Semantic processing in alcoholics with and without antisocial symptomatology

OBJECTIVE: Chronic alcoholics with a comorbid diagnosis of antisocial personality (ASP) symptomatology often exhibit early onset, severe course, and poor treatment outcomes. In addition, antisocial characteristics have been associated with a variety of cognitive deficits, including abnormalities of semantic processing, a deficit also found in alcoholics. Using the N400 task, this study investigated whether comorbid ASP symptomatology in alcoholics and community controls contributes to deficits in cognitive efficiency. METHOD: The N400 component of the event-related potential was elicited in detoxified alcoholics (n = 71; 56 male) and community controls (n = 36; 22 female) by sentences with congruent, related/incongruent or unrelated/incongruent terminal words. Difference waveforms were derived, and both amplitude and latency measures were obtained. Antisocial personality symptomatology was assessed using the ASP section of the Diagnostic Interview Schedule IV. RESULTS: Data were analyzed via linear regression using alcoholism, ASP positive (ASP+) status and their interaction term as predictors of N400 amplitude and latency. Significant latency findings were noted in the related/incongruent sentence condition. Increased N400 latency was predicted by ASP+ status at electrode site Pz (p = .01). The interaction of alcoholism and ASP+ status predicted increased N400 latency at electrode site P4 (p = .009), with ASP+ alcoholics demonstrating the greatest latency. CONCLUSIONS: The presence of N400 latency differences in response to related/incongruent semantic information in the current study differs from previous findings in studies of chronic alcoholism that do not account for ASP. These data suggest that antisocial personality disorder and alcoholism may affect cognitive function via different underlying mechanisms.     

Three clusters of male alcoholics

The study comprises 296 male alcoholics in whom detailed studies of family history, clinical factors, psychopathology of dependence as well as psychological and neurophysiological tests were made. On the basis of five clinical factors: age of onset of dependence, history of familial alcoholism, severity of alcohol-related problems and the prevalence of psychiatric and somatic diseases, K-means cluster analysis delineated three types of alcoholics. Type 1 was characterized by late onset of dependence, low prevalence of familial alcoholism and mild course. Type 2 was characterized by early onset of dependence, high familial alcoholism in fathers, frequent antisocial personality, severe intensity of alcohol-related problems. Type 3 was characterized by early onset of dependence, familial history of psychiatric diseases, severe intensity of alcohol-related problems and high prevalence of psychiatric disturbances and somatic diseases. Type 3 may be characterized as alcoholism associated with high predisposition and comorbidity. This may make a distinct type of male alcoholics.     

Dopamine transporter and D2-receptor density in late-onset alcoholism

Rationale: Late onset type 1 alcoholism has been suggested to be associated with an underlying dopaminergic defect. Therefore, it is relevant to study both postsynaptic D₂-receptor and presynaptic dopamine transporter (DAT) densities among alcoholics. Objective: We investigated DAT densities, along with striatal and extrastriatal dopamine D₂-receptor densities, in nine non-violent late-onset male alcoholics, who had no major mental disorder nor antisocial personality disorder (ASPD), and nine healthy controls. Methods: [¹²³I]PE2I and [¹²³I]epidepride were used in SPECT imaging. Results: DAT occupancy ratios (striatum/cerebellum) were significantly lower among alcoholics than in controls. Extrastriatal D₂-receptor occupancy ratios (temporal pole/cerebellum) were not significantly different between the groups. Conclusions: Striatal presynaptic DAT densities are decreased among type 1 alcoholics, and this finding is not associated with recent alcohol abuse. Received: 22 March 1999 / Final version: 25 June 1999     

Parenting influences on the development of alcohol abuse and dependence

Both alcohol-specific and non-alcohol-specific parenting influences affect the development of alcohol abuse and dependence in the offspring. Alcohol-specific influences (e.g., the modeling of parental drinking behavior, the development of alcohol expectancies, and certain aspects of the parent-child relationship) are particularly relevant to the development of alcohol abuse and dependence in children of alcoholics. In contrast, non-alcohol-specific influences generally promote deviant behavior, including alcohol problems, in the offspring and affect children of alcoholics and nonalcoholics equally. These influences, which include inadequate parenting and other parent-child interaction patterns that promote aggressive, antisocial behavior in children, increase the offspring's risk of an alcoholism subtype associated with antisocial personality disorder. A different set of non-alcohol-specific family influences may contribute to an alcoholism subtype that emerges after the onset of depression.     

