- Email: [email protected]
Hypothalamic-pituitary-adrenal (HPA) axis and suicide risk in mood disorders
Abstracts / Journal of Affective Disorders 107 (2008) S53–S122
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studies. The marker on chromosome 13q the peak nonparametric multipoint LOD score was at the marker D13S779 (LOD = 1.5, p = 0.004). On chromosome Xq, evidence for linkage was observed across a large region spanning two regions previously linked to bipolar disorder; Xq24 to Xq28, with a peak at marker TTTA062 (LOD 2.10, p = 0.0009) in Xq28. Results for these regions exceed the recommended p-value for a replication study of p b 0.01 and thus provide evidence for these two loci as contributing to mood disorders with juvenile onset. Discussion: Our genome scan of juvenile-onset mood disorders points to 2 chromosomal regions previously identified as linked to bipolar disorder supporting continuity for child and adult genetic risks at least for these two loci. Keywords: Mood disorders, Children, Genetics, Linkage
tions were observed for marker Val66Met in two parietal (P3/4 and P7/8) regions in the depressed group only. Conclusions: In general our findings extend our previous work showing significance of the BDNF gene in mood disorders (see Neves-Periera et al, 2002; Strauss et al, 2004; 2005). Using a direct measure of brain activity, EEG, as a phenotype in mood disorder, our results suggest that the functional Val66Met polymorphism affects theta EEG asymmetry in parietal brain regions specifically in individuals with COMD. Keywords: BDNF, Child, Depression, EEG
doi:10.1016/j.jad.2007.12.030
J. Jokinen*, A.-L. Nordström, P. Nordström
doi:10.1016/j.jad.2007.12.031
[O3.7] Hypothalamic-pituitary-adrenal (HPA) axis and suicide risk in mood disorders
Karolinska Institutet, Sweden Karolinska Institutet, Sweden [O3.6] Theta EEG asymmetry and BDNF gene variants in childhood-onset mood disorder J. Kennedya, J. Straussa, N. Foxc, C. Barra, M. Kovacsb, J. Kennedy*,c a
University of Toronto, Canada University of Pittsburgh, USA c University of Maryland, USA b
Childhood-onset mood disorders (COMD) include various serious, disabling psychiatric conditions that are heterogeneous in presentation and etiology. Because intermediate phenotypes may help to identify genetic contributors to COMD, we tested for an association between variants in the brain-derived neurotrophic factor (BDNF) gene and theta EEG asymmetry, both of which have been independently implicated in affective disorders. Methods: Theta EEG asymmetry measures from 24 lead EEG recordings were calculated for a total of 191 individuals with COMD (including unipolar and bipolar mood disorder) and 93 controls, who were also genotyped at seven BDNF SNPs, two intergenic flanking SNPs, and one SNP in the lin-7 homolog C (C. elegans) (LIN7C) gene. Results: Adjusting for sex and ethnicity in linear models of asymmetry scores at ten brain regions, significant genotype and genotype-by-ethnicity interac-
Several studies have implicated the hypothalamicpituitary-adrenal axis (HPA axis) in the pathogenic processes underlying many psychiatric conditions including major depressive disorder (MDD). The association of suicidal behaviour clinically with aggressive impulsive traits and pessimism or hopelessness, and biologically with deficits in serotonergic function related to behavioural inhibition and mood, and abnormalities in stress–response systems such as HPA axis are components of the stress-diathesis model. A recent meta-analysis (1) concluded that non-suppressors in the DST have more than 4.6-fold increased risk of suicide compared with suppressors. DST data from a cohort of 382 mood disorder inpatients with and without suicide attempt was analysed in relation to subsequent death by suicide. Optimal threshold of DST in suicide prediction was analysed using receiver operating characteristics, ROC. DST nonsuppression was a biologic predictor of suicide in mood disorder inpatients with index suicide attempt yielding a risk ratio of 2.8 (2). The optimal threshold for DST nonsuppressor status in suicide prediction was different for males and females (3). For the clinician there is emerging evidence that biological testing can supplement clinical judgement in predicting the risk of suicidal behaviour. Support was lent to reintroduction of the DST as a complementary measurement of biological vulnerability in clinical high-risk groups.
