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Background: Longitudinal studies have demonstrated that childhood conduct disorder is a significant risk factor for a wide range of adult psychiatric disorders. The present study attempted to identify neurophysiologic differences that might underlie this risk factor., Methods: The study examined 158 subjects, aged 14 to 20 years. Each subject was assigned to one of four groups defined by the factorial combination of the subject's gender and the relative number (-/+) of conduct problems exhibited before age 15. Event-related electroencephalographic potentials were recorded from each subject while he or she performed a memory scanning task. Each trial consisted of the brief presentation of either two or four consonant letters, a 2-sec memorization period, and a single "probe" letter. The subject was instructed to mentally compare the probe with the memory set and execute a discriminative (match vs. mismatch) key-press response., Results: Analyses of P300 event-related potentials elicited by the probe stimuli revealed a significant interaction between probe stimulus membership and conduct problems: the P300 difference between trials with matching versus mismatching probes was significantly greater in the control (CP-) group than in the CP+ group. Current source density analyses, utilizing a realistic head-shape boundary element model, revealed that CP- subjects exhibited a robust activation of the left prefrontal cortex on matching versus mismatching trials. Among CP+ subjects, the degree of prefrontal cortex activation was not significant., Conclusions: The P300 results are consistent with those reported from previous studies of adolescents with conduct problems. Our study is unique in implementing current source density-boundary element method techniques for modeling P300 sources in "at-risk" adolescents. These techniques lend greater anatomical precision to the conclusion that conduct problems are associated with a specific dysfunction of the frontal brain.

Background: The purpose of this study was to evaluate the effects of conduct disorder problems, family history, gender, and age on P300 electroencephalographic potentials in teenagers., Methods: The 257 subjects, aged 15 to 20 years, were assigned to one of twelve groups defined by the crossing of three between-subjects factors: 1) gender; 2) ranking below vs above the median number of conduct disorder problems for their gender; and 3) no family history of alcohol or drug dependence vs familial alcohol dependence vs familial heroin or cocaine dependence., Results: P300 amplitude was smaller among subjects reporting a greater number of conduct problems prior to age 15 vs those reporting fewer problems of this type. No family history effects were detected. Another set of analyses examined the effects of age on conduct problem-related decrements in P300. Smaller P300 amplitudes within the posterior scalp region were associated with a greater number of conduct problems among subjects younger than 16.5 years. Among subjects greater than this median age, the effects of these behaviors were only apparent over the frontal scalp., Conclusions: It is concluded that P300 decrements previously attributed to familial alcohol/substance dependence might be the result of a coincident increase in the prevalence of conduct disorder problems. The analysis of age interactions suggests that P300 amplitude decrements observed at posterior scalp sites among subjects with more conduct problems disappear at approximately 16 to 17 years of age. After that age, decrements in frontal brain function may begin to emerge in the subset of conduct problem subjects who are at risk for developing adult antisocial personality disorder.

The goal of the present study was to identify neurophysiological differences associated with a family history of substance dependence, and its subtypes (paternal alcohol, cocaine, or opiate dependence), and with conduct disorder, and its subtypes (aggression, deceitfulness/theft, and rules violations). P300 event-related brain potentials were recorded from 210 males and females, aged 15-20 years while they performed the Stroop color-word compatibility test. Analyses revealed no significant effects of familial substance dependence on P300. However, an elevated number of conduct disorder problems was associated with a statistically significant reduction in P300 amplitude. The P300 amplitude reduction was related to the severity of the "rules violation" subtype, but was unrelated to aggression or deceitfulness and theft. It is concluded that conduct disorder can explain many of the P300 findings previously attributed to a family history of alcohol dependence. Furthermore, it appears that conduct disorder may be a heterogenous classification comprised of neurophysiologically different subtypes.

Objective: The DSM-IV work group asked researchers and clinicians to subtype substance dependent individuals according to the presence or absence of physiological symptoms. A recent report from the Collaborative Study on the Genetics of Alcoholism demonstrated that among alcohol-dependent men and women, a history of tolerance or withdrawal was associated with a more severe clinical course, especially for individuals with histories of alcohol withdrawal. This article evaluates similar distinctions among subjects in the collaborative study who were dependent on marijuana, cocaine, amphetamines, or opiates., Method: Structured interviews gathered information from 1,457 individuals with a lifetime diagnosis of marijuana dependence, 1,262 with histories of cocaine dependence, 647 with amphetamine dependence, and 368 subjects with opiate dependence. For each drug, the clinical course was compared for subjects whose dependence included a history of withdrawal (group 1), those dependent on each drug who denied withdrawal but reported tolerance (group 2), and those who denied both tolerance and withdrawal (group 3)., Results: The proportion of dependent individuals who denied tolerance or withdrawal (group 3) ranged from 30% for marijuana to 4% for opiates. For each substance, individuals in groups 1 and 2 evidenced more severe substance-related problems and at least a trend for greater intensities of exposure to the drug; those reporting withdrawal (group 1) showed the greatest intensity of problems., Conclusions: The designation of dependence in the context of tolerance or withdrawal identifies individuals with more severe clinical histories. These results support the importance of the designation of a physiological component to dependence, especially for people who have experienced a withdrawal syndrome.

