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Julien Mendlewicz

Publications and source records attributed to Julien Mendlewicz.

At least 19 recordsLinked to original sources
PubMed2006

Glucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression.

Dysregulation of the hypothalamic-pituitary-adrenal axis, one of the stress-response systems, is one of the key neurobiological features of major depression (MDD). Data supporting the notion that glucocorticoid-mediated feedback inhibition is impaired in MDD come from a multitude of studies demonstrating nonsuppression of cortisol secretion following administration of the synthetic glucocorticoid dexamethasone. We examined whether genetic variations in the glucocorticoid receptor gene (Nuclear Receptor Subfamily 3, Group C, Member 1; NR3C1) could be associated with increased susceptibility for MDD using a whole gene-based association analysis of single nucleotide polymorphisms (SNPs). Four SNPs were identified in NR3C1 and genotyped in two well-diagnosed samples of patients with MDD ascertained in Belgium and northern Sweden, and matched control samples. In total, 314 MDD patients and 354 control individuals were included in the study. In the Belgian sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with an SNP in the promoter region (NR3C1-1); in the Swedish sample, we observed significant allele (p=0.02) and genotype (p=0.02) association with the R23K SNP. The haplotype association studies showed modest evidence for an involvement of the 5' region of the NR3C1 gene in the genetic vulnerability for MDD. This study suggests that polymorphisms in the 5' region of the NR3C1 gene may play a role in the genetic vulnerability for MDD.

Belgium↗
PubMed2006

Acetylsalicylic acid accelerates the antidepressant effect of fluoxetine in the chronic escape deficit model of depression.

Evidence has accumulated suggesting that major depression is associated with dysfunction of inflammatory mediators. Moreover, antidepressants show an anti-inflammatory action possibly related to their clinical efficacy. An improvement in psychiatric symptoms has been recently reported in patients treated with anti-inflammatory drugs for other indications. These data imply that inflammation may be involved in the pathogenesis of depression and that anti-inflammatory drugs may be used as an adjunctive therapy. The aim of the present study was to evaluate the behavioural effect of the co-administration of acetylsalicylic acid (ASA, 45 mg/kg or 22.5 mg/kg) and fluoxetine (FLX, 5 mg/kg) in the chronic escape deficit model of depression. The chronic escape deficit model is based on the modified reactivity of rats to external stimuli induced by exposure to unavoidable stress and allows evaluation of the capacity of a treatment to revert the condition of escape deficit. In this model, FLX alone needs to be administered for at least 3 weeks to revert this condition. Our results show that combined treatment of fluoxetine and ASA completely reverted the condition of escape deficit by as early as 7 days, the effect being already partially present after 4 days. The effect was maintained after 14 and 21 days of treatment. ASA alone was ineffective at any time tested and the effect of fluoxetine was significant only at 21 days. These results, together with clinical data from preliminary results, suggest that ASA might accelerate the onset of action of selective serotonin reuptake inhibitor antidepressants.

Animals↗
PubMed2006

Shortened onset of action of antidepressants in major depression using acetylsalicylic acid augmentation: a pilot open-label study.

Based on our preclinical data showing a potential accelerating effect of acetylsalicylic acid (ASA) in combination with fluoxetine in an animal model of depression, we examined the effect of ASA augmentation therapy on selective reuptake inhibitors (SSRI) in major depressed non-responder patients. Twenty-four non-responder patients having received at least 4 weeks of an adequate SSRI treatment were included in a pilot open-label study. Participants were treated openly during 4 weeks with 160 mg/day ASA in addition to their current antidepressant treatment. The combination SSRI-ASA was associated with a response rate of 52.4%. Remission was achieved in 43% of the total sample and 82% of the responder sample. In the responder group, a significant improvement was observed within week 1 (mean Hamilton Depression Rating Scale-21 items at day 0=29.3+/-4.5, at day 7=14.0+/-4.1; P<0.0001) and remained sustained until day 28. Despite limitations due to the open nature of this study, our preliminary results confirm our preclinical findings and are in favour of an accelerating effect of ASA in combination with SSRIs in the treatment of major depression. Potential physiological and biochemical mechanisms may involve an anti-inflammatory and/or neurotrophic effect.

