PAC1 receptor (ADCYAP1R1) genotype is associated with PTSD's emotional numbing symptoms in Chinese earthquake survivors

Background

Genetic factors are important in the development of posttraumatic stress disorder (PTSD) following exposure to traumatic events. However, the molecular genetic underpinnings of this disorder remain largely unresolved. The present study investigated the association between ADCYAP1R1 rs2267735 genotype and PTSD symptoms in a highly traumatized sample of Chinese adults.

Methods

Participants included 326 victims who experienced 2008 Wenchuan earthquake and lost their children during the disaster. PTSD symptoms were assessed with the PTSD Checklist (PCL). The ADCYAP1R1 rs2267735 SNP was genotyped with the Sequenom iPlex chemistries and the MassARRAY system.

Results

The results indicated that although the rs2267735 ‘CC’ genotype was not associated with total PTSD symptoms, it could significantly predict severity of PTSD's emotional numbing symptoms in women.

Limitations

A relatively small sample exposed to specific traumatic events was used, and PTSD was assessed using a self-reported instrument.

Conclusions

The findings suggest that the PACAP–PAC1 receptor pathway may play an important role in female human responses to traumatic stress, and carry implications for better understanding and treating of posttraumatic psychopathology.     

Alternatives to debriefing and modifications to cognitive behavior therapy for posttraumatic stress disorder

BACKGROUND: Psychological debriefing uses brief unsystematic exposure, and is ineffective for posttraumatic stress symptoms and disorder. Systematic exposure alone and cognitive restructuring alone are each effective. Other approaches too may be useful. METHODS: The treatment of 3 posttraumatic stress disorder (PTSD) patients is detailed in which there was no exposure to the main traumatic event.There was exposure to related cues in case 1, exposure to related and other cues followed by well-being therapy (WBT) in case 2 and WBT in case 3. RESULTS: The 3 patients improved enduringly, confirming earlier findings that exposure to the main trauma is not essential for PTSD to improve. CONCLUSIONS: A study is needed of therapeutic mechanisms in PTSD and of the value of WBT in a randomized controlled trial.     

Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population

Major depressive disorder (MDD) and panic disorder (PD) are common and disabling medical disorders with stress and genetic components. Dysregulation of the stress response of the hypothalamic-pituitary-adrenal axis, including the corticotrophin-releasing hormone (CRH) signaling via primary receptors (CRHR1 and CRHR2), is considered to play a major role for onset and recurrence in MDD and PD. To confirm the association of CRHR1 and CRHR2 with MDD and PD, we investigated 12 single nucleotide polymorphisms (SNPs) (rs4076452, rs7209436, rs110402, rs242924, rs242940, and rs173365 for CRHR1 and rs4722999, rs3779250, rs2267710, rs1076292, rs2284217, and rs226771 for CRHR2) in MDD patients (n = 173), PD patients (n = 180), and healthy controls (n = 285). The SNP rs110402 and rs242924 in the CRHR1 gene and the rs3779250 in the CRHR2 gene were associated with MDD. The SNP rs242924 in the CRHR1 gene was also associated with PD. The T-A-T-G-G haplotype consisting of rs7209436 and rs173365 in CRHR1 was positively associated with MDD. The T-A haplotype consisting of rs7209436 and rs110402 in CRHR1 was positively associated with MDD. The C-C haplotype consisting of rs4722999 and rs37790 in CRHR1 was associated with PD. These results provide support for an association of CRHR1 and CRHR2 with MDD and PD.     