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Abstracts / Journal of Affective Disorders 107 (2008) S53–S122
References Mann J.J., Currier D., Stanley B., Oquendo M.A., Amsel L.V., Ellis S.P., 2006. Can biological tests assist prediction of suicide in mood disorders? International Journal of Neuropsychopharmacology 21, 1–10. Jokinen J., Carlborg A., Mårtensson B., Forslund K., Nordström A.-L., Nordström P., 2007. DST nonsuppression predicts suicide after attempted suicide. Psychiatry Research 150(3), 297–303. Jokinen J., Nordström A.-L., Nordström P., ROC analysis of dexamethasone suppression test threshold in suicide prediction after attempted suicide. Journal of Affective Disorders e-publication July 2007. Keywords: HPA axis, Suicide risk, DST, Mood disorder doi:10.1016/j.jad.2007.12.032
with these diseases. Other examples of genetic disorders, (with video clips from self-advocates) will include Prader Willi, Smith Magenis, and Rubenstein Taybi syndromes, which may explain connectivity in molecular pathways in obsessionality and impulsivity, while Klinefelter's and other X chromosomal disorders will help us dissect aspects of psychosis. A new hypothesis and connectivity for bipolar disorder and schizophrenias will be outlined. Those who are doubly genetically wounded with an intellectual disability and a mental illness, whom society has often forgotten, ignored, rejected and devalued, I believe have given us valuable gifts and will have contributed their lives and suffering to the discovery of molecular disease etiologies for many neuropsychiatric diseases. Keywords: Genetic disorders, Etiopathobiologies, Affective disorders, Intellectual disabilities with behavioral phenotypes doi:10.1016/j.jad.2007.12.033
[O3.8] Shifting paradigms: From bloodletting and asylums to the gifts of the genetically wounded for our understanding of the molecular etiopathobiologies in neuropsychiatric diseases
Poster presentations Poster session one
E.M. Peter-Ross* University of Cape Town, South Africa The historical treatments for psychiatric diseases have altered with increasing knowledge and the introduction of psychopharmacological medications. However, until we have a clearer understanding of the molecular basis of these disabling and devastating disorders, and we formulate some new hypotheses of the etiologies and of the connectivity in the shared aspects of the pathophysiological pathways, further advances will not be forthcoming. The 21st century ushers in the era of the human genome, and it is for this reason that those persons with intellectual disability with a known genetic disorder are able to provide molecular information. Through hearing their stories, recognizing the neurodevelopmental effects that produced their disorders and the resultant behavioural phenotypes, and analyzing the psychiatric disorders that manifest, we are able to postulate aspects of the etiopathobiologies in many neuropsychiatric diseases. My presentation will speculate that the deletion syndromes, such as William Beuren syndrome, and the trisomy syndromes with some genetic overexpression, such as Down's syndrome, will inform us about aspects of mood and anxiety disorders, making us question why sufferers are or not afflicted
[P1.1] The effects of antipsychotic drugs on BDNF promoter activity in SH-SY5Y human neuroblastoma cells — An involvement of PI3K-AKT signaling pathway Y.H. Kima, J.G. Lee*,b, S.W. Parka, H.Y. Choa, J.S. Leea a
Inje University, Republic of Korea Masan Dong Suh Hospital, Republic of Korea
b
Instruction: Recent clinical studies have suggested that treatment with atypical antipsychotic drugs such as olanzapine may prevent progressive alterations of brain structure in patients with schizophrenia. However, the molecular mechanisms underlying these effects remain to be determined. We investigated the neuroprotective effects of antipsychotic drugs and the mechanisms of action of olanzapine in human neuroblastoma SH-SY5Y cells. Method: Luciferase assays were adapted for the evaluation of the effect of antipsychotic drug on the BDNF (Brain-derived neurotrophic factor) promoter activity. To explore the drugs action, western blot was performed to examine the expression of p-GSK3β (glycogen synthase kinase-3β), downstream of PI3K (phosphatidylinositol 3-kinase)–AKT pathway, and a possible
