[What can be expected today of pharmacotherapy in the Alcohol Use Disorders?]. / Quelles attentes peut-on avoir aujourd'hui de la pharmacothérapie des troubles liés à l'usage d'alcool?

During the last past years, numerous drug have been proposed to treat Alcohol Use Disorders. Besides classical drugs as acomprosate or naltrexone, new compounds are developed in this new indication. They are used in substitution therapies (baclofen), either when the aim of the treatment is total abstinence from alcohol or as an aid for craving reduction facilitating a "controlled drinking", or also for the maintaining of abstinence (nalmefene). Those drugs, availaible in diferent countries, are now marketed in France (nalmefene). As yet, baclofen may be prescribed in France by the mean of a Temporary Utilisation Recommandation, according to the settlement of the National Medicament Agency. Despite the emphasis of some spectacular effects of baclofen, highly publicised by the media and some enthousiastic practitioners, the drug dosage/frequency has to be assessed by two ongoing controlled studies. The pharmacotherapy remains, however, only one element in the treatment of alcoholism, a complex biopsychosocial disorder. Various forms of psychotherapy remain necessary, the pharmacotherapy being only one, sometimes useful, additionnal treatment.

Frequency of gambling problems among parents of pathological, versus nonpathological, casino gamblers using slot machines.

Familial and twin studies suggest the implication of a genetic factor in pathological gambling, but mainly assess probands through treatment settings or advertisements. The question raised here is: are parents of casino pathological gamblers using slot machines more affected with pathological gambling than nonpathological gamblers, all interviewed on site at the same casino? Three hundred and fifty-five casino gamblers on slot machines, which included 96 pathological gamblers, 116 problem gamblers, and 143 nonproblem gamblers, were recruited in situ at the largest casino in the Paris suburbs. We evaluated pathological gambling and two addictive disorders (alcohol dependence and tobacco consumption) in the gamblers and their 690 parents (through the proband). Familial aggregation of pathological gambling was confirmed, with a risk of 3.3 for being a pathological gambler when at least one of the parents has problematic gambling. No familial co-aggregation of pathological gambling with alcohol or tobacco dependence was observed. Pathological gambling is found in excess in the parents of pathological casino gamblers, in accordance with previous aggregation studies devoted to other types of gambling, and with studies recruiting gamblers in different settings.

Presence of co-morbid substance use disorder in bipolar patients worsens their social functioning to the level observed in patients with schizophrenia.

Bipolar disorder has been considered to have a better prognosis than schizophrenia at the very beginning of its definition. However, psychosocial functioning may vary not only because of the characteristics of the disorder, but also of co-morbid conditions, especially regarding substance use disorder (SUD). The purpose of this study was to compare the social adjustment level of patients with bipolar disorder with that observed in patients with schizophrenia, taking into account substance use disorder (SUD). Forty subjects with schizophrenia and 40 subjects with bipolar disorder, in the stable phase of the disorder, were matched for age, gender and presence of SUD (DSM-IV criteria). The social adjustment scale was completed with socio-demographic and clinical characteristics of illness. The global adaptation score of bipolar patients with SUD was poorer than bipolar patients without SUD, but was not observed as being significantly different from that of patients with schizophrenia, with or without associated SUD. Suicide attempts, poor compliance, longer hospitalisation, shorter remissions and criminal activity were also more frequently observed in the group of patients with bipolar disorder and SUD. Presence of substance use disorder seems to have a greater weight than the main diagnostic (schizophrenia versus bipolar disorder) to predict worse social adjustment and poorer outcome.

[Depression and addictions: links and therapeutic sequence]. / Dépression et addictions: quels liens et quelle séquence thérapeutique?

