Cigarette Smoking Among Youth with Attention-Deficit/Hyperactivity ...

P1: GVG/GCR Journal of Clinical Psychology in Medical Settings

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Style file version Oct. 19, 2000

C 2002) Journal of Clinical Psychology in Medical Settings, Vol. 9, No. 1, March 2002 (°

Cigarette Smoking Among Youth With Attention-Deficit/Hyperactivity Disorder: Clinical Phenomenology, Comorbidity, and Genetics Kenneth P. Tercyak,1,2,6 Beth N. Peshkin,1,2 Leslie R. Walker,3 and Mark A. Stein4,5

Cigarette smoking and other forms of tobacco use among children and adolescents is a significant public health concern. The negative consequences of prolonged exposure to such substances are numerous, and include higher prevalence rates of cardiopulmonary dysfunction and certain cancers, and may lead to other forms of drug use. Identifying subgroups of youth who may be at greater risk than others to develop a nicotine habit is an important step forward in preventing smoking initiation, and controlling tobacco use. One such subgroup is children with attention-deficit/hyperactivity disorder (ADHD). This is because the prevalence of smoking among these youngsters is nearly twice as high as it is among those who are unaffected with ADHD. However, the etiology of this association is not known. It is possible that a constellation of social, behavioral, and biological factors influences this process, resulting in higher prevalence rates. To further our understanding of this problem, we reviewed each of these factors in relationship to smoking and to ADHD. Using the primary care population as a model, we then discuss clinical research methods that may shed additional light on this topic, as well as the strengths and limitations of current smoking prevention and cessation options for ADHD-affected youth who are assessed and treated in medical settings. KEY WORDS: children; adolescents; smoking; ADHD; genetics.

Pediatric cigarette smoking in the United States is a significant public health concern. Each day, it is estimated that as many as 3,000 youngsters start smoking, and many will grow-up to become daily smokers dependent upon nicotine (Pierce, Fiore, Novotny, Hatziandreu, & Davis, 1989). Of those who try smoking, 33–50% eventually transition to a pattern of

regular tobacco use, and a portion will also go on to use other drugs (U.S. Department of Health and Human Services [USDHHS], 1994). Thus, the prevention and treatment of pediatric smoking is critical to decrease the morbidity and mortality from smoking-related illnesses such as cancer, as well as other drug use. When designing pediatric prevention and intervention programs, it is important to have as complete an understanding as possible of the nature and scope of the problem at hand, the individuals most likely to be affected by it, and the environment in which it occurs (Ialongo, Kellam, & Poduska, 2000). In the case of pediatric cigarette smoking, data from national studies (e.g., the Monitoring the Future Project, the Youth Risk Behavior Surveillance System, and the National Youth Tobacco Survey) are instrumental in reporting on such trends and patterns. Through these and other efforts, a profile of risk factors has emerged to estimate the degree of probability of cigarette

1 Lombardi

Cancer Center, Washington, District of Columbia. of Oncology, Georgetown University School of Medicine, Washington, District of Columbia. 3 Department of Pediatrics, Georgetown University School of Medicine, Washington, District of Columbia. 4 Department of Psychology, Children’s National Medical Center, Washington, District of Columbia. 5 Departments of Pediatrics and Psychiatry, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia. 6 Correspondence should be addressed to Kenneth P. Tercyak, Lombardi Cancer Center, Cancer Control Program, 2233 Wisconsin Avenue, NW, Suite 317, Washington, District of Columbia 20007-4104; e-mail: [email protected]. 2 Department

35 C 2002 Plenum Publishing Corporation 1068-9583/02/0300-0035/0 °


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36 smoking occurring under certain social, behavioral, and biological conditions. Included among the factors that place children and adolescents at a rather high risk for adopting a smoking habit is attention-deficit/hyperactivity disorder (ADHD)—a common neurobehavioral condition that affects approximately 3–5% of children and adolescents (American Psychiatric Association [APA], 1994) and roughly 4–5% of adults (Barkley, 1998). Current estimates of regular tobacco use by adolescents with ADHD are twice as high as they are among unaffected adolescents (Lambert & Hartsough, 1998). Although patterns of comorbid conduct problem behaviors, including substance use, have been wellstudied in ADHD, comorbid cigarette smoking has not. The recent reporting that ADHD is so highly associated with cigarette smoking raises important questions as to why this finding might exist. One of the more intriguing possibilities is that the nicotine released when cigarettes are burned remediates or partially treats symptoms of ADHD, including inattention and impulsivity (Levin et al., 1996; Pritchard, 1991). This leaves open the possibility that smoking is a form of self-medication for ADHD symptoms (Conners, Levin, et al., 1996). A more complete understanding of this complex relationship requires a careful examination of its social, behavioral, and biological contributions. Ultimately, developing a better understanding of how each of these factors operate, both independently and in combination with one another, will be a step forward in smoking prevention science. One way to expedite achieving this goal may be to focus on available clinical populations of children and adolescents who are being assessed and treated for ADHD, and to monitor their smoking habits. As the majority of these individuals receive care in traditional medical settings, the pediatric primary care environment may provide a natural opportunity in which to screen for, and ultimately to intervene upon, pediatric smoking behavior. Coupled with the fact that many pediatric providers are encouraged to address tobacco use among all of their patients, and that child health psychology collaborators are often available to pediatricians to assist them in facilitating behavior change among their patients, the rationale for utilizing this setting is further enhanced. In light of the challenges and opportunities for behavior change that are posed by cigarette smoking among children and adolescents with ADHD, the goal of this paper is provide a detailed review of key in-

Tercyak, Peshkin, Walker, and Stein formation regarding the prevalence, distribution, and control of youth smoking, particularly among those with ADHD. Specifically, we will focus on the social, behavioral, and biological factors associated with smoking and with ADHD, and we will explore opportunities within primary care to advance our understanding of these factors. Along with a general discussion of preventing and treating tobacco use among all youth, we highlight new opportunities to forge clinical research collaborations among child health psychologists, basic scientists, and pediatric care providers that could result in tailored smoking treatments for patients with ADHD.

