A family study of alcohol dependence: coaggregation of multiple disorders in relatives of alcohol-dependent probands

BACKGROUND: Alcohol dependence tends to aggregate within families. We analyzed data from the family collection of the Collaborative Study on the Genetics of Alcoholism to quantify familial aggregation using several different criterion sets. We also assessed the aggregation of other psychiatric disorders in the same sample to identify areas of possible shared genetic vulnerability. DESIGN: Age-corrected lifetime morbid risk was estimated in adult first-degree relatives of affected probands and control subjects for selected disorders. Diagnostic data were gathered by semistructured interview (the Semi-Structured Assessment for the Genetics of Alcoholism), family history, and medical records. Rates of illness were corrected by validating interview and family history reports against senior clinicians' all sources best estimate diagnoses. Sex, ethnicity, comorbidity, cohort effects, and site of ascertainment were also taken into account. RESULTS: Including data from 8296 relatives of alcoholic probands and 1654 controls, we report lifetime risk rates of 28.8% and 14.4% for DSM-IV alcohol dependence in relatives of probands and controls, respectively; respective rates were 37.0% and 20.5% for the less stringent DSM-III-R alcohol dependence, 20.9% and 9.7% for any DSM-III-R diagnosis of nonalcohol nonnicotine substance dependence, and 8.1% and 5.2% for antisocial personality disorder. Rates of specific substance dependence were markedly increased in relatives of alcohol-dependent probands for cocaine, marijuana, opiates, sedatives, stimulants, and tobacco. Aggregation was also seen for panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and major depression. CONCLUSIONS: The risk of alcohol dependence in relatives of probands compared with controls is increased about 2-fold. The aggregation of antisocial personality disorder, drug dependence, anxiety disorders, and mood disorders suggests common mechanisms for these disorders and alcohol dependence within some families. These data suggest new phenotypes for molecular genetic studies and alternative strategies for studying the heterogeneity of alcohol dependence.     

Long-term stability of alcohol and other substance dependence diagnoses and habitual smoking: an evaluation after 5 years

CONTEXT: A major criterion to validate diagnoses is stability over time. OBJECTIVE: To examine the stability of several classification systems for lifetime diagnosis of alcohol dependence, to identify characteristics predicting stability of alcoholism, and to study stability of lifetime assessments of habitual smoking (1 pack per day for at least 6 months) and other drug dependence. DESIGN: Participants in the Collaborative Study on the Genetics of Alcoholism were interviewed using the Semi-Structured Assessment for the Genetics of Alcoholism and reevaluated 5 years later. Initial and follow-up interviews were available for 1728 individuals (641 index cases, 800 siblings, 287 controls) with lifetime diagnoses of alcohol dependence, other substance dependence (marijuana, cocaine, other stimulants, sedatives, opioids), or habitual smoking at first interview. The likelihood that an individual with a lifetime history of substance dependence or habitual smoking at the first interview retained this classification after 5 years was examined to assess stability of diagnosis. RESULTS: Stability of a lifetime diagnosis of alcohol dependence varied among the subject groups of index cases, siblings, and community-based controls. Alcohol dependence as defined by DSM-III-R criteria was highly stable in the index cases (90.5% women, 94.7% men) but much less stable in the community-based controls (27.5% women, 64.7% men). The most important characteristic associated with stability of diagnosis of alcohol dependence was severity, defined by the number of alcohol-related symptoms. Other DSM-III-R substance dependence disorders varied in the stability of diagnosis over a 5-year period. Lifetime history of habitual smoking was highly stable in all subject groups (96.0% overall). CONCLUSIONS: Stability of lifetime assessment of alcohol dependence varies depending on severity of illness. Severe cases of alcohol dependence are more likely to be stable, whereas general population cases of alcohol dependence are less likely to have stable diagnoses. The stability of diagnosis for other substance dependence varies from substance to substance.     

Psychopathology in drug abusers and their families

Demographic, clinical, and family pedigree data obtained on 350 hospitalized drug-dependent patients showed that 52% also met DSM-III criteria for alcohol abuse or dependence, while 37% met DSM-III criteria for a concurrent axis I psychiatric disorder other than substance abuse. Cyclothymic disorder was significantly more common among cocaine abusers, while generalized anxiety disorder and panic disorder were more common among sedative-hypnotic abusers. Data on 1,478 first-degree relatives revealed that the prevalence of alcoholism and affective disorder was highly correlated with the occurrence of similar psychopathology in the probands. These findings suggest a relationship between drug of choice and comorbid psychopathology, a role for familial factors in the transmission of these disorders, and the importance of diagnostic subtypes in the evaluation and treatment of substance abusers.     

