Search the Library

Abstract: Abstinence from drinking represents the primary treatment target for alcohol use disorders (AUD) in youth, but few adolescents who engage in problematic drinking seek treatment. A reduction in World Health Organization (WHO) drinking risk level has been established as a valid and reliable non-abstinent treatment target for AUD in adults but remains unstudied in youth. The present study used data from the NIDA-CTN-0028 trial (Osmotic-Release Methylphenidate for ADHD in Adolescents with Substance Use Disorders) to examine associations between reductions in WHO drinking risk level and changes in global functioning and attention-deficit hyperactivity disorder (ADHD) symptoms during treatment in a sample of adolescents (ages 13-18) with ADHD and comorbid substance use disorder (SUD) (n=297, 61% with AUD) receiving a 16-week intervention that combined ADHD pharmacotherapy (OROS-methylphenidate vs. placebo) and drug-focused cognitive-behavioral therapy. Shifts in drinking risk level during treatment were highly variable in adolescents treatment for ADHD/SUD and influenced by AUD diagnostic status. In the total sample, 15% of participants had a 2-level or greater reduction in WHO drinking risk level, with 59% and 24% showing no change or an increase in risk-level during treatment respectively. Achieving at least a 2-level change in WHO drinking risk level during treatment was associated with greater reduction in ADHD symptoms and better functional outcomes. Conclusions: These findings parallel the adult AUD literature and provide preliminary support for the use 2-level reductions in WHO risk levels for alcohol use as a clinical valid non-abstinent treatment outcome for youth with ADHD and comorbid AUD.

Abstract:

In a multisite, randomized study (CTN-0029), a 3-month course of osmotic-release oral system mehtylphenidate (OROS-MPH) improved smoking cessation in a group of patients with higher baseline severity in Attention Deficit/Hyperactivity Disorder (ADHD). This treatment, however, worsened smoking cessation outcome in the group with lower baseline ADHD severity. This studied aimed to examine whether this differential treatment effect persisted after OROS-MPH was discontinued.

A secondary analysis of the 1-month follow-up data from CTN-0029 after discontinuation of OROS-MPH was conducted (N=134). Nicotine patch was tapered during this month. Researchers tested whether OROS-MPH had an effect on self-reported 7-day abstinence by week, as well as possible treatment by baseline ADHD severity interactions.

Abstinence diminished overall in time after the end of the treatment. In the high baseline severity group, patients who received OROS-MPH had an advantage in 7-day abstinence at week 15 (40% for OROS-MPH vs. 32% for placebo). In the lower severity group (n=121), no difference was detected (29% for OROS-MPH vs. 32% for placebo) between the two treatment groups. There was also a significant treatment by baseline ADHD severity interaction.

Conclusions: OROS-MPH promotes abstinence beyond the course of treatment for patients with more severe ADHD, while the paradoxical effects in the lower baseline severity group is not persistent after medication discontinuation. Targeting ADHD in smoking cessation as a comorbidity therefore can have broader impact with more precise patient selection.

Related protocols: CTN-0029

Abstract:

A double blind, placebo-controlled randomized trial evaluation osmotic-release oral system methylphenidate (OROS-MPH) for smoking cessation revealed a significant interaction effect in which participants with higher baseline ADHD severity had better abstinence outcomes with OROS-MPH while participants with lower baseline ADHD severity had worse outcomes (CTN-0029). This study examined secondary outcomes that might bear on the mechanism for this differential effect treatment effect. Longitudinal analyses were conducted to evaluate the effect of OROS-MPH on three secondary outcomes (ADHD symptom severity, nicotine craving, and withdrawal) in the total sample (N=255, 56% male) and in the high (N=134) and low (N=121) baseline ADHD severity groups.

Results found that OROS-MPH significantly improved ADHD symptoms and nicotine withdrawal symptoms in the total sample, and exploratory analyses showed that in both higher and lower baseline severity groups, OROS-MPH statistically significantly improved these two outcomes. No effect on craving overall was detected, though exploratory analyses showed statistically significantly decreased craving in the high ADHD severity participants on OROS-MPH. No treatment by ADHD baseline severity interaction was detected for the outcomes.

