Preadolescent children of substance-dependent fathers with antisocial personality disorder: psychiatric disorders and problem behaviors.

We compared psychiatric disorders and problem behavior scores in pre-adolescent children of fathers with alcohol or other drug dependence and ASP (SD+/ASP+), children whose fathers had substance dependence without ASP (SD+/ASP-), and children whose fathers were without either disorder (SD-/ASP-). SD+/ASP+ children showed elevated rates of major depression, conduct disorder, attention deficit hyperactivity disorder, oppositional defiant disorder, and separation anxiety disorder when compared to SD+/ASP- and SD-/ASP- children. SD+/ASP+ children had higher internalizing and externalizing problem behavior scores than the other two groups of children. The results suggest that SD+/ASP+ children are at significant risk for internalizing and externalizing psychopathology.

Comorbid disruptive behavior disorder symptoms and their relationship to adolescent alcohol use disorders.

This investigation evaluated the relationship between comorbid Disruptive Behavior Disorder (DBD) and Alcohol Use Disorder (AUD) symptoms in adolescents. The factor structure of both DBD and AUD symptoms was evaluated and a structural model then examined the relationships between comorbid DBD symptoms and AUD symptoms. A full model and a sex differentiated model were evaluated. For the full model, only Conduct Disorder (CD) symptoms were associated with AUD symptoms. In the sex differentiated model, male adolescents demonstrated direct effects of CD and Attention Deficit Hyperactivity Disorder (ADHD) on AUD. For female adolescents we found only a robust direct effect of CD on AUD. We concluded that CD symptoms have the strongest concurrent association with AUD symptoms in adolescents. However, there is preliminary evidence of sex heterogeneity.

Serotonin, impulsivity, and alcohol use disorders in the older adolescent: a psychobiological study.

BACKGROUND: Alcohol use disorders (AUDs) among adolescents are associated with a high prevalence of conduct disorder (CD), much as type II alcoholism in adults is associated with impulsive-aggressive behavior and antisocial personality traits. Adults with impulsive personality disorders and AUD demonstrate diminished central serotonergic responsiveness to serotonergic agonists. Dysregulation of central serotonergic function may contribute to a vulnerability to impulsive-aggressive behavior, CD, and AUD. We studied older adolescents, both male and female, to examine the relationships between sex, dispositional impulsivity, aggressivity, CD, and responsiveness to serotonergic challenge with d,l fenfluramine (FEN) early in the development of AUD. METHODS: Thirty-six adolescents between the ages of 16 and 21 years were assessed for DSM-IV AUD and other Axis I disorders by using the Psychoactive Substance Use Disorders section of the Structured Clinical Interview for DSM III-R, the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, and CD interviews. Impulsivity and aggressivity were assessed by the Barratt Impulsiveness Scale, Lifetime History of Aggression, Buss-Durkee Hostility Inventory, Eysenck Impulsiveness Questionnaire, Youth Self Report, and Multidimensional Personality Questionnaires. FEN was administered as 0.8 mg/kg to a maximum of 60 mg, and blood was sampled at fixed intervals for prolactin, cortisol, fenfluramine, and norfenfluramine levels. RESULTS: Eighteen adolescents (12 male, 6 female) with AUD scored significantly higher on all measures of impulsivity and aggressivity compared with 18 healthy controls (12 male, 6 female). There were no significant differences between groups in peak prolactin or cortisol responses (minus baseline), or area-under-the-curve determinations (AUC); however, 9 subjects with AUD and comorbid CD had significantly elevated cortisol AUC levels compared with subjects with AUD and no CD or with normal controls. In the total sample, cortisol AUC was associated positively with measures of aggression. CONCLUSIONS: Adolescents with early-onset AUD are characterized by impulsivity and aggressivity compared with healthy peers but do not demonstrate the diminished prolactin or cortisol responses to FEN characteristic of adult alcoholics with impulsive-aggression.

Antisociality, substance dependence, and the DRD5 gene: a preliminary study.