Substance use disorders and major depression are currently associated in clinical population where depression criteria have concerned twenty-five to fifty percent of addict people. The co-occurrence is also showed widespread among the general population for all kind of substance, alcohol and illicit drugs. This comorbidity has pejorative influence on prognosis for each disorder, with particular acuteness on suicide. Furthermore, presentation of major depression is often complicated by consumption or withdrawal. Clinical studies and general population surveys help to describe nature of the causal relationship with three main explanations: self-medication of mood disorders, independent co-occurrence, and substance-induced depressive disorders. Guidelines for treatment of depression on addict people are: no antidepressant medication before complete withdrawal, improvement of mood in the first two weeks of abstinence, indication to treat depression if no improvement after fifteen days. Dual diagnosis units offering psychiatric and addiction competencies could be relevant for this particular comorbidity.

The 3' part of the dopamine transporter gene DAT1/SLC6A3 is associated with withdrawal seizures in patients with alcohol dependence.

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.

The CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia.

Neurobiological research suggests a significant role of the endocannabinoid system in schizophrenia vulnerability and also in the quality of response to antipsychotics. Genetics offer an opportunity to disentangle its involvement in the disease vulnerability vs an influence on antipsychotics' effects. The possible role of a tag SNP (the 1359G/A polymorphism) of the gene encoding the cannabinoid receptor type 1 (CNR1) in schizophrenia and/or therapeutic response to atypical antipsychotics was assessed in a cohort of 133 French schizophrenic patients compared to 141 normal control subjects. No difference in 1359G/A polymorphism was observed between patients and control subjects, and no relationships were noted between this polymorphism and any clinical parameter considered as potential intermediate factor. However, the G allele frequency was significantly higher among non-responsive vs responsive patients, with a dose effect of the G allele. In contrast, no association was found for three other genetic polymorphisms of the CNR1 gene. The G allele of the CNR1 gene polymorphisms could be a psychopharmacogenetic rather than a vulnerability factor regarding schizophrenia and its treatment.

Lifetime positive symptoms in patients with schizophrenia and cannabis abuse are partially explained by co-morbid addiction.

Recent prospective findings have shown that cannabis use by young people could be a risk factor for psychotic symptoms in adulthood, but the long-term impact of cannabis abuse on the clinical features of declared schizophrenia remains to be explored. We assessed the independent influence of cannabis abuse on the clinical symptoms of schizophrenia, after controlling for frequently co-occurring addictive disorders. Patients with schizophrenia, and with (N=66), or without (N=139) cannabis abuse, were compared for lifetime positive and negative symptoms, taking into account presence of any other addictive disorders. The incidence of the abuse of drugs other than cannabis was nearly five times greater amongst patients with both schizophrenia and cannabis abuse. When the analyses were limited to subjects with no other abuse, less avolution and fewer apathy symptoms were still detected in patients with schizophrenia and cannabis abuse than in those with no abuse (p=0.0001). In contrast, between-group differences for positive symptoms were abolished when multiple substance abuses were taken into account. The strong association between cannabis abuse and fewer negative symptoms in schizophrenia was thus replicated in this sample, but once co-morbid addictive disorders had been controlled no influence of cannabis abuse on hallucinations was detected. Distinguishing the effects of co-occurring addictive disorder(s) in patients with schizophrenia and cannabis dependence may thus be important when attempting to analyse the impact of cannabis abuse.

Male-specific association between the 5-HTTLPR S allele and suicide attempts in alcohol-dependent subjects.

Changes in serotoninergic neurotransmission have been implicated in the pathogenesis of suicidal behavior and alcohol dependence. Previous studies have demonstrated an association between suicide attempts and the 5-HTTLPR S allele in alcohol-dependent subjects. We investigated the frequency of the S allele of 5-HTTLPR in a sample of 100 French Caucasian alcohol-dependent inpatients (48 men and 52 women) with and without a history of suicide attempts. The frequencies of 5-HTTLPR genotypes did not differ significantly between men and women. A history of at least one suicide attempt was more frequent in women than in men (57.5% versus 31.3%, respectively, p=0.008). Logistic regression analysis showed that the presence of the S allele of 5-HTTLPR was related to a life-time risk of suicide attempts, but only in male subjects (p=0.05). There seems to be an allelic association between the 5-HTTLPR S allele and suicidal behavior in alcohol-dependent subjects, but this relationship is restricted to male subjects.

