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Alain Malafosse

Publications and source records attributed to Alain Malafosse.

At least 19 recordsLinked to original sources
PubMed2007

The influence of four serotonin-related genes on decision-making in suicide attempters.

Genetic factors have been associated with the vulnerability to suicidal behavior. We previously reported decision-making impairment in suicide attempters and hypothesized that these cognitive alterations may represent an endophenotype of suicidal behavior. In this study, we aimed to investigate the influence of four serotonin-related genes relevant to suicidal behavior on decision-making, in a large population of suicide attempters. The Iowa Gambling Task was used to assess decision-making in 168 patients with a personal history of attempted suicide. Patients were genotyped for four serotonergic polymorphisms: 5HTTLPR, TPH1 A218C, MAOA u-VNTR, and TPH2 rs1118997. Patients carrying the 5HTTLPR-ll and -sl, TPH1-CC and -AC, MAOA-HH (in women) and TPH2-AA genotypes significantly improved their performance during the task, suggesting a genetic modulation of the learning process required for advantageous decision-making. In contrast, genotypes previously associated with a higher risk of suicidal behavior, a greater sensitivity to the environment and a higher propensity to negative feelings are those conferring poorer learning abilities. We hypothesize that the influence of genetic factors on the vulnerability to suicidal behavior may partly be achieved through their modulation of decision-making and particularly its learning component.

Adolescent↗
PubMed2006

Impaired decision-making in suicide attempters may increase the risk of problems in affective relationships.

BACKGROUND: Decision-making has been found to be altered in suicide attempters and may represent a neuropsychological trait of vulnerability to suicidal behaviour. Environmental stressors such as adverse life events and interpersonal problems have been demonstrated to precipitate suicidal acts in vulnerable people. However, the link between vulnerability and stressors is complex and may even be circular. In the present study, we hypothesized that impaired decision-making may be associated with an increased risk of negative life events in suicide attempters. METHODS: Forty-eight patients with a history of attempted suicide were assessed with the Iowa Gambling Task and interviewed regarding life events experienced over the past 12 months. RESULTS: Decision-making performance was negatively correlated with interpersonal difficulties in the affective--namely marital and family--domain (rs=-0.39, p=0.006) but not with interpersonal difficulties in other social contexts, stressful life events or somatic health problems. LIMITATIONS: The relatively small sample size and the use of non-parametric methods may lead to a risk of type II errors. Furthermore, data on life events were retrospectively collected. CONCLUSIONS: Altered decision-making may increase the risk of problematic affective relationships. These results underline the complex and possibly reciprocal link between environmental stress factors and cognitive vulnerability traits. This could be useful for the design of intervention strategies for suicidal behaviour.

Adult↗
PubMed2006

Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3beta in ventral prefrontal cortex of depressed suicide victims.

BACKGROUND: Past studies in the neurobiology of suicide have reported alterations in serotonin and downstream effectors, such as Akt/protein kinase B. In this study, we aimed to examine possible abnormality in the Akt/glycogen synthase kinase-3beta (GSK-3beta) axis of depressed suicide victims' brains. METHODS: Twenty suicide victims and 20 drug-free non-suicide subjects were included for a postmortem study. The ventral prefrontal cortex area (BA'11) was used, and antemortem diagnoses of major depression disorder (MDD) (DSM-IV) were made from Institution's records. The protein levels of GSK-3alpha/beta and Akt-1 were assayed with the Western blot method, and the kinase activity of Akt and GSK-3alpha/beta were determined by phosphorylation of specific substrates. RESULTS: There was no change either in GSK-3alpha/beta and Akt-1 protein levels or in lithium-inhibitable total GSK-3alpha/beta enzyme activity of the ventral prefrontal cortex. The enzyme activity of Akt decreased significantly [analysis of variance (ANOVA): F(3,36)=5.372; p= .003], whereas GSK-3beta activity increased significantly [ANOVA: F(3,36)=8.567; p= .002] in depressed suicide victims and non-suicide subjects but not in non-depressed suicide victims. CONCLUSIONS: This study indicated that the activity rather than the protein levels of Akt and GSK-3beta was altered. The alteration was associated with MDD rather than with suicide per se.

Adult↗
PubMed2006

No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects.