Objective: DSM-IV indicates that diagnoses of substance dependence should be further characterized with regard to the presence of a physiological component, defined by tolerance or withdrawal. This study evaluated the possible meaning of this distinction in alcohol-dependent men and women., Method: As part of the Collaborative Study on the Genetics of Alcoholism, structured interviews were carried out with 3,395 DSM-III-R-defined alcohol-dependent individuals divided into 2,949 subjects (86.9%) with evidence of tolerance and/or withdrawal (group 1), 51.3% of whom evidenced withdrawal symptoms, and 446 subjects (13.1%) without a physiological component (group 2). Data were evaluated to determine differences between the two groups., Results: Group 1 reported greater severity of alcohol dependence as demonstrated by a larger maximum number of drinks in 24 hours, more persons reporting binges, more alcohol-related life problems, more relevant DSM-III-R criteria endorsed, more physiological complications, and more alcohol-related emotional/psychiatric symptoms such as depression and anxiety. Each of these severity indicators for problems in group 1 was significant in the presence of the others in a logistic regression, and similar items remained significant when tolerance alone, withdrawal alone, or their combination was used as the criterion for group 1 membership; however, for withdrawal a larger proportion of the variance was explained by the predictor variables. The regression results were independent of gender, proband status, and history of antisocial personality disorder., Conclusions: The results support the clinical relevance of distinguishing between alcohol-dependent patients with and without a physiological component. The data indicate a potential advantage to limiting that definition to withdrawal only.

Aims: While psychiatric symptoms are common in the general population and even more prevalent in alcoholics, their clinical implications are not clear. The goal of this study was to establish the life-time rates of several independent and concurrent mood and anxiety disorders in alcoholics, controls and their relatives., Design: Structured interviews were administered to alcoholics entering treatment, their relatives, and controls., Setting: The study was carried out in six different centers in the United States as part of the Collaborative Study on the Genetics of Alcoholism (COGA)., Participants: Data were gathered from 2713 alcohol dependent subjects (probands and their alcoholic relatives) and 919 controls., Measurements: The timeline-based Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview was administered face to face by trained, closely supervised interviewers. The life-time rates for concurrent and independent disorders were determined for three DSM-III-R major mood and four major anxiety disorders., Findings: Some form of independent mood disorder was seen during the life-time in slightly fewer alcoholics than controls (14.0% and 17.1%), but alcoholics did show higher rates of independent bipolar disorder (2.3% vs. 1.0%). The life-time rate for independent anxiety disorders was significantly higher in alcoholics than controls (9.4% vs. 3.7%), with most of the differential related to panic disorder (4.2% vs. 1.0%) and social phobia (3.2% vs. 1.4%), but no significant group differences for agoraphobia or obsessive-compulsive disorder. In general, these findings regarding mood and anxiety disorders were reflected in close relatives., Conclusions: The large majority of alcohol-dependent men and women in this sample did not have any of the independent mood or anxiety disorders evaluated here. However, there was evidence of enhanced risks among alcoholics for independent bipolar, panic and social phobic disorders. Studies which do not distinguish carefully between independent and concurrent mood and anxiety disorders in alcoholics are likely to report much higher rates of co-morbid psychiatric disorders than those that distinguish between the two types of syndromes.

Objective: Depressive episodes among alcohol-dependent men and women are heterogeneous in causation and clinical course. This study tested three hypotheses regarding the rates and clinical characteristics of two potential subtypes of these affective states: those that appear to be substance-induced mood disorders and those that are independent major depressive episodes., Method: Semistructured, detailed interviews were administered to 2,945 alcohol-dependent subjects as part of the Collaborative Study on the Genetics of Alcoholism. With the use of a time line method for determining the type of mood disorder among probands, relatives, and comparison subjects, individuals with histories of the two types of mood disorders were compared., Results: Major depressive episodes with an onset before the development of alcohol dependence or during a subsequent long abstinence period (i.e., independent depressions) were observed in 15.2% of the alcoholics, while 26.4% reported at least one substance-induced depressive episode. According to a logistic regression analysis, the subjects with independent (as compared to substance-induced) major depressive episodes were more likely to be married, Caucasian, and female, to have had experience with fewer drugs and less treatment for alcoholism, to have attempted suicide, and, on the basis of personal interviews with family members, to have a close relative with a major mood disorder., Conclusions: These results support the contention that it is possible to differentiate between what appear to be substance-induced and independent depressive episodes in alcoholics. Such differentiation might be important for establishing prognosis and optimal treatment.

