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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:

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:

Major depressive disorder (MDD) frequently co-occurs in adolescents with substance use disorders (SUDs) and attention deficit hyperactivity disorder (ADHD), but the impact of MDD on substance treatment and ADHD outcomes and implications for clinical practice are unclear. To examine this impact, adolescents aged 13-18 meeting DSM-IV criteria for ADHD and SUD were randomized to osmotic release methylphenidate (OROS-MPH) or placebo and 16 weeks of cognitive behavioral therapy, as part of protocol CTN-0028 (“Osmotic-Release Methylphenidate for ADHD in Adolescents with Substance Use Disorders”). Adolescents with (n=38) and without (n=265) MDD were compared on baseline demographic and clinical characteristics as well as non-nicotine substance use and ADHD treatment outcomes. Results found that adolescents with MDD reported more non-nicotine substance use days at baseline and continued using more throughout treatment compared to those without MDD. There was no difference between adolescents with and without MDD in retention or CBT sessions attended. ADHD symptom severity (based on DSM-IV ADHD rating scale) followed a slightly different course of improvement although with no difference between groups in baseline or 16-week symptom severity or 16-week symptom reduction. There was no difference in days of substance use or ADHD symptom outcomes over time in adolescents with MDD or those without MDD treated with OROS-MPH or placebo. Depressed adolescents were more often female, older, and not court ordered.

Conclusions: These preliminary findings suggest that compared to non-depressed adolescents with ADHD and SUD, those with co-occurring MDD have more severe substance use at baseline and throughout treatment. Such youth may require interventions targeting depression. Adequately powered trials evaluating treatments focused on MDD in the context of SUD and other frequently present, co-occurring psychiatric disorders are needed. In the interim, mechanisms for assessing and treating these disorders are essential in SUD treatment settings since their presence appears to interfere with maximizing SUD outcomes.

Related protocols: CTN-0028

Abstract:

Little is known about the relationship between attention-deficit/hyperactivity disorder (ADHD) subtypes and substance-use disorder (SUD). As there is literature suggesting different subtype phenotypes, there may be subtype differences in regard to the risk for developing SUD and substance treatment response. The purpose of this study was to characterize the sample in a National Drug Abuse Treatment Clinical Trials Network (CTN) study (protocol CTN-0029, “A Pilot Study of Osmotic-Release Methylphenidate in Initiating and Maintaining Abstinence in Smokers with ADHD”), according to ADHD subtypes and baseline psychosocial and substance-use characteristics and to compare subtypes on response to treatment. Secondary analyses were performed on data collected from adolescents diagnosed with ADHD and SUD (non-nicotine) and treated with stimulant medication or placebo and cognitive behavioral therapy for substance abuse. Participants were characterized as inattentive or combined ADHD subtype and compared on baseline characteristics and treatment outcome. Results found that the combined subtype presented with more severe SUDs and higher rates of conduct disorder. There were a greater proportion of boys with inattentive subtype, and the inattentive subtype also appeared less ready for treatment with poorer coping skills at baseline. However, the two subtypes responded equally to treatment even after controlled for baseline differences.

Conclusions: Findings from this large community sample indicate that there were no subtype differences in treatment response, although there were differences in terms of substance use, antisocial behavior, readiness for treatment, and gender prior to treatment. This study is the first to report on subtype differences for treatment response for non-nicotine substance use disorder in a comorbid ADHD-SUD population. Despite some baseline differences, the fact both subtypes responded equally to treatment suggests that subtype designation may not be relevant when assessing treatment needs for an adolescent with comorbid ADHD-SUD.

Related protocols: CTN-0028

Abstract:

Multisite trials, the gold standard for conducting studies in community-based settings, can mask variability across sites resulting in misrepresentation of effects in specific sites. In a placebo-controlled trial of osmotic-release oral system methylphenidate (OROS-MPH) as augmentation treatment for smokers with attention deficit hyperactivity/impulsivity disorder (ADHD) (protocol CTN-0029), three types of sites were selected according to their clinical research specialty (ADHD, smoking cessation, and general mental health). Analysis was conducted to determine if clinical outcomes, that is, reduction in ADHD symptoms and smoking cessation rates, and the effect of treatment on these outcomes would differ by type of site. A total of 255 adult smokers diagnosed with ADHD were enrolled in three clinic types: 72 in ADHD, 79 in tobacco dependence, and 104 in the mental health clinics. The three site-types were similar in demographic characteristics, smoking history, baseline level of ADHD symptoms, and history of psychiatric illness. Site-type but not site-type-by-treatment-interaction predicted prolonged smoking abstinence. A significant three-way interaction of site-type, treatment, and time predicted improvement in ADHD symptoms. Moderate to strong effects of OROS-MPH relative to placebo were observed in the mental health and the ADHD clinics, while only a weak effect was observed in the tobacco dependence clinics. Accordingly, had the study only been conducted in tobacco dependence clinics, an erroneous null or, at best, weak effect of OROS-MPH on ADHD symptoms might have emerged.