EPIDEMIOLOGY OF YOUTH SMOKING Clinical Description Tobacco use is the leading preventable cause of death in the United States (McGinnis & Foege, 1993). The majority of individuals who experiment with tobacco do so before the age of 18, with cigarettes as the most popular form (Lynch & Bonnie, 1994). However, other sources of tobacco do exist. These include smokeless tobacco, cigars, pipes, bidis (sweet flavored cigarettes from southeast Asia), and kreteks (clove cigarettes), and recent data suggest that use of these alternate products is on the rise (Healton et al., 2000). Pediatric tobacco use can result in nicotine dependence for 8–56% of adolescents who smoke (Kassel, 2000). According to DSM-IV, adult nicotine dependence may be characterized by symptoms of tolerance (e.g., a need to use larger amounts of nicotine over time to achieve the desired effect), withdrawal (e.g., insomnia, anxiety, difficulty concentrating, restlessness), a desire to cut down or control use, a great deal of time spent using the substance (e.g., chain smoking), and limits in social, occupational, or recreational activities as a result of use (APA, 1994). Additional developmentally appropriate criteria for adolescents have yet to be put forth (Kassel, 2000), although examples might include skipping class in order to smoke, being reprimanded by parents or teachers for smoking, or being ineligible to participate in a club, activity, or sport because of tobacco use. Early consequences of youth smoking include respiratory symptoms (cough, phlegm, wheezing, dyspnea), lung function (reduced air flow, lung growth), respiratory illnesses (tract infections), lipid profiles that predispose to cardiovascular disease later in life, and compromised physical fitness (performance,


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Youth Cigarette Smoking and ADHD endurance) (USDHHS, 1994; Woolf, 1997). Of course, the adult health implications of youth smoking as well as sustained smoking in adulthood include greatly increased risks of developing chronic obstructive pulmonary disease, coronary heart disease, stroke, and lung and other cancers (USDHHS, 1994; Woolf, 1997).

Prevalence It is estimated that approximately 5,500 youth experiment with cigarettes for the first time, and nearly 3,000 become established smokers each day (Gilpin, Choi, Berry, & Pierce, 1999). The prevalence of current cigarette use (defined as smoking 1 or more cigarettes within the past 30 days) in Grade 9 is approximately 28%, and the prevalence of current frequent cigarette use (defined as smoking 20 or more cigarettes within the past 30 days) is approximately 11% (Kann et al., 2000). By Grade 12, those estimates increase to 43 and 23%, respectively. Adolescent smoking patterns can vary by gender, race/ethnicity, and grade in school: males, white students, and students in higher grade levels are among those most likely to smoke (Kann et al., 2000).

Adoption/Stages of Smoking There are several stages in the development of pediatric smoking, and these stages have been extensively reviewed and researched (see Mayhew, Flay, & Mott, 2000, for review). The six stages that represent key transitions in youth smoking behavior are displayed in Fig. 1. During the first stage, adolescents have never smoked and have little interest in smoking. In the second stage, adolescents begin to think about smoking, including having perceptions about the functions of smoking and may experience social pressure to smoke. In the third stage, smoking is tried just a few times, followed by a fourth stage of increased experimentation or irregular use. By the fifth stage, a pattern of regular use begins to emerge (usually at least weekly), with more frequent smoking, smoking across a greater number of situations, and smoking in response to more events. In the sixth stage, the adolescent may become nicotine dependent, which is characterized by a physiological need for nicotine. Although much research has described the uptake of smoking behavior as developing through these stages in a forward fashion over time, it is possible that some adolescents transition back and forth


37 between these stages. Further, some adolescents transition through the stages quite rapidly, whereas others do not progress at all. In order to answer questions about how an adolescent with ADHD may progress through none, some, or all of these stages, it is critical to examine differences between individuals which may explain such behavior. These differences include smoking’s social, behavioral, as well as biological determinants, which are reviewed in greater detail below.

Social Factors Social influences on youth smoking behavior have received considerable investigation. For example, both peer and parent smoking affect adolescent smoking rates, although the relative influence of these factors is debated. In one study, peer smoking was found to be both a direct and indirect influence on the initiation of adolescent smoking, while parent smoking exerted only an indirect effect (Flay et al., 1994). Wang, Fitzhugh, Westerfield, and Eddy (1995) reported on the smoking behaviors of over 6,000 adolescents and their family members and peers. Smoking among peers was the strongest and most consistent predictor of adolescent smoking; having a steady boyfriend/girlfriend who smoked was also highly associated with adolescent smoking. It has been speculated that smoking among peers and parents provides social reinforcement for smoking, early models for the behavior, and ready access to tobacco products.

Behavioral Factors In addition to social influences, several studies conducted with both adults (Hughes, Hatsukami, Mitchell, & Dahlgren, 1986) and adolescents (Brown, Lewinsohn, Seely, & Wagner, 1996) suggest that behavioral distress is associated with smoking (Glassman, 1993; Moolchan, Ernst, & Henningfield, 2000). For example, depression has consistently been linked to adolescent and adult smoking (Brown et al., 1996; Choi, Patten, Gillin, Kaplan, & Pierce, 1997; Covey & Tam, 1990; Patton et al., 1996). Anxiety is also a risk factor for smoking. Patton et al. (1998) found that anxiety predicted the initiation of experimental smoking among adolescents, and increased the risks associated with peer smoking. Why behavioral distress promotes smoking is unknown. However, nicotine contained in tobacco


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38

Tercyak, Peshkin, Walker, and Stein

Fig. 1. Stages in the development of adolescent smoking.

products acts as a psychostimulant that may induce feelings of euphoria, relaxation, enhanced shortterm memory, and increased attention and problemsolving abilities for some smokers (Woolf, 1997), which could ameliorate anhedonic states. Thus, it is possible that distressed adolescents who experiment with using tobacco products continue to do so to selfmedicate their symptoms and regulate their affect and level of arousal (Carmody, 1989). So far, we have described two major areas of influence on youth smoking. These include social and behavioral factors. Developing a fuller understanding of how these factors function independently, in conjunction with one another, and in combination with nicotine’s physiological effects on adoles-

cents with ADHD will require additional research. However, at this time it is worthwhile to examine the problem of ADHD, its impact on adolescent development, and comorbid smoking behavior in order to derive hypotheses regarding the causal mechanisms which possibly underlie both conditions.