A pilot population-based study of a microsatellite polymorphism at the DRD5 locus in adult European-Americans showed its association with childhood symptom counts for oppositional defiant disorder (ODD) in males and females and adult antisocial personality disorder (ASPD) in females. No association with childhood conduct disorder symptom count was observed. ODD mediated the genotype-ASPD relationship in females. Neither ODD nor ASPD significantly mediated the relationship between the genotype and the liability to substance dependence (SD). The data suggest involvement of the DRD5 locus in the variation and sexual dimorphism of SD liability and antisociality and in the developmental continuity of antisociality.

Platelet dense granule secretion and aggregation in adolescents with conduct disorder: effects of marijuana use.

BACKGROUND: We had previously reported a decrease in agonist-induced platelet dense granule secretion in blood samples from male adolescents with and without Conduct Disorder (CD). In an augmented sample, we have now employed multivariate modeling to examine the simultaneous effects of CD and regular monthly alcohol and marijuana use on both the dense granule secretion and aggregation phases of agonist-induced platelet responses. METHODS: Blood samples were obtained from adolescents with and without a CD diagnosis. Platelet dense granule secretion and aggregation responses to a variety of agonists were examined in the laboratory. RESULTS: Significant multivariate interactions of CD status with regular marijuana use were found for responses to collagen, ADP alone, and ADP plus 0.2 microgram. of serotonin. Responses in platelets from youth with CD, but without regular marijuana use differed from other subjects. Multivariate main effects of marijuana use alone on platelet responses to arachidonic acid and ADP plus 1.0 microgram. of serotonin were found. No effects of alcohol use were found. CONCLUSIONS: The results demonstrate an interaction between CD and the effects of chronic marijuana use for several agonists in this platelet model system, and further support the possibility of a variation in signal transduction mechanisms in CD.

Hormonal and behavioral homeostasis in boys at risk for substance abuse.

This study modeled the influences of cortisol reactivity, androgens, age-corrected pubertal status, parental personality, family and peer dysfunction on behavioral self-regulation (BSR), in boys at high (HAR) and low average risk (LAR) for substance abuse. Differences between risk groups in cortisol and androgen concentrations, and cortisol reactivity were also examined. Subjects were 10- through 12-year-old sons of substance abusing fathers (HAR; n = 150) and normal controls (LAR; n = 147). A multidimensional construct of BSR was developed which utilized multiple measures and multiple informants. Boys reported on family dysfunction and deviant behavior among their peers. Parents reported on their propensity to physically abuse their sons, and their own number of DSM-III-R Antisocial Personality Disorder symptoms. Endocrine measures included plasma testosterone, dihydrotestosterone, and salivary cortisol. HAR boys, compared to LAR boys, had lower mean concentrations for testosterone, dihydrotestosterone, salivary cortisol prior to evoked related potential testing, and lower cortisol reactivity. The number of maternal Antisocial Personality Disorder symptoms, parental potential for physical abuse, degree of family dysfunction, and peer delinquency were significantly associated with BSR. Parental aggression antisocial personality symptoms and parental physical abuse potential are likely to influence sons' behavioral dysregulation and homeostatic stress reactivity. These key components of liability are posited to increase the likelihood of developing suprathreshold Psychoactive Substance Use Disorder (PSUD).

Salivary cortisol responses in prepubertal boys: the effects of parental substance abuse and association with drug use behavior during adolescence.

BACKGROUND: The purpose of this investigation was three-fold. First, we extended our original observation of decreased cortisol reactivity to an anticipated stressor in sons of fathers with a substance use disorder (SUD). Second, we examined the hypothesis that salivary cortisol underresponsivity in these high-risk prepubertal boys is an adaptation to the stress associated with having a father with a current, rather than remitted, SUD. Third, we tested the hypothesis that prepubertal cortisol underreactivity might be associated with subsequent drug use behavior during adolescence. METHODS: Preadolescent salivary cortisol responses were examined in the context of risk-group status, paternal substance abuse offsets, and subsequent adolescent drug use behavior. RESULTS: The results confirmed a decreased salivary cortisol response to an anticipated stressor among sons of SUD fathers in our expanded sample. In addition, sons of fathers with a current SUD and boys whose fathers had a SUD offset from their 3rd to 6th birthdays had lower anticipatory stress cortisol levels compared with sons of control fathers. Finally, lower preadolescent anticipatory cortisol responses were associated with regular monthly cigarette smoking and regular monthly marijuana use during adolescence. CONCLUSIONS: Hyporeactivity as an adaptation to chronic stress may be salient to the intergenerational transmission of substance abuse liability.

