Frédéric Rouillon

Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: Association with subtype, body-mass index, severity and age of onset.

Anorexia nervosa (AN) affects 0.3% of young girls with a mortality of 6%/decade and is strongly familial with genetic factors. Ghrelin is an upstream regulator of the orexigenic peptides NPY and AgRP and acts as a natural antagonist to leptins effects on NPY/AgRP-expressing neurons, resulting in an increase in feeding and body weight. Obestatin which counteracts ghrelin action on feeding is derived from the same propeptide than ghrelin. BDNF has been involved in body weight regulation and its Val66Met polymorphism associated with AN. We therefore re-investigated the association between AN and the Leu72Met and Gln90Leu polymorphisms of the prepro-ghrelin/obestatin gene, the Ala67Thr polymorphism of AgRP and the Val66Met polymorphism of BDNF taking into account clinical subtypes (restrictive--ANR--and bingeing/purging--ANB--subtypes). Family trios study of these 4 single nucleotide polymorphisms were performed in 114 probands with AN and both their parents recruited in two specialized French centres. A transmission disequilibrium was observed for the Leu72Met SNP of the preproghrelin gene and for the Ala67Thr SNP of the AgRP gene. When stratified by clinical subtype, these two polymorphisms were preferentially transmitted for the trios with a bingeing/purging proband. An excess of transmission of the Gln90Leu72 preproghrelin/obestatin haplotype in patients with AN was observed. These results do not provide evidence for a preferential transmission of the 66Met allele of BDNF but support the hypothesis that ghrelin and AGRP polymorphisms confers susceptibility to AN. Further simultaneous analysis of genetic variants of the biological determinants of energy metabolism and feeding behaviour in very large populations should contribute to the understanding of the high degree of heritability of eating disorders and to the description of pathophysiological patterns leading to life-threatening conditions in a highly redundant system.

Association between the dopamine receptor D4 (DRD4) gene and obsessive-compulsive disorder.

Obsessive‐compulsive disorder (OCD) is a frequent and disabling anxiety disorder. Dopamine (DA) might be involved in its pathophysiology, therefore DA receptors are candidate genes in OCD. A 48‐base pairs (bp) polymorphism located in the third exon of the dopamine receptor type 4 (DRD4) gene has been described. Previous case control studies, however, have reported inconclusive results in OCD. The aim of the study was to study this polymorphism in a family‐based association study of 55 trios. Extended transmission‐disequilibrium test (ETDT) for preferential allele transmission in this group showed an absence of transmission of the allele 2 for the 48 bp repeat polymorphism of the DRD4 gene (P = 0.005). Moreover, in a population‐based association study, we found a significantly lower frequency of the allele 2 in patients suffering from OCD compared to ethnically‐matched controls (P = 0.02). We found no association of DRD4 48 bp polymorphism with OCD in the subgroup of patients with comorbid tics. This study is the first to report on a significant association of variants of the DRD4 gene in OCD, found on both family‐ and population‐based studies. The results suggest that the 2 allele or a nearby genetic variation could have a protective effect against OCD symptoms.

Association Between Dopamine Receptor D1 Gene Dde I polymorphism and Sensation Seeking in Alcohol-Dependent Men

BACKGROUND Among genetic and biopsychological factors involved in alcohol-dependence vulnerability, dopamine receptor subtypes genes and temperaments dimensions, such as sensation seeking, have been particularly incriminated. Moreover, it is suggested that higher levels of sensation seeking could be associated with a modification of sensitivity to dopamine in postsynaptic receptors. METHODS We investigated whether the DRD1 DdeI polymorphism could be associated with the sensation-seeking level among a sample of 72 alcohol-dependent male and female patients. Analyses of variance were performed to test for an effect between the DRD1 DdeI genotypes and sensation-seeking scores according to the 40-item Zuckerman scale. RESULTS When comparing the DRD1 DdeI genotypes and the Zuckerman scores, we found a significant association only in men (p = 0.01). CONCLUSIONS That is the first report of a male limited association between the DRD1 gene polymorphism and sensation-seeking score in alcohol-dependent subjects.

