Genes, environments, and developmental research: methods for a multi-site study of early substance abuse.

The importance of including developmental and environmental measures in genetic studies of human pathology is widely acknowledged, but few empirical studies have been published. Barriers include the need for longitudinal studies that cover relevant developmental stages and for samples large enough to deal with the challenge of testing gene-environment-development interaction. A solution to some of these problems is to bring together existing data sets that have the necessary characteristics. As part of the National Institute on Drug Abuse-funded Gene-Environment-Development Initiative, our goal is to identify exactly which genes, which environments, and which developmental transitions together predict the development of drug use and misuse. Four data sets were used of which common characteristics include (1) general population samples, including males and females; (2) repeated measures across adolescence and young adulthood; (3) assessment of nicotine, alcohol, and cannabis use and addiction; (4) measures of family and environmental risk; and (5) consent for genotyping DNA from blood or saliva. After quality controls, 2,962 individuals provided over 15,000 total observations. In the first gene-environment analyses, of alcohol misuse and stressful life events, some significant gene-environment and gene-development effects were identified. We conclude that in some circumstances, already collected data sets can be combined for gene-environment and gene-development analyses. This greatly reduces the cost and time needed for this type of research. However, care must be taken to ensure careful matching across studies and variables.

Predicting persistent alcohol problems: a prospective analysis from the Great Smoky Mountain Study.

BACKGROUND: Rates of alcohol disorders peak in late adolescence and decrease substantially into the mid-20s. Our aim was to identify risk factors that predict alcohol problems that persist into the mid-20s. METHOD: Data are from the prospective, population-based Great Smoky Mountains Study (GSMS; n=1420), which followed children through late adolescence and into young adulthood. Alcohol persisters were defined as subjects with an alcohol disorder (abuse or dependence) in late adolescence (ages 19 and 21 years) that continued to meet criteria for an alcohol disorder at the mid-20s assessment. RESULTS: The 3-month prevalence of having an alcohol disorder (abuse or dependence) decreased markedly from late adolescence into the mid-20s. A third of late adolescents with an alcohol disorder continued to meet criteria for an alcohol disorder in young adulthood (37 of 144 who met criteria in late adolescence). Risk factors for persister status included multiple alcohol abuse criteria during late adolescence but no alcohol dependence criteria. Risk factors for persister status also included associated features of alcohol dependence such as craving alcohol and drinking to unconsciousness. Persister status was also associated with depression, cannabis dependence and illicit substance use, but not with other psychiatric disorders. More than 90% of late adolescents with three or more of the risk factors identified met criteria for a young adult alcohol disorder. CONCLUSIONS: Symptoms of alcohol abuse, not dependence, best predict long-term persistence of alcohol problems. The set of risk factors identified may be a useful screen for selective and indicated prevention efforts.

Generalized anxiety and C-reactive protein levels: a prospective, longitudinal analysis.

BACKGROUND: Generalized anxiety disorder (GAD) is highly co-morbid with depression. Depression is associated with elevated levels of the inflammation marker C-reactive protein (CRP), cross-sectionally and over time. To date, no studies have looked at the association between CRP and GAD. METHOD: A total of nine waves of data from the prospective population-based Great Smoky Mountains Study (n=1420) were used, covering children in the community aged 9-16, 19 and 21 years old. Structured interviews were used at each assessment to assess GAD symptoms, diagnosis and cumulative episodes. Blood spots were collected and assayed for high-sensitivity CRP levels. RESULTS: GAD was associated with increased levels of CRP in bivariate cross-sectional analyses. These bivariate associations, however, were attenuated after accounting for demographic, substance-use and health-related covariates. In longitudinal models, there was little evidence that CRP predicted later GAD. Associations from GAD to later CRP were attenuated in models adjusted for health-related coavariates and there was evidence that the GAD-CRP association was mediated by body mass index (BMI) and medication use. CONCLUSIONS: Similar to depression, GAD was associated with elevated levels of CRP, but the effect of GAD on CRP levels was explained by the effect of GAD on health-related behaviors such as BMI and medication use. This study suggests differences in the association between inflammation and depression and GAD.