Conclusions: Methylphenidate improved secondary outcomes during smoking cessation independent of baseline ADHD severity, with no evident treatment-baseline severity interaction. Results suggest divergent responses to smoking cessation treatment in the higher and lower severity groups cannot be explained by concordant divergence in craving, withdrawal, and ADHD symptoms severity, and alternative hypotheses may need to be identified.

Related protocols: CTN-0029

Abstract:

In randomized controlled trials (RCTs), a common strategy to increase power to detect a treatment effect is adjustment for baseline covariates. However, adjustment with partly missing covariates, where complete cases are only used, is inefficient. This paper considers different alternatives in trials with discrete-time survival data, where subjects are measured in discrete-time intervals while they may experience an event at any point in time. The results of a Monte Carlo simulation study, as well as a case study of randomized trials in smokers with attention deficit hyperactivity disorder (CTN-0029), indicated that single and multiple imputation methods outperform the other methods and increase precision in estimating the treatment effect. Missing indicator method, which uses a dummy variable in the statistical model to indicate whether the value for that variable is missing and sets the same value to all missing values, is comparable to imputation methods. Nevertheless, the power level to detect the treatment effect based on missing indicator method is marginally lower than the imputation methods, particularly when the missingness depends on the outcome.

In conclusion, complete case analysis is wasteful and drops the power level to a large degree, resulting in an undetectable treatment effect. Also, it can introduce bias in the estimate of the treatment effects when the missingness mechanism depends on the outcome variable. This method is therefore invalid and the authors do not recommend it. Instead, it appears that imputation of partly missing (baseline) covariates should be preferred in the analysis of discrete-time survival data.

Related protocols: CTN-0029

Abstract:

Researchers often want to examine two comorbid conditions simultaneously. One strategy to do so is through the use of parallel latent growth curve modeling (LGCM). This statistical technique allows for the simultaneous evaluation of two disorders to determine the explanations and predictors of change over time. Additionally, a piecewise model can help identify whether there are more than two growth processes within each disorder (e.g., during a clinical trial). A parallel piecewise LGCM was applied to self-reported attention-deficit/hyperactivity disorder (ADHD) and self-reported substance use symptoms in 303 adolescents enrolled in cognitive-behavioral therapy treatment for a substance use disorder and receiving either oral-methylphenidate or placebo for ADHD across 16 weeks (protocol CTN-0028). Assessing these two disorders concurrently allowed us to determine whether elevated levels of one disorder predicted elevated levels or increased risk of the other disorder. First, a piecewise growth model measured ADHD and substance use separately. Next, a parallel piecewise LGCM was used to estimate the regressions across disorders to determine whether higher scores at baseline of the disorders (i.e., ADHD or substance use disorder) predicted rates of change in the related disorder. Finally, treatment was added to the model to predict change.

Conclusions: While the analyses revealed no significant relationships across disorders, this study explains and applies a parallel piecewise growth model to examine the developmental processes of comorbid conditions over the course of a clinical trial. Strengths of piecewise and parallel LGCMs for other addictions researchers interested in examining dual processes over time are discussed.

Related protocols: CTN-0028

Abstract:

A preponderance of relevant research has indicated reduction in anxiety and depressive symptoms following smoking abstinence. This secondary analysis of data from the National Drug Abuse Treatment Clinical Trials Network study CTN-0029 investigated whether the phenomenon extends to smokers with attention deficit hyperactivity disorder (ADHD). The study setting was an 11-week double-blind placebo-controlled randomized trial of osmotic release oral system methylphenidate (OROS-MPH) as a cessation aid when added to nicotine patch and counseling. Participants were 255 adult smokers with ADHD. The study outcomes were: anxiety (measured by the Beck Anxiety Inventory (BAD)) and depressed mood (Beck Depression Inventory II (BDI)), measured 1 week and 6 weeks after a target quit day (TQD). The main predictor was point-prevalence abstinence measured at weeks 1 and 6 after TQD. Covariates were treatment (OROS-MPH vs. placebo), past major depression, past anxiety disorder, number of cigarettes smoked daily, demographics (age, gender, education, marital status) and baseline scores on the BAI, BDI, and DSM-IV ADHD Rating Scale.

