DBH*444G/A polymorphism of the dopamine-β-hydroxylase gene is associated with alcoholism but not with severe alcohol withdrawal symptoms

Summary. As the enzyme dopamine-β-hydroxylase (DβH) converts dopamine to norepinephrine and both transmitters seem to be involved in the pathology of alcoholism and severe alcohol withdrawal symptoms, the gene encoding DβH (DBH) was applied to explore the genetic background of alcoholism and severe withdrawal symptoms. 102 healthy control subjects and 208 alcoholics, including 97 patients with a history of mild withdrawal symptoms, 57 with a history of alcohol withdrawal seizure (AWS) and 82 with a history of delirium tremens (DT) were genotyped for the DBH^*444G/A polymorphism revealing a significantly elevated frequency of genotypes carrying the A-allele (p = 0.02; after Bonferroni adjustment for multiple tests) in alcoholics compared to healthy controls. Frequencies of alleles and genotypes of individuals with mild withdrawal symptoms did not differ significantly from those of patients with DT or AWS.     

Norepinephrine transporter gene polymorphism is not associated with susceptibility to alcohol dependence

Abnormalities in monoamine neurotransmission have been implicated in the pathogenesis of alcoholism, mood disorders and schizophrenia. Murine norepinephrine transporter gene (NET) has been mapped to a region on chromosome 8 where a quantitative trait locus for ethanol sensitivity. Therefore we tested whether norepinephrine transporter (NET) gene variants confer susceptibility to either alcohol dependence or severe alcohol withdrawal symptoms. There is a highly polymorphic silent G1287A mutation in the NET gene. In our study 157 alcoholics and 185 healthy unrelated matched control subjects were analyzed for a silent G1287A mutation. No significant differences in allele and genotype distribution between control subjects f(A)=0.33 and alcoholics f(A)=0.29 were found. No significant results were found in more homogenous subgroups, i.e. alcoholics with severe alcohol withdrawal (seizures, delirium), early onset age<26 nor dependent patients with positive familial history of alcoholism. These results suggest that the NET gene polymorphism in exon 9 accession number: mRNA: NM_001043, genomic contig.: NT_019610, is unlikely to be involved in the susceptibility to alcoholism and severe alcohol withdrawal.     

Folsäure gegen Hyperhomocysteinämie

There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Excitatory aminoacids such as glutamate, aspartate, and homocysteine have been shown to be increased in patients with chronic alcoholism who underwent alcohol withdrawal. Furthermore, sustained hyperhomocysteinemia occurred in chronic alcoholics with active drinking pattern. Excitotoxicity can be induced by increased hormocysteine levels via rebound activation of NMDA receptor-mediated glutamatergic neurotransmission upon the removal of ethanol-evoked inhibition. Therefore, hyperhomocysteinemia may be responsible for the higher incidence of complications during alcohol withdrawal (e.g.stroke,convulsions). In addition, an association between brain atrophy and increased levels of homocysteine in chronic alcoholism was shown. This may have important implications for the pathogenesis of brain atrophy in alcoholics. Taking into account that high plasma homocysteine levels are helpful in the prediction of alcohol withdrawal seizures, early anti-convulsive therapy could prevent this severe complication. Supplementation of folate, a cofactor of the homocysteine metabolism, lowers raised homocysteine levels and therefore could be established as a new therapeutic strategy in alcohol withdrawal treatment. The results of various studies highlight the need for further research to prove whether alcoholics benefit from a reduced homocysteine level with respect to both, alcohol-related disorders and alcohol withdrawal symptoms.     

mu-opioid receptor variants and dopaminergic sensitivity in alcohol withdrawal.

