[Posted 2/Jun/2023]

AUDIENCE: Psychiatry, Family Medicine

DETAILS: Today, the U.S. Food and Drug Administration approved Brixadi (buprenorphine) extended-release injection for subcutaneous use (under the skin) to treat moderate to severe opioid use disorder (OUD). Brixadi is available in two formulations, a weekly injection that can be used in patients who have started treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine, and a monthly version for patients already being treated with buprenorphine.

“Buprenorphine is an important treatment option for opioid use disorder. Today’s approval expands dosing options and provides people with opioid use disorder a greater opportunity to sustain long-term recovery,” said FDA Commissioner Robert M. Califf, M.D. “The FDA will continue to take the critical steps necessary to pursue efforts that advance evidence-based treatments for substance use disorders, which is a strategic priority under the FDA’s Overdose Prevention Framework.”

Buprenorphine is a safe and effective medication for the treatment of OUD. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), patients receiving medication for their OUD cut their risk of death from all causes in half.

The FDA continues to implement a comprehensive approach to increase options to treat OUD. Earlier this month, the agency issued a joint letter with SAMHSA to clarify the importance of counseling and other services as part of a comprehensive treatment plan for OUD, and to also reiterate that supplying buprenorphine should not be made contingent upon participation in such services. The agency also held a virtual public workshop that highlighted the need for additional strengths and dosing regimens for extended-release formulations.

Brixadi is approved in both weekly and monthly subcutaneous injectable formulations at varying doses, including lower doses that may be appropriate for those who do not tolerate higher doses of extended-release buprenorphine that are currently available. The weekly doses are 8 milligrams (mg), 16 mg, 24 mg, 32 mg; and the monthly doses are 64 mg, 96 mg, 128 mg. The approved weekly formulation in various lower strengths offers a new option for people in recovery who may benefit from a weekly injection to maintain treatment adherence. Brixadi will be available through a Risk Evaluation and Mitigation Strategy (REMS) program and administered only by health care providers in a health care setting.

The most common adverse reactions (occurring in >=5% of patients) with Brixadi include injection-site pain, headache, constipation, nausea, injection-site erythema, itchy skin at the injection site (injection-site pruritus), insomnia and urinary tract infections.

The safety and efficacy of Brixadi were evaluated in a behavioral pharmacology study assessing the ability of two weekly doses of Brixadi to block the subjective effects of opioids, and one randomized, double-blind, active-controlled clinical trial in 428 adults with a diagnosis of moderate-to-severe OUD. After an initial test dose of transmucosal buprenorphine, patients were randomized to treatment with Brixadi plus a sublingual placebo, or active sublingual buprenorphine plus placebo injections. After titration over the first week, patients were treated with weekly injections over 12 weeks and then transitioned to monthly injections for an additional 12 weeks. A response to treatment was measured by urine drug screening and self-reporting of illicit opioid use during the treatment period. Patients were considered responders if they had negative opioid assessments at the end of each of the two treatment phases. The proportion of patients meeting the responder definition was 16.9% in the Brixadi group and 14.0% in the sublingual buprenorphine group.

The FDA granted approval of Brixadi to Braeburn Inc.

The agency remains focused on responding to all facets of substance use, misuse, substance use disorders, overdose and death in the U.S. through its FDA Overdose Prevention Framework. The framework’s priorities include: supporting primary prevention by eliminating unnecessary initial prescription drug exposure and inappropriate prolonged prescribing; encouraging harm reduction through innovation and education; advancing development of evidence-based treatments for substance use disorders; and protecting the public from unapproved, diverted or counterfeit drugs presenting overdose risks.

Copyright © FDA. All rights reserved.

Source: FDA Approves New Buprenorphine Treatment Option for Opioid Use Disorder. FDA. Published: May 23, 2023.

A Randomized Clinical Trial

[Posted 26/Aug/2024]

AUDIENCE: Psychiatry, Family Medicine

KEY FINDINGS: Xanomeline-trospium was efficacious and well tolerated in people with schizophrenia experiencing acute psychosis. These findings, together with the previously reported and consistent results from the EMERGENT-1 and EMERGENT-2 trials, support the potential of xanomeline-trospium to be the first in a putative new class of antipsychotic medications without D2 dopamine receptor blocking activity.

BACKGROUND: A significant need exists for new antipsychotic medications with different mechanisms of action, greater efficacy, and better tolerability than existing agents. Xanomeline is a dual M1/M4 preferring muscarinic receptor agonist with no direct D2 dopamine receptor blocking activity. KarXT combines xanomeline with the peripheral muscarinic receptor antagonist trospium chloride with the goal of reducing adverse events due to xanomeline-related peripheral muscarinic receptor activation. In prior trials, xanomeline-trospium chloride was effective in reducing symptoms of psychosis and generally well tolerated in people with schizophrenia. Purpose of this study is to evaluate the efficacy and safety of xanomeline-trospium vs placebo in adults with schizophrenia.

