Abstract: BACKGROUND: The D1 dopamine receptor has been involved in a number of brain functions, including motor control, inattentive symptoms and reward and reinforcement mechanisms. Indeed, DRD1 antagonists may reduce cocaine-seeking behavior and the acquisition of cocaine-cue associations. The D1.1/r4532 marker of the DRD1 gene has been associated with a large set of phenotypes including addictive behaviors, but none with alcohol dependence per se. METHODS: We analyzed a population of 134 patients with alcohol dependence, also assessing more homogeneous (severe) phenotypes, comparing this sample with a healthy control population, assessing two SNPs within the DRD1 gene in order to depict the role of DRD1 polymorphisms and haplotypes. RESULTS: The T allele of the rs686 polymorphism within DRD1 gene was significantly more frequent in patients with alcohol dependence (p = 0.0008), with a larger excess for patients with severe dependence (p = 6 x 10(-6)), and even more for patients with severe complications such as withdrawal seizures (p = 7 x 10(-7)). A specific haplotype rs686*T-rs4532*G within the DRD1 gene was significantly more precisely associated with alcohol dependence in our sample (p = 5 x 10(-6)). CONCLUSIONS: Even though chance finding cannot be ruled out, convergent evidence is given that the DRD1 gene is a susceptibility gene in alcohol dependence, regarding the fact that relying on more homogeneous phenotypes (i.e., more severe patients) and more informative genetic markers (i.e., haplotypes) reinforce the initial association.
Abstract: BACKGROUND: Some studies have reported that the A9 allele of the variable nucleotide tandem repeat (VNTR) of the gene which encodes the dopamine transporter (DAT1/SLC6A3) is associated with alcoholism withdrawal symptoms such as alcohol withdrawal seizures (WSs), whereas others did not. We investigated whether polymorphisms within the DAT1 gene are associated with WS taking into account some of the confounding factors such as the severity of alcohol dependence. METHODS: To further assess the role of this gene in WS, we genotyped the VNTR and 7 single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene in a sample of 250 alcohol-dependent subjects (175 men and 75 women), of whom 24% exhibited WSs, taking into account the severity of alcohol dependence. RESULTS: The VNTR is associated with an increased risk of WSs (odd ratio = 3.5; p = 0.019), even when controlling for confounding factors (p = 0.031). As 2 SNPs, in roughly the same location of the gene (namely rs27072 and rs27048), are also associated with WSs, it is possible that the initial association of the VNTR polymorphism was tagging a specific haplotype of this gene. Indeed, in our sample of alcohol-dependent patients, 2 haplotypes were associated with a significantly different risk of WSs. CONCLUSIONS: The present study adds evidence for a significant role of the 3' part of the DAT1 gene in WS of alcohol-dependent patients, not only because it is in accordance with previous work, but also because of larger statistical power (as relying on a sample over sampled with the studied phenotype), as it gives a more precise analysis of different SNPs within the DAT1 gene, and as it confirms the association when major potentially confounding factors are taken into account in a logistical regression analysis.
Abstract: "To quit drinking" is not the panacea of alcohol dependence treatment; it is only its first step. Abstinence should be considered more as a mean than a purpose of the after-withdrawal cares. The frequent resistance of the alcoholic patient to undertake in a long term abstinence can be by-passed by suggesting to fix himself renewable terms for periods during which he feels rather confident to raise the bet of a "most accomplished possible" abstinence. To facilitate the realization and the preservation of this abstinence in the best conditions (potentiation of the profits and minimization of the difficulties), a "therapeutic menu" will be proposed to the patient besides a "minimum plan" containing a medical follow-up over one year, with variable frequency of visits according to the evolution and the prescription of one or two anti-craving drugs registered. Psychotherapies using different techniques as Cognitive Behavioural Therapy, group therapy or psychoanalysis could be proposed after a necessary clarification to the patients of the mechanism of action of each and the waited profits. In the final, two thirds of the patients with alcohol dependence fire in one year a profit of their treatments; the practitioner takes, actually, no risk and should propose systematically a project to the only 20% of them who come to consult him.