Child-, adolescent- and young adult-onset depressions: differential risk factors in development?

BACKGROUND: Previous research reported that childhood adversity predicts juvenile- onset but not adult-onset depression, but studies confounded potentially genuine differences in adversity with differences in the recency with which adversity was experienced. The current study paper took into account the recency of risk when testing for differences among child-, adolescent- and young adult-onset depressions. METHOD: Up to nine waves of data were used per subject from two cohorts of the Great Smoky Mountains Study (GSMS; n=1004), covering children in the community aged 9-16, 19 and 21 years. Youth and one of their parents were interviewed using the Child and Adolescent Psychiatric Assessment (CAPA) between ages 9 and 16; these same youth were interviewed using the Young Adult Psychiatric Assessment (YAPA) at ages 19 and 21. The most common psychosocial risk factors for depression were assessed: poverty, life events, parental psychopathology, maltreatment, and family dysfunction. RESULTS: Consistent with previous research, most childhood psychosocial risk factors were more strongly associated with child-onset than with adolescent-/adult-onset depression. When potentially genuine risk differences among the depression-onset groups were disentangled from differences due to the recency of risk, child- and young adult-onset depression were no longer different from one another. Adolescent-onset depression was associated with few psychosocial risk factors. CONCLUSIONS: There were no differences in putative risk factors between child- and young adult-onset depression when the recency of risk was taken into account. Adolescent-onset depression was associated with few psychosocial risk factors. It is possible that some adolescent-onset depression cases differ in terms of risk from child- and young adult-onset depression.

The Great Smoky Mountains Study of Youth. Functional impairment and serious emotional disturbance.

BACKGROUND: Federal regulations require states to estimate the prevalence and incidence of serious emotional disturbance (SED) in children, defined as a DSM-III-R diagnosis in the presence of impaired functioning in 1 or more areas. We reviewed the published data on SED and examined rates and correlates of SED in an ongoing epidemiologic study of children. METHODS: Rates of DSM-III-R disorders, functional impairment, and their co-occurrence (SED) were examined in a representative population sample of 9-, 11-, and 13-year-olds from a predominantly rural area of North Carolina. Three measures of functional impairment were used, and their interrelationship and impact on rates of SED were examined. RESULTS: Serious emotional disturbance was identified in 4% to 8% of the study population, depending on the measure of impairment; the rate of DSM-III-R disorder ignoring impairment was 20.3%. One quarter of children identified as having SED on any measure were identified by all 3, and one half by 2 or more. Behavioral disorders, emotional disorders, and comorbidity were associated with a significant increase in the likelihood of SED; enuresis and tic disorders in the absence of comorbidity were not. Diagnosis and impairment made independent contributions to the increase in service use seen in children with SED. Poverty greatly increased the likelihood of SED. CONCLUSIONS: Specific areas of functional impairment should be examined when SED is assessed and treatment is planned. Plans to target mental health care resources to children with SED need to be accompanied by efforts to ensure access to those resources.

The Great Smoky Mountains Study of Youth. Goals, design, methods, and the prevalence of DSM-III-R disorders.

BACKGROUND: The Great Smoky Mountains Study of youth focuses on the relationship between the development of psychiatric disorder and the need for and use of mental health services. METHODS: A multistage, overlapping cohorts design was used, in which 4500 of the 11758 children aged 9, 11, and 13 years in an 11-county area of the southeastern United States were randomly selected for screening for psychiatric symptoms. Children who scored in the top 25% on the screening questionnaire, together with a 1 in 10 random sample of the rest, were recruited for 4 waves of intensive, annual interviews (n = 1015 at wave 1). In a parallel study, all American Indian children aged 9, 11, and 13 years were recruited (N = 323 at wave 1). RESULTS: The 3-month prevalence (+/-SE) of any DSM-III-R axis I disorder in the main sample, weighted to reflect population prevalence rates, was 20.3% +/- 1.7%. The most common diagnoses were anxiety disorders (5.7% +/- 1.0%), enuresis (5.1% +/- 1.0%), tic disorders (4.2% +/- 0.9%), conduct disorder (3.3% +/- 0.6%), oppositional defiant disorder (2.7% +/- 0.4%), and hyperactivity (1.9% +/- 0.4%). CONCLUSIONS: The prevalence of psychiatric disorder in this rural sample was similar to rates reported in other recent studies. Poverty was the strongest demographic correlate of diagnosis, in both urban and rural children.

