David J. McCann

A novel, nonbinary evaluation of success and failure reveals bupropion efficacy versus methamphetamine dependence: reanalysis of a multisite trial.

A multisite, double‐blind, placebo‐controlled trial of bupropion for methamphetamine dependence was reanalyzed using a novel, nonbinary method of evaluating success and failure. The original analysis focused on a group response endpoint (the change in percentage of participants with methamphetamine‐free urines each week over the course of the trial) and no significant bupropion effect was observed in the total population of study participants. In this reanalysis, individual participants were regarded as treatment success if they achieved multiple weeks of abstinence lasting through the end of the study, and their degree of success was quantified by calculating the number of beyond‐threshold weeks of success (NOBWOS). Thus, setting the threshold at 1 week of end‐of‐study abstinence (EOSA), treatment successes were assigned NOBWOS values ranging from 1 to 11, with 1 corresponding to 2 weeks EOSA and 11 corresponding to abstinence throughput the entire 12‐week trial. Treatment failures were assigned a value of 0. Comparison of NOBWOS values revealed a significant effect of bupropion to facilitate abstinence (P= 0.0176). In the bupropion group, 20% of participants achieved 2 or more weeks EOSA, 14% achieved 6 or more weeks EOSA, and 6% were abstinent throughout the trial; this compares with 7%, 4%, and 1% in the placebo group, respectively. On the basis of the NOBWOS analysis, bupropion seems to effectively facilitate the achievement of abstinence in methamphetamine‐dependent individuals.

Haloperidol competitively inhibits the binding of (+)-[3H]SKF-10,047 to σ sites

Scatchard plots of equilibrium saturation binding data revealed that haloperidol inhibits the binding of (+)-[3H]SKF-10,047 to σ sites in a competitive manner. In experiments using membranes from both guinea pig and rat brain the apparent Kd of (+)-[3H]SKF-10,047 for σ sites was significantly increased, whereas the apparent Bmax was not altered by the addition of 10 nM haloperidol.

Change in non-abstinent WHO drinking risk levels and alcohol dependence: a 3 year follow-up study in the US general population

BACKGROUND Alcohol dependence is often untreated. Although abstinence is often the aim of treatment, many drinkers prefer drinking reduction goals. Therefore, if supported by evidence of benefit, drinking reduction goals could broaden the appeal of treatment. Regulatory agencies are considering non-abstinent outcomes as efficacy indicators in clinical trials, including reduction in WHO drinking risk levels-very high, high, moderate, and low-defined in terms of mean ethanol consumption (in grams) per day. We aimed to study the relationship between reductions in WHO drinking risk levels and subsequent reduction in the risk of alcohol dependence. METHODS In this population-based cohort study, we included data from 22 005 drinkers who were interviewed in 2001-02 (Wave 1) and re-interviewed 3 years later (2004-05; Wave 2) in the US National Epidemiologic Survey on Alcohol and Related Conditions. Alcohol consumption (WHO drinking risk levels) and alcohol dependence (at least three of seven DSM-IV criteria in the previous 12 months) were assessed at both waves. We used logistic regression to test the relationship between change in WHO drinking risk levels between Waves 1 and 2, and alcohol dependence at Wave 2. FINDINGS At Wave 1, 2·5% (weighted proportion) of the respondents were very-high-risk drinkers, 2·5% were high-risk drinkers, 4·8% were moderate-risk drinkers, and most (90·2%) were low-risk drinkers. Reduction in WHO drinking risk level predicted significantly lower odds of alcohol dependence at Wave 2, particularly among very-high-risk drinkers (adjusted odds ratios 0·27 [95% CI 0·18-0·41] for reduction by one level, 0·17 [0·10-0·27] for two levels, and 0·07 [0·05-0·10] for three levels) and high-risk drinkers (0·64 [0·54-0·75] for one level and 0·12 [0·09-0·15] for two levels), and among those with alcohol dependence at Wave 1 (0·29 [0·15-0·57] for one level, 0·06 [0·04-0·10] for two levels, and 0·04 [0·03-0·06] for three levels in very-high-risk drinkers). INTERPRETATION Our results support the use of reductions in WHO drinking risk levels as an efficacy outcome in clinical trials. Because these risk levels can be readily translated into standard drink equivalents per day of different countries, the WHO risk levels could also be used internationally to guide treatment goals and clinical recommendations on drinking reduction. FUNDING US National Institute on Alcohol Abuse and Alcoholism, New York State Psychiatric Institute, the Alcohol Clinical Trials Initiative.

Mitigating the Effects of Nonadherence in Clinical Trials.

Accounting for subject nonadherence and eliminating inappropriate subjects in clinical trials are critical elements of a successful study. Nonadherence can increase variance, lower study power, and reduce the magnitude of treatment effects. Inappropriate subjects (including those who do not have the illness under study, fail to report exclusionary conditions, falsely report medication adherence, or participate in concurrent trials) confound safety and efficacy signals. This paper, a product of the International Society for CNS Clinical Trial Methodology (ISCTM) Working Group on Nonadherence in Clinical Trials, explores and models nonadherence in clinical trials and puts forth specific recommendations to identify and mitigate its negative effects. These include statistical analyses of nonadherence data, novel protocol design, and the use of biomarkers, subject registries, and/or medication adherence technologies.