OBJECT: The endogenous opioid system plays an important role in the reinforcing properties of alcohol by an interconnected activation of the mesolimbic dopamine system. The Asn40Asp substitution polymorphism of the human mu-opioid-receptor (OPRM) influences binding of opioids and signal transduction and may, thereby, contribute to the development of alcoholism. The present study tested whether the Asn40Asp substitution polymorphism of the OPRM gene is associated with a variation in central dopaminergic sensitivity during alcohol withdrawal in alcoholics. METHOD: Sensitivity of central dopamine receptors was assessed by apomorphine-induced growth hormone (GH) secretion in 97 alcohol-dependent patients before and 1 week after alcohol cessation, and in a subgroup of 19 alcoholics after 3 months of abstinence. GH response was defined as area under the hormone/time curve. Comparisons of the GH response were conducted between alcoholics carrying the Asn40Asp genotype versus those with the Asn40Asn genotype using U-test statistics. RESULTS: Marginal differences in apomorphine-induced GH response were found between both genotype groups before detoxification (P = 0.799 (n = 97)/P = 0.459 (n = 19)) and after 3 months of abstinence (P = 0.331 (n = 19)). In contrast, the GH response measured seven days after alcohol withdrawal was significantly increased in alcoholics with the Asn40Asp genotype compared with those carrying the Asn40Asn genotype (P = 0.013 (n = 97)/P = 0.026 (n = 19)). CONCLUSION: Our results suggest that genetic variation of the mu-opioid receptor modulates the central dopaminergic sensitivity during acute alcohol withdrawal.     

The social complications of chronic alcohol abuse: relative influence of family history and severity of alcohol dependence

Alcoholics with a family history of the disease are said to present more severe consequences than alcoholics without such a history. This study examined the frequency distribution of severe alcohol dependence and police arrests for public drunkenness across samples of alcoholics with (n = 77) and without (n = 37) a family history of alcoholism. Both the percentage of subjects presenting severe dependence and the history of police arrests were greater in the positive family history group, but these differences did not reach conventional levels of statistical significance. However, results of logistic regression analyses demonstrate that male sex, younger age and, above all, severity of alcohol dependence, are better correlates of the occurrence of police arrests than is the subject's family history of alcoholism. The picture presented by this sample of outpatient alcoholics appears to qualify some currently held assumptions of the influence of family history on the phenomenology of alcoholism.     

Depression among alcoholics. Relationship to clinical and cerebrospinal fluid variables

Although depression is common among alcoholics, its determinants are poorly understood. Among 339 alcoholics, 111 (33%) had a history of major depression. Depressed, compared with never-depressed alcoholics, had a higher daily alcohol intake, more lifetime diagnoses of other anxiety and affective disorders and drug abuse, more had attempted suicide, and more reported alcoholism in both parents. Depressed alcoholics also had significantly lower cerebrospinal fluid levels of the dopamine metabolite homovanillic acid and of gamma-aminobutyric acid. Among subgroups of depressed alcoholics, secondary compared with primary depressives were more often divorced, of lower social status, with an earlier onset of alcoholism, and higher Michigan Alcohol Screening Test scores. Secondary depressives also had significantly lower cerebrospinal fluid concentrations of homovanillic acid than never depressed alcoholics. These results suggest that certain psychosocial variables, alcohol consumption, and neurochemical variables may be specifically associated with depression in alcoholics.     

Alcoholism and panic disorder: is the comorbidity more than coincidence?

Studies on alcoholic patients have found a higher than expected prevalence of panic disorder, and suggest a positive correlation between the level of alcohol consumption and severity of anxiety. Conversely, there is an increased prevalence of alcoholism among patients with panic disorder and their blood relatives. A comparison of symptoms, physiological and neurochemical changes known to occur in both alcohol withdrawal and panic disorder reveals a degree of similarity between the 2 conditions. Based on the data, we propose that the chemical and cognitive changes occurring as the result of repeated alcohol withdrawals may kindle and condition coincidence of panic attacks in susceptible individuals. Implications of our postulates for treatment of alcohol withdrawal and panic disorder in alcoholics and for future studies are discussed.     

Evaluation of psychomotor agility during the period of withdrawal symptom dissipation in patients with alcohol dependence type 1 and 2 or Cloninger's

28 alcohol dependent men were examined three times (on the 1st, 3rd or 4th and 7th day of withdrawal). The results confirmed the reported differences in the course of withdrawal syndrome in type 1 and type 2 alcoholics. Patients with type 2 alcoholism had more pronounced psychophysiological and cognitive disturbances. Tremor was more intensive in these patients and their reaction time was slower. Also, impaired estimation of passing time lasted longer, but at the same time their mood improved faster with the diminished intensity of withdrawal symptoms than in patients with type 1 alcoholism. The results confirm the possibility of diverse etiology in alcohol dependence.     