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.

Serotonin Syndrome: Incidence, Symptoms and Treatment

SummaryIn animals, the occurrence of a behavioural syndrome consisting of hyperactivity, stereotyped movements and increased body temperature can be induced by monoamine oxidase inhibitors (MAOIs), the serotonin (5-hydroxytryptamine; 5-HT) precursor, tryptophan, and serotonin reuptake inhibitors, alone or in combination. Most of these manifestations can be specifically blocked by pretreatment with an inhibitor of serotonin synthesis.The associated symptoms of myoclonus, diarrhoea, confusion, hypomania, agitation, hyperreflexia, shivering, incoordination, fever and diaphoresis can occur in patients treated with serotonergic agents. This constitutes the ‘serotonin syndrome’. Cases of the serotonin syndrome were reported after treatments with tryptophan, MAOIs, serotonin reuptake inhibitors and tricyclic antidepressants, alone or in combination. In some cases, the serotonin syndrome corresponds to a toxic reaction induced by a combination of serotonergic agents at high dosages. In other cases, a toxic and potentially fatal interaction can occur between MAOIs, tricyclic agents and selective serotonin reuptake inhibitors (SSRIs) given at therapeutic dosages.The serotonin syndrome also provides a heuristic model of the putative mode of action of antidepressants. Serotonin-related symptoms are the physical and objective expression of an antidepressant-induced increase in serotonin neurotransmission.

Continuing clozapine treatment despite neutropenia

RationaleApproximately 1–2% of patients treated with the atypical antipsychotic clozapine develop severe neutropenia and agranulocytosis. The usual recommendation is to discontinue treatment with the drug when the peripheral neutrophil count drops below 1,500/mm3. MethodsWe have reviewed several reports describing procedures that allowed the patients to continue clozapine treatment despite the occurrence of these haematological side effects.ResultsThe therapeutic procedures described (symptomatic treatment of neutropenia by co-administration of lithium or granulopoiesis-stimulating factors, management of the adjunctive medication) seem to be efficient strategies that allow continuation of clozapine treatment despite the occurrence of neutropenia. However, these types of therapy have only been used in a limited number of cases, and the evidence supporting their use remains anecdotal.ConclusionAlthough the procedures adopted in the cases described in this review are uncommon, they potentially provide an alternative to the discontinuation of clozapine treatment in patients with complex symptomatologies for whom treatment with other antipsychotic medication is insufficient.

Treatment response in major depression: Effects of personality dysfunction and prior depression

BACKGROUND The impact of personality dysfunction on the outcome of treatment for depression remains debated. AIMS To examine the relationship between the number of prior depressive episodes, personality dysfunction and treatment response for depression. METHOD In a large sample (n = 8229) of adult out-patients with a major depressive episode (DSM-IV), personality dysfunction was assessed using the Standardised Assessment of Personality - Abbreviated Scale (SAPAS). Potential predictors of treatment response at 6 weeks were examined via structural equation modelling. RESULTS The amount of personality dysfunction and number of prior episodes of depression were both associated with poor response to treatment. Once personality dysfunction was controlled for, the number of prior episodes of depression was not associated with treatment response. CONCLUSIONS Personality dysfunction is associated with impaired short-term response to antidepressant treatment in major depression. The apparent detrimental effect of prior depression on treatment response may be accounted for by pre-existing personality dysfunction.