Negative symptoms of schizophrenia could explain discrepant data on the association between the 5-HT2A receptor gene and response to antipsychotics.

Pharmacogenetic studies assessing the role of 5-HT(2A) receptor gene in antipsychotic efficacy yielded conflicting data. Phenotypical heterogeneity of schizophrenia might explain such discrepancies. For example, negative symptoms are known to reflect severity of illness and to restrain therapeutic response. On this basis, we re-assessed the possible influence of the -1438A/G polymorphism of the 5-HT(2A) receptor gene on the clinical efficacy of atypical antipsychotics with focus on several relevant dimensions. One hundred and sixteen French schizophrenic subjects treated for at least 1 month by atypical antipsychotics were screened for treatment response according to the May and Dencker scale. Gender, age at onset, duration and severity of illness, intensity of negative and positive symptoms at discharge were investigated. The intensity of negative symptoms at discharge was the only variable explaining May and Dencker score (p < 0.001), and was significantly associated with the AA genotype of the -1438A/G polymorphism of the 5-HT(2A) receptor gene (p = 0.03). However, the A allele was not independently associated with refractoriness to atypical antipsychotics. Accordingly, the score reached in the Scale for the Assessment of Negative Symptoms (SANS) appeared as a confounding factor between therapeutic response and the -1438A/G polymorphism of the 5-HT(2A) receptor gene, at least in our sample. This data indicate that negative symptoms are worth being systematically assessed in pharmacogenetic studies aimed at analysing candidate genes in schizophrenia.

The A9 allele of the dopamine transporter gene is associated with delirium tremens and alcohol-withdrawal seizure.

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.

Male limited association of the dopamine receptor D2 gene TaqI a polymorphism and alcohol dependence.

Association studies of the TaqI A allele of the dopamine receptor D2 (DRD2) gene with alcohol dependence have produced conflicting findings. Although a wide series of clinical features have been considered in the different association studies performed, very few studies specifically analyzed the role of gender. We compared the TaqI A polymorphisms of the DRD2 gene in 120 French Caucasian alcohol-dependent inpatients (62 males and 58 females) and 107 healthy ethnically matched controls (66 males and 41 females). We observed that 55% of alcohol-dependent males have at least one A1 allele, a prevalence that is significantly above that observed in the control males (38%). On the contrary, no differences were found in females between the alcohol-dependent inpatients and controls for the A1 allele prevalence. In our sample, this male-specific association was not explained by gender specificities of alcohol dependence, such as age at onset and severity measures (mean numbers of social, somatic, and withdrawal complications). On the other hand, alcohol-dependent women with the A1 allele reported more frequently a major depressive disorder (70% vs. 40%, P = 0.03). We thus replicated the allelic association of the A1 allele of the DRD2 gene with alcohol dependence, but showed a male-limited effect of this "vulnerability allele." Recent evidence for gender difference in dopamine D2-like receptor levels and affinity may explain this discrepancy.

The 3' region of the DRD2 gene is involved in genetic susceptibility to schizophrenia.

The gene coding for the D2 dopamine receptor (DRD2) is considered as one of the most relevant candidate genes in schizophrenia. Previous genetic studies focusing on this gene yielded conflicting results, for example because of differences in methodology (linkage versus association studies) and variability in the loci analyzed (the DRD2 gene having many polymorphic sites). We used a progressive strategy with two different approaches (case-control and transmission disequilibrium test) and investigated six genetic polymorphisms spanning the DRD2 gene in 103 patients with DSM-IV criteria of schizophrenia, their 206 parents and 83 matched healthy control subjects. We found a significant excess of the A2 allele in subject with schizophrenia compared to unaffected controls. An excess of transmission of the A2 allele (and haplotypes containing this marker) from the parents to the affected children was also observed. Interestingly, the TaqI A1/A2 polymorphism, located 9.5 kb downstream from the DRD2 gene, maps in a novel gene, untitled "X-kinase", and leads to a 713Glu-->Lys substitution in exon 8. As the analysis of the other markers within the DRD2 gene does not improve the strength of the association, our data are in favor of a specific role of the 3' chromosomic region of the DRD2 gene in the vulnerability to schizophrenia.

