Nominal association with CHRNA4 variants and nicotine dependence.

Nicotine binds to nicotinic acetylcholine receptors and studies in animal models have shown that α4ß2 receptors mediate many behavioral effects of nicotine. Human genetics studies have provided support that variation in the gene that codes for the α4 subunit influences nicotine dependence (ND), but the evidence for the involvement of the ß2 subunit gene is less convincing. In this study, we examined the genetic association between variation in the genes that code for the α4 (CHRNA4) and ß2 (CHRNB2) subunits of the nicotinic acetylcholine receptor and a quantitative measure of lifetime DSM-IV ND symptom counts. We performed this analysis in two longitudinal family-based studies focused on adolescent antisocial drug abuse: the Center on Antisocial Drug Dependence (CADD, N = 313 families) and Genetics of Antisocial Drug Dependence (GADD, N = 111 families). Family-based association tests were used to examine associations between 14 single nucleotide polymorphisms (SNPs) in CHRNA4 and CHRNB2 and ND symptoms. Symptom counts were corrected for age, sex and clinical status prior to the association analysis. Results, when the samples were combined, provided modest evidence that SNPs in CHRNA4 are associated with ND. The minor allele at both rs1044394 (A; Z = 1.988, P = 0.047, unadjusted P-value) and rs1044396 (G; Z = 2.398, P = 0.017, unadjusted P-value) was associated with increased risk of ND symptoms. These data provide suggestive evidence that variation in the α4 subunit of the nicotinic acetylcholine receptor may influence ND liability.

Developmental epidemiology of drug use and abuse in adolescence and young adulthood: Evidence of generalized risk.

Past studies highlight a narrowing gender gap and the existence of a shared etiology across substances of abuse; however, few have tested developmental models using longitudinal data. We present data on developmental trends of alcohol, tobacco, and marijuana use, abuse and dependence assessed during adolescence and young adulthood in a community-based Colorado twin sample of 1733 respondents through self-report questionnaires and structured psychiatric interviews. Additionally, we report on the rates of multiple substance use and disorders at each developmental stage, and the likelihood of a substance use disorder (SUD; i.e., abuse or dependence) diagnosis in young adulthood based on adolescent drug involvement. Most notably, we evaluate whether the pattern of multiple substance use and disorders and likelihood ratios across substances support a model of generalized risk. Lastly, we evaluate whether the ranked magnitudes of substance-specific risk match the addiction liability ranking. Substance use and SUDs are developmental phenomena, which increase from adolescence to young adulthood with few and inconsistent gender differences. Adolescents and young adults are not specialized users, but rather tend to use or abuse multiple substances increasingly with age. Risk analyses indicated that progression toward a SUD for any substance was increased with prior involvement with any of the three substances during adolescence. Despite the high prevalence of alcohol use, tobacco posed the greatest substance-specific risk for developing subsequent problems. Our data also confirm either a generalized risk or correlated risk factors for early onset substance use and subsequent development of SUDs.

Mate similarity for substance dependence and antisocial personality disorder symptoms among parents of patients and controls.

UNLABELLED: Substance dependence (SD) and antisocial personality disorder (ASPD) are highly comorbid and aggregate in families. Mating assortment may be an important process contributing to this familial aggregation. HYPOTHESIS: Symptom counts of substance dependence, antisocial personality disorder, and retrospectively assessed conduct disorder (CD) will be correlated significantly among parents of youth in treatment for substance use and conduct problems and, separately, among parents of community controls. METHODS: We examined SD, ASPD, and CD among 151 pairs of parents of adolescents in treatment for substance use and conduct problems, and in 206 pairs of parents of control subjects. RESULTS: For average dependence symptoms (ADS) (the sum of across-drug substance dependence symptoms divided by the number of substance categories meeting minimum threshold use) mother-father correlations were 0.40 for patients and 0.28 for controls. Mother--father correlations for ASPD symptom count were 0.33 for patients and 0.26 for controls and for CD symptom count were 0.31 for patients (all P < 0.01) and 0.10 for controls (P = 0.14). CONCLUSIONS: Spousal correlations for ADS and ASPD, suggest substantial non-random mating. Results support gender differences in homogamy for SD. Behavior genetic studies of these disorders need to account for assortment to avoid biases in estimates of genetic and environmental effects.

Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates.

