Karl Mann

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.

Reversible brain shrinkage in abstinent alcoholics, measured by MRI.

SummaryMagnetic resonance imaging of the intracranial CSF volume was compared before and after 5 weeks of confirmed abstinence in 9 alcohol-dependent patients. All patients showed a highly significant reduction in CSF volume in accordance with reexpansion of the brain after alcohol abstinence. T2 values for white matter, estimated by linear regression from 16 echoes of a CPGM sequence, however, showed no significant increase such as occurs in rehydration. This indicates, that alcohol-induced reversible brain atrophy cannot be attributed to fluctuation of free water in the brain only.

Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate

In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated. This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo. The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period (P<0.01). Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate (P<0.01). In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes (P<0.01) was found. Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels. These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.

Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking

Plasma norharman and harman levels were measured by solvent extraction and HPLC with fluorescence detection in alcohol-dependent patients undergoing in-patient abstinence treatment and in control subjects. In both groups, randomly collected samples from smokers contained higher mean norharman levels than those from non-smokers. In three volunteers norharman concentrations rose sharply after smoking of one or two cigarettes and declined to near-basal levels within one hour after one cigarette. When 12 patients kept a smoking-free interval of at least 6 h, they had similarly low plasma norharman concentrations (20 +/- 8 pg/ml) as 18 non-smoking control subjects (17 +/- 8 pg/ml) or as 13 smoking controls who had abstained from smoking (20 +/- 6 pg/ml). Ten of the patients smoked one cigarette and within 5-10 min attained norharman levels of 177 +/- 147 pg/ml plasma. The high prevalence of smokers among chronic alcoholics probably explains the previous finding of elevated norharman plasma levels in these patients.

Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate

Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P=4.6 × 10−5). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P=0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P=0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.

Fluorinated psychopharmacological agents: Noninvasive observation by flourine-19 nuclear magnetic resonance

Fluorinated psychopharmacological agents were measured with fluorine-19 nuclear magnetic resonance spectroscopy in the brain of intact rats that had been treated with fluphenazine. These in vivo experiments were compared to in vitro measurements of fluphenazine-treated rats. A high-field shift was observed in both in vivo and in vitro measurements. On the basis of the in vitro measurements, fluphenazine concentration in the brains of treated rats was estimated. Our observations demonstrate the feasibility of this technique for determining fluorinated neuroleptics in live mammals.

19F nuclear magnetic resonance spectroscopy of neuroleptics: The first in vivo pharmacokinetics of trifluoperazine in the rat brain and the first in vivo spectrum of fluphenazine in the human brain

In vivo 19F nuclear magnetic resonance (19F-NMR) spectroscopy measurements of trifluorinated neuroleptics (fluphenazine--FL and trifluoperazine--TFP) were made in rat brain as well as in human brain. Animal studies were performed at 4.7 Tesla. Using rats that have been treated with FL over a period of 3 weeks, a NMR signal could be detected within 8-15 min. Following a single intravenous injection of TFP, brain levels could be monitored with a time resolution of 30 min. The first 19F-NMR examination of a patient was made at 3.0 Tesla 1 day after injection of FL decanoate (37.5 mg) in the course of which a signal could be detected within 30 min. It is expected that 19F-NMR will become an important tool in psychopharmacological research.

Entwicklung einer evidenzbasierten Psychotherapie bei Alkoholismus

ZusammenfassungIn den vergangenen Jahrzehnten hat die Entwicklung einer evidenzbasierten Psychotherapie bei Alkoholismus enorme Fortschritte zu verzeichnen. Angefangen von psychoanalytisch orientierten Verfahren über erste Anwendungen verhaltenstherapeutischer Konzepte liegt mittlerweile eine Reihe von Behandlungsansätzen vor, die sich bei Menschen mit einer Alkoholabhängigkeit bewährt haben. Einen Schwerpunkt evidenzbasierter Verfahren bilden der Motivationssteigerungsansatz und kognitiv-verhaltenstherapeutische Verfahren, bei denen eine funktionale Analyse des Problemverhaltens im Mittelpunkt steht und verschiedene Techniken zur Modifikation vorausgehender und aufrechterhaltender Bedingungen zur Anwendung kommen. Zu erwähnen ist hier beispielsweise das Bewältigungstraining, das soziale Kompetenztraining oder auch ein gemeindenaher Verstärkeransatz. Die „alkoholismusspezifische Psychotherapie“ ist eine aktuelle Weiterentwicklung therapeutischer Verfahren. Ausgehend von den Ergebnissen des Projekts MATCH, einer der größten Therapiestudien, werden Motivationssteigerung und kognitiv-verhaltenstherapeutische Verfahren als bewährte Therapieelemente miteinander kombiniert, mit dem Ziel, die therapeutischen Erfolgsquoten weiter zu verbessern. Angesichts dieser viel versprechenden Entwicklungen besteht ein großes Problemfeld darin, dass nur wenige der evidenzbasierten Verfahren im deutschen Suchthilfesystem etabliert sind und nur ein geringer Prozentsatz der Menschen mit Alkoholproblemen den Weg in das Versorgungssystem findet. Eine frühere Erfassung in der Arztpraxis aber auch die betriebliche Suchtprävention stellen Möglichkeiten dar, Menschen mit Alkoholproblemen besser in das Versorgungssystem zu integrieren.SummaryPast decades have seen enormous advances in the development and validation of evidence-based approaches to psychotherapy for alcoholism. While psychoanalytic and early behavioral techniques were the original basis of psychotherapy in this field, evidence-based approaches are now built up on the principles of motivational interviewing and cognitive-behavior therapy. Different techniques have been developed to modify preceding and persisting conditions favoring problem behavior, e.g., training in coping/social skills and the community reinforcement approach. According to the results of the project MATCH, one of the largest treatment trials, “cognitive-behavioral intervention” combines motivational enhancement therapy, the 12-step approach, and cognitive-behavior therapy, with the aim of providing new and even more efficacious psychotherapy for alcohol dependent patients. These very promising developments are beset with huge problems, however, insofar as few of the new evidence-based treatment approaches are accepted as standard treatment in Germany, in addition to which only a fraction of all alcohol-dependent persons in the country find their way into the care system, for various reasons. Early diagnosis and facilitation of access to the various treatment options available could be a future task for general practitioners and also for company / industrial medical schemes.

Self-regulation of slow cortical potentials in psychiatric patients: Alcohol dependency

Ten unmedicated alcohol-dependent male inpatients participated in a Slow Cortical Potential (SCP) self-regulation task utilizing biofeedback and instrumental conditioning. These patients were hospitalized for treatment of alcohol dependency after chronic abuse of alcoholic beverages. Somatic withdrawal symptomatology had occurred recently and the patients were free of any withdrawal symptoms of the autonomic nervous system. Immediately after hospitalization patients were unable to control their SCPs without the reinforcement of immediate feedback across 4 sessions. Seven patients participated in a fifth session an average of 4 months later. Six out of these 7 patients had not had a relapse at the follow-up. In the fifth session these patients were immediately able to differentiate between the required negativity and negativity suppression, whereas the seventh patient, who had relapsed, was unable to control his brain potentials successfully. Results are further evidence that some of the frontocortical dysfunctions in alcohol-dependent patients are reversible. This could covary with a morphological restitution of the cortex.

Intracranial CSF volumetry in alcoholics: Studies with MRI and CT

The assessment of the intracranial CSF volume both with CT and MRI confirmed the reversibility of brain shrinkage in abstinent alcoholics. Length of addiction correlated significantly with CSF volumes, even when the effects of age were taken into account