The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

A fatal case of bupropion (Zyban) hepatotoxicity with autoimmune features: Case report

<p>Abstract</p> <p>Background</p> <p>Bupropion is approved for the treatment of mood disorders and as an adjuvant medication for smoking cessation. Bupropion is generally well tolerated and considered safe. Two randomized controlled trials of bupropion therapy for smoking cessation did not report any hepatic adverse events. However, there are three reports of severe but non-fatal bupropion hepatotoxicity published in the literature.</p> <p>Case Presentation</p> <p>We present the case of a 55-year old man who presented with jaundice and severe hepatic injury approximately 6 months after starting bupropion for smoking cessation. Laboratory evaluation demonstrated a mixed picture of hepatocellular injury and cholestasis. Liver biopsy demonstrated findings consistent with severe hepatotoxic injury due to drug induced liver injury. Laboratory testing was also notable for positive autoimmune markers. The patient initially had clinical improvement with steroid therapy but eventually died of infectious complications.</p> <p>Conclusion</p> <p>This report represents the first fatal report of bupropion related hepatotoxicity and the second case of bupropion related liver injury demonstrating autoimmune features. The common use of this medication for multiple indications makes it important for physicians to consider this medication as an etiologic agent in patients with otherwise unexplained hepatocellular jaundice.</p

Alcohol Consumption Among Older Adults in Primary Care

BACKGROUND: Alcohol misuse is a growing public health concern for older adults, particularly among primary care patients. OBJECTIVES: To determine alcohol consumption patterns and the characteristics associated with at-risk drinking in a large sample of elderly primary care patients. DESIGN: Cross-sectional analysis of multisite screening data from 6 VA Medical Centers, 2 hospital-based health care networks, and 3 Community Health Centers. PARTICIPANTS: Patients, 43,606, aged 65 to 103 years, with scheduled primary care appointments were approached for screening; 27,714 (63.6%) consented to be screened. The final sample of persons with completed screens comprised 24,863 patients. MEASUREMENTS: Quantity and frequency of alcohol use, demographics, social support measures, and measures of depression/anxiety. RESULTS: Of the 24,863 older adults screened, 70.0% reported no consumption of alcohol in the past year, 21.5% were moderate drinkers (1–7 drinks/week), 4.1% were at-risk drinkers (8–14 drinks/week), and 4.5% were heavy (>14 drinks/week) or binge drinkers. Heavy drinking showed significant positive association with depressive/anxiety symptoms [Odds ratio (OR) (95% CI): 1.79 (1.30, 2.45)] and less social support [OR (95% CI): 2.01 (1.14, 2.56)]. Heavy drinking combined with binging was similarly positively associated with depressive/anxiety symptoms [OR (95%): 1.70 (1.33, 2.17)] and perceived poor health [OR (95% CI): 1.27 (1.03, 1.57)], while at-risk drinking was not associated with any of these variables. CONCLUSIONS: The majority of participants were nondrinkers; among alcohol users, at-risk drinkers did not differ significantly from moderate drinkers in their characteristics or for the 3 health parameters evaluated. In contrast, heavy drinking was associated with depression and anxiety and less social support, and heavy drinking combined with binge drinking was associated with depressive/anxiety symptoms and perceived poor health

Integration of priority population, health and nutrition interventions into health systems: systematic review

Objective of the study was to assess the effects of strategies to integrate targeted priority population, health and nutrition interventions into health systems on patient health outcomes and health system effectiveness and thus to compare integrated and non-integrated health programmes. Systematic review using Cochrane methodology of analysing randomised trials, controlled before-and-after and interrupted time series studies. We defined specific strategies to search PubMed, CENTRAL and the Cochrane Effective Practice and Organisation of Care Group register, considered studies published from January 1998 until September 2008, and tracked references and citations. Two reviewers independently agreed on eligibility, with an additional arbiter as needed, and extracted information on outcomes: primary (improved health, financial protection, and user satisfaction) and secondary (improved population coverage, access to health services, efficiency, and quality) using standardised, pre-piloted forms. Two reviewers in the final stage of selection jointly assessed quality of all selected studies using the GRADE criteria. Of 8,274 citations identified 12 studies met inclusion criteria. Four studies compared the benefits of Integrated Management of Childhood Illnesses in Tanzania and Bangladesh, showing improved care management and higher utilisation of health facilities at no additional cost. Eight studies focused on integrated delivery of mental health and substance abuse services in the United Kingdom and United States of America. Integrated service delivery resulted in better clinical outcomes and greater reduction of substance abuse in specific sub-groups of patients, with no significant difference found overall. Quality of care, patient satisfaction, and treatment engagement were higher in integrated delivery models. Targeted priority population health interventions we identified led to improved health outcomes, quality of care, patient satisfaction and access to care. Limited evidence with inconsistent findings across varied interventions in different settings means no general conclusions can be drawn on the benefits or disadvantages of integrated service delivery

