Ann C. Schwartz

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.

Trauma exposure and stress-related disorders in inner city primary care patients

OBJECTIVE This study was undertaken to increase understanding of environmental risk factors for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) within an urban, impoverished, population. METHOD This study examined the demographic characteristics, patterns of trauma exposure, prevalence of PTSD and MDD, and predictors of posttraumatic stress and depressive symptomatology using a verbally presented survey and structured clinical interviews administered to low-income, primarily African-American (>93%) women and men seeking care in the primary care and obstetrics-gynecology clinics of an urban public hospital. RESULTS Of the sample, 87.8% (n=1256) reported some form of significant trauma in their lifetime. Accidents were the most common form of trauma exposure followed by interpersonal violence and sexual assault. Childhood level of trauma and adult level of trauma separately, and in combination, predicted level of adult PTSD and depressive symptomatology. The lifetime prevalence of PTSD was 46.2% and the lifetime prevalence of MDD was 36.7%. CONCLUSIONS These data document high levels of childhood and adult trauma exposure, principally interpersonal violence, in a large sample of an inner-city primary care population. Within this group of subjects, PTSD and depression are highly prevalent conditions.

Effects of the 2011 Duty Hour Reforms on Interns and Their Patients: A Prospective Longitudinal Cohort Study

IMPORTANCE In 2003, the first phase of duty hour requirements for US residency programs recommended by the Accreditation Council for Graduate Medical Education (ACGME) was implemented. Evidence suggests that this first phase of duty hour requirements resulted in a modest improvement in resident well-being and patient safety. To build on these initial changes, the ACGME recommended a new set of duty hour requirements that took effect in July 2011. OBJECTIVE To determine the effects of the 2011 duty hour reforms on first-year residents (interns) and their patients. DESIGN As part of the Intern Health Study, we conducted a longitudinal cohort study comparing interns serving before (2009 and 2010) and interns serving after (2011) the implementation of the new duty hour requirements. SETTING Fifty-one residency programs at 14 university and community-based GME institutions. PARTICIPANTS A total of 2323 medical interns. MAIN OUTCOME MEASURES Self-reported duty hours, hours of sleep, depressive symptoms, well-being, and medical errors at 3, 6, 9, and 12 months of the internship year. RESULTS Fifty-eight percent of invited interns chose to participate in the study. Reported duty hours decreased from an average of 67.0 hours per week before the new rules to 64.3 hours per week after the new rules were instituted (P < .001). Despite the decrease in duty hours, there were no significant changes in hours slept (6.8 → 7.0; P = .17), depressive symptoms (5.8 → 5.7; P = .55) or well-being score (48.5 → 48.4; P = .86) reported by interns. With the new duty hour rules, the percentage of interns who reported concern about making a serious medical error increased from 19.9% to 23.3% (P = .007). CONCLUSIONS AND RELEVANCE Although interns report working fewer hours under the new duty hour restrictions, this decrease has not been accompanied by an increase in hours of sleep or an improvement in depressive symptoms or well-being but has been accompanied by an unanticipated increase in self-reported medical errors.

Treatment barriers for low-income, urban African Americans with undiagnosed posttraumatic stress disorder

African Americans in low-income, urban communities are at high risk for exposure to traumatic events as well as for symptoms of posttraumatic stress disorder (PTSD). Approximately 22% of 220 participants recruited from urban hospital medical clinics met survey criteria for PTSD. Among the common traumas were having relatives/friends murdered (47%), being attacked with weapons (64% of men), and being sexually attacked (36% of women). Although desiring mental health services, only 13.3% of those with PTSD had prior trauma-focused treatment. Barriers to treatment included limited transportation and finances, family disapproval, and unfamiliarity with accessing treatment, among others. These data highlight the need for an awareness of the high prevalence of trauma and PTSD in this population.

Pain Symptomatology and Pain Medication Use in Civilian PTSD

Summary Participants with posttraumatic stress disorder (PTSD) had higher self‐reported pain and were significantly more likely to have used opioid analgesics for pain control compared to those without PTSD. Abstract The comorbidity of pain syndromes and trauma‐related syndromes has been shown to be high. However, there have been limited data, especially in civilian medical populations, on the role of trauma‐related disorders such as posttraumatic stress disorder (PTSD) on chronic pain and pain medication use. We analyzed 647 general hospital patients in primary care and obstetrics and gynecological waiting rooms for the experience of trauma and PTSD‐related stress disorders. PTSD symptoms were found to be significantly positively correlated with pain ratings (r = .282, P < 0.001) and pain‐related functional impairment (r = 0.303, P < 0.001). Those with a current PTSD diagnosis had significantly higher subjective pain and pain‐related impairment ratings than those with no PTSD. Furthermore, those with a current diagnosis of PTSD were significantly more likely to have used opioid analgesics for pain control compared to those without a diagnosis of PTSD (χ2 = 8.98, P = 0.011). When analyzing the separate PTSD symptom subclusters (re‐experiencing, avoidance, and hyperarousal), all symptom clusters were significantly related to pain and pain‐related impairment ratings, but only the avoidance cluster was significantly related to prior opioid pain medication use. We conclude that PTSD and trauma‐related disorders are common in impoverished medical populations and that their presence should be examined in patients with pain syndromes. Furthermore, these data suggest that PTSD and pain may share a vulnerability pathway, including the endogenous opioid neurotransmission systems.