Erratum: Association of CRHR1 and CRHR2 with major depressive disorder and panic disorder in a Japanese population

Major depressive disorder (MDD) and panic disorder (PD) are common and disabling medical disorders with stress and genetic components. Dysregulation of the stress response of the hypothalamic–pituitary–adrenal axis, including the corticotrophin‐releasing hormone (CRH) signaling via primary receptors (CRHR1 and CRHR2), is considered to play a major role for onset and recurrence in MDD and PD. To confirm the association of CRHR1 and CRHR2 with MDD and PD, we investigated 12 single nucleotide polymorphisms (SNPs) (rs4076452, rs7209436, rs110402, rs242924, rs242940, and rs173365 for CRHR1 and rs4722999, rs3779250, rs2267710, rs1076292, rs2284217, and rs226771 for CRHR2) in MDD patients (n = 173), PD patients (n = 180), and healthy controls (n = 285). The SNP rs110402 and rs242924 in the CRHR1 gene and the rs3779250 in the CRHR2 gene were associated with MDD. The SNP rs242924 in the CRHR1 gene was also associated with PD. The T–A–T–G–G haplotype consisting of rs7209436 and rs173365 in CRHR1 was positively associated with MDD. The T–A haplotype consisting of rs7209436 and rs110402 in CRHR1 was positively associated with MDD. The C–C haplotype consisting of rs4722999 and rs3779250 in CRHR2 was associated with PD. These results provide support for an association of CRHR1 and CRHR2 with MDD and PD. © 2012 Wiley Periodicals, Inc.     

A meta-analysis of risk factors for post-traumatic stress disorder in children and adolescents

Post-traumatic stress disorder (PTSD) is a complex and chronic disorder that causes substantial distress and interferes with social and educational functioning. Consequently, identifying the risk factors that make a child more likely to experience traumatic distress is of academic, clinical and social importance. This meta-analysis estimated the population effect sizes of 25 potential risk factors for PTSD in children and adolescents aged 6-18 years across 64 studies (N=32,238). Medium to large effect sizes were shown for many factors relating to subjective experience of the event and post-trauma variables (low social support, peri-trauma fear, perceived life threat, social withdrawal, comorbid psychological problem, poor family functioning, distraction, PTSD at time 1, and thought suppression); whereas pre-trauma variables and more objective measures of the assumed severity of the event generated small to medium effect sizes. This indicates that subjective peri-trauma factors and post-event factors are likely to have a major role in determining whether a child develops PTSD following exposure to a traumatic event. Such factors could potentially be assessed following a potentially traumatic event in order to screen for those most vulnerable to developing PTSD and target treatment efforts accordingly. The findings support the cognitive model of PTSD as a way of understanding its development and guiding interventions to reduce symptoms.     

Clinical relevance of tag single nucleotide polymorphisms within the CAT gene in patients with PTSD in the Chongqing Han population

Background: Free radical-induced oxidative damage of the brain has been implicated in a number of psychiatric disorders, including post-traumatic stress disorder (PTSD). Catalase (CAT) is a major antioxidant enzyme and a number of polymorphisms in CAT have been shown to be associated with several diseases, including hypertension, diabetes mellitus, Alzheimer’s disease, and vitiligo. The aim of this study was to evaluate the association of CAT gene polymorphisms with PTSD in a case-control study. Materials and methods: A total of 460 unrelated adult Chinese Han adults, including 287 healthy volunteers and 173 patients with PTSD. Six tag single-nucleotide polymorphisms (tSNPs) were selected from the entire CAT gene through construction of haplotype bins, and they were genotyped using an improved multiplex ligation detection reaction (iMLDR) technique. Allelic frequencies and clinical characteristics were compared in two independent Chinese Han populations. Results: Six tag SNPs were identified in the Chinese Han population and all were common SNPs. However, we could detect no evidence of genetic association between six tag SNPs in the CAT gene and PTSD in the Chinese Han population. Conclusions: This result suggests that six tag SNPs of the CAT gene may not be associated with PTSD, and that CAT gene might not influence the development of PTSD in patients following exposure to a traumatic event, also may be the sample sizes too small to allow a meaningful test.     

