Dirk van West

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.

Differences in hypothalamic-pituitary-adrenal axis functioning among children with ADHD predominantly inattentive and combined types.

Some evidence suggests that the HPA axis may be dysfunctional in children with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to investigate whether a different pattern of HPA axis activity is found between the inattentive (I) and combined (C) subtypes of ADHD, in comparison with healthy control children. A total of 100 prepubertal subjects [52 children with ADHD combined type (ADHD-C), 23 children with ADHD predominantly inattentive type (ADHD-I), and 25 healthy control subjects] were studied. The effects of stress were studied by comparing cortisol responses to a psychosocial stressor, consisting of a public speaking task. Children with ADHD-I showed an elevated cortisol response to the psychosocial stressor, in contrast to children with ADHD-C who showed a blunted cortisol response to the psychosocial stressor. When a distinction was made between responders and non-responders (a subject was classified as a responder when there was an increase in cortisol reactivity), hyperactivity symptoms were clearly related to a lower cortisol reactivity to stress. The results indicate that a low-cortisol responsivity to stress may be a neurobiological marker for children with ADHD-C, but not for those with ADHD-I. Directions for future research and clinical implications are discussed.

Hypothalamic-pituitary-adrenal reactivity in prepubertal children with social phobia

BACKGROUND The aim of this study was to investigate whether a different pattern of HPA axis activity is found between children with social phobia (SP) and healthy control children. METHODS A total of 50 prepubertal subjects (25 children with SP and 25 healthy control subjects) were studied. The effects of stress were studied by comparing cortisol responses to a psychosocial stressor, consisting of a public speaking task. RESULTS Children with SP showed an elevated cortisol response to the psychosocial stressor as compared with healthy controls. Trait but not state anxiety levels are associated with higher HPA axis activity. LIMITATIONS Limited sample size. CONCLUSIONS The results indicate that a higher cortisol responsivity to stress may be a neurobiological marker for prepubertal children with SP. Directions for future research and clinical implications are discussed.

Lower serum activity of prolyl endopeptidase in anorexia and bulimia nervosa.

The aim of this study was to examine whether anorexia and bulimia nervosa are accompanied by lower serum activity of prolyl endopeptidase (PEP;EC 3.4.21.26; post-proline cleaving enzyme), a cytosolic endopeptidase which cleaves peptide bonds on the carboxyl side of proline in proteins of relatively small molecular mass. Substrates of PEP are, amongst others, neuroactive peptides, such as arginine vasopressin, luteinizing hormone-releasing hormone, thyrotropin releasing hormone,alpha-melanocyte secreting hormone, substance P, oxytocin, bradykinin, neurotensin and angiotensin (Ag) I and II. Serum PEP activity was measured in the serum of 18 normal women, 21 anorexia nervosa and 21 bulimia nervosa women by means of a fluoremetric method. The Bulimic Investigatory Test, Edinburgh (BITE), the Eating Disorder Inventory (EDI) and the Hamilton Depression Rating Scale (HDRS) were scored. Serum PEP activity was significantly lower in patients with bulimia nervosa and anorexia nervosa, irrespective of the restricted or binging subtype, than in normal controls. There were significant and inverse correlations between serum PEP activity and the HDRS and BITE. In anorectic patients, but not in normal or bulimic patients, there was a significant correlation between serum PEP and body mass index. In bulimic patients, but not in normal or anorectic patients, there was a significant correlation between serum PEP and duration of illness. It is concluded that lowered serum PEP activity takes part in the pathophysiology of anorexia and bulimia nervosa. It is hypothesized that a combined dysregulation of PEP and neuroactive peptides, which are substrates of PEP, could be an integral component of eating disorders.

Lower Baseline Plasma Cortisol and Prolactin together with Increased Body Temperature and Higher mCPP-Induced Cortisol Responses in Men with Pedophilia

There is some evidence that hormonal and serotonergic alterations may play a role in the pathophysiology of paraphilias. The aims of the present study were to examine: 1) baseline plasma cortisol, plasma prolactin, and body temperature; and 2) cortisol, prolactin, body temperature, as well as behavioral responses to meta-chlorophenylpiperazine (mCPP) and placebo in pedophiles and normal men. Pedophiles showed significantly lower baseline plasma cortisol and prolactin concentrations and a higher body temperature than normal volunteers. The mCPP-induced cortisol responses were significantly greater in pedophiles than in normal volunteers. In normal volunteers, mCPP-induced a hyperthermic response, whereas in pedophiles no such response was observed. mCPP induced different behavioral responses in pedophiles than in normal men. In pedophiles, but not in normal men, mCPP increased the sensations “feeling dizzy, ” “restless,” and “strange” and decreased the sensation “feeling hungry”. The results suggest that there are several serotonergic disturbances in pedophiles. It is hypothesized that the results are compatible with a decreased activity of the serotonergic presynaptic neuron and a 5-HT2 postsynaptic receptor hyperresponsivity.