Abstract: The gene coding for the dopamine receptor D3 (DRD3) is considered as a major candidate gene in various addictive disorders. Association studies in alcohol-dependence for this gene are nevertheless controversial. We made the hypothesis that phenotypical heterogeneity of alcohol-dependence (i.e. the DRD3 gene is a vulnerability gene in a specific subgroup of patients only) could explain these spurious findings, focusing on a core dimension of addictive disorders, namely impulsiveness. In our sample of 108 French alcohol-dependent patients, patients above the median value for cognitive impulsiveness (one of the three dimensions of the Barratt scale) were more frequently heterozygous than both alcohol-dependent patients with lower impulsiveness (OR = 2.51, P = 0.019) and than 71 healthy controls (OR = 2.32, P = 0.025). Age at interview, antisocial personality disorder, other comorbid addictive disorder, age at onset of alcohol-dependence, and lifetime mood disorders did not constitute confusing intermediate factors.
Abstract: BACKGROUND: The revelation of an acceptable rate of users still treated one year after initiation of a substitution program with high-dose buprenorphine (HDB) has contributed in the validation of the interest of the molecule in this indication. However the frequency of early drop-outs (after the first consultation), when treatment is set-up, is frequently evoked, although undocumented, by general practitioners. OBJECTIVE: During analysis of a survey on the follow-up of opiate addicts starting substitution therapy with HDB, we attempted to assess the frequency of early drop-outs and identify the contributing factors. METHOD: Among the 1085 patients included in the study and in whom induction therapy had been prescribed, 656 were assessed after 12 months' follow-up. RESULTS: Age, precariousness, lack of social support and partial access to care (lack of health insurance, previous contact with the prescriber) were significantly associated with early drop-out. The consumption of psychoactive products and their administration mode, during the 30 days prior to the first consultation of those loss to follow-up, also differed from those of patients who remained within the care system. CONCLUSION: Knowledge of the factors related to frequent early drop-out during induction of HDB substitution therapy, and bearing this in mind, would permit the organisation of more attentive management and hence reduce the drop-out rate.
Abstract: BACKGROUND: The dopamine transporter (DAT) plays a key role in homeostatic regulation of dopaminergic neurotransmission and could thus be involved in the variability of two severe alcohol-withdrawal symptoms, alcohol-withdrawal seizure (AWS) and delirium tremens (DT). Interestingly, an association was found between the DAT gene (9-copy repeat) and the risk for these symptoms in two previous case-control studies. METHODS: We reanalyzed the role of the DAT gene in the lifetime risk for AWS and DT in 120 alcohol-dependent patients, taking into account potentially confounding factors. RESULTS: Alcohol-dependent patients with the A(9) allele had experienced AWS or DT at least once (odds ratio [OR] = 2.52, p =.03). This association persisted when excluding patients with antisocial personality comorbidity (OR = 3.48, p =.02) or limiting the analysis to older patients (OR = 8.3, p =.0008). CONCLUSIONS: This study provides convergent data in favor of a significant role of the DAT gene in the risk for some severe withdrawal symptoms. If further replicated in larger samples, the DAT genetic polymorphism could be one of the factors to be analyzed to further assess the risk of some severe alcohol-withdrawal symptoms.
Abstract: AIM: To evaluate 5-year survival predictive factors in hospitalised patients with excessive alcohol intake and cirrhosis, including in a multivariate analysis the severity of the liver disease, gastrointestinal bleeding, concomitant viral B or C infection, smoking status, presence of alcoholic hepatitis at inclusion and abstinence from alcohol during follow-up. METHODS: In a non-concurrent cohort study, 122 patients with excessive alcohol intake and cirrhosis were followed up at least five years or till death. Two patients were lost to follow-up. RESULTS: The 5-year survival rates were 43% in the 122 patients and 66%, 50% and 25% in Child-Pugh class A, B and C patients, respectively. In multivariate analysis, age (P = 0.01), Child-Pugh score (P = 0.0001), gastrointestinal bleeding (P = 0.01), presence of HBs Ag and/or anti-HCV (P = 0.03), smoking (P = 0.01), absence of histologically proven alcoholic hepatitis (P = 0.05) and persistent alcohol intake (P = 0.002) were associated with significantly increased risk ratios of death. CONCLUSIONS: In hospitalised patients with excessive alcohol intake and cirrhosis: (1) age, liver failure, gastrointestinal bleeding, concomitant viral B or C infection and persistent alcohol intake are independent poor prognostic markers, (2) smoking may contribute to the aggravation of cirrhosis, and (3) alcoholic hepatitis, being a potentially reversible cause of liver failure, has a favourable prognostic significance.