BACKGROUND: It was recently reported that a rare functional variant, R441H, in the human tryptophan hydroxylase-2 gene (hTPH2) could represent an important risk factor for unipolar major depression (UP) since it was originally found in 10% of UP patients (vs. 1.4% in control subjects). METHODS: We explored the occurrence of this variation in patients with affective disorders (n = 646), autism spectrum disorders (n = 224), and obsessive-compulsive disorder (OCD) (n = 201); in healthy volunteers with no psychiatric disorders (n = 246); and in an ethnic panel of control individuals from North Africa, Sub-Saharan Africa, India, China, and Sweden (n = 277). RESULTS: Surprisingly, we did not observe the R441H variant in any of the individuals screened (3188 independent chromosomes). CONCLUSIONS: Our results do not confirm the role of the R441H mutation of the hTPH2 gene in the susceptibility to UP. The absence of the variant from a large cohort of psychiatric patients and control subjects suggests that the findings reported in the original study could be due to a genotyping error or to stratification of the initial population reported. Additional data by other groups should contribute to the clarification of the discrepancy between our results and those previous published.

Adult↗
PubMed2005

Suicidal behavior: relationship between phenotype and serotonergic genotype.

The basis of suicidal behavior (SB) is complex and multifactorial. Numerous risk factors have been identified. Epidemiological genetics studies (family studies, twin studies, adoption studies) suggest that there is a genetic basis to SB and that this genetic basis is specific and independent from the genetic factors implicated in predisposition to psychiatric disorders associated with SB (bipolar disorder, schizophrenia, alcoholism). Recently, new molecular genetics tools have been designed to identify the genetic factors that predispose certain individuals to disorders of complex etiology. Biological psychiatry studies have suggested that the physiopathology of SB involves dysfunctioning of the serotonin system. The first genetic association studies tested candidate genes encoding proteins involved in serotonin metabolism. The results of these studies suggest that the gene coding for the limiting enzyme in the synthesis of serotonin, tryptophan hydroxylase (TPH), and the gene encoding the serotonin transporter are involved in predisposition to SB. Furthermore, it is likely that these genes interact with each other and with environmental factors (early) and that they have different phenotypic consequences. One of the main aims of studies currently underway is to identify the precise phenotypes associated with genes that predispose to SB or intermediate phenotypes (impulsivity, inability to control anger, etc.).

Emotions↗
PubMed2005

Collecting saliva by mail for genetic and cotinine analyses in participants recruited through the Internet.

The authors assessed whether collection by mail of saliva and buccal cells for genetic analysis was feasible in participants recruited through the Internet. In 2003, 14,773 visitors of a smoking cessation website were invited by e-mail to take part in the study. Salivettes (plastic vials containing a cotton roll) were mailed to participants, for collection of saliva and buccal cells. Because of limited resources, the authors stopped recruitment when 392 participants (3% of 14,733) were registered. They received 315 saliva samples back (80% of 392). Salivary cotinine was analyzed in 145 daily smokers. Cotinine concentration could be assessed in 141 samples (97%) (range 0.7-899 ng/ml, median 260 ng/ml). DNA extraction was achieved in all the 285 samples in which it was attempted. Quality of DNA was assessed by optical density measurements and by polymerase chain reaction amplification of a gene coding for the alpha-4 nicotinic receptor, with the detection of a known polymorphism. Successful results were obtained in 235 samples (82% of 285). Thus collecting saliva by mail for cotinine and DNA analysis in participants recruited through the internet produced samples of good quality at a reasonable cost. This approach should be valuable for genetic epidemiology and pharmacogenetic research.

Adult↗
PubMed2005

The monoamine oxidase A gene may influence the means used in suicide attempts.