Pedophilia is accompanied by increased plasma concentrations of catecholamines, in particular epinephrine

Plasma epinephrine and norepinephrine concentrations were measured in pedophiles and normal men both in placebo conditions and after administration of meta-chlorophenylpiperazine (mCPP), a post-synaptic 5-HT2 receptor agonist. The plasma concentrations of catecholamines, in particular epinephrine, were significantly increased in pedophiles. It is concluded that pedophiles may have an increased activity of the sympathoadrenal system.

Associations between common arginine vasopressin 1b receptor and glucocorticoid receptor gene variants and HPA axis responses to psychosocial stress in a child psychiatric population

On the one hand, a suitable response to daily stressors is crucial for adequate functioning in any natural environment. On the other hand, depending on the individuals genetic makeup, prolonged stress that is accompanied by an inappropriate level of responsiveness may lead to physiological and psychiatric disorders. Several psychiatric conditions have been linked with stress and alterations in hypothalamic-pituitary-adrenal (HPA) activity. While stress is a general phenomenon, illness is only seen in a proportion of individuals, suggesting that genetic factors may play a role in the ability to cope with stress. In children, relatively little research has been conducted to determine the impact of genetic factors on the variability in HPA axis functioning. In the present exploratory investigation, 106 prepubertal children were studied to estimate the impact of four glucocorticoid receptor gene (NR3C1) polymorphisms (NR3C1-1 [rs10482605], ER22/23EK [rs6190], N363S [rs6195], N766N [rs6196]) and five arginine vasopressin (AVP) receptor 1b gene (AVPR1b) polymorphisms (AVPR1b_s1 [rs28536160], AVPR1b_s2 [rs28373064], AVPR1b_s3 [rs33976516], AVPR1b_s4 [rs33985287], AVPR1b_s5 [rs33933482]) on cortisol responses after a psychosocial stress test (public speaking task). ER22/23EK carriers had significantly lower cortisol responses to psychosocial stress compared with noncarriers. These findings provide evidence for the relevance of the ER22/23EK polymorphism in childhood HPA axis regulation. However, the small number of ER22/23EK subjects does not allow us to draw definitive conclusions about the genotypic effect.

The genetics of panic disorder: state of the art

Panic disorder (PD) is a highly prevalent, debilitating disorder. The heritability of the disease has been estimated by twin studies to be between 30 and 60%. The vulnerability for PD overlaps with an increased risk of bipolar disorder in some families. Classical genetic methods such as linkage analysis and association studies have not yet identified genetic risk factors beyond doubt. However, two independent studies confirm linkage of a specific syndrome characterized by PD, bladder problems, severe headaches, mitral valve prolapse and thyroid dysfunction to genetic markers on chromosome 13q. Association studies, although showing divergent results, give some support to a causative role for the genes encoding for monoamine oxidase A (MAO-A), cholecystokinin (CCK) and catechol-O-methyltransferase (COMT). Finally, a somatic duplication of a 19-Mb region on chromosome 15 has been associated with PD, but this intriguing finding awaits confirmation.

Arginine vasopressin receptor gene-based single-nucleotide polymorphism analysis in attention deficit hyperactivity disorder.

Department of Molecular Genetics, Applied Molecular Genomics Group, Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, University of Antwerp (UA), University Center of Child and Adolescent Psychiatry Antwerp (UKJA), Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp, Antwerp and University Psychiatric Center, Campus Leuven, University of Leuven, Leuven, Belgium Correspondence to Dr Dirk van West, MD, MSc, University Center of Child and Adolescent Psychiatry (UKJA), ZNA Middelheim, University of Antwerp, Lindendreef 1, Antwerp B-2020, Belgium Tel: + 32 3 280 49 00; fax: + 32 3 280 49 14; e-mail: dirk.vanwest@zna.be

Role of glucocorticoid receptor gene in vulnerability for major depression: commentary on Neigh and Nemeroff

