[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.

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.

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.

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.

Association of DISC1 gene with schizophrenia in families from two distinct French and Algerian populations.

OBJECTIVE: The Disrupted-in-Schizophrenia-1 (DISC1) gene is a promising genetic risk factor for major mental illnesses, especially schizophrenia. Several variants encompassing the DISC1 gene have been associated with schizophrenia and specific clinical features. Negative results were nevertheless observed, stratification biases, heterogeneity of the analyzed samples and low statistical power being potentially involved. METHODS: We analyzed four single nucleotide polymorphisms (SNPs), including three non-synonymous SNPs, of DISC1 in two independent samples of trios, from France and Algeria, using family-based association tests to elude statistical limits. RESULTS: In 114 French schizophrenia trios, the C allele of non-synonymous rs6675281/Leu607Phe/C1872T was significantly over-transmitted [odds ratio (OR)=2.3, 95% confidence interval (CI)=1.1-4.4]. This same SNP was also more frequently transmitted in the 100 Algerian schizophrenia trios (OR=2.6, 95% CI=0.9-7.3). In the combined 214 trios, a significant over-transmission of the C allele of rs6675281 to the affected probands was observed (P=0.002), even after correction for multiple testing (P corrected=0.01 OR=2.4 and 95% CI=1.3-4.2). Assessing if a dimension of schizophrenia could be more specifically involved, we found that patients with the C allele had a significantly higher Scale for the Assessment of Negative Symptoms total score (P=0.0002). CONCLUSION: The analysis adds convergent evidence in favor of a significant role of the DISC1 gene as a risk factor for schizophrenia, as present in two different samples, in family trios rather than with a case--control approach, and even when multiple tests are controlled for. We could further potentially attribute this effect to the negative dimension of schizophrenia.

A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes.

BACKGROUND: The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1. METHODS: We investigated eleven single nucleotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case-control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1. RESULTS: Case-control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rs1800497 (p=0.01, Odds Ratio=1.5, 95% Confidence Interval=1.1-2.2), and the intergenic rs2242592 (p=2.10(-4), OR=1.8, 95%CI=1.3-2.5). A significant SNP-SNP interaction was also found (p<10(-5), OR=2.0, 95%CI=1.6-2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage. CONCLUSIONS: Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKK1 rs1800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia.

The role of brief motivational intervention on self-efficacy and abstinence in a cohort of patients with alcohol dependence.

OBJECTIVES: Brief interventions are effective in reducing heavy drinking in the general population but few studies examined whether it is also effective in alcohol dependent patients, and whether brief intervention increases self-efficacy. METHOD: One hundred and seven patients with alcohol-dependence were randomized in a controlled trial examining the efficacy of a brief motivational intervention on both self-efficacy level and days of abstinence. RESULTS: We found that brief motivational interventions had no effect on days of abstinence, nor on self-efficacy, but that high self-efficacy was consistently correlated with a longer period of abstinence, at all assessment-points. CONCLUSION: Self-efficacy appears to be a crucial prognosis factor, and is not influenced by brief motivational interventions. Other types of specific psychotherapy, probably more intensive, may be more efficient in alcohol-dependent patients than motivational interventions.

[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 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.

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.

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.

Study of compulsive buying in patients presenting obsessive-compulsive disorder.

OBJECTIVE: The authors assessed the prevalence of compulsive buying (CB) among patients presenting an obsessive-compulsive disorder (OCD). They compared the buying style of patients with and without CB. METHOD: One thousand five hundred consecutive patients were assessed by a general practitioner in Paris (France). Sixty patients presenting with OCD were included. Patients with CB associated with OCD (n = 14) were compared with those with "pure" OCD (n = 46). Sixty patients paired for sex and age and free from OCD, depression, and anxiety were also recruited among the clients of the same general practitioner. We compared 3 groups: controls, patients with OCD, and patients with OCD + CB. RESULTS: Prevalence of CB was 23% (14 cases) among patients with OCD and 6% (4 cases) in controls (chi(2)(1) = 5.3, P = .02). Patients presenting with OCD + CB had a higher number of Diagnostic and Statistical Manual of Mental Disorders, Revised Fourth Edition diagnostic criteria for OCD than patients with pure OCD (6.1 and 5.4, respectively, P = .001). Depression was more frequent in the OCD + CB group (78%) than in the OCD group (42%) and in controls (10%) (P = .02). Patients from the OCD + CB group had higher score at the CAGE questionnaire than those of the OCD group (2 vs 0.7, P = .003). Patients with OCD + CB considered 42% of their purchases as occasions not to be passed up compared with 15.4% in the OCD group and 8.6% in controls. OCD+CD patients used the items they bought after a longer delay than controls and patients with pure OCD (8.2 vs 3 and 3.1 days, respectively). CONCLUSION: Compulsive buying is more frequent in OCD than in controls. Patients presenting with OCD + CB show more depressive disorders and drink more alcohol. They are more highly implicated in the items they buy and they are more often disappointed by the items once they possess them.

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.

Family-based association study of the 5-HT transporter gene and schizophrenia.

The gene coding for the 5-HT transporter (5-HTT) is considered as a candidate gene for schizophrenia, because this transporter plays a key role in serotonin neurotransmission. Previous genetic studies focusing on this gene yielded conflicting results, presumably because of stratification biases linked to the case-control association study approach, and the potential genetic and phenotypic heterogeneity of schizophrenia. We investigated the 5-HTTLPR and 17-bp VNTR (variable number of tandem repeats) polymorphisms of this gene in 103 trios using the transmission disequilibrium test. No preferential transmission of either allele of the 17-bp VNTR was observed, but an excess of transmission of the L allele of the 5-HTTLPR polymorphism was detected (p = 0.03). As the haplotype analyses did not improve the strength of the association, our data provide convergent evidence for a significant role of the 5-HTTLPR promoter polymorphism of the 5-HTT gene in the vulnerability to schizophrenia.

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.

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.

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.