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Specific Associations Between Type of Childhood Abuse and Elevated C-Reactive Protein in Young Adult Psychiatric Rehabilitation Participants

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Background: Early life adversity such as childhood emotional, physical, and sexual trauma is associated with later-life psychiatric and chronic medical conditions, including elevated inflammatory markers. Although previous research suggests a role for chronic inflammatory dysfunctions in several disease etiologies, specific associations between childhood trauma types and later life inflammation and health status are poorly understood. Methods: We studied patients (n=280) admitted to a psychiatric rehabilitation center. Self-reported histories of childhood emotional, physical, and sexual trauma were collected with a standard instrument. At the time of admission, we also assessed individuals' body mass index (BMI) and collected blood samples used to examine inflammatory marker C-reactive protein (CRP) levels. Results: The prevalence of all three types of abuse was relatively high, at 21% or more. 50% of the sample had elevations in CRP, with clinically significant elevations in 26%. We found that compared to a history of emotional or physical abuse, a history of childhood sexual trauma was more specifically associated with elevated CRP. This result held up when using linear regressions to examine the contribution of BMI. Limitation: Our sample is relatively young, with an average age of 27.2 years and minimal representation of ethnic and racial minority participants. Conclusion: Relative to childhood emotional and physical trauma, childhood sexual trauma may lead to elevated inflammatory responses, confirmed in our finding of an association between CRP and sexual abuse. Future studies need to assess the causal link between childhood sexual trauma and poorer health outcomes later in life.

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Depression and inflammation fuel one another. Inflammation plays a key role in depression's pathogenesis for a subset of depressed individuals; depression also primes larger cytokine responses to stressors and pathogens that do not appear to habituate. Accordingly, treatment decisions may be informed by attention to questions of how (pathways) and for whom (predispositions) these links exist, which are the focus of this article. When combined with predisposing factors (moderators such as childhood adversity and obesity), stressors and pathogens can lead to exaggerated or prolonged inflammatory responses. The resulting sickness behaviors (e.g., pain, disturbed sleep), depressive symptoms, and negative health behaviors (e.g., poor diet, a sedentary lifestyle) may act as mediating pathways that lead to further, unrestrained inflammation and depression. Depression, childhood adversity, stressors, and diet can all influence the gut microbiome and promote intestinal permeability, another pathway to enhanced inflammatory responses. Larger, more frequent, or more prolonged inflammatory responses could have negative mental and physical health consequences. In clinical practice, inflammation provides a guide to potential targets for symptom management by signaling responsiveness to certain therapeutic strategies. For example, a theme across research with cytokine antagonists, omega-3 fatty acids, celecoxib, and exercise is that anti-inflammatory interventions have a substantially greater impact on mood in individuals with heightened inflammation. Thus, when inflammation and depression co-occur, treating them in tandem may enhance recovery and reduce the risk of recurrence. The bidirectional links between depression, inflammation, and disease suggest that effective depression treatments could have a far-reaching impact on mood, inflammation, and health.
Article
Perinatal mood and anxiety disorders (PMADs) compromise maternal and child well-being and may be influenced by traumatic experiences across the life course. A potent and common form of trauma is childhood maltreatment, but its specific impact on PMADs is not well understood. A systematic review was undertaken to synthesize empirical literature on the relationship between maternal histories of childhood maltreatment and PMADs. Of the 876 citations retrieved, 35 reports from a total of 26,239 participants met inclusion criteria, documenting substantial rates of childhood maltreatment and PMADs. Robust trends of association were observed between childhood maltreatment and perinatal depression, as well as post-traumatic stress disorder, but findings for anxiety were less consistent. Examining multivariate results suggested that childhood maltreatment predicts PMADs above and beyond sociodemographic, psychiatric, perinatal, and psychosocial factors, but may also be partially mediated by variables such as later victimization and moderated by protective early relationships. Future research should test mediating and moderating pathways using prospective cohorts, expanding to cross-cultural settings and other disorder outcomes. Treatment and prevention of childhood maltreatment and its sequelae may help mitigate risk for perinatal psychopathology and its impact on maternal and child outcomes. © The Author(s) 2015.