Clinical and etiopathogenic specificities of the French concept of psychose hallucinatoire chronique compared to schizophrenia.

The French concept of psychose hallucinatoire chronique (PHC) is characterized by late-onset psychosis, occurring predominantly in females. Symptoms are rich and frequent hallucinations but almost no dissociative features or negative symptoms. This diagnosis is classified among schizophrenia disorders (paranoid type) according to DSM-IV. PHC may also describe a group of patients with original clinical presentation and etiopathogenic factors. We compared 38 female PHC patients with two groups of female schizophrenia patients, matched for age at interview for the first group (n = 35), and duration of the disorder for the second group (n = 36). PHC subjects were relatively older patients with homogeneous clinical features characterized by predominantly positive symptoms without deterioration and fewer relatives with schizophrenia than schizophrenia patients. This first controlled study underscores clinical, phenomenological, and possibly etiopathogenic factors that characterized the PHC patients, even when the impact of late onset and late age at interview were taken into account. This study provides evidence that PHC may be a possible diagnosis in clinical practice, although it is difficult to reach a conclusion on its relationship with schizophrenia.

The A9 allele of the dopamine transporter gene increases the risk of visual hallucinations during alcohol withdrawal in alcohol-dependent women.

Previous studies have found an association between the A9 allele (nine-copy repeat) of the dopamine transporter (DAT) gene and two complications of alcohol withdrawal, namely delirium tremens (DT) and alcohol withdrawal seizures (AWS). Most of these studies only included male alcohol-dependent patients. Even those that included a small proportion of women did not look at the effect of gender. We compared the frequency of the A9 allele in 64 French Caucasian alcohol-dependent women with a history of alcohol withdrawal complications. Women carrying the A9 allele had more visual hallucinations during withdrawal than those without this allele (P = 0.03). However, women with the A9 allele were not more susceptible to DT or AWS than those without (P = 0.48 and P = 1.00, respectively). Our results suggest that the A9 allele of the DAT gene is involved in vulnerability to alcohol withdrawal complications in women, but that these complications differ from those associated with this polymorphism in alcohol-dependent men.

Reappraisal of the serotonin 5-HT(1B) receptor gene in alcoholism: of mice and men.

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.

Screening for domestic violence among patients admitted to a French emergency service.

OBJECTIVE: The authors assessed the prevalence of domestic violence among patients examined in the emergency service of a general hospital. They compared the socio-demographic status and psychiatric comorbidity of victims of domestic violence and other patients. METHOD: An assessment was made on 126 consecutive patients received by the emergency service of Bichat-Claude Bernard hospital (Paris, France). Assessment of domestic violence was made through the use of a specific questionnaire. RESULTS: The prevalence rate of domestic violence was 18% among patients examined by the emergency service. Thirty-five percent of the cases were physical violence, 22% sexual violence, 17% psychological violence and 26% multiple forms of domestic violence. Domestic violence had been going on for less than 1 month in only one case. In 74% of the cases, violence lasted for more than 1 year. No differences were found in terms of socio-demographic characteristics (age, marital status, rate of unemployment, sex ratio) and psychiatric comorbidity between victims of domestic violence and others. CONCLUSION: Patients seen in an emergency service must be identified as a population at risk for domestic violence (18%). These situations can be identified only by a systematic assessment using a standardized questionnaire.

Study of Internet use by customers of a large French store for computers.

