The contribution of parental alcohol use disorders and other psychiatric illness to the risk of alcohol use disorders in the offspring.

BACKGROUND: Few population-based studies have investigated associations between parental history of alcoholism and the risk of alcoholism in offspring. The aim was to investigate in a large cohort the risk of alcohol use disorders (AUD) in the offspring of parents with or without AUD and with or without hospitalization for other psychiatric disorder (OPD). METHODS: Longitudinal birth cohort study included 7,177 men and women born in Copenhagen between October 1959 and December 1961. Cases of AUD were identified in 3 Danish health registers and cases of OPD in the Danish Psychiatric Central Register. Offspring registration with AUD was analyzed in relation to parental registration with AUD and OPD. Covariates were offspring gender and parental social status. RESULTS: Both maternal and paternal registration with AUD significantly predicted offspring risk of AUD (odds ratios 1.96; 95% CI 1.42 to 2.71 and 1.99; 95% CI 1.54 to 2.68, respectively). The association between maternal, but not paternal, OPD and offspring AUD was also significant (odds ratios 1.46; 95% CI 1.15 to 1.86 and 1.26; 95% CI 0.95 to 1.66, respectively). Other predictors were male gender and parental social status. A significant interaction was observed between paternal AUD and offspring gender on offspring AUD, and stratified analyses showed particularly strong associations of both paternal and maternal AUD with offspring AUD in female cohort members. CONCLUSIONS: Parental AUD was associated with an increased risk of offspring AUD independent of other significant predictors, such as gender, parental social status, and parental psychiatric hospitalization with other diagnoses. Furthermore, this association appeared to be stronger among female than male offspring. The results suggest that inherited factors related to alcoholism are at least as important in determining the risk of alcoholism among daughters as among sons.

A double-blind, placebo-controlled study of valproate for aggression in youth with pervasive developmental disorders.

OBJECTIVE: The aim of this study was to study valproate efficacy and safety for aggression in children and adolescents with pervasive developmental disorders (PDD). METHODS: In this prospective double-blind, placebo-controlled study, 30 subjects (20 boys, 10 girls) 6-20 years of age with PDD and significant aggression were randomized and received treatment with valproate (VPA) or placebo (PBO) for 8 weeks as outpatients. Mean VPA trough blood levels were 75.5 mcg/mL at week 4 and 77.8 mcg/mL at week 8. RESULTS: No treatment difference was observed statistically between VPA and PBO groups. The Aberrant Behavior Checklist--Community Scale (ABC-C) Irritability subscale was the primary outcome measure (p = 0.65), and CGI--Improvement (p = 0.16) and OAS (p = 0.96) were secondary outcome measures. Increased appetite and skin rash were significant side effects. Only 1 subject was dropped from the study owing to side effects, notably a spreading skin rash, which then resolved spontaneously. Two subjects receiving VPA developed increased serum ammonia levels, one with an associated parent report of slurred speech and mild cognitive slowing. Poststudy, of 16 VPA and PBO subjects receiving VPA, 10 subjects demonstrated sustained response, 4 of whom later attempted taper, with significant relapse of aggression. CONCLUSION: The present negative findings cannot be viewed as conclusive, partly owing to the large placebo response, subject heterogeneity, and size of the groups. Larger studies are needed to expand upon these findings.

Neonatal vitamin K might reduce vulnerability to alcohol dependence in Danish men.

OBJECTIVE: Levels of oxidative defenses and blood-clotting factors are normally reduced in newborns, increasing the risk of injury to developing brain structures around the time of birth. This early neonatal vulnerability corresponds to a timeframe in which the development of reward-related limbic structures is particularly active. Taking advantage of a serendipitous event in the history of treating newborns, we tested the hypothesis that vitamin K supplementation, administered to facilitate the synthesis of blood-clotting proteins within this critical timeframe, might also reduce the development of alcohol dependence later in life. METHOD: Subjects were approximately full-term male infants, selected from a large Danish birth cohort. Two thirds of the original 330 subjects in this study were high-risk sons of alcoholic fathers; 241 of the total completed the 30-year follow-up. Of subjects reported on for this article (N = 238), 44 received vitamin K supplementation at birth; 161 were considered high risk, and 66 were categorized as having lower birth weight (<6 lbs). A comprehensive series of measures was obtained on each subject before, during and shortly after birth as well as at 1 year of age. The Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, diagnosis of alcohol dependence and a measure of lifetime problem drinking served as the 30-year outcome variables. RESULTS: Vitamin K treatment, inherited risk and low birth weight each independently predicted alcohol dependence and problem drinking at age 30. Vitamin K treatment was associated with significantly lower rates of alcohol dependence and fewer symptoms of problem drinking. CONCLUSIONS: Vitamin K treatment at birth might protect against the development of alcoholism in adults by reducing early postnatal hemorrhage and oxidative brain damage.