Personality traits in subtypes of alcoholics

Earlier studies have identified at least two distinct subgroups of alcoholics: Type II with early onset and high genetic loading and Type I with late onset in which genetic factors seem to be of minor importance. In the present study, type I and type II alcoholics are compared on stable personality traits determined by the Karolinska Scales of Personality. Both groups were found to have high scores on scales that measured somatic anxiety, psychic anxiety, muscular tension, impulsiveness, detachment, psychastenia, suspicion, guilt and inhibition of aggression. Both groups had low scores on the scale that measured socialization. Type II alcoholics had significantly higher scores than type I alcoholics on Somatic Anxiety and Verbal Aggression scales and significantly lower scores on Socialization and Inhibition of Aggression scales. On the Impulsive Sensation-Seeking Psychopathy factor (Impulsiveness + Monotony Avoidance - Socialization), type II alcoholics were significantly differentiated from both type I alcoholics and healthy volunteers. Results of this study were consistent with those of other studies indicating that alcoholism accompanied by antisocial behavior should be kept separate from alcoholism that is unrelated to antisocial behavior.     

Pharmacogenomics of alcohol response and addiction

Alcoholism is a complex psychiatric disorder that has high heritability (50-60%) and is relatively common; in the US the lifetime prevalence of alcohol dependence is 20% in men and 8% in women. Current psychosocial and pharmacological therapies have relatively modest effects. Treatment is complicated by the fact that alcoholism is often co-morbid with other disorders, including anxiety, depression, and antisocial personality disorder. Approximately 80% of alcoholics smoke cigarettes and there is considerable genetic overlap between nicotine and alcohol addiction. Convergent evidence supports the classification of alcoholics into two broad categories: type 1 - later onset with feelings of anxiety, guilt, and high harm avoidance; and type 2 - early age of onset, usually men, impulsive, antisocial, and with low levels of brain serotonin. The pharmacogenomics of alcohol response is well established; genetic variants for the principal enzymes of alcohol metabolism influence drinking behavior and protect against alcoholism. Vulnerability to alcoholism is likely to be due to multiple interacting genetic loci of small to modest effects. First-line therapeutic targets for alcoholism are neurotransmitter pathway genes implicated in alcohol use. Of particular interest are the 'reward pathway' (serotonin, dopamine, GABA, glutamate, and beta endorphin) and the behavioral stress response system (corticotrophin-releasing factor and neuropeptide Y). Common functional polymorphisms in these genes are likely to be predictive (although each with small effect) of individualized pharmacological responses. Genetic studies, including case-control association studies and genome wide linkage studies, have identified associations between alcoholism and common functional polymorphisms in several candidate genes. Meanwhile, the current pharmacological therapies for alcoholism are effective in some alcoholics but not all. Some progress has been made in elucidating the pharmacogenomic responses to these drugs, particularly in the context of the type 1/type 2 classification system for alcoholics.     

Antisocial alcoholics: are there clinically significant diagnostic subtypes?

Of 360 alcoholic male inpatients assessed with a diagnostic interview, 106 (29%) were found to have a co-occurring diagnosis of antisocial personality. Of these ASP alcoholics, 86 were further subdivided into those with only ASP and alcoholism (n = 38), those with ASP, alcoholism and drug dependence (n = 30) and those with ASP, alcoholism and depression (n = 18; 9 of whom also had drug abuse). Comparisons among the three antisocial groups indicated that they differed in measures of psychopathology and course and severity of alcoholism. When the ASP groups were compared to an alcoholism only group, an earlier onset, more rapid course and increased percentage of many alcoholism symptoms were found in the ASP groups, confirming the findings of other studies.     