Making sense of informant disagreement for overanxious disorder.

A community sample of 2798 8-17-year-old twins and their parents completed a personal interview about the child's current psychiatric history on two occasions separated by an average of 18 months. Parents also completed a personal interview about their own lifetime psychiatric history at entry to the study. Results indicate that informant agreement for overanxious disorder (OAD) was no better than chance, and most cases of OAD were based on only one informant's ratings. Disagreement about level of OAD symptoms or presence of another disorder (mostly phobias or depression) accounted for most cases of informant disagreement: 60% of cases based only on child interview, 67% of cases based only on maternal interview, and 100% of cases based only on paternal interview. OAD diagnosed only by maternal interview was also distinguished by an association with maternal alcoholism and increasingly discrepant parental reports of marital difficulties. Given the substantial overlap in case assignments for DSM-III-R OAD and DSM-IV GAD, these findings may identify sources of informant disagreement that generalize to juvenile GAD.

Depressive comorbidity in children and adolescents: empirical, theoretical, and methodological issues.

OBJECTIVE: The purpose of the study was to examine comorbidity in the context of child and adolescent depression. METHOD: The authors reviewed recent epidemiological studies using standardized interviews and DSM-III or DSM-III-R criteria. RESULTS: There was a high rate of comorbidity in children and adolescents with major depressive disorders or dysthymia. Comorbidity with conduct disorder/oppositional defiant disorder ranged from 21% to 83%; comorbidity with anxiety disorder ranged from 30% to 75%; and comorbidity with attention deficit disorder ranged from 0% to 57.1%. Rates of depressive comorbidity found in community studies were similar to the rates found in clinical studies. In almost all cases, the disorders were more common in depressed children than expected by chance, and the rates of other disorders in depressed children were higher than the rates of depression in those with depression. CONCLUSIONS: The mechanisms by which comorbidity occurs are obscure at present. Several possibilities and their implications for nosology, epidemiology, and treatment research are discussed.

Toward establishing an empirical basis for the diagnosis of oppositional defiant disorder.

OBJECTIVES: (1) To determine the frequency of occurrence of oppositional defiant behaviors in the general population with a view to establishing empirical frequency cutoffs for the evaluation of oppositional defiant disorder (ODD). (2) To examine the effects of changes in the definition of ODD between DSM-III-R and DSM-IV. METHOD: The Great Smoky Mountains Study is a general population study of 9-, 11-, and 13-year-olds. Subjects and their parents were interviewed with the Child and Adolescent Psychiatric Assessment at baseline and again 1 year later. RESULTS: Ninetieth percentile frequency cutoffs for ODD symptoms are given. Although rates of ODD were little different between DSM-III-R and DSM-IV, fewer than half of those who met criteria by one or the other definition met criteria according to both. DSM-IV defined a more disturbed group of children than did DSM-III-R. Requiring only two or three ODD symptoms plus impairment identified children with substantial evidence of disturbance who did not otherwise meet criteria for any diagnosis. CONCLUSIONS: The DSM-IV criteria represent an improvement over DSM-III-R. However, a reduction in the number of ODD symptoms required for diagnosis is indicated. Symptom frequency criteria for ODD symptoms are suggested for clinical use.

The Child and Adolescent Psychiatric Assessment (CAPA).

