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Roy A.,Psychiatry service | Hodgkinson C.A.,U.S. National Institutes of Health | DeLuca V.,Center for Addiction and Mental Health | Goldman D.,U.S. National Institutes of Health | Enoch M.-A.,U.S. National Institutes of Health
Journal of Psychiatric Research | Year: 2012

Childhood trauma is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Both factors increase risk for suicidal behavior. Corticotropin releasing hormone (CRH) regulates the HPA axis and its actions are moderated by a high-affinity binding protein (CRHBP). We hypothesized that CRHBP variation and interaction with childhood trauma might influence suicidal behavior. Moreover, there might be an additive effect with FKPB5, another HPA axis gene previously associated with suicidality in this dataset. African Americans were recruited: 398 treatment seeking patients with substance dependence (90% men; 120 suicide attempters) and 432 non-substance dependent individuals (40% men; 21 suicide attempters). A total of 474 participants (112 suicide attempters) completed the Childhood Trauma Questionnaire (CTQ). Haplotype-tagging SNPs were genotyped across CRHBP and, for completeness, across CRH, CRHR1 and CRHR2. FKBP5 genotypes were available. Three CRHBP SNPs rs6453267, rs7728378 and rs10474485 showed a nominally significant interaction with the continuous CTQ score to predict suicide attempt; rs7728378 remained significant after FDR correction. There was an additive effect with FKBP5: in the group exposed to high trauma, the prevalence of suicide attempt was 0.35-0.30 in carriers of either the FKBP5 rs3800373 major homozygote or the CRHBP rs7728378 major homozygote and 0.58 in carriers of both major homozygotes. Individuals without either major homozygote were resilient to the effects of childhood trauma (suicide attempt prevalence 0.24). Main effects of CRHBP rs6453267 and CRHR1 rs9900679, both unique to African ancestry, were detected. CRHBP variation may predispose, independently and additively, to suicidal behavior in individuals who have experienced childhood trauma. © 2011 . Source


Jin H.,University of California at San Diego | Folsom D.,University of California at San Diego | Sasaki A.,University of Hawaii at Manoa | Mudaliar S.,University of California at San Diego | And 5 more authors.
Schizophrenia Research | Year: 2011

Objective: The Framingham 10-risk of coronary heart disease (CHD) has been a widely studied estimate of cardiovascular risk in the general population. However, few studies have compared the relative risk of developing CHD in antipsychotic-treated patients with different psychiatric disorders, especially in older patients with psychotic symptoms. In this study, we compared the 10-year risk of developing CHD among middle-aged and older patients with psychotic symptoms to that in the general population. Method: We analyzed baseline data from a study examining metabolic and cardiovascular effects of atypical antipsychotics in patients over age 40 with psychotic symptoms. After excluding patients with prior history of CHD and stroke, 179 subjects were included in this study. Among them, 68 had a diagnosis of schizophrenia, 42 mood disorder, 38 dementia, and 31 PTSD. Clinical evaluations included medical and pharmacologic treatment history, physical examination, and clinical labs for metabolic profiles. Using the Framingham 10-year risk of developing CHD based on the Framingham Heart Study (FHS), we calculated the risk CHD risk for each patient, and then compared relative risk in each psychiatric diagnosis to the risks reported in the FHS. Results: The mean age of entire sample was 63 (range 40-94) years, 68% were men. The Framingham 10-year risk of CHD was increased by 79% in schizophrenia, 72% in PTSD, 61% in mood disorder with psychosis, and 11% in dementia relative to the risk in general population from the FHS. Conclusions: In this sample of middle-aged and older patients with psychotic symptoms, we found a significantly increased 10-year risk of CHD relative to the estimated risk from FHS, with the greatest increased risk for patients with schizophrenia and PTSD. Development of optimally tailored prevention and intervention efforts to decrease different risk components in these patients could be an important step to help decrease the risks of CHD and overall mortality in this vulnerable population. © 2010. Source


Enoch M.-A.,U.S. National Institutes of Health | Hodgkinson C.A.,U.S. National Institutes of Health | Gorodetsky E.,U.S. National Institutes of Health | Goldman D.,U.S. National Institutes of Health | Roy A.,Psychiatry service
Journal of Psychiatric Research | Year: 2013