Adult↗
PubMed2006

Lack of genetic association between the phospholipase A2 gene and bipolar mood disorder in a European multicentre case-control study.

The possible association between phospholipase A2 gene and bipolar mood disorder was examined in 557 bipolar patients and 725 controls (all personally interviewed), recruited from seven countries (Belgium, Bulgaria, Croatia, Germany, Greece, Italy, and UK). The frequencies of the eight alleles that were identified did not differ between patients and control individuals in the whole population, while the power to detect an association based on our sample was relatively high. Some differences were noted among the various ethnic groups, but no significant trends existed, suggesting that population stratification by country may not be responsible for a type II error. On the basis of these results, mutations of the phospholipase A2 gene, at least in the region close to the polymorphism examined between exons 1 and 2, are not involved in the pathogenesis of bipolar mood disorder.

Base Pairing↗
PubMed2006

Neurologic soft signs in borderline personality disorder.

OBJECTIVE: Borderline personality disorder is a disabling and dramatic psychiatric condition. To date, its pathophysiology remains unclear. Scientific evidence seems to have found underlying, nonfocal, central nervous system dysfunction in borderline personality disorder. Neurologic soft signs are anomalies only evidenced by specific motor, sensory, or integrative testing when no other sign of a neurologic lesion is present. Neurologic soft signs have been proposed to be nonfocal in origin and to reflect central nervous system failure. The assessment of neurologic soft signs now appears reliable and stable. Assuming that neurologic soft signs reflect nonfocal central nervous system dysfunction, we hypothesized that patients with borderline personality disorder should have an increased frequency of neurologic soft signs, therefore enhancing the possibility of the existence in borderline personality disorder of a nonlocalized brain dysfunction. METHOD: To test this hypothesis, we compared 29 neurologic soft signs in 20 drug-free patients with DSM-III-R borderline personality disorder and 20 controls, using an examination adapted from the literature on neurologic soft signs. The study was conducted from February 1991 to March 1993. RESULTS: Thirteen neurologic soft signs were significantly more frequent in the borderline group. Patients with borderline personality disorder showed more left side, right side, and total neurologic soft signs than controls (p = .0001). All patients in the borderline group exhibited at least 1 neurologic soft sign, while only 7 controls did (p = .0001). CONCLUSION: Our hypothesis was confirmed. These results add evidence to the possibility of the existence of a nonfocal central nervous system failure in borderline personality disorder.

Adult↗
PubMed2006

Consensus document on European brain research.

Brain disease psychiatric and neurologic disease combined represents a considerable social and economic burden in Europe. Data collected by the World Health Organization (WHO) suggest that brain diseases are responsible for 35% of Europe's total disease burden. An analysis of all health economic studies of brain diseases in Europe, published by the European Brain Council (EBC) in June 2005, estimated the total cost of brain disease in Europe in 2004 to be Euro 386 billion. That burden is set to grow, mainly due to the fact that the European population is ageing. Investment in brain sciences does not match that burden now, let alone in the future. Brain research received only 8% of the life science budget in the European Commission's Fifth Framework Programme, which represents less than 0.01% of the annual cost of brain disorders for that period. Over the last decade, Europe has been losing ground to the USA and Japan in terms of both basic and clinical research. Many of Europe's young researchers are taking up posts in the USA and staying there. Big pharmaceutical companies are fleeing Europe for the USA, taking their drug development programmes with them. Research in the brain sciences now holds the promise of therapies that halt and even reverse neurodegeneration, of better diagnostic tools, neural prostheses for the paralysed and drugs for depression and anxiety that are tailored to the individual, thereby eliminating or reducing side effects. Our growing understanding of the normal brain could lead to better prevention of brain disease and to more effective teaching methods. The need for innovative treatments has never been greater, and Europe boasts clusters of excellent researchers in biotechnology who could collaborate with brain scientists and the pharmaceutical industry to realise this promise. But if Europe is to seize these opportunities and meet the challenge of brain disease, it needs to go forward on the basis of greater collaboration between countries, greater collaboration between industry, academia and patient organisations, and increased investment in the brain sciences. The EBC was formed in 2002 to bring together scientists, clinicians, the pharmaceutical industry, charities and patient organisations from all over Europe to campaign for these goals. It takes a novel, bottom-up approach to research policy, and in developing this consensus document, it aims to promote a greater and more focused effort in this area, to improve public understanding of the brain sciences and above all, to support brain research as a priority under the European Commission's Seventh Framework Programme (FP7, 2007-2013). The research programme outlined here was first conceived by the EBC board. An outline was sent to all member organisations and a number of individual experts for comments. Following that, a table of contents was developed. The 45 research themes were written by groups of experts from across Europe who represent a wide range of disciplines. Each one contains a proposal for future research on a specific brain-related theme which the EBC believes could form the basis of one or more integrated projects or strategic targeted research projects (STREP) funded under FP7. The EBC has deliberately focused on the major diseases and then described the basic research needed to understand and treat or perhaps even cure those diseases. The programme is therefore constructed "from man to molecule" and not the other way round, with equal importance attached to basic and clinical research. The EBC suggests that each of the proposed integrated projects or STREP should be awarded a budget in the order of Euro 10 to 15 million. In addition, brain research should be treated as an important element of many other parts of FP7, such as the European Research Council and research programmes on information technology and the causes of violence. Any research programme that concerns human behaviour should, by definition, take account of brain research. The EBC envisages that the priority for brain research it proposes at the European level will translate into higher priority for brain research at the national level, and this document may also serve as a starting point for the development of national consensus programmes. It seems likely that consensus conferences on brain research in Europe may further develop the themes and ideas discussed here. An EBC task force may also be established to further the consensus process. In general, increasing funding in the brain sciences would bring enormous economic returns by lightening the burden on healthcare systems and increasing the productivity of affected individuals-and might easily pay for itself. The human and social returns of such an investment are inestimable. And the time to act is now.