Late-onset PTSD in unaccompanied refugee minors: exploring the predictive utility of depression and anxiety symptoms

Following resettlement in Western countries, unaccompanied refugee minors (URM) are at risk of developing posttraumatic stress disorder (PTSD). It is unclear to what extent PTSD in this group may become manifest at later stages following resettlement and which factors are associated with late onset. We examined data from URM collected 1 (T1) and 2 years (T2) following resettlement for differences between groups with no PTSD, PTSD at T1, and late-onset PTSD (at T2 only) using multinomial regression and path analysis. Of the children and adolescents (ages 12-18) completing both assessments (N = 554), 223 (40%) met criteria for PTSD at T1, and 88 (16%) endorsed late-onset PTSD. Late-onset PTSD was associated with traumatic event exposure, older age, and low education. In the late-onset PTSD group, the predictive effects of traumatic event exposure on symptom severity at T2 were fully mediated by depression and anxiety symptoms at T1. These results suggest that late-onset PTSD is a clinically relevant problem among URM that may be heralded by early depression and anxiety symptoms.     

Association of corticotropin-releasing hormone receptor1 gene SNP and haplotype with major depression

The dysregulation of the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis system is one of the major neuroendocrine abnormalities in major depression (MD). Many pieces of evidence supported that corticotropin-releasing hormone (CRH) play a role in the pathophysiology of major depression. In this article, whether genetic variations in the corticotropin-releasing hormone receptor1 (CRHR1) gene might be associated with increased susceptibility to major depression was studied by using a gene-based association analysis of single-nucleotide polymorphisms (SNPs). Three SNPs were identified in CRHR1 gene and genotyped in the samples of patients diagnosed with major depression and matched controls. We observed significant allele (P=0.0008) and genotype (P=0.0002) association with rs242939, and the haplotype defined by alleles G-G-T for the represent rs1876828, rs242939 and rs242941 was significantly over-represented in major depression patients compared to controls. These results support the idea that the CRHR1 gene is likely to be involved in the genetic vulnerability for major depression.     

Sex dependent influence of a functional polymorphism in steroid 5‐α‐reductase type 2 (SRD5A2) on post‐traumatic stress symptoms

A non‐synonymous, single nucleotide polymorphism (SNP) in the gene coding for steroid 5‐α‐reductase type 2 (SRD5A2) is associated with reduced conversion of testosterone to dihydrotestosterone (DHT). Because SRD5A2 participates in the regulation of testosterone and cortisol metabolism, hormones shown to be dysregulated in patients with PTSD, we examined whether the V89L variant (rs523349) influences risk for post‐traumatic stress disorder (PTSD). Study participants (N = 1,443) were traumatized African‐American patients of low socioeconomic status with high rates of lifetime trauma exposure recruited from the primary care clinics of a large, urban hospital. PTSD symptoms were measured with the post‐traumatic stress symptom scale (PSS). Subjects were genotyped for the V89L variant (rs523349) of SRD5A2. We initially found a significant sex‐dependent effect of genotype in male but not female subjects on symptoms. Associations with PTSD symptoms were confirmed using a separate internal replication sample with identical methods of data analysis, followed by pooled analysis of the combined samples (N = 1,443, sex × genotype interaction P < 0.002; males: n = 536, P < 0.001). These data support the hypothesis that functional variation within SRD5A2 influences, in a sex‐specific way, the severity of post‐traumatic stress symptoms and risk for diagnosis of PTSD. © 2013 Wiley Periodicals, Inc.     