OBJECTIVE: Compelling evidence suggests that serotonin system dysfunction is associated with certain behavioral disorders, including suicidal behavior and impulsive aggression. A functional polymorphism in the promoter region of the monoamine oxidase A gene (uVNTR) was recently identified and the presence of the 2-3 alleles was found to be associated with a higher level of transcription, central nervous system serotonergic responsivity and impulsive aggression. A dinucleotide repeat in intron 2 of the gene (monoamine oxidase A-CAn) has been described previously, and is in linkage disequilibrium with the variable number of tandom repeats (VNTR). The aim of the study was to investigate, in a large sample, whether the monoamine oxidase A gene was involved in the susceptibility to suicidal behavior. METHODS: We genotyped 738 West European Caucasians, who had made suicide attempts, and 222 controls of the same ethnic origin, with no history of suicidal behavior. The two variants of the monoamine oxidase A gene have been tested. RESULTS: We did not find any association between the two monoamine oxidase A gene variants and suicidal behavior. However, the frequency of the uVNTR 2-3 alleles was significantly higher in men who had attempted suicide by violent means than in men who had used non-violent means. The odds ratio for the uVNTR 2-3 alleles versus the uVNTR 1-4 alleles was 2.17 [95% confidence interval (1.08-4.35)]. Haplotypes did not allow strengthening the effect observed with the uVNTR. CONCLUSION: These results suggest that an excess of high-activity monoamine oxidase A gene promoter alleles may be associated with traits orienting suicidal behavior towards a violent act.

Adult↗
PubMed2005

GABA receptor 1 polymorphism (G1465A) and temporal lobe epilepsy.

PURPOSE: To reevaluate the genetic contribution of the polymorphism G1465A of the gene coding for gamma-aminobutyric acid (GABA)(B) receptor 1 subunit [GABA(B)(1)] in a sample of French patients with temporal lobe epilepsy (TLE) and to perform an exploratory analysis in other phenotypic subgroups. METHODS: The 134 patients were genotyped for the polymorphism G1465A. This sample was divided in two groups. The first one had patients with nonlesional TLE, and the second one, with lesional TLE. Then these two groups were compared with a sample of 145 healthy individuals. RESULTS: The genotype and allele distributions for the polymorphism G1465A showed no difference between patients and controls. CONCLUSIONS: The association between the variant G1465A and the sample of patients could not be replicated, so these results exclude a major effect of this polymorphism in the susceptibility to nonlesional TLE. Larger samples should be tested to determine whether the G1465A in exon 7 of the GABA(B)(1) receptor gene is a susceptibility factor for nonlesional TLE.

Adolescent↗
PubMed2005

Impaired decision making in suicide attempters.

OBJECTIVE: The understanding of suicidal behavior is incomplete. The stress-diathesis model suggests that a deficit in serotonergic projections to the orbitofrontal cortex is involved in susceptibility to suicidal behavior. The orbitofrontal cortex has been implicated in decision making, a cognitive function dealing with complex choices that may be under serotonergic modulation. In this preliminary study, the authors assessed decision making in suicide attempters. METHOD: The authors used the Iowa Gambling Task to investigate patients with a history of violent (N=32) or nonviolent (N=37) suicidal behavior, patients suffering from affective disorders with no history of suicidal behavior (N=25), and healthy comparison subjects (N=82). Patients were assessed when they were not suffering from a current axis I disorder. The authors also assessed the correlation of Iowa Gambling Task performance with psychometric measures of impulsivity, hostility, anger, aggression, and emotional instability. RESULTS: Both groups of suicide attempters scored significantly lower than healthy comparison subjects, and violent suicide attempters performed significantly worse than affective comparison subjects. No significant differences were observed between the groups of suicide attempters or between the two comparison groups. The differences in performance could not be accounted for by age, intellectual ability, educational level, number of suicide attempts, age at first suicide attempt, history of axis I disorder, or medication use. Iowa Gambling Task performances were correlated positively with affective lability and with anger expression but not with impulsivity. CONCLUSIONS: Impaired decision making, possibly due to emotional dysfunction, may be a neuropsychological risk factor for suicidal behavior.

Adult↗
PubMed2005

Monoamine oxidase a and tryptophan hydroxylase gene polymorphisms: are they associated with bipolar disorder?

Most of the candidate gene studies in bipolar disorder have focused on the major neurotransmitter systems that are influenced by drugs used in the treatment of this disorder. The monoamine oxidase A (MAOA) and the tryptophan hydroxylase (TPH1, TPH2) genes are two of the candidates that have been tested in a series of association studies using unrelated or family-based controls. This review summarizes the existing association studies regarding these genes. Most of these studies were based on the unrelated case-control design with samples of 50 to 600 subjects. Regarding MAOA, three meta-analyses with partially overlapping samples supported a modest effect of this gene in bipolar disorder in female Caucasians. However, as several studies could not replicate these findings, more work is necessary to demonstrate unequivocally the involvement of MAOA in bipolar disorder and establish the biological mechanism underlying the genetic association. With respect to TPH1 and TPH2, the majority of studies did not provide evidence for an association between these genes and bipolar disorder. The genes are more likely to be related to suicidal behavior than to bipolar disorder.