Alcoholic women in fertile age treated at an alcohol clinic

The consumption of alcohol by women in Sweden is strongly increasing, especially in younger individuals. Since the rediscovery of the teratological properties of alcohol most of the studies concerning foetal alcohol damage in man have covered female skid row alcoholics. This investigation describes the medical and social characteristics of a group of women (n = 92) receiving inpatient care for alcoholism compared with an age-matched control group, in relation to obstetrical history. The conditions in the control group were in accord with those of the general population. Social problems and degree of alcoholism were noticeably advanced among the probands. The proband women who gave birth after established regular alcohol consumption were younger, showed more psychiatric complications during the treatment period, had started drinking and developing signs of advanced alcoholism earlier in life compared with probands who gave birth before established regular alcohol consumption. They also exhibited more social disturbances. The social problems caused by the mothers' alcohol abuse are expected to aggravate the biological consequences to their children.     

Neuropsychological consequences of posttreatment drinking behavior in male alcoholics

A prospective study was designed to determine the neuropsychological consequences of continued alcohol consumption after treatment for alcoholism. Performance on 24 commonly used clinical neuropsychological tests was examined in 56 male alcoholics approximately 7 months after completion of an inpatient alcoholism treatment program. Abstainers (n=17) performed better than those who resumed alcohol consumption. Although there was a significant decrease in alcohol consumption, posttreatment drinking behavior still predicted cognitive performance, with increased frequency and quantity per occasion having more deleterious consequences even at consumption levels that are deemed by some to be socially acceptable. It is concluded that continued alcohol consumption by former alcoholics might serve to maintain cognitive performance at reduced levels, and that this possibility should be considered in determining appropriate treatment goals for alcoholic patients.     

Parkinsonism provoked by alcoholism

Seven chronic alcoholics, aged 53 to 70, ENmonstrated transient signs of parkinsonism provoked by alcohol withdrawal or chronic severe intoxication. All showed improvement or recovery when they abstained or ENcreased their alcohol intake for several days to weeks. Animal studies have ENmonstrated impaired striatal dopaminergic function during severe ethanol intoxication or withdrawal. Chronic alcoholism apparently can exacerbate or uncover latent central dopaminergic ENficiency.     

Homocysteine and alcoholism

Chronic alcohol consumption can induce alterations in the function and morphology of most if not all brain systems and structures. However, the exact mechanism of brain damage in alcoholics remains unknown. Partial recovery of brain function with abstinence suggests that a proportion of the deficits must be functional in origin (i.e. plastic changes of nerve cells) while neuronal loss from selected brain regions indicates permanent and irreversible damage. There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Recently, it has been shown that excitatory amino acid (EAA) neurotransmitters and homocysteine levels are elevated in patients who underwent withdrawal from alcohol. Furthermore, it has been found that homocysteine induces neuronal cell damage by stimulating NMDA receptors as well as by producing free radicals. Homocysteine neurotoxicity via overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both brain shrinkage and withdrawal seizures linked to alcoholism.     

Chronic alcohol consumption does not cause hippocampal neuron loss in humans

High alcohol consumption for long periods of time causes significant hippocampal neurodegeneration in rodents. A single study using neuronal density measures has reported similar findings in humans. The present study aims to substantiate these findings in human alcoholics using unbiased stereological techniques. Both amnesic (n = 5) and nonamnesic (n = 7) chronic alcoholics were selected and compared with nonalcoholic controls (n = 8) and patients with marked memory loss and hippocampal neurodegeneration caused by Alzheimer's disease (n = 4). Hippocampal volume was significantly reduced in the alcoholics and in patients with Alzheimer's disease. However, in alcoholics the volume reduction occurred exclusively in the white matter, whereas both the gray and white matter were reduced in the patients with Alzheimer's disease. Neuron loss occurred exclusively from the CA1 and subiculum subregions of the hippocampus in Alzheimer's disease. No neuron loss occurred from any subregion of the hippocampus in alcoholics. There were no correlations with age and any of the volume or neuron number measures. Hippocampal volume correlated with brain volume and with the regional gray and white matter volumes within the hippocampus. In addition, hippocampal gray matter volume correlated with the number of CA1 pyramidal neurons. These results do not support the theory that chronic alcohol consumption is neurotoxic to hippocampal pyramidal neurons in humans. Further, the present results suggest that changes observed in rodent models of alcoholism do not parallel those observed in humans, questioning the validity of such models. Hippocampus 7:78–87, 1997. © 1997 Wiley-Liss, Inc.     