Conclusions: OROS-MPH benefit varied by site for reducing ADHD symptoms but not for improving smoking abstinence. The uneven presence of site-type effects, observed in this analysis, affirms the need for a priori consideration and measurement of potentially influential site-related factors in the design and analysis of multisite trials. Scientific assessment of site-type effects can indicate the generalizability of findings from multisite trials and should be routinely incorporated in the design of multisite trials.

Related protocols: CTN-0029

Abstract:

This is the primary outcomes paper for CTN-0028.

National Drug Abuse Treatment Clinical Trials Network protocol CTN-0028 was designed 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). The study was a 16-week, randomized controlled multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18) 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. Analysis of the results found no group differences on reduction in ADHD-RS scores or reduction in days of substance use. Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 and 16 weeks, and more negative urine drug screens in OROS-MPH compared with placebo.

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.

Abstract:

Psychostimulants are effective treatments for attention-deficit/hyperactivity disorder (ADHD) but may be associated with euphoric effects, misuse/diversion, and adverse effects. These risks are perceived by some clinicians to be greater in substance-abusing adolescents relative to non–substance-abusing adults. The present study evaluates the subjective effects, misuse/diversion, and adverse effects associated with the use of osmotic-release oral system methylphenidate (OROS-MPH), relative to placebo, for treating ADHD in adolescents with a substance use disorder (SUD) as a function of substance use severity and compared these risks with those associated with the treatment of ADHD in adults without a non-nicotine SUD. Datasets from two randomized placebo-controlled trials of OROS-MPH for treating ADHD, one conducted with 303 adolescents (CTN-0028) with at least one non-nicotine SUD and one with 255 adult smokers (CTN-0029), were analyzed. Outcome measures included the Massachusetts General Hospital Liking Scale, self-reported medication compliance, pill counts, and adverse events (AEs). Euphoric effects and misuse/diversion of OROS-MPH were not significantly affected by substance use severity. The euphoric effects of OROS-MPH did not significantly differ between the adolescent and adult samples. Adults rated OROS-MPH as more effective in treating ADHD, whereas adolescents reported feeling more depressed when taking OROS-MPH. The adolescents lost more pills relative to the adults regardless of treatment condition, which suggests the importance of careful medication monitoring. Higher baseline use of alcohol and cannabis was associated with an increased risk of experiencing a treatment-related AE in OROS-MPH, but baseline use did not increase the risk of serious AEs or of any particular category of AE and the adolescents did not experience more treatment-related AEs relative to the adults.

Conclusions: With good monitoring, and in the context of substance abuse treatment, OROS-MPH can be safely used in adolescents with an SUD despite non-abstinence.

Related protocols: CTN-0028, CTN-0029

Abstract:

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric condition subclassified in the DSM-IV according to its core symptom domains as (a) predominantly inattentive (ADHD-IN), (b) predominantly hyperactive/impulsive (ADHD-H), and (c) combined inattentive and hyperactive/impulsive (ADHD-C). Whether these subtypes represent distinct clinical entities or points on a severity continuum is controversial. Divergence in treatment response is a potential indicator of qualitative heterogeneity. This study, an ancillary investigation of data from protocol CTN-0029 (“A Pilot Study of Osmotic-Release Methylphenidate in Initiating and Maintaining Abstinence in Smokers with ADHD”), examined smoking cessation response by ADHD subtype to osmotic-release oral system methylphenidate (OROS-MPH). The analysis found that the subtypes were similar in baseline demographic, smoking, and psychiatric history, but differed in smoking cessation response to OROS-MPH or placebo as a function of nicotine dependence level. Among highly dependent smokers, the prolonged abstinence rates were greater with OROS-MPH than with placebo in the ADHD-C group, but higher with placebo than with OROS-MPH in the ADHD-IN group. Abstinence rates did not differ by subtype or treatment among smokers who were less nicotine dependent. Contrasting treatment response and divergence in the impact of nicotine dependence level support the hypothesis of ADHD subtypes as distinct clinical entities and may indicate the need and directions for personalized targeted treatments of smokers with ADHD.

Related protocols: CTN-0029

Abstract:

This presentation provides an overview of the design and main findings of protocol CTN-0028, which evaluated the efficacy of osmotic-release methylphenidate (OROS-MPH, sold under the brand name Concerta), relative to placebo, in treating co-occurring attention deficit hyperactivity disorder (ADHD) and substance use in adolescents. Both groups experienced clinically and statistically significant reductions in ADHD symptoms and (past-28-days) drug use, but there was no significant difference between the two groups. OROS-MPH appears to be safe and well-tolerated, but the similar reduction in ADHD symptoms between the OROS-MPH and placebo groups suggests that cognitive behavioral therapy (CBT), which was given to both groups, may have been the primary contributing factor. The presentation continues by examining emerging research on the use of CBT to treat ADHD, and then presents secondary objectives of the protocol, including an examination of depression, marijuana, and cigarette smoking in the study population.