Bipolar Disorder↗
PubMed2004

Lack of association between 5HT2A receptor gene haplotype, bipolar disorder and its clinical subtypes in a West European sample.

Bipolar affective disorder (BPAD) is a complex psychiatric disorder with a major genetic contribution. Abnormalities in serotonergic function have been implicated in its aetiology. The 5HT2A receptor (5HT2AR) gene is a strong candidate gene for involvement in BPAD, but previous association studies have reported conflicting results. These data are difficult to interpret because most negative results were obtained with small samples. The aim of this study was to test the association between the 5HT2AR gene and BPAD in a large West European sample. We studied the -1438G/A and the His452Tyr polymorphisms, for haplotype analysis to increase both informativity and the likelihood of detecting an association between BPAD and the 5HT2AR gene. We analysed the genotype, allele and haplotype distributions of two 5HT2AR gene variants in a population of 356 BPAD patients, which we compared with 208 healthy controls. We also carried out exploratory analysis in clinical subgroups of patients defined according to personal history of mood disorders, suicidal behaviour, comorbid psychiatric disorders and family history of affective disorders. We found no difference between BPAD patients and controls for allele, genotype and haplotype distributions. Exploratory analysis in subgroups of BPAD patients showed only a marginal difference in haplotype distribution between controls and BPAD patients with antidepressant-induced mania (P = 0.018). This difference was not significant after correction for multiple testing. Our study suggests that the 5HT2AR gene is unlikely to be involved in genetic susceptibility to BPAD but should be further investigated in a pharmacogenetic study.

Adult↗
PubMed2004

No association between DUP25 and anxiety disorders.

Gratacos et al. [2001: Cell 106:367-379] described an interstitial duplication dup(15)q24q26 (DUP25) in patients with anxiety disorders; this duplication was found in approximately 90% of patients and in 7% of controls. In order to determine if DUP25 is present in additional individuals susceptible to panic attacks, we tested 44 patients with anxiety disorders, using probes 251c23 and 216c14 mapping in the 15q24 and 15q26 region. We have not detected any DUP25. Our results suggest that DUP25 is not common in people with anxiety disorders in the population tested here.

Adolescent↗
PubMed2004

Association between the TPH gene A218C polymorphism and suicidal behavior: a meta-analysis.

Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of suicidal behavior. The tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a major candidate gene and has been extensively studied in association studies of suicidal behavior, providing conflicting results. It is difficult to interpret these conflicting results due to lack of power, ethnic heterogeneity, and variations in the sampling strategies (in particular for controls) and in the polymorphism of the TPH gene studied. Meta-analyses can improve the statistical power for the analysis of the effects of candidate vulnerability factors. The analysis of the sources of heterogeneity that contribute to these conflicting results is an important step in the interpretation of these conflicting association results and in the interpretation of the results of a meta-analysis. We selected all of the published association studies between the TPH gene polymorphism and suicidal behavior. Nine association studies between the A218C TPH polymorphism and suicidal behavior fulfilled the inclusion criteria. A significant association was observed between the A218C polymorphism and suicidal behavior using the fixed effect method (odds ratio (OR) = 1.62; 95% confidence interval (CI) = [1.26; 2.07]) and the random effect method (OR = 1.61; 95% CI = [1.11; 2.35]). The analysis of the sources of heterogeneity showed that two studies (one positive and one negative) significantly deviated from the calculated global effect. The meta-analysis performed after removing those two studies also revealed a significant association between the TPH A218C polymorphism and suicidal behavior. Both analyses suggested that the A allele has a dose-dependent effect on the risk of suicidal behavior.

Alleles↗
PubMed2004

Serotonin transporter gene may be involved in short-term risk of subsequent suicide attempts.

