Comorbid alcohol use disorder and posttraumatic stress disorder: A proof-of-concept randomized placebo-controlled trial of buprenorphine and naltrexone combination treatment.

BACKGROUND: Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ-opioid antagonist and a partial agonist of mu (µ) opioid receptors. Whereas naltrexone blocks all µ-mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no κ-opioid receptor antagonist it available for clinical use, we tested this combination in a proof-of-concept study. METHODS: Consenting participants were enrolled in a Phase II, multisite, double-blind, randomized, placebo-controlled trial evaluating the effectiveness of sublingual (SL) buprenorphine combined with extended-release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (n = 75) were randomized (1:1:1) to receive either buprenorphine 2 mg/day plus naltrexone-XR (n = 35), buprenorphine 8 mg/day plus naltrexone-XR (n = 6) or SL plus injectable placebo (n = 34) for 12 weeks. The buprenorphine 8 mg/day plus naltrexone-XR arm was dropped early in the trial due to the negative impact of COVID-19 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of ≥10 points on the past week Clinician-Administered PTSD Scale (CAPS-5) and a reduction of ≥1 of past month alcohol risk level, as defined by the World Health Organization (WHO) and measured by the Timeline Follow-Back. RESULTS: Based on the results of a futility analysis, enrollment was stopped prior to reaching the initial goal of 90 participants. At the week eight primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone-XR and placebo group for the primary composite outcome (OR = 0.63; p-value = 0.52), or the subcomponents of the PTSD outcome (OR = 0.76; p-value = 0.69) and AUD outcome (OR = 0.17; p-value = 0.08). The placebo arm had a significantly higher proportion of participants with ≥1 WHO risk level reduction than the buprenorphine plus naltrexone-XR arm (OR = 0.18, p value = 0.02). CONCLUSIONS: This is the first study to evaluate the potential of κ-opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone-XR showed no significant improvement over placebo for the composite, PTSD, or alcohol measures.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Characteristics of U.S. Veteran Patients with Major Depressive Disorder who require "next-step" treatments: A VAST-D report.

OBJECTIVE: Finding effective and lasting treatments for patients with Major Depressive Disorder (MDD) that fail to respond optimally to initial standard treatment is a critical public health imperative. Understanding the nature and characteristics of patients prior to initiating "next-step" treatment is an important component of identifying which specific treatments are best suited for individual patients. We describe clinical features and demographic characteristics of a sample of Veterans who enrolled in a "next-step" clinical trial after failing to achieve an optimal outcome from at least one well-delivered antidepressant trial. METHODS: 1522 Veteran outpatients with nonpsychotic MDD completed assessments prior to being randomized to study treatment. Data is summarized and presented in terms of demographic, social, historical and clinical features and compared to a similar, non-Veteran sample. RESULTS: Participants were largely male and white, with about half unmarried and half unemployed. They were moderately severely depressed, with about one-third reporting recent suicidal ideation. More than half had chronic and/or recurrent depression. General medical and psychiatric comorbidities were highly prevalent, particularly PTSD. Many had histories of childhood adversity and bereavement. Participants were impaired in multiple domains of their lives and had negative self-worth. LIMITATIONS: These results may not be generalizable to females, and some characteristics may be specific to Veterans of US military service. There was insufficient data on age of clinical onset and depression subtypes, and three novel measures were not psychometrically validated. CONCLUSIONS: Characterizing VAST-D participants provides important information to help clinicians understand features that may optimize "next-step" MDD treatments.

Prescribing in prison: minimizing psychotropic drug diversion in correctional practice.

Correctional facilities are a major provider of mental health care throughout the United States. In spite of the numerous benefits of providing care in this setting, clinicians are sometimes concerned about entering into correctional care because of uncertainty in prescribing practices. This article provides an introduction to prescription drug use, abuse, and diversion in the correctional setting, including systems issues in prescribing, commonly abused prescription medications, motivation for and detection of prescription drug abuse, and the use of laboratory monitoring. By understanding the personal and systemic factors that affect prescribing habits, the clinician can develop a more rewarding correctional practice and improve care for inmates with mental illness.