Results found that abstinence was significantly associated with lower anxiety ratings throughout the post-quit period (p<0.001). Depressed mood was lower for abstainers than non-abstainers at week 1 (p<0.05), but no longer at week 6 (p=0.83). Treatment with OROS-MPH relative to placebo showed significant reductions at week 6 after TQD for both anxiety (p<0.05) and depressed mood (p<0.001), but not at week 1. Differential abstinence effects of gender were observed. Anxiety and depression ratings at baseline predicted increased ratings of corresponding measures during the post-quit period.

Conclusions: Stopping smoking yielded reductions in anxiety and depressed mood in smokers with ADHD treated with nicotine patch and counseling. Treatment with OROS-MPH produced better outcomes on the post-cessation mood ratings compared to placebo, albeit in a delayed manner, suggesting that OROS-MPH could be an important adjunct for achieving smoking abstinence in this population. Validation of findings from this secondary analysis could advance discovery and development of treatments for persons dually diagnosed with nicotine dependence and ADHD.

Related protocols: CTN-0029

Abstract:

Traditional approaches to subgroup analyses that test each moderating factor as a separate hypothesis can lead to erroneous conclusions due to the problems of multiple comparisons, model misspecification, and multicollinearity. This study aimed to demonstrated a novel, systematic approach to subgroup analyses that avoids these pitfalls. A Best Approximating Model (BAM) approach that identifies multiple moderators and estimates their simultaneous impact on treatment effect sizes was applied to a randomized, controlled, 11-week, double-blind efficacy trial on smoking cessation of adult smokers with attention-deficit/hyperactivity disorder (ADHD), randomized to either OROS-methylphenidate (n=127) or placebo (n=128) and treated with nicotine patch (National Drug Abuse Treatment Clinical Trials Network protocol CTN-0029). Binary outcomes measures were prolonged smoking abstinence and point prevalence smoking abstinence.

Although the original clinical trial data analysis showed no treatment effect on smoking cessation, the BAM analysis showed significant subgroup effects for the primary outcome of prolonged smoking abstinence: (1) lifetime history of substance use disorders, and (2) more severe ADHD symptoms. A significant subgroup effect was also shown for the secondary outcome of point prevalence smoking abstinence — age 18-29 years.

Conclusions: The BAM analysis resulted in different conclusions about subgroup effects compared to a hypothesis-driven approach. These divergent findings underscore the need for investigators to consider more advanced statistical methods to better analyze subgroup effect sizes. By examining moderator independence and avoiding multiple testing, BAMs have the potential to better identify and explain how treatment effects vary across subgroups in heterogeneous patient populations, thus providing better guidance to more effectively match individual patients with specific treatments.

Related protocols: CTN-0029

Abstract:

Osmotic-release oral system methylphenidate (OROS-MPH) did not show overall benefit as an adjunct smoking cessation treatment for adult smokers with ADHD in a randomized, placebo-controlled, multicenter study in the National Drug Abuse Treatment Clinical Trials Network (CTN-0029). A secondary analysis revealed a significant interaction between ADHD symptom severity and treatment-response to OROS-MPH, but did not account for other baseline covariates or estimate the magnitude of improvement in outcome if treatment were optimized. This present study addressed the gaps in how this relationship should inform clinical practice. Using data from the CTN trial (N=255, six sites in five US states), researchers built predictive models to calculate the probability of achieving prolonged abstinence, verified by self-report, and expired carbon monoxide measurement. The potential improvement in achieving prolonged abstinence was evaluated, both with and without stratification on baseline ADHD severity. Predictive modeling demonstrated that the interaction between baseline ADHD severity and treatment group was not affected by adjusting for other baseline covariates. A clinical trial simulation showed that giving OROS-MPH to patients with baseline Adult ADHD Symptom Rating Scale (ADHD-RS) >35 and placebo to those with ADHD-RS <= 35 would significantly improve the prolonged abstinence rate.

Conclusions: In smokers with ADHD, utilization of a simple decision rule that stratifies patients based on baseline ADHD severity can enhance overall achievement of prolonged smoking abstinence. This type of personalized treatment based on baseline ADHD symptom severity alone could significantly improve clinical outcome over randomized assignment. Similar analysis methods should be considered for future clinical trials for other substance use disorders.