BACKGROUND: In the first year following a suicide attempt, patients are at high risk for reattempt and for completed suicide. We aim to determine the predictive value of two serotonin-related genes, the tryptophan hydroxylase (TPH) and serotonin transporter (5-HTTLPR) genes that have been involved in the susceptibility to suicidal behavior. METHODS: After a one-year follow-up study of 103 patients hospitalized after a suicide attempt, patients have been genotyped for both the A218C TPH and the functional S/L 5-HTTLPR polymorphisms. RESULTS: Patients who reattempted suicide during the follow-up period had significantly higher frequencies of the S allele and the SS genotype. The odds ratio for the SS genotype vs. the LL genotype was 6.5 (95% CI [1.18-35.84]). No difference was observed for TPH gene. Patients carrying the SS genotype were more impulsive. However, multivariate analysis suggested an independent effect of both the SS genotype and impulsivity on the risk of repeated suicide attempts. CONCLUSIONS: These results suggest that the 5-HTTLPR SS genotype is associated with further suicide attempts among patients who have previously attempted suicide.

Adult↗
PubMed2004

A history of major depressive disorder influences intent to die in violent suicide attempters.

BACKGROUND: The inconsistency of the results obtained in biological studies of suicidal behavior may be due to the use of broad categories lacking validity. In previous genetic studies, in which we identified an association between a serotonin-related gene and violent suicide attempts, we suggested that a history of major depressive disorder (MDD) might influence this association. In this study, we aimed to clarify the relationships between the violence of suicide attempts, intent to die, and depression in a large sample of suicide attempters. METHOD: We investigated intent to die, according to history of violent suicide attempts and MDD, in 502 consecutively admitted suicide attempters. We characterized patients in terms of lifetime DSM-IV Axis I diagnoses, suicidal intent (Beck Suicide Intent Scale), and history of violent suicide attempts. RESULTS: Suicidal intent, for both the last suicide attempt before admission and the most lethal suicide attempt, was higher in those with history of MDD (p =.03 and p =.04, respectively) but was not affected by history of violent suicide attempt. In violent suicide attempters, suicidal intent was higher in patients with a history of MDD than in patients with no such history (p =.04 for last suicide attempt and p =.02 for most lethal attempt), whereas MDD had no effect on suicidal intent in nonviolent suicide attempters. CONCLUSION: Violent suicide attempters constitute a heterogeneous group in terms of suicidal intent. Our results suggest that biological and genetic studies should take into account the method used to attempt suicide, intent to die, and history of MDD.

Adult↗
PubMed2004

[Implication of genes of the serotonergic system on vulnerability to suicidal behavior].

There are many risk factors associated with vulnerability to suicidal behaviour, and the results of family studies, twin studies and adoption studies suggest that they include a genetic predisposition. Moreover, this gentic susceptibility may be specific and independent of the genetic susceptibility to psychiatric disorders associated with suicidal behaviour (e.g., bipolar disorders, schizophrenia, alcoholism). Several groups have carried out association studies using a "candidate gene strategy", with the goal of identifying the genes involved in susceptibility to suicidal behavior. There is compelling evidence from research in biological psychiatry that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of suicidal behavior, and the results of association studies suggest that the gene coding for tryptophan hydroxylase, which is the serotonin synthesis enzyme, and the serotonin transporter gene are involved in susceptibility to suicidal behavior. Furthermore, these genes may influence the suicidal phenotype through different gene-gene interactions and gene-early environment interactions. Current studies aim to identify either the precise phenotypes associated with genes for vulnerability to suicidal behaviour or the intermediate phenotypes (e.g., impulsivity, anger dyscontrol) associated with these genes.

Humans↗
PubMed2003

No association between non-violent suicidal behavior and the serotonin transporter promoter polymorphism.

There is compelling evidence that suicidal behavior is associated with the dysfunction of the serotonin system. A functional polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) was recently identified and the presence of the short allele was associated with lower gene expression, lower 5-HT uptake and violent suicidal behavior. Thus, we attempted to determine whether 5-HTTLPR is also involved in the susceptibility to non-violent suicidal behavior. We compared the genotype from 166 West European Caucasians who attempted suicide by a non-violent mean with 139 controls with no history of suicidal behavior from the same ethnic origin. The frequencies of the S allele and the SS genotype in the sample who attempted non-violent suicide were not statistically different to those in the controls. Thus, the genetically altered expression of the 5-HT transporter might be associated with more severe or violent suicidal behavior, but not with non-violent suicidal behavior.

Adult↗