Cigarette Smoking and Psychiatric Comorbidity in Children and Adolescents

HIMANSHU P. UPADHYAYA, M.B.B.S., M.S., DEBORAH DEAS, M.D., M.P.H., KATHLEEN T. BRADY, M.D., PH.D., AND MARKUS KRUESI, M.D.

ABSTRACT Objective: To review the current state of knowledge of psychiatric comorbidity in adolescent cigarette smokers. Method: Medline assisted literature search was conducted and seminal articles were cross-referenced for comprehensiveness of the search. For each disorder, a synopsis of knowledge in adults is provided and compared with the knowledge in adolescents. Results: Psychiatric comorbidity is common in adolescent cigarette smokers, especially disruptive behavior disorders (such as oppositional defiant disorder, conduct disorder, and attention-deficit/hyperactivity disorder), major depressive disorders, and drug and alcohol use disorders. Anxiety disorders are modestly associated with cigarette smoking. Both early onset (<13 years) cigarette smoking and conduct problems seem to be robust markers of increased psychopathology, including substance abuse, later in life. In spite of the high comorbidity, very few adolescents have nicotine dependence diagnosed or receive smoking cessation treatment in child and adolescent psychiatric treatment settings. Conclusions: There is increasing evidence for high rates of psychiatric comorbidity in adolescent cigarette smokers. Cigarette smoking in adolescence appears to be a strong marker of future psychopathology. Child and adolescent psychiatry treatment programs may be a good setting for prevention efforts and treatment, which should focus on both nicotine dependence and psychiatric disorders. J. Am. Acad. Child Adolesc. Psychiatry, 2002, 41(11):12941305. Key Words: nicotine, smoking, psychiatry, comorbidity.

Even though nicotine use among adolescents has stabilized recently, it is an area of considerable concern because of the significant prevalence. Almost 21% of high school seniors smoke daily (Johnston et al., 2000). While the prevalence of nicotine use in children and adolescents is well documented in periodic surveys, e.g., Monitoring the Future survey, Centers for Disease Control (CDC) surveys (CDC, 1989; Johnston et al., 2001), there is a relative lack of research on the comorbidity of psychiatric disorders and nicotine use in adolescents. Tobacco is related to more than 400,000 deaths in the United States annually (United States Department of Health and Human Services, 2000) and is
Accepted May 21, 2002. From the Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston. Financial support for this project was provided by the career development K12 award, grant DA00357-01, given jointly from the AACAP and NIDA to Dr. Upadhyaya. Reprint requests to Dr. Upadhyaya, 2N IOP, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 67 President Street, Charleston, SC 29425. 0890-8567/02/41111294 2002 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.CHI.0000024845.60748.8F

among the most addictive substances known. While approximately 32% of people who initiate tobacco use become dependent, only 23%, 16.7%, and 15.4% of individuals who initiate heroin, cocaine, and alcohol use, respectively, become dependent (Anthony et al., 1994). Out of the more than 50 million smokers in the United States, 4 million are adolescents. It is estimated that 3,000 adolescents start smoking every day; hence, cigarette smoking is considered a pediatric disease. Also, 80% of adult smokers become addicted to tobacco by age 18 (American Health Association, 1995). Tobacco is generally one of the rst drugs tried by individuals who use illicit drugs (Kandel and Yamaguchi, 1993; Kandel et al., 1978). In both adults and adolescents, having a psychiatric disorder is one of several factors associated with cigarette smoking (see Moolchan et al., 2000, for a comprehensive review). Better understanding of the role of these factors in the initiation and continued use of cigarettes may help in the development of specic treatment(s) and prevention strategies. Adults with mental illness consume approximately 44.3% of the cigarettes smoked in the United States. The odds ratio (OR) for current and lifetime smoking in persons with mental illness was 2.7 in the large,

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community-based National Comorbidity Study (Lasser et al., 2000). In a large (n = 12,057) longitudinal British study, subjects 16 to 21 years of age with previous mental disorders were 50% more likely to increase their smoking during a 12-month period (Ismail et al., 2000). Both adult and adolescent cigarette smoking is frequently undiagnosed and untreated in psychiatric treatment facilities (Upadhyaya et al., in press). The study of risk factors for smoking is crucial in adolescents because this can provide a unique opportunity for prevention and treatment. This article reviews the current state of literature on cigarette smoking and psychiatric disorders in adolescents. We performed a Medline search using the key words smoking, adolescence, nicotine, tobacco, and psychiatric disorders. We also cross-checked references in articles to ensure comprehensiveness of the search. Most reports have examined current (previous 30 days) cigarette smoking, rather than nicotine dependence as dened by the DSM-IV (American Psychiatric Association, 1994). There is some evidence that nicotine dependence is more robustly associated with psychiatric comorbidity (Breslau, 1995; Dierker et al., 2001); hence, studies addressing nicotine dependence (comparatively few) may be more valuable in exploring the link between nicotine use and psychiatric disorders. Because most reports address cigarette smoking only, relatively less is known about smokeless tobacco use and psychiatric disorders. Hence, we have focused on cigarette smoking in this review. Although the relationship between psychotic disorders and cigarette smoking in adults has been an active and productive area of research, psychotic disorders, e.g., schizophrenia, are relatively uncommon in children and adolescents. Because there is a dearth of reports linking smoking to psychotic disorders in adolescents specically, this topic is not included in this review. Based on the current literature, we have reported the association between cigarette smoking and disruptive behavior disorders, mood disorders, anxiety disorders, and substance use disorders. An important point to remember while interpreting the studies cited is that an association does not imply causal relationship and, as discussed later, could be caused by other factors.
ADHD AND SMOKING Adult Studies