Related protocols: CTN-0029

Abstract:

The purpose of this study was to examine sensitivity to missing data procedures on treatment effects in a randomized controlled trial (RCT) of osmotic-release methylphenidate (OROS) for adolescents with co-occurring attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD). Data came from a National Drug Abuse Treatment Clinical Trials Network study (CTN-0028, N=303), which evaluated the safety/efficacy of a 16-week RCT of OROS vs. placebo in adolescents aged 13-18 with ADHD who were also receiving cognitive-behavioral therapy for their SUD. The two primary outcomes were clinician-reported ADHD symptoms and self-reported past 28 days of substance use (SU). A parallel grow model was used to assess the effect sizes assuming missing at random (MAR) compared to two missing not at random (MNAR) models: Diggle-Kenward (DK) selection model and Wu-Carroll (WC) selection model.

The MAR model found no significant treatment effect on ADHD or SU, and the effect sizes were small for both ADHD and SU. The MNAR DK model also produced non-significant treatment effects with similar effect sizes of ADHD and SU. The MNAR WC model evidenced a significant effect of OROS relative to placebo on SU, and the effect sizes for both ADHD and SU were larger than reported in the other models.

Conclusions: While the MAR model and one MNAR model found similarly sized effects as the original RCT, the second MNAR model produced different results for both of the outcomes. This sensitivity analysis highlights an important need for future RCTs of co-morbid mental illness and SUDs to carefully evaluate the missing data assumptions made when assessing treatment effects.

Related protocols: CTN-0028

Abstract:

This secondary analysis of data from National Drug Abuse Treatment Clinical Trials Network protocol CTN-0029 (NIDA-CTN-0029 A Pilot Study of Osmotic-Release Methylphenidate in Initiating and Maintaining Abstinence in Smokers with ADHD) aimed to determine whether treatment of attention deficit/hyperactivity disorder (ADHD) with osmotic-release oral system (OROS) methylphenidate promotes abstinence from smoking among smokers with ADHD who have greater severity of ADHD symptoms at baseline or greater improvement in ADHD during treatment. CTN-0029 was a randomized, double-blind, 11-week trial conducted between December 2005 and January 2008 at 6 clinical sites. Adult cigarette smokers (aged 18-55 years) who met DSM-IV criteria for ADHD were randomly assigned to OROS methylphenidate (72 mg/d) (n=127) or matching placebo (n=128). All participants received nicotine patches (21 mg/d) and weekly individual smoking cessation counseling. Logistic regression was used to model prolonged abstinence from smoking (ascertained by self-report and breath carbon monoxide testing) as a function of treatment, baseline ADHD Rating Scale-IV (ADHD-RS) score, change in ADHD-RS score during treatment, and their interactions.

Results found that treatment interacted with both ADHD-RS score at baseline and change in ADHD-RS score during treatment. Among patients with higher ADHD-RS scores (>36) at baseline and the most improvement in ADHD during treatment (change score > 24), 70% of those who took OROS methylphenidate achieved abstinence from smoking compared to 36.8% of those who took placebo. In contrast, among patients with the lowest ADHD-RS baseline scores (< 30), 30.3% of those who took OROS methylphenidate achieved abstinence from smoking compared to 60.7% of those who took placebo.

Conclusions: OROS methylphenidate, in combination with nicotine patch, may be an effective treatment for nicotine dependence among smokers with more severe ADHD and more robust response of ADHD symptoms to medication. OROS methylphenidate may be counterproductive among smokers with lower severity of ADHD. The identification and aggressive treatment of ADHD and other comorbidities hold out the promise of a treatment strategy complementary to existing medication and behavioral approaches.