Segregation analysis of attention deficit hyperactivity disorder.

We performed segregation analysis on 495 nuclear families, ascertained for the father's substance abuse diagnosis, in an attempt to determine the role of genetic and other influences in determining the variability of DSM-III-R-defined attention deficit hyperactivity disorder (ADHD). For our analyses, ADHD was treated as a quantitative variable, utilizing the semicontinuous scale provided by the 15-item symptom count within DSM-III-R. Analyses consisted of both class A and class D regressive models for which covariate effects (socioeconomic status) and sex dependence were estimated. Segregation analysis of the quantitative trait (ADHD symptom count) in the entire data set supported a transmissible non-Mendelian major effect. Models which were sex-dependent and included covariate effects provided the best fit to the data. In addition, similar analyses were performed on a 130-nuclear family subgroup of the data set in which at least one of the members of the nuclear family met DSM-III-R diagnostic criteria for ADHD. The sex-dependent Mendelian codominant model was best supported by the data, while other models could be rejected. Incorporating covariate effects did not provide a better fit for the data. Thus, this study is consistent with Mendelian transmission of ADHD symptom count in a clinically relevant population. Overall, our results support the presence of a heritable continuous trait of which ADHD represents an extreme.

Substance abuse and associated psychosocial problems among Argentina adolescents: sex heterogeneity and familial transmission.

OBJECTIVE: The goal of this investigation was to clarify the effects of sex and familial transmission in the psychosocial concomitants of substance abuse problems among adolescents. METHOD: Male (n = 956) and female (n = 303) adolescents in school, and male adolescents in a drug treatment program (n = 51) in Buenos Aires Province, Argentina were administered a translated version of the Drug Use Screening Inventory. Use of substances, familial substance abuse and associations between psychosocial problem domains and substance abuse problems were examined. RESULTS: Sex heterogeneity was broadly observed in terms of both substance abuse and psychosocial problems. Female adolescents in the school-based sample were found to generally report higher levels of psychosocial problems and greater use of minor tranquillizers than school boys or boys in treatment for substance abuse. Conduct deviancy was associated with substance abuse problems only in males, while health problems were associated only in females. However, among all youth, substance abuse problems were found to be associated with older age, greater social competency, problems in school performance, and involvement with deviant peers. Familial substance abuse was associated with substance abuse problems among all adolescents, however, the pattern of associations with other psychosocial problems differed between males and females. CONCLUSIONS: Sex heterogeneity was found in the associations between psychosocial problems, adolescent substance abuse, and familial substance abuse. Furthermore, the results are consistent with a syndrome of problem behaviors.

Executive cognitive functioning in alcohol use disorders.

Executive cognitive functioning (ECF) has been identified as an important determinant in the etiology of alcoholism. ECF represents a "higher-order" cognitive construct involved in the self-regulation of goal-directed behavior. The prefrontal cortex and its subcortical connections represent the primary neurological substrate that subserves ECF. Both alcoholics and individuals at high risk for alcoholism exhibit a mild dysfunction in ECF. However, this deficit appears to be significantly stronger in alcoholics with a comorbid diagnosis of an antisocial personality disorder. Individuals with other disorders that are also highly comorbid with alcoholism, such as attention deficit hyperactivity disorder and conduct disorder, also demonstrate deficits in ECF. As such, compromised ECF may not be specific to alcoholism, but instead, might be a potential underlying etiologic substrate for a number of disorders of behavioral excess-disinhibition. Subsequent to reviewing the literature implicating ECF deficits in alcoholism and comorbid disorders, the authors present a heuristic cognitive-neurobehavioral model of alcoholism implicating the frontostriatal system. Finally, recommendations for the prevention and treatment of alcoholism, based on this model, are discussed.

Early adolescent gateway drug use in sons of fathers with substance use disorders.