DETAILS: EMERGENT-3 (NCT04738123) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 5-week trial of xanomeline-trospium in people with schizophrenia experiencing acute psychosis, conducted between April 1, 2021, and December 7, 2022, at 30 inpatient sites in the US and Ukraine. Data were analyzed from February to June 2023. Participants were randomized 1:1 to receive xanomeline-trospium chloride (maximum dose xanomeline 125 mg/trospium 30 mg) or placebo for 5 weeks. The prespecified primary end point was change from baseline to week 5 in Positive and Negative Syndrome Scale (PANSS) total score. Secondary outcome measures were change from baseline to week 5 in PANSS positive subscale score, PANSS negative subscale score, PANSS Marder negative factor score, Clinical Global Impression-Severity score, and proportion of participants with at least a 30% reduction in PANSS total score. Safety and tolerability were also evaluated. A total of 256 participants (mean [SD] age, 43.1 [11.8] years; 191 men [74.6%]; 156 of 256 participants [60.9%] were Black or African American, 98 [38.3%] were White, and 1 [0.4%] was Asian) were randomized (125 in xanomeline-trospium group and 131 in placebo group). At week 5, xanomeline-trospium significantly reduced PANSS total score compared with placebo (xanomeline-trospium , -20.6; placebo, -12.2; least squares mean difference, -8.4; 95% CI, -12.4 to -4.3; P < .001; Cohen d effect size, 0.60). Discontinuation rates due to treatment-emergent adverse events (TEAEs) were similar between the xanomeline-trospium (8 participants [6.4%]) and placebo (7 participants [5.5%]) groups. The most common TEAEs in the xanomeline-trospium vs placebo group were nausea (24 participants [19.2%] vs 2 participants [1.6%]), dyspepsia (20 participants [16.0%] vs 2 participants [1.6%]), vomiting (20 participants [16.0%] vs 1 participant [0.8%]), and constipation (16 participants [12.8%] vs 5 participants [3.9%]). Measures of extrapyramidal symptoms, weight gain, and somnolence were similar between treatment groups.

Copyright © American Medical Association. All Rights Reserved.

Source: Kaul, I., Sawchak, S., Walling, D. P., et al. (2024). Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry. 2024; 81(8): 749-756. Published: August, 2024. DOI: 10.1001/jamapsychiatry.2024.0785.

A Stage 2 Registered Report

[Posted 7/Aug/2024]

AUDIENCE: Psychiatry, Family Medicine

KEY FINDINGS: The results indicated AVGs showed superior spatial working memory and complex attention abilities while showing no difference from NGs on simple attention performance. Additionally, authors found that our cognitive fatigue and control interventions did not differentially affect the cognitive performance of AVGs and NGs in this study. This pre-registered study provides evidence that AVGs show superior cognitive abilities in comparison to a non-gaming population, but do not appear more resilient to cognitive fatigue.

BACKGROUND:

DETAILS: Recent work demonstrates that those who regularly play action video games (AVGs) consistently outperform non-gamer (NG) controls on tests of various cognitive abilities. AVGs place high demands on several cognitive functions and are often engaged with for long periods of time (e.g., over 2 h), predisposing players to experiencing cognitive fatigue. The detrimental effects of cognitive fatigue have been widely studied in various contexts where accurate performance is crucial, including aviation, military, and sport. Even though AVG players may be prone to experiencing cognitive fatigue, this topic has received little research attention to date. In this study, authors compared the effect of a cognitively fatiguing task on the subsequent cognitive performance of action video game players and NG control participants.

Copyright © The British Psychological Society. All rights reserved.

Source: Campbell, M. J., Cregan, S. C., Joyce, J. M., et al. (2024). Comparing the Cognitive Performance of Action Video Game Players and Age-Matched Controls Following a Cognitively Fatiguing Task: A Stage 2 Registered Report. Br. J. Psychol. 2024; 115(3): 363-385. Published: August, 2024. DOI: 10.1111/bjop.12692.

A Systematic Review With Meta-Regression Analyses

[Posted 3/Jun/2024]

AUDIENCE: Psychiatry, Ob/gyn

KEY FINDINGS: Prison services worldwide, and particularly in Europe, should prioritise suicide prevention. Assessment and management of suicide risk in female individuals living in prison need particular attention due to excess mortality relative to community-based populations. Interpretation of synthesised data needs to be done with caution due to high heterogeneity between jurisdictions.

BACKGROUND: Suicide is a leading cause of death during imprisonment. This systematic review aimed to synthesise available evidence of prison suicide incidence worldwide.