The objective of this work was to study the relation to the Internet of subjects who own a computer and who use it for professional or personal reasons. We interviewed 150 customers of the biggest French store that specializes in computers. Each day, the mean of duration for connecting time was 6.2 h (SD = 4). Customers were connected 3.7 h (SD = 3.3) between 8:00 a.m. and 6:00 p.m., 1.8 h (SD = 1.6) between 6:00 p.m. and 11:00 p.m., and 0.5 hours at night (SD = 1.3). Men were more often connected between 6:00 p.m. and 11:00 p.m. We found a negative correlation between age and duration of connection to internet. Age was negatively correlated to the time of connection between 6:00 p.m. and 11:00 p.m. and between 11:00 a.m. and 8:00 a.m. The number of days of holidays was negatively correlated to total time of connection (p < 0.001) and to connection between 6:00 p.m. and 11:00 p.m. (p = 0.04). No correlation was found between the time spent watching television or speaking on a cellular phone and parameters of Internet use. High consumers of games are connected 3.4 h every evening and 1.2 h each night. They spend, in addition, 30 min each day connected to virtual casinos. The typical high consumer of the Internet is young and interested in games on-line, he takes fewer days of holiday than others, and he sends and receives more e-mails than other computer users.

Memory deficits in late-onset schizophrenia.

Late-onset schizophrenia (LOS) is a controversial diagnosis, mainly characterized by more positive symptoms and less deterioration. LOS could be considered as either an extreme of typical schizophrenia (but for old age patients, and short duration of the disorder), or an independent group of patients with a specific diagnosis, with no clear evidence in favor or against any of these hypotheses. The aim of the present study is to characterize the memory cognitive profile of LOS patients without related organic factors (N=25), compared to early-onset schizophrenic patients (EOS, N=44), matched for the duration of the disorder, and healthy controls (HC, N=23), matched for the age of patients. Lifetime clinical symptoms and functioning were collected using the DIGS and the PANSS, and components of memory capacity were assessed with the Forward and Backward Digit Span Tasks, Rey Complex Figure and Verbal Fluency Tests. LOS patients were performing significantly better than EOS patients on the digit span task, Rey's complex figure at T1 score and phonemic verbal fluency. However, LOS had significantly lower performances than healthy controls on the digit span task and on both verbal fluency tests. This study provides evidence that LOS had intermediate outcome compared to EOS and controls. LOS can therefore be in line with a dimensional clinical approach of schizophrenia, whereby it presents few memory deficits and few disorganization and negative symptoms with mostly positive symptoms and possibly etiopathogenic specificities. Further studies including more specific memory assessment tests and larger samples are needed to confirm the present finding.

The executive control of attention differentiates patients with schizophrenia, their first-degree relatives and healthy controls.

Attentional and executive impairments have been reported in patients with schizophrenia and in their healthy first-degree relatives. However, its nature remains unclear and discrepancies between studies have been observed. These might be due to differences in the clinical severity of the illness or in sociodemographic factors. The objective of the present work was to explore the efficiency of three attention networks: alerting, orienting and executive control (conflict inhibition) defined anatomically, using patients, their relatives and controls, assessing the possibility to use them as endophenotypes. We used three tests, the Attention Network Test (ANT), the Wisconsin Card Sorting Test (WCST) and the Stroop Test, and compared 52 patients with schizophrenia, 55 of their first-degree relatives and 53 unrelated healthy controls, taking into account demographic variables (age, sex and years of education) and clinical symptoms of schizophrenia. Patients had a longer overall mean reaction-time (p<0.001), and took longer to resolve the ANT conflict (ANTc) (p=0.04) than the control group. In the schizophrenia group, the SSPI disorganization score was significantly correlated to the ANTc performance. Additionally, first-degree relatives of patients with schizophrenia also performed significantly worse than controls in attention performance test. Our findings support a specific deficit in executive control of attention in patients with schizophrenia. This deficit was shown to be correlated with the intensity of the disorganization score in patients. Relative presented an intermediate phenotype between patients and controls; the ANT reaction time (but not the ANTc) may thus be considered as possible endophenotype marker for schizophrenia.