Faculty Bibliography

BACKGROUND: Regular exercise is thought to be associated with low rates of mental illness, but this association has been inadequately studied. The purpose of this study was to test the hypotheses that the recommended amount of self-reported vigorous exercise would be cross-sectionally associated with reduced prevalence and incidence of various DSM-IV psychiatric disorders, as well as increased rates of remission. METHOD: Data were collected from 2001 to 2005 as part of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a 2-wave face-to-face survey conducted by the National Institute on Alcohol Abuse and Alcoholism. For this study, the sample consisted of 23,505 nondisabled adults aged between 18 and 65 years. RESULTS: Individuals who engaged in vigorous exercise at Wave 2 were significantly more likely than were nonexercisers to be diagnosed with a current psychiatric disorder (adjusted odds ratio [AOR] = 1.22, 95% CI, 1.12-1.34 for the nationally recommended amount vs no exercise), significantly less likely to attain remission from a psychiatric disorder between waves (AOR = 0.77, 95% CI, 0.65-0.91), and significantly more likely to relapse or be newly diagnosed with a psychiatric disorder between waves (AOR = 1.15, 95% CI, 1.02-1.30). Alcohol dependence and bipolar II disorder were the disorders most strongly associated with exercise. CONCLUSIONS: This investigation suggests that the pursuit of vigorous exercise is associated with a vulnerability to mental illness. This surprising finding may be due to reward-related factors that influence both exercise engagement and the expression of certain psychiatric disorders. Prospective trials will be helpful in further clarifying the associations between exercise and mental illness, as the relationships between the 2 are more complex than previously believed.

A feasibility study was conducted to pilot test the ability of 5 sites to recruit, treat, and retain opioid-dependent offenders in a trial of extended-release injectable naltrexone (XR-NTX). The participants, 61 previously opioid-dependent individuals under legal supervision in the community, received up to 6 monthly injections of Depotrex brand naltrexone and completed a 6-month follow-up interview. Six-month outcomes showed that those who completed treatment had significantly fewer opioid-positive urines and were less likely to have been incarcerated than those who had not completed treatment. The findings indicate that XR-NTX holds promise as a feasible, effective treatment option for opioid-dependent offenders.

OBJECTIVE:To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). METHOD/METHODS:This was a 16-week, randomized, controlled, multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18 years) meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcome measures included the following: for ADHD, clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; for substance use, adolescent-reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS). RESULTS:There were no group differences on reduction in ADHD-RS scores (OROS-MPH: -19.2, 95% confidence interval [CI], -17.1 to -21.2; placebo, -21.2, 95% CI, -19.1 to -23.2) or reduction in days of substance use (OROS-MPH: -5.7 days, 95% CI, 4.0-7.4; placebo: -5.2 days, 95% CI, 3.5-7.0). Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 (mean difference = 4.4, 95% CI, 0.8-7.9) and 16 weeks (mean difference =6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean = 3.8) compared with placebo (mean = 2.8; p = .04). CONCLUSIONS:OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. Clinical Trial Registration Information-Attention Deficit Hyperactivity Disorder (ADHD) in Adolescents with Substance Use Disorders (SUD); http://www.clinicaltrials.gov; NCT00264797.

The female condom is effective in reducing unprotected sexual acts; however, it remains underutilized in the United States. This study examined whether a five-session HIV prevention intervention (Safer Sex Skills Building [SSB]), including presentation, discussion, and practice with female condoms, improved female condom skills and attitude among women in outpatient substance abuse treatment. Mixed-effects modeling was used to test the effect of SSB on skills and attitude over 3- and 6-month posttreatment among 515 randomized women. SSB was significantly associated with increases in skills and attitude, and the female condom demonstration session was primarily responsible for skills improvement. Attitude was a partial mediator of the intervention effect in reducing unprotected sex. Findings emphasize the utility of integrating female condom messages targeting proximal behavioral outcomes into HIV prevention. The study supports the use of female condom skill instruction via brief, hands-on exercises, as well as further research to enhance attitudinal change to reduce sexual risk.

BACKGROUND:In clinical trials of behavioral health interventions, outcome variables often take the form of counts, such as days using substances or episodes of unprotected sex. Classically, count data follow a Poisson distribution; however, in practice such data often display greater heterogeneity in the form of excess zeros (zero-inflation) or greater spread in the values (overdispersion) or both. Greater sample heterogeneity may be especially common in community-based effectiveness trials, where broad eligibility criteria are implemented to achieve a generalizable sample. OBJECTIVES/OBJECTIVE:This article reviews the characteristics of Poisson model and the related models that have been developed to handle overdispersion (negative binomial (NB) model) or zero-inflation (zero-inflated Poisson (ZIP) and Poisson hurdle (PH) models) or both (zero-inflated negative binomial (ZINB) and negative binomial hurdle (NBH) models). METHODS:All six models were used to model the effect of an HIV-risk reduction intervention on the count of unprotected sexual occasions (USOs), using data from a previously completed clinical trial among female patients (N = 515) participating in community-based substance abuse treatment (Tross et al. Effectiveness of HIV/AIDS sexual risk reduction groups for women in substance abuse treatment programs: Results of NIDA Clinical Trials Network Trial. J Acquir Immune Defic Syndr 2008; 48(5):581-589). Goodness of fit and the estimates of treatment effect derived from each model were compared. RESULTS:The ZINB model provided the best fit, yielding a medium-sized effect of intervention. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE/CONCLUSIONS:This article illustrates the consequences of applying models with different distribution assumptions on the data. If a model used does not closely fit the shape of the data distribution, the estimate of the effect of the intervention may be biased, either over- or underestimating the intervention effect.