S65
studies. The marker on chromosome 13q the peak nonparametric multipoint LOD score was at the marker D13S779 (LOD = 1.5, p = 0.004). On chromosome Xq, evidence for linkage was observed across a large region spanning two regions previously linked to bipolar disorder; Xq24 to Xq28, with a peak at marker TTTA062 (LOD 2.10, p = 0.0009) in Xq28. Results for these regions exceed the recommended p-value for a replication study of p b 0.01 and thus provide evidence for these two loci as contributing to mood disorders with juvenile onset. Discussion: Our genome scan of juvenile-onset mood disorders points to 2 chromosomal regions previously identified as linked to bipolar disorder supporting continuity for child and adult genetic risks at least for these two loci. Keywords: Mood disorders, Children, Genetics, Linkage
tions were observed for marker Val66Met in two parietal (P3/4 and P7/8) regions in the depressed group only. Conclusions: In general our findings extend our previous work showing significance of the BDNF gene in mood disorders (see Neves-Periera et al, 2002; Strauss et al, 2004; 2005). Using a direct measure of brain activity, EEG, as a phenotype in mood disorder, our results suggest that the functional Val66Met polymorphism affects theta EEG asymmetry in parietal brain regions specifically in individuals with COMD. Keywords: BDNF, Child, Depression, EEG
doi:10.1016/j.jad.2007.12.030
J. Jokinen*, A.-L. Nordström, P. Nordström
doi:10.1016/j.jad.2007.12.031
[O3.7] Hypothalamic-pituitary-adrenal (HPA) axis and suicide risk in mood disorders
Karolinska Institutet, Sweden Karolinska Institutet, Sweden [O3.6] Theta EEG asymmetry and BDNF gene variants in childhood-onset mood disorder J. Kennedya, J. Straussa, N. Foxc, C. Barra, M. Kovacsb, J. Kennedy*,c a
University of Toronto, Canada University of Pittsburgh, USA c University of Maryland, USA b
Childhood-onset mood disorders (COMD) include various serious, disabling psychiatric conditions that are heterogeneous in presentation and etiology. Because intermediate phenotypes may help to identify genetic contributors to COMD, we tested for an association between variants in the brain-derived neurotrophic factor (BDNF) gene and theta EEG asymmetry, both of which have been independently implicated in affective disorders. Methods: Theta EEG asymmetry measures from 24 lead EEG recordings were calculated for a total of 191 individuals with COMD (including unipolar and bipolar mood disorder) and 93 controls, who were also genotyped at seven BDNF SNPs, two intergenic flanking SNPs, and one SNP in the lin-7 homolog C (C. elegans) (LIN7C) gene. Results: Adjusting for sex and ethnicity in linear models of asymmetry scores at ten brain regions, significant genotype and genotype-by-ethnicity interac-
Several studies have implicated the hypothalamicpituitary-adrenal axis (HPA axis) in the pathogenic processes underlying many psychiatric conditions including major depressive disorder (MDD). The association of suicidal behaviour clinically with aggressive impulsive traits and pessimism or hopelessness, and biologically with deficits in serotonergic function related to behavioural inhibition and mood, and abnormalities in stress–response systems such as HPA axis are components of the stress-diathesis model. A recent meta-analysis (1) concluded that non-suppressors in the DST have more than 4.6-fold increased risk of suicide compared with suppressors. DST data from a cohort of 382 mood disorder inpatients with and without suicide attempt was analysed in relation to subsequent death by suicide. Optimal threshold of DST in suicide prediction was analysed using receiver operating characteristics, ROC. DST nonsuppression was a biologic predictor of suicide in mood disorder inpatients with index suicide attempt yielding a risk ratio of 2.8 (2). The optimal threshold for DST nonsuppressor status in suicide prediction was different for males and females (3). For the clinician there is emerging evidence that biological testing can supplement clinical judgement in predicting the risk of suicidal behaviour. Support was lent to reintroduction of the DST as a complementary measurement of biological vulnerability in clinical high-risk groups.