We present data on the lifetime prevalence of substance use, abuse and dependence in adolescents obtained through structured psychiatric interviews and self-report questionnaires. Most notably, we evaluate symptom profiles based on DSM-IV abuse and dependence criteria for tobacco, alcohol and marijuana, including a gender comparison. Participants are 3,072 adolescents (12-18 years) drawn from three community-based family samples in Colorado. Age trends suggest that substance use is a developmental phenomenon, which increases almost linearly from early to late adolescence. Substance use disorders are less common than experimentation in adolescence, but approximately 1 in 4 adolescents in the oldest cohorts meets criteria for abuse for at least one substance, and 1 in 5 meets criteria for substance dependence. By age 18 nearly 1 in 3 adolescents report daily smoking and 8.6% meet criteria for tobacco dependence. Although alcohol is the most commonly abused substance (10%), a slightly larger proportion of adolescents meet criteria for dependence on marijuana (4.3%) than alcohol (3.5%). Gender differences in prevalence of use more often show greater use in males than females. Males more frequently meet criteria for dependence on alcohol and marijuana in late adolescence, while females are more often nicotine dependent. A comparison of abuse and dependence symptom profiles shows some interesting variability across substances, and suggests that manifestations of a subset of symptoms are gender specific.

Validity of structured clinical evaluations in adolescents with conduct and substance problems.

OBJECTIVE: To determine discriminative and convergent validity for certain structured diagnostic assessments among adolescents with conduct and substance problems. METHOD: Patients were 87 adolescents (both genders) in treatment for conduct and substance problems. Most controls (n = 85; both genders) came from patients' neighborhoods. Assessments included Diagnostic Interview Schedule for Children, Composite International Diagnostic Instrument-Substance Abuse Module, Child Behavior Checklist, and others. Patients' data guided clinical care. RESULTS: Youths' self-reports significantly discriminated patients from controls in DSM-IVconduct and substance use disorders (CD, SUD) and in numerous associated measures. CD and SUD symptoms correlated strongly. However, some patients apparently minimized symptoms. Youths' self-reports did not discriminate patients from controls in attention-deficit/hyperactivity disorder (ADHD) or major depression (MDD). Parent information raised prevalence rates of ADHD and MDD, which then discriminated patients from controls. However, patients and parents usually disagreed on MDD and ADHD diagnoses. CONCLUSIONS: Despite some dissimulation, patients' self-reports of CD and SUD correlated highly and had superb discriminative validity, making them useful for treatment and research. Self-reports of ADHD and MDD, apparently lacking discriminative validity, are less useful. Parent reports improve these discriminations but present additional problems.

Concordance between DSM-III-R and DSM-IV diagnoses of substance use disorders in adolescents.

Except for cannabis and alcohol, concordance between DSM-III-R and DSM-IV substance use disorder diagnoses has not been reported in adolescents. We assessed a clinical sample of 102 adolescents using CIDI-SAM. Prevalence of either an abuse or dependence diagnosis was lower with DSM-IV than DSM-III-R except for cannabis and alcohol, and concordance rates were better for dependence than for abuse. For most substances, rates of DSM-IV withdrawal were lower than in DSM-III-R, but rates of DSM-IV physiological dependence remained high. Changes in DSM-IV criteria appear to have impacted diagnoses in these adolescents, particularly for the substances they use most--i.e. alcohol, tobacco, and cannabis.

Heroin use among adolescents in treatment for substance use disorders.

OBJECTIVE: To clarify prevalence rates and describe patterns of adolescent heroin users who are in treatment for substance use disorders. METHOD: The Treatment Episode Data Set (TEDS) was examined for trends in the number of adolescents admitted to substance abuse treatment centers and for changes in the routes of heroin administration. Thirteen adolescents who used heroin from one treatment program were compared with 536 adolescents who did not. RESULTS: Between 1992 and 1996, heroin-using youths represented 2.0% of youths in treatment and in 1997 they represented 2.6%. Heroin-using youths represented 56% of those using injection drugs. Heroin-using youths from one treatment program had significantly more polysubstance dependence in comparison with adolescents who did not use heroin. CONCLUSIONS: Nationally, there has been an increasing number, but not percentage, of heroin-using youths in treatment between 1992 and 1996. In 1997 there was an increase in both the number and percentage of heroin-using youths in treatment. Heroin-using adolescents have the highest rate of injection drug use when compared with youths using other substances. Because of their greater risk of contracting human immunodeficiency virus through injection drug use, treatment trials for these adolescents are needed.