EPIDEMIOLOGY OF ADHD Clinical Description ADHD is a heterogeneous, neurobehavioral syndrome that begins in childhood and refers to


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Youth Cigarette Smoking and ADHD individuals who display developmentally inappropriate levels of attention problems or hyperactivity, along with impairments in functioning at home, school, or in social settings (APA, 1994; Stein, Szumowski, Blondis, & Roizen, 1995). ADHD is currently diagnosed on the basis of DSM-IV criteria, which include a long-standing history of ADHD symptoms. There appears to be a wide range of severity of ADHD, and much variability in the range of associated problems. Mild ADHD is more common than severe or pervasive ADHD. Younger children display more ADHD symptoms than do older children or adults. One form of ADHD, the Combined Type, refers to individuals with significant levels of hyperactivity/impulsivity and inattention, while the Predominantly Inattentive Type of ADHD refers to individuals who mostly display symptoms of inattention (Rucklidge & Tannock, 2001). However, many youngsters display fewer overactive symptoms as they become older, and when reevaluated no longer meet the criteria for Combined Type. Others, especially younger children, may be diagnosed with the Predominately Hyperactive–Impulsive Type, which is characterized by restlessness and overactivity, but not inattention.

Prevalence Depending on how it is defined, the prevalence of ADHD ranges from 2 to 9% of children (Cantwell, 1996; Tannock, 1998). It is more common in males, especially in clinic settings where the male/female ratio can range from 9:1 to 3:1, depending on the clinic. There is still a male preponderance in community ascertained samples, but much lower than in clinic settings. The vast majority of our knowledge of the disorder comes from studies of elementary school-age boys, although in recent years there has been increased interest in studying ADHD in preschoolers, females, older adolescent age groups, and adults (Bellak & Black, 1992; Gaub & Carlson, 1997; Rucklidge & Tannock, 2001).

Social and Behavioral Factors The syndrome of ADHD continues into adolescence for approximately 70% of those who displayed it in childhood (Barkley, Fischer, Edelbrock, & Smallish, 1990), and persists into young adulthood for

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39 about 30–60% (Weiss & Hechtman, 1993). Moreover, for a small but significant subgroup (approximately 10–15%), ADHD is strongly associated with severe antisocial behavior and substance abuse (Gittelman, Mannuzza, Shenker, & Bonagura, 1985; Hechtman & Weiss, 1986; Lambert, 1988). Thus, children with ADHD are at risk for continuing to display ADHD, as well as other problems, as they move into adolescence. However, ADHD does remit in some adolescents. According to Cantwell (1996), approximately 30% of children with ADHD display a “developmental delay” type of outcome in that their symptoms dissipate over time. Biederman et al. (1996) found that persistence of ADHD was predicted by its familial presence, psychosocial adversity, and either comorbid conduct or mood disorders. Of the 15% who remitted, half did so in childhood and half in adolescence. Howell, Huessy, and Hassuk (1985) reported a higher rate of normal outcome in those whose ADHD symptoms were rated on only one occasion. Barkley et al. (1990) summarized the predictors of adolescent outcome, noting that no single predictor seems useful in predicting outcome. Factors thought to predispose children with ADHD to especially poor outcomes as they mature include low socioeconomic status, intelligence, and academic achievement; poor peer relationships; comorbid conduct symptoms; parental psychopathology; and conflict and hostility in the family. The diagnosis of ADHD in adolescence is difficult because the ADHD symptoms are often obscured or pale in comparison to comorbid disorders, especially severe behavioral, substance abuse, or mood disorders (Biederman et al., 1996). On the other hand, there are some adolescents with the Predominantly Inattentive Type of ADHD who typically do not display significant disruptive behavior disorders and may be diagnosed at a later age or even missed. In contrast to the high male preponderance in the Combined Type group, individuals with the Predominantly Inattentive Type display a more even gender ratio and are slightly older at age of peak referral. These individuals are usually referred because of declining school grades, more typically after the fourth grade. Very little is known about the life course of individuals with the Predominantly Inattentive Type, as few longitudinal studies have been conducted employing appropriate diagnostic criteria. However, in light of the effects of nicotine on attention levels (see below), the smoking habits of this subgroup of individuals is of particular interest.


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40 CIGARETTE SMOKING WITHIN THE CONTEXT OF ADHD Clinical Description Like many youth, those who are affected with ADHD are likely to experiment with smoking prior to reaching adulthood. However, unlike most other youth, their risk of developing a smoking habit is further impacted by their psychopathology. For example, youth with ADHD are likely to be more impulsive decision makers about smoking, especially when exposed to peer pressure to smoke. Since approximately one-third of children with ADHD also develop conduct disorders, and these disorders are important risk factors for smoking and substance abuse, it is likely that children with ADHD may also have higher tendencies to become members of peer groups overrepresented by other conduct disordered adolescents and smokers. One important study found that youth with ADHD were more likely to be involved in cigarette use than were youth without ADHD (Hartsough & Lambert, 1987). In a prospective study by Barkley et al. (1990), hyperactive children followed into adolescence had higher rates of using cigarettes compared to normal control children. In light of these early findings, additional reports of this phenomenon soon followed. For example, in a study of the developmental history of tobacco use among ADHD-affected youth and unaffected controls, Lambert and Hartsough (1998) found that by age 17, 46% of ADHD participants reported daily cigarette smoking, and this was significantly higher than the rate of smoking among controls (24%). These trends also persisted into adulthood, where ADHD-affected current smokers and those dependent on tobacco outnumbered unaffected current smokers and tobacco dependents by nearly 2:1. With smoking defined as any amount of smoking on a daily basis for a month, Milberger et al. (1997a) found that 19% of the 140 adolescents with ADHD versus 10% of the nonADHD adolescents were smokers. Adolescents with ADHD were also found to begin smoking at an earlier age (15.5 years vs. 17.4 years) than controls. Additionally, adolescents with ADHD and comorbid psychiatric disorders had even higher rates of smoking (27%) than those who did not have comorbid psychiatric disorders (10%). Others investigating the relationship between ADHD and nicotine dependence have also shown ADHD to be associated with an earlier onset of regular smoking (Riggs, Mikulich,

