1. OROS-methylphenidate or placebo for adult smokers with attention deficit hyperactivity disorder: Racial/ethnic differences Lirio S. Covey, 1 Mei-Chen Hu, 1 Theresa Winhusen, 2 Judith Weissman, 1 Ivan Berlin 1, Edward Nunes, 1 1 Columbia University Medical Center, 2 University of Cincinnati, Manuscript on line – Drug and Alcohol Dependence, March 2010, Funded by U10 DA13035 (NIDA-CTN) and K24 DA022412 (Nunes) 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). Abstinence outcomes: continuous abstinence (no slips or lapses Weeks 7- 10); prolonged abstinence (slips or lapses allowed Weeks 7-10), point-prevalence (7- day abstinence during Week 10) Mixed effects models examined the interaction of treatment and race/ethnicity. Conducted by the Clinical Trials Network (CTN) of the National Institute on Drug Abuse between December 2005 and January 2008. Table 1: Baseline characteristics Table 2: Mixed effects models on continuous abstinence Abstinence rates by race/ethnicity and treatment OROS-MPH versus placebo treatment produced higher rates of prolonged, point- prevalence, and continuous abstinence among NW than Wh. ADHD symptoms ADHD symptoms declined in all groups. The mixed effects model predicting ADHD symptoms yielded a significant treatment by time interaction (χ2(1)=11.87, p-value=0.0006), reflecting the greater decline over time with OROS-MPH than placebo. No significant difference in medication effect by race/ethnicity, and no interactions between ethnicity and treatment or time. Desire to Smoke The effect of OROS-MPH vs. placebo on desire to smoke differed by race/ethnicity. Among NW, desire to smoke was significantly lower in the OROS-MPH than placebo group during the first week after quit day (week 5, p=0.01), and remained lower compared to placebo during the rest of the planned quit period (weeks 5-11, p=0.098). Among Wh, no significant difference in desire to smoke by treatment status at week 5 (p=0.91) and during the entire planned quit period (p=0.58). Withdrawal Symptoms For tobacco withdrawal symptoms, the linear model yielded a significant main effect of treatment (χ2(1)=16.13, p-value<0.0001), indicating a significant effect of OROS-MPH over placebo for both racial/ethnicity groups. The medication-placebo difference was greater among the non-whites, consistent with a significant treatment race/ethnic group interaction effect (χ2(1)=4.44, p- value=0.035). Findings Higher abstinence rates with OROS-MPH than placebo in NW, not Wh participants. OROS-MPH reduced ADHD symptoms and tobacco withdrawal symptoms in Wh and NW. OROS-MPH reduced desire to smoke in NW only. Decrease in desire to smoke from baseline predicted continuous abstinence during Weeks 7-10. The effect of the treatment/race interaction on continuous abstinence was attenuated upon adjustment for change in desire to smoke (Table 2, Model B). These results suggesting that decrease in desire to smoke mediates the treatment effect on continuous abstinence should be tested with larger and more homogenous samples of nonwhites. Strengths: 1) the randomized, double-blind, placebo controlled design; 2) a high retention rate regardless of randomization status, with 84.3% of participants completing the 11-week active study phase; and 3) high compliance with taking OROS-MPH or placebo (94%). Limitations: 1) Selection biases due to clinical nature of the sample, 2) small NW sample size, 3) NW sample included several race/ethnic groups. Comments: The complexity of race/ethnicity, a theoretical amalgam of participants’ socio-cultural and biological histories, tempers inferences. The use of racial/ethnic information to guide treatment selection, a clinical tool in many areas of medicine, could be a useful tool as well for tailoring the use of methylphenidate for ADHD or for smoking cessation. Clinical,pharmacological, and pharmacogenetic considerations warrant research to replicate and understand the racial/ethnic differences in response to OROS-MPH observed in this study. OROS-MPH could be a useful cessation treatment for some smokers. Who they are and how to identify them needs further study. lsc3@columbia.edu Tel: 212-543-5736 Fax: 212-543-6835 Specific Aims To explore racial/ethnic difference in: the efficacy of OROS-Methylphenidate (OROS- MPH) on smoking abstinence as a function of ADHD treatment, the efficacy of OROS-MPH on ADHD symptoms, desire to smoke, and tobacco withdrawal symptoms, when added to nicotine patch and behavioral counseling, the effects of changes in those symptoms on the abstinence rate. Rationale Race-related variations in drug response is recognized; but scant information exists on racial/ethnic differences in responses to smoking cessation treatments or methylphenidate.

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4. Background Prenatal tobacco exposure have consistently been found to be associated with increased rates of behavior problems, irritability, attention deficit hyperactivity disorder, substance abuse, violence, criminality and increased risk of tobacco consumption in the offspring. Behavioral modifications such as hypertonicity and excitation in association with prenatal smoking has also been observed in 9 to 30 day old newborns. Animal models show that monoamine oxidase (MAO) A inhibition during pregnancy may result in aggressive behavior in the offspring. Tobacco smoking is associated with reduced MAO A and B activities.