This study determined the relevance of preadolescent psychopathology and substance use for predicting early adolescent alcohol and cannabis involvement in boys of fathers with and without substance use disorders (SUD). Fathers of preadolescent boys (ages 10 through 12 years) were recruited to represent families of boys with paternal SUD (High Risk or HR: N = 102) and boys without paternal SUD (Low Average Risk or LAR: n = 166). These boys and a parental informant participated in semistructured diagnostic interviews at baseline and 2-year follow-up assessments (ages 12 through 14 years). Preadolescent tobacco experimentation and early adolescent regular alcohol use were more prevalent in HR than in LAR subjects. Logistic regression analyses were utilized to develop prediction equations. The presence of oppositional defiant disorder and the absence of anxiety disorders predicted preadolescent tobacco use. Preadolescent conduct disorder predicted early adolescent regular alcohol use. Preadolescent tobacco use and conduct disorder were highly predictive of early adolescent cannabis use, achieving 100% sensitivity with 76% specificity. Children with tobacco use prior to adolescence, as well as those with disruptive behavior disorders, may be important to target for interventions to prevent cannabis use.

Familial and nonfamilial factors in the prediction of disruptive behaviors in boys at risk for substance abuse.

This study aims to identify (1) a core disruptive behavior disorder (DBD) postulated to presage a substance use disorder, and (2) the relative importance of parental DBD phenotypes, and familial and nonfamilial environmental factors in the determination of DBD in male children. DBD symptom counts and measures of familial and nonfamilial environmentals were collected from intact families ascertained through the presence (SA+) or absence (SA-) of substance dependence in fathers. Multivariate analyses revealed that both behavioral symptoms and environmental measures were significant discriminators of the families. In SA+ families, the child's score DBD was best predicted by magnitudes of parental dyssocial behaviors and by familial environmental factors. However, in SA- families only familial environmental factors were significant predictors of the child's DBD. These findings suggest that in addition to independent actions of familial transmissible and nonfamilial factors, strong genotype-environment interactions may determine DBD in children and that may contribute to the liability for a substance use disorder.

An association between a microsatellite polymorphism at the DRD5 gene and the liability to substance abuse: pilot study.

We have conducted a population-based association study of substance abuse and a microsatellite at the dopamine D5 receptor locus (DRD5) in a sample of European-American males and females with substance dependence (SA) or without any psychiatric disorder. Overrepresentation of the most frequent allele (148 bp) was found in males in the SA group (OR = 2.2, P = .02); this finding was reproduced in females (OR = 5.4, p < .001). The difference in the frequencies of this allele between SA males and SA females was statistically significant. The genotype coded in accordance with the dose of this allele correlated with substance abuse liability in males and females (stronger in females) and with novelty seeking in females. There was no evidence of correlation between the genotypes of spouses that could be induced by assortative mating for the liability to substance abuse. The data suggest that the DRD5 locus is involved in the variation and sex dimorphism of substance abuse liability.

Drug use problem awareness and treatment readiness in dual-diagnosis patients.

Problem awareness and treatment readiness are factors that influence treatment-seeking behavior, and thus, morbidity and outcome. The authors elucidated patterns of problem awareness and treatment readiness among hospitalized dually diagnosed patients by administering the Problem Awareness and Readiness for Treatment subscales of the Alcohol Use Inventory to 67 psychiatric inpatients with comorbid substance-related disorders and using a multivariate model approach to data analysis. The results suggested differential and interactive effects of gender, ethnicity, voluntary admission status, and a diagnosis of major depression (MDD) on drug abuse problem awareness and treatment readiness. Female gender, voluntary admission status, and a comorbid diagnosis of MDD were associated with increased awareness and readiness for treatment.

Psychopathology in preadolescent sons of fathers with substance use disorders.