Risk factors that predicted problem drinking in Danish men at age thirty.

OBJECTIVE: The Danish Longitudinal Study of Alcoholism utilized a prospective, high-risk research paradigm to identify putative markers of adult male alcoholism from a comprehensive database that began with the birth of the subject and extended over three decades. This article focuses on measures antedating abusive drinking that predicted lifetime alcohol abuse/dependence at age 30 years. METHOD: The original 330 subjects of this study were drawn from a large Danish birth cohort (N = 9,125) born between 1959 and 1961. The sample included 223 sons of treated alcoholic fathers (high-risk group) and 107 matched sons whose biological fathers had no record of treatment for alcoholism (low-risk group). This sample has been thoroughly investigated with a variety of methods representing multiple domains that included perinatal records, pediatric records, school records, teacher ratings, school physician records and a series of structured interviews and psychometric tests at ages 19-20 and 30 years. The present analysis focuses on the degree to which premorbid differences between the high- and low-risk groups later predicted lifetime drinking problems at age 30 (n = 241). RESULTS: As expected lifetime alcohol abuse/dependence by age 30 was reported significantly more often in the high-risk group. Of the 394 premorbid variables tested, 68 were found to distinguish the high- from the low-risk group before any subjects had developed a drinking problem. Of these 68 variables, 28 (41%) were also associated with DSM-III-R alcohol abuse/dependence at age 30. These 28 putative markers were reduced to 12 that were entered into a multiple regression analysis to search for the most powerful unique predictors of alcoholism. Four of the 28 putative markers were independently associated with problem drinking at age 30: low birth weight, number of life crises in childhood, ratings of childhood unhappiness and antisocial personality disorder. The regression model accounted for 46% of the drinking outcome variance. A father's alcoholism by itself no longer independently contributed to the prediction of his son's drinking and with one exception, did not systematically interact with the putative markers to facilitate the prediction of alcohol dependence at age 30. CONCLUSIONS: Risk itself. which significantly predicted problem drinking at age 30, was not uniquely associated with the development of alcoholism in adulthood. These findings, rather, provide broad support for the biopsychosocial model of alcoholism, especially for those models that emphasize the cumulative influence over time of internal and external variables in biologically vulnerable individuals.

Effects of premature birth on the risk for alcoholism appear to be greater in males than females.

OBJECTIVE: A large Danish birth cohort was used to test the independent and joint effects of perinatal measures associated with premature birth as predictors of the development of alcoholism in male and female subjects. METHOD: Subjects were born at the Copenhagen University Hospital between 1959 and 1961 (N = 9,125). A comprehensive series of measures was obtained for each of the 8,109 surviving and eligible infants before birth, during birth, shortly after birth, and at 1 year. The adult alcoholism outcome was defined as any ICD-10 F10 diagnosis (Mental and behavioral disorders due to alcohol use) or an equivalent ICD-8 diagnosis found in the Danish Psychiatric Central Research Register or the Municipal Alcohol Clinics of Copenhagen by 2007. RESULTS: Multiple perinatal markers of premature birth independently predicted the development of an alcoholism diagnosis in male (n = 310) but not female (n = 138) subjects. Logistic regression modeling with a global prematurity score, adjusted for social status, maternal smoking, and gender, indicated a significant association of prematurity score for males (p < .02), but not females (p = .51), on the risk of developing an alcohol use disorder. CONCLUSIONS: The results suggest that neurodevelopmental sequelae of premature birth are associated with gender-specific effects on the development of alcoholism in the male baby: small, premature, or growth-delayed male babies appear to be selectively vulnerable to alcoholic drinking years later. The findings implicate neurodevelopmental influences in alcoholism pathophysiology in males and suggest the possibility of distinct, gender-specific pathways in the etiology of severe problem drinking.

Do premorbid predictors of alcohol dependence also predict the failure to recover from alcoholism?