Familial relationship between mood disorders and alcoholism

Clinical and epidemiological studies have consistently revealed an association between alcohol use disorders and both bipolar and nonbipolar mood disorders. However, the evidence regarding the nature of these associations is unclear. The familial patterns of alcohol and affective disorders were examined using data from a controlled family study of probands with alcohol and anxiety disorders who were sampled from treatment settings and the community. The substantial degree of comorbidity between mood and anxiety disorders among probands allowed for the examination of comorbidity and familial aggregation of alcohol and mood disorders. The major findings are that (1) alcoholism was associated with bipolar and nonbipolar mood disorders in the relatives; (2) there was a strong degree of familial aggregation of alcohol dependence and both types of mood disorders were observed; and (3) there was no evidence of cross-aggregation (i.e., increase in mood disorders among probands with alcohol dependence, and vice versa) between alcoholism and mood disorders. The independent familial aggregation of bipolar disorder and alcoholism and the finding that the onset of bipolar disorder tended to precede that of alcoholism are compatible with a self-medication hypothesis as the explanation for the frequent co-occurrence of these disorders. In contrast, the independent familial aggregation and the tendency of an earlier onset of alcoholism than that of nonbipolar depression suggest that unipolar mood disorders are frequently secondary to alcoholism.     

Depression and familial risk for substance dependence: a P300 study of young women

The present study evaluated the effects of depression and a family history of alcohol or substance dependence on P300 event-related potentials in young women aged 14 to 20 years. Of the 130 female subjects, 29 met DSM-III-R diagnostic criteria for a lifetime history of a Major Depressive Episode. Event-related electroencephalographic potentials were recorded from each subject while she performed a complex visual oddball task. Analyses indicated a decrement in P300 amplitude in the depressed group as compared to girls with no history of depression. No effects of family history of alcoholism or drug dependence were detected. Current source density analyses, utilizing a realistic head-shape boundary element model, indicated that the difference between the depressed and non-depressed groups was maximal in the right prefrontal region. These results provide further support for the notion that the cognitive difficulties associated with depression are subtle and best detected with sensitive neurophysiological indices, such as P300.     

Familial psychiatric illness and posttraumatic stress disorder: findings from a family study of substance abuse and anxiety disorders.

BACKGROUND: Aside from the possibility of a direct relationship between individual and familial posttraumatic stress disorder (PTSD), there is accumulating evidence that implicates a family history of psychiatric and substance use disorders as an important risk factor in the development of PTSD and associated symptoms. METHOD: The familial risk of DSM-III-R PTSD was examined within a family study of clinical- and community-ascertained probands (N = 263) and their 1206 adult first-degree relatives. RESULTS: Although PTSD among probands was not found to significantly elevate the risk of PTSD among first-degree relatives, an elevated rate of PTSD was found among the relatives of drug abusing probands compared with the relatives of probands with alcoholism, other anxiety disorders, and normal controls. Additionally, affective disorders were significantly associated with PTSD in relatives (p < .01). When these familial and individual associations were examined according to gender, drug disorders in probands were significantly associated with PTSD only among male relatives (p < .01), while the association between PTSD and comorbid affective disorders was seen primarily among female relatives (p < .01). CONCLUSION: Although probands in the present family study were not selected specifically for PTSD, the data afforded a unique opportunity to examine the profile of familial psychopathology as a part of the complex picture of susceptibility for PTSD. Future family study research will be able to determine the generalizability of the present findings through more complete measurement of diverse forms of trauma.     

Nicotine dependence, major depression, and anxiety in young adults.

To determine whether nicotine dependence, classified by level of severity, was associated with other substance dependence, major depression, and anxiety disorders, we studied a random sample of 1007 young adults in the Detroit (Mich) area using the National Institute of Mental Health Diagnostic Interview Schedule, revised according to DSM-III-R. The systematic coverage of DSM-III-R criteria of nicotine dependence provides an unprecedented opportunity to separate persons with nicotine dependence from the larger class of persons with a history of smoking and to examine the prevalence of psychiatric disorders among persons with nicotine dependence and among nondependent smokers. The lifetime prevalence of nicotine dependence was 20%. Nicotine dependence was associated with alcohol, cannabis, and cocaine dependence. Controlling for the effects of other substance dependencies, persons with nicotine dependence had higher rates of major depression and anxiety disorders. The strength of these associations varied by level of severity of nicotine dependence. Nondependent smokers had higher rates of other substance dependencies, but not of major depression or anxiety disorders.     

