Amine Benyamina

Pharmacological approaches to methamphetamine dependence: a focused review

Methamphetamine dependence is a serious worldwide public health problem with major medical, psychiatric, socioeconomic and legal consequences. Various neuronal mechanisms implicated in methamphetamine dependence have suggested several pharmacological approaches. A literature search from a range of electronic databases (PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov) was conducted for the period from January 1985 to October 2009. There were no restrictions on the identification or inclusion of studies in terms of publication status, language and design type. A variety of medications have failed to show efficacy in clinical trials, including a dopamine partial agonist (aripiprazole), GABAergic agents (gabapentin) and serotonergic agents (SSRI, ondansetron, mirtazapine). Three double-blind placebo-controlled trials using modafinil, bupropion and naltrexone have shown positive results in reducing amphetamine or methamphetamine use. Two studies employing agonist replacement medications, one with d-amphetamine and the other with methylphenidate, have also shown promise. Despite the lack of success in most studies to date, increasing efforts are being made to develop medications for the treatment of methamphetamine dependence and several promising agents are targets of further research.

Understanding impulsivity in severe depression? A psychometrical contribution

BACKGROUNDnDepression, especially severe depression, is strongly associated with suicidality. Impulsivity is one of the main dimensions of suicidality. The objective of this study was to assess the structure of impulsivity in severe depression and its relationships to suicide attempts.nnnMETHODSn127 depressed in-patients were assessed at admission and after 4 weeks of treatment for depression and impulsivity with the Impulsivity Rating Scale (IRS) and the Impulse Control Scale (ICS) or the Baratt Impulsivity Scale (BIS).nnnRESULTSnThree dimensions of impulsivity were evidenced in these severely depressed patients, i.e., behavioral loss of control, nonplanning and cognitive. These three dimensions are state dependent. Recent suicide attempts in severe depression are related to loss of control and cognitive impulsivity but not to nonplanning. IRS ad ICS may assess primarily behavioral impulsivity, i.e., loss of control and nonplanning, whereas BIS may assess primarily cognitive impulsivity.nnnCONCLUSIONSnIn the future, these three dimensions should be correlated to biological and genetic markers of impulsivity [serotonergic (5-HT) system] and prospective studies should assess the predictive value of the three dimensions of impulsivity in the occurrence of suicide attempts in depressed patients.

Off-Label Baclofen Prescribing Practices among French Alcohol Specialists: Results of a National Online Survey

Objective To evaluate, among alcohol specialists belonging to the Société Française d’Alcoologie (SFA), i.e., the French Alcohol Society, the proportion of physicians who prescribed off-label baclofen for alcohol use disorders (AUDs). The secondary objective was to depict the features of individual prescribing and monitoring practices. Methods On-line survey among 484 French alcohol specialists. Physicians were asked whether they prescribed baclofen for AUDs. If they did not, the reasons for this choice were investigated. If they did, the features of the physician’s prescribing practice were explored, including the number of patients treated, the mean and maximum doses, the monitoring precautions and the pharmacovigilance reporting. Participants were also asked about their empirical findings on HDB’s efficacy and safety. Results In total, 302 physicians (response rate of 62.4%) participated in the survey. Data from 296 participants were analysed, representing 59.4% of all active prescribing physicians belonging to the SFA. HDB use was declared by 74.6% of participants (mean dose 109.5±43.6 mg/d; maximum dose 188±93.3 mg/d). However, 79.2% of prescribers had treated less than 30 patients, and 67.8% used HDB as a second-line medication. Although HDB was perceived as more efficacious than approved drugs by 54.3% of prescribers, it was also declared less safe by 62.8%. Nonetheless, 79.7% of prescribers had never filed any pharmacovigilance report. Non-prescribers (25.6%) were primarily deterred by the current lack of scientific data and official regulation. Conclusion A majority of French alcohol specialists reported using HDB, although often on a limited number of their patients. HDB was considered efficacious but also potentially hazardous. Despite this, physicians reported minimal safety data to the health security system. While French health authorities are planning to draft a specific regulatory measure for framing off-label HDB prescribing practices, the sustained education of prescribers on spontaneous pharmacovigilance reporting should be enhanced.

Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism.