OBJECTIVE: In a search for viable endophenotypes of alcoholism, this longitudinal study attempted to identify premorbid predictors of alcohol dependence that also predicted the course of alcoholism. METHOD: The 202 male subjects who completed a 40-year follow-up were originally selected from a Danish birth cohort (N = 9,182). Two thirds of the subjects were high-risk biological sons of treated alcoholics. A large number of measures (361) were obtained at different periods before any subject had developed an alcohol-use disorder. At age 40, a psychiatrist provided mutually exclusive lifetime diagnoses of alcohol abuse or alcohol dependence that were characterized as currently active or currently in remission according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, course specifiers. RESULTS: The majority of subjects with a diagnosis of alcohol abuse were in remission at age 40 compared with those with a diagnosis of alcohol dependence (88% vs. 58%). Treatment did not predict remission. Fourteen of the 18 predictors of remission that also predicted dependence were submitted to an exploratory factor analysis (varimax). Two premorbid dimensions were identified: cognitive efficiency and early behavioral dyscontrol in childhood. Both factors predicted the failure to remit (low cognitive efficiency and high behavioral dyscontrol) even when lifetime alcoholism severity was controlled. CONCLUSIONS: This 4-decade study found a striking disconnect between measures that predicted alcohol dependence and measures that predicted remission from alcohol dependence. Reduced cognitive efficiency and increased behavioral dyscontrol may be basic to gaining a fuller understanding of the etiology of alcoholism.

Minor versus major depression: a comparative clinical study.

OBJECTIVE: To examine whether minor depression differs from major depression in clinically relevant ways. METHOD: Structured interviews, Symptom Checklist-90-Revised (SCL-90-R) scores, and physicians' treatment recommendations were obtained systematically from 1,458 admissions to an outpatient teaching clinic during a 5-year period from 1981 to 1986. Of these, 1,002 (69%) satisfied inclusive DSM-III lifetime criteria for a major depressive episode. Of the 456 outpatients who did not formally satisfy criteria for a major depressive episode, 79 (17%) acknowledged significant depressive symptoms that caused major interference in their lives. These 79 outpatients were classified as suffering from minor depression. RESULTS: No gender or other sociodemographic differences were found between the 2 outpatient groups except that the minor depression group had achieved a higher level of education. No differences were found for a family history of psychiatric illness among first-degree relatives, including a family history of depression. Ratings of childhood unhappiness/problems did not distinguish the 2 groups. The major depression group endorsed more lifetime depressive symptoms and met criteria for more co-occurring disorders, principally mania and the anxiety disorders. The group with major depression reported poorer psychosocial functioning when first seen and more past psychiatric treatment. The Symptom Checklist-90-Revised (SCL-90-R) profile was significantly elevated in both groups. The type of initial treatment recommended did not distinguish the major from minor depression groups. CONCLUSIONS: Minor depression seems to represent the same illness as major depression but in a less severe form that, nevertheless, requires the attention of professional health care providers in both primary and specialized care settings.

Childhood ADHD and conduct disorder as independent predictors of male alcohol dependence at age 40.

OBJECTIVE: The Danish Longitudinal Study on Alcoholism was designed to identify antecedent predictors of adult male alcoholism. The influence of premorbid behaviors consistent with childhood conduct disorder (CD) and attention-deficit/hyperactivity disorder (ADHD) on the development of alcohol misuse was examined. METHOD: Subjects were selected from a Danish birth cohort (9,125), which included 223 sons of alcoholic fathers (high risk) and 106 matched sons of nonalcoholic fathers (low risk). These subjects have been studied systematically over the past 40 years. They were evaluated in their teens (n=238), later as adults at age 30 (n=241), and more recently at age 40 (n=202). At 19-year/20-year follow-ups, an ADHD scale was derived from teacher ratings and a CD scale was derived from a social worker interview. At 30-year and 40-year follow-ups, a psychiatrist used structured interviews and criteria from the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised, to quantify lifetime alcoholism severity and to diagnose alcohol-use disorder. Of the original subjects, 110 had complete data for the two childhood measures and the adult alcoholism outcomes. RESULTS: In this smaller subsample, paternal risk did not predict adult alcohol dependence. Subjects who were above a median split on both the ADHD and the CD scales were more than six times more likely to develop alcohol dependence than subjects who scored below the median on both. Although the two childhood measures were correlated, a multiple regression showed that each independently predicted a measure of lifetime alcoholism severity. CONCLUSIONS: ADHD comorbid with CD was the strongest predictor of later alcohol dependence.

