Cu, Zn- and Mn-superoxide dismutase levels in brains of patients with schizophrenic psychosis.

Impaired oxidative stress defense has been reported in blood of both drug-naïve and antipsychotic-treated patients suffering from schizophrenic psychosis, indicating the involvement of free radical metabolism in the pathogenetic processes of schizophrenia. In this study, the concentrations of two isoenzymes of superoxide dismutase (SOD), Cu, Zn- and MnSOD, were determined with ELISA in various cortical (frontal, parietal, temporal and occipital cortex) and subcortical areas (putamen, caudate nucleus, thalamus, and substantia innominata) of post-mortem brain tissue from patients diagnosed with a schizophrenia spectrum disorder and compared with those of controls. Post-mortem brain tissue from individuals without neuropsychiatric disorders served for control. Cu, Zn- and MnSOD levels were significantly increased in frontal cortex and substantia innominata of the index group, respectively. In all other areas both types of SOD remained virtually unchanged. Detection of SOD changes in the brain supports previous reports of alterations of antioxidant indices in blood cells of patients with schizophrenia and suggests a specific neuroanatomical distribution pattern of oxidative stress processes possibly related to the pathophysiology of schizophrenia.

The candidate gene approach in alcoholism: are there gender-specific differences?

It is well established that genetic factors play a major role in the development of alcoholism in both sexes. Several twin studies demonstrated a nearly equally high magnitude of genetic influence for men and women. However, the genetic sources of vulnerability are supposed to only partially overlap in men and women. Therefore, we evaluated the gender-specific effects of two single nucleotide polymorphisms affecting dopaminergic neurotransmission (dopamine D2 receptor: -141C Ins/Del polymorphism; Dopamine D3 receptor: Bal I) in our large sample of primary alcoholics. Only a gender-specific analysis of subgroups with a putatively high genetic load, e.g., family-history-positive or presence of severe withdrawal complications, revealed significant differences in allele-/genotype-frequency. Our results demonstrate that a varying sex distribution in the samples investigated might contribute to the heterogeneous results reported in association studies for candidate genes in alcoholism and, therefore, should be taken into account in future studies.

Gender and personality in alcoholism.

The topic gender and personality in alcoholism is discussed on the background of a research project on clinical aspects of alcoholism at the University of Würzburg, Germany. The data of this study are presented in the context of two questions: Which personality differences are there between women and men dependent on alcohol, and is there a connection between these personality differences and features of the alcohol dependence? Additionally, we take a look at gender-related differences in the development of alcoholism. In a first step, gender differences in the development and the course of alcoholism are investigated. The data revealed only weak differences between female and male alcoholics when important confounding variables like age and education are taken into consideration. Secondly, the female and male alcoholics are matched according to age and education and their personality structures are compared by using several well-established and standardized self-report questionnaires. No serious gender differences concerning the main characteristics of alcohol dependence could be discovered. However, some remarkable personality differences between female and male alcoholics are found: women scored significantly higher on Neuroticism and Harm-Avoidance while men reached significantly higher scores on Venturesomeness and Sensation-Seeking. In order to detect a possible connection between alcoholism and gender-related personality differences, both males and females are subdivided into two groups using the scores of Neuroticism, Harm-Avoidance, Venturesomeness and Sensation-Seeking, respectively. We have found no indication for a gender-specific relevance of personality differences between female and male alcoholics with regard to Harm-Avoidance, Venturesomeness or Sensation-Seeking. However, differences in Neuroticism have revealed a greater relevance in alcohol-dependent women than in men.

Gender-related differences in pharmacological relapse prevention with flupenthixol decanoate in detoxified alcoholics.

A study recently finished by our research group elucidated the effectiveness of flupenthixol decanoate (FLX) in maintaining abstinence in detoxified alcoholics. Flupenthixol decanoate is an established antipsychotic drug, which is well known for its mild antidepressant and anxiolytic activity as well as for its minimal sedation at low doses. It blocks dopamine binding at a number of receptor subtypes, primarily at D-1, D-2, D-3 and with less affinity at D4-receptors. It also affects serotonin binding at 5-HT2A and 5-HT2C receptors. In a double-blind placebo-controlled multicenter trial, 77 women and 204 men suffering from moderate or severe DSM-II-R alcohol dependence were randomly assigned to either 10 mg FLX or placebo both injected every second week over a period of 24 weeks (treatment phase) succeeded by a medication-free 24-weeks follow-up period. In the overall analysis the number of patients relapsed after 24 weeks of treatment (=main criterion of efficacy) was significantly higher in the FLX treated group (85.2%) than under placebo (65.5%). However, when differentiating this result according to sex the analysis revealed a gender-related discrepancy: while male patients had an almost 4-fold higher risk to relapse under FLX than under placebo (OR=3.95) this risk was barely elevated for female patients (OR=1.51). A significantly negative outcome due to FLX treatment was restricted to male alcoholics solely. In conclusion, gender-related differences to pharmacological relapse prevention with FLX have probably contributed to a better treatment outcome in women than in men.