Tercyak, Peshkin, Walker, and Stein Whitmore, & Crowley, 1999), with inattention (versus hyperactivity-impulsivity) being particularly strongly associated with smoking outcome (Burke, Loeber, & Lahey, 2001). In a follow-up study, Milberger et al. (1997b) investigated whether the presence of ADHD in a family member is a risk factor for the development of cigarette smoking in siblings of ADHD probands. As in the previous study, the authors found that ADHD was associated with higher rates of smoking in siblings, and that these siblings also started smoking earlier in life. Further, their cigarette smoking was associated with a host of other problem behaviors, including conduct disorder, depression, and drug abuse, and appeared to be strongly familial in nature. In terms of the familial influence of smoking, at least one study has found that in utero exposure to nicotine is itself a risk factor for the development of ADHD in children (Milberger et al., 1996). Exactly what happens to the smoking habits of adolescents with ADHD as they mature is not yet known. One study conducted with 71 ADHDaffected male and female adults showed that among men, 42% were current smokers, 13% were former smokers, and 45% were never smokers. Among women, these estimates were 38, 31, and 31% respectively. Compared to the general population, rates of smoking among ADHD-affected adults were considerably higher and the rates of quitting among men were considerably lower (Pomerleau, Downey, Stelson, & Pomerleau, 1995). A key question is the specificity of this relationship, and whether or not these rates are higher than smoking rates in children who grew-up with other forms of psychopathology, such as conduct or anxiety disorders. As there may also be smoking-prone personality differences in adults with ADHD who smoke compared to adults with ADHD who do not smoke (Downey, Pomerleau, & Pomerleau, 1996), [there is a pressing need to understand the origins of smoking behavior in childhood and adolescence, its developmental course, and its expression in community contexts (Tercyak, Lerman, & Audrain, in submission)]. Biological Factors In this section, we review two areas related to the biological basis for smoking that are highly relevant to ADHD: (1) the physiological effects of nicotine on attention and (2) the role of dopamine and dopamine genes in smoking and attention.


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Youth Cigarette Smoking and ADHD

Nicotine As mentioned previously, the association between nicotine use and various forms of psychopathology, most notably depression, has been well studied. One of the possible reasons for this association is that upon entering the body, nicotine acts as a powerful central nervous system stimulant. The stimulation derived from nicotine may help some smokers with ADHD compensate for their low levels of attention, arousal, and stimulation. Nicotine has been shown to enhance sustained attention in animal models (Mirza & Stolerman, 1998). In humans, several studies suggest nicotine’s usefulness in reducing symptoms of adult ADHD (Levin et al., 1996, 1998; Levin, Conners, Silva, Canu, & March, 2001; Levin & Rezvani, 2000) and focusing attention in smokers and nonsmokers (Ernst, Heishman, Spurgeon, & London, 2001). Although we are aware of no studies which have administered nicotine (e.g., via nicotine nasal spray, transdermal patch, or gum) to youth with ADHD, psychostimulants are commonly given to children to treat ADHD symptoms (Conners, Casat, et al., 1996). Many of these stimulants act upon the same neural systems, predominantly dopaminergic, as does nicotine. Below, we review biological mechanisms that are genetic in origin, which may partly explain these effects.

Molecular Genetics of Smoking and ADHD The identification of a single etiology for cigarette smoking, ADHD, or any complex trait, is a difficult undertaking. To determine the relative contributions of genetic, or heritable, components versus environmental (i.e., nongenetic) components that lead to the development of these and other conditions, standard quantitative methods in genetic epidemiology have been utilized. These methods include family, twin, and adoption studies, as well as combinations of approaches (Neiderhiser, 2001). Ultimately, such methods may lead to the identification of specific candidate genes that may relate to various forms of child psychopathology (see Alsobrook & Pauls, 1998, for review). Child health psychologists can help in the identification of disease-causing genes in a number of different ways. First, for complex traits or conditions, reliably defining the phenotype (i.e., the behavioral expression of genes) is a prerequisite to the effective use of molecular genetic techniques. Although

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41 one early study suggested that ADHD was genetically linked to mutations in the thyroid hormone receptor gene (Hauser et al., 1993), psychological assessment that went beyond ADHD symptom counts and included intelligence testing revealed that the phenotype of resistance to thyroid hormone was dissimilar from ADHD (Stein & Leventhal, 1993). Thus, our expertise in the measurement of behaviors such as those related to ADHD and to smoking, and our knowledge of the influence of environmental factors on behavior, are essential components of this process. Second, child health psychologists should be prepared to use genetic findings once they are available (Plomin, 1998). As genetic discoveries in the laboratory are translated into clinical practice, it is highly foreseeable that child health psychologists will be involved in explaining the implications of genetic risk factors to children and their families. We are clearly in the midst of a genetic revolution which is influencing all of medicine and health science. In light of this emerging trend, we have provided an overview on genetic methods below. We focused this discussion on genetic methods relevant to the dopamine system, which has been implicated both in cigarette smoking and in ADHD. Family Methods. Family studies, which are most informative with large families when the histories of distant relatives are elicited, examine the incidence of ADHD among biological relatives of an affected index case (proband), and reveal whether there is an excess familial incidence of the disorder (Niederhiser, 2001). Evidence for the importance of genetic factors in ADHD and in smoking comes from a variety of twin, family, and adoption studies. There is also a significant body of animal research suggesting high heritability for activity level (Faraone & Doyle, 2001). In the case of ADHD, relatives of probands with ADHD compared to relatives of adoptive controls, unaffected controls, or psychiatric controls have revealed an increased prevalence of ADHD in their biological relatives (Alberts-Corush, Firestone, & Goodman, 1986; Biederman et al., 1992; Biederman, Faraone, Keenan, Knee, & Tsuang, 1990; Cantwell, 1972). Familial models of smoking have also been studied, which suggest a strong pattern of intergenerational occurrence (Cheng, Swan, & Carmelli, 2000). Twin studies, which involve comparisons between monozygotic (MZ; identical) and dizygotic (DZ; fraternal) twins, can further distinguish potential genetic and environmental contributions to ADHD and to smoking, with the underlying assumption that if