Indicators of mania in depressed outpatients: a retrospective analysis of data from the Kansas 1500 study.

OBJECTIVE: Previous prospective studies have shown that unipolar depressed patients often switch to a manic episode. Some of these studies have reported that the conversion to bipolar disorder is predicted by an early onset of depression, a positive family history for mania, and psychotic symptoms. The present study examines the strength of the relationship between these 3 indicators, both alone and in combination, and the presence of mania in a large retrospective analysis. METHOD: 1458 consecutive admissions to a large, Midwestern university outpatient clinic between 1981 and 1986 were interviewed, and 1002 patients met DSM-III inclusive criteria for major depressive disorder. Of these, information about age at onset of depression, family history of mania, and psychotic symptoms was available on 744 outpatients. Two structured interviews were used to assess the 3 indicators. RESULTS: In this large depressed outpatient sample, the incidence of lifetime mania was 27%. Each of the 3 indicators was significantly associated with the report of mania (p < .0001 for all 3 indicators). The rates of mania increased as the number of indicators increased. Psychotic symptoms were the strongest indicator, followed by a family history of mania and an early age at onset of depression. CONCLUSION: Depressed patients with 1 or more of these 3 indicators should be monitored for the presence of bipolar disorder. Patients with 2 or more of these indicators are especially at risk to develop mania.

The overt aggression scale for rating aggression in outpatient youth with autistic disorder: preliminary findings.

Aggression is a common and costly problem in youth with developmental disabilities. Rating scales that accurately capture and measure subtypes of aggression phenomenology, frequency and severity are urgently needed, in both clinical practice and research. The authors studied the Overt Aggression Scale (OAS) in a preliminary sample of eight outpatients who participated in an ongoing placebo-controlled study of valproate for aggression in autism. Subjects' OAS aggression scores showed significant correlation with the already validated retrospectively rated Aberrant Behavior Checklist Community Scale irritability subscale. Further study of the OAS in outpatients with aggression and developmental disabilities is warranted.

Developmental differences in childhood motor coordination predict adult alcohol dependence: proposed role for the cerebellum in alcoholism.

BACKGROUND: The Danish Longitudinal Study of Alcoholism has identified a number of early biological indicators that predicted alcohol dependence 30 years later. In light of recent evidence linking deficits of the cerebellum to certain neuropsychiatric disorders often comorbid with alcoholism, we hypothesized that developmental deficits in the cerebellar vermis may also play a role in the initiation of adult alcohol dependence. The present study evaluated whether measures of motor development in the first year of life predict alcohol dependence three decades later. METHODS: A total of 241 subjects of the original 330 infants who were entered into this study completed the 30-year follow-up (12 had died). The subjects were men who were drawn from a large birth cohort born in Copenhagen, Denmark, from 1959 to 1961. A comprehensive series of measures were obtained on each subject before, during, and shortly after birth as well as at 1 year of age. Muscle tone at birth and day 5 as well as 1-year measures of motor coordination--age to sitting, standing, and walking--were examined. A DSM-III-R diagnosis of alcohol dependence and a measure of lifetime problem drinking served as the 30-year outcome variables. RESULTS: Several measures of childhood motor development significantly predicted alcohol dependence at 30 years of age. These included deficits in muscle tone 5 days after birth, delays in the age to sitting, and delays in the age to walking. CONCLUSIONS: Relationships found between adult alcoholism and early delays in motor development offer support for the theory that cerebellar deficits may play a causal role in the addiction process.

Comparison of desipramine or carbamazepine to placebo for crack cocaine-dependent patients.

The authors compared the effects of desipramine or carbamazepine to placebo in an intensive outpatient program for cocaine abuse. Subjects recruited from an urban drug treatment program were randomly assigned to a double-blind, placebo-controlled, eight-week trial of desipramine, carbamazepine, or placebo. Patient ratings, urine drug screens, and blood samples were obtained weekly. Using survival analysis, the three groups did not differ in time to drop out of treatment. While subjects improved over time on all self-ratings related to cocaine use, mood, and craving, only two items related to mood were significantly different over time as a function of treatment group. Subjects in the two treated groups reported significantly more improvement on self-ratings of depression and irritability. No treatment differences were noted for sustained abstinence or for proportion of positive urine drug screens. Desipramine subjects who attained a minimum blood level were retained in treatment significantly longer than placebo or other non-compliant treatment groups. This finding supports previous reports of a possible role for desipramine in cocaine abuse treatment.