caused increased vigor, reduction in reaction time on the Continuous Performance Test, and improved accuracy of time estimation (Conners et al., 1996; Levin et al., 1996). Pomerleau and colleagues (1995) found that adults with ADHD are more likely to smoke and may have a harder time quitting. Smokers with ADHD had a signicantly higher number of ADHD symptoms and higher score on the novelty scale when compared with never smokers with ADHD.
Child and Adolescent Studies

Several longitudinal studies indicate a link between ADHD and smoking (Table 1). Interestingly, in one report involving siblings of subjects with ADHD, there is also a signicant correlation between cigarette smoking and conduct disorder (CD), major depression, and drug abuse (Milberger et al., 1997a). In another report, the authors also found a lower rate of smoking in subjects who had received treatment with stimulant medication. The magnitude of the lower rate of smoking was proportional to the length of treatment (Lambert, 1998). Another longitudinal study reported that children with ADHD at age 6 years had an increased risk of cigarette smoking at 11 years of age (adjusted for sex, site of birth, and birth weight) as compared with children without ADHD (Chilcoat and Breslau, 1999). At least one cross-sectional study suggests a link between ADHD and smoking (Riggs et al., 1999). The results indicate that the severity of CD, ADHD, and major depressive disorders (MDD) is associated with severity (number of symptoms) of nicotine dependence. In males, ADHD and CD were also associated with earlier onset of regular smoking (Riggs et al., 1999). The nature of the association between ADHD and cigarette smoking is complex. Individuals with ADHD seem to initiate smoking earlier and have more difculty quitting. However, in terms of absolute rates of smoking the evidence is equivocal. Some studies have reported ADHD not to be independently associated with cigarette smoking (Dierker et al., 2001; Upadhyaya et al., in press)
ODD/CD AND SMOKING

At least two reports indicate that, in a small sample of smokers and nonsmokers with attention-deficit/ hyperactivity disorder (ADHD), a nicotine transdermal patch improved the Clinical Global Impression scores and

Evidence from studies involving genetic and epidemiological approaches in both community and psychiatric samples indicates a strong link between disruptive behavior disorders and cigarette smoking. Cigarette smoking in subjects with oppositional defiant disorder (ODD)/CD may represent a general pattern of deant
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TABLE 1 ADHD and Cigarette Smoking in Adolescents Authors Hartsough and Lambert, 1987 Barkley et al., 1990 Milberger et al., 1997a Milberger et al., 1997b Lambert, 1998 Sample 54 hyperactives (1318 yr) 123 hyperactive children 174 siblings of probands with ADHD 128 boys with ADHD (617 yrs) 214 boys and girls with ADHD 367 boys and girls (1319 yr) Type/Comparison Group 1-yr longitudinal/ 47 controls 8-yr longitudinal/ 66 normal controls 4-yr longitudinal/ 129 siblings of nonADHD probands 4-yr longitudinal/ 109 non-ADHD boys Longitudinalchildhood through adulthood cross-sectional/ no comparison group 5-yr longitudinal Measures Clinical interviews and self-report of substance abuse Structured ADHD interviews, questions on substance abuse and conduct problems Structured psychiatric interviews Conclusions Smoking initiation higher in hyperactives vs. controls Adolescents with ADHD more likely to smoke

Riggs et al., 1999

Chilcoat and Breslau, 1999

412 low-birth-weight and 305 normal-birthweight children 135 high-risk vs. 57 controls (724 yr) 120 (818 yr)

Dierker et al., 2001 Upadhyaya et al., in press

4-yr longitudinal Cross-sectional

Signicant correlation between cigarette smoking and conduct disorder, major depression, and drug abuse Structured psychiatric Earlier initiation and interviews higher current smoking rates in subjects with ADHD Clinical interviews Earlier initiation (by 1.52 yr), and structured higher rate (46% vs. 24% psychiatric interviews in controls) of current daily smoking Structured psychiatric/ In subjects with conduct substance abuse disorder and ADHD, interviews more symptoms of nicotine dependence and earlier smoking onset Structured psychiatric ADHD at age 6 interviews, neurorelated to higher OR psychological (1.7) of substance use performance parent disorder, including monitoring, peer drug use smoking Semistructured psychADHD not associated iatric interviews with smoking or nicotine dependence Clinical interviews ADHD not associated and self-report with smoking