The serotonin transporter, encoded by the SLC6A4 gene, influences the synaptic actions of serotonin and is responsive to stress hormones. We hypothesized that 5-HTTLPR, a functional SLC6A4 promoter polymorphism, and two tightly-linked, putatively functional 3' UTR SNPs (rs3813034, rs1042173) might have independent effects on suicidal behavior in the context of childhood trauma (CT).DNA and Childhood Trauma Questionnaire scores were available for a total of 474 African Americans, including 112 suicide attempters and 362 non-suicide attempters. Genotyping was performed for the triallelic 5-HTTLPR polymorphism, 14 SLC6A4 haplotype-tagging SNPs, and 186 ancestry informative markers.There were independent G × E interactive effects of 5-HTTLPR (p = 0.017) and the rs3813034-rs1042173 diplotype (p = 0.011) on suicidal behavior. In individuals exposed to high CT the risk of suicide attempt was 0.52 in carriers of the low activity 5-HTTLPR variant and 0.32 in medium/high activity variant carriers. Likewise, CT exposed carriers of the major rs3813034-rs1042173 ATAT diplotype had an increased risk of suicidal behavior relative to the ATCG/CGCG diplotype carriers (0.40 vs 0.31). Neither the 5' nor the 3' functional variants had an effect in individuals without CT: suicide attempt risk = 0.12-0.22. In individuals exposed to high CT the prevalence of suicide attempt was 0.56 in carriers of both 5' and 3' risk variants, 0.39 in carriers of one risk variant and 0.25 in individuals without either risk variant.Our findings suggest that the 5' and 3' SLC6A4 functional variants have independent effects on the risk for suicidal behavior in CT exposed individuals. © 2013 . Source


Enoch M.-A.,U.S. National Institutes of Health | Gorodetsky E.,U.S. National Institutes of Health | Hodgkinson C.,U.S. National Institutes of Health | Roy A.,Psychiatry service | Goldman D.,U.S. National Institutes of Health
Molecular Psychiatry | Year: 2011

The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory serotonin (5-HT) transmission that modulates dopamine release in the reward circuitry. The 5-HT transporter regulates synaptic 5-HT availability. Functional polymorphisms in genes encoding the transporter and receptor may therefore influence addiction vulnerability. In this study, 360 treatment-seeking African American male patients with single and comorbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4) and 16 haplotype-tagging single-nucleotide polymorphisms (SNPs) across HTR3B (including the functional rs1176744 Tyr129Ser) and HTR3A, genes encoding 5-HT3 receptors. The HTR3B rs1176744 gain-of-function Ser129 allele predicted alcohol dependence (P=0.002) and low 5-HTTLPR activity predicted cocaine/heroin dependence (P=0.01). Both the HTR3B Ser129 allele (P=0.014, odds ratio (OR)=1.7 (1.1-2.6)) and low 5-HTTLPR activity (P=0.011, OR=2.5 (1.3-4.6)) were more common in men with alcohol+drug dependence compared with controls. Moreover, the HTR3B Ser129 allele and low 5-HTTLPR activity had an additive (but not an interactive) effect on alcohol+drug dependence (OR=6.0 (2.1-16.6)) that accounted for 13% of the variance. One possible explanation of our findings is that increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness may result in enhanced dopamine transmission in the reward pathway, a predictor of increased risk for addiction. Our results may have pharmacogenetic implications for 5-HT3 therapeutic antagonists such as ondansetron. © 2011 Macmillan Publishers Limited All rights reserved. Source


Gil F.,Institute Catala dOncologia | Costa G.,Psychiatry service | Perez F.J.,Clinical Research Unit
Palliative and Supportive Care | Year: 2010

Objective: The purpose of this study was to assess the psychological care needs of cancer patients throughout the healthcare process: after diagnosis, after medical treatment (surgery, chemotherapy, radiotherapy) and during follow-up. Method: A total of 703 ambulatory cancer patients were assessed in this study. The inclusion period was from April 1, 2005 to April 30, 2007. The first psychological scales used were the 14-item Hospital Anxiety and Depression Scales (HADS), which has two sub-scales for anxiety (7 items) and for depression (7 items). All patients with a score ≥14 were assessed through the Structured Clinical Interview for Psychiatric Disorder (SCID-I) of the DSM-IV. All data were compared with sociodemographic and medical characteristics. Results: Of the 703 cancer patients in the study, 349 were men and 354 women, with a mean age of 53 years. The median time between the cancer diagnosis and our clinical interview was 6 months (range, 12 days to 190 months). Overall, the screening tools indicated that one in four patients needed psychological care. The most common psychiatric diagnosis was adjustment disorder (129 cases), whereas 10 patients were diagnosed with major depression. Using a HADS cut-off score of >7 for anxiety and depression, 28% and 17% of patients, respectively, were classified as "possible clinical cases." Risk factors for distress included age <65 years, asthenia, constipation, and a low performance status. However, chemotherapy treatment was found to be a protector against distress in cancer patients. Significance of results: Chemotherapy treatment is interpreted by the patients as a protector against cancer, thereby reducing distress levels. Copyright © Cambridge University Press 2010. Source

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