Effect of major depression and antisocial personality on alcoholism: course and motivational patterns

Major depression and antisocial personality are two diagnoses often associated with alcoholism. The relationship of these two diagnoses to the course of alcoholism and on the motivation for alcohol use was examined in a sample of 321 persons receiving inpatient treatment for alcoholism. Major depression did not alter the course of alcoholism in either men or women. However, patients with a history of major depression more frequently reported drinking to relieve symptoms related to depression than patients without a history of major depression. Patients with antisocial personality had an earlier onset of alcohol-related problems than patients without antisocial personality. The motivational patterns for drinking did not distinguish patients with antisocial personality from patients without antisocial personality. These findings indicate the etiological logical importance of antisocial personality for the development of alcoholism and highlight the patients' perception of depression as an explanation for their drinking.     

Alcoholism in men patients subtyped by family history and antisocial personality

Alcoholism is known to be a familial disorder and the presence of a family history of alcoholism is recognized as an important variable in alcoholism research. The course and consequences of alcoholism in a group of men alcoholics are examined in relation to family pedigree for alcoholism. Consideration was also given to antisocial personality, a variable that may underlie and contribute to a positive family history of alcoholism. The presence of antisocial personality affected the course of alcoholism to a greater extent than having a positive pedigree for alcoholism. On the other hand, having a pedigree positive for alcoholism was more important in explaining the consequences of alcohol misuse than antisocial personality. The theoretical and methodological implications of these findings for future research are discussed.     

5-HT uptake inhibitors and tricyclic antidepressants: relation between tryptophan availability and clinical response in depressed patients

The amount of tryptophan (Trp) available for transport from plasma into the brain was estimated in patients with major depression before treatment for 4 weeks with a 5-HT potentiating tricyclic antidepressant (TCA), amitriptyline (n = 21) or clomipramine (n = 17), or a selective 5-HT uptake inhibitor, citalopram (n = 14) or paroxetine (n = 27). The ratio in plasma of Trp to the sum of the other large neutral amino acids (LNAA) was significantly inversely correlated with improvement on TCA, and patients with ratio Trp/LNAA below the mean improved significantly more than patients with a higher ratio but with comparable serum steady-state drug levels. The Trp concentration was a bit stronger inversely correlated with improvement on 5-HT uptake inhibitors than the ratio Trp/LNAA, and patients with Trp level below the mean improved significantly more than those with a higher level but with comparable serum steady-state drug levels. Plasma amino acid variables may be a useful tool for increasing the efficacy of antidepressant treatment.     

Psychopathy and antisocial personality disorder among alcoholic inpatients.

OBJECTIVE: The purpose of this study was to compare the adequacy of two measurement systems--the Revised Psychopathy Checklist (PCL-R) and DSM-III diagnosed antisocial personality disorder (APD)--to distinguish alcoholic inpatients with regard to alcoholism characteristics, criminal activities and psychiatric disorders. METHOD: The 740 patients, who included 440 men, 387 blacks and 199 Hispanics, were admitted to one of five New York State alcohol treatment inpatient centers. Each patient was interviewed, and DSM-III diagnoses and other characteristics were recorded, and trained interviewers completed the PCL-R. RESULTS: There was a statistically nonsignificant association between DSM-III-based APD diagnosis and PCL-based psychopathy diagnosis. APD (relative to non-APD) alcoholics had an earlier onset of problem drinking, higher levels of pathological drinking and social impairment, and a higher prevalence of familial alcoholism; a similar pattern was not indicated for PCL-R diagnosed psychopaths relative to nonpsychopaths. APD alcoholics also engaged in higher levels of criminal activities and violent acts. APD alcoholics had a higher prevalence of substance abuse disorders, and psychopaths had a higher prevalence of generalized anxiety disorder, panic disorder and schizophrenia. CONCLUSIONS: Distinct subpopulations of alcoholic inpatients are identified via the APD criteria of DSM-III and the psychopathy criterion of the PCL-R. The majority of the identified psychopathic alcoholics in this sample were likely to be secondary psychopaths, characterized by features of psychopathy (e.g., callousness, manipulativeness) and emotional dysregulation and/or thought disturbance.     