Involvement of plasma atrial natriuretic peptide in protracted alcohol withdrawal

OBJECTIVE: Atrial natriuretic peptide (ANP) has been shown to inhibit the effects of corticotrophin releasing hormone, corticotrophin and cortisol, and to influence affective and anxiety symptoms in man. We tested the hypothesis of whether ANP is associated with endocrine and psychopathological disturbances during acute alcohol withdrawal. METHOD: ANP and cortisol plasma concentrations were studied in alcoholics during in-patient detoxification and in healthy controls. Additionally, craving, depressive mood and anxiety were assessed. RESULTS: Although mean ANP levels increased significantly in alcoholics between days 1 and 14, they remained diminished compared to controls. Separating a subgroup of alcoholics with a decrease of ANP levels during withdrawal, these individuals revealed significantly elevated scores for mean and maximum craving and a trend to an elevated self-rated anxiety on day 14. CONCLUSION: We suggest that a dysregulation of ANP plasma levels during alcohol withdrawal may contribute to symptoms of protracted withdrawal such as craving and anxiety.     

Alcohol consumption and the CAGE test in outpatients with schizophrenia or schizoaffective disorder and in the general population

We conducted a survey of 151 outpatients with schizophrenia or schizoaffective disorder in Geneva, Switzerland, in 2000, and a mail survey in a representative sample of the general population of Geneva in 1996 (n = 742), to compare alcohol consumption and alcoholism in these two samples. Fewer patients with schizophrenia than participants in the general population drank alcohol daily (9.9% vs. 18.3%, p < 0.001). Excluding participants who said they currently never drank, alcohol consumption was similar in both groups (3 vs. 4 glasses/week, p = 0.22). However, more patients with schizophrenia than participants in the population sample had a CAGE score > or = 2 (21.2% vs. 10.1%, p < 0.001), indicating a suspicion of alcoholism. Thus, asking about alcohol consumption produced different results from assessing hidden alcoholism with the CAGE. Either patients with schizophrenia under-reported their alcohol consumption, or the CAGE produced higher scores in these patients, for any given level of alcohol consumption. Previous research has shown, however, that the CAGE is a valid test in patients with schizophrenia, which suggests that in Geneva, alcoholism is more prevalent in patients with schizophrenia than in the general population.     

Neuropeptide y: role in emotion and alcohol dependence

Neuropeptide Y (NPY) is considered to be an important neuromodulator in the regulation of emotional behavior. For example, NPY is consistently involved in anxiety-related behaviors and there is increasing support for a role of this peptide in mood disorders such as depression. Furthermore, recent evidence suggests that NPY has a significant role in the neurobiological response to alcohol, including alcohol consumption, dependence, and withdrawal. In addition, NPY is beginning to emerge as an important modulator in the etiology of alcoholism that is independent from the addictive and reinforcing properties of the traditional system commonly associated with dopamine and instead, is strongly associated with innate emotionality. The recent developments elucidating the role of NPY in emotion and alcohol dependence are reviewed and the potential of the NPY system as a novel therapeutic strategy in the treatment of anxiety, depression and alcohol-related disorders is examined.     

Diagnostic and treatment strategies for depressive disorders in alcohol dependence

Alcohol dependence is one of most common chronic diseases in Germany. Many alcoholics attribute mental disorders as causative for their elevated alcohol consumption intending to cope with these disorders. Epidemiological studies show that alcoholics have a high lifetime prevalence of psychiatric illnesses, particularly of depressive disorders. The complex relationships between elevated alcohol consumption and depressive symptoms frequently lead to problems in finding the diagnosis and thereafter in planning therapeutic strategies. The indication for drug treatment should be based on the psychopathological findings about 14 days after cessation of drinking, since in many subjects depressive symptomatology abates within the first weeks of abstinence without any treatment. Up to now no specific recommendations can be given because the results of the few published controlled studies showed some discrepancies. Summing up, thus far the efficacy of psychopharmacological drugs in treating alcoholics with depressive disorders have not been investigated sufficiently.     

