Editorial: Adolescent Substance Use Prevention and Treatment Is Our Wheelhouse.

In this issue of the Journal, Welsh et al.5 revise and update the National Institute on Drug Abuse (NIDA) "Principles of Adolescent Substance Use Disorder Treatment,"6 and the practice recommendations based on these principles, published by Winters et al. in 2018.7 These principles and recommendations are solidly grounded in current research and reemphasize individualized, voluntary, readily available, comprehensive, and integrated long-term treatment that is not solely focused on detoxification; that addresses biopsychosocial issues and comorbid psychiatric diagnoses; and that is tailored to specific populations. They also recommend addressing misuse without disorder, using annual routine medical visits as opportunities for screening, and engaging families and legal systems to promote treatment adherence. However, the problem of adolescent substance use has been presented with new challenges.

Using empirical Bayes predictors from generalized linear mixed models to test and visualize associations among longitudinal outcomes.

Medical research is often designed to investigate changes in a collection of response variables that are measured repeatedly on the same subjects. The multivariate generalized linear mixed model (MGLMM) can be used to evaluate random coefficient associations (e.g. simple correlations, partial regression coefficients) among outcomes that may be non-normal and differently distributed by specifying a multivariate normal distribution for their random effects and then evaluating the latent relationship between them. Empirical Bayes predictors are readily available for each subject from any mixed model and are observable and hence, plotable. Here, we evaluate whether second-stage association analyses of empirical Bayes predictors from a MGLMM, provide a good approximation and visual representation of these latent association analyses using medical examples and simulations. Additionally, we compare these results with association analyses of empirical Bayes predictors generated from separate mixed models for each outcome, a procedure that could circumvent computational problems that arise when the dimension of the joint covariance matrix of random effects is large and prohibits estimation of latent associations. As has been shown in other analytic contexts, the p-values for all second-stage coefficients that were determined by naively assuming normality of empirical Bayes predictors provide a good approximation to p-values determined via permutation analysis. Analyzing outcomes that are interrelated with separate models in the first stage and then associating the resulting empirical Bayes predictors in a second stage results in different mean and covariance parameter estimates from the maximum likelihood estimates generated by a MGLMM. The potential for erroneous inference from using results from these separate models increases as the magnitude of the association among the outcomes increases. Thus if computable, scatterplots of the conditionally independent empirical Bayes predictors from a MGLMM are always preferable to scatterplots of empirical Bayes predictors generated by separate models, unless the true association between outcomes is zero.

A one-session human immunodeficiency virus risk-reduction intervention in adolescents with psychiatric and substance use disorders.

OBJECTIVE: To explore change in human immunodeficiency virus (HIV) risk among teens in outpatient treatment for substance use disorders (SUDs). METHOD: From December 2002 to August 2004, 50 adolescents (13-19 years) with major depressive disorder, conduct disorder, and one or more non-nicotine SUD completed the Teen Health Survey (THS) at the beginning and end of 16 weeks of outpatient cognitive behavioral SUD treatment, which included a one-session HIV intervention. Changes in THS scale scores and specific item responses targeted by the intervention were assessed with paired t tests and Wilcoxon signed rank tests. RESULTS: Pre/post mean THS scores significantly improved for two subscales: Measures of HIV Information (14.8-17.6; p < .001) and Beliefs about Condom Use (17.6-18.5; p < .05). Analyses of specific items showed trends for improvement in intentions to carry condoms and in the number of teens who obtained condoms. Not all of the risks targeted by the intervention showed significant change, but no change was observed in any area that was not specifically targeted. CONCLUSIONS: Results from this preliminary study are consistent with the need for specific assessment and targeted intervention to reduce HIV risk in outpatient adolescent SUD treatment.

On estimating and testing associations between random coefficients from multivariate generalized linear mixed models of longitudinal outcomes.

Different types of outcomes (e.g. binary, count, continuous) can be simultaneously modeled with multivariate generalized linear mixed models by assuming: (1) same or different link functions, (2) same or different conditional distributions, and (3) conditional independence given random subject effects. Others have used this approach for determining simple associations between subject-specific parameters (e.g. correlations between slopes). We demonstrate how more complex associations (e.g. partial regression coefficients between slopes adjusting for intercepts, time lags of maximum correlation) can be estimated. Reparameterizing the model to directly estimate coefficients allows us to compare standard errors based on the inverse of the Hessian matrix with more usual standard errors approximated by the delta method; a mathematical proof demonstrates their equivalence when the gradient vector approaches zero. Reparameterization also allows us to evaluate significance of coefficients with likelihood ratio tests and to compare this approach with more usual Wald-type t-tests and Fisher's z transformations. Simulations indicate that the delta method and inverse Hessian standard errors are nearly equivalent and consistently overestimate the true standard error. Only the likelihood ratio test based on the reparameterized model has an acceptable type I error rate and is therefore recommended for testing associations between stochastic parameters. Online supplementary materials include our medical data example, annotated code, and simulation details.

Substance Abuse Prevention.

