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RationaleDisorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms.ObjectivesThis study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses.MethodsWe applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design. We compared seven models using a bridge sampling estimate of the marginal likelihood.ResultsStimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo). Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward). Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects.ConclusionsWe provide a parsimonious computational account of how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD. D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects.

Optimal adherence to pre-exposure prophylaxis (PrEP) is critical, but challenging. Men who have sex with men and transgender women have high rates of HIV incidence and substance use. Substance use is associated with reduced adherence to other medications, but associations between substance use and adherence to PrEP are less clear. Thus, the current review 1) systematically evaluates the measurement of substance use and PrEP adherence in studies examining both and 2) summarizes reported findings. Peer-reviewed articles published between 2010 - April 2021 examining associations between substance use and PrEP adherence were reviewed. Fifty studies met inclusion criteria. Assessment of substance use (i.e., mostly via self-reports at baseline) and PrEP adherence (i.e., often via tenofovir diphosphate [TFV-DP] concentration levels at follow-up) varied considerably across studies. Many studies used categorical variables (e.g., substance use: yes/no). Studies using TFV-DP levels defined adherence consistently (i.e., TFV-DP ≥ 700 fmol/punch), with slight variations. Qualitative studies (n = 10) indicated that substance use (mainly alcohol) is related to poorer PrEP adherence. While quantitative findings to date are equivocal for alcohol, there is a pattern of findings linking stimulant use with poorer PrEP adherence. This review reveals four methodological gaps, which can be addressed in future research by: 1) use of uniform benchmarks for substance use measures, 2) prospective assessment for substance use, 3) use of continuous outcome variables wherever possible, and 4) more extensive consideration of potential confounders. Addressing these methodological gaps may help us reach more definitive conclusions regarding associations between substance use and PrEP adherence.

Mobile health apps can serve as a critical tool in supporting the overall health of uninsured and underinsured individuals and groups who have been historically marginalized by the medical community and may be hesitant to seek health care. However, data on uptake and engagement with specific app features (eg, in-app messaging) are often lacking, limiting our ability to understand nuanced patterns of app use. This study aims to characterize sociodemographic differences in uptake and engagement with a smartphone app (uMAT-R) to support recovery efforts in a sample of individuals with opioid and stimulant use disorders in the Greater St. Louis area. We enrolled individuals into the uMAT-R service program from facilities providing recovery support in the Greater St. Louis area between January 2020 and April 2022. Study participants were recruited from service project enrollees. We describe the number of logins and electronic health coach (eCoach) messages participants sent in the first 30 days following enrollment using medians and IQRs and counts and proportions of those who ever (vs never) logged in and sent their eCoach a message. We compare estimates across sociodemographic subgroups, by insurance status, and for those who did and did not participate in the research component of the project using Wilcoxon rank-sum tests and Pearson chi-square tests. Of all 695 participants, 446 (64.2%) logged into uMAT-R at least once during the 30 days following enrollment (median 2, IQR 0-8 logins). Approximately half of those who logged in (227/446) used the eCoach messaging feature (median 1, IQR 0-3 messages). Research participants (n=498), who could receive incentives for app engagement, were more likely to log in and use the eCoach messaging feature compared to others (n=197). Younger individuals, those with higher educational attainment, and White, non-Hispanic individuals were more likely to log in at least once compared to their counterparts. The median number of logins was higher among women, and those who were younger, employed, and not on Medicaid compared to their counterparts. Among those who logged in at least once, younger individuals and those with lower educational attainment were more likely to send at least one eCoach message compared to others. Mobile apps are a viable tool for supporting individuals in recovery from opioid and stimulant use disorders. However, older individuals, racial and ethnic minorities, and those with lower educational attainment may need additional login support, or benefit from alternative mechanisms of recovery support. In addition, apps may need to be tailored to achieve sustained engagement (ie, repeat logins) among men, and individuals who are older, unemployed, or on Medicaid. Older individuals and those with higher educational attainment who may be less likely to use eCoach messaging features could benefit from features tailored to their preferences.