Biomedical Research↗
PubMed2005

Patient-control association study of substance P-related genes in unipolar and bipolar affective disorders.

In the search of genes potentially implicated in the aetiology of affective disorders (AD), SUBSTANCE P (SP) pathway is receiving increased interest. SP receptor antagonists, such as MK-869 and L-759274, have been shown to have antidepressant effect. Results from preclinical and human studies implicate SP and its pathway in the pathophysiology of mood disorders. We investigated a possible association between 20 single nucleotide polymorphisms (SNPS) among four SP-related genes and unipolar and bipolar ad (UPAD and BPAD) in a first sample of 92 UPAD patients and 92 control individuals and in a replication sample of 92 UPAD patients and 92 control individuals. An additional sample of 113 BPAD patients has also been ascertained. Our results showed a significant association between the angiotensin-converting enzyme gene (ACE1) and UPAD in our first sample, but not in the replication sample. No significant evidence of association was found in other SP-related genes. We did not find any association in the BPAD sample. When pooling first and replication UPAD samples, an association was found between ACE1 and a subgroup of patients remaining depressed after an adequate antidepressant treatment. In conclusion, our findings do not support a major contribution of SP-related genes in UPAD and BPAD, but provides some evidence of an ace influence in treatment response to antidepressants.

Adult↗
PubMed2005

No implication of brain-derived neurotrophic factor (BDNF) gene in unipolar affective disorder: evidence from Belgian first and replication patient-control studies.

Several lines of evidence have suggested an implication of brain-derived neurotrophic factor (BDNF) in unipolar affective disorder (UPAD). In the present study, we investigated the role of BDNF gene in UPAD in two independent samples of 92 patients/92 controls and 156 patients/197 controls. Two single nucleotide polymorphisms (SNPs) were investigated. We found no significant differences of BDNF gene SNPs distribution between UPAD patients and controls in both samples. Haplotype analyses were performed on both samples. A statistical difference was found between cases and controls in the first sample but not in the second. These results are not in favour of an implication of BDNF in UPAD but need to be replicated before final conclusion.

Adult↗
PubMed2004

Is the biological nature of depressive symptoms in borderline patients without concomitant Axis I pathology idiosyncratic? Sleep EEG comparison with recurrent brief, major depression and control subjects.