A variable (GT)n repeat in the 5′‐regulatory region of N‐methyl‐D‐aspartate GRIN2A subtype has recently been identified and associated with psychiatric disorders. In this study, we examined the association of this polymorphism with alcohol dependence. Subject–control analysis included 206 alcohol‐dependent and 168 control subjects. Average observed repeat numbers and genotype distributions were significantly different (P‐valueu2003=u20030.001) in alcohol‐dependent subjects versus control subjects. Short alleles were significantly less frequent among alcohol‐dependent subjects (odds ratiou2003=u20030.58, P‐valueu2003=u20037u2003×u200310−4). These results could be replicated in an independent sample of 116 alcohol‐dependent subjects. For the first time, a significant association was identified between this polymorphism and alcoholism.

Association between MTHFR 677C-T polymorphism and alcohol dependence according to Lesch and Babor typology.

Prior studies have associated 677C‐T Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with decreased enzymatic activity and modified homocysteine regulation. This study determines and compares MTHFR 677C‐T distribution and examines its consequences on homocysteine metabolism and alcohol dependence in alcoholic patients classified according to the Babor and Lesch typologies. MTHFR TT genotype was more prevalent in AD patients with milder alcohol dependence (Babor type A) and with Lesch type 3, associated with depression. MTHFR TT was also associated with hyperhomocysteinemia. Determining MTHFR 677C‐T genotype, folate and vitamin B12 levels could assist physicians in identifying type 3 patients and improve addictions management.

A damage/benefit evaluation of addictive product use

AIMSnTo obtain damage/benefit assessments of eight commonly used addictive products and one addictive behaviour from French addiction experts and link these to overall evaluations.nnnDESIGN AND SETTINGnCriteria-based evaluation by experts in addiction. Specific statistical modelling to estimate the relative contribution of various criteria to formulating expert general opinion on products.nnnPARTICIPANTSnForty-eight French experts in addiction.nnnMEASUREMENTSnTwelve criteria covering the whole spectrum of damages and benefits to users and to society evaluated using visual analogue scales (VAS). Direct measure of expert overall subjective opinions on products from user and from social perspectives.nnnFINDINGSnDamage scoring identified alcohol (damage score = 48.1), heroin (damage score = 44.9) and cocaine (damage score = 38.5) as the most harmful products to users and to society; gambling was considered the least harmful (score = 22.5), replicating previous results. Damage scoring correlated poorly with legal status or with overall subjective expert opinions of products. Benefit perception scores indicated alcohol as a clear outlier (benefit score = 45.5) followed by tobacco (benefit score = 34.3) and cannabis (benefit score = 31.1). Statistical modelling suggested that experts attributed 10 times more importance to benefit perception than to damages when making their subjective opinion from a user perspective and two times more importance to benefit perception than to damages in formulating their opinion from a social perspective.nnnCONCLUSIONSnThe perceived benefits of addictive products appear to have a major impact on the opinion of those products expressed by a number of French addiction experts.

Why do liver transplant patients so often become obese? The addiction transfer hypothesis

In patients who receive transplantation for alcohol liver disease, obesity and metabolic syndrome are highly prevalent after transplantation and both contribute to a significant proportion of cardiovascular complications, late morbidity and mortality in this population. Although immunosuppressive medications have been hypothesised to explain some of these post-liver transplantation (LT) metabolic complications, they cannot be considered the sole cause of obesity and metabolic syndrome, and the high prevalence of these illnesses remains unexplained. Given the significant overlap between the neurobiological, psychiatric and psychological factors that underlie alcohol addiction and reward-related behavioural dyscontrol disorders such as food addiction (FA), we hypothesised that the high prevalence of obesity and metabolic syndrome reported in patients who receive transplantation for alcohol liver disease could be explained at least partially by a switch in some individuals from a previous alcohol addiction to post-transplantation FA (i.e., addiction transfer = addiction switch). In our integrative model, we also speculate that an increased prevalence of FA or alcohol addiction may occur in patients with both specific psychobiological profiles and shared risk factors. We further hypothesise that in the subpopulation of patients who develop either alcohol addiction or FA after LT, those with high insight with regard to the consequences of alcohol use could be at higher risk for FA, whereas those with low insight could be at higher risk for alcohol addiction. We discuss here evidence for and against this hypothesis and discuss which patients could be more vulnerable to these two addictions after LT. Because it will not be either possible or ethical to test some of our hypotheses in humans, future studies should test these hypotheses using a translational strategy, using both clinical and preclinical approaches. If our hypotheses could account for the significant increase in obesity and metabolic syndrome after LT, this would lead to new avenues for research and preventive as well as therapeutic interventions for alcohol-related LT patients. All patients with previous or current alcohol addiction should be systematically screened for FA and followed up for subsequent risk of obesity and metabolic syndrome. Such strategies might be effective in improving survival, outcomes and quality of life after LT and also in the overall population of patients with alcohol addiction. By determining common risk factors for both alcohol addiction and FA using a translational approach, our model could help to find novel psychopharmacological and psychological strategies that might be effective in both FA and alcohol addiction.