Background The treatment of methamphetamine dependence is a continuing global health problem. Agonist type pharmacotherapies have been used successfully to treat opioid and nicotine dependence and are being studied for the treatment of methamphetamine dependence. One potential candidate is lisdexamfetamine, a pro-drug for dexamphetamine, which has a longer lasting therapeutic action with a lowered abuse potential. The purpose of this study is to determine the safety of lisdexamfetamine in this population at doses higher than those currently approved for attention deficit hyperactivity disorder or binge eating disorder. Methods/design This is a phase 2 dose escalation study of lisdexamfetamine for the treatment of methamphetamine dependence. Twenty individuals seeking treatment for methamphetamine dependence will be recruited at two Australian drug and alcohol services. All participants will undergo a single-blinded ascending-descending dose regime of 100 to 250 mg lisdexamfetamine, dispensed daily on site, over an 8-week period. Participants will be offered counselling as standard care. For the primary objectives the outcome variables will be adverse events monitoring, drug tolerability and regimen completion. Secondary outcomes will be changes in methamphetamine use, craving, withdrawal, severity of dependence, risk behaviour and other substance use. Medication acceptability, potential for non-prescription use, adherence and changes in neurocognition will also be measured. Discussion Determining the safety of lisdexamfetamine will enable further research to develop pharmacotherapies for the treatment of methamphetamine dependence. Trial registration Australian and New Zealand Clinical Trials Registry ACTRN12615000391572 Registered 28 th April 2015.

Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality. Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity. We assessed the effects of anamorelin on body composition, strength, quality of life, biochemical markers, and safety in patients with cancer anorexia-cachexia. Data were pooled, a priori, from two completed phase 2, multicentre, placebo-controlled, double-blind trials in patients with advanced or incurable cancer and weight loss of 5% or more. Patients were stratified by weight loss severity (5–15%, >15%) and randomly allocated (1:1) with a computer-generated randomisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks. Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment. We assessed safety in all patients who received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT00219817 and NCT00267358. Between June 29, 2005, and Oct 26, 2006, we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group. 74 patients were eligible for the efficacy analyses. Over 12 weeks, lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1·89 kg (95% CI 0·84 to 2·95) compared with a decrease of a least-squares mean of −0·20 kg (−1·23 to 0·83) for 36 patients in the placebo group (difference 2·09 kg [0·94–3·25]; p=0·0006). 42 (95%) of 44 patients treated with anamorelin and 33 (87%) of 38 patients treated with placebo had adverse events. The most common grade 3–4 adverse events (treatment-related or not) in the anamorelin group were fatigue, asthenia, atrial fibrillation, and dyspnoea (two [5%] each); in the placebo group, such events were pneumonia (three [8%]) and anaemia, thrombocytopenia, abdominal pain, anxiety, and dyspnoea (two [5%] each). Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome. These findings support further investigation in this setting. Helsinn Therapeutics (US), Helsinn Healthcare SA.

Abuse of amphetamine-type stimulants (ATS) has become a global public health problem. ATS causes severe neurotoxicity, which could lead to addiction and could induce psychotic disorders or cognitive dysfunctions. However, until now, there has been a lack of effective medicines for treating ATS-related problems. Findings from recent studies indicate that in addition to the traditional dopamine-ergic system, the GABA (gamma-aminobutyric acid)-ergic system plays an important role in ATS abuse. However, the exact mechanisms of the GABA-ergic system in amphetamine-type stimulant use disorders are not fully understood. This review discusses the role of the GABA-ergic system in ATS use disorders, including ATS induced psychotic disorders and cognitive dysfunctions. We conclude that the GABA-ergic system are importantly involved in the development of ATS use disorders through multiple pathways, and that therapies or medicines that target specific members of the GABA-ergic system may be novel effective interventions for the treatment of ATS use disorders.

Background Amphetamine-type stimulant use and overdoses have increased sharply across the US in recent years, largely driven by methamphetamine. Increased access to treatments for amphetamine-type stimulant use disorder (AT-StUD), including in primary care settings, is needed to mitigate these problems, yet effective behavioral treatments are often inaccessible and there are no FDA-approved medications for AT-StUD. In the current study, we characterize how often patients with clinically documented AT-StUD in predominantly rural-serving Pacific Northwest primary care clinics received medications that have been conditionally recommended in practice guidelines for treatment of AT-StUD. Methods Electronic health record data from 23 primary care clinics in the Pacific Northwest US were obtained through the Data QUEST network. Adult patients with clinically documented “other stimulant abuse” or “other stimulant dependence” diagnoses typically reflecting AT-StUD between 01/2017 and 12/2021 were included. Prescription records were used to identify orders for bupropion, mirtazapine, topiramate, naltrexone-bupropion combination, methylphenidate, dextroamphetamine, and modafinil. Statistical analyses quantified the percentage of patients with medication orders placed within one year after any documented AT-StUD diagnosis. Results Patients (N = 963) were predominantly female (53.3%), White (81.7%), and non-Hispanic (70.5%). In total, 14.3% of patients received orders for a non-stimulant medication conditionally recommended in practice guidelines; 2.7% received orders for a stimulant medication. Consistent with clinical guidelines, medications were more often prescribed when patients had documented co-occurring disorders for which the medications could also be effective. Conclusions In this sample of rural-serving primary care clinics, approximately 1 in 7 primary care patients with AT-StUD received orders for medications with preliminary evidence of effectiveness. Efforts are needed to increase access to AT-StUD treatments within primary care. These efforts could include training health professionals to consider judicious use of pharmacotherapy consistent with clinical guidelines, increasing capacity for behavioral health services including contingency management, and continuing research on pharmacologic agents.