The relationship between borderline personality disorder (BPD) and the affective disorders is controversial, and we have previously compared BPD and major depression (MD) with endocrinological measures and sleep electroencephalography (S-EEG). We have also compared BPD, MD and recurrent brief depression (RBD) using endocrine tests. We have proposed that depressive symptoms in BPD might have a biological substrate that is distinct from those in depressive illness without comorbid BPD. BPD has been proposed to overlap with RBD, which has been found to share perturbed biological substrates with MD, but we have not found the same biological pattern in BPD. When endocrinological data in BPD, MD and RBD were compared, we did not find evidence of biological linkage between BPD and RBD. To clarify the biological nature of depressive symptoms in BPD, we examined S-EEG characteristics in BPD, RBD, MD and controls. Among 20 BPD patients, 12 were also diagnosed as having clinical RBD. BPD patients showed differences in sleep continuity and especially in sleep architecture compared with RBD, MD and controls. BPD with or without clinical RBD did not show significant differences in any parameter. BPD with or without clinical RBD had less slow sleep activity not only than MD but also than non-borderline RBD patients. We propose that although BPD patients can have concomitant MD, they often exhibit a specific BPD-associated affective syndrome that is different from both MD and non-borderline RBD in the quality and duration of symptoms and the biological substrate.

Adult↗
PubMed2004

Non-replication of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: a Belgian patient-control study.

This patient-control association study was conducted to investigate a possible association of two single nucleotide polymorphisms (SNPs), g.11757C > G and g.196G > A, in the brain-derived neurotrophic factor (BDNF) with bipolar affective disorder (BPAD). Two hundred seventy-five individuals of Belgian origin (at least two generations of Belgian ancestors) were genotyped (112 BPAD and 163 controls). No significant differences were found in the frequency of genotypes and alleles of g.196G > A (P = 0.37 and 0.94, respectively) and g.11757C > G (P = 0.49 and 0.59, respectively) between controls and BPAD patients. An haplotype analysis revealed no difference between patients and controls (P = 0.44). We failed to replicate previous findings implicating BDNF in the aetiology of BPAD. However, BDNF remains an interesting target for future genetic studies and should be tested in prospective pharmacogenetic therapeutic trials.

Adult↗
PubMed2004

Expanded RED products and loci containing CAG/CTG repeats on chromosome 17 (ERDA1) and chromosome 18 (CTG18.1) in trans-generational pairs with bipolar affective disorder.

The purpose of the present study was to further test if expanded CAG repeats detected by the repeat expansion detection (RED) method in bipolar affective disorder (BPAD) are correlated with ERDA1 (17q21.3) and/or CTG18.1 (18q21.1) loci expansions, and changes of phenotype severity in successive generations (anticipation). The sample was designed to analyze ERDA1 and CTG18.1 expansions in trans-generational pairs of affected individuals (parent-offspring pairs: G1 and G2). Clinical and genetic information was available on 95 two-generations pairs. We found in our sample no one patient carrying an expanded allele at the CTG18.1 locus. This observation is true for all individuals in G1 and G2. Using the conditional logistic regression, no statistical difference was observed between the two generations for ERDA1 alleles (chi(2) = 0.2, P = 0.65). These data do not support the correlation between expanded RED products (RED fragments >120) and expanded alleles at ERDA1 in trans-generational pairs with BPAD. We were not able to detect any correlation for CTG18.1. Earlier age at onset in offspring generation was also not associated with expanded RED products explained by expanded ERDA1 alleles.

Adult↗
PubMed2004

Molecular genetics of affective disorders.

Evidence for familial aggregation in Affective Disorders (AD) has been provided in classical studies. Linkage and association genetic studies have been proposed to detect genetic factors implicated in AD. However, findings from molecular genetic studies remain inconclusive. Nevertheless, current research is focusing on the phenotypes, both sub- and endophenotypes. In addition, recent advances in technology, such as microarrays, provide new tools in psychiatric genetics. These different approaches offer a new optimism era in the search of genetic factors in AD.

Biogenic Monoamines↗
PubMed2004

Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study.