Substance use disorders account for approximately 6% of deaths worldwide and cost about $700 billion in the United States. Approximately 80% of drug users begin using during adolescence, underscoring the public health importance of effective substance prevention programs for youth and families. Prevention science designates 3 intervention categories: (1) universal prevention, targeting all individuals in the population, (2) selective interventions, targeting high-risk groups, and (3) indicated prevention interventions for youth with risk-taking behaviors. School-based and non-school-based interventions are reviewed, as well as the limitations of existing research, gaps in access and availability, and directions for future research and development.

Cooccurring Psychiatric and Substance Use Disorders.

Research shows that the majority of adolescents with substance use disorders also have other cooccurring psychiatric disorders, which has been associated with poorer treatment outcomes. Despite considerable consensus that treatment of cooccurring disorders should be integrated or concurrent, most such youth do not receive it. In addition to systemic and economic barriers, few studies have been conducted that inform evidence-based integrated treatment approaches. This article provides a review of current research from which empirically derived principles of integrated treatment can originate and which have informed the development of at least one evidence-based model of integrated mental health and substance treatment.

Integrated substance use and mental health treatment for adolescents: aligning organizational and financial incentives.

The high prevalence of the dual diagnosis of mental and substance use disorders (SUD) has been increasingly documented for both adolescents and adults (Crowley and Riggs 1995; Kandel et al. 1999; Whitmore et al. 1997). For more than a decade, the National Institute of Drug Abuse (NIDA) has included integrated treatment of comorbid psychiatric disorders as one of nine core treatment principles (National Institute on Drug Abuse 1999). Despite empirically supported practice guidelines, implementation of integrated treatment has been slow (New Freedom Commission on Mental Health 2003; U.S. Department of Health and Human Services 1999). In response to the growing call for integrated treatments and systems of care, this paper: (1) identifies systemic and economic barriers that have impeded widespread implementation of integrated care for adolescents with co-occurring SUD, specifically the supply of treatment providers, shifting priorities of gatekeepers to specialty care, and financing streams; and (2) describes possibilities for aligning economic incentives in order to facilitate the dissemination and implementation of integrated care for adolescents with co-occurring SUD.

What came first, major depression or substance use disorder? Clinical characteristics and substance use comparing teens in a treatment cohort.

This study utilized data on a treatment cohort from a randomized clinical trial that recruited adolescents with co-occurring major depression and substance use disorder (N=126). The purpose of this study was to compare adolescents for whom the onset of depression was first versus those for whom the onset of substance use disorder was first or in the same year as depression. Intake clinical evaluations were abstracted to yield common stressors that included childhood abuse, early loss or death, exposure to violence, and attachment problems. Tobacco, alcohol, and cannabis initiation and dependence were compared for the depression first and substance use disorder first groups, and within those groups by gender. Among the substances studied, only cannabis dependence was significantly more prevalent among those with depression first. Comparisons suggest some differences in the developmental path toward comorbid depression and substance use disorders, but remarkable similarity in measures of dependence and severity. Although small samples limited statistical significance, observed differences suggest possible avenues for prevention or intervention.

A randomized controlled trial of pemoline for attention-deficit/hyperactivity disorder in substance-abusing adolescents.

OBJECTIVE: In adolescents with substance use disorder (SUD), comorbid attention-deficit/hyperactivity disorder (ADHD) is associated with greater severity of substance abuse, conduct problems, and worse treatment outcomes. Although many controlled trials have established the efficacy of psychostimulants, including pemoline, for ADHD in children and adolescents, none have been conducted in adolescents with SUD. This randomized, placebo-controlled trial, conducted between 1996 and 2000, evaluated the safety and efficacy of pemoline on substance abuse and conduct problems. METHOD: Sixty-nine adolescents (aged 13-19) with conduct disorder (CD), SUD, and ADHD were recruited from the community and randomly assigned to a 12-week clinical trial of pemoline (n = 35) or placebo (n = 34), titrated over 4 weeks to a single morning dose of 75 to 112.5 mg as tolerated. RESULTS: Pemoline had greater efficacy than placebo for ADHD as determined by significantly more Clinician's Global Impression-Improvement (CGI-I) ratings of 1 (very much improved) or 2 (much improved) at the study endpoint (n = 69; p <.05). There was also greater reduction in ADHD severity on the parent-rated Conners Hyperactivity-Impulsivity scale in pemoline-treated study completers compared to placebo-treated completers (pemoline, n = 17; placebo, n = 16; p <.01), but no difference between groups in the intent-to-treat analysis (n = 68; p <.13). Substance use did not decline in either group, and there was no difference between groups in baseline to study endpoint change in substance use or CD symptoms. Overall, pemoline was well tolerated, demonstrating a good safety profile and no elevation in liver enzyme levels. CONCLUSIONS: Pemoline was efficacious for ADHD but did not have an impact on CD or substance abuse in the absence of specific treatment for SUD.

Major depression and treatment response in adolescents with ADHD and substance use disorder.

BACKGROUND: 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. METHODS: Adolescents (n=303; ages 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 (CBT). 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: Adolescents with MDD reported more non-nicotine substance use days at baseline and continued using more throughout treatment compared to those without MDD (p<0.0001 based on timeline followback; p<0.001 based on urine drug screens). 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.