OBJECTIVE: While preadolescent children of parents with substance use disorders (SUDs) are known to have more behavior problems, depression, and anxiety than expected, psychiatric disorders in these children and their relationships with parental disorders have not been systematically investigated. This study compares the psychiatric disorders of preadolescent boys of fathers with and without SUDs and examines the relationships between offspring and parental psychopathology. METHOD: Fathers (i.e., probands) of boys 10 through 12 years old were recruited to represent families of boys with paternal SUD (high risk or HR: n = 113) and boys without paternal SUD (low average risk or LAR: n = 170). These boys (i.e., index cases) and their biological parents participated in structured diagnostic interviews, and diagnoses were determined by the best-estimate method. RESULTS: Disruptive behavior disorders and anxiety disorders were more prevalent in HR than in LAR index cases. Logistic regression analyses examining the relationships between parental and index case psychopathology indicated that parental childhood psychiatric disorders were more strongly predictive of index case psychiatric disorders than parental adulthood psychiatric disorders, including SUDs. CONCLUSIONS: Inasmuch as HR boys had increased rates of disruptive behavior disorders and anxiety disorders, these disorders may be important targets for early intervention to prevent the development of SUD, as well as the morbidity associated with these disorders. Prevention efforts and studies of the transmission of liability for psychiatric disorders in children should carefully consider parental childhood characteristics.

Timing of paternal substance use disorder cessation and effects on problem behaviors in sons.

The developmental timing of paternal substance use disorder (SUD) offset on internalizing and externalizing problem behaviors was examined in prepubertal sons. Analyses revealed a significant main effect of the developmental timing of SUD offset on both internalizing and externalizing problems. No differences were found between sons of control-subject fathers and SUD+ fathers whose offsets occurred before the son's sixth birthday. However, when paternal SUD extended beyond the boys' sixth year, significant increases in internalizing and externalizing problem behaviors were found. The results suggest the importance of early parental SUD intervention in prevention of the intergenerational transmission of behavioral problems.

Event-related potential negative shift in sons of polysubstance- and alcohol-use disorder fathers.

Previous research has considered event-related potentials (ERPs) in relation to liability for alcohol and other substance use. This study explored ERPs in preadolescent boys at elevated risk for substance use due to paternal history of substance abuse or dependence. Sons (age 10-12) of fathers with an alcohol-use disorder (ALC, n = 29) were matched by age, IQ, education and parental alcohol use with sons of fathers with a polysubstance abuse or dependence diagnosis (POLY, n = 37). These two groups were matched with a low-risk comparison group (LOW, n = 29) of boys whose fathers had no substance-use disorder diagnosis. No boy in the study met criteria for a substance-use disorder. ERPs were collected from midline (Fz, Cz, Pz) and parietal (P3, P4) electrode leads during an auditory oddball task. ERPs of boys from the ALC and POLY groups showed a slow negative shift prominent at Cz and Pz. This negative shift, evident by 100 ms post-stimulus and lasting for the duration of the 1000-ms recording period, overlapped temporally with N1, N2 and P3 amplitude differences distinguishing the ALC and POLY groups from the LOW group. The ALC and POLY groups differed from each other in N2 amplitude at Cz, which was larger for ALC subjects. These findings offer a possible alternative explanation for previously observed amplitude anomalies noted in children at risk for substance-use disorders and suggest new avenues of inquiry.

Basal plasma beta-endorphin in prepubertal sons of alcoholics and drug addicts: lack of association with problem behaviors.

Several reports have speculated that variations in beta-endorphin functioning may actually proceed the development of alcoholism and other drug use disorders, and is consequently a genetic mechanism of some etiologic importance. The goal of this investigation was to determine whether differences in basal plasma beta-endorphin concentrations could be confirmed in prepubertal children naive to alcohol and drugs, yet at parental risk for alcoholism, or drug dependence. Consequently, we have examined fasting basal plasma beta-endorphin concentrations in a sample of prepubertal sons of alcoholic fathers and compared them to both our existing sample of sons of drug dependent fathers and normal control boys. In addition, we examined the relationship between plasma beta-endorphin concentrations and maternal reports of problem behaviors posited to be related to the liability for alcoholism or drug abuse. The results reveal no differences in fasting basal plasma beta-endorphin concentrations. Although the at-risk groups differ significantly from normal boys having elevated scale scores for internalizing and externalizing problem behaviors, no association between plasma beta-endorphin and these behavioral risk factors could be found. Overall, the results fail to support an inherited 'opioid deficiency hypothesis' for the development of alcoholism or drug dependence.