The comparative validity of eleven alcoholism typologies

OBJECTIVE: This study directly compared the clinical validity of 11 empirically defined alcoholism typologies to determine whether some typologies are clinically more valid than others. METHOD: A sample of 360 hospitalized alcoholic men were extensively evaluated at entry into the study and again 1 year later. Twenty-three measures of clinical validity were employed; 15 were postdictive and 8 were predictive. Postdictive retrospective measures obtained at entry into the study included family history, age of onset and lifetime course characteristics associated with alcoholism severity, general psychopathology and psychosocial functioning. Predictive outcome measures drawn from information obtained during the 1-year follow-up included: abstinence, alcoholism severity and clinician ratings of outcome. The measures were subjected to various statistical analyses, including factor analysis. RESULTS: We found that all of the alcoholism typologies met at least 7 of the 23 a priori measures of clinical validity. The correlations between these conceptually and methodologically disparate typologies were often striking. Exploratory factor analysis, which explained 35% of the variance, suggested three possible underlying dimensions to account for the overlap among typologies: (1) age and its correlates, including age-of-alcoholism onset; (2) "pure" alcoholism versus psychiatrically heterogeneous alcoholism that encompassed antisocial personality disorder; and (3) current severity of psychiatric distress, impairment and dysfunction. CONCLUSIONS: No single method of subtyping alcoholics clearly emerged as superior. All demonstrated some degree of predictive and postdictive clinical validity. Most methods of subtyping correlated positively with each other at moderate, but typically significant, levels.     

Alcoholism in Males with Antisocial Personality Disorder

Two hundred and sixty men entering an inpatient program for alcohol and drug treatment were interviewed and tested for cognitive disturbances and hepatic function. When the treatment group was separated by the presence or absence of antisocial personality disorder, the antisocial group was distinguished by several factors. Antisocial alcoholics were more likely to have an early onset of alcoholism and to be involved with other illicit drugs, and showed evidence of more problems with control of their drinking. They reported more alcohol-related problems as defined in DSM-III. Despite histories of a more severe form of alcoholism, the antisocials were no more likely to develop alcohol dependence or show signs of cognitive or hepatic toxicity.     

Cognitive-perceptual deficit in an alcoholism spectrum disorder

It was hypothesized that alcoholics and antisocial patients would resemble one another with respect to their pattern of performance on three cognitive-perceptual tasks related to frontal lobe functioning. Using a discriminant function analysis, it was found that alcoholics and antisocial patients were both significantly differentiated from psychiatric controls and college students on the basis of their cognitive-perceptual performance. Moreover, as predicted, alcoholics and antisocial patients were themselves indistinguishable. Consistent with the etiological model, these findings held for both younger and older alcoholics. In addition, it was found that cognitive-perceptual deficit among alcoholics was positively related both to the amount of alcohol consumed per drinking occasion and to the experience of arrest by the police. The results point to a psychological affinity between primary alcoholism and antisocial personality and affirm the relevance of prefrontal-type deficits to problems of control and socialization.     

Dependence and obsession]