Note: ADHD = attention-decit/hyperactivity disorder; OR = odds ratio.

behaviors or individuals with CD may have an increased vulnerability to the development of nicotine dependence (Donovan et al., 1988; Jessor and Jessor, 1977). Pomerleau and colleagues (1995), in a sample of adults with ADHD, found that smokers were more likely to have received a diagnosis of ODD or CD as compared with those who had never smoked and that as adults smokers were more likely to have antisocial personality disorder. Smokers also had more ODD symptoms that persisted into adulthood as compared with never smokers. In a retrospective study of 1,007 young adults, early conduct problems (before age 13) were associated with increased odds (OR = 1.8) for nicotine dependence among smokers and with early initiation of smoking (61.6% versus 4044% in other groups). In the study, the odds of early conduct problems was higher among early smoking initiators as
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compared with those who initiated smoking after age 14 or nonsmokers (OR = 2.4 versus 2.0, respectively). Among the six conduct problems explored, starting ghts, truancy, and telling lies were most prevalent (Table 2). Other
TABLE 2 Adolescent Conduct Problems and Early Initiation of Cigarette Smoking Conduct Problem Expelled/suspended Starting ghts Truancy Running away Trouble at school Telling lies One or more problems Percentage 19.4 31.8 26.4 5.4 17.4 18.2 61.6

Note: Percentage of adolescents with a particular conduct problem who initiate smoking before age 13 (Breslau, 1995).

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problems explored were expulsions and suspensions, running away, and trouble at school (Breslau, 1995). In a community-based 4-year longitudinal study, Dierker and colleagues found that nicotine dependence was associated with an almost six-fold increased risk for ODD (Dierker et al., 2001). In a group of 120 children and adolescents (817 years) consecutively admitted to an inpatient psychiatric unit, subjects with CD had increased odds (OR = 12.96) of being a current smoker as compared with inpatients without CD (Upadhyaya et al., in press). At nine high schools in Oregon, Brown and colleagues (1996) assessed 1,709 adolescents at baseline and 1 year later with semistructured psychiatric interviews and questionnaires. After controlling for demographics, parental education, number of biological parents in household, and psychiatric disorders, the OR at baseline of disruptive behavior disorder was 3.27 in smokers. A recent cross-sectional study of 337 female twins found that twin pairs with CD had much higher rate of nicotine dependence as compared with control twin pairs (40% versus 5.56%) (Marmorstein and Iacono, 2001).
SMOKING AND MOOD DISORDERS

Major depression is the mood disorder most consistently and robustly associated with cigarette smoking.
Adult Studies

Adult smokers have more severe and a higher rate of major depression than nonsmokers (Anda et al., 1990; Breslau et al., 1991; Glassman, 1993; Glassman et al., 1990; Jorm et al., 1999; Kendler et al., 1993). Patients with major depressive disorder (Breslau et al., 1991; Breslau and Klein, 1999; Glassman et al., 1990) or major depressive symptoms (Anda et al., 1990; Jorm et al., 1999) have a harder time quitting cigarette smoking and higher relapse rates (Covey et al., 1990) when compared with nonsmokers. Signicantly, current or past major depression is a predictor of poor prognosis in treatment studies of nicotine dependence in adults (Anda et al., 1990; Covey et al., 1990; Glassman et al., 1988; Glassman et al., 1990). In a longitudinal study of 995 young adults, Breslau and colleagues (1993) found that subjects with MDD are more likely to develop nicotine dependence and vice versa.
Child and Adolescent Studies

Major depression among adolescents is consistently associated with cigarette smoking. Although evidence exists for a bidirectional association between cigarette