Dopamine D2 (DAD2) and dopamine D3 (DAD3) receptor gene polymorphisms and treatment outcome in alcohol dependence.

The dopaminergic system is critically involved in reward mechanisms mediating the reinforcing effects of alcohol. The intention of this study was to investigate the genotypic frequencies of the -141C Ins/Del polymorphism of the DAD2 receptor gene as well as the Bal I polymorphism of the DAD3 receptor and their potential association with treatment outcome in alcoholism. Therefore, individuals suffering from primary alcohol dependence were clinically and genetically characterized and followed prospectively over a period of one year after inpatient treatment. No association was found between DAD2 or DAD3 receptor gene variants and treatment outcome as reflected by abstinence/relapse after one year. Taking into account potential stratification effects, such as family history, gender, age of onset, or severity of the disease an association with DAD2 or DAD3 gene variants could neither be found. In conclusion, we found no evidence that the DAD2 or DAD3 gene variants investigated have a major influence on treatment outcome in primary alcohol dependence.

[Wender Utah rating scale. The short-version for the assessment of the attention-deficit hyperactivity disorder in adults]. / Wender Utah Rating Scale (WURS-k) Die deutsche Kurzform zur retrospektiven Erfassung des hyperkinetischen Syndroms bei Erwachsenen.

This work presents a statistical analysis of the German version of the Wender Utah rating scale (WURS) for the retrospective diagnosis of attention-deficit/hyperactivity disorder (ADHD) in adults. Data were obtained from 703 subjects. Item selection according to item-total correlation scores, frequency, and plausibility led to a short version of the scale that includes 21 items with item-total correlations from 0.19 to 0.61. Retest reliability of the WURS-k was r=0.9.

Sequential MR imaging and proton MR spectroscopy in patients who underwent recent detoxification for chronic alcoholism: correlation with clinical and neuropsychological data.

BACKGROUND AND PURPOSE: Chronic alcohol abuse may cause neuropsychological disorders and result in brain atrophy. The purpose of this study was to evaluate the metabolic, morphologic, and functional cerebral changes in the early stage of abstinence from chronic alcoholism. METHODS: Seventeen alcohol-dependent patients underwent MR imaging and MR spectroscopy on days 1 through 3 and days 36 through 39 of abstinence. In addition, psychological performance measures testing intelligence, concentration, attention, and memory were applied. Neuropsychological data were correlated with spectroscopic and volumetric results by using a Pearson's product moment correlation. The same measurements were also performed in 12 healthy, age-matched control subjects. Peak integral values for N-acetylaspartate (NAA) and choline (Cho) were referred to the peak integral value of creatine (Cr) as the internal reference. RESULTS: NAA/Cr was decreased in the patients in both the frontal lobes and cerebellum immediately after cessation of drinking (days 1 through 3). After 36 to 39 days of abstinence, NAA/Cr had significantly increased in the patients and corresponded to performance on psychological tests. The Cho/Cr ratio was decreased in the cerebellum during early abstinence but was recovered on days 36 through 39. The patients had enlarged CSF spaces 1 to 3 days after detoxification, which decreased during sobriety. The extent of brain atrophy did not correspond to performance on psychological performance tests. CONCLUSION: Regression of brain atrophy and metabolic recovery occurs at an early stage after abstinence from chronic alcohol abuse. MR spectroscopy findings return to normal metabolic levels within weeks after detoxification. The recovery of NAA/Cr is associated with improved performance on neuropsychological tests.

Alcohol cue-reactivity in heavy and light social drinkers as revealed by event-related potentials.