BACKGROUND:No consensus is available for identifying the best primary outcome for substance use disorder trials, making interpretation across trials difficult. Abstinence is the most desirable treatment outcome although a wide variety of other endpoints have been used. OBJECTIVES/OBJECTIVE:This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials. The framework was developed based on a trial for stimulant abuse using exercise as an augmentation treatment, delivered within the NIDA Clinical Trials Network. The use of a common endpoint across trials will facilitate comparisons of treatment efficacy. METHODS:Primary endpoint options in existing substance abuse studies were evaluated. This evaluation included surveys of the literature for endpoints and measurement approaches, followed by assessment of endpoint choices against study design issues, population characteristics, tests of sensitivity, and tests of clinical meaningfulness. CONCLUSION/CONCLUSIONS:We concluded that the best current choice for a primary endpoint is percent days abstinent, as measured by the Time Line Follow Back interview conducted three times a week with recall aided by a take-home Substance Use Diary. To improve the accuracy of the self-reported drug use, the results of qualitative urine drug screens will be used in conjunction with the Time Line Follow Back results. SCIENTIFIC SIGNIFICANCE/CONCLUSIONS:There is a need for a standardized endpoint in this field to allow for comparison across treatment studies, and we suggest that the recommended candidate endpoint be considered. However, the study design and goals ultimately must guide the final decision.

BACKGROUND:Preclinical findings suggest that the inhibition of NMDA glutamatergic neurotransmission may have beneficial effects in the treatment of opioid dependence. AIMS/OBJECTIVE:We hypothesized that memantine, a low-potency, uncompetitive NMDA receptor antagonist, would be safe and effective when used as an adjunct to oral naltrexone in the treatment of opioid dependence, particularly in preventing relapse to opiate use in detoxified individuals. METHODS:Opioid-dependent participants (N=112) were enrolled. Following detoxification all participants were inducted onto oral naltrexone and were randomized to receive memantine 15 mg bid (N=27), memantine 30 mg bid (N=27) or placebo (N=27) for 12-weeks in combination with naltrexone 50mg/day and individual relapse-prevention therapy. The primary outcome was the retention in treatment since treatment dropout is most commonly associated with relapse to opiate use. RESULTS:Twenty-six percent of participants withdrew from treatment prior to starting naltrexone. Of those that were randomized 35% completed 4 weeks only, and 24% completed all 12 weeks of treatment. There was no significant difference in treatment retention or heroin use, opiate withdrawal symptoms and craving between the groups treated with memantine vs. placebo. CONCLUSION/CONCLUSIONS:Thus, the efficacy of memantine 30 or 60 mg/day as an adjunct to oral naltrexone for the treatment of opiate dependence was not supported.

BACKGROUND:Opioid dependence is associated with low rates of treatment-seeking, poor adherence to treatment, frequent relapse, and major societal consequences. We aimed to assess the efficacy, safety, and patient-reported outcomes of an injectable, once monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) for treatment of patients with opioid dependence after detoxification. METHODS:We did a double-blind, placebo-controlled, randomised, 24-week trial of patients with opioid dependence disorder. Patients aged 18 years or over who had 30 days or less of inpatient detoxification and 7 days or more off all opioids were enrolled at 13 clinical sites in Russia. We randomly assigned patients (1:1) to either 380 mg XR-NTX or placebo by an interactive voice response system, stratified by site and gender in a centralised, permuted-block method. Participants also received 12 biweekly counselling sessions. Participants, investigators, staff , and the sponsor were masked to treatment allocation. The primary endpoint was the response profile for confirmed abstinence during weeks 5–24, assessed by urine drug tests and self report of non-use. Secondary endpoints were self-reported opioid-free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00678418. FINDINGS/RESULTS:Between July 3, 2008, and Oct 5, 2009, 250 patients were randomly assigned to XR-NTX (n=126) or placebo (n=124). The median proportion of weeks of confirmed abstinence was 90·0% (95% CI 69·9–92·4) in the XR-NTX group compared with 35·0% (11·4–63·8) in the placebo group (p=0·0002). Patients in the XR-NTX group self-reported a median of 99·2% (range 89·1–99·4) opioid-free days compared with 60·4% (46·2–94·0) for the placebo group (p=0·0004). The mean change in craving was –10·1 (95% CI –12·3 to –7·8) in the XR-NTX group compared with 0·7 (–3·1 to 4·4) in the placebo group (p<0·0001). Median retention was over 168 days in the XR-NTX group compared with 96 days (95% CI 63–165) in the placebo group (p=0·0042). Naloxone challenge confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group (p<0·0001). XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events. INTERPRETATION/CONCLUSIONS:XR-NTX represents a new treatment option that is distinct from opioid agonist maintenance treatment. XR-NTX in conjunction with psychosocial treatment might improve acceptance of opioid dependence pharmacotherapy and provide a useful treatment option for many patients. FUNDING/BACKGROUND:Alkermes.

This study examined the treatment history and intention to seek treatment among 489 individuals interested in substance use disorder clinical trial participation. Opioid and cocaine users were more likely than cannabis users to report having received treatment for substance use in the past and more likely than cannabis users to report planning to seek treatment for substance use before exposure to recruitment advertising. Free cost was the aspect of clinical trial participation that most influenced the decision to make an intake evaluation appointment for opioid-dependent patients as compared with cocaine- and cannabis-dependent participants, and the availability of individual psychotherapy most influenced those who were cannabis dependent. Cannabis-dependent individuals evaluated for clinical trial participation reported that recruitment advertising was an important factor in leading them to seek treatment. These results have implications for clinical trial recruitment and public health efforts directed at encouraging cannabis-dependent individuals to seek treatment.