smoking and major depression as indicated in Table 3, at present, there is more evidence that major depression may be a risk factor for smoking than vice versa. There are two rigorous longitudinal studies indicating that depressive disorders are a risk factor for smoking (Table 3). In a 9-year longitudinal study of adolescents with depressive symptoms, Kandel and Davies (1986) found higher rates of lifetime and current smoking in subjects with depressive disorders. Depressive disorders preceded cigarette smoking in the study. Similarly, a 16year longitudinal study of 947 New Zealand children aged 0 to 16 years found increased odds (2.3) of nicotine dependence in subjects with depressive disorders (controlling for family criminality, social position, common social/contextual factors, parental smoking, parental attachment, and family life events) (Fergusson et al., 1996) as compared with those without depressive disorders. In a community-based, 4-year longitudinal study, Dierker and colleagues found that nicotine dependence was associated with almost 10-fold increased odds of developing affective disorders and vice versa (Dierker et al., 2001). The overwhelming majority of affective disorder cases were depressive disorders. Several cross-sectional studies also indicate that depressive disorders are associated with smoking in adolescents. A large cross-sectional community-based study of nicotine use in German youths found higher rates of affective disorders (OR = 2.18), mainly major depression, in nicotine dependent subjects (Nelson and Wittchen, 1998; Sonntag et al., 2000). Other cross-sectional studies also indicate association of depressive symptoms and smoking (Covey and Tam, 1990) (Table 3). One study of 1,056 public school students reported a correlation (r = 0.31) between smoking and symptoms of depression in girls only (Hawkins et al., 1992). A study using phone interviews of a national household probability sample (ages 1217) in the United States found that depression increased the risk for smoking in females (Acierno et al., 2000). Another recent study of 337 female twins found that twins with major depressive disorder had a higher rate of nicotine dependence as compared with controls (Marmorstein and Iacono, 2001). In a sample of adolescents in a psychiatric inpatient unit, OR of smoking was 4.02 in subjects with MDD (Upadhyaya et al., in press). However, some longitudinal studies indicate an association between smoking and depressive disorders in the opposite direction, i.e., smoking may be a risk factor for major depression. A recent analysis of the National
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TABLE 3 Mood Disorders and Cigarette Smoking in Adolescents Authors Kandel and Davies 1986 Covey and Tam, 1990 Hawkins et al., 1992 Fergusson et al., 1996 Brown et al., 1996 Patton et al., 1996, 1998 Nelson and Wittchen, 1998; Sonntag et al., 2000 Hanna and Grant, 1999 Wu and Anthony, 1999 Acierno et al., 2000 Goodman and Capitman, 2000 Dierker et al., 2001 Marmorstein and Iacono, 2001 Upadhyaya, in press Sample 1,004 youths from age 1516 yr followed to age 25 205 eleventh graders 1,056 high school students 947 children Type/ Comparison Group 9-yr longitudinal Cross-sectional Cross-sectional 16-yr longitudinal Measures Structured individual interviews Brief self-report questionnaire and partial CES-D scale Self-report questionnaires (CES-D scores) Psychiatric interview using abbreviated DISC assessment K-SADS semistructured psychiatric interviews Computerized Clinical Interview Schedule M-CIDI psychiatric interviews AUDA-DIS interview Standardized face to face private interviews Phone interview based on DSM-IV CES-D scale Semistructured psychiatric interviews Structured SCID and DICA-P interviews Clinical interviews and self-report Conclusions Adolescents with depressive symptoms had higher rates of current and lifetime smoking Depressive mood linked to smoking, and depression scores correlated to number of cigarettes smoked Smoking related to depressive symptoms in girls only Adjusted OR of nicotine dependence = 2.3 for children and adolescents with depressive disorders Smokers at baseline had a higher OR (1.89) of major depressive disorder, during the ensuing year Depressive symptoms increase risk for smoking only in subjects with peers who smoke Nicotine-dependent subjects had an increased OR (4.02) for major depression Early onset (<13 yr) smokers had earlier and more episodes of major depressive disorder compared to later (<17 yr) onset smokers OR of depressed mood with 1.66 in students with antecedent smoking Depression increased risk for smoking only in females (OR = 2.23) Cigarette smoking at baseline was linked to depressive symptoms at 1-yr follow-up (OR = 3.9) Nicotine dependence associated with 10-fold increased risk of affective disorders. Twins with major depression had higher rate (13.21% vs. 5.56% of nicotine dependence OR of smoking 4.02 in subjects with major depressive disorders

1,507 adolescents (1418 yr) 2,034 high school students 3,021 14- to 24-yr-olds 42,862 subjects 18 yr and older 1,731 youths aged 89 followed to age 1314 4,023 adolescents Secondary data analysis of ADD-Health Study (15,651 adolescents) 135 high-risk vs. 57 controls (724 yr) 337 female twins aged 17 yr 120 children and adolescents consecutively admitted to a psychiatric inpatient unit

1-yr longitudinal 6-month longitudinal Cross-sectional

Retrospective survey Longitudinal Cross-sectional 1-yr longitudinal 4-yr longitudinal Cross-sectional Cross-sectional

Note: CES-D = Center for Epidemiologic Studies Depression scale; OR = odds ratio; DISC = Diagnostic Interview Schedule for Children; K-SADS = Schedule for Affective Disorders and Schizophrenia for School-Age Children; M-CIDI = Munich-Composite Diagnostic Interview; ADD-Health = National Longitudinal Study of Adolescent Health; SCID = Structured Clinical Interview for DSM-III; DICA-P = Diagnostic Interview for Children and Adolescents-Parent Version; AUDA-DIS = Alcohol Use Disorders and Associated Disabilities Interview Schedule.