Measures of outcome for stimulant trials: ACTTION recommendations and research agenda.

BACKGROUND The development and approval of an efficacious pharmacotherapy for stimulant use disorders has been limited by the lack of a meaningful indicator of treatment success, other than sustained abstinence. METHODS In March, 2015, a meeting sponsored by Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) was convened to discuss the current state of the evidence regarding meaningful outcome measures in clinical trials for stimulant use disorders. Attendees included members of academia, funding and regulatory agencies, pharmaceutical companies, and healthcare organizations. The goal was to establish a research agenda for the development of a meaningful outcome measure that may be used as an endpoint in clinical trials for stimulant use disorders. RESULTS AND CONCLUSIONS Based on guidelines for the selection of clinical trial endpoints, the lessons learned from prior addiction clinical trials, and the process that led to identification of a meaningful indicator of treatment success for alcohol use disorders, several recommendations for future research were generated. These include a focus on the validation of patient reported outcome measures of functioning, the exploration of patterns of stimulant abstinence that may be associated with physical and/or psychosocial benefits, the role of urine testing for validating self-reported measures of stimulant abstinence, and the operational definitions for reduction-based measures in terms of frequency rather than quantity of stimulant use. These recommendations may be useful for secondary analyses of clinical trial data, and in the design of future clinical trials that may help establish a meaningful indicator of treatment success.

An absence of changes in σ receptor subtypes in the brains of genetically dystonic (dt) rats

Binding sites for the σ ligand [3H]di-o-tollylguanidine [3H]DTG) have been reported to be altered in the brains of genetically dystonic rats. In the present study, selective σ1 and σ2 assay conditions were utilized in an effort to define which subpopulation of [3H]DTG binding sites is altered in the dystonic strain (dt). Both this approach and a re-examination using conditions similar to the previous report failed to confirm a difference between the brains of dystonic and normal rats in terms of σ binding. Although not directly negating the possible involvement of σ receptors in dystonia, these results indicate that σ1 and σ2 receptors appear unchanged in dystonic rats.

Tris inhibits (+)-[3H]SKF-10,047 binding to σ receptors

Abstract Tris-HCl is the most commonly used buffer in studies of radioligand binding to σ receptors, with concentrations as high as 50 or 100 mM often used. We report here that these concentrations of Tris substantially inhibit (+)-[ 3 H]SKF-10,047 binding to σ receptors. The well-established inhibitory effect of Tris-HCl on ligand binding to PCP receptors did not contribute to the presently reported inhibition of (+)-[ 3 H]SKF-10,047 binding. The IC 50 of Tris, determined in the presence of 10 mM potassium phosphate buffer, was 15.4±1.2 mM ( n =3, pH 8.0, 25°C, 1 nM radioligand). Equilibrium saturation studies revealed an apparent competitive inhibition of binding.

Drug Discovery and Development for Reward Disorders: Views from Government

Publisher Summary This chapter discusses governments outlook in the drug discovery and development for reward disorders. The National Institute on Drug Abuse (NIDA) is the worlds largest research institution dedicated to funding research on drugs of abuse, prevention of drug abuse, and treatment of substance abuse disorders. The Division of Pharmacotherapies and Medical Consequences of Drug Abuse (DPMC) initiated a discovery and development program in 1990. The initial program intended to perform standardized tests and clinical studies to facilitate the discovery and development of addiction medications and to facilitate the involvement of the pharmaceutical industry and academia. The primary objective of this discovery program was to discover putative medications for the treatment of cocaine dependence. The structure, objectives, and testing scheme of the NIDA drug discovery programs have changed as a result of the maturing of the science and efforts to improve efficiency. Medication targets have expanded and relapse prevention has become the number one focus. The motivation for Federal involvement in the development of medications for the treatment of addictive disorders is from a public health viewpoint. They are heavily invested in the treatment of addictive disorders and views new medications to treat these disorders as a way to expand treatment and improve the public health of the United States.

Linear-rank testing of a non-binary, responder-analysis, efficacy score to evaluate pharmacotherapies for substance use disorders

The design of pharmacological trials for management of substance use disorders is shifting toward outcomes of successful individual-level behavior (abstinence or no heavy use). While binary success/failure analyses are common, McCann and Li (CNS Neurosci Ther 2012; 18: 414–418) introduced “number of beyond-threshold weeks of success” (NOBWOS) scores to avoid dichotomized outcomes. NOBWOS scoring employs an efficacy “hurdle” with values reflecting duration of success. Here, we evaluate NOBWOS scores rigorously. Formal analysis of mathematical structure of NOBWOS scores is followed by simulation studies spanning diverse conditions to assess operating characteristics of five linear-rank tests on NOBWOS scores. Simulations include assessment of Fisher’s exact test applied to hurdle component. On average, statistical power was approximately equal for five linear-rank tests. Under none of conditions examined did Fisher’s exact test exhibit greater statistical power than any of the linear-rank tests. These linear-rank tests provide good Type I and Type II error control for comparing distributions of NOBWOS scores between groups (e.g. active vs. placebo). All methods were applied to re-analyses of data from four clinical trials of differing lengths and substances of abuse. These linear-rank tests agreed across all trials in rejecting (or not) their null (equality of distributions) at ≤ 0.05.