OBJECTIVE: To describe the Child and Adolescent Psychiatric Assessment (CAPA). The base interview covers the age range from 9 to 17 years. METHOD: The interview glossary that provides detailed operational definitions of symptoms and severity ratings is described, and psychometric data and further developments of the interview are presented. RESULTS: Across 5,962 parent-child interviews, the core sections of the CAPA (psychiatric symptoms, functional impairment, demographics, family structure and functioning) took on average 59 minutes for children and 66 minutes for parents. Test-retest reliability for diagnoses ranged from kappa = 0.55 for conduct disorder (CD) to kappa = 1.0 for substance abuse/dependence. Validity as judged by 10 different criteria was good. Developments of the CAPA include a shorter "gateway" version using core symptoms as screen items, a Spanish version, and versions for twin studies, use with young adults (YAPA), and preschool-age children (PAPA). CONCLUSIONS: There is a place in both research and clinical settings for a rigorously operationalized interview (such as the CAPA) that focuses on ensuring that respondents understand what is being asked and on clearly defining levels of symptom severity and functional impairment.

Adolescent outcomes of childhood disorders: the consequences of severity and impairment.

OBJECTIVE: To examine the adolescent consequences of clinical and threshold-level psychiatric disorders, with and without significant functional impairment; to predict serious emotional disturbance (SED: clinical-level diagnosis with impairment); and to examine sex differences in the consequences of emotional and behavioral disorders. METHOD: 300 children aged 7 through 11 years were recruited from urban and suburban offices of a large health maintenance organization (HMO). Child and parent were interviewed at home using the Diagnostic Interview Schedule for Children (DISC), version 1.3. Five to 7 years later, 278 (93%) of the sample were reinterviewed using the DISC-2.1. RESULTS: There was considerable continuity of psychopathology, particularly in children with functional impairment. Behavioral disorders at every level of severity predicted adolescent SED in both sexes. For emotional disorders, girls but not boys with childhood SED had significantly higher levels of adolescent SED. CONCLUSIONS: Childhood disorders falling below the level of severity required to meet criteria for treatment set by many HMOs or insurance companies nevertheless can carry a significantly increased risk for severe pathology years later. Functional impairment played an important role in the adolescent consequences of childhood psychiatric disorder.

Headaches and psychopathology in children and adolescents.

OBJECTIVE: To examine the association between chronic headaches and DSM-III-R-defined psychiatric disorders, including depression, anxiety disorders, conduct disorder, oppositional defiant disorder and attention-deficit hyperactivity disorder, in a population-based sample of children and adolescents. METHOD: 1,013 children aged 9 to 15 years in the Great Smoky Mountains Study were evaluated annually over a 3-year period using the Child and Adolescent Psychiatric Assessment, a child and parent diagnostic psychiatric interview. Headaches that lasted at least 1 hour and occurred at least once a week during the 3 months prior to the interview were studied. RESULTS: Girls with depression and anxiety disorders had a significantly greater prevalence of headaches than girls without an internalizing disorder. This association was not found for boys. Conduct disorder was significantly associated with headaches in boys. Each of these associations was constant with age. CONCLUSIONS: This study suggests that a distinct gender difference exists between boys and girls in the associations between headaches and psychopathology. Carroll's theory of dysfunction in central pain regulation as an underlying cause of depression is discussed in relation to the proposed serotonergic dysregulation common to headaches, depression, anxiety, aggression, and pain.

Stimulant treatment for children: a community perspective.

OBJECTIVE: To examine the use of prescribed stimulants in relation to research diagnoses of attention-deficit hyperactivity disorder (ADHD) in a community sample of children. METHOD: Data from 4 annual waves of interviews with 9- to 16-year-olds from the Great Smoky Mountains Study were analyzed. RESULTS: Over a 4-year period, almost three quarters of children with an unequivocal diagnosis of ADHD received stimulant medications. However, girls and older children with ADHD were less likely to receive such treatment. Most children with impairing ADHD symptoms not meeting full criteria for DSM-III-R ADHD did not receive stimulant treatment. Stimulant treatment in this group was significantly related to the level of symptoms reported by parents and teachers and was much more common in individuals who met criteria for oppositional defiant disorder. The majority of individuals who received stimulants were never reported by their parents to have any impairing ADHD symptoms. They did have higher levels of nonimpairing parent-reported ADHD symptoms, higher levels of teacher-reported ADHD symptoms, and interviewer-observed ADHD behaviors, but these typically fell far below the threshold for a DSM-III-R diagnosis of ADHD. CONCLUSIONS: In this area of the Great Smoky Mountains, stimulant treatment was being used in ways substantially inconsistent with current diagnostic guidelines.