Longitudinal Study of Adolescent Health (Add Health) data indicates that current smoking predicted a high level of depressive symptoms over 1 year of follow-up. The risk of becoming a smoker was assessed as a function of depressive symptoms in 6,947 adolescents. High depres1298

sive symptoms increased odds of heavy smoking (OR = 3); however, this effect was not statistically significant after controlling for other factors (Goodman and Capitman, 2000). Wu and Anthony found similar results in their 1year longitudinal study (Wu and Anthony, 1999). Data

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from the National Longitudinal Alcohol Epidemiologic Survey (NLAES), a retrospective survey of 42,862 subjects 18 years and older conducted in 1992 by the US Census Bureau, revealed early onset smokers (before 13 years) had earlier (21.7 versus 26.2 years) and more episodes (7.34 versus 5.06) of major depressive disorder as compared with individuals with smoking onset after age 17 (Hanna and Grant, 1999). Peer inuence has been found to moderate the impact of psychiatric symptoms on smoking as indicated in Table 3 (Patton et al., 1996; Patton et al., 1998). One small study reports a higher rate of smoking in adult patients with bipolar affective disorder compared with subjects without bipolar affective disorder (Gonzalez-Pinto et al., 1998).
SMOKING AND ANXIETY DISORDERS Adult Studies

Research on anxiety disorders and nicotine dependence in adults is limited, although most studies exploring mood disorders assess or query about anxiety symptoms or disorders. Despite systematic assessment of anxiety symptoms, there is a dearth of research focused specically on anxiety disorders and comorbid nicotine dependence. Breslau and colleagues (1991) used the National Institute of Mental Health Diagnostic Interview Schedule (Robins et al., 1981) to investigate the OR of major depression and anxiety disorders in smokers without nicotine dependence and those with mild and moderate nicotine dependence. There was an association between nicotine dependence and the diagnosis of depression and anxiety; however, when controlling for depression, the association of nicotine dependence and anxiety disorders was not signicant. Similarly, Jorm and colleagues (1999) suggest increased symptoms of anxiety in adult smokers. One longitudinal study suggests that smoking was associated with increased risk of agoraphobia (OR = 6.79), generalized anxiety disorder (OR = 5.53), and panic disorder (OR = 15.58) (Johnson et al., 2000). In a prospective study conducted by Breslau and associates (1993), a history of an anxiety disorder did not increase the odds of progression to nicotine dependence.
Child and Adolescent Studies

most of his or her friends smoked. In a large, prospectivelongitudinal community study of 3,021 adolescents and young adults, Sonntag and colleagues (2000) found that social fears as well as DSM-IV social phobia were signicantly associated with higher rates of nicotine dependence. Increased rates of nicotine dependence have been found among adolescents with anxiety disorders in other studies (Nelson and Wittchen, 1998; Wittchen et al., 1999). The literature suggests that anxiety disorders among adolescents, especially social fears and social phobia, are more closely associated with nicotine dependence than anxiety disorders among adults. Interestingly, a longitudinal study of 1,420 children, aged 9,11, and 13, suggests that anxiety disorders may delay the onset of smoking by an average of 8.4 months in girls (ages 13.6 versus 12.9) and 15 months in boys (ages 13.3 versus 12.0) (Costello et al., 1999). The long-term outcome of such a delay is not known. Adolescents may use nicotine to calm some of the anxiety symptoms experienced in public. Since smoking is socially accepted in some settings, adolescents with social anxiety disorder may use cigarettes to distract from their difculty with social interactions in the peer group or public.
SMOKING AND OTHER DRUG AND ALCOHOL ABUSE/DEPENDENCE Adult Studies

Patton and colleagues (1998) conducted a prospective 3-year study of adolescent health in Victoria, Australia, revealing that depression and anxiety predicted smoking initiation and transition to daily smoking. This nding was more robust in cases where the individual reported that

Not surprisingly, early tobacco use increases the risk of developing nicotine dependence (Breslau et al., 1993). Cigarette smoking has also been associated with increased odds of alcohol and drug use in several reports (Black et al., 1999; Burling and Ziff, 1988; Golding et al., 1983; Henningeld et al., 1990; Hughes and Frances, 1995; Joseph et al., 1990; Kao et al., 2000; Revell et al., 1985; Torabi et al., 1993). Several reports indicate that smokers are more likely to drink alcohol than nonsmokers, and drinkers more likely to smoke than nondrinkers (Burke et al., 1988; CDC, 1989; Covey et al., 1994; Cummins et al., 1981; Glassman et al., 1990; Golding et al., 1983; Istvan and Matarazzo, 1984; Revell et al., 1985; Zacny, 1990). Besides being bidirectional, this relationship is dose-dependent (i.e., people who smoke more drink more; the reverse is also the case) (Istvan and Matarazzo, 1984; Johnson and Jennison, 1992; Zacny, 1990). Additionally, Breslau reported increased rate of cannabis and cocaine dependence in smokers (Breslau et al., 1991). Cigarette smoking has also been associated with increased lifetime (OR = 6.35) and past year (OR = 7.42) risk of nonprescribed stimulant use (Wu and Anthony, 1999). Twin studies indicate that genetic factors contribute
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to the link between alcohol use and smoking (Madden et al., 1993; Reed et al., 1994; Sher et al., 1996).
Child and Adolescent Studies