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42 the behavior is due, in large part, to hereditary factors, MZ twins will exhibit higher concordance (i.e., presence of the behavior) than DZ twins, whereas if environmental factors are strongly implicated, MZ and DZ twins will both be highly concordant. Twin studies are consistent with moderate to high heritability of attentional dysfunction (Stevenson, 1992; Willerman, 1973), as well as smoking (Carmelli, Swan, Robinette, & Fabsitz, 1992). Candidate Gene Methods. Pursuant to the establishment of familial/genetic associations with behaviors of interest, the next step has been to employ molecular genetic methods to determine the specific gene or genes involved. In the case of cigarette smoking, individual differences in responses and sensitivities to nicotine administration are largely under the control of biological systems, and strong evidence suggests these systems are influenced by genes involved in regulating the neurotransmission of dopamine. The release of dopamine in the brain has been strongly associated with reward, pleasure, and reinforcement (Wise, Bauco, Carlezon, & Trojniar, 1992). For example, in laboratory studies animals will self-deliver painful stimuli if those stimuli cause the release of dopamine (see Gardner, 2000, for review). In the case of ADHD, pharmacotherapy with agents that inhibit the dopamine transporter (DAT), such as methylphenidate, dextroamphetamine, and bupropion, are effective in mitigating the effects of ADHD (Conners, Casat, et al., 1996; Cook et al., 1995). Recently, the DAT gene and its polymorphisms (normal variations of the gene; normal, alternate forms of the same gene) have been investigated in relation to smoking. The DAT gene is responsible for the reuptake of dopamine back into neurons, and also has a role in modulating communication among neurons. Some DAT polymorphisms result in decreased efficiency of the reuptake process and high levels of dopamine; others result in enhanced reuptake efficiency and low dopamine levels (Pomerleau & Kardia, 1999). Dopamine regulation is considered important in cigarette smoking because the reinforcing properties of nicotine have been attributed to nicotine’s putative effects on dopamine transmission. Much like cocaine and alcohol, nicotine stimulates dopamine release and disturbs reuptake. The end result is an increase in brain levels of dopamine, pleasurable stimulation, and enhanced task performance, which highly reinforces the smoking habit (Carmody, 1989). Pursuing this biological model of smoking further, it follows that individuals with DAT gene polymorphisms associated with greater availability of

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Tercyak, Peshkin, Walker, and Stein dopamine should be less likely to smoke. A study by Lerman et al. (1999) found this to be true, and a related study showed that more former than current smokers shared this characteristic as well (Sabol et al., 1999). These results offer preliminary evidence for a genetic basis of cigarette smoking. Candidate genes associated with ADHD have been identified based on a combination of findings ranging from therapeutic observations to results of neuroimaging and animal studies—all of which implicate the dopaminergic system (Heinz et al., 2000; Payton et al., 2001). Interestingly, most research has focused on the DAT gene and related genes such as the dopamine D4 receptor (DRD4) gene. If the DAT gene is mutated, recycling of excess dopamine may be impaired. On the other hand, when the DRD4 gene is mutated, receptors may be unable to perform adequate uptake of dopamine to be transported to the neurons. These genes are highly active in areas of the brain that are involved in the regulation of attention. Regarding ADHD, a significant association between DAT genes and ADHD has been reported by Cook et al. (1995). This finding has subsequently been replicated (Gill, Daly, Heron, Hawi, & Fitzgerald, 1997; Waldman et al., 1998). With respect to the DRD4 gene, a meta-analysis of over 20 case control and family-based studies supported a small association between a 7-repeat allele of DRD4 and ADHD (Faraone, Doyle, Mick, & Biederman, 2001). The plausibility of DRD4 as a susceptibility gene for ADHD is supported by previous research demonstrating an association between the gene and high novelty seeking behavior, which may also be observed in individuals with ADHD (LaHoste et al., 1996). A recent investigation concluded that the DRD4 gene is associated with both normal and abnormal attention processes (Schmidt, Fox, Perez-Edgar, Hu, & Hamer, 2001). In addition, further support for this association is derived from in vivo and in vitro studies of the DRD4 gene function and pathophysiology of ADHD, although more research in this area is warranted (Faraone et al., 2001). Limitations of Behavioral Genetic Methods. Although published studies regarding the association of DAT genes with ADHD and DAT genes with smoking are informative, future research with larger sample sizes is critical to determine the functional significance of this association. The available studies are limited by confounding factors, such as clinical heterogeneity in subject ascertainment (e.g., lack of uniform criteria in diagnosis, inclusion of subjects with comorbid psychiatric conditions and conditions with nongenetic


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Youth Cigarette Smoking and ADHD etiologies such as acquired brain damage) and the likely occurrence of genetic heterogeneity (i.e., that more than one gene alteration may contribute to the disorder and the effects of each one may be relatively small). Overcoming these limitations might be facilitated by focusing on available clinical populations of youth with ADHD, including those treated in primary care settings, and surveying their tobacco habits. To the extent that social, behavioral, and biological factors for tobacco use could be studied within this clinical context, it is likely that these findings will soon guide and inform practice. In the next section, we focus on the importance of screening and treating tobacco use in all youth, as well as the importance of treating ADHD, to minimize the likelihood of the development of negative childhood outcomes, including smoking and other substance use.