Implications of early versus late onset of attention-deficit/hyperactivity disorder symptoms.

OBJECTIVE: The current diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD) require that symptoms emerge prior to age 7 in order for a formal diagnosis to be considered. However, this age-of-onset criterion (AOC) has recently been questioned on both theoretical and empirical grounds. METHOD: Data from 4 annual waves of interviews with 9- to 16-year-olds from the Great Smoky Mountains Study were analyzed. RESULTS: Confirming previous studies, a majority of youths who had enough symptoms to meet criteria for ADHD were reported to have first exhibited these symptoms prior to age 7. Early onset of ADHD symptoms was associated with worse clinical outcomes in youths with the combined subtype of ADHD but not youths with the inattentive subtype. CONCLUSIONS: Findings support the continued inclusion of the AOC for the assessment of the combined but not necessarily the inattentive subtype of ADHD. Too few youths had a late onset of solely hyperactive-impulsive symptoms to evaluate the AOC for that group. However, regardless of the age of onset, youths who had elevated levels of ADHD symptoms were at increased risk for negative outcomes that may necessitate intervention.

How can epidemiology improve mental health services for children and adolescents?

Epidemiology, the study of patterns of disease distribution in time and space, can help to improve mental health services for children and adolescents by increasing understanding of the causes, development, and course of psychiatric disorders. For the purpose of service delivery, epidemiologic research on child psychopathology can provide information on need for services, availability of services, and effectiveness of services. For both scientific and planning purposes, epidemiologic research can inform us about (1) the developmental course of psychiatric disorders during childhood and adolescence, (2) the effect of psychiatric disorder on the course of normal childhood development, and (3) the effect of childhood development on the developmental course of psychiatric disorder. Information about prevalence and incidence is useful for planning primary, secondary, and tertiary prevention and treatment services. The same information is scientifically useful to the extent that it helps to answer questions about causation, course, and outcome. However, one aim of this paper is to show that epidemiology is about a great deal more than rates of disorder.

The effects of age and sex on depression ratings in children and adolescents.

The self-reports of depressive symptomatology of the 89 children and the parental reports of 62 parents whose children had such symptoms from a sample of 220 children, aged 6 to 23 years, in a family-genetic study of children at high and low risk of depression were examined for the effects of the age and sex of the child. The age of the child at interview proved to have a significant effect upon the dating of the onset of dysphoric episodes and the dating of the worst ever episode of dysphoria. The older girls reported about two more depressive symptoms on average than the younger girls. This finding was obscured unless account was taken of the age at which the subjects were interviewed. However, these effects did not apply to a group of melancholia-related symptoms. There were no consistent effects of age at interview or age at episode on the symptom reports of the boys or in the reports from the parents about both their male and female children.

Somatic complaints and psychopathology in children and adolescents: stomach aches, musculoskeletal pains, and headaches.

OBJECTIVE: To examine the associations of somatic complaints with DSM-III-R-defined depression, anxiety disorders, conduct disorder, oppositional defiant disorder, and attention-deficit hyperactivity disorder in a population-based sample of children and adolescents. METHODS: Data from 4 annual waves of interviews with 9- to 16-year-olds from the Great Smoky Mountains Study were analyzed. RESULTS: Overall, somatic complaints were strongly associated with emotional disorders in girls and with disruptive behavior disorders in boys. For girls, stomach aches and headaches together and musculoskeletal pains alone were associated with anxiety disorders. For boys, stomach aches were associated with oppositional defiant disorder and attention-deficit hyperactivity disorder. Musculoskeletal pains were associated with depression in both girls and boys. CONCLUSIONS: There were gender-, illness- and complaint-specific associations between somatic complaints and psychopathology. It appears likely that there are differences in the psychobiological processes underlying these associations in boys and girls. Clinical recommendations include screening children and adolescents with persistent complaints of headaches, stomach aches, or musculoskeletal pains for psychiatric disorders with an awareness that gender may affect the type of psychopathology associated with the somatic complaints.