Cigarette smoking has been conceptualized by some authors as a gateway to other substance abuse (Kandel et al.,

1978; Kandel and Yamaguchi, 1993), whereas others have not supported the gateway theory. As in adults, adolescent drinking and smoking are related in a bidirectional, dose-dependent manner (Istvan and Matarazzo, 1984; Sutherland and Willner, 1998; Zacny, 1990;). Several longitudinal studies (Table 4) indicate that cigarette smok-

TABLE 4 Cigarette Smoking and Other Substance Use Disorders in Adolescents Authors Myers and Brown, 1994 Brown et al., 1996 Koopmans et al., 1997 Sample 166 substanceabusing adolescents 1-yr longitudinal study of 1,507 adolescents (1418 yr) Twin genetic mail survey (2,712 families) Type/ Comparison Group Cross-sectional Prospective longitudinal Cross-sectional Measures Smoking rates K-SADS semistructured psychiatric interviews Health and lifestyle questionnaires Conclusions 75% daily smokers; 61% smoked at least half pack per day Smokers at baseline had a higher OR (7.05) during ensuing year of drug use disorder Common environmental factors, e.g., peers, may be important for initiation, but genetic factors may be more important in persistence of comorbid nicotine and alcohol use disorders Daily smokers had high odds of substance abuse (OR = 8.1), disruptive behavior disorder (OR = 5.7), and anxiety disorder (OR = 3.9) Subjects with nicotine dependence had higher rate of substance use disorders (OR = 3.9815.41) Cigarette use was linked to subsequent alcohol and marijuana use Cigarette smoking associated with alcohol and drug use in a dose dependent manner Lifetime smoking increased odds of future alcohol, cannabis, hard drugs, and multiple drug use at age 24 (OR 1.672.75) Early onset (<13 yr) smokers more likely to have substance use disorders (17.37%) compared with later onset smokers (9.76%) or nonsmokers (3.43%) Smoking before to ages 13 and 17 linked to increased OR (3.11 and 2.31, respectively) of cannabis use Nicotine dependence associated with 915-fold increased risk of alcohol and drug use disorders Smoking associated with 25-fold increased risk of marijuana dependence

Kandel et al., 1997

1,285 subjects (918 yr)

Cross-sectional

DISC structured psychiatric interviews (MECA study) M-CIDI psychiatric interviews Self-report questionnaires Self-report (YRBS) Semistructured psychiatric interviews at baseline, 12 months, and at age 24 AUDA-DIS interview

Nelson and Wittchen, 1998; Sonntag et al., 2000 Duncan et al., 1998 Everett et al., 1998 Lewinsohn et al., 1999; Rohde et al., 2001 Hanna and Grant, 1999

3,021 14 to 24yearolds 763 families 10,904 high school students Adolescents in high school

Cross-sectional Prospective longitudinal Cross-sectional Prospective longitudinal

42,862 subjects 18 yr and older

Retrospective

Merrill et al., 1999 Dierker et al., 2001 Upadhyaya, in press

10,904 high school students 135 high-risk vs. 57 controls (724 yr) 120 children and adolescents (818 yr)

Retrospective

Annual in-school survey (YRBS) Semistructured psychiatric interviews Clinical interviews and self-report

4-yr longitudinal Cross-sectional

Note: K-SADS = Schedule for Affective Disorders and Schizophrenia for School-Age Children; DISC = Diagnostic Interview Schedule for Children; MECA = Methods for the Epidemiology of Child and Adolescent Mental Disorders; M-CIDI = Munich-Composite Diagnostic Interview; AUDA-DIS = Alcohol Use Disorders and Associated Disabilities Interview Schedule; YRBS = Youth Risk Behavior Survey; OR = odds ratio.