Abstract: Network practise is important in the care of addictive pathologies. It aims to fulfill patient needs on a social and health level, as part of a concertive approach from the different health workers. Co-ordinated practise seems to provide an adapted and proven response for more than twenty years now, but has only recently been recognised as such by the health authorities. It was originally initiated by militant care workers in response to a daily reality too complex to be managed alone. The bringing together of experience and competencies, an adapted response to the demands in a context of dependency, patient care facilitated by exchanges, complementarily and the sharing of competencies are the objectives of a rich and beneficial network. However, it seems necessary to supplement with financial, human and legal help in order maintain the continuity and improve this novel approach.
Abstract: Because pharmacological and genetic data supported the idea that serotonin receptors of the 5-HT(1B) type can play a modulatory role in alcohol consumption in both human and rodents, the 5-HT(1B) receptor gene is considered as a candidate gene for alcohol dependence. However, contradictory results have been reported as a positive association between alcohol dependence, and either the 861C or the 861G allele of the G861C polymorphism of the 5-HT(1B) receptor gene can be found in the literature. Further investigations in a population of 136 male alcoholics compared with 72 male control subjects demonstrated that none of these alleles was actually associated with alcohol dependence. In addition, in contrast with previous results of the literature, ethanol intake under free choice conditions (i.e., ethanol solution vs. water) was found to be similar in 5-HT(1B)-/- knock mice and paired wild-type controls. The 5-HT(1B) receptor gene may thus not be a key component in the genetic background underlying alcohol dependence in human and alcohol preference in rodents, although these results should be considered as preliminary according to the small size of our sample.
Abstract: The purpose of this study was to analyze the impact of high-dose buprenorphine substitution therapy in opiate-dependent patients in terms of use of psychoactive substances, associated risks, social integration, and the social cost generated by the use of these substances. This was a longitudinal quantitative survey carried out in 1083 patients who were evaluated at three times: at the beginning of substitution therapy (D0), at 6 months and then at 12 months follow up (M6, M12). Data were collected with an anonymous self-administered questionnaire, completed in the presence of an investigating physician. Results demonstrated that patients treated with high-dose buprenorphine for 6 months, consumed fewer psychoactive drugs (heroin, cocaine, benzodiazepines) and had fewer associated risks. Additionally, several criteria involved in social integration showed improvement; morbidity and mortality decreased after the first 6 months of substitution therapy. These improvements were followed by a reduction in the social cost of drug use generated by the group of patients considered. These initial results require confirmation in the final analysis of the study taking into account the 12-month follow up.
Abstract: Alcohol-dependence is a complex phenotype, with behavioral, psychological, pharmacological, medical and social dimensions. Aggregation studies, adoption and twin researches have demonstrated that the vulnerability to alcohol-dependence is at least in part linked to genetic factors, the genetic vulnerability to alcoholism being mainly not substance-specific. There are numerous candidate genes, but the D3 dopamine receptor is specifically located in the limbic area, and in particular in the nucleus accumbens, which are involved in reward and reinforcement behavior. Furthermore, a previous collaborative study showed that homozygosity for the Ball DRD3 locus was more frequently observed in opiate dependent patients with high sensation seeking scores. In this study, we analyzed the distribution of Ball DRD3 polymorphism in a new sample of 131 French male alcoholic-patients (DSM III-R criteria) and 68 healthy controls matched for sex and origins. Although we replicated the higher sensation seeking score in alcohol-dependent patients with comorbid dependence, we found no significant difference in the DRD3 gene polymorphism between controls and alcoholic patients, regardless of sensation seeking score, addictive or psychiatric comorbidity, alcoholism typology, and clinical specificities of alcoholism. There is good evidence that gene coding for the dopamine receptor D3 does not play a major role in the genetic vulnerability to alcoholism.
Abstract: We analysed the impact of the TaqI A1 allele of the D2 dopamine receptor gene on the risk for alcoholism, trying to depict three explanations frequently proposed to explain discrepancies in association and linkage studies: that the A1 allele may act as a marker rather than as a vulnerability factor, that stratification biases and unevaluated controls may explain positive results, and that the A1 allele is modifying the phenotype rather than increasing the risk for alcoholism. We thus tested another (dinucleotide STRP) marker within the DRD2 gene, selected a new homogenous sample of 113 alcoholic patients and 49 unaffected controls strictly matched for ethnic origins, and systematically assessed both samples with a semi-structured interview to detect (in both samples) alcohol dependence, but also such related traits as specificities of complications. The frequency of the A1 allele was not significantly different between alcoholics and controls but when comparing different subgroups of alcoholics, the A1 allele was significantly more frequent in alcoholic patients with somatic complications (OR = 3.00, CI[1.37-6.62]), social and professional complications (OR = 2. 72, CI[1.25-5.90]), or with co-morbid dependence (OR = 2.88, 95% IC [1.16-7.15]). The association for co-morbid dependence and somatic complications was also positive when taking into consideration both STRP and TaqIA polymorphisms. The A1 allele does not increase the risk for alcoholism per se in our sample, but may be involved in a related trait which is partially dependent on the diagnosis of alcoholism, through a disequilibrium with another close mutation.