The available data from preclinical and pharmacological studies on the role of the serotonin transporter (5-HTT) support the hypothesis that a dysfunction in brain serotonergic system activity contributes to the vulnerability to affective disorders (AD). 5-HTT is the major site of serotonin reuptake into the presynaptic neuron, and it has been shown that the polymorphic repeat polymorphism in the 5-HTT promotor region (5-HTTLPR) may affect gene-transcription activity. 5-HTT maps to chromosome 17 at position 17q11.17-q12, and the 5-HTTLPR polymorphisms have been extensively investigated in AD with conflicting results. The present study tested the genetic contribution of the 5-HTTLPR polymorphism in a large European multicenter case-control sample, including 539 unipolar (UPAD), 572 bipolar patients (BPAD), and 821 controls (C). Our European collaboration has led to efforts to optimize a methodology that attenuates some of the major limitations of the case-control association approach. No association was found with primary psychiatric diagnosis (UPAD and BPAD) and with phenotypic traits (family history of AD, suicidal attempt, and presence of psychotic features). Our negative findings are not attributable to the lack of statistical power, and may contribute to clarify the role of 5-HTTLPR polymorphism in AD.

Bipolar Disorder↗
PubMed2003

Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: Bipolar disorder.

Genome scans of bipolar disorder (BPD) have not produced consistent evidence for linkage. The rank-based genome scan meta-analysis (GSMA) method was applied to 18 BPD genome scan data sets in an effort to identify regions with significant support for linkage in the combined data. The two primary analyses considered available linkage data for "very narrow" (i.e., BP-I and schizoaffective disorder-BP) and "narrow" (i.e., adding BP-II disorder) disease models, with the ranks weighted for sample size. A "broad" model (i.e., adding recurrent major depression) and unweighted analyses were also performed. No region achieved genomewide statistical significance by several simulation-based criteria. The most significant P values (<.01) were observed on chromosomes 9p22.3-21.1 (very narrow), 10q11.21-22.1 (very narrow), and 14q24.1-32.12 (narrow). Nominally significant P values were observed in adjacent bins on chromosomes 9p and 18p-q, across all three disease models on chromosomes 14q and 18p-q, and across two models on chromosome 8q. Relatively few BPD pedigrees have been studied under narrow disease models relative to the schizophrenia GSMA data set, which produced more significant results. There was no overlap of the highest-ranked regions for the two disorders. The present results for the very narrow model are promising but suggest that more and larger data sets are needed. Alternatively, linkage might be detected in certain populations or subsets of pedigrees. The narrow and broad data sets had considerable power, according to simulation studies, but did not produce more highly significant evidence for linkage. We note that meta-analysis can sometimes provide support for linkage but cannot disprove linkage in any candidate region.

Bipolar Disorder↗
PubMed2003

Lack of association between the 5HT2A receptor polymorphism (T102C) and unipolar affective disorder in a multicentric European study.

We report here a case-control association study with T102C polymorphism in the serotonin 2A receptor gene (HTR2A) in patients affected by unipolar affective disorder (UPAD) and in controls. A total of 284 subjects were genotyped (142 UPAD and 142 controls). All subjects were interviewed using standard diagnostic interviews and matched. A homogenous population of unipolar patients with suicidal attempt was identified. Conditional logistic regression was applied. No association of the HTR2A polymorphism was found in the overall sample of 142 UPAD-control pairs regarding allele and genotype frequencies (P=0.36 and P=0.52 respectively) and homo-heterozygote distributions (P=0.91). This study confirms, in a multicentric European sample, the earlier observations that the T102C HTR2A polymorphism is not associated with UPAD. Nevertheless, a type 2 statistical error cannot be excluded. Therefore, to exclude the implication of HTR2A in UPAD, this result must be replicated in larger samples and in other populations using the transmission disequilibrium test and different polymorphisms around HTR2A.

Case-Control Studies↗
PubMed2003

Molecular genetics of affective disorders.

Family studies have provided evidence for familial transmission in suicide in major psychiatric disorders, and in particular affective disorders. Even though they may seem contradictory, linkage studies have suggested several genetic regions implicated in affective disorders. Association studies have mainly focused on genes related to serotonergic and monoaminergic pathways. Other genes involved in GABAergic and substance P pathways have also been studied in association studies. Another way to approach the genetics of affective disorders is the definition of more detailed phenotypes. Suicidal behaviour is one of the more largely studied subphenotypes within affective disorders. Tryptophan hydroxylase and serotonin transporter genes, related to the serotonergic pathway, have been found to be associated to suicidal behaviour, in particular violent suicidal behaviour but need to be replicated before definitive conclusion. Improved methodologies and updated tools in genetic studies will improve in the future our knowledge of affective disorders.

DNA↗