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ing is a possible risk factor for the development of subsequent substance use disorders. Lewinsohn and colleagues (1999) followed 1,709 high school students and conducted semistructured psychiatric interviews at baseline, 1 year later, and at age 24. Having ever smoked increased the OR of future alcohol, cannabis, hard drugs, and polydrug use disorders at age 24. Being a past smoker at either of the follow-up assessments did not decrease the risk of other substance abuse, but smoking cessation for at least 12 months was associated with decreased rates of alcohol use disorder at age 24 follow-up. Daily cigarette smoking at follow-up predicted future cannabis and hard drug use. In a follow-up report of the study, Rohde and colleagues (2001) reported that a history of daily smoking in adolescence was associated with future alcohol use disorders. In a report based on the NLAES study, early onset regular smokers were more likely to have substance use disorders compared with later onset smokers or nonsmokers (3.43%) (Hanna and Grant, 1999). In another report based on NLAES, Grant found that individuals with early onset smoking (before age 13) were more likely to have early onset of drinking, family history of alcoholism, heavier current tobacco consumption, and were twice as likely to develop alcohol use disorders as compared with individuals with smoking onset at 17 and older. Individuals with smoking onset at ages 14 to16 were 1.6 times more likely to develop alcohol dependence. Nonsmokers were less likely to develop alcohol use disorders as compared with all smokers in general. Severity of alcohol use disorders and amount of daily drinking was inversely related to the age of smoking onset (Grant, 1998). Early onset smoking as a risk factor for subsequent drug use has been reported before (Kandel and Yamaguchi, 1993; Yu and Williford, 1994). Brown and colleagues (1996) found early cigarette use was signicantly associated with lifetime substance use disorders (43% in early versus 18% in late-onset smokers) (controlling for demographics, parental education, number of biological parents in household, and psychiatric disorders). Among smokers at baseline there was a higher OR of a drug use disorder during the ensuing year as compared with subjects who did not smoke at baseline. Several cross-sectional studies also indicate that cigarette smoking is associated with an increased risk for the development of other substance use disorders. Merrill and colleagues (1999) analyzed demographics, substance use, sexual activity, violence, suicidality, eating, and sports data from the 1995 Youth Risk Behavior Survey administered by the CDC involving 9th to 12th grade students.

Age of onset of alcohol, cigarette, and cannabis use was associated with increased odds of cannabis and other drug use. Students in the 12th grade who started smoking tobacco before age 13 or 17 were more likely to use cannabis compared with nonsmokers. In another report based on the Youth Risk Behavior Survey, cigarette smoking was associated with alcohol and drug use in a dose-dependent manner (Everett et al., 1998). Kandel and colleagues (1997) analyzed data from the Methods for the Epidemiology of Child and Adolescent Mental Disorders study, involving 1,285 children and adolescents in four geographical areas of the United States. The authors found that the prevalence of psychiatric disorders was 70% in female and 76.9% in male daily smokers. Daily smokers had a higher adjusted OR for substance use as compared with smokers who smoked less than one cigarette per day (Kandel et al., 1997). In a cross-sectional twin genetic mail survey of 2,712 families, Koopmans and colleagues (1997) found alcohol use and smoking were positively correlated in individuals aged 12 to 25. In all age groups, smokers were more likely to drink. This association was also seen in twin pairs, suggesting familial factors. The association was strongest for the 12 to 14 age group. The authors note that for 12- to 16-year-olds, shared environmental factors were more important whereas for 17- to 25-year-olds, both genetic and environmental factors contribute, with genetic factors having the greater impact. This suggests that common environmental factors (e.g., peers, parents, access) may be important for initiation, but genetic factors may be more important in the persistence of comorbid nicotine and alcohol use disorders. In a 4-year follow-up of mainly white adolescents, 115 smokers with no previous alcohol use, 199 drinkers with no smoking history, and 287 drinkers and smokers with no cannabis use were surveyed. Among the nondrinkers, smoking at baseline predicted drinking at follow-up. An increase in cigarette use also predicted an increase in alcohol use. Baseline drinking did not predict smoking but an increase in alcohol use predicted an increase in cigarette smoking at follow-up. Only baseline cigarette smoking predicted cannabis use and initiation at follow-up. An increase in cigarette use also predicted initiation of cannabis use at follow-up (Duncan et al., 1998). A cross-sectional, community-based study of nicotine use in 14- to 24-year-old German youths found higher rates of alcohol use disorders and illicit substance use disorders in nicotine dependent subjects (Nelson and Wittchen, 1998; Sonntag et al., 2000).
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POSSIBLE MECHANISMS FOR THE LINK BETWEEN SMOKING AND PSYCHIATRIC DISORDERS