Related protocols: CTN-0029

Abstract:

This article reports on a study examining predictors of methylphenidate-induced increases in blood pressure (BP). In this secondary analysis of CTN-0029, a randomized, double-blind, placebo-controlled smoking cessation trial, non-hypertensive adult smokers with attention deficit hyperactivity disorder randomized to osmotic-release oral system methylphenidate (OROS-MPH) (n=115) were matched one-to-one on baseline systolic BP (SBP) (+/-5 mm Hg) with participants randomized to placebo (n=115) and followed for 10 weeks. In adjusted mixed linear models of SBP and diastolic BP (DBP), baseline normal SBP (P<.0001) and DBP (P<.0001) were associated with significant OROS-MPH–induced increases compared with placebo, whereas significant increases were not observed in participants with baseline prehypertensive SBP (P=.27) and DBP (P=.79). Participants randomized to OROS-MPH with baseline normal BP had increased odds of developing either systolic (odds ratio [OR], 3.32; 95% confidence interval [CI], 1.41–8.37; P=.006) or diastolic prehypertension (OR, 4.32; 95% CI, 1.56–14.0; P=.004) compared with placebo using simple logistic regression.

Conclusions: This study suggests two findings: (1) adult ADHD participants with baseline normal blood pressure are more susceptible to the BP-raising effects of OROS-MPH than those with baseline prehypertensive BP, and (2) normotensive adults with ADHD have significantly greater odds of developing prehypertension when treated with OROS-MPH compared with placebo. Since previous studies have shown adverse cardiovascular outcomes associated with prehypertension, further studies are needed to clarify the long-term consequences, especially given the growing consensus of ADHD as a treatable lifelong illness.

Related protocols: CTN-0029

Abstract:

Few studies have evaluated predictors of smoking cessation outcomes in smokers with attention-deficit/hyperactivity disorder (ADHD), which could help to improve suboptimal treatment outcomes in this population. The purpose of this study was to examine pretreatment thoughts about smoking abstinence (i.e., desire to quit, perceived difficulty quitting, and expected success in quitting) as predictors of smoking cessation outcomes in smokers with ADHD and to determine the extent to which treatment adherence mediates these relationships.

Participants in this CTN ancillary investigation were adult smokers with ADHD (n=255) who were enrolled in National Drug Abuse Treatment Clinical Trials Network protocol CTN-0029 (“A Pilot Study of Osmotic-Release Methylphenidate in Initiating and Maintaining Abstinence in Smokers with ADHD”) and received either osmotic-release oral system methylphenidate (OROS-MPH) or placebo in combination with transdermal nicotine replacement and brief cessation counseling. Bootstrapped logistic regression models were generated to test main effects of thoughts about abstinence on smoking cessation outcomes and to examine treatment adherence as a mediator of these relationships. Desire to quit and expected success in quitting, but not perceived difficulty of quitting, predicted smoking cessation outcomes, as did all of the treatment adherence variables (i.e., percent sessions attended, counselor ratings of counseling adherence, and percent patch adherence). Counseling adherence partially mediated the relationship between smoking cessation outcomes and both pretreatment desire to quit and expected success.

Conclusions: Smokers with ADHD who have higher self-efficacy (i.e., expected success) and motivation (i.e., desire) to quit are more adherent to smoking cessation counseling and have better smoking cessation outcomes. Additional research is needed to determine whether treatment-seeking smokers with ADHD would benefit from an intervention designed to increase self-efficacy and motivation to quit. Interventions such as contingency management, for example, have been shown to increase motivation and self-efficacy for quitting in non-treatment-seeking adult smokers and might effectively promote long-term abstinence in smokers with ADHD as well.

Related protocols: CTN-0029

Abstract:

Adults with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for both cigarette smoking and being overweight or obese. Although smoking cessation tends to result in weight increase, potentially initiating or exacerbating weight problems, adults with ADHD who are treated with osmotic release system methylphenidate (OROS-MPH) tend to lose weight. It is unclear how the use of OROS-MPH during a smoking-cessation attempt might affect the typical weight gain that accompanies cessation. This study focused on changes in weight and hunger during a smoking cessation attempt in 215 adults with ADHD who completed National Drug Abuse Treatment Clinical Trials Network trial CTN-0029 (“A Pilot Study of Osmotic-Release Methylphenidate in Initiating and Maintaining Abstinence in Smokers with ADHD”). Patients in this study were randomized to either OROS-MPH (n=107) or placebo (n=108), with both groups also receiving open-label transdermal nicotine replacement and counseling. Participants who received OROS-MPH lost an average of 1.6% of their body weight during the 11-week study, whereas those who received placebo gained an average of 1.3% of their weight (p<.001). Hunger ratings were lower in the OROS-MPH group than in the placebo group.

