUSIONS: The WoRQ is suitable for use in schizophrenia clinical trials to assess patient work functional potential.

Long-term safety and tolerability of iloperidone: results from a 25-week, open-label extension trial.

INTRODUCTION/OBJECTIVE: Long-term use of the atypical antipsychotic iloperidone has not been investigated at doses above 16 mg/d. This article describes safety and tolerability results from the 25-week open-label extension of a 4-week placebo- and ziprasidone-controlled clinical trial of iloperidone. METHODS: Patients received a dose of 24 mg/d (given as 12 mg twice daily; mean dose = 21.6 mg) that could be reduced to 12 mg/d (given once daily at bedtime) any time after day 35 at the investigator's discretion. RESULTS: A total of 72/173 patients (41.6%) completed the open-label extension. Treatment-emergent adverse events (TEAEs), most mild to moderate in severity, included headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), and insomnia (5.2%). The only notable dose-related TEAEs were increased weight and headache. Levels of serum glucose, lipids, and prolactin were essentially unchanged or decreased during treatment. In general, akathisia and extrapyramidal symptoms (EPS) improved or were unchanged during treatment. There was no signal of worsening of efficacy based on changes from baseline in the Positive and Negative Syndrome Scale-Total. DISCUSSION/CONCLUSION: This study further supports the long-term safety and tolerability of iloperidone for the treatment of schizophrenia, including iloperidone's favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.

Women who marry men with alcohol-use disorders.

BACKGROUND: Women who marry men with alcohol-use disorders (AUDs) might have unique characteristics that could affect the clinical course of their partner's AUD and the risk for problems in the offspring. Most data available on spouses of such men come from subjects in treatment, which might bias results to more severely impaired individuals. Our data were gathered as part of a prospective study of an original sample of 453 sons of alcoholics and controls who were originally selected as students or nonacademic staff at a university. METHODS: Personal interviews were performed with 327 women who were married to men who had been personally evaluated on multiple occasions over the prior 15 years. The data compare characteristics of the 235 women (71.9%) whose husbands had never developed alcohol abuse and dependence with the 92 (28.1%) for whom these disorders had been documented. RESULTS: The women who married men with an AUD were less likely to be homemakers, were more likely to meet criteria for alcoholism (especially abuse) themselves, were more likely to report use of illicit substances, and to be current smokers. However, spouses of men with AUDs in this highly functional sample had no higher risk for other major psychiatric disorders and did not report a higher rate of alcohol abuse or dependence or psychiatric conditions in their parents. CONCLUSIONS: The results demonstrate increased risks for the use of illicit substances and for AUDs in women married to alcoholics, despite the overall high level of functioning of the sample. This information may be relevant to enhancing our understanding of the environment in which their offspring are being raised. The descriptive aspects of the work might also help researchers and clinicians working with alcoholic families.