脑源性神经营养因子相关基因与创伤后应激障碍患者的人格特征关联性

目的:分析脑源性神经营养因子(BDNF)主要传导通路中BDNF、PKB1、GSK-3B、PRKCG基因多态性与创伤后应激障碍(PTSD)康复人群艾森克人格的关联性,探讨其单基因及联合作用对人格的影响。方法:严格按照入组标准筛选创伤后应激障碍患者114例,采用PTSD进行诊断,用艾森克人格问卷(EPQ)测量人格特征。采用聚合酶链反应(PCR)直接测序法检测BDNF、PKB1、GSK-3B以及PRKCG基因的单核苷酸多态性(SNP)。结果:Hardy-Weinberg遗传平衡检验到BDNF、PKBI、GSK-3B、PRKCG 4个基因的6个SNPs,即BDNF rs6265和rs712444,PKBl rs2494746和rs2494738,GSK-3Brs6782799以及PRKCG rs3745406间PTSD患者临床痊愈后所测人格差别无统计学意义。6个SNP基因型分布在总样本中均符合Hardy-weinberg遗传平衡(P0.05),样本具有群体代表性。结论:BDNF rs6265,BDNF rs712444,PKB1rs2494746,PKB1rs2494738,GSK-3Brs6782799,PRKCG rs3745406位点与PTSD患者临床痊愈后所测人格可能无关联。     

创伤后应激障碍的临床研究新进展(DSM-5新标准)

创伤后应激障碍(PTSD)是一种严重的心理障碍。PTSD常在一个人暴露于一个或多个创伤性事件后产生,如重大的刺激、性侵犯、恐怖事件或对一个人生活其他严重威胁。主要症状包括令人不安重复闪回,对事件的回避或记忆麻木,警觉性增高等。PTSD的诊断是在创伤性事件发生后持续1个月以上。美国精神病学会在2013年5月出版了《精神疾病诊断与统计手册》第5版(DSM-5)。DSM-5将PTSD的核心症状修改为4组:1在创伤事件发生后,存在1种(或多种)与创伤事件有关的重新体验症状;2创伤事件后开始持续地回避与创伤事件有关的刺激;3与创伤性事件有关的认知和心境方面的消极改变,在创伤事件发生后开始出现或加重;4与创伤事件有关的警觉性或反应性有显著的改变,在创伤事件发生后开始或加重。近年来,对PTSD的临床研究成为精神病学、心身医学和临床心理学的热点。根据DSM-5的标准和新的临床研究成果,本文对PTSD的病因和发病机制、临床表现、诊断标准、诊断和鉴别诊断、治疗、预防和预后进行了分析。     

Commentary on Braude's “Dissociation and Latent Abilities

ABSTRACT

This retrospective study investigated peritraumatic predictors (peritraumatic dissociation, negative emotions and physical anxiety symptoms experienced at the time of the traumatic event) of posttraumatic stress disorder (PTSD) symptoms among 98 French-speaking university students. Participants rated their lifetime experiences of traumatic events and, in response to their “most stressful” event, completed measures of PTSD symptoms and peritraumatic reactions. Approximately 67% of respondents (N = 75) reported at least one traumatic event. Negative emotions, peritraumatic dissociation, and physical anxiety symptoms at the time of the trauma were strong predictors of PTSD symptoms. These variables explained 38% of the variance in PTSD symptoms. Results are discussed with respect to immediate reactions to traumatic events as potential precursors of PTSD symptomatology.     

Insomnia symptoms predict the development of post‐traumatic stress symptoms following an experimental trauma

Insomnia symptoms prior to traumatic event exposure predict the development of post‐traumatic stress symptoms. However, potential mechanisms underlying the association between insomnia and risk for post‐traumatic stress disorder symptoms have not been prospectively tested. The current study used the trauma film paradigm to test whether insomnia symptoms prior to analogue trauma exposure predict subsequent analogue post‐traumatic stress disorder symptoms, and potential mediators of this relationship, among an at‐risk sample of 108 participants. Results indicated that, after covarying for negative affectivity, insomnia symptoms in the 2 weeks prior to analogue trauma exposure significantly predicted increased post‐traumatic stress disorder symptoms 3 days and 1 week post‐exposure. Moreover, distress immediately after exposure and post‐traumatic avoidance mediated the association between insomnia symptoms and post‐traumatic stress disorder symptoms 1 week after exposure. Effect sizes were small. The current study uses an analogue trauma and analogue post‐traumatic stress disorder symptoms to model clinical symptoms, includes an additional intervention prior to analogue trauma, and lacks a control film. Findings suggest increased reactivity to trauma exposure and subsequent reminders, and attempts to suppress trauma memories may be mechanisms in the association between insomnia symptoms and risk for post‐traumatic stress disorder symptoms.     