Effects of major depression on remission and relapse of substance dependence

BACKGROUND: The effects of major depressive disorder (MDD) on the course of substance dependence may differ depending on the temporal relationship of depression to dependence. We investigated the effects of MDD on the outcome of substance dependence under 3 circumstances: (1) lifetime onset of MDD prior to lifetime onset of dependence onset, (2) current MDD occurring during a period of abstinence, and (3) current MDD during substance use that exceeded the expected effects of intoxication or withdrawal. METHODS: A sample of 250 inpatients with DSM-IV cocaine, heroin, and/or alcohol dependence were followed up at 6, 12, and 18 months. The Psychiatric Research Interview for Substance and Mental Disorders (PRISM) was used to make DSM-IV diagnoses. Using Cox proportional hazards models, stable remissions (those lasting at least 26 weeks) from DSM-IV cocaine, heroin, and/or alcohol dependence and from use were studied, as well as subsequent relapses of dependence and use. RESULTS: Patients with current substance-induced MDD were less likely to remit from dependence (adjusted hazards ratio, 0.11) than patients with no baseline MDD. A history of MDD prior to lifetime onset of substance dependence also reduced the likelihood of remission relative to the absence of such a history (adjusted hazard ratio, 0.49). Major depressive disorder during sustained abstinence predicted dependence relapse (adjusted hazards ratio, 3.07) and substance use after hospital discharge compared with those without abstinence MDD (adjusted hazards ratio, 1.45). CONCLUSION: The timing of depressive episodes relative to substance dependence served as an important factor in the remission and relapse of substance dependence and substance use.     

Psychopathology in offspring from multiplex alcohol dependence families with and without parental alcohol dependence: a prospective study during childhood and adolescence

Multiplex families ascertained through multiple alcohol dependent individuals appear to transmit alcohol and drug use disorders at higher rates than randomly selected families of alcoholics. Our goal was to investigate the risk of developing specific psychiatric diagnoses during childhood or adolescence in association with familial risk status (high-risk [HR] or low-risk [LR]) and parental diagnosis. Using a prospective longitudinal design, HR offspring from three generation multiplex alcohol dependence families and LR control families were followed yearly. Data analysis was based on consensus diagnoses from 1738 yearly evaluations conducted with the offspring and a parent using the K-SADS, and separately modeled the effects of familial susceptibility and exposure to parental alcohol dependence. Multiplex family membership and parental alcohol and drug dependence significantly increased the odds that offspring would experience some form of psychopathology during childhood or adolescence, particularly externalizing disorders. Additionally, parental alcohol dependence increased the odds that adolescent offspring would have major depressive disorder (MDD). While it is well known that parental substance dependence is associated with externalizing psychopathology, the increased risk for MDD seen during adolescence in the present study suggests the need for greater vigilance of these children.     

The 5-year clinical course of high-functioning men with DSM-IV alcohol abuse or dependence

OBJECTIVE: One goal of diagnostic criteria is to predict the course of clinically relevant future problems. This study evaluated the ability of the DSM-IV categories of alcohol abuse and alcohol dependence to predict the onset and cessation of the 11 DSM-IV abuse/dependence criterion items. METHOD: The DSM-IV categorical approach was used to determine alcohol diagnoses for 435 highly educated young adult men, who constituted 97.3% of the 447 men appropriate for this study. Structured face-to-face follow-up interviews were administered 5 years later. RESULTS: At the beginning of the study, 14.5% (N=63) of the subjects were alcohol dependent, 18.2% (N=79) reported alcohol abuse, and 67.4% (N=293) carried no alcohol diagnosis. Across these three diagnostic groups, 68.3%, 46.8%, and 15.4%, respectively, experienced at least one of the 11 DSM-IV abuse/dependence criterion items over the next 5 years. Only 11.4% of those who reported alcohol abuse went on to develop alcohol dependence. In addition to their diagnosis, characteristics that predicted subsequent problems with alcohol included a family history of alcoholism, higher levels of alcohol intake and a greater number of alcohol problems in the 10 years preceding the diagnosis, and a history of drug use. CONCLUSIONS: Even in this highly educated and high-functioning group of men, alcohol abuse and dependence predicted the onset and cessation of alcohol-related problems.     