We have read the article by Neigh and Nemeroff with a lot of interest [1xReduced glucocorticoid receptors: consequence or cause of depression?. Neigh, G.N. and Nemeroff, C.B. Trends Endocrinol. Metab. 2006; 17: 124–125Abstract | Full Text | Full Text PDF | PubMed | Scopus (33)See all References[1]. The authors discussed the study by Ridder et al. [2xMice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions. Ridder, S. et al. J. Neurosci. 2005; 25: 6243–6250Crossref | PubMed | Scopus (239)See all References[2] as a starting point to review the current status of the glucocorticoid receptor (GR) hypothesis of major depressive disorder (MDD). In their excellent paper, they argue that GR dysfunction might not be the primary source of the hypothalamic–pituitary–adrenal (HPA) axis dysfunction in MDD. Although we agree that several molecular mechanisms might lead to HPA axis dysfunction, we would like to draw the attention to some recent genetic studies in humans. Concerning the causal involvement of the GR in the pathogenesis of MDD, it is important to mention two studies that have been published very recently [3xGlucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. van West, D. et al. Neuropsychopharmacology. 2006; 31: 620–627Crossref | PubMed | Scopus (107)See all References, 4xPolymorphisms of the glucocorticoid receptor gene and major depression. van Rossum, E.F. et al. Biol. Psychiatry. 2006; 59: 681–688Abstract | Full Text | Full Text PDF | PubMed | Scopus (223)See all References]. Both studies are related to the ground breaking work by van Rossum et al. that was reviewed previously in Trends in Endocrinology and Metabolism [5xGenetic polymorphisms and multifactorial diseases: facts and fallacies revealed by the glucocorticoid receptor gene. van Rossum, E.F. et al. Trends Endocrinol. Metab. 2005; 16: 445–450Abstract | Full Text | Full Text PDF | PubMed | Scopus (37)See all References[5].Our research group examined whether genetic variations in the GR-encoding gene (NR3C1, gene ID 2908) were associated with MDD, using a gene-based association analysis of single nucleotide polymorphisms (SNPs) [3xGlucocorticoid receptor gene-based SNP analysis in patients with recurrent major depression. van West, D. et al. Neuropsychopharmacology. 2006; 31: 620–627Crossref | PubMed | Scopus (107)See all References[3]. In a Belgian sample, we observed a significant association of MDD with a SNP in the promoter region (NR3C1–1, rs10482605). In a Swedish sample, there was a significant association between MDD and SNP R23K (rs6190). The two SNPs were located close to each other in the 5′ region of the gene. Interestingly, SNP R23K was shown to be associated with resistance to glucocorticoids [6xA polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. van Rossum, E.F. et al. Diabetes. 2002; 51: 3128–3134Crossref | PubMedSee all References[6], a major feature in MDD [7xThe corticosteroid receptor hypothesis of depression. Holsboer, F. Neuropsychopharmacology. 2000; 23: 477–501Crossref | PubMed | Scopus (1358)See all References, 8xGlucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Pariante, C.M. and Miller, A.H. Biol. Psychiatry. 2001; 49: 391–404Abstract | Full Text | Full Text PDF | PubMed | Scopus (667)See all References]. The proposed underlying molecular mechanism of the GR resistance caused by the R23K polymorphism is a change in balance between two translocational variants of the GR proteins (GR-A and GR-B). More precisely, R23K leads to a reduced production of the transcriptionally more active GR-B and to an increased production of the less active GR-A [9xIncreased expression of the glucocorticoid receptor-A translational isoform as a result of the ER22/23EK polymorphism. Russcher, H. et al. Mol. Endocrinol. 2005; 19: 1687–1696Crossref | PubMed | Scopus (69)See all References[9].Almost simultaneously, van Rossum et al. [4xPolymorphisms of the glucocorticoid receptor gene and major depression. van Rossum, E.F. et al. Biol. Psychiatry. 2006; 59: 681–688Abstract | Full Text | Full Text PDF | PubMed | Scopus (223)See all References[4] reported a significant association between the R23K SNP and MDD in a German population. In this study, patients who were heterozygote for the R23K SNP responded more quickly to antidepressant treatment. The authors also observed an association of MDD with BclI, a restriction length polymorphism associated with hypersensitivity to glucocorticoids. The latter finding does not match with the GR hypothesis for MDD, although the authors emphasized the tissue-specific effects of BclI. More specifically, they suggested that increased GR activation in the limbic system might also contribute to the development of MDD. Clearly, this issue requires further investigation.Taken together, these two studies on the association between polymorphisms in the GR-encoding gene and MDD provide further evidence for a role of the GR receptor in the vulnerability for MDD. It seems likely that, at least in a proportion of MDD patients, GR dysfunction is the primary source of HPA axis abnormalities.