S66
Abstracts / Journal of Affective Disorders 107 (2008) S53–S122
References Mann J.J., Currier D., Stanley B., Oquendo M.A., Amsel L.V., Ellis S.P., 2006. Can biological tests assist prediction of suicide in mood disorders? International Journal of Neuropsychopharmacology 21, 1–10. Jokinen J., Carlborg A., Mårtensson B., Forslund K., Nordström A.-L., Nordström P., 2007. DST nonsuppression predicts suicide after attempted suicide. Psychiatry Research 150(3), 297–303. Jokinen J., Nordström A.-L., Nordström P., ROC analysis of dexamethasone suppression test threshold in suicide prediction after attempted suicide. Journal of Affective Disorders e-publication July 2007. Keywords: HPA axis, Suicide risk, DST, Mood disorder doi:10.1016/j.jad.2007.12.032
with these diseases. Other examples of genetic disorders, (with video clips from self-advocates) will include Prader Willi, Smith Magenis, and Rubenstein Taybi syndromes, which may explain connectivity in molecular pathways in obsessionality and impulsivity, while Klinefelter's and other X chromosomal disorders will help us dissect aspects of psychosis. A new hypothesis and connectivity for bipolar disorder and schizophrenias will be outlined. Those who are doubly genetically wounded with an intellectual disability and a mental illness, whom society has often forgotten, ignored, rejected and devalued, I believe have given us valuable gifts and will have contributed their lives and suffering to the discovery of molecular disease etiologies for many neuropsychiatric diseases. Keywords: Genetic disorders, Etiopathobiologies, Affective disorders, Intellectual disabilities with behavioral phenotypes doi:10.1016/j.jad.2007.12.033
[O3.8] Shifting paradigms: From bloodletting and asylums to the gifts of the genetically wounded for our understanding of the molecular etiopathobiologies in neuropsychiatric diseases
Poster presentations Poster session one
E.M. Peter-Ross* University of Cape Town, South Africa The historical treatments for psychiatric diseases have altered with increasing knowledge and the introduction of psychopharmacological medications. However, until we have a clearer understanding of the molecular basis of these disabling and devastating disorders, and we formulate some new hypotheses of the etiologies and of the connectivity in the shared aspects of the pathophysiological pathways, further advances will not be forthcoming. The 21st century ushers in the era of the human genome, and it is for this reason that those persons with intellectual disability with a known genetic disorder are able to provide molecular information. Through hearing their stories, recognizing the neurodevelopmental effects that produced their disorders and the resultant behavioural phenotypes, and analyzing the psychiatric disorders that manifest, we are able to postulate aspects of the etiopathobiologies in many neuropsychiatric diseases. My presentation will speculate that the deletion syndromes, such as William Beuren syndrome, and the trisomy syndromes with some genetic overexpression, such as Down's syndrome, will inform us about aspects of mood and anxiety disorders, making us question why sufferers are or not afflicted
[P1.1] The effects of antipsychotic drugs on BDNF promoter activity in SH-SY5Y human neuroblastoma cells — An involvement of PI3K-AKT signaling pathway Y.H. Kima, J.G. Lee*,b, S.W. Parka, H.Y. Choa, J.S. Leea a
Inje University, Republic of Korea Masan Dong Suh Hospital, Republic of Korea
b
Instruction: Recent clinical studies have suggested that treatment with atypical antipsychotic drugs such as olanzapine may prevent progressive alterations of brain structure in patients with schizophrenia. However, the molecular mechanisms underlying these effects remain to be determined. We investigated the neuroprotective effects of antipsychotic drugs and the mechanisms of action of olanzapine in human neuroblastoma SH-SY5Y cells. Method: Luciferase assays were adapted for the evaluation of the effect of antipsychotic drug on the BDNF (Brain-derived neurotrophic factor) promoter activity. To explore the drugs action, western blot was performed to examine the expression of p-GSK3β (glycogen synthase kinase-3β), downstream of PI3K (phosphatidylinositol 3-kinase)–AKT pathway, and a possible