Yi-Lang Tang

Association of FKBP5 Polymorphisms and Childhood Abuse With Risk of Posttraumatic Stress Disorder Symptoms in Adults

CONTEXT In addition to trauma exposure, other factors contribute to risk for development of posttraumatic stress disorder (PTSD) in adulthood. Both genetic and environmental factors are contributory, with child abuse providing significant risk liability. OBJECTIVE To increase understanding of genetic and environmental risk factors as well as their interaction in the development of PTSD by gene x environment interactions of child abuse, level of non-child abuse trauma exposure, and genetic polymorphisms at the stress-related gene FKBP5. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study examining genetic and psychological risk factors in 900 nonpsychiatric clinic patients (762 included for all genotype studies) with significant levels of childhood abuse as well as non-child abuse trauma using a verbally presented survey combined with single-nucleotide polymorphism (SNP) genotyping. Participants were primarily urban, low-income, black (>95%) men and women seeking care in the general medical care and obstetrics-gynecology clinics of an urban public hospital in Atlanta, Georgia, between 2005 and 2007. MAIN OUTCOME MEASURES Severity of adult PTSD symptomatology, measured with the modified PTSD Symptom Scale, non-child abuse (primarily adult) trauma exposure and child abuse measured using the traumatic events inventory and 8 SNPs spanning the FKBP5 locus. RESULTS Level of child abuse and non-child abuse trauma each separately predicted level of adult PTSD symptomatology (mean [SD], PTSD Symptom Scale for no child abuse, 8.03 [10.48] vs > or =2 types of abuse, 20.93 [14.32]; and for no non-child abuse trauma, 3.58 [6.27] vs > or =4 types, 16.74 [12.90]; P < .001). Although FKBP5 SNPs did not directly predict PTSD symptom outcome or interact with level of non-child abuse trauma to predict PTSD symptom severity, 4 SNPs in the FKBP5 locus significantly interacted (rs9296158, rs3800373, rs1360780, and rs9470080; minimum P = .0004) with the severity of child abuse to predict level of adult PTSD symptoms after correcting for multiple testing. This gene x environment interaction remained significant when controlling for depression severity scores, age, sex, levels of non-child abuse trauma exposure, and genetic ancestry. This genetic interaction was also paralleled by FKBP5 genotype-dependent and PTSD-dependent effects on glucocorticoid receptor sensitivity, measured by the dexamethasone suppression test. CONCLUSIONS Four SNPs of the FKBP5 gene interacted with severity of child abuse as a predictor of adult PTSD symptoms. There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non-child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD.

Influence of child abuse on adult depression: Moderation by the corticotropin-releasing hormone receptor gene

CONTEXT Genetic inheritance and developmental life stress both contribute to major depressive disorder in adults. Child abuse and trauma alter the endogenous stress response, principally corticotropin-releasing hormone and its downstream effectors, suggesting that a gene x environment interaction at this locus may be important in depression. OBJECTIVE To examine whether the effects of child abuse on adult depressive symptoms are moderated by genetic polymorphisms within the corticotropin-releasing hormone type 1 receptor (CRHR1) gene. DESIGN Association study examining gene x environment interactions between genetic polymorphisms at the CRHR1 locus and measures of child abuse on adult depressive symptoms. SETTING General medical clinics of a large, public, urban hospital and Emory University, Atlanta, Georgia. PARTICIPANTS The primary participant population was 97.4% African American, of low socioeconomic status, and with high rates of lifetime trauma (n = 422). A supportive independent sample (n = 199) was distinct both ethnically (87.7% Caucasian) and socioeconomically (less impoverished). MAIN OUTCOME MEASURES Beck Depression Inventory scores and history of major depressive disorder by the Structured Clinical Interview for DSM-IV Axis I Disorders. RESULTS Fifteen single-nucleotide polymorphisms spanning 57 kilobases of the CRHR1 gene were examined. We found significant gene x environment interactions with multiple individual single-nucleotide polymorphisms (eg, rs110402, P = .008) as well as with a common haplotype spanning intron 1 (P < .001). Specific CRHR1 polymorphisms appeared to moderate the effect of child abuse on the risk for adult depressive symptoms. These protective effects were supported with similar findings in a second independent sample (n = 199). CONCLUSIONS These data support the corticotropin-releasing hormone hypothesis of depression and suggest that a gene x environment interaction is important for the expression of depressive symptoms in adults with CRHR1 risk or protective alleles who have a history of child abuse.

Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder.