An elevated cue-reactivity evoked by alcohol-related stimuli (cues) in alcohol-dependent patients has been described for different physiological variables, including electrophysiological measures, such as event-related potentials (ERPs). Cue-reactivity has, however, also been reported for social drinkers. The aim of this study is to assess the effect of the drinking behaviours of social drinkers on cue-reactivity as measured with ERPs. Forty alcohol-related and 40 neutral pictures were presented to 15 heavy and 15 light drinkers (all males). ERPs were recorded using 21 scalp electrodes. Stimuli were presented for 500 ms with an inter-stimulus interval of 2000 ms. Heavy social drinkers displayed a cue-reactivity of significantly higher amplitude at the frontal electrode location Fz, elicited by alcohol-related, as compared to neutral, pictures. This effect was not found in light social drinkers. The results indicate that the cue-reactivity previously found in alcohol-dependent patients is also present in social drinkers, and that electrophysiological cue-reactivity is associated with alcohol consumption.

Neuroendocrine responses to fenfluramine and its relationship to personality in alcoholism.

This study investigates the relationship between personality and serotonergic reactivity in alcohol dependence. Personality characteristics were assessed according to the Temperament and Character model of Cloninger, the five-factor model of McCrae and Costa, Zuckerman's Sensation Seeking as well as Eysenck's impulsiveness/venturesomeness. Placebo-controlled prolactin response to the serotonin (5-HT) reuptake inhibitor/releaser fenfluramine served as an indicator for the reactivity of serotonergic neurotransmission. Forty abstinent alcohol-dependent men were subdivided into high and low prolactin responders according to their level of neuroendocrine response. High responders were characterized by decreased harm avoidance while their extraversion and venturesomeness scores were increased in comparison to low responders. The data demonstrates that harm avoidance on the one hand and extraversion/venturesomeness on the other are inversely correlated to serotonergic neurotransmission. These results support a specific relationship between personality traits and the serotonergic system.

Flupenthixol decanoate and relapse prevention in alcoholics: results from a placebo-controlled study.

Flupenthixol, with its broad receptor profile, interacts with a variety of dopamine and serotonin binding sites which are important in the neurobiology of alcohol dependence. Its pharmacology, together with encouraging results from both animal studies and clinical trials with cocaine users, led us to postulate that flupenthixol would significantly prevent relapse in detoxified alcohol-dependent individuals. We conducted a prospective, randomized, double-blind, placebo-controlled, multi-centre trial with two parallel groups and appropriate statistical evaluation. Subjects met criteria for moderate to severe alcohol dependence (DSM-III-R), without any concomitant psychiatric disorder. After complete detoxification, 281 women and men received either 10 mg of flupenthixol decanoate or placebo as i.m. injection every second week for 6 months on an out-patient basis, followed by 6 months of follow-up. Efficacy was based on absolute abstinence, with relapse being defined as consumption of any alcohol after inclusion in the study. In contrast to the hypothesis, flupenthixol did not reduce, but was associated with more, relapses. Though well tolerated, relapse rates after 6 months of treatment were 85.2% (flupenthixol) versus 65.5% (placebo), a highly significant difference from the medication. Flupenthixol was also inferior to placebo with regard to other secondary criteria of efficacy (cumulative abstinence duration, relapse rate after 12 months). These results indicate that a 10 mg dose of flupenthixol decanoate does not have a beneficial effect on abstinence maintenance in alcohol-dependent individuals.

Event-related potentials and cue-reactivity in alcoholism.

BACKGROUND: Relapse is a major problem in the treatment of addictive behaviors. Conditioning models of alcohol addiction suggest that stimuli associated with previous drug use (cues) may initiate relapse in a definite group of alcoholics. Event-related potentials (ERPs) might be useful to reveal the brain functional substrates of cue-reactivity. METHODS: In a preliminary investigation, 11 alcohol-dependent patients who did not take part in the electrophysiological study completed a structured interview to rate 80 words as to the degree of relatedness to alcohol. Based on these results, cue-reactivity for 15 alcohol-related and 15 unrelated word cues, each repeated eight times, was investigated in 19 alcohol-dependent men (44.2 +/- 8.5 years) and 19 healthy control men (42.5 +/- 12.5 years). RESULTS: A cue-reactivity that consisted of significantly higher amplitudes in the ERPs after alcohol-related words compared with unrelated words was found in alcohol-dependent patients, but not in controls, at the electrode location Pz [F(1,36) = 5.2,p < 0.05]. CONCLUSIONS: Consistent with the hypothesis, only alcohol-dependent patients were characterized by signs of increased cerebral activity associated with alcohol-related compared with unrelated cues. Therefore, the results support the concept of cue-reactivity in alcoholism based on a neurobiological measurement. Future investigations will show whether this cue-reactivity can be applied to assess the risk of relapse in individual alcohol-dependent patients.

The effects of ritanserin on mood, sleep, vigilance, clinical impression, and social functioning in alcohol-dependent individuals. Ritanserin in Alcoholism Work Group.

In an international double-blind placebo-controlled trial with 493 detoxified alcohol-dependent individuals, ritanserin, a specific 5-hydroxytryptamine, antagonist, was tested in three different dosages (2.5, 5, and 10 mg/day) against placebo over a period of 6 months. Data on changes in mood state, sleep quality, morning vigilance, clinical impression, and social functioning were analysed. None of the three dosages of ritanserin given revealed any significant effect against placebo on the above-mentioned parameters either at the end of treatment or upon relapse. Therefore, we conclude that patients suffering from alcohol dependence without concomitant psychiatric disorders do not benefit from additional treatment with (2.5, 5, or 10 mg/day) ritanserin.

Genome polymorphism and alcoholism.

Different gene variants have been identified as risk or protective factors in alcoholism. The genes coding for dopamine receptors, serotonin transporters, and dehydrogenases represent susceptibility loci for addictive behaviour. However, alcoholism represents a complex psychiatric symptomatology which is caused by multiple factors, both genetic and environmental. Furthermore, there are probably different subtypes of alcoholism each with a distinct pathophysiology, and thus a different genetic background. Genetic research can help to identify such subtypes, which may require different therapeutic approaches. However, gene polymorphisms are not only responsible for a predisposition to alcoholism, but also for personality traits which influence the likelihood of developing addictive behaviour. Moreover, genetic polymorphisms are probably involved in the way an individual responds to treatment. Also, the severity of secondary diseases resulting from chronic alcohol uptake may depend on the genetic makeup of an individual. New treatment strategies focusing on genes contributing towards drug and alcohol dependence (such as gene therapy) are already under examination in animal models. However, further research is required before these developments will considerably change today's clinical handling of alcoholism.

[Temperament- and character traits as well as trait patterns in alcoholic men and controls]. / Temperament- und Charakter-Merkmale sowie-Merkmalmuster bei alkoholkranken Männern und Kontrollen.

This study is on the personality of alcoholics, an empirical investigation based on Cloninger's biopsychological temperament- and character-traits. His Temperament and Character Inventory (TCI) was applied to 94 detoxified men suffering from primary alcohol dependence as well as to controls matched for sex and sociodemographic data. The following questions were the matter of interest: (1) Do alcoholics and controls differ in their personality as reflected by the TCI and (2) are there indicators based on personality with potential relevance for differential therapies? A multiple univariate statistical comparison yielded significant differences between alcoholics and controls on only 2 subscales (Sentimentality, Resourcefulness). A multivariate analysis of the TCI temperament traits using two-sample configural frequency analysis revealed no statistically significant difference between the two groups. Temperament patterns associated with Cloninger's Type-I/Type-II alcoholics could not be demonstrated. Analyzing the temperament and character traits of the alcohol dependent subjects with a log-linear model revealed two bivariate temperament-/character classifications on the scales "Harm Avoidance" and "Self-Directedness" as well as "Reward Dependence" and "Self Transcendence"-both making it possible to define subgroups which may be relevant for different therapeutical approaches. Taken together, the results of this study suggest that it may be useful to closer investigate the personality of alcoholics even if it is not principally different from that of control subjects.

Dopamine D3 receptor gene polymorphism and alcohol dependence: relation to personality rating.

Hereditary dopaminergic mechanisms have been implicated in the aetiology of alcoholism. For this study, the distribution of a dopamine D3 receptor gene polymorphism (Ball) has been investigated in patients suffering from alcohol dependence, and compared with non-dependent controls. The allele A1 occurred significantly more frequently among patients compared to controls. Patients with the genotype A1/A2 showed significantly higher novelty seeking (NS) scores in the tridimensional personality questionnaire (TPQ) than patients with the genotype A1/A1. The distribution of patients with high and low NS scores in heterozygotes (A1/A2) did not follow a random distribution. There were significantly more individuals with higher NS scores, and fewer individuals with lower NS scores than expected. The results of this study support the hypothesis of a genetically determined involvement of the dopaminergic system in alcohol dependence. This is probably related to the modulation of personality traits. The observed effects are relatively small, but statistically significant. Thus, the genetics of the dopaminergic neurotransmitter system alone cannot explain the aetiopathogenesis of alcoholism.

Ritanserin in relapse prevention in abstinent alcoholics: results from a placebo-controlled double-blind international multicenter trial. Ritanserin in Alcoholism Work Group.

Ritanserin, a long-acting specific 5-HT2 receptor antagonist, revealed promising effects on alcohol intake behavior in both animal and preliminary human studies. To test its effectiveness in alcohol dependence this phase III clinical trial was initiated. In a placebo-controlled, randomized, double-blind international multicenter study 493 patients with moderate or severe alcohol dependence (DSM-III-R) were treated with three doses of ritanserin 2.5 mg/day (n = 122), 5 mg/day (n = 123), 10 mg/day (n = 126), or placebo (n = 122) over a period of 6 months. Ritanserin was well tolerated. The most frequent adverse experiences were headache and insomnia. A small increase in weight in the ritanserin-treated patients was observed. There were no significant differences between any dose of ritanserin and placebo in the relapse-rate, the time to relapse, craving for alcohol, or quantity and frequency of drinking after relapse. So far, neither ritanserin nor any other serotonergic medication has shown its specific effectiveness in relapse prevention in alcohol dependence.

Event-related correlates of response suppression as indicators of novelty seeking in alcoholics.

Novelty Seeking including impulsive behaviour is a personality dimension which has been shown to be related to early-onset alcoholism and to high relapse rates. The cued Continuous Performance Test (CPT) is an experimental paradigm for active response control requiring a choice reaction between execution (Go) and inhibition (NoGo) of a prepared motor response. Metabolic functional methods have shown right frontal brain activation throughout the period of a CPT, and the spatial analysis of the associated event-related brain electrical (ERP) field potentials revealed that this right frontal activation was due to the NoGo subset of the task. The ERP fields allow distinction between the Go and NoGo conditions with one spatial parameter (NoGo-anteriorization) in single cases. and the magnitude of this parameter is thought to be related to inhibitory frontal lobe control. Twenty patients with severe alcohol dependence and 20 age- and sex-matched healthy controls were included in the study and investigated with a 21-channel electroencephalogram while performing a cued CPT. Consistent with previous studies, NoGo-anteriorization was present in every case in both groups. The ERP field differed between alcoholics and controls in the Go condition (P < 0.05) and NoGo-anteriorization in alcoholics was correlated inversely with Novelty Seeking in Cloninger's Temperament and Character Inventory (r= 0.67, P < 0.01). This indicates a reduced frontal lobe contribution during response control in alcoholics with impulsive behaviour and identifies a possible biological marker for the clinical evaluation of the risk of relapse in alcoholism.

Growth hormone response to placebo, apomorphine and growth hormone releasing hormone in abstinent alcoholics and control subjects.

Abstinent alcoholics and control subjects were challenged with placebo (saline), growth hormone releasing hormone (GHRH) and apomorphine (APO). While both groups did not differ in their growth hormone response (HGH) to placebo and GHRH, the alcoholics revealed a significant lower HGH response to dopamine receptor stimulation with APO. These findings provide no evidence that in abstinent alcoholics HGH blunting after dopamine receptor stimulation could be related to an alteration at the pituitary level but they give neuroendocrinological support to the hypothesis of a lower dopamine receptor sensitivity in abstinent alcoholics.

Locomotor activity and defecation of rats observed alone and in pairs in repeated open-field sessions.

Several experiments with independent groups have shown social effects on open-field defecation and locomotor activity in male rats. In this experiment these social effects were studied with a different methodological approach, namely, with repeated measurements. One group of 8 animals was tested always alone in an open field over 10 trials on successive days. The second group of 16 animals was also tested alone on Days 1 to 4 and on Day 9, while they were placed in the open field with a conspecific on Days 5 to 8 and again on Day 10. There was markedly reduced defecation and enhanced locomotion with the conspecific present, while with the absence of the conspecific on Day 9 the scores again reached the level of the rats always tested alone. Therefore, the social effects on defecation and locomotion are very robust phenomena which can also be shown with dependent measurements.