Effectiveness of nonresidential specialty mental health services for children and adolescents in the "real world".

OBJECTIVE: Although many studies demonstrate the efficacy of a variety of treatments for child and adolescent psychiatric disorders, studies showing the effectiveness of such treatments in ordinary clinical settings have not been forthcoming. This report presents a study of the effectiveness of outpatient treatment in a community sample of 9- to 16-year-olds. METHOD: Four annual waves of data were collected from a representative sample of 1,422 children and their parents in the southeastern United States. Interviews were conducted with the Child and Adolescent Psychiatric Assessment to determine clinical status and the Child and Adolescent impact Assessment to measure the impact of psychiatric disorder on the lives of the children's families. RESULTS: Treated individuals were more severely disturbed and showed deterioration in their clinical status, even before they received treatment, indicating that comparisons with untreated individuals required controls not only for pretreatment clinical status, but for pretreatment clinical trajectory. A significant dose-response relationship was found between the number of specialty mental health treatment sessions received and improvement in symptoms at follow-up. However, no effect of treatment on secondary psychosocial impairment or parental impact was identified. CONCLUSIONS: Child and adolescent outpatient psychiatric treatment has positive effects on psychiatric symptoms, even when conducted outside the academic units where efficacy research usually takes place. The dose of treatment required to produce such effects (more than 8 sessions) suggests that attempts to limit child psychiatric treatment to very short-term interventions may be counterproductive.

Impaired but undiagnosed.

OBJECTIVE: To investigate the prevalence and outcomes of individuals with psychosocial impairment not meeting DSM-III-R criteria for any of 29 well-defined disorders and to suggest operational definitions for not otherwise specified (NOS) diagnoses and V codes. METHODS: Two-stage general population sampling resulted in 1,015 youths aged 9, 11, and 13 years being interviewed in the first wave of the Great Smoky Mountains Study. They were reinterviewed 1 year later using the Child and Adolescent Psychiatric Assessment. RESULTS: The weighted prevalence of sibling relational problems was found to be 1.4%. That of parent-child relational problems was 3.6% and that of relational problems NOS was 0.6%. The overall rate of symptomatic impairment was 9.4%. Across a variety of "caseness measures," those with symptomatic impairment proved to be more disturbed than those without either a diagnosis or impairment, and as disturbed as those with a diagnosis but without impairment. CONCLUSION: Children and adolescents who do not meet DSM-III-R criteria for any well-defined disorder but who have symptoms associated with psychosocial impairment should be regarded as suffering from a psychiatric disorder. It is suggested that researchers adopt this definition for the many NOS diagnoses included in the DSM nosology and implement it in their research diagnostic algorithms.

Multimodal treatment of ADHD in the MTA: an alternative outcome analysis.

OBJECTIVE: To conduct a post hoc investigation of the utility of a single composite measure of treatment outcome for the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) at 14 months postbaseline. BACKGROUND: Examination of multiple measures one at a time in the main MTA intent-to-treat outcome analyses failed to detect a statistically significant advantage of combined treatment (Comb) over medication management (MedMgt). A measure that increases power and precision using a single outcome score may be a useful alternative to multiple outcome measures. METHOD: Factor analysis of baseline scores yielded two "source factors" (parent and teacher) and one "instrument factor" (parent-child interactions). A composite score was created from the average of standardized parent and teacher measures. RESULTS: The composite was internally consistent (alpha = .83), reliable (test-retest over 3 months = 0.86), and correlated 0.61 with clinician global judgments. In an intent-to-treat analysis, Comb was statistically significantly better than all other treatments, with effect sizes ranging from small (0.28) versus MedMgt, to moderately large (0.70) versus a community comparison group. CONCLUSIONS: A composite of ADHD variables may be an important tool in future treatment trials with ADHD and may avoid some of the statistical limitations of multiple measures.