DNA methylation may mediate persistent changes in gene function following chronic stress. To examine this hypothesis, we evaluated African American subjects matched by age and sex, and stratified into four groups by post‐traumatic stress disorder (PTSD) diagnosis and history of child abuse. Total Life Stress (TLS) was also assessed in all subjects. We evaluated DNA extracted from peripheral blood using the HumanMethylation27 BeadChip and analyzed both global and site‐specific methylation. Methylation levels were examined for association with PTSD, child abuse history, and TLS using a linear mixed model adjusted for age, sex, and chip effects. Global methylation was increased in subjects with PTSD. CpG sites in five genes (TPR, CLEC9A, APC5, ANXA2, and TLR8) were differentially methylated in subjects with PTSD. Additionally, a CpG site in NPFFR2 was associated with TLS after adjustment for multiple testing. Notably, many of these genes have been previously associated with inflammation. Given these results and reports of immune dysregulation associated with trauma history, we compared plasma cytokine levels in these subjects and found IL4, IL2, and TNFα levels associated with PTSD, child abuse, and TLS. Together, these results suggest that psychosocial stress may alter global and gene‐specific DNA methylation patterns potentially associated with peripheral immune dysregulation. Our results suggest the need for further research on the role of DNA methylation in stress‐related illnesses.

Gender differences in 542 Chinese inpatients with schizophrenia

OBJECTIVE To investigate gender differences in the onset and other clinical features of Han Chinese inpatients with schizophrenia. METHODS Five-hundred-and-forty-two Han Chinese inpatients with DSM-IV schizophrenia were assessed with the Positive and Negative Symptoms Scale (PANSS), the Brief Psychiatric Rating Scale (BPRS), the Global Assessment of Function scale (GAF) and locally-developed standardized data collection forms. Comparisons were made between male and female patients. RESULTS This is the largest study of gender differences in schizophrenia to be conducted in a Chinese population. In our sample, we found that schizophrenia onset occurred at a significantly earlier age in male patients compared to female patients and that late-onset schizophrenia (as defined by onset> or =45 years) was significantly more common in female patients. The paranoid subtype of schizophrenia was less common in male patients, males received higher daily doses of antipsychotics and demonstrated a different pattern of antipsychotic usage, being less likely to be treated with SGAs. Further, cigarette smoking was more common in male patients and male patients were more likely to be single or never married. By contrast, female patients showed a different pattern of ongoing symptoms and severity, being more likely to have persistent positive symptoms, more severe positive and affective symptoms, and a greater number of suicide attempts whereas male patients were more likely to show severe deterioration over time. CONCLUSIONS There are notable gender differences in the age at onset, treatment and a range of other clinical features in Han Chinese patients with schizophrenia. Such differences were largely consistent with those reported in Western studies. These gender differences need to be considered in the assessment and management of Chinese patients with schizophrenia.

Alcohol and alcohol-related harm in China: policy changes needed

In China, alcohol consumption is increasing faster than anywhere else in the world. A steady increase in alcohol production has also been observed in the country, together with a rise in alcohol-related harm. Despite these trends, Chinas policies on the sale and consumption of alcoholic beverages are weak compared with those of other countries in Asia. Weakest of all are its policies on taxation, drink driving laws, alcohol sale to minors and marketing licenses. The authors of this descriptive paper draw attention to the urgent need for public health professionals and government officials in China to prioritize population surveillance, research and interventions designed to reduce alcohol use disorders. They describe Chinas current alcohol policies and recent trends in alcohol-related harm and highlight the need for health officials to conduct a thorough policy review from a public health perspective, using as a model the World Health Organizations global strategy to reduce the harmful use of alcohol.

Clozapine in China.

Clozapine remains one of the most commonly used antipsychotic medications in China. As China has the largest population internationally on clozapine treatment, its experience and research findings are of keen interest to Western psychiatrists. However, most of the related papers have hitherto been published only in Chinese language journals. Here we review mainly Chinese-language publications on the use of clozapine in China. A descriptive study based on literature identified from searches of Medline and the China National Knowledge Infrastructure (CNKI) databases (1979-2007), and other hand-picked references. Unlike the situation in other countries, clozapine is still widely used for a number of psychiatric disorders in China, though the prescription of other second-generation antipsychotics (SGAs) is also increasing. About 25-60% of all treated patients with schizophrenia receive clozapine; and clozapine is preferred by some as a first-line treatment for schizophrenia. Clozapine is also used for other conditions such as mania, treatment-resistant depression and drug abuse. The average daily dose is between 200 and 400 mg. The incidence of leukopenia is 3.92% and agranulocytosis 0.21% in China, with about one third of reported cases of patients with agranulocytosis dying. Weight gain and clozapine-associated diabetes are also commonly reported in the Chinese population. Clozapine is currently the most commonly used treatment for schizophrenia in China. Chinese psychiatrists need to pay more attention to its potential toxic side effects when they make drug choices.

