OSTTRAUMATIC STRESS DISORder (PTSD) is a debilitating stress-related psychiatric disorder, with prevalence rates of at least 7% to 8% in the US population, and with much higher rates among combat veterans and those living in high-violence areas. 1-3 Initially viewed as a potentially normative response to traumatic exposure, 4 it became clear that not everyone experiencing trauma develops PTSD. Thus, a central question in research on PTSD is why some individuals are more likely than others to develop the disorder in the face of similar levels of trauma exposure. 5-8 Although PTSD is the single disorder within the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) 9 that requires a specific environmental insult within its diagnostic criteria, it is becoming increasingly clear that there are critical roles for predisposing genetic and environmental influences in differentially mediating psychological risk to the traumatized individual. 10-13

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.

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.

Objective: Exposure to traumatic experiences, especially those occurring in childhood, has been linked to substance use disorders (SUDs), including abuse and dependence. SUDs are also highly comorbid with Posttraumatic Stress Disorder (PTSD) and other mood-related psychopathology. Most studies examining the relationship between PTSD and SUDs have examined veteran populations or patients in substance treatment programs. The present study further examines this relationship between childhood trauma, substance use, and PTSD in a sample of urban primary care patients. Method: There were 587 participants included in this study, all recruited from medical and OB/GYN clinic waiting rooms at Grady Memorial Hospital in Atlanta, GA. Data were collected through both screening interviews as well as follow-up interviews. Results: In this highly traumatized population, high rates of lifetime dependence on various substances were found (39% alcohol, 34.1% cocaine, 6.2% heroin/opiates, and 44.8% marijuana). The level of substance use, particularly cocaine, strongly correlated with levels of childhood physical, sexual, and emotional abuse as well as current PTSD symptoms. In particular, there was a significant additive effect of number of types of childhood trauma experienced with history of cocaine dependence in predicting current PTSD symptoms, and this effect was independent of exposure to adult trauma. Conclusions: These data show strong links between childhood traumatization and SUDs, and their joint associations with PTSD outcome. They suggest that enhanced awareness of PTSD and substance abuse comorbidity in high-risk, impoverished populations is critical to understanding the mechanisms of substance addiction as well as in improving prevention and treatment. Depression and Anxiety, 2010. © 2010 Wiley-Liss, Inc.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

No abstract

China faces substantial drug abuse problems that appear to be worsening with time. Opiate dependence is a major threat to the public health and social security of China because of its devastating medical effects, its impact on risk for HIV/AIDS and criminal behaviors, low rates of recovery and high rates of relapse. There is an urgent need to implement MMT and other modern treatments for opiate dependence more widely in China.

No abstract