Potential role of cortical 5-HT2A receptors in the anxiolytic action of cyamemazine in benzodiazepine withdrawal

The antipsychotic cyamemazine is a potent serotonin 5-HT(2A) receptor (5-HT(2AR)) antagonist. A positron emission tomography (PET) study in human patients showed that therapeutic doses of cyamemazine produced near saturation of 5-HT(2AR) occupancy in the frontal cortex, whereas dopamine D(2) occupancy remained below the level for motor side effects observed with typical antipsychotics. Recently, numerous studies have revealed the involvement of 5-HT(2AR) in the pathophysiology of anxiety and a double-blind, randomized clinical trial showed similar efficacy of cyamemazine and bromazepam in reducing the anxiety associated with benzodiazepine withdrawal. Therefore, we reviewed the above articles about 5-HT(2AR) and anxiety in order to understand better the anxiolytic mechanisms of cyamemazine in benzodiazepine withdrawal. The 5-HT(2AR) is the most abundant serotonin receptor subtype in the cortex. Non-pharmacological studies with antisense oligodeoxynucleotides and genetically modified mice clearly showed that cortical 5-HT(2AR) signaling positively modulates anxiety-like behavior. With a few exceptions, most other studies reviewed here further support this view. Therefore, the anxiolytic efficacy of cyamemazine in benzodiazepine withdrawal can be due to a 5-HT(2AR) antagonistic activity at the cortical level.

Tracking online poker problem gamblers with player account-based gambling data only

The aim was to develop and validate an instrument to track online problem poker gamblers with player account‐based gambling data (PABGD). We emailed an invitation to all active poker gamblers on the online gambling service provider Winamax. The 14,261 participants completed the Problem Gambling Severity Index (PGSI). PGSI served as a gold standard to track problem gamblers (i.e., PGSIu2009≥u20095). We used a stepwise logistic regression to build a predictive model of problem gambling with PABGD, and validated it. Of the sample 18% was composed of online poker problem gamblers. The risk factors of problem gambling included in the predictive model were being male, compulsive, younger than 28 years, making a total depositu2009>u20090 euros, having a mean loss per gambling sessionu2009>u20091.7 euros, losing a total ofu2009>u200945 euros in the last 30 days, having a total stakeu2009>u2009298 euros, havingu2009>u200960 gambling sessions in the last 30 days, and multi‐tabling. The tracking instrument had a sensitivity of 80%, and a specificity of 50%. The quality of the instrument was good. This study illustrates the feasibility of a method to develop and validate instruments to track online problem gamblers with PABGD only. Copyright

Genetics and psychotic disorders: A fresh look at consanguinity.

Consanguineous unions refer to marriages between related individuals who share a common ancestor. These unions are still commonplace in certain regions of the world such as the southern coast of the Mediterranean, throughout the Middle East and South-East Asia. According to available data, couples of second cousins or closer and their offspring currently represent 10.4% of the worlds population, thus resulting in increased frequencies of autosomal recessive disorders. Furthermore, consanguinity may be implicated in the increased frequency of multifactorial pathologies such as mental disorders. The few existing epidemiological studies in consanguineous and/or geographically isolated populations confirm that there is a significant association between consanguinity and mental disorders and a higher risk of schizophrenia or bipolar disorders among offspring from consanguineous couples. There exists a strong and complex genetic component in the predisposition to psychotic disorders that has been confirmed in numerous studies. However, the genetic basis of these disorders remains poorly understood. GWAS studies (Genome Wide Association Studies) over the past 10 years have identified a few weak associations, thus refuting the common diseases-common variants hypothesis. A model implicating numerous rare variants has been supported by the recent discovery of CNVs (Copy Number Variants) and their statistically significant association with psychiatric disorders such as schizophrenia, bipolar disorders and autism. The study of consanguineous families may contribute to identifying rare variants in homogenous populations who have conserved certain alleles. Major developments in molecular biology techniques would facilitate these studies as well as contributing to identifying major genes. These results emphasize the need for genetic counseling in high-risk communities and the importance of implementing preventive actions and raising awareness concerning the risk of consanguineous unions.