Taste sensitivity to bitter substances, including ethanol, may play a moderating role both in the initiation of drinking and in the intensity and frequency of drinking once it is initiated. A study (Pelchat and Danowski, Physiol Behav 51:1261-1266, 1992) showed an association between the capacity to taste PROP (6-n-propylthiouracil), a bitter tasting compound, and a family history of alcoholism. The implication of that finding is that family-history-negative individuals may be protected from early initiation of drinking or heavy consumption of alcohol once drinking is initiated. The present study sought to replicate those findings by using direct interview methods (versus history methods) to obtain alcohol use and alcohol problem information from the parents of "at risk" individuals and by examining a larger number of subjects. A bimodal distribution of the ability to taste PROP was found, similar to that observed in the general population. No association was found between the ability to taste PROP and a paternal history of alcoholism, regardless of the taste threshold employed or after controlling for several potentially confounding variables. A lack of association with alcoholism risk was also observed for subjects' self-reports of reasons for drinking or not drinking alcohol based upon taste preference: high-risk and low-risk for alcoholism groups were not distinguished by either a stated preference for the taste of alcohol as a reason for drinking or a stated dislike for the taste of alcohol as a reason for limiting drinking. Thus, neither taste sensitivity for PROP nor the palatability of ethanol appear to influence the choice to drink among adolescent and young adult individuals at high risk for developing alcohol-related problems.

We attempt to identify distinctive subtypes of alcoholics using latent class analysis with data from 2551 relatives of alcoholic probands, all participants in the Collaborative Study of the Genetics of Alcoholism. Latent class analysis is a multivariate technique using cross-classified data to identify unobserved ("latent") classes that explain the relationships among observed variables. Data on 37 life-time symptoms of alcohol dependence from 1360 female and 1191 male relatives were analyzed, with a 4 class solution selected as the best fitting among the 2 through 6 class solutions that were examined. We observed the following classes: class 1, nonproblem drinkers (39.6% male, 50% female); class 2, mild alcoholics (persistent desire to stop, tolerance, and blackouts) (31.8% male, 28.7% female); class 3, moderate alcoholics (social, health, and emotional problems) (18.9% male, 14.6% female); and class 4, severely affected alcoholics (withdrawal, inability to stop drinking, craving, health, and emotional problems) (9.7% male, 6.7% female). There was little evidence for the construct of alcohol abuse; endorsement probabilities for abuse symptoms (e.g., arrest and DWIs) were very low for all classes, whereas hazardous use was common among men in class 1. In addition to those in class 3 and class 4, a majority of men in class 2 qualified for DSM-III-R alcohol dependence, suggesting a biomodal distribution of drinkers and alcoholics, with little nondependent problem drinking among men in this high-risk sample. We conclude that, in this sample, alcoholism is not differentiated by symptom profiles but rather lies on a continuum of severity, with the possible exception of withdrawal, which characterized only class 4 individuals.

Objective: Many of the studies linking anorexia nervosa and bulimia nervosa to substance use disorders suffer from problems with small samples; some lack rigorous definitions of the syndromes, and it is difficult to determine whether eating problems were primarily temporary consequences of heavy substance use or drugs were temporarily used in an effort to control appetite. The goal of this study was to evaluate the relationship between alcohol dependence and eating disorders., Method: Structured interviews were carried out with 2,283 women and 1,982 men as part of the Collaborative Study on the Genetics of Alcoholism. Data on drug abuse and dependence, psychiatric disorders, and symptoms of anorexia and bulimia were evaluated among alcohol-dependent probands, their relatives, comparison probands, and their relatives., Results: Lifetime rates for anorexia and bulimia were 1.41% and 6.17%, respectively, for the alcohol-dependent women, and bulimia was observed in 1.35% of the alcoholic men. However, once the impact of additional primary diagnoses was controlled for, anorexia was seen in only 1.26% of the women with primary alcohol dependence and none of the alcohol-dependent men; the rates for bulimia were 3.46% and 0.72%, respectively. There was no evidence of a strong familial crossover between alcohol dependence and anorexia or bulimia., Conclusions: While the rate of anorexia was not elevated in alcoholics after controlling for other disorders, bulimia did occur at a greater than expected rate. However, both eating disorders were relatively rare, and much of the association with alcoholism occurred in the context of additional preexisting or secondary psychiatric disorders.