DETAILS: Authors systematically searched the scientific literature, data repositories, and prison system reports, supplemented by correspondence with prison administrations. Authors included reports on people living in prison but excluded studies in preselected groups (by age or offence type). Absolute numbers and incidence rates of suicide mortality per 100,000 person-years by sex and country were extracted from 2000 to 2021. IQRs were used to describe the suicide incidence in different world regions. Incidence rate ratios comparing suicides of people living in prison with age-standardised general populations were calculated. Authors conducted meta-regression analyses on national-level and prison-level factors to examine heterogeneity. Authors included three scientific studies, 124 official reports, and 11 datasets from email correspondence. Between 2000 and 2021, there were 29,711 reported suicides during 91.2 million person-years of imprisonment in 82 jurisdictions worldwide (sex-specific data available for 13,289 individuals: 12,544 [94.4%] male and 745 [5.6%] female individuals). There were large variations between countries, with most studies reporting suicide rates in the range of 24-89 per 100,000 person-years in both sexes (22-86 in male individuals and 25-107 in female individuals). In meta-regression analyses, Europe (vs other regions), high-income countries (vs low-income and middle-income countries), and countries with lower incarceration rates (vs those with higher incarceration rates) had higher suicide rates. Incidence rate ratios between people who are incarcerated and age-standardised general populations in the same jurisdictions were typically in the range of 1.9-6.0 in male and 10.4-32.4 in female individuals.

Copyright © Elsevier Ltd. All rights reserved.

Source: Mundt, A. P., Cifuentes-Gramajo, P. A., Baranyi, G. et al. (2024). Worldwide Incidence of Suicides in Prison: A Systematic Review With Meta-Regression Analyses. The Lancet. 2024; Published: May 29, 2024. DOI: 10.1016/S2215-0366(24)00134-2.

[Posted 1/Apr/2024]

AUDIENCE: Neurology, Internal Medicine

KEY FINDINGS: GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a highly efficacious treatment for cervical dystonia, but its mechanism of action is not fully understood. Here, we investigate the brain metabolic effects of GPi-DBS in cervical dystonia.

DETAILS: Eleven patients with GPi-DBS underwent brain 18F-fluorodeoxyglucose positron emission tomography imaging during stimulation on and off. Changes in regional brain glucose metabolism were investigated at the active contact location and across the whole brain. Changes in motor symptom severity were quantified using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), executive function using trail making test (TMT) and parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS). The mean (SD) best therapeutic response to DBS during the treatment was 81 (22)%. The TWSTRS score was 3.2 (3.9) points lower DBS on compared with off (p=0.02). At the stimulation site, stimulation was associated with increased metabolism, which correlated with DBS stimulation amplitude (r=0.70, p=0.03) but not with changes in motor symptom severity (p>0.9). In the whole brain analysis, stimulation increased metabolism in the GPi, subthalamic nucleus, putamen, primary sensorimotor cortex (PFDR0.05). Acute improvement in TWSTRS correlated with metabolic activation in the sensorimotor cortex and overall treatment response in the supplementary motor area. Worsening of TMT-B score was associated with activation of the anterior cingulate cortex and parkinsonism with activation in the putamen.

Copyright © BMJ Publishing Group Ltd. All rights reserved.

Source: Honkanen E. A., Rönkä J., Pekkonen E., et al. (2024). GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia. Journal of Neurology, Neurosurgery & Psychiatry. 2024; 95(4): 300-308. Published: April, 2024. DOI: 10.1136/jnnp-2023-331668.

[Posted 12/Mar/2024]

AUDIENCE: Nursing

KEY FINDINGS: Making Time for Exercise Self-efficacy was more significant than Resisting Relapse for both physical function and functional exercise capacity. Interventions to promote achievement of physical activity need to use multiple measurement strategies.

BACKGROUND: Objective of this study is to determine if there were differences between the subjective and objective assessments of physical activity while controlling for sociodemographic, anthropometric, and clinical characteristics. A total of 810 participants across eight sites located in three countries. Both univariate and multivariant analyses were used.

DETAILS: Subjective instruments were the two subscales of Self-efficacy for Exercise Behaviors Scale: Making Time for Exercise and Resisting Relapse and Patient-Reported Outcomes Measurement Information System, which measured physical function. The objective measure of functional exercise capacity was the 6-minute Walk. Physical function was significantly associated with Making Time for Exercise (β = 1.76, p = .039) but not with Resisting Relapse (β = 1.16, p = .168). Age (β = -1.88, p = .001), being employed (β = 16.19, p < .001) and race (βs = 13.84–31.98, p < .001), hip–waist ratio (β = -2.18, p < .001), and comorbidities (β = 7.31, p < .001) were significant predictors of physical functioning. The model predicting physical function accounted for a large amount of variance (adjusted R2 = .938). The patterns of results predicting functional exercise capacity were similar. Making Time for Exercise self-efficacy scores significantly predicted functional exercise capacity (β = 0.14, p = .029), and Resisting Relapse scores again did not (β = -0.10, p = .120). Among the covariates, age (β = -0.16, p < .001), gender (β = -0.43, p < .001), education (β = 0.08, p = .026), and hip–waist ratio (β = 0.09, p = .034) were significant. This model did not account for much of the overall variance in the data (adjusted R2 = .081). We found a modest significant relationship between physical function and functional exercise capacity (r = 0.27).

Copyright © SAGE Publications. All rights reserved.

Source: Nokes, K. M., Sokhela, D. G., Orton, P, M., et al. (2024). Exploring the Interrelationships Between Physical Function, Functional Exercise Capacity, and Exercise Self-Efficacy in Persons Living with HIV. XXXXXXXX. 2024; 33(2-3): 165-175. Published: March, 2024. DOI: 10.1177/10547738241231626.