Abstract: Epidemiologic studies in the general population and those based on the clinical assessment of schizophrenic populations have revealed a high degree of overlap between schizophrenia and addictive disorders. The abuse of psychoactive substances (including alcohol) throughout life is so frequent (50%) that the possibility of a specific link inevitably arises. Various hypotheses have been suggested to explain the high co-morbidity between schizophrenia and addiction: 1) The social-environmental hypothesis has been developed but studies have provided poor evidence to validate it. 2) The possible shared biological vulnerability between schizophrenia and addictions led researchers to explore common genetic determinants and study the involvement of the dopaminergic and opioid systems in the aetiology of both schizophrenia and the abuse of and dependence on psychoactive drugs. 3) Finally, the theory of self-medication suggests that schizophrenics may be attempting to counter the deficit linked to their disorders by using the substances they take or their dependency-type behaviour to cope with their emotional problems. The clinical profile of schizophrenic addicts does seem to display some distinctive features, such as the high level of depressive co-morbidity, very high nicotine and alcohol dependence, with a very poor prognosis. These patients are difficult to manage; the possibility of pharmacologic interactions between the substances they are taking and neuroleptic medication calls for prudence, and their compliance is also poor. Addictive disorders in schizophrenics are currently a topic of active research intended to lead to identifying specific treatments. The early identification of addictive disorders in schizophrenics should make it possible to limit their development and improve the prognosis.
Abstract: The alcoholic withdrawal syndrome (AWS) arises variably within hours following the hospitalization of an alcohol dependent patient. Delay usually observed between admission and the first symptoms depends above all on alcohol serum level concentration at arrival and on the degree of severity of physical dependence. The case reported here describes the very late onset severe alcoholic withdrawal syndrome observed in a 57-year-old alcohol dependent patient hospitalized for leg trauma and operated within hours followed admission. The first symptoms of AWS appeared only the 4-th day after hospitalization and the patient quickly developed a clinical state of delirium tremens. Delay in the onset of this AWS is discussed.
Abstract: BACKGROUND: Dysfunction of serotoninergic transmission could predispose to excessive alcohol consumption and dependence. The functional polymorphism of the serotonin transporter gene (5-HTTLPR) has been associated with different disorders, including alcoholism. Considering the likelihood of heterogeneity in the "alcohol dependence" phenotype, 5-HTTLPR may be more specifically implicated in subsamples of patients or in related traits of alcoholism, such as impulsivity. METHODS: We analyzed the role of this functional polymorphism in the risk for suicide attempt in a population of male alcohol-dependent subjects. One hundred ten male alcohol-dependent patients (DSM-III-R criteria), French for at least two generations, were personally interviewed with the Diagnostic Interview for Genetic Studies and compared with 61 unaffected blood donors. RESULTS: The "short" (S) allele of the 5-HTTLPR appeared to be unrelated to alcohol dependence and comorbid depression in our sample, but was found associated with an increased risk for suicide attempts. This association was predominantly observed in severe and repetitive suicide attempts, with a significant dose effect of the S allele (0, 1, or 2) on the number and the severity of suicide attempts. CONCLUSIONS: Mood disorders and alcohol dependence may interact with a genetic (relative) deficiency in serotonin reuptake, thereby increasing the risk for aggressive/impulsive behaviors such as suicide attempts.
Abstract: Contrary to widely held belief, physical dependency is not systematic in alcohol dependence. Alcohol withdrawal syndrome can appear even without stopping (or sharply decreasing) high or chronic alcohol intake. It occurs through revelation of a physicochemical cerebral response (membrane changes and decrease in modulation systems) to chronic intoxication. Given the differences in severity, the lability of symptoms and the rapid evolution of the syndrome, the repeated use of scales to evaluate intensity is suggested. Management should be based on this index in order to treat minor forms and to avoid a course to severe forms, which should be transferred to the intensive care unit.