特大爆炸事故幸存者创伤后应激障碍的初步研究

目的 :了解特大意外爆炸事故对幸存者心理健康水平、PTSD的发生、PTSD的临床特征及其相关因素的影响。方法 :在爆炸事故后 3 -5个月期间 ,调查事故幸存者 ( 2 8例 ,研究组 )的一般情况、创伤经历、受伤程度及对善后处理的满意程度 ,采用创伤后应激反应症状清单、事件影响量表 (IES)、SCL -90、康奈尔医学指数 (CMI)、SDS、SAS评定 ,并与对照 ( 3 0例 )进行比较 ,分析PTSD诊断的相关因素。结果 :研究组IES、SDS、SAS、CMI、总分、CMIMR和SCL -90各统计指标与对照组的差异极其显著 (P <0 0 1)。诊断为PTSD者 78 6% ,PTSD的诊断与IES总分、现场暴露程度和对善后处理的满意程度相关。结论 :特大爆炸事故可导致暴露者出现不同程度的心理痛苦 ,PTSD的发生与创伤事件的暴露程度和对善后处理的满意程度相关。     

Gender differences in sleep during the aftermath of trauma and the development of posttraumatic stress disorder

Women have a greater risk of developing posttraumatic stress disorder (PTSD) after exposure to trauma. Although sleep abnormalities have been implicated in the development of PTSD, gender differences in sleep soon after a traumatic event have not been investigated. This secondary analysis examined sleep characteristics using polysomnography in 13 female and 22 male trauma patients within a month of their traumatic injuries and assessed PTSD symptoms at 2-months post-injury. Results revealed more wake after sleep onset in women who developed PTSD compared to men who developed PTSD. Women with subsequent PTSD also had less total sleep time than women without subsequent PTSD. Findings suggest possible contributions of impaired sleep maintenance to the development of PTSD in women.     

Gene expression and methylation signatures of MAN2C1 are associated with PTSD

As potential regulators of DNA accessibility and activity, epigenetic modifications offer a mechanism by which the environment can moderate the effects of genes. To date, however, there have been relatively few studies assessing epigenetic modifications associated with post-traumatic stress disorder (PTSD). Here we investigate PTSD-associated methylation differences in 33 genes previously shown to differ in whole blood-derived gene expression levels between those with vs. without the disorder. Drawing on DNA samples similarly obtained from whole blood in 100 individuals, 23 with and 77 without lifetime PTSD, we used methylation microarray data to assess whether these 33 candidate genes showed epigenetic signatures indicative of increased risk for, or resilience to, PTSD. Logistic regression analyses were performed to assess the main and interacting effects of candidate genes' methylation values and number of potentially traumatic events (PTEs), adjusting for age and other covariates. Results revealed that only one candidate gene - MAN2C1} - showed a significant methylation x PTE interaction, such that those with both higher MAN2C1 methylation and greater exposure to PTEs showed a marked increase in risk of lifetime PTSD (OR 4.35, 95% CI: 1.07, 17.77, p=0.04). These results indicate that MAN2C1 methylation levels modify cumulative traumatic burden on risk of PTSD, and suggest that both gene expression and epigenetic changes at specific loci are associated with this disorder.     