PEDIATRIC PRIMARY CARE Screening and Treating Tobacco Use Pediatricians, nurses, and others who provide primary care to children and adolescents are strongly recommended to intervene with cases of pediatric smoking wherever and whenever possible (Elster & Kuznets, 1994; Fiore et al., 2000; Glynn, 1993). Professional practice guidelines also suggest that all adolescents have an annual, confidential preventive services visit during which primary care providers screen, educate, and counsel patients on medical, emotional, behavioral, and social areas that threaten their wellbeing (Halpern-Felsher et al., 2000). As youth with ADHD are frequently seen by health professionals for treatment of their ADHD, this provides a natural opportunity to address smoking behavior. Despite these opportunities, actual provision rates of such services to the general population are rather low (Lando & Hatsukami, 1999). For example, data collected as part of a national survey found that only 21% of 10–16 year olds, 29% of 17–19 year olds, and 34% of 20–22 year olds reported that a health care provider (e.g., physician, dentist, nurse) ever discussed cigarette smoking with them (Centers for Disease Control and Prevention, 1995). Males were less likely than females to have received such advice (24% vs. 27%), as were adolescents in excellent health compared to those in poor health (24% vs. 29%), and those without any history of smoking compared to those with one or more experiences (21% vs. 50%).

43 Nationally, counseling about the hazards of smoking is provided in only about 2–3% of all adolescent visits (Goodwin, Flocke, Borawski, Zyzanski, & Stange, 1999; Thorndike, Ferris, Stafford, & Rigotti, 1999). In California, a state with relatively progressive antitobacco public health initiatives, there is a much higher rate of physician screening of all adolescents for regular smoking. One study found the rate of screening of younger and older adolescents to be 76 and 86%, respectively (Ellen, Franzgrote, Irwin, & Millstein, 1998); however, California physician screening rates for experimental smoking among younger (18%) and older (36%) adolescents remain suboptimal (Franzgrote, Ellen, Millstein, & Irwin, 1997). Although these statistics may seem discouraging, they are amenable to change. In a study by Klein et al. (2001), the authors evaluated the implementation of a comprehensive preventive care program for adolescents, including screening and counseling for smoking and other health behaviors, in the context of medical visits. The results suggested that after the program was implemented, positive changes occurred in the process of care, as well as the amount and content of preventive care. Such an approach is highly consistent with the majority of youth-oriented policies on tobacco, which advocate abstinence and prevention. In the case of adolescents with ADHD who are known to be at high risk for smoking, these prevention efforts are critically necessary. It is unclear as to what impact the interaction of nicotine with other stimulants has on youth with ADHD. However, for the subset of youth who have already experimented with smoking and are on their way to developing a tobacco habit, interventions to promote quitting are necessary as well. This is particularly important as the more risk factors an adolescent has for smoking, the less likely he or she may be in quitting successfully (Zhu, Sun, Billings, Choi, & Malarcher, 1999).

Behavior Therapy for Smoking Among ADHD-Affected Youth To date, very few published studies have shown behavior therapy for smoking cessation during adolescence to be highly effective. In a comprehensive review on the subject, Sussman, Lichtman, Ritt, and Pallonen (1999) reported that the natural quit smoking rate among adolescents is low (range of 0–11%), and that most interventions achieve an immediate quit rate of around 21% (range of 0–36%). This being the case, there are substantial opportunities to


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44

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Table I. Six A’s for Addressing Pediatric Smoking in Medical Settings 1. Anticipate: Provide age-appropriate education, and congratulate youth who are nonsmokers. 2. Ask: Inquire about environmental exposure to tobacco smoke and tobacco use by patient and family members, and record it in the patient’s chart. 3. Advise: Use clear, personal, relevant messages to advise tobacco users to quit. 4. Assess: Assess readiness to quit; use motivational interviewing to promote readiness. 5. Assist: Offer self-help materials and referral information for quitting smoking. 6. Arrange follow-up: Schedule follow-up visits to monitor success with quitting and relapse prevention. Source. American Academy of Pediatrics Committee on Substance Abuse (2001).

improve these rates, especially among adolescent subgroups that may be particularly difficult to reach with traditional quitting strategies (e.g., self-help booklets, group counseling), such as those with ADHD. Although no published studies have specifically addressed how to conduct quit smoking counseling session for adolescents with ADHD, there are several suggestions for non-ADHD-affected youth who smoke that could be modified. For example, in an article published by the American Academy of Pediatrics Committee on Substance Abuse (2001), six components recommended by a variety of federal guidelines to address tobacco use by children seen in medical settings were reviewed (see Table I). These components (all of which begin with the letter “A” to facilitate provider recall) are: (1) Anticipate that youth will encounter pressures to smoke, and to educate patients and parents about the dangers of smoking; (2) Ask about exposure to environmental smoking and tobacco use by patients and family members and to record this information in the medical record; (3) Advise those who are using tobacco to quit; (4) Assess if the tobacco user is ready to quit, and motivate those who are not yet ready to quit to do so; (5) Assist in quitting by offering self-help and referral information; and (6) Arranging follow-up to monitor patient progress. (p. 796)

From this framework, it is clear that child health psychologists have an important role to play in reducing tobacco use among young people. Our skills in providing patient education and counseling about health behavior and behavior change are critical to the quit smoking process. It will be necessary to conduct research on how to best tailor these basic strategies to meet the needs of adolescents with ADHD and other

forms of psychological distress who smoke, and child health psychologists are in an excellent position to do so. In the case of ADHD, this research will clearly involve behavior management for both ADHD and smoking, as well as consulting with other providers about appropriate pharmacotherapeutic options that might be available to address both the symptoms of ADHD and the comorbid cigarette smoking. Similar work addressing substance use within the context of ADHD has also been proposed (Aviram, Rhum, & Levin, 2001; Sullivan & Rudnik-Levin, 2001). In the next section, we review the use of psychostimulants, antidepressants, and other agents that might be beneficial in achieving these ends.