Abstract: The present study investigated the onset of maternal nest building in pregnant Fischer rats following chronic repeated cocaine administration. Pregnant Fischer rats were injected with saline or cocaine, 15 mg/kg, three times daily at 1-h intervals for 10 days starting on gestation day 8. Cocaine-exposed females incorporated less material into their nests and built fewer fully completed circular nests than control animals. The overall quality of the nest in cocaine exposed dams was significantly lower than that of control animals. Furthermore, cocaine exposed dams gained less weight than control females. However, no difference in number of pups, weight, or length of pups was observed between groups. Thus, it seems that cocaine disrupts the interest and skill in nest building of pregnant rats.
Abstract: The aim of this review is to evaluate the extent to which Quality of Life (QoL) assessment has been incorporated into clinical oncological trials in the last 15 years. All phase II and III trials published in the Journal of Clinical Oncology, Cancer, The British Journal of Cancer and the European Journal of Cancer during the years 1980, 1985, 1990 and 1995 were reviewed (n = 827). During this period, while the number of studies assessing performance status (PS) increased from 15% in 1980 to 56% in 1995, the number of trials noting a QoL assessment increased only slightly, from 0% in 1980 to 3% in 1995. Moreover, only four of the 13 studies with a QoL evaluation met our criteria for adequate QoL assessment. Thus, despite an increasing interest in QoL, it is still rarely included as an objective in clinical trials, or adequately assessed.
Abstract: Many patients received in emergency units (EU) of hospitals present alcohol-related problems. Most are alcohol dependent or abusers and enter for drunkenness, stay a few hours and return home. To assess the effectiveness of a letter referring these patients to an outpatient alcoholism treatment clinic, we performed a randomized study. For 6 months, all the patients who had been diagnosed as alcoholic, who had an address and who had not consulted a physician for alcoholism in the 6 previous months were selected from the records of the EU of a French university hospital. At least 2 days after their stay in the EU, we sent a letter to 181 patients of an experimental group (group E) suggesting they make an appointment with a physician specializing in alcoholism. No letter was sent to 181 patients in a control group (group C). Six months later, 21 patients (11.2%) of group E had called the outpatient alcoholism treatment clinic to make an appointment and came to a consultation. Two of the 181 patients of group C came to the consultation. The effectiveness of this method for referring alcoholics to a clinic had been controlled by another prospective study. We concluded that sending a letter 2 days after the passage of an alcoholic to an EU for drunkenness is a useful method of referral to an outpatient alcoholism treatment clinic.
Abstract: Outpatients followed in an alcoholic clinic and who fulfilled DSM-III-R criteria for alcohol dependence and had used both tobacco (at least one cigarette every day) and alcohol in the preceding week were studied. For each patient, two experimenters assessed: (1) the amount of tobacco and alcohol used; (2) the severity of dependence for each product. Results showed that: (a) The prevalence of smoking in this population of current alcohol dependents was 88%; (b) 91.6% of this sample of smoker alcoholics were dependent on nicotine; (c) the amount of tobacco smoked was correlated to the amount of alcohol consumed and the severity of alcohol dependence; and (d) there was a correlation between the severity of alcohol and nicotine dependencies. The results of this study may help to clarify the difficulty of treating tobacco dependence in alcoholics.
Abstract: Despite a recent decline in per capita alcohol consumption, alcoholism remains a serious public health problem in France. Pharmacotherapy is used to make withdrawal from alcohol easier and to help maintain abstinence. The recent development of effective pharmacologic treatments for alcoholism has increased interest in this approach to therapy. To determine the most appropriate form of pharmacotherapy for treating alcohol dependence, a meta-analysis of randomized controlled studies published between 1960 and 1993 was performed. We found that several pharmacotherapeutic agents had demonstrated safety and efficacy on different periods of follow-up, including acamprosate (long term), naltrexone (intermediate term), fluoxetine and citalopram (short term). Studies of zimeldine, nialamide, L-dopa, viloxazine, and tetrabamate failed to demonstrate efficacy for these agents in the treatment of alcoholism. Results were ambiguous or mixed for lithium, phenytoin, bromocriptine, apomorphine, and buspirone. Continued research is needed to identify the most appropriate patients to receive treatment with specific forms of pharmacotherapy.