A family study of major depressive disorder in a community sample of adolescents

BACKGROUND: Family studies provide a useful approach to exploring the continuities and discontinuities between major depressive disorder (MDD) in children and adolescents and MDD in adults. We report a family study of MDD in a large community sample of adolescents. METHODS: Probands included 268 adolescents with a history of MDD, 110 adolescents with a history of nonmood disorders but no history of MDD through age 18 years, and 291 adolescents with no history of psychopathology through age 18 years. Psychopathology in their 2202 first-degree relatives was assessed with semistructured direct and family history interviews, and best-estimate diagnoses were derived with the use of all available data. RESULTS: The relatives of adolescents with MDD exhibited significantly elevated rates of MDD (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.46-2.31), dysthymia (HR, 1.79; 95% CI, 1. 11-2.87), and alcohol abuse or dependence (HR, 1.29; 95% CI, 1.05-1. 53), but not anxiety disorders, drug abuse or dependence, or antisocial and borderline personality disorder. In contrast, anxiety, substance use, and disruptive behavior disorders in adolescents were not associated with elevated rates of MDD in relatives. However, the relatives of probands with anxiety and substance use disorders exhibited elevated rates of anxiety and substance use disorders, respectively. CONCLUSIONS: The results provide evidence of the familial aggregation of adolescent MDD, and also indicate that there is a considerable specificity in the pattern of familial transmission. In addition, we found preliminary evidence of the familial aggregation of adolescent anxiety and substance use disorders.     

Behavioral symptoms and psychiatric diagnoses among 162 children in nonalcoholic or alcoholic families

OBJECTIVE: People with alcoholic relatives have high rates of alcohol abuse and dependence as adults, but their patterns of problems earlier in life are less clear. Many studies have not controlled for parental disorders other than alcoholism or for parents' socioeconomic status and general life functioning. The authors' goal was to conduct a study controlling for such factors. METHOD: Personal structured interviews and a behavioral checklist were administered to the parents of 162 children 7 years old or older whose fathers had participated in the 15-year follow-up of 453 sons of alcoholics with no history of antisocial personality disorder and sons of nonalcoholic comparison subjects originally selected from a university population. RESULTS: There was no significant relationship between a family history of alcoholism and childhood diagnoses of conduct, oppositional, or attention deficit disorders or with behavioral checklist summary scores. However, children with alcoholic relatives apparently have a slightly higher risk for drug abuse or dependence than those without alcoholic relatives. CONCLUSIONS: Once familial antisocial disorders and familial socioeconomic status are controlled for, a family history of alcoholism does not appear to relate to childhood externalizing disorders.     

Examining the association between attention deficit hyperactivity disorder and substance use disorders: A familial risk analysis

ObjectiveThe main aim of this study was to use familial risk analysis to examine the association between attention deficit hyperactivity disorder (ADHD) and substance use disorders (SUDs) attending to sex effects and the specificity of alcohol and drug use disorder risks.MethodsSubjects were derived from two longitudinal case-control family studies of probands aged 6–17 years with and without DSM-III-R ADHD of both sexes and their first degree relatives followed from childhood onto young adult years. Cox proportional hazard models were used to estimate rates of ADHD and SUDs (any SUD, alcohol dependence, and drug dependence). Logistic regression was used to test both co-segregation and assortative mating.ResultsOur sample included 404 probands (ADHD: 112 boys and 96 girls; Control: 105 boys and 91 girls) and their 1336 relatives. SUDs in probands increased the risk for SUDs in relatives irrespective of ADHD status. The risk for dependence to drug or alcohol in relatives was non-specific. There was evidence that even in the absence of a SUD in the proband, ADHD by itself increased the risk of SUDs in relatives. Proband sex did not moderate the familial relationship between ADHD and SUDs. There was evidence of co-segregation between ADHD and SUD.ConclusionsFindings indicate that various independent pathways are involved in the transmission of SUD in ADHD and that these risks were not moderated by proband sex. ADHD children and siblings should benefit from preventive and early intervention strategies to decrease their elevated risk for developing a SUD.     