One-year outcome of adolescent females referred for conduct disorder and substance abuse/dependence.

We investigated whether substance abuse/dependence, conduct disorder, and other psychiatric disorders improved in adolescent females who were referred to outpatient treatment and which variables were related to 1-year outcome. Forty-six out of 60 conduct-disordered (CD) adolescent females with substance abuse or dependence were re-evaluated approximately 1 year after discharge. Treatment length averaged 16 weeks. Significant improvements were seen in three areas: (1) criminality and CD; (2) attention deficit hyperactivity disorder (ADHD); and (3) educational and vocational status. However, neither substance involvement nor depression improved, regardless of length of stay in treatment, and these females demonstrated significant risky sexual behaviors. In contrast to our previous work with adolescent males (Crowley, T.J., Mikulich, S.K., Macdonald, M., Young, S.E., Zerbe, G.O., 1998. Substance-dependent, conduct-disordered adolescent males: severity of diagnosis predicts 2-year outcome. Drug Alcohol Depend. 49, 225-237), we were not able to identify pre-intake variables, other than performance IQ, that were related to substance use and conduct outcomes. Only two post-treatment factors (peer problems and number of ADHD symptoms at follow-up) were found to be related to CD and substance use disorders outcomes. The overall lack of pre- and post-treatment predictors presents interesting challenges for future research on adolescent females with these disorders.

Neoproterozoic 'snowball Earth' simulations with a coupled climate/ice-sheet model.

Ice sheets may have reached the Equator in the late Proterozoic era (600-800 Myr ago), according to geological and palaeomagnetic studies, possibly resulting in a 'snowball Earth'. But this period was a critical time in the evolution of multicellular animals, posing the question of how early life survived under such environmental stress. Here we present computer simulations of this unusual climate stage with a coupled climate/ice-sheet model. To simulate a snowball Earth, we use only a reduction in the solar constant compared to present-day conditions and we keep atmospheric CO2 concentrations near present levels. We find rapid transitions into and out of full glaciation that are consistent with the geological evidence. When we combine these results with a general circulation model, some of the simulations result in an equatorial belt of open water that may have provided a refugium for multicellular animals.

Respiration during snow burial using an artificial air pocket.

CONTEXT: Asphyxia is the most common cause of death after avalanche burial. A device that allows a person to breathe air contained in snow by diverting expired carbon dioxide (CO2) away from a 500-cm3 artificial inspiratory air pocket may improve chances of survival in avalanche burial. OBJECTIVE: To determine the duration of adequate oxygenation and ventilation during burial in dense snow while breathing with vs without the artificial air pocket device. DESIGN: Field study of physiologic respiratory measures during snow burial with and without the device from December 1998 to March 1999. Study burials were terminated at the subject's request, when oxygen saturation as measured by pulse oximetry (SpO2) dropped to less than 84%, or after 60 minutes elapsed. SETTING: Mountainous outdoor site at 2385 m elevation, with an average barometric pressure of 573 mm Hg. PARTICIPANTS: Six male and 2 female volunteers (mean age, 34.6 years; range, 28-39 years). MAIN OUTCOME MEASURES: Burial time, SpO2, partial pressure of end-tidal CO2 (ETCO2), partial pressure of inspiratory CO2 (PICO2), respiratory rate, and heart rate at baseline (in open atmosphere) and during snow burial while breathing with the device and without the device but with a 500-cm3 air pocket in the snow. RESULTS: Mean burial time was 58 minutes (range, 45-60 minutes) with the device and 10 minutes (range, 5-14 minutes) without it (P=.001). A mean baseline SpO2 of 96% (range, 90%-99%) decreased to 90% (range, 77%-96%) in those buried with the device (P=.01) and to 84% (range, 79%-92%) in the control burials (P=.02). Only 1 subject buried with the device, but 6 control subjects buried without the device, decreased SpO2 to less than 88% (P=.005). A mean baseline ETCO2 of 32 mm Hg (range, 27-38 mm Hg) increased to 45 mm Hg (range, 32-53 mm Hg) in the burials with the device (P=.02) and to 54 mm Hg (range, 44-63 mm Hg) in the control burials (P=.02). A mean baseline PICO2 of 2 mm Hg (range, 0-3 mm Hg) increased to 32 mm Hg (range, 20-44 mm Hg) in the burials with the device (P=.01) and to 44 mm Hg (range, 37-50 mm Hg) in the control burials (P=.02). Respiratory and heart rates did not change in burials with the device but significantly increased in control burials. CONCLUSIONS: In our study, although hypercapnia developed, breathing with the device during snow burial considerably extended duration of adequate oxygenation compared with breathing with an air pocket in the snow. Further study will be needed to determine whether the device improves survival during avalanche burial.