Alcoholism, especially the urge to drink and relapse from abstinence, is deeply associated with obsession. And also alcoholics on abstinent 10 years or more are still higher on the obsessive-compulsive symptom dimension more than the depression and interpersonal sensitivity. Obsession was introduced by Kraepelin in 1915 and has been studied extensively since. When a person with obsession becomes exhausted with chronic rumination accompanied suspicion, he or she is driven to impulsive acts like alcoholics, and develops a personality disorder that displays persistent abnormal activities. Impulsive-compulsive spectrum characterizes by dimensions of risk-aversive/risk-seeking and harm-avoidant/harm- minimizing behaviors. Disorders on the compulsive end of the spectrum include obsessive-compulsive disorder, hypochondriasis, body dysmorphic disorder, anorexia nervosa an depersonalization. Mixed compulsive and impulsive disorders include Tourette's disorder, trichotillomania, pathologic gambling, sexual compulsions and alcoholism. Disorders on the impulsive end of the spectrum include borderline personality disorder and antisocial personality disorder. Using 123I-IMP SPECT, regional cerebral blood flow significantly decreased in alcoholics without Korsakoff sign (WAIS FIQ 90 or over) than alcoholics with Korsakoff signs (WAIS FIQ 89 or under) and control on the frontal lobe and thalamus. Recent model of obsessive-compulsive pathophysiology demonstrating that cortical regions have different effects on the direct and indirect pathways, indicates that the the different effects of serotonergic agents in the cortex alone could result in a change in balance between the direct versus indirect basal ganglia pathway. This article reviews alcoholism and obsession, ego dystonic and ego syntonic, approach-avoidance conflict, a recent biological approach to alcoholics and a spectrum for obsession.     

Neuropharmacology: Amitriptyline and Clomipramine Increase the Concentration of Administered L-Tryptophan in the Rat Brain

The tricyclic antidepressant amitriptyline has been shown to reduce concentrations of large neutral amino acids (LNAA) in rat plasma. Compounds with that property might interact with such amino acids used as therapeutic agents with a central site of action by causing a change in the relationship between the administered LNAA and its endogenous LNAA competitors for carrier-mediated transport through the blood–brain barrier into the brain. This study was performed to investigate if the antidepressant agents amitriptyline and clomipramine could, by such a mechanism, increase brain concentrations of administered tryptophan. Intraperitoneal administration of L-tryptophan alone (100 mg kg^?1) resulted in an increase in the concentration of tryptophan in the rat brain from 14 ±0.7 to 100 ± 4.3 nmol g^?1 compared with rats given saline only. When rats were given tryptophan with amitriptyline (25 mg kg^?1, i.p.) or clomipramine (25 mg kg^?1, i.p.) brain concentrations of tryptophan were increased even further, to 150 ±4.5 and 157 ± 10.2 nmol g^?1, respectively. Administration of L-tryptophan alone resulted in an increase in the rat plasma tryptophan ratio [(concentration of tryptophan)/(total concentration of LNAAs)] from 0.14±0.003 to 0.42±0.011 compared with rats given saline only. When rats were given tryptophan with amitriptyline or clomipramine the plasma tryptophan ratios were increased even further to 0.52 ±0.017 and 0.54 ±0.025, respectively. All these effects were statistically significant (P < 0.001). These findings support the hypothesis that tricyclic antidepressants could interact with administered tryptophan by changing the relationship in plasma between tryptophan and its endogenous LNAA competitors for transport into the brain, resulting in higher concentrations of tryptophan in the brain. It is possible that this could be the mechanism of the previously reported finding that clomipramine and tryptophan potentiate each other in the treatment of depression.     

Genetic Heterogeneity and the Classification of Alcoholism

Recent progress toward a systematic pathophysiological model of alcoholism has led to indentification of two distinct subtypes of alcoholism. These subtypes may be distinguished in terms of distinct alcohol-related symptoms, personality traits, ages of onset, and patterns of inheritance. Type 1 alcoholism is characterized by anxious (passive-dependent) personality traits and rapid development of tolerance and dependence on the anti-anxiety effects of alcohol. This leads to loss of control, difficulty terminating binges once they start, guilt feelings, and liver complications following socially encouraged exposure to alcohol intake. In contrast, type 2 alcoholism is characterized by antisocial personality traits and persistent seeking of alcohol for its euphoriant effects. This leads to early onset on inability to abstain entirely, as well as fighting and arrests when drinking. Empirical findings about sex differences, ages of onset, associated personality traits, and longitudinal course are described in a series of adpotion and family studies in Sweden and the United States. Implications for future research and clinical practice are discussed.     

Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers

Rationale Disorders associated with low levels of serotonin (5-HT) are characterized by mood and cognitive disturbances. Acute tryptophan depletion (ATD) is an established method for lowering 5-HT levels and an important tool to study the effects of reduced 5-HT on mood and cognition in human subjects. The traditional ATD method, i.e., administration of separate amino acids (AAs), has several disadvantages. The AA mixture is costly, unpalatable and associated with gastrointestinal discomfort.Objectives The University of Maastricht developed a new and inexpensive method for ATD: a natural collagen protein (CP) mixture with low tryptophan (TRP) content. The reductions in plasma TRP after taking this CP mixture were compared with the reductions achieved taking the traditional AA mixture, and effects on memory and reversal learning were studied.Methods Fifteen healthy young volunteers participated in a double-blind, counterbalanced within-subject study. Reversal learning, verbal memory and pattern recognition were assessed at baseline and 3–4 h after taking the CP mixture.Results The new ATD method significantly reduced plasma TRP by 74% and the ratio between TRP and the other large AAs (TRP/LNAA) by 82%. The placebo mixture did not change these measures. Delayed recognition reaction time on the verbal learning task was increased following ATD. No other cognitive effects were found.Conclusions The CP mixture was shown to be an efficient tool for lowering plasma TRP in humans. The validity of this method with regard to behavioral changes remains to be established in healthy, vulnerable and clinical populations.Errata to this article can be found at and at An updated version of this article can be found at     

Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers

Rationale Disorders associated with low levels of serotonin (5-HT) are characterized by mood and cognitive disturbances. Acute tryptophan depletion (ATD) is an established method for lowering 5-HT levels and an important tool to study the effects of reduced 5-HT on mood and cognition in human subjects. The traditional ATD method, i.e., administration of separate amino acids (AAs), has several disadvantages. The AA mixture is costly, unpalatable and associated with gastrointestinal discomfort.Objectives The University of Maastricht developed a new and inexpensive method for ATD: a natural collagen protein (CP) mixture with low tryptophan (TRP) content. The reductions in plasma TRP after taking this CP mixture were compared with the reductions achieved taking the traditional AA mixture, and effects on memory and reversal learning were studied.Methods Fifteen healthy young volunteers participated in a double-blind, counterbalanced within-subject study. Reversal learning, verbal memory and pattern recognition were assessed at baseline and 3–4 h after taking the CP mixture.Results The new ATD method significantly reduced plasma TRP by 74% and the ratio between TRP and the other large AAs (TRP/LNAA) by 82%. The placebo mixture did not change these measures. Delayed recognition reaction time on the verbal learning task was increased following ATD. No other cognitive effects were found.Conclusions The CP mixture was shown to be an efficient tool for lowering plasma TRP in humans. The validity of this method with regard to behavioral changes remains to be established in healthy, vulnerable and clinical populations.This article was originally published under the DOI 10.1007/s00213-004-1933-4. Unfortunately an unrelated paper appeared in print and in the PDF version online. For this reason, all versions of the correct article are now published here under the new DOI, 10.1007/s00213-004-2141-y.     

Two Contrasting Alcoholism Treatment Programs: A Comparison of Outcomes

Participants in two 60-day alcoholism treatment programs with contrasting treatment philosophies and rationale were followed-up 1 year after discharge from the hospital. Widely different resuits were obtained with distinctly different alcoholic veteran populations. Response to treatment was highly favorable for less symptomatic alcoholics when direct emphasis was placed upon the alcoholism per se and complete abstinence. Less favorable responses were achieved with overt neurotic alcoholics when treatment was designed to resolve underlying personality disturbances. Self-reports of marked depression, anxiety, and prior treatment for alcoholism were three pretreatment variables found significantly related to unsuccessful drinking outcome. The implication of these findings is that treatment outcome is largely dependent upon both the characteristics of the population treated and the treatment approach.