Cross-sectional volumetric analysis of brain atrophy in alcohol dependence: effects of drinking history and comorbid substance use disorder

OBJECTIVE: The authors assessed whether individual differences in drinking history as well as lifetime incidence of comorbid cocaine or marijuana use disorder underlie differential patterns of brain atrophy in subjects with alcohol dependence. METHOD: Segmented magnetic resonance images were used to compare whole brain cerebral gray matter and white matter in 134 male subjects age 30-50 with alcohol dependence, either alone or with comorbid cocaine or marijuana use disorder. RESULTS: Across all subjects, drinking history variables correlated negatively with both gray matter and white matter after age was controlled. Alcohol-dependent subjects with no comorbid substance use disorder (N=51) showed a steeper negative correlation between age and the gray matter/white matter ratio than did alcohol-dependent subjects with a comorbid lifetime cocaine use disorder diagnosis (N=50). Alcohol-dependent subjects with comorbid cocaine use disorder tended to have a steeper negative correlation between age and white matter (adjusted for intracranial volume) than did alcohol-dependent subjects with no comorbid substance use disorder. After age and the greater estimated cumulative alcohol consumption of alcohol-dependent subjects with comorbid cocaine use disorder were controlled in a multiple regression analysis, however, comorbid cocaine use disorder did not account for any independent variance in any volumetric measure. CONCLUSIONS: Brain atrophy among subjects with alcohol dependence reflects individual differences in exposure to alcohol, and the data provide mixed evidence that comorbid cocaine use disorder may exacerbate white matter atrophy in alcoholism.     

Are personality traits familial risk factors for substance use disorders? Results of a controlled family study

OBJECTIVE: The well-documented association between maladaptive personality traits and substance use disorders has given rise to diverse explanatory models. In this investigation the authors examined one such explanation, that certain personality traits are familial risk factors for the development of substance abuse or dependence. METHOD: Data were collected from a controlled family study using direct diagnostic interviews. The Multidimensional Personality Questionnaire was used to assess the personality traits of 325 probands, 205 of whom had diagnoses of substance abuse or dependence, and 262 of their first-degree relatives. RESULTS: Probands with substance use disorders scored higher on alienation and negative emotionality than did probands without substance use disorders, and they scored lower on control, harm avoidance, and constraint. Relatives with substance use disorders also differed from relatives without these conditions on several of these same dimensions. To examine whether such personality traits could be conceptualized as familial risk factors for substance use disorders, a second set of analyses were limited to relatives without substance use disorders themselves but varying in terms of family history for these conditions. These groups of relatives did not differ significantly from each other on any of the identified personality traits. CONCLUSIONS: These findings argue for caution in characterizing the personality correlates of substance use disorders as representing familial or heritable risk factors.     

Factors predicting the onset of adolescent drinking in families at high risk for developing alcoholism.

BACKGROUND: With a longitudinal prospective design, the purpose of this study was 1) to assess, with survival analysis, the age of onset of drinking in relation to family history of alcoholism; 2) to examine the importance of selected neurobiological and psychosocial risk factors in predicting the onset to drink; and 3) to determine if the age of onset of substance dependence problems differed by risk group status. METHODS: One hundred twenty-five children and adolescents were evaluated annually (N = 638 evaluations), providing up to seven annual waves of longitudinal data. Survival analyses were performed to determine the age of onset of regular drinking and the age of onset for substance abuse/dependence. The age of onset of regular drinking outcome was modeled using familial density of alcoholism and four factors, which included neurobiological indices of development (postural sway and P300), personality characteristics, academic achievement, self-esteem, and trait anxiety. RESULTS: High-risk children/adolescents showed a significantly earlier age of onset of drinking and an earlier age of onset for substance abuse problems. Familial density of alcoholism predicted an earlier onset of drinking, as did having deficits in reading achievement, reduced P300 (visual and auditory), and greater postural sway for age. Higher scores on the Extraversion scale of the Junior version of the Eysenck Personality Inventory also predicted an earlier onset of drinking. CONCLUSIONS: Familial density of alcoholism (number of alcoholic first- and second-degree relatives) is an important predictor of adolescent alcohol initiation. Evidence is presented suggesting that part of the familial/genetic variation in outcome may be due to neurobiological factors and temperament.     

Alcohol dependence in panic disorder patients.

The present study examined the prevalence of alcohol dependence among panic disorder patients. Twenty-four of 100 patients had a history of alcohol dependence according to DSM-III-R criteria; only one patient met criteria for current alcohol dependence. The lifetime prevalence obtained for this clinic sample exceeded that for the general population, and appeared to be due primarily to higher than expected rates among women. A childhood history of anxiety disorders and co-morbid diagnoses of social phobia and major depression were each associated with relatively higher rates of alcohol dependence. The clinical implications of these findings are discussed.     