Relationship of ADHD, depression, and non-tobacco substance use disorders to nicotine dependence in substance-dependent delinquents.

This study used standardized interviews to examine the relationship of attention deficit hyperactivity disorder (ADHD), major depression (MDD), and other illicit substance use disorders (SUD) to onset and severity of nicotine dependence in 82 female and 285 male adolescents with conduct disorder (CD) and SUD. Results indicate that both ADHD and MDD significantly contribute to severity of nicotine dependence in delinquents with SUD. ADHD is further associated with earlier onset of regular smoking in males. Severity of non-tobacco SUD also was related directly to nicotine dependence severity in both males and females, and to earlier onset of smoking in males. Our findings illuminate the contribution of comorbidity to nicotine dependence and its relationship to other SUD severity among adolescents with CD and SUD and highlight the need for coordinated assessment and treatment of smoking cessation along with concurrent treatment of other drug use and psychiatric comorbidity such as ADHD and MDD in such youths.

Relating the classical covariance adjustment techniques of multivariate growth curve models to modern univariate mixed effects models.

The relationship between the modern univariate mixed model for analyzing longitudinal data, popularized by Laird and Ware (1982, Biometrics 38, 963-974), and its predecessor, the classical multivariate growth curve model, summarized by Grizzle and Allen (1969, Biometrics 25, 357-381), has never been clearly established. Here, the link between the two methodologies is derived, and balanced polynomial and cosinor examples cited in the literature are analyzed with both approaches. Relating the two models demonstrates that classical covariance adjustment for higher-order terms is analogous to including them as random effects in the mixed model. The polynomial example clearly illustrates the relationship between the methodologies and shows their equivalence when all matrices are properly defined. The cosinor example demonstrates how results from each method may differ when the total variance-covariance matrix is positive definite, but that the between-subjects component of that matrix is not so constrained by the growth curve approach. Additionally, advocates of each approach tend to consider different covariance structures. Modern mixed model analysts consider only those terms in a model's expectation (or linear combinations), and preferably the most parsimonious subset, as candidates for random effects. Classical growth curve analysts automatically consider all terms in a model's expectation as random effects and then investigate whether "covariance adjusting" for higher-order terms improves the model. We apply mixed model techniques to cosinor analyses of a large, unbalanced data set to demonstrate the relevance of classical covariance structures that were previously conceived for use only with completely balanced data.

Cannabis dependence, withdrawal, and reinforcing effects among adolescents with conduct symptoms and substance use disorders.

The prevalence of cannabis use is rising among adolescents, many of whom perceive little risk from cannabis. However, clinicians who treat adolescent substance users hear frequent reports of serious cannabis-use disorders and problems. This study asked whether cannabis produced dependence and withdrawal among such patients, and whether patients' reports supported previous laboratory findings of reinforcing effects from cannabis. This was a screening and diagnostic study of serial treatment admissions. The diagnostic standard was the DSM-III-R dependence criteria, and the setting was a university-based adolescent substance treatment program with male residential and female outpatient services. The patients were 165 males and 64 females from consecutive samples of 255 male and 85 female 13-19-year-olds referred for substance and conduct problems (usually from social service or criminal justice agencies). Eighty-seven patients were not evaluated, usually due to early elopement. Twenty-four others did not meet study admission criteria: > or = one dependence diagnoses and > or = three lifetime conduct-disorder symptoms. The main measures were items from diagnostic interview instruments for substance dependence, psychiatric disorders, and patterns of substance use. Diagnoses were substance dependence, 100%; current conduct disorder, 82.1%; major depression, 17.5%; attention-deficit/hyperactivity disorder, 14.8%. The results show that most patients claimed serious problems from cannabis, and 78.6% met standard adult criteria for cannabis dependence. Two-thirds of cannabis-dependent patients reported withdrawal. Progression from first to regular cannabis use was as rapid as tobacco progression, and more rapid than that of alcohol, suggesting that cannabis is a reinforcer. The data indicate that for adolescents with conduct problems cannabis use is not benign, and that the drug potently reinforces cannabis-taking, producing both dependence and withdrawal. However, findings from this severely affected clinical population should not be generalized broadly to all other adolescents.