A previous report showed that the use of caffeine to treat apnea of prematurity reduces the risk of bronchopulmonary dysplasia, but whether it has long-term effects on neurodevelopment and growth is unknown. In this placebo-controlled, randomized trial, treatment with caffeine significantly improved the rate of survival without neurodevelopmental disability at 18 to 21 months. Treatment with caffeine significantly improved the rate of survival without neurodevelopmental disability at 18 to 21 months. Apnea of prematurity is one of the most common reasons for the initiation of drug therapy in neonatal medicine. 1 The methylxanthines — aminophylline, theophylline, and caffeine — have been administered to preterm infants as respiratory stimulants for more than 30 years. 2 Caffeine is presently one of the 10 most frequently prescribed medications in neonatal intensive care. 1 Despite their widespread use, caffeine and the other methylxanthines have been evaluated in only a few small, short-term studies. 3 – 5 It has been uncertain whether these drugs might adversely affect the development of the preterm brain and of other organs. Methylxanthines are inhibitors of . . .

Methylphenidate is a widely used and effective treatment for attention-deficit/hyperactivity disorder (ADHD), yet the underlying neural mechanisms and their relationship to changes in behavior are not fully understood. Specifically, it remains unclear how methylphenidate affects brain and behavioral dynamics, and the interplay between these dynamics, in individuals with ADHD. To address this gap, we used a novel Bayesian dynamical system model to investigate the effects of methylphenidate on latent brain states in 27 children with ADHD and 49 typically developing children using a double-blind, placebo-controlled crossover design. Methylphenidate remediated greater behavioral variability on a continuous performance task in children with ADHD. Children with ADHD exhibited aberrant latent brain state dynamics compared to typically developing children, with a single latent state showing particularly abnormal dynamics, which was remediated by methylphenidate. Additionally, children with ADHD showed brain state-dependent hyper-connectivity in the default mode network, which was also remediated by methylphenidate. Finally, we found that methylphenidate-induced changes in latent brain state dynamics, as well as brain state-related functional connectivity between salience and default mode networks, were correlated with improvements in behavioral variability. Taken together, our findings reveal a novel latent brain state dynamical process and circuit mechanism underlying the therapeutic effects of methylphenidate in childhood ADHD. We suggest that Bayesian dynamical system models may be particularly useful for capturing complex nonlinear changes in neural activity and behavioral variability associated with ADHD. Our approach may be of value to clinicians and researchers investigating the neural mechanisms underlying pharmacological treatment of psychiatric disorders.

Background and Objective Although there are several treatments for narcolepsy type 2 and idiopathic hypersomnia, studies that assess amphetamines, symptoms beyond sleepiness, and comparative effectiveness are needed. We performed a randomized, fully blinded, noninferiority trial of modafinil versus amphetamine–dextroamphetamine in these disorders. Methods Forty-four adults were randomized to modafinil or amphetamine–dextroamphetamine, individually titrated to a maximum of modafinil 200 mg twice daily or amphetamine–dextroamphetamine 20 mg twice daily, for 12 weeks. Primary outcome was change in Epworth from baseline to week 12, with a noninferiority threshold of 2 points. Secondary outcomes were (1) patient global impression of change measures of disease severity, sleepiness, sleep inertia, and cognition; (2) change from baseline in Hypersomnia Severity Index; and (3) change from baseline in Sleep Inertia Questionnaire. Adverse events were compared between groups. Results Epworth improved 5.0 [± standard deviation (SD) 2.7] points with modafinil and 4.4 (± SD 4.7) with amphetamine–dextroamphetamine; noninferiority of amphetamine–dextroamphetamine was not demonstrated ( P = 0.11). Noninferiority of amphetamine-dextroamphetamine was demonstrated for change scores of severity, sleepiness, sleep inertia, Hypersomnia Severity Index, and Sleep Inertia Questionnaire. Dropouts due to adverse events were 31.8% for modafinil (including two severe events) and 9.1% for amphetamine–dextroamphetamine, P = 0.13. Anxiety was more common with modafinil and appetite suppression with amphetamine-dextroamphetamine. Conclusion Noninferiority of amphetamine–dextroamphetamine to modafinil was not demonstrated for the primary outcome. However, amphetamine–dextroamphetamine was noninferior on multiple secondary measures of disease severity and symptomatology. These data may inform shared decision-making regarding treatment for idiopathic hypersomnia and narcolepsy type 2. Registration Clinicaltrials.gov Registration (NCT03772314) 12/10/18. .