Conclusions: The use of OROS-MPH during a smoking-cessation attempt prevents weight gain in adults with ADHD who substantially reduce or quit smoking. Although its effects on hunger and weight did not translate into better overall efficacy for smoking cessation in this study (see Winhusen et al., 2010), when coupled with OROS-MPH’s previously established safety in smokers with ADHD and its efficacy in reducing ADHD symptoms, this clear indication of its effects on postcessation weight gain suggests that future research on the potential benefit of OROS-MPH among particular subgroups of smokers with ADHD — such as those who are deterred from making a quit attempt due to weight concerns or who are prone to relapse as a result of weight gain — may be in order.

Related protocols: CTN-0029

Abstract:

Attention-Deficit/Hyperactivity Disorder (ADHD) frequently co-occurs with substance use disorder (SUD) and is associated with poor substance-use treatment outcomes. A National Drug Abuse Treatment Clinical Trials Network study (CTN-0028) evaluating osmotic-release oral system methylphenidate (OROS-MPH) for adolescents with ADHD and SUD, concurrently receiving behavioral therapy, revealed inconsistent medication effects on ADHD or SUD. Clinical care for this population would be advanced by knowledge of treatment outcome predictors. Data from the randomized placebo-controlled trial (n=299) were analyzed. Significant treatment predictors included: 1) Substance use severity, associated with poorer ADHD and SUC outcomes, 2) ADHD severity, associated with better ADHD and SUD outcomes, 3) comorbid conduct disorder, associated with poorer ADHD outcomes, and 4) court-mandated status, associated with better SUD outcomes by poorer treatment completion. An interaction effect showed that OROS-MPH improved SUD outcomes in adolescents with comorbid conduct disorder compared to placebo.

Conclusions: Individuals with ADHD and SUD who are also diagnosed with conduct disorder could benefit from concurrent treatment with OROS-MPH in addition to treatment for SUD. The study also found that individuals with more severe ADHD but less severe SUD showed better treatment outcomes. With regards to mandating treatment, better SUD outcomes were found in adolescents court-mandated to receive treatment, but there were also lower treatment completion rates in the court-mandated group. Thus, particular focus on treatment retention efforts might be important for this group in order to achieve better SUD outcomes.

Related protocols: CTN-0028

Abstract:

Pharmacotherapy trials for treating tobacco dependence would benefit from behavioral interventions providing treatment consistent with clinical practice guidelines but not directing participants to treatment not evaluated in the trial. The Smoke Free and Living It behavioral intervention manual includes participant and interventionist guides and is designed to provide both practical counseling and intra-treatment support. In protocol CTN-0029, researchers utilized this intervention manual as part of their multicenter, randomized clinical trial of smokers with attention deficit hyperactivity disorder. In the study, they evaluated how the interventional manual performed in a “train-the-trainer” model requiring uniform counseling across 6 sites and 15 interventionists. The skill-adherence of the interventionists and the intervention-adherence of the participants was analyzed. The 2555 randomized participants completed 9.3 +/- 2.8 sessions (mean +/- SD), with 157 participants (61.6%) completing all 11 of the sessions and 221 (86.7%) completing at least 6 of the 11 sessions. Of the 163 sessions for which the study interventionists were evaluated, 156 (95.7%) were rated as adherent to protocol and “meeting expectations” on at least 6 of 7 established criteria, illustrating that fidelity can be maintained with minimal supervision.

Conclusions: The self-help and interventionists guides of the Smoke Free and Living It manual can thus be used to provide behavioral intervention with a high rate of adherence by both the interventionists and the participants. This manual can be used as a self-help guide, an interventionist guide, or both, and can be tailored to a specific research protocol, regardless of the size of the study or number of study sites. The Smoke Free and Living It manual meets the requirements of the United States Public Health Service Clinical Practice Guideline, can be adapted to specific research protocols, and provides a useful option for behavioral intervention during clinical trials for smoking cessation.

Related protocols: CTN-0029