The exact mechanism of the comorbidity between smoking and psychiatric disorders is not known. The comorbidity may be explained by the combination of one or more of the following factors: chance, common vulnerability to both psychiatric disorders and smoking (familial/genetic or environmental), self-medication, and common neurobiological alterations. For example, a yet unidentied substance in cigarette smoke inhibits brain monoamine oxidase (MAO) A activity by an average of 28% in the various brain regions of smokers (Fowler et al., 1996). Fowler and colleagues also found lower levels of MAO B in the brains of smokers as compared with nonsmokers and former smokers (Fowler et al., 1998). MAO inhibition is also reported in animals exposed to cigarette smoke (Pavlin and Sket, 1993) and among smokers, both peripherally in platelets (Berlin et al., 1995) and in vitro (Carr and Basham, 1991; Yu and Boulton, 1987). MAO A oxidizes catecolamines including serotonin, norepinephrine, and dopamine (Glover et al., 1980; Riederer and Youdim, 1986). The antidepressant effect of clinically used MAO inhibitors is thought to be caused by activity on MAO A, which results in decreased catabolism of serotonin, norepinephrine, and dopamine (Caldecott-Hazard and Schneider, 1992). As such, nicotine may be acting as an antidepressant in some individuals. This could explain the high comorbidity of MDD and cigarette smoking and the difculty that individuals with MDD have in smoking cessation. Similarly, the relationship between cigarette smoking and ADHD may include self-medication, and/or neurochemical correlates. Nicotine may be efcacious in improving attention through alteration in catecholamines available in the synapse. Some authors have proposed that nicotine dependence may develop in an attempt to self-medicate symptoms of ADHD through actions on the dopaminergic systems (Conners et al., 1996; Levin et al., 1996). Mesolimbic dopamine systems are involved in the pathophysiology of nicotine dependence as well as the pathophysiology of virtually all drugs of abuse (Di Chiara, 1995; Wise and Bozarth, 1987). Common alterations in mesolimbic systems may be one of the mechanisms underlying the comorbidity of nicotine dependence with other substance use disorders. With the exception of ADHD and anxiety disorders, the onset of cigarette smoking generally precedes the onset of other psychiatric disorders (Dierker et al., 2001). ADHD
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has been associated with early onset of smoking, difculty quitting, and possibly, higher rates of smoking. ODD and CD have also been robustly associated with cigarette smoking in adolescents. Cigarette smoking, like other substance misuse, is usually associated with a general pattern of deant behavior (e.g., getting into ghts, problems at school, truancy, telling lies, and other substance misuse). MDD is also robustly linked with adolescent onset smoking. The association between anxiety disorders and cigarette smoking is less rmly established. The tobacco and alcohol link may be caused by common vulnerability factors or the exposure to the initial drug causes biobehavioral changes (e.g., cross tolerance, synergistic physiological effects, or cuing effects) (Grant, 1998). Longitudinal epidemiological studies together with twin genetic and studies exploring common neurobiological factors are necessary to rene our knowledge base regarding comorbidity of cigarette smoking and psychiatric disorders in adolescents.
SUMMARY AND CLINICAL IMPLICATIONS

Many psychiatric disorders are highly comorbid with cigarette smoking in adolescents. Most studies have examined the relationship between loosely dened regular cigarette smoking and psychiatric disorders, whereas the emerging evidence indicates that DSM-IV based diagnosis of nicotine dependence is even more robustly associated with psychiatric comorbidity (Breslau, 1995; Dierker et al., 2001). In clinical settings, it is important to assess adolescent smokers for psychiatric disorders and to assess adolescents with psychiatric disorders for cigarette smoking. Both nicotine dependence and the psychiatric comorbidity should be addressed simultaneously, since psychiatric comorbidity could complicate smoking cessation attempts. There is also evidence that initiation, maintenance, and cessation of smoking may affect psychiatric symptoms (Breslau et al., 1991; Breslau and Klein, 1999; Covey et al., 1990; Glassman et al., 1990; Pomerleau et al., 1995). Although cigarette smoking is associated with major depression and inhibition of MAO, there is lack of evidence that either cigarette smoking or nicotine improves symptoms of major depression. Evidence suggests that we need to target prevention and treatment of adolescent smoking before age 13. Early onset smoking (<13 years) may be a particularly robust marker of future substance misuse and other psychiatric disorders (Breslau, 1995). Both prevention and treatment

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should involve interventions (e.g., parenting skills, MultiSystemic Therapy etc.) to reduce disruptive behavior disorders, e.g., ODD, CD. Future research is needed to understand the relationship between cigarette smoking, nicotine dependence, and psychiatric disorders. It is likely that the relationship is bidirectional in which the presence of one disorder may worsen the course and prognosis of the other. In adolescents, there is an opportunity to study these relationships with regard to order of onset and careful study of smoking initiation. The treatment of nicotine dependence in adolescents with psychiatric comorbidity also deserves further attention and investigation (see Moolchan et al., 2000, for review). Research on the treatment of nicotine dependence in adolescents may need to include adolescentspecic issues, such as improving parental monitoring of patients peer group and better parenting skills. Careful exploration of the connection between nicotine dependence and psychiatric comorbidity is necessary to design specic treatments and improve outcomes.
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