Genotypic and haplotypic associations of the DBH gene with plasma dopamine β -hydroxylase activity in African Americans

Several variants at DBH are significantly associated with plasma DβH activity (pDβH). However, the overwhelming majority of data on this genotype–phenotype relationship has been gathered in samples from Europeans and European Americans (EAs). In this study, we examined the relationship between DBH polymorphisms and pDβH in samples from African-American (AA) subjects. Genotypes were determined at a 19-bp insertion/deletion polymorphism (ins/del) and four single-nucleotide polymorphisms (SNPs) at DBH in 109 samples. Analyses were performed using analyses of variance (ANOVAs) (for individual SNPs) and regression procedures (to assess the joint effects and the specific SNP-based haplotypes). We found: (1) single-variant analysis of all polymorphisms revealed apparent associations to pDβH, with rs1611115 accounting for the largest proportion of the variance in pDβH (28.7%) and ins/del the smallest (6.5%); (2) modest but significant linkage disequilibrium (LD) existed between ins/del and rs1611115; (3) LD between all other pairs of variants was not observed; (3) stepwise regression showed that a model containing rs1611115, rs2519152 and rs6271 accounted for 37.6% of the variance in pDβH, with rs6271 showing additional 7.6% above the effect of rs1611115, and rs2519152 showing additional 2% above rs1611115 and rs6271; (4) two common haplotypes, C-T-C and T-C-C at rs1611115-rs2519152-rs6271 were significantly associated with pDβH (P=0.0025 and 0.0036, respectively). The data support the validity of prior reported associations and underscore the importance of analyzing multiple SNPs across DBH in future association studies examining disease and biochemical phenotypes.

Clozapine for Treatment-Resistant Bipolar Disorder: A Systematic Review

To evaluate the efficacy and safety of clozapine for treatment‐resistant bipolar disorder (TRBD).

Catechol-O-methyltransferase modulation of cortisol secretion in psychiatrically at-risk and healthy adolescents.

Objective Recent research implicates the catechol-O-methyltransferase (COMT) Val108/158Met polymorphism in stress sensitivity, through modulation of hypothalamic-pituitary-adrenal (HPA) function. In healthy samples, Met homozygosity has been associated with greater HPA activity (i.e., cortisol) and stress sensitivity, though findings are mixed among clinical samples. To date, there are no reports examining baseline or longitudinal changes in HPA activity as a function of COMT genotype in youth. This study tested the hypothesis that COMT genotype would be associated with cortisol secretion in normal and at-risk adolescents; specifically, that COMT genotype would be linked in a dose-response manner such that Met homozygotes would have the highest salivary cortisol levels, followed by heterozygotes, then Val homozygotes. In addition, this study examined the relation of COMT genotype with longitudinal changes in cortisol. Methods This study examined the association of COMT with salivary cortisol across a 1-year period in healthy and at-risk adolescents with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision Axis II diagnoses. Results Results indicated higher cortisol levels for Met homozygotes (compared with heterozygotes and Val homozygotes) at the 1-year follow-up, and increased mean cortisol levels across a 1-year period among Met carriers, suggesting that COMT associates with differences in cortisol secretion during adolescence. Conclusion Findings are discussed with respect to COMT genotype as a potential genetic indicator of psychiatric risk that modulates developmental changes in HPA activity.

Adjunctive Aripiprazole Versus Placebo for Antipsychotic-Induced Hyperprolactinemia: Meta-Analysis of Randomized Controlled Trials

Objective To compare the safety and efficacy of adjunctive aripiprazole versus placebo for antipsychotic-induced hyperprolactinemia. Methods Population: adult patients presenting with antipsychotic-induced hyperprolactinemia diagnosed by prolactin level with or without prolactin-related symptoms. Interventions: adjunctive aripiprazole vs. adjunctive placebo. Outcome measures: adverse events and efficacy of treatment. Studies: randomized controlled trials. Results Five randomized controlled trials with a total of 639 patients (326 adjunctive aripiprazole, 313 adjunctive placebo) met the inclusion criteria. Adjunctive aripiprazole was associated with a 79.11% (125/158) prolactin level normalization rate. Meta-analysis of insomnia, headache, sedation, psychiatric disorder, extrapyramidal symptom, dry mouth, and fatigue showed no significant differences in the adjunctive aripiprazole treatment group compared with the placebo group (risk difference (Mantel-Haenszel, random or fixed) −0.05 to 0.04 (95% confidence interval −0.13 to 0.16); I2 = 0% to 68%, P = 0.20 to 0.70). However, sedation, insomnia, and headache were more frequent when the adjunctive aripiprazole dose was higher than 15 mg/day. Meta-analysis of the prolactin level normalization indicated adjunctive aripiprazole was superior to placebo (risk difference (Mantel-Haenszel, random) 0.76 (95% confidence interval 0.67 to 0.85); I2 = 43%, P<0.00001). The subgroup analysis confirmed that the subjects who received adjunctive aripiprazole 5 mg/day showed a degree of prolactin normalization similar to that of all participants. No significant differences between groups in discontinuation and improvements of psychiatric symptoms. Conclusion Adjunctive aripiprazole is both safe and effective as a reasonable choice treatment for patients with antipsychotic-induced hyperprolactinemia. The appropriate dose of adjunctive aripiprazole may be 5 mg/day.