Implications of family history of alcoholism, antisocial personality, and sex differences in alcohol dependence

In this study of 210 male and female alcoholic inpatients, significant associations were found 1) between antisocial personality diagnosis and early onset of all stages in alcohol dependence; 2) between bilineal family history of alcoholism and greater frequency of the consequences of impaired control, withdrawal symptoms, and the pathologic symptoms associated with chronic alcoholism; and 3) between being female and older at onset of the initial, but not final, stages of alcoholism and having more symptoms associated with chronic alcohol use. Antisocial personality, type of family history, and sex of the proband were not interactive but contributed separate additive effects.     

Familial risk analyses of attention deficit hyperactivity disorder and substance use disorders

OBJECTIVE: A robust and bidirectional comorbidity between attention deficit hyperactivity disorder (ADHD) and psychoactive substance use disorder (alcohol or drug abuse or dependence) has been consistently reported in the extant literature. METHOD: First-degree relatives from a large group of pediatrically and psychiatrically referred boys with (112 probands, 385 relatives) and without (105 probands, 358 relatives) ADHD were comprehensively assessed by blind raters with structured diagnostic interviews. Familial risk analysis examined the risks in first-degree relatives for ADHD, psychoactive substance use disorder, alcohol dependence, and drug dependence after stratifying probands by the presence and absence of these disorders. RESULTS: ADHD in the proband was consistently associated with a significant risk for ADHD in relatives. Drug dependence in probands increased the risk for drug dependence in relatives irrespective of ADHD status, whereas alcohol dependence in relatives was predicted only by ADHD probands with comorbid alcohol dependence. In addition, ADHD in the proband predicted drug dependence in relatives, and drug dependence in comparison probands increased the risk for ADHD in relatives. Both alcohol dependence and drug dependence bred true in families without evidence for a common risk between these disorders. CONCLUSIONS: Patterns of familial risk analysis suggest that the association between ADHD and drug dependence is most consistent with the hypothesis of variable expressivity of a common risk between these disorders, whereas the association between ADHD and alcohol dependence is most consistent with the hypothesis of independent transmission of these disorders. Findings also suggest specificity for the transmission of alcohol and drug dependence.     

Schizophreniform disorder,delusional disorder and psychotic disorder not otherwise specified: clinical features,outcome and familial psychopathology

The relationship between DSM-III-R schizophreniform disorder, delusional disorder (DD) and psychotic disorder not otherwise specified (PD-NOS) and schizophrenia and affective illness (AI) remains uncertain. We explore this question in the Roscommon Family Study by examining symptoms, outcome and patterns of psychopathology in relatives. Probands were selected from a population-based case registry in the west of Ireland with an ICD-9 diagnosis of schizophrenia or AI. Personal interviews were conducted with 88% of traceable, living probands, a mean of 16 years after onset, and 86% of traceable, living first-degree relatives. Best-estimate diagnoses were made at follow-up. Schizophreniform disorder, DD and PD-NOS constituted 6.4%, 2.8% and 7.5%, respectively, of all probands with a registry diagnosis of schizophrenia. Probands with schizophreniform disorder had prominent positive psychotic symptoms, negligible negative symptoms and a good outcome, comparable to that seen in AI probands. Their relatives had an excess risk of schizophrenia spectrum illness but not AI. Probands with DD had prominent delusions but no other psychotic symptoms, few negative symptoms, fair to good outcome and an increased risk in relatives for alcoholism. Probands with PD-NOS had both moderate positive and negative psychotic symptoms, a poor to fair outcome and a substantially elevated risk in relatives of schizophrenia and schizophrenia spectrum disorders but not AI. These results suggest that i) DSM-III-R criteria for schizophreniform disorder define a good outcome disorder with prominent positive psychotic symptoms that probably has a familial relationship to schizophrenia, but not AI; ii) DD is a rare, monosymptomatic psychosis that may have a modest etiologic relationship with alcoholism, but probably not with schizophrenia or AI and iii) PD-NOS is probably heterogeneous but, of these 3 disorders, most closely resembles schizophrenia with respect to symptoms, outcome and familial psychopathology. These results should be seen as tentative given the small number of probands and relatives evaluated.