Psychopathology of alcoholics during withdrawal and early abstinence

Epidemiologic surveys show a high lifetime co-morbidity with psychiatric disorders (e.g., depression and anxiety) in alcoholics. However, alcoholics frequently complained about psychopathologic symptoms, particularly during alcohol withdrawal. There is some evidence that symptomatology decreases spontaneously with prolonged abstinence. Thus, the question arises whether high levels of psychopathology could be accounted for by withdrawal effects. This study was aimed at examining the impact of the alcohol withdrawal severity (assessed by the AWS scale) on psychopathologic symptoms. The psychopathologic profile of 110 alcoholics as measured by the Symptom Checklist-90 revised (SCL-90-R) was compared to that of 253 patients with adjustment, anxiety or depressive disorders (according to ICD-10 criteria). No relationship between the severity of alcohol withdrawal and psychopathology could be found which might hint at two different neurobiological processes underlying these phenomena. The comparison with patients suffering from depression or anxiety disorders revealed that the global symptom severity of alcoholics undergoing withdrawal was similar, but recovery was achieved more rapidly than in the other groups. On the other hand, the self-rated psychopathologic symptom profile of alcoholics was rather similar to that of patients with adjustment disorders. While about one-quarter of the alcoholics reported severe psychopathology on admission, only about 10% showed symptomatology at discharge about three weeks later, predominantly depression or anxiety. These results underline the notion that much of the psychopathology described by alcoholics decreases within 2-3 weeks after withdrawal without specific treatment.     

Concurrent cocaine withdrawal is associated with reduced severity of alcohol withdrawal

The purpose of this study was to implement an empirical assessment of the clinical response to standard alcohol detoxification during withdrawal from both alcohol and cocaine. One hundred forty-nine males consecutively admitted in acute alcohol withdrawal to a hospital-based detoxification unit were studied. All subjects completed a 4-day chlordiazepoxide detoxification. Patients who used drugs other than cocaine were excluded. Fifty-five subjects withdrawing only from alcohol and 94 subjects withdrawing from both alcohol and cocaine, as evidenced by positive urinalysis and history, were studied. Both groups reported similar amounts of daily alcohol intake and had a similar age of onset of alcohol dependence. Parental alcoholism was equally frequent in both groups. Statistically, several variables were directly related to severity of alcohol withdrawal, including associated cocaine abuse, age, abnormal laboratory values, and duration of homelessness. As measured by the Alcohol Withdrawal Scale (AWS), alcohol withdrawal was less severe among cocaine users, not only at intake but throughout the 4-day detoxification. Singly addicted alcoholics were older and had longer drinking histories, more prior detoxifications, and more abnormal laboratory values than cocaine users. A multiple regression analysis demonstrated a significant relationship between cocaine and severity of alcohol withdrawal. Cocaine users more frequently requested reductions in chlordiazepoxide dosages than singly addicted alcoholics, complaining of dysphoria, sedation, and weakness. The severity of alcohol withdrawal was associated with recent cocaine use, age, laboratory abnormalities, and duration of homelessness. Concurrent cocaine withdrawal in the sample was associated with reduced severity of alcohol withdrawal. Possible neurobiological mechanisms, as well as study limitations affecting interpretation of the findings, are discussed. Tailored detoxification as opposed to standard detoxification regimens may be more appropriate for the clinical management of combined alcohol-cocaine withdrawal.     

Specificity of the DST and the TRH test for major depression in alcoholics

The authors examined dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) test results in 32 chronic alcoholics without depression or hepatic disease to see if alcoholism alone might lead to positive test results. After 3 weeks of sobriety there were no DST abnormalities, but blunted TRH test results were observed in eight of the 32 alcoholics. More of the 15 patients also tested during alcohol withdrawal than of the 20 normal subjects or the 32 alcoholics without alcohol withdrawal had DST and TRH test abnormalities. When performed after 3 weeks of sobriety, the DST but not the TRH test has potential as a specific laboratory adjunct in the diagnosis of depression in alcoholics.