Related protocols: CTN-0028

Abstract:

Protocol CTN-0029 was a multisite, randomized, double-blind placebo-controlled trial of long-acting OROS-methylphenidate (OROS-MPH) for treatment of patients with both nicotine dependence and attention deficit hyperactivity disorder (ADHD). The principal outcome analysis found, as expected, a robust beneficial effect of OROS-MPH in improving symptoms of ADHD, but no clear effect of OROS-MPH on cigarette smoking outcomes. Since OROS-MPH is primarily a treatment for ADHD, it is reasonable to hypothesize that a beneficial effect on smoking outcome might occur only in those patients who experience a substantial improvement in their ADHD during treatment. This ancillary investigation used a linear model in which prolonged abstinence at week 10 (end of the acute treatment phase) was modeled as a function of medication treatment (OROS-MPH versus placebo), the change in the ADHD symptom severity score between baseline and end of study, and the interaction between ADHD improvement and treatment. The interaction was significant, suggesting that among those patients with the greatest improvement in ADHD symptoms during treatment, OROS-MPH was superior to placebo in promoting prolonged abstinence from nicotine. This secondary analysis suggests that OROS-MPH may be effective in promoting smoking cessation among the subset of patients whose ADHD response well to methylphenidate treatment.

Abstract:

This presentation provides an overview of protocol CTN-0028, which had three study aims: 1) to evaluate the efficacy of osmotic-release methylphenidate (OROS-MPH) vs. placebo in adolescents with ADHD, 2) to evaluate the impact of OROS-MPH plus cognitive behavioral therapy (CBT) vs. placebo plus CBT on substance abuse outcomes in this population, and 3) to evaluate the overall safety, tolerability, and abuse potential of OROS-MPH. The main study findings are presented, in terms of both ADHD outcomes and substance abuse outcomes, which found the OROS-MPH was safe and well-tolerated, ADHD outcomes were as good or better for the study group than they were for adolescents without substance use disorder, and that the contribution of CBT to both SUD and ADHD outcomes was beneficial for adolescents.

The presentation ends with a discussion of the implications of both the design and outcomes of this study on future research. For example, the results suggest that ADHD clinical response may be important to substance abuse outcomes, and that in the context of CBT (for substance use disorders), significant reduction in ADHD symptoms may occur with or without pharmacotherapy. The study also demonstrated the feasibility of recruitment and enrollment, as well as high compliance, with the difficult-to-recruit population of adolescents with co-occurring disorders.

Related protocols: CTN-0028

Abstract:

This presentation provides an overview of protocol CTN-0028, which had three study aims: 1) to evaluate the efficacy of osmotic-release methylphenidate (OROS-MPH) vs. placebo in adolescents with ADHD, 2) to evaluate the impact of OROS-MPH plus cognitive behavioral therapy (CBT) vs. placebo plus CBT on substance abuse outcomes in this population, and 3) to evaluate the overall safety, tolerability, and abuse potential of OROS-MPH. The main study findings are presented, in terms of both ADHD outcomes and substance abuse outcomes, which found the OROS-MPH was safe and well-tolerated, ADHD outcomes were as good or better for the study group than they were for adolescents without substance use disorder, and that the contribution of CBT to both SUD and ADHD outcomes was beneficial for adolescents. Results of CTN-0028 were inconsistent with most controlled trials of psychostimulants vs. placebo (alone) for ADHD, but consistent with three controlled psychostimulant trials in adults concurrently receiving weekly individual CBT for substance use disorders. This suggests that in the context of individual CBT (for substance use disorder), significant reductions in ADHD symptoms may occur with or without pharmacotherapy, and that reductions in co-occurring ADHD symptoms may be important in helping adolescents achieve greater abstinence during substance treatment.

Related protocols: CTN-0028

Abstract:

Adolescents with substance use disorders (SUDs) have a higher prevalence of ADHD (30%-50%) compared to adolescents in the general population (5%-10%), but little is known about the safety and efficacy of pharmacotherapy for ADHD in adolescents with co-occurring disorders. Clinicians are reluctant to prescribe medications for ADHD in substance-involved adolescents due to their exclusion from pharmacotherapy trials, commonly first referring them for substance treatment. A number of studies have shown that such youths have poorer treatment outcomes. The researchers could find no previous controlled trials evaluating the impact of psychostimulant treatment on both ADHD and substance treatment outcomes in comorbid adolescents concurrently enrolled in substance treatment.

This study, protocol CTN-0028, was a randomized controlled multisite trial of OROS-MPH + CBT vs placebo + CBT. It found that, overall, OROS-MPH was well-tolerated, had low abuse liability, and had a good safety profile despite non-abstinence. There was no difference between OROS-MPH and placebo on primary ADHD and substance outcome measures. However, secondary measures suggested some added benefit of OROS-methylphenidate (OROS-MPH) compared to placebo based on lower parent-rated DSM-IV ADHD-RS scores at 8 and 16 weeks. Greater than expected reduction in ADHD symptoms in both groups suggests that CBT may have contributed to ADHD response consistent with findings from adult studies. However, if ADHD does not respond to CBT early in treatment, OROS-MPH may be considered, even in youths who have not yet achieved abstinence.

Related protocols: CTN-0028