Lisa Blecha

CNR1 gene polymorphisms in addictive disorders: a systematic review and a meta-analysis

The aim of the present work was to systematically review all association studies of cannabis receptor 1 (CNR1) polymorphisms with dependence syndrome and to perform a meta‐analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the ‘high risk’ versus ‘low risk’ alleles in cases with dependence versus controls. Studies were analyzed by random‐effects meta‐analysis using pooled OR. Eleven full text articles met our eligibility criteria and nine meta‐analyses were performed on three polymorphisms of CNR1: rs1049353, rs806379 and the AAT repeat. Of these, only the AAT polymorphism showed a significant association with illicit substance dependence but only in the Caucasian population samples and using a risk allele definition of ≥u200316 repeats. Our analysis showed a small effect size (ORu2003=u20031.55, Pu2003=u20030.045), with strong heterogeneity (Qu2003=u200319.87, Pu2003<u20030.01 with I2u2003=u200385%). In line with the polygenic model, our meta‐analysis supports a minor implication for CNR1 AAT polymorphism in illicit substance dependence vulnerability. Further studies in well‐phenotyped samples and using more polymorphisms are needed to conclude on the actual influence of cannabinoid receptor polymorphisms.

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.

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.

Meta-analysis and review of dopamine agonists in acute episodes of mood disorder: Efficacy and safety:

The objective of this meta-analysis is to assess the efficacy and safety of partial and complete dopamine agonists in the treatment of acute mood disorder episodes. Randomized, double-blind and placebo-controlled trials of dopamine agonists in the treatment of acute mood disorder episodes were identified in the MEDLINE and PsycINFO databases and included in the meta-analysis. In monotherapy of mania, improved remission rates were found for cariprazine (odds ratio (OR): 2.08, P < 0.01) and for high-dose aripiprazole (OR: 3.00; P = 0.05), but not for low-dose aripiprazole. In bipolar depression, no improvement of remission and response rates was found for aripiprazole in monotherapy, whereas improved response rate (OR: 10.27, P < 0.01) was found for pramipexole only as an add-on to another mood stabilizer. In major depressive disorder, relatively similar improvements of remission rates were found for high-dose (OR: 1.96, p < 0.01) and low-dose aripiprazole (OR: 1.68, P = 0.01), as well as brexpiprazole (OR: 1.52, P = 0.05) as an add-on to antidepressant medication. Our meta-analysis shows that partial dopamine agonists at high doses are effective in treating acute mania. In major depressive disorder, which is resistant to classical antidepressants, low doses of partial dopamine agonists as adjunct therapy may represent a relatively safe and effective alternative.

Neuropsychological Impairment in Detoxified Alcohol-Dependent Subjects with Preserved Psychosocial Functioning

Background Chronic alcoholism and its related cognitive impairments are associated with increased social, relational, and professional deficits which have a variable overall impact on social integration. These impairments are known to have varying severities and have rarely been studied among healthy alcohol-dependent subjects with preserved psychosocial functioning. Thus, the objective of this study is to describe neuropsychological performance in this particular population. Method Twenty-nine socially adjusted alcohol-dependent men, hospitalized for a first or second withdrawal and abstinent for 3u2009weeks minimum, were compared to 29 healthy non-alcoholic controls. All subjects underwent clinical and psychiatric examination, neuropsychological tests of memory (M), working memory (WM), and executive functions (EF). Comparisons were performed using Student’s t-tests or Mann–Whitney U tests. Results No group differences were found on the Self-Reported Social Adjustment Scale (SAS-SR) or in the Mini-Mental State Examination. Compared to controls, patients had greater episodic, spatial, and WM deficits as well as slightly altered executive functions. In contrast, their executive functions (spontaneous flexibility, criteria generation, rule maintenance, and inhibitory control) were relatively preserved. Conclusion Our sample of socially and professionally integrated alcoholic patients shows fewer cognitive deficits than described in previous studies. Our results suggest that early on, alcohol-dependent subjects develop compensatory adaptation processes to preserve social function and adaptation. Minor cognitive impairments should be screened early in the disease to integrate cognitive interventions into the health-care plan to thus eventually prevent further socio-professional marginalization.

ABCB1 C3435T polymorphism is associated with tetrahydrocannabinol blood levels in heavy cannabis users

ABCB1 polymorphisms are known to modify drug pharmacokinetics but have yet to be studied for their role in generating and maintaining cannabis dependence. The objective of this study is to determine if ABCB1 C3435T (rs1045642) polymorphism may modulate Δ9-Tetrahydrocannabinol (THC) blood levels in a sample of heavy cannabis users. The study sample includes 39 Caucasian individuals, recruited in two French addictology centres, with isolated cannabis dependence and heavy use (defined as ≥ 7 joints per week). Each underwent clinical evaluation, cannabis blood metabolite dosage (THC, 11-OH-THC, and THC-COOH) and genotyping of ABCB1 C3435T polymorphism. In this population (males: 74.4%, average age 29.5 +/- 9), average cannabis use was 21 joints per week (median 12; range 7 - 80). T carriers (TT/CT) had significantly lower plasma THC levels (ng/ml) versus non T carriers (8 vs 15.70, significant), controlling for level of weekly use, 11-OH-THC and THC-COOH levels. Our results show that ABCB1 C3435T polymorphism may modulate serum THC levels in chronic heavy cannabis users. The exact mechanisms and roles that this may play in cannabis dependence genesis and evolution remain to be elucidated. These results should be controlled in a replication study using a larger population.