Subjective effects, misuse, and adverse effects of osmotic-release methylphenidate treatment in adolescent substance abusers with attention-deficit/hyperactivity disorder.

OBJECTIVE: 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. METHOD: Datasets from two randomized placebo-controlled trials of OROS-MPH for treating ADHD, one conducted with 303 adolescents (13-18) with at least one non-nicotine SUD and one with 255 adult smokers (18-55), were analyzed. Outcome measures included the Massachusetts General Hospital Liking Scale, self-reported medication compliance, pill counts, and adverse events (AEs). RESULTS: 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.

Cigarette and cannabis use trajectories among adolescents in treatment for attention-deficit/hyperactivity disorder and substance use disorders.

BACKGROUND: Cigarette smoking is common in adolescents with attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD). However, little is known about the relationship between cigarette and cannabis use trajectories in the context of treatment for both ADHD and SUD. To address this research gap, we report collateral analyses from a 16-week randomized, controlled trial (n=303) of osmotic-release methylphenidate (OROS-MPH) in adolescents with ADHD concurrently receiving cognitive behavioral therapy (CBT) targeting non-nicotine SUD. METHODS: Participants completed cigarette and cannabis use self-report at baseline and throughout treatment. Analyses were performed to explore the relationships between cigarette smoking, cannabis use, and other factors, such as medication treatment assignment (OROS-MPH versus placebo). RESULTS: Baseline (pre-treatment) cigarette smoking was positively correlated with cannabis use. Negligible decline in cigarette smoking during treatment for non-nicotine SUD was observed in both medication groups. Regular cigarette and cannabis users at baseline who reduced their cannabis use by >50% also reduced cigarette smoking (from 10.8±1.1 to 6.2±1.1 cigarettes per day). CONCLUSIONS: Findings highlight the challenging nature of concurrent cannabis and cigarette use in adolescents with ADHD, but demonstrate that changes in use of these substances during treatment may occur in parallel.

Randomized controlled trial of osmotic-release methylphenidate with cognitive-behavioral therapy in adolescents with attention-deficit/hyperactivity disorder and substance use disorders.

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: 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.

How adolescents with substance use disorder spend research payments.

There is concern that research reimbursements to adolescents may increase substance use. However, these concerns have not been examined empirically. Participants were 70 adolescents (13-19 years) with at least one non-nicotine substance use disorder (SUD) enrolled in a 12-week clinical trial of atomoxetine/placebo for attention/deficit-hyperactivity disorder (ADHD). Adolescent participants received cash reimbursement after each study visit (maximum possible = $425 over 12 weeks). Participants reported each week how they spent the previous reimbursement. Results were tallied, and correlates of spending a payment on substances were examined. Results showed that 26 of 70 subjects reported spending at least one research payment on alcohol or drugs, and 25 of 70 subjects reported spending at least one payment on tobacco. Comparing those who did and did not spend a research payment on alcohol/drugs, those who did had more frequent baseline alcohol/drug use but did not differ in demographics (age, gender) or other clinical characteristics (ADHD severity, diagnosis of conduct disorder, number of SUD diagnoses, number of treatment sessions attended, or pre/post-change in number of days used substances in the past 28 days). Comparing those who did and did not spend a payment on tobacco, those who did were slightly older and had more frequent baseline tobacco use. In conclusion, a significant proportion of subjects used at least a portion of one research payment to buy alcohol, drugs or tobacco. However, there was little indication that research payments increased substance use.

Randomized, controlled trial of atomoxetine for attention-deficit/hyperactivity disorder in adolescents with substance use disorder.

OBJECTIVE: To evaluate the effect of atomoxetine hydrochloride versus placebo on attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) in adolescents receiving motivational interviewing/cognitive behavioral therapy (MI/CBT) for SUD. METHOD: This single-site, randomized, controlled trial was conducted between December 2005 and February 2008. Seventy adolescents (13 through 19 years of age) with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) ADHD, a DSM-IV ADHD checklist score greater than or equal to 22, and at least one nontobacco SUD were recruited from the community. All subjects received 12 weeks of atomoxetine hydrochloride + MI/CBT versus placebo + MI/CBT. The main outcome measure for ADHD was self-report DSM-IV ADHD checklist score. For SUD, the main outcome was self-report number of days used nontobacco substances in the past 28 days using the Timeline Followback interview. RESULTS: Change in ADHD scores did not differ between atomoxetine + MI/CBT and placebo + MI/CBT (F4,191 = 1.23, p = .2975). Change in days used nonnicotine substances in the last 28 days did not differ between groups (F3,100 = 2.06, p = .1103). CONCLUSIONS: There was no significant difference between the atomoxetine + MI/CBT and placebo + MI/CBT groups in ADHD or substance use change. The MI/CBT and/or a placebo effect may have contributed to a large treatment response in the placebo group. Clinical Trials Registry Information-A Randomized, Placebo-Controlled Trial of Atomoxetine for Attention-Deficit/Hyperactivity Disorder in Adolescents with Substance Use Disorder. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00399763.