Association study of corticotropin-releasing hormone receptor1 gene polymorphisms and antidepressant response in major depressive disorders

Hypothalamic-pituitary-adrenal (HPA) axis appears to play a key role in the pathogenesis of major depressive disorders (MDD). Treatment of certain selective serotonin reuptake inhibitors (SSRIs) has been shown to reduce the activity of corticotropin-releasing hormone (CRH) neurons and may contribute to their therapeutic action. It has been proposed that the downregulation of CRH activity is final and common step of antidepressant treatment. In this study, we tested whether the polymorphisms of three sites (rs1876828, rs242939 and rs242941) in corticotropin-releasing hormone receptor1 (CRHR1) gene are related to 6 weeks fluoxetine antidepressant effect in 127 Han Chinese patients with MDD. The results show that the rs242941 G/G genotype and homozygous GAG haplotype of the three single-nucleotide polymorphisms (SNPs) are associated with fluoxetine therapeutic response in MDD patients of high-anxiety (HA). The results support the idea that the CRHR1 gene is likely to be involved in the antidepressant response in MDD.     

Comparing the Diagnostic Accuracy of Five Instruments for Detecting Posttraumatic Stress Disorder in Youth

The purpose of the study was to compare diagnostic accuracy of five posttraumatic stress disorder (PTSD) measures in a large outpatient sample of youths 11–18 years of age. Index tests included a parent report (a rationally derived scale from the Child Behavioral Checklist), a teacher report (the Teacher Report Form), and three youth reports—a PTSD scale from the Youth Self Report (YSR), Child PTSD Symptom Scale, and Child and Adolescent Trauma Survey. Interviews with the youth and caregiver using Schedule for Affective Disorders and Schizophrenia for School-Age Children generated criterion diagnoses of PTSD. Diagnoses were blind to scores on the index tests. Based on consensus diagnoses (N = 458), 10% of youth had PTSD. Area under the curve (AUC) from receiver operating characteristic analyses and multilevel likelihood ratios evaluated test performance. All youth reports (AUCs .67–.73) outperformed the teacher report (AUCs .42–.48) at identifying PTSD. The YSR outperformed the caregiver reports (AUCs .57–.58). Combining tests did not improve prediction of PTSD. The YSR predicted PTSD even after controlling for a self-reported traumatic event, but checklist ratings of traumatic events had no incremental value after controlling for YSR scores. When a youth endorsed few symptoms, the likelihood of the youth having PTSD was low. Very high scores on the YSR were associated with a moderate increase in the likelihood of PTSD diagnosis. The YSR appeared to be a useful diagnostic aid for youth PTSD and could facilitate differential diagnosis of youth PTSD in outpatient settings.     

Trauma exposure and sleep: using a rodent model to understand sleep function in PTSD

Post-traumatic stress disorder (PTSD) is characterized by intrusive memories of a traumatic event, avoidance behavior related to cues of the trauma, emotional numbing, and hyper-arousal. Sleep abnormalities and nightmares are core symptoms of this disorder. In this review, we propose a model which implicates abnormal activity in the locus coeruleus (LC), an important modifier of sleep–wake regulation, as the source of sleep abnormalities and memory abnormalities seen in PTSD. Abnormal LC activity may be playing a key role in symptom formation in PTSD via sleep dysregulation and suppression of hippocampal bidirectional plasticity.     

Identification of traumatic stress reactions in women at increased risk for breast cancer

It has been shown that the diagnosis and treatment of cancer may constitute a traumatic event that generates in patients and some of their family members traumatic reactions that are consistent with the symptom profile of posttraumatic stress disorder (PTSD). The present study was conducted to establish the degree to which women at increased familial risk for breast cancer showed such traumatic reactions and to establish which demographic or psychological variables may contribute to the experience of such traumatic reactions in at-risk individuals. Seventy-three women from the Revlon UCLA Breast Center High Risk Clinic were assessed for traumatic reactions that might be consistent with the DSM-IV criteria for PTSD. The results showed that women at increased risk for breast cancer exhibited traumatic responses similar to those reported by cancer patients. When the authors used a self-report instrument that maps onto DSM-IV criteria, 4% of the study subjects reported symptoms consistent with criteria for a potential diagnosis of PTSD, and an additional 7% of the subjects reported symptoms consistent with potentially subclinical levels of PTSD, according to DSM-IV criteria.