A first national survey of knowledge, attitudes and behaviours towards schizophrenia, bipolar disorders and autism in France

BackgroundIn order to support evidence-based policies for reduction of stigma, a better understanding of its components: ignorance (knowledge), prejudice (attitude) and discrimination (behaviour) is necessary. This study explores public perceptions and quantifies stigma for three chronic mental disorders: autism, schizophrenia and bipolar disorders in France.MethodsSurvey of 1000 adults selected from an established market research panel. The 21-item questionnaire explored knowledge, attitudes and behaviours toward each disorder.ResultsAlthough 95% respondents recognized the names of each disorder fewer than 70% could report specific characteristics and only 33% considered that publically available information was adequate; most respondents identified the media as their main resource. Labeling of conditions in a negative way was frequent (61%) when referring to mental disorders in general, but fell significantly (18%) when linked to an individual with a disorder. Individuals with schizophrenia are assumed to be dangerous; 65% respondents would engage in social distancing from such an individual, versus 29% for bipolar disorders and 7% for autism (p < 0.001). In contrast to other disorders, discrimination against schizophrenia was only partly attenuated in those with familiarity with mental disorders (through personal or family illness).ConclusionThis first population-based survey in France shows that attitudes towards bipolar disorders and autism are less prejudicial than towards schizophrenia. However, most public attitudes and behaviours towards different disorders appear to be based on assumptions rather than knowledge or evidence suggesting a generic information or anti-stigma programme is unlikely to be effective.

Risk of Death Related to Psychotropic Drug Use in Older People During the European 2003 Heatwave: A Population-Based Case–Control Study

OBJECTIVE The authors investigated the association between death of older people and use of psychotropic drugs before and during the Western European August 2003 heatwave. METHOD A retrospective population-based case-control study was conducted using the French social security insurance national database. Exposure to psychotropic drugs in cases aged 70-100 years who died before (N = 2,093) and during (N = 9,531) the August 2003 heatwave was compared with those of survivors matched for age, gender, and presence of chronic illness, by using conditional logistic regressions. RESULTS The association between death and psychotropic drug use was modified by level of external temperature (Wald chi(2) = 13.1, degree of freedom = 1, p <0.001). Use of any psychotropic drug was associated with a 30% increased risk of death during the heatwave, with a significant dose-response relationship between the number of psychotropic drugs and the risk of death (adjusted odds ratio [aOR] for linear trend 1.25, 95% confidence interval [95% CI]: 1.21-1.29). During the heatwave, therapeutic classes independently associated with an increased risk of death were antidepressants (aOR 1.71, 95% CI: 1.57-1.86) and antipsychotics (aOR 2.09, 95% CI: 1.89-2.35), whereas exposure to anxiolytics/hypnotics use (aOR 0.85, 0.79-0.91) was associated with a decreased risk. Findings remained unchanged after adjustment on cardiotropic, antidementia, or anti-parkinsonian drug use. CONCLUSION Our findings suggest that a causal relationship may exist between psychotropic drug use during a heatwave and increased risk of death in older people. The risk/benefit ratio of antidepressant and antipsychotic drugs should be carefully assessed in older people during a heatwave.

Platelet serotonergic predictors of clinical improvement in obsessive compulsive disorder.

Objective: Serotonin reuptake inhibitors (SRIs) are the most efficient pharmacological treatment of obsessive-compulsive disorders (OCD). Previous studies have suggested that some peripheral serotonergic parameters can be used to predict the clinical outcome of the treatment of OCD patients with SRIs. We tried to identify further peripheral serotonergic parameters that could help predict the clinical outcome of SRI treatment in a sample of patients with OCD. Methods: We compared 19 OCD patients before and after 8 weeks of SRI treatment with 19 sex-matched and age-matched controls. We assessed clinical improvement and whole-blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor binding characteristics and platelet IP3 content. Results: Before treatment, OCD patients had higher platelet IP3 content and fewer 5-HTT binding sites than the controls. Treatment with SRIs further lowered the number of 5-HTT binding sites, normalized platelet IP3 contents, and lowered the number of platelet 5-HT2A binding sites and whole-blood 5-HT concentrations below control values. The patients who improved most following SRI treatment had higher whole-blood 5-HT concentrations before treatment. Conclusion: Our results confirm that whole-blood 5-HT concentration is a predictor for clinical improvement and indicate that abnormal intracellular mechanisms may be involved in OCD patients, in particular, the overstimulation of the phosphoinositide signaling system.