A small proportion of alcohol-dependent men and women experience delirium tremens (DTs) and/or convulsions during alcohol withdrawal. While some characteristics of individuals most likely to show these severe sequelae of the abstinence syndrome have been described, it is not clear whether these risk factors operate independently in their association with severe withdrawal. The Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) interview was used to evaluate 1648 alcohol dependent men and women (including 540 women). The background characteristics and drinking histories of the 160 men and 51 women (12.8% of the subjects) who reported ever having had at least one episode of DTs and/or convulsions during withdrawal were compared with the characteristics of the remaining alcohol dependent individuals. Compared to other alcohol-dependent subjects, those with histories of severe withdrawal reported a greater maximum number of drinks in any 24-hour period (40.9 +/- 25.71 versus 24.9 +/- 17.72), more withdrawal episodes (28.2 +/- 33.74 versus 15.9 +/- 26.84), more non-medicinal use of sedative-hypnotics (56.4% versus 32.9%) and a greater number of medical problems. Hierarchical logistic regression analysis revealed that the most powerful differences between those with histories of more and less severe withdrawals related to the maximum number of drinks per day and the total number of withdrawal episodes. The remaining variables still added significantly to the relationship to more severe withdrawal. The etiology of DTs and convulsions is complex and involves the interaction of diverse characteristics representing relatively unique domains. It is hoped that these data will help clinicians identify individuals most likely to have experienced severe withdrawal syndromes and will aid researchers attempting to understand more about the etiology of these problems.

Evaluations of 1539 alcohol-dependent subjects (including 512 women) were carried out in an attempt to replicate the Type A/B dichotomy suggested by Babor et al. (1992). The subjects are participants in the Collaborative Study on the Genetics of Alcoholism (COGA), and each was evaluated using a face-to-face structured interview. Following the procedure of Babor et al. (1992), data were used to create 17 domains, and a k-means clustering method was invoked to generate a two-cluster solution. Thirty-one per cent of the males and 25% of the females fell into the Type B group, with overall R2 of 0.22 and 0.24 for males and females, respectively. The scores in each of the 17 domains and the analyses of the clinical characteristics for Type A and B subjects were, in general, consistent with the earlier onset and more severe course for Type B men and women. The ability of the domains to identify subgroups of alcoholics remained robust even after the exclusion of alcohol dependent subjects with antisocial personality disorder (ASPD) and those with an onset of alcohol dependence before age 25 years. The present analyses suggest that five of the 17 domains might be especially useful in identifying Type A and B groups.

Using data from The Collaborative Study on the Genetics of Alcoholism, we compare direct interview diagnoses of alcohol dependence to those obtained by history from family members. Using a requirement of three or more positive implications by history, the specificity, sensitivity, and positive predictive values are 98%, 39%, and 45%, respectively. A logistic analysis found the gender of the relative and alcoholism in the informant to be significant, but not the gender of the informant. The partial odds ratio of a diagnosis at interview associated with a positive family history diagnosis was 13.6. The relationship between the informant and relative was significant, with negative reports from an offspring or mate more influential than a negative report from a parent or second-degree relative. We derived a recursive equation to combine a variable number of family history reports, wherein the probabilities associated with a single report are computed from the logistic analysis. This permits the use of family history information both as a proxy for an uninterviewed relative, as well as a second source of information to be used in the analysis of genetic family data.

Event-related potentials (ERPs) were recorded from 83, 21- to 25-year-old nonalcoholic men varying in alcoholism vulnerability due to the presence/absence of an alcoholic family history or a personal history of antisocial personality disorder. ERPs were elicited by a visual oddball task in which the target was presented more frequently than the nontarget, in order to elicit impulsive or perseverative responding. Analyses of N200 and P300 revealed no group differences in the nontarget response. However, analyses of the target response revealed a significantly smaller P300 in the antisocial personality (ASP)+ group compared with the ASP- groups. The P300 decrement was limited to frontal electrode sites and is interpreted as indicating the presence of subtle anterior brain dysfunction among ASP+ subjects.

The present study investigated the potential mediating influence of childhood and early adolescent temperament and problem behaviors on the relation between parental alcoholism and adult drinking behaviors in a sample of 153 offspring of alcoholics and their controls. The influence of the alcoholic parent's and the offspring's gender on this relation was also assessed. Both gender of the parent and gender of the offspring were found to have important differential effects. More specifically, individuals with an alcoholic father consumed more alcohol, were more concerned about their drinking, and were more concerned about the possibility of developing a drinking problem than those without an alcoholic father. In contrast, no significant relations emerged between maternal alcoholism and drinking behaviors. Gender differences among the offspring were also observed, with males drinking more frequently to "get high" and scoring higher on the MAST than females. Finally, gregariousness was found to significantly mediate the relation between paternal alcoholism and frequency of drinking to "get high" and frequency of drinking to "get drunk" for males. Possible explanations regarding the differential results pertaining to gender and the lack of significant findings concerning mediation are discussed.