A qualitative study of service provision for alcohol related health issues in mid to later life

AIMS:Epidemiological surveys over the last 20 years show a steady increase in the amount of alcohol consumed by older age groups. Physiological changes and an increased likelihood of health problems and medication use make older people more likely than younger age groups to suffer negative consequences of alcohol consumption, often at lower levels. However, health services targeting excessive drinking tend to be aimed at younger age groups. The aim of this study was to gain an in-depth understanding of experiences of, and attitudes towards, support for alcohol related health issues in people aged 50 and over. METHODS:Qualitative interviews (n = 24, 12 male/12 female, ages 51-90 years) and focus groups (n = 27, 6 male/21 female, ages 50-95 years) were carried out with a purposive sample of participants who consumed alcohol or had been dependent. FINDINGS:Participants' alcohol misuse was often covert, isolated and carefully regulated. Participants tended to look first to their General Practitioner for help with alcohol. Detoxification courses had been found effective for dependent participants but only in the short term; rehabilitation facilities were appreciated but seen as difficult to access. Activities, informal groups and drop-in centres were endorsed. It was seen as difficult to secure treatment for alcohol and mental health problems together. Barriers to seeking help included functioning at a high level, concern about losing positive aspects of drinking, perceived stigma, service orientation to younger people, and fatalistic attitudes to help-seeking. Facilitators included concern about risk of fatal illness or pressure from significant people. CONCLUSION:Primary care professionals need training on improving the detection and treatment of alcohol problems among older people. There is also a compelling need to ensure that aftercare is in place to prevent relapse. Strong preferences were expressed for support to be provided by those who had experienced alcohol problems themselves

Telephone Cognitive-Behavioral Therapy for Subthreshold Depression and Presenteeism in Workplace: A Randomized Controlled Trial

Subthreshold depression is highly prevalent in the general population and causes great loss to society especially in the form of reduced productivity while at work (presenteeism). We developed a highly-structured manualized eight-session cognitive-behavioral program with a focus on subthreshold depression in the workplace and to be administered via telephone by trained psychotherapists (tCBT).We conducted a parallel-group, non-blinded randomized controlled trial of tCBT in addition to the pre-existing Employee Assistance Program (EAP) versus EAP alone among workers with subthreshold depression at a large manufacturing company in Japan. The primary outcomes were depression severity as measured with Beck Depression Inventory-II (BDI-II) and presenteeism as measured with World Health Organization Health and Work Productivity Questionnaire (HPQ). In the course of the trial the follow-up period was shortened in order to increase acceptability of the study.The planned sample size was 108 per arm but the trial was stopped early due to low accrual. Altogether 118 subjects were randomized to tCBT+EAP (n = 58) and to EAP alone (n = 60). The BDI-II scores fell from the mean of 17.3 at baseline to 11.0 in the intervention group and to 15.7 in the control group after 4 months (p<0.001, Effect size = 0.69, 95%CI: 0.32 to 1.05). However, there was no statistically significant decrease in absolute and relative presenteeism (p = 0.44, ES = 0.15, -0.21 to 0.52, and p = 0.50, ES = 0.02, -0.34 to 0.39, respectively).Remote CBT, including tCBT, may provide easy access to quality-assured effective psychotherapy for people in the work force who present with subthreshold depression. Further studies are needed to evaluate the effectiveness of this approach in longer terms. The study was funded by Sekisui Chemicals Co. Ltd.ClinicalTrials.gov NCT00885014

Relapse prevention for addictive behaviors

The Relapse Prevention (RP) model has been a mainstay of addictions theory and treatment since its introduction three decades ago. This paper provides an overview and update of RP for addictive behaviors with a focus on developments over the last decade (2000-2010). Major treatment outcome studies and meta-analyses are summarized, as are selected empirical findings relevant to the tenets of the RP model. Notable advances in RP in the last decade include the introduction of a reformulated cognitive-behavioral model of relapse, the application of advanced statistical methods to model relapse in large randomized trials, and the development of mindfulness-based relapse prevention. We also review the emergent literature on genetic correlates of relapse following pharmacological and behavioral treatments. The continued influence of RP is evidenced by its integration in most cognitive-behavioral substance use interventions. However, the tendency to subsume RP within other treatment modalities has posed a barrier to systematic evaluation of the RP model. Overall, RP remains an influential cognitive-behavioral framework that can inform both theoretical and clinical approaches to understanding and facilitating behavior change

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders