Helmut Nakovics

Neuroimaging of Gender Differences in Alcohol Dependence: Are Women More Vulnerable?

BACKGROUND Alcoholic brain damage has been demonstrated in numerous studies using neuropathology and brain imaging techniques. However, gender differences were addressed only in a few studies. Recent research has shown that development, course, and consequences of alcohol dependence may differ between female and male patients. Our investigation was built upon earlier research where we hypothesized that women develop alcoholic brain damage more readily than men do. To further compare the impact of alcohol dependence between men and women, we examined brain atrophy in female and male alcoholics by means of computed tomography (CT). METHODS The study group consisted of a total of 158 subjects (76 women: 42 patients, 34 healthy controls; 82 age-matched men: 34 patients, 48 healthy controls). All patients had a DSM-IV and ICD-10 diagnosis of alcohol dependence. CT with digital volumetry was performed twice in patients (at the beginning and end of the 6-week inpatient treatment program) and once in controls. RESULTS Patients of both genders had consumed alcohol very heavily. Although the average alcohol consumption in the year before the study was significantly lower in female alcoholics, this gender difference disappeared when controlled for weight. However, women had a significantly shorter duration of alcohol dependence. Despite this fact, both genders developed brain atrophy to a comparable extent. Brain atrophy was reversible in part after 6 weeks of treatment; it did not reach the level in the control groups. CONCLUSIONS Gender-specific differences in the onset of alcohol dependence were confirmed. This is in line with the telescoping effect, where a later onset and a more rapid development of dependence in women were described. Under the assumption of a gradual development of consequential organ damage, brain atrophy seems to develop faster in women. As shown in other organs (i.e., heart, muscle, liver), this may confirm a higher vulnerability to alcohol among women.

Impairment of cognitive abilities and decision making after chronic use of alcohol: the impact of multiple detoxifications.

AIMS In the present study, the effect of previous detoxifications on prefrontal function and decision making was examined in alcohol-dependent patients. Further, we examined whether the length of abstinence affects cognitive function. METHODS Forty-eight alcohol-dependent patients were recruited from an inpatient detoxification treatment facility and cognitive function was compared to a control group of 36 healthy controls. The patient population was then divided into a group of patients with less than two previous detoxifications (LO-detox group, n = 27) and a group of patients with two or more previous detoxifications (HI-detox group, n = 21) and cognitive function was compared. In addition, cognitive function of recently (i.e. less than 16 days; median split) and longer abstinent patients was compared. We assessed prefrontal function, memory function and intelligence. RESULTS Alcoholics, when compared to healthy controls, performed worse with regard to the performance index Attention/Executive function. Cognitive impairment in these tasks was pronounced in recently abstinent patients. We found no significant differences between HI-detox and LO-detox patients with regard to the Attention/Executive function. However, in the IOWA gambling Task, the HI-detox group seemed to be less able to learn to choose cards from the more advantageous decks over time. CONCLUSIONS Our results provide additional evidence for cognitive impairment of alcohol-dependent patients with regard to tasks sensitive to frontal lobe function and underline the importance of abstinence for these impairments to recover. We found only little evidence for the impairing effects of repeated withdrawal on prefrontal function and we suggest that executive function is affected earlier in dependence.

Orexin and leptin are associated with nicotine craving: A link between smoking, appetite and reward

OBJECTIVE Preclinical data suggest modulating effects of both orexin/hypocretin and leptin on dopaminergic transmission in mesolimbic reward pathways. This indicates a possible role of both peptides in reward function and motivation, and thus in addictive diseases. The aim of this study was to examine the possible association between orexin and leptin, and nicotine craving in smokers in a clinical case-control study under standardized conditions. METHODS We compared orexin and leptin, ACTH and cortisol plasma concentrations (RIA) between tobacco smokers (n=60) during early nicotine withdrawal and healthy controls (n=64). Motivational aspects of nicotine craving were additionally assessed in the smoking participants using the Questionnaire of Smoking Urges (QSU). RESULTS As main results we detected a significant negative correlation between orexin plasma concentration and nicotine craving (r=-0.28; p<.05), and a positive association between craving and leptin plasma concentration (r=0.29; p<.05). CONCLUSIONS Our results show an association between craving for nicotine and plasma concentrations of orexin and leptin suggesting that both peptides interfere with the dopaminergic transmission during nicotine withdrawal in a bidirectional manner and, thus, modulate craving for nicotine.

Investigating the Structure of Craving Using Structural Equation Modeling in Analysis of the Obsessive-Compulsive Drinking Scale: A Multinational Study

BACKGROUND Currently, there is no agreement among researchers on the definition of craving and its underlying theoretical model. The Obsessive-Compulsive Drinking Scale (OCDS) seems to measure certain aspects of craving, but its theoretical basis remains unclear. The aim of this study was to investigate the structure of alcohol craving, using OCDS data. METHODS OCDS data from four studies were pooled to obtain a large and heterogeneous sample of 505 participants. All participants were treatment-seeking alcoholics meeting DSM-IV criteria for alcohol dependence. The factor structures of the OCDS previously found were evaluated using confirmatory factor analyses. The goodness of fit of these solutions was compared with those of alternative causal models: an obsessive-compulsive disorder model, an inhibition model, and a cognitive-behavioral model. These alternative models were based on modern theories about craving and were tested in the OCDS data, using structural equation modeling. In this way, the current study replaced simple correlational analysis by a more sophisticated causal way of analyzing the underlying structure of the OCDS items. The best fitting model was selected by comparing the mean discrepancy between the implied and observed matrices of the models. RESULTS The data showed that the previously reported factor structures had to be rejected. Also, the inhibition model and obsessive-compulsive disorder model did not fit the data. The cognitive-behavioral model showed encouraging fit. Optimizing strategies were applied to further improve the fit of this model, which resulted in a model with close fit to the data. CONCLUSIONS The causal cognitive-behavioral model proved to be superior. It showed that the OCDS contains many items that do not represent the core concept of craving but instead are indicators for the consequences of craving. From this model, it seems that craving, in a narrow sense, can be reliably assessed with only five items of the OCDS.

The startle reflex in alcohol-dependent patients: Changes after cognitive-behavioral therapy and predictive validity for drinking behavior : A pilot study

Background: Previous studies demonstrated an attenuation of the affect-modulated startle reflex when alcohol-dependent patients were viewing alcohol-associated pictures. This indicates an appetitive valence of these stimuli. We used the affect-modulated startle reflex to assess the effects of behavioral treatment on the emotional processing of alcohol-associated stimuli. Further, we examined whether the affect-modulated startle reflex is a predictor of treatment success. Methods: Forty-three alcohol-dependent patients (21 females, mean age 45.67 years, SD 9.45) were recruited consecutively from an inpatient alcohol detoxification facility where patients attended a 3-week detoxification program including cognitive-behavioral treatment to successfully handle high-risk situations. The eye blink component of the affect-modulated startle response, self-reported cue-induced craving and skin conductance responses to alcohol-associated and control slides were assessed before and after treatment. Changes were analyzed using repeated measures analysis of variance. Drinking behavior was assessed in the 6 months following treatment, and a regression analysis was performed to evaluate the predictive validity of the affect-modulated startle response for drinking behavior. Results: Drinking behavior as well as craving and skin conductance responses decreased significantly over time. The pattern of the affective modulation of the startle reflex was not altered over time. However, startle modulation and relapse were related, and within the group of relapsers, startle modulation was a significant predictor of drinking behavior. Conclusions: Our results suggest that the modulation of the startle reflex may reflect more enduring and permanent processes of emotional responding to alcohol-related cues than autonomic arousal and self-reported craving, and that startle modulation by alcohol-associated cues may be a better predictor of drinking behavior for relapsers than other measures. Further studies including a control condition are necessary to validate these findings.

Effects of treatment with acamprosate on β-endorphin plasma concentration in humans with high alcohol preference

Treatment with acamprosate, a compound used for relapse prevention treatment of alcoholism, was recently shown to be associated with increased plasma concentration of beta-endorphin in rats selectively bred for high alcohol preference. The aim of our study was to prove this result in a comparative clinical study with a corresponding design. We studied 51 alcohol dependent patients following alcohol withdrawal during treatment with acamprosate versus placebo for 4 weeks. Data were analyzed for patients with high alcohol preference (HP) and low alcohol preference (LP) by dichotomizing the sample according to median alcohol intake prior to detoxification. In line with pre-clinical data, beta-endorphin plasma concentration in HP patients was significantly lower compared with LP patients. Four weeks of treatment with acamprosate resulted in a significantly increased beta-endorphin plasma concentration compared with placebo and a significant difference in HP patients but not in LP patients. In conclusion, acamprosate seems to modulate the endogenous opioid system. Our data are in accordance with the assumption that the effect of acamprosate on endorphin plasma concentrations is mainly based on the effect in the high preferring subgroup. Since beta-endorphin deficiency was earlier associated with alcohol craving and anxiety during withdrawal, abstinence maintaining effects of acamprosate might at least be partially related with the ability to modulate opioidergic activity especially in the subsample of HP patients with an attenuated opioidergic activity during this state.

The Vicious Circle of Perceived Stigmatization, Depressiveness, Anxiety, and Low Quality of Life in Substituted Heroin Addicts

Background: Perceived stigmatization of drug addicts may interact with negative mood states and thus may contribute to the maintenance of addictive behavior. Methods: Opiate maintenance patients (n = 106) and an unselected comparison group (n = 144) rated self-report questionnaires about perceived stigmatization, quality of life (QoL), depressiveness, anxiety, self-esteem, addiction characteristics, and social support. Results: 63% of opiate maintenance patients felt discriminated in contrast to 16% of the comparison group. Perceived stigmatization was rated higher by opiate maintenance patients, and all domains of QoL were rated lower, even when statistically controlling depressiveness, anxiety and social factors. Perceived stigmatization was correlated to depressiveness, anxiety, low self-esteem and low QoL, but not addiction characteristics and social support. Structural equation models revealed anxiety and the pathway depressiveness enhancing feelings of being stigmatized resulting in low self-esteem to explain 74% of variance in mental QoL, whereas anxiety and a pathway stigmatization inducing depressiveness leading to low self-esteem explained 49% of variance in physical QoL. Conclusions: A vicious circle of stigmatization, negative affective states and low QoL was confirmed. In addition to societal antistigma campaigns, antidepressive and anxiolytic therapy might have the potential to diminish feelings of being stigmatized and to improve QoL.

Factors affecting cognitive function of opiate-dependent patients.

BACKGROUND A wide range of studies found that opiate-dependent patients suffer from cognitive impairment due to a number of different factors. However, this issue has never been examined systematically. Thus, the aim of the present study is to provide a comprehensive analysis of factors that might contribute to cognitive impairment of opiate-dependent patients and specifically differentiates between various cognitive abilities as these might be impacted differently. METHODS Based on a comprehensive review of the literature with regard to previous findings and suggestions about which factors might affect cognitive functioning, we assessed a wide variety of variables related to substance use and opiate-dependence as well as demographic and socioeconomic variables. Cognitive functioning was assessed through a neuropsychological test-battery. RESULTS We found that the duration of opiate dependence and maintenance treatment, as well as additional substance consumption (alcohol, amphetamines, and cocaine) are the main variables contributing to cognitive impairment in the domains of attention and executive function. Comorbid depressive symptoms negatively affected reaction times. There was no evidence for the role of demographic variables like age and education on cognitive functioning. CONCLUSIONS Our findings suggest that it might be important in the treatment of opiate dependence to address the consumption of additional substances and to closely monitor the negative effects of maintenance treatment on cognitive functioning.

Modifications of the Obsessive Compulsive Drinking Scale (OCDS-G) for use in longitudinal studies

Since the application of the Obsessive Compulsive Drinking Scale (OCDS) has been reported to be problematic when used to measure alcohol craving in longitudinal studies, we examined the following questions: (1) Is it possible to skip problematic quantity items? (2) Is the score calculation rule using the higher value of item pairs necessary? (3) Can the shortened version of the OCDS be applied alternatively? We examined two samples including a total of 355 alcohol-dependent patients: a multi center study sample (n=149) and a validation control sample (n=206). Neither an advantage of the score calculation rule nor the necessity of including items regarding alcohol consumption could be demonstrated. The exclusion of consumption items lead to a clear, stable 2-factor structure with a maximum stability (.81-.91). Retest-reliability ranged from r(tt)=.73 to r(tt)=.76 at an average time interval of 5 weeks. Concerning stability (.68-.81) and reliability (r(tt)=.76), the short version turned out to be equivalent. The short version of the OCDS seems to be sufficient. If different effects on cognitive and behavioral levels are expected, the 12-item version without the quantity items should be applied.

Rivastigmine Reduces Tobacco Craving in Alcohol-dependent Smokers

INTRODUCTION Although alcohol-dependent smokers represent an important group for applying smoking interventions, a sufficient pharmacotherapy has not been established in this high-risk group so far. METHODS In order to examine the effect of the acetylcholinesterase inhibitor rivastigmine on tobacco dependence, we performed a 12-week, randomized, placebo-controlled trial. 26 alcohol-dependent smokers were randomized to rivastigmine 6 mg/day (n=14) or placebo (n=12). Assessments on addictive behavior included carbon monoxide (CO), severity of tobacco dependence (FTND), daily smoked cigarettes (diaries), and craving for tobacco (QSU) and alcohol (AUQ). RESULTS ANOVA revealed a significant treatment-by-time interaction for tobacco consumption and tobacco craving (each p<0.0001). The rivastigmine group showed a decrease in daily smoked cigarettes (-30%), in exhaled carbon monoxide (-32%) and in tobacco craving (-18%) whereas controls did not show significant changes. ANCOVA revealed rivastigmine effects to be more prominent in smokers suffering from more severe tobacco dependence. None of the patients developed an alcohol relapse or an increase in alcohol craving. DISCUSSION Our preliminary data indicate an effect of rivastigmine on tobacco craving and consumption. This pilot study encourages further investigation of acetylcholinesterase-inhibitors as a promising treatment approach regarding tobacco dependence.