Pharmacotherapy of ADHD That May Impact Upon Youth Smoking Behavior Pharmacological treatment of childhood ADHD is increasingly common, especially in North America (Safer et al., 1996). In the last decade, growing numbers of adolescents and adults were treated for ADHD as there is a greater awareness that, for many, this is a chronic disorder. In the past, the mistaken belief was that children “grew out of” their hyperactivity and thus no longer needed medication. Over the last decade or so it has become apparent that adolescents and adults who suffer from untreated ADHD experience negative effects such as increased car accidents (Barkley, 1996), increased cigarette smoking, and decreased ability to successfully quit smoking (Pomerleau et al., 1995). They also have increased rates of conduct and psychoactive substance use disorders (PSUDs; Biederman et al., 1995), a higher divorce rate, job instability, and decreased attainment of educational goals (Searight, Burke, & Rottnek, 2000). In the following, we review the predominant pharmacotherapies for ADHD and discuss their relevance to comorbid tobacco use.

Psychostimulants The first line choice of medications for ADHD after age 6 is the stimulant medications. The most commonly prescribed are methylphenidate (Ritalin ), amphetamine (Dexedrine ), an amphetamine and dextroamphetamine mixture (Adderall ), and OROS methylphenidate (Concerta). Concerta is finding increasing popularity in the treatment of ADHD, especially with adolescents because of its


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Youth Cigarette Smoking and ADHD 10–12-hr duration and once a day dosing pattern, which eliminates the need for in-school dosing. There is also less risk for diversion or abuse if administered once a day at home. In the past, long-acting forms of methylphenidate had variable duration of effect and thus could be unreliable in predicting the effect of the medication day to day. The amphetamine and dextroamphetamine mixture Adderall is commonly used in adolescents and adults as well because its dose effect lasts approximately 6 hr compared to methylphenidate which has a dose effect lasting approximately 4 hr. These medications have been shown to increase attentiveness and concentration and decrease impulsivity in youth and adults (Dulcan, 1997; Wilens, Biederman, & Mick, 1998). Stimulant medication studies with adolescents suggest efficacy similar to that observed in young children. If adolescents are correctly treated with these psychostimulants, they may be somewhat less driven to self-medicate with nicotine. However, adolescents in general are more nonadherent with medication recommendations and often discontinue treatment. It is unclear how common stimulant abuse and diversion are, but these issues are concerns in a population at risk for tobacco and substance use.

45 Presently, because of a favorable safety profile and several studies documenting its efficacy, bupropion is often the first choice for someone who is refractory to stimulant treatment. Bupropion (dually marketed as Wellbutrin [for depression] and Zyban [for smoking cessation]) may decrease aggression, hyperactivity, and improve cognitive performance in those with ADHD (Conners, Casat, et al., 1996; Popper, 2000). Bupropion is also the first nonnicotinic agent approved in treatment for smoking cessation (Prochazka, 2000), and is currently being tested in adolescents (Backinger & Leischow, 2001). This dual capability may be helpful in treating ADHD adolescents and young adults who are also candidates for aggressive smoking cessation, although it would not be appropriate for those with comorbid anxietyspectrum disorders (such as obsessive–compulsive disorder) as bupropion may exacerbate their symptom profile. At this time, more research is needed to understand the interaction of nicotine with other drugs so that appropriate therapies can be planned (see Zevin & Benowitz, 1999, for review), especially among youth.

Progression to Substance Use in Adolescents With ADHD

Antidepressants Antidepressants are used as a second tier treatment for ADHD. There is considerable research documenting the efficacy of tricyclic antidepressants in the treatment of ADHD. However, because of potential cardiotoxicity, these medications have limited utility. The newer serotonin-specific reuptake inhibitor antidepressants can increase impulsivity and disinhibition; thus they have little role in the management of ADHD unless there is a co-occurring mood disorder. Agents that modify synaptic norepinephrine transmission and improve nicotine withdrawal symptoms include the tricyclic antidepressant nortriptyline. Although nortriptyline has shown some signs of being effective in the treatment of ADHD and in smoking cessation, a concern with tricyclic antidepressants is that the potential side effects are serious (Dulcan, 1997; Ferry, 1999). Nortriptyline does have the benefit of a longer duration of action—eliminating the need for in-school administration. It also addresses potential comorbidities such as depression and nicotine dependence, but the risk of cardiotoxicity and the small window of therapeutic efficacy require monitoring blood levels and caution in its use.

Because early cigarette smoking is clearly linked to illicit substance abuse (Kandel & Yamaguchi, 1993), some individuals with ADHD are prone to develop a PSUD later on in life as well. Along with comorbid conduct disorder, substance use is one of the most visible and debilitating outcomes in adolescents with ADHD. Previous studies suggest that approximately 10–30% of children with ADHD display an extremely poor outcome characterized by continual display of ADHD symptoms and the development of more serious psychopathology in the form of alcoholism, substance abuse, and antisocial personality disorder (Abikoff & Klein, 1992; Cantwell, 1996). A frequent question asked in relation to children with ADHD who have been treated with stimulant medications is whether or not they are more likely to participate in drug use during adolescence than individuals treated without stimulant medications. Although ADHD is associated with increased rates of later substance abuse, particularly when there are comorbid conduct disorder symptoms (Cantwell, 1972), there is no evidence that stimulant medication use increases this risk (Weiss & Hechtman, 1993). In fact, several recent studies suggest that treatment with stimulant medication may exert a protective


