Does Improvement in Symptoms of Attention Deficit Hyperactivity Disorder (ADHD) Mediate an Effect of Long- Acting OROS-Methylphenidate on Cigarette Smoking? A Secondary Analysis of CTN-0029 Edward V Nunes 1, Lirio Covey 1, Mei-Chen Hu 1, Martina Pavlicova 1, Eugene Somoza 2, Theresa Winhusen, 2 1 Columbia University Medical Center (CTN Long Island Node), 2 University of Cincinnati (CTN Ohio Valley Node), Funded by U10 DA13035 (NIDA-CTN) and K24 DA (Nunes)

ABSTRACT 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 among those patients who experience a substantial improvement in their ADHD during treatment. We therefore fit 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 responds well to methylphenidate treatment.

Specific Aim –To explore, among smokers with Attention Deficit Hyperactivity Disorder (ADHD), whether a beneficial effect of OROS-Methylphenidate (OROS- MPH) on smoking cessation is mediated by improvement in symptoms of ADHD Rationale –Stimulant treatment, such as with OROS-Methylphenidate (OROS- MPH), is effective for symptoms of ADHD. –A multisite, placebo-controlled CTN trial of OROS-MPH among ADHD adults with cigarette smoking found the expected effect of OROS-MPH to improve ADHD symptoms, but no main effect of OROS-MPH on cigarette smoking –However, a beneficial effect of stimulant treatment on smoking outcome may occur only among those patients whose ADHD symptoms improve –This would be consistent with the self-medication hypothesis If: among patients with ADHD, nicotine is used for its stimulant properties to improve attention Then: stimulant treatment should increase nicotine abstinence only among those patients whose ADHD gets much better in response to the stimulant

Background ADHD is a neuropsychiatric condition that begins in childhood and, in many cases, persists to adolescence and adulthood. In the U.S., ADHD is estimated to affect 2% to 18% of children and adolescents, and about 4.4% of adults. ADHD has been linked with nicotine dependence. Persons with ADHD are more likely to become regular smokers, begin smoking earlier, smoke more heavily, and experience greater difficulty to stop smoking, compared to persons without ADHD. Evidence that nicotine ameliorates inattentiveness and performance deficits and that nicotine can reduce deficits in dopaminergic function related to inattentiveness suggests a “self-medication” rationale for greater tobacco use among persons with ADHD.

Methods A randomized, double-blind, placebo-controlled trial comparing OROS- MPH vs. placebo as adjunctive smoking cessation treatment (nicotine patch and counseling). Whites = 202; Non-whites = 51 (African-American=15, Hispanic = 16, Other=20). Males=56.5%, mean age=37.8 years (s.d. =10.0), mean years school =14.4 years (s.d. =2.4). Six study sites, located in Cambridge Massachusetts, Columbus Ohio, New York City New York (2 sites), Portland Oregon, and Rochester Minnesota, recruited participants. Study approved by Institutional Review Board at each study site. The trial included an 11- week treatment phase (OROS-MPH vs. placebo) consisting of a four-week pre-quit phase and seven weeks of a planned abstinence period. All participants received brief counseling(11 weeks) and nicotine patch (during Weeks 4-11). Conducted in CTN between December 2005 and January 2008

Outcome and Data Analysis Abstinence outcome: Prolonged abstinence for four weeks at end of medication treatment (weeks 7 to 10) –Standard categorical measure of treatment success recommended by Society for Research on Nicotine and Tobacco Mediator: Change from baseline to end of study in the ADHD symptom severity score (ADHD Rating Scale (DuPaul, Power, et al., 1998)) –A continuous score, where higher change scores indicate greater improvement in ADHD during treatment. Analysis: A mixed effect model was fit, modeling prolonged abstinence as a function of: –Treatment (OROS-MPH vs Placebo) –Mediator (change in ADHD symptom severity during treatment) –Cigarettes per day at baseline as covariate Graph of the model: Although the mediator was a continuous covariate, for the purposes of graphical presentation the score was divided into four quartiles, from low to high change.

Table 1: Baseline characteristics

Model A: Effect of Medication Treatment without Accounting for Improvement in ADHD Term in the model D.FChi-SquarePComment Site Treatment No Treatment Effect Cigarettes per day at baseline Abstinence is less likely for heavier nicotine use

Model B: Effect of Medication Treatment Improvement in ADHD included in the Model Term in the Model D.F.Chi-SquarePComment Site Treatment Cigarettes per day at baseline Abstinence is less likely for heavier nicotine use Change in ADHD More improvement in ADHD associated with more abstinence Interaction: Treatment by ADHD change Effect of treatment on abstinence differs by level of ADHD change

Percent of patients achieving prolonged abstinence, as a function of medication treatment, and improvement in ADHD during treatment: --When ADHD improvement is high, medication is superior to placebo in promoting abstinence --When ADHD improvement is lower, medication trends to being worse than placebo in abstinence

Summary of Findings There was a significant interaction of treatment with change in ADHD score during treatment This suggests that ADHD change during treatment mediates the impact of OROS-MPH on outcome When OROS-MPH produces a large improvement in ADHD symptoms, it improves smoking outcome compared to placebo When OROS-MPH produces little improvement in ADHD symptoms, the trend is that smoking may get worse

Implications Stimulant treatment, such as with OROS-MPH, may be an effective intervention for smoking cessation among smokers with ADHD--if the stimulant produces a large improvement in ADHD symptoms. This is consistent with the self-medication hypothesis, which would predict that unless ADHD symptoms get very much better, patients will continue to smoke to get the attention-improving effects of the nicotine

Clinical Implications ADHD responds quickly to stimulant treatment--within a few weeks, depending on how long it takes to adjust the dose Several different stimulants, and stimulant formulations, as well as non-stimulant medications may be effective for ADHD, and individuals differ in their response Therefore, an effective strategy for cigarette smokers with ADHD may be to treat the ADHD aggressively, and change medications if needed until a robust improvement in ADHD is achieved More research is needed to test algorithmic approaches such as this for the treatment of patients with ADHD and nicotine dependence, and perhaps for patients with co-occurring psychiatric disorders and addictions in general

Implications for Research on Treatment of Co- Occurring Disorders Addictions are associated with increased rates of many psychiatric disorders, and the co-occurrence carries a poor prognosis –Depression, bipolar disorder, PTSD, other anxiety disorders, ADHD Many research studies have sought to improve addiction treatment outcome by treating co-occurring disorders These studies may be inherently underpowered if the effect of treatment on addiction outcome resides only in the subgroup of patients whose co- occurring disorder responds well. –For most co-occurring psychiatric disorders different patients respond to different treatments, and only a minority of patients will respond to any one treatment. Clinically, it may be that treatment of the co-occurring disorder needs to be adjusted aggressively until a good response is achieved In designing studies of treatment of co-occuring psychiatric and addictive disorders, we should consider studying algorithms that seek to maximize response of the co-occurring disorder, by adjusting doses and changing treatments, rather than testing single treatment strategies.