The Renin-Angiotensin Pathway in Posttraumatic Stress Disorder: Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Are Associated With Fewer Traumatic Stress Symptoms

OBJECTIVE Posttraumatic stress disorder (PTSD) is a debilitating stress-related illness associated with trauma exposure. The peripheral and central mechanisms mediating stress response in PTSD are incompletely understood. Recent data suggest that the renin-angiotensin pathway, essential to cardiovascular regulation, is also involved in mediating stress and anxiety. In this study, the authors examined the relationship between active treatment with blood pressure medication, including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), and PTSD symptom severity within a highly traumatized civilian medical population. METHOD Cross-sectional, observational data were analyzed from a larger study; patients were recruited from Grady Memorial Hospitals outpatient population from 2006 to November 2010. Multivariable linear regression models were fit to statistically evaluate the independent association of being prescribed an ACE inhibitor or ARB with PTSD symptoms, using a subset of patients for whom medical information was available (n = 505). Categorical PTSD diagnosis was assessed using the modified PTSD Symptom Scale (PSS) based on DSM-IV criteria, and PTSD symptom severity (the primary outcome of interest) was measured using the PSS and Clinician Administered PTSD Scale. RESULTS A significant association was determined between presence of an ACE inhibitor/ARB medication and decreased PTSD symptoms (mean PSS score 11.4 vs 14.9 for individuals prescribed vs not prescribed ACE inhibitors/ARBs, respectively [P = .014]). After adjustment for covariates, ACE inhibitor/ARB treatment remained significantly associated with decreased PTSD symptoms (P = .044). Notably, other blood pressure medications, including β-blockers, calcium channel blockers, and diuretics, were not significantly associated with reduced PTSD symptoms. CONCLUSIONS These data provide the first clinical evidence supporting a role for the renin-angiotensin system in the regulation of stress response in patients diagnosed with PTSD. Further studies should examine whether available medications targeting this pathway should be considered for future treatment and potential protection against PTSD symptoms.

Developing a Modern Standard to Define and Assess Professionalism in Trainees.

ObjectiveAssessing professionalism in medical education poses many challenges. The authors discuss common themes and principles in managing professionalism in medical education.MethodsThe authors review the development of standards of professionalism in medical education. They define educational goals for professionalism and also discuss the practical problems with assessing professionalism and addressing it with the trainees. Strategies for remediation of unprofessional conduct are outlined.ResultsGiven the importance of role models in the development of professional behavior, maintaining an environment that fosters professionalism is an implicit feature of teaching professionalism. Professionalism should be a part of the objectives for each course and clinical rotation, using clearly defined goals and objectives. Assessment of professionalism should begin early and be conducted frequently, giving trainees the opportunity to change. A formal mentoring system can be an effective mechanism to develop role models and teach professionalism.ConclusionTeaching professionalism through formal curricula is paramount in helping develop new generations of compassionate and responsible physicians. Additional strategies such as consistent role modeling of professional behaviors are also needed to encourage the development of professional physicians.

Review of sertraline in post-traumatic stress disorder

Sertraline (Zoloft™, Pfizer) is a selective serotonin re-uptake inhibitor (SSRI) with proven efficacy in the treatment of post-traumatic stress disorder (PTSD). PTSD is a serious, complex and often chronic mental illness that may follow exposure to a traumatic event. The high prevalence of traumatic events and PTSD in the general population and the resulting distress and dysfunction present a need for the systematic study of the efficacy and effectiveness of treatments for PTSD. Sertraline offers advantages over the older antidepressants, including demonstrated efficacy in PTSD, improved tolerability and low risk of lethality in overdose. Sertraline’s efficacy, favourable tolerability profile and relatively weak effect on the cytochrome P450 system are factors that contribute to make it a first-line agent of choice in the treatment of PTSD.

Clozapine-Induced Myocarditis: Prevention and Considerations in Rechallenge

The incidence of clozapine-induced myocarditis is 0.2%–3%, and it can be life threatening, with a mortality rate as high as 50%. It can be subtle in its presentation, with the most common symptoms including flulike symptoms, fever, fatigue, and dyspnea. Approximately 80% of cases of clozapineinduced myocarditis occur within 4 weeks of drug initiation, and 90% occur within 8 weeks. The diagnosis is typically guided by a preponderance of clinical evidence, as even the diagnostic gold standard of endomyocardial biopsy has limited sensitivity and specificity. We present the case of a 44-year-old woman who developed clinical signs and symptoms of clozapineinduced myocarditis, approximately 2 weeks following the initiation of clozapine treatment for psychosis.