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46 effect in terms of reducing risk of later substance abuse (Biederman, Wilens, Mick, Spencer, & Faraone, 1999; Paternite, Loney, Salisbury, & Whaley, 1999). Several studies have shown a small but not statistically significant increased risk for PSUDs in grown-up ADHD children (Biederman et al., 1995). Biederman et al. (1997) found a 15% rate of PSUD in ADHD and normal control subjects. Independent of ADHD status, both conduct and bipolar disorders predicted PSUD. Although family history of ADHD was not associated with PSUD, a family history of substance dependence and antisocial behavior were associated with PSUD in controls, but less clearly so in ADHD probands. Thus, the question of whether or not youth with ADHD are at increased risk for alcohol or drug abuse or dependence is complicated by multiple factors including the presence of comorbid psychiatric and learning disorders, family history, and adversity. For example, several studies suggest that the association between ADHD and later substance abuse disorders is almost completely moderated by previous conduct problems (Disney, Elkins, McGue, & Iacono, 1999; Lynskey & Fergusson, 1995), thus highlighting the importance of taking the interaction of ADHD with other frequently occurring associated risk factors into account.

SUMMARY AND RESEARCH AND TREATMENT IMPLICATIONS To date, little attention has been paid to the intersection of cigarette smoking and ADHD among youth, and additional work is called for. To facilitate these efforts, a partial list of research priorities is provided in Table II. When considering research on the treatment of smoking in the context of ADHD, the role of behavioral counseling cannot be understated. Although there is limited data on effectiveness, the poor outcome and resistance of ADHD and smoking to brief interventions suggest the need for long-term, comprehensive treatment programs that include social, behavioral, and biological management. Although some medications alone may be effective in promoting smoking cessation, issues regarding maintenance, generalization, and relapse to smoking further highlight the need for additional interventions in order to promote lasting change. This is especially true among adolescents with ADHD, as their initial motivation to quit smoking may be low, and their skills and resources for self-direction and self-management may

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Tercyak, Peshkin, Walker, and Stein Table II. Areas for Basic, Translational, and Applied Biobehavioral Research Basic To elucidate the unique and shared environmental, genetic, neurobiological, and neuropsychological underpinnings of ADHD and smoking To more fully characterize the reward pathways for smoking among those with ADHD and other comorbid behavior disorders To study the biobehavioral basis of smoking motivations among youth with ADHD Translational To explore patient and family attitudes about genetic markers of ADHD and smoking risks To determine if youths’ decisions to start smoking or to quit are influenced by feedback about their susceptibility To determine if success with quitting smoking can be influenced by knowledge of individual variations in treatment response Applied To compare the efficacy of comprehensive smoking prevention/ intervention programs delivered to youth with ADHD that incorporate social, behavioral, and biological management To develop comprehensive health care networks that address pediatric tobacco use at home and in medical, school, and community contexts To develop and test targeted educational campaigns to discourage tobacco use among youth with ADHD

be rather limited. In this case, motivational interviewing may be helpful (Colby et al., 1998), along with more intensive behavior management training. Having said that, the future of research on smoking cessation interventions for teenagers appears to lie in combining behavioral and biological approaches (Fiore et al., 2000), and tailoring interventions to match key patient characteristics and readiness to change. These tailoring strategies may be based on many of the same social, behavioral, and biological characteristics already mentioned throughout this paper. Regarding social and behavioral factors, expert systems have been developed to promote smoking cessation among adolescents (Pallonen et al., 1998), although more research is necessary before they can be fully integrated into pediatric primary care. Regarding biological factors, the field of pharmacogenetics is a rapidly emerging one. Pharmacogenetics attempts to understand individual variation in response to drugs and, someday, may affect prescribing advice for a range of neurobehavioral conditions (Wolf, Smith, & Smith, 2000), including ADHD and smoking. Part of this process involves the development of reliable DNA testing services to determine individual genotypes and their significance, as well as patient willingness to participate in this process. If safe and


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Youth Cigarette Smoking and ADHD effective genetic testing is available, informing individuals about their susceptibility to smoking could affect their decisions to start smoking or interest in quitting (Marteau & Lerman, 2001). Researchers have already combined information about genetic susceptibility to the harms of smoking with behavioral counseling in an effort to promote quitting among adults (Lerman et al., 1997; McBride et al., 2000); similar work with pediatric populations remains to be conducted. Thus, the potential to incorporate biomarker feedback about risks for smoking into behavioral prevention and intervention programs for adolescents is an exciting research opportunity for child health psychologists, and one which is highly relevant to adolescents with ADHD. Transdisciplinary research collaborations on the most effective ways to combine pharamacological and behavioral treatments to coaddress this problem are possible as well. These opportunities arise out of new developments taking place within the field of molecular genetics and our deep understanding of the biobehavioral aspects of ADHD and of smoking. Alongside basic science researchers and pediatric providers, child health psychologists are well-poised to explore the application of these findings to the prevention and treatment of youth smoking. ACKNOWLEDGMENTS The authors thank Dr Randi Streisand for commenting on this manuscript, and Susan Marx for assistance with manuscript preparation. Support for Dr Stein was provided by a grant from the National Institute of Mental Health (MH01823). REFERENCES Abikoff, H., & Klein, R. G. (1992). Attention-deficit hyperactivity and conduct disorder: Comorbidity and implications for treatment. Journal of Consulting and Clinical Psychology, 60, 881–892. Alberts-Corush, J., Firestone, P., & Goodman, J. T. (1986). Attention and impulsivity characteristics of the biological and adoptive parents of hyperactive and normal control children. American Journal of Orthopsychiatry, 56, 413–423. Alsobrook, J. P., II, & Pauls, D. L. (1998). Molecular approaches to child psychopathology. Human Biology, 70, 413–432. American Academy of Pediatrics Committee on Substance Abuse. (2001). Tobacco’s toll: Implications for the pediatrician. Pediatrics, 107, 794–798. American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: Author. Aviram, R. B., Rhum, M., & Levin, F. R. (2001). Psychotherapy of adults with comorbid attention-deficit/hyperactivity

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