Substance-dependent, conduct-disordered adolescent males: severity of diagnosis predicts 2-year outcome.

Most delinquent youths have conduct disorder (CD), often with comorbid substance use disorder (SUD), attention-deficit/hyperactivity disorder (ADHD) and depression. Some youths' conduct problems later abate, while those of others persist into adult antisocial personality disorder. Earlier CD onset and ADHD reportedly predict persisting antisocial problems, but predictors of persisting SUD are poorly understood. Males aged 13-19 years (n = 89), most referred by criminal justice and social service agencies, received residential treatment for comorbid CD and SUD. They had diagnostic assessments for SUD at intake and for CD, ADHD, and depression (as well as drug-use assessments) at intake and 6, 12 and 24 months later. At intake nearly all had DSM-III-R substance dependence (usually on alcohol and marijuana) and CD with considerable violence and criminality. The 2-year follow-ups revealed improvements in criminality, CD, depression and ADHD, but substance use remained largely unchanged. Various aspects of conduct, crime and substance outcomes at 2 years were predicted by intake measures of intensity of substance involvement, and by CD severity and onset age, but not by severity of either ADHD or depression, nor by treatment duration. Earlier CD onset, more severe CD and more drug dependence predicted worse outcomes, supporting the validity of these diagnoses in adolescents.

A family history and direct interview study of the familial aggregation of substance abuse: the adolescent substance abuse study.

The adolescent substance abuse (ASA) study collected information concerning drug use and psychopathology on male adolescent probands in treatment for substance abuse and also on matched control adolescents, as well as all available family members of both groups. Information was obtained through direct interview and the family history method of assessment. Both methods revealed greater alcohol and drug use, conduct disorder (CD) and antisocial personality disorder (ASP) in the relatives of treatment probands as compared with control relatives. These results suggest familial transmission, not only for alcohol abuse, but also for non-alcohol substance abuse. Familial transmission for CD and ASP is also evident for both male and female relatives, although the prevalence of these disorders is significantly greater in males than females.

Family variables in substance-misusing male adolescents: the importance of maternal disorder.

Selected family variables, especially maternal behaviors, were studied as predictors of alcohol and drug misuse in severely disturbed adolescent boys from largely father-absent homes. The families of 50 male youths (mean age 15.8 years) in a residential center for alcohol and substance misuse were compared with the families of a community control group (mean age 16.3 years). Within-subject group comparisons also were made. Family structure, interactive processes, maternal and paternal alcohol and substance use, and criminality were assessed through direct interview and/or self-report. The families of alcohol- and substance-misusing boys were markedly disadvantaged or impaired on numerous family structure, process, and substance-misusing behavioral variables in comparison with community controls. Within the alcohol- and substance-misusing group itself, family process variables, maternal alcohol symptoms, and maternal criminality differentiated boys with more vs. less severe drug-dependence symptoms. Maternal alcohol problems and criminality were more important than family process variables. Paternal alcohol or substance misuse or criminality did not differentiate proband symptom severity. We concluded that maternal alcohol symptoms and criminality differentiate severity of drug dependence in severely disturbed, substance-misusing adolescent males from largely father-absent homes. Maternal substance misuse should be evaluated carefully in adolescent substance abuse treatment settings.

Influences on adolescent substance dependence: conduct disorder, depression, attention deficit hyperactivity disorder, and gender.

OBJECTIVE: In adolescents, conduct disorder (CD), attention deficit hyperactivity disorder (ADHD), and depression are frequently comorbid with substance dependence (SD). We hypothesized that the prevalence and severity of CD, major depressive disorder (MDD), and ADHD would differ by gender, and that these conditions would associate differentially with severity of SD in males and females. METHODS: We examined these issues, using standardized diagnostic interviews, in 285 male and 82 female adolescents referred for comorbid CD and SD. RESULTS: Males and females did not differ significantly in severity of substance involvement, MDD, or ADHD, but males had more severe CD. MDD severity was the only variable significantly associated with SD severity for females, while for males, severity of CD combined with MDD and ADHD was significantly associated with SD severity. CONCLUSIONS: Among referred adolescents, CD, MDD, and ADHD may all be important concomitants of SD in males, while in females, depression may be the primary variable related to SD.