Article
Objective: Childhood trauma is known to be related to inflammatory processes in adulthood, but underlying psychological/behavioral mechanisms have not been fully characterized. To investigate associations between childhood trauma and inflammation (indexed by C-reactive protein [CRP]), we used a structural equation modeling approach on a subsample of the Midlife in the United States biomarker project. Methods: Participants included 687 men and women without history of cancer, diabetes, cardiovascular disease, or stroke who completed a physical examination and extensive questionnaires and provided blood. To test for sex differences, we held as many parameters invariant across sexes as possible while still retaining good model fit. Results: Tests of direct and indirect effects revealed that childhood trauma was significantly associated with elevated CRP, via elevated body mass index (BMI; p < .001). This relationship was mediated by a broad latent measure of distress, which was associated with using food as a coping mechanism. Men and women differed in reported levels of physical abuse, sexual abuse, and physical neglect. Compared with men, women showed a stronger association between BMI and CRP, whereas men had a stronger association between use of food to cope and elevated BMI. Conclusions: Our results are consistent with a model in which childhood trauma is associated with elevated CRP, a relationship associated with stress reactivity and compensatory emotional eating. Men and women may experience trauma in qualitatively distinct patterns but share many vulnerabilities, which can lead to elevated health risks. Emotional eating may be an important target for intervention in this population.
Article
The epidemiology of traumatic experiences in childhood is a key context for research, clinical treatment, program management, and policy development. This article discusses the conceptual, methodological, and programmatic challenges in precisely answering even relatively simple questions concerning the basic prevalence and incidence of important trauma types among American youth. Findings from studies using nationally representative samples and directly interviewing youth about their trauma histories are reviewed, and lifetime prevalence rates for various types of traumatic experience presented. Clinical application of this information and future directions are discussed.
Article
Elevated inflammation biomarkers are associated with incident cardiovascular disease. Several studies suggest that childhood abuse may be associated with inflammation later in life. This study examined whether childhood abuse predicted elevated levels of C reactive protein (CRP) and whether the association was due to body size. Participants were 326 (104 Black, 222 White) women from the Pittsburgh site of the Study of Women's Health Across the Nation (SWAN). SWAN included a baseline assessment of premenopausal or early perimenopausal women in midlife (mean age = 45.7), and CRP, depressive symptoms, body mass index (BMI), and other covariates were measured over 7 annual follow-up visits. The Childhood Trauma Questionnaire, a standardized measure that retrospectively assesses abuse and neglect in childhood and adolescence, was administered at year 8 or 9 of follow-up. Approximately 37% of the participants reported a history of abuse or neglect. Generalized estimating equations showed that sexual and emotional abuse, emotional and physical neglect, and the total number of types of abuse were associated with higher CRP levels over 7 years, adjusting for race, age, education, smoking status, use of hormone therapy, depressive symptoms, occurrence of heart attack or stroke, and medications for hypertension. The coefficients for indirect effects for emotional and sexual abuse, physical neglect, and total number of types of abuse on CRP levels through BMI were significant. A history of emotional abuse and neglect was related to percent change in CRP over the 7 years but not through percent change in BMI over the 7 years. A history of childhood abuse and neglect retrospectively reported is related to overall elevated inflammation in mid-life women, perhaps through obesity. A history of some types of abuse and neglect (emotional) may be related to change in inflammation, independent of simultaneously measured change in BMI.
Article
Childhood trauma is associated with smaller gray matter volume, similar to the pattern seen in psychotic disorders. We explored the relationship between childhood abuse, psychosis, and brain volume in a group of 60 individuals with a psychotic disorder and 26 healthy control subjects. We used voxel-based morphometry (VBM) to quantify gray and white matter volume and the Childhood Trauma Questionnaire (CTQ) to measure childhood abuse. Within the psychotic disorder group, total gray matter volume was inversely correlated with the severity of childhood sexual abuse (r=-.34, p=.008), but not the other types of abuse. When the 24 patients with sexual abuse were compared with demographically matched samples of 23 patients without sexual abuse and 26 control subjects, only patients with a history of sexual abuse had reduced total gray matter volume (t(48)=2.3, p=.03; Cohen's d=.63). Voxel-based analysis revealed a cluster in the prefrontal cortex where volume was negatively correlated with sexual abuse severity. Voxel based comparison of the three matched groups revealed a similar pattern of results, with widespread reductions in psychosis patients with sexual abuse relative to controls that were not found in psychosis patients without sexual abuse. These findings indicate that some of the variance of gray matter volume in psychotic disorders can be explained by a history of sexual abuse.
Article
In addition to neuroendocrine changes PTSD pathophysiology may also involve dysfunction of the innate immune inflammatory system. PTSD patients have been found to exhibit increased concentrations of circulating inflammatory markers such as C-reactive protein and interleukin-6, suggesting dysfunction of the innate immune inflammatory system. However, few studies have investigated molecular signaling pathways known to critically regulate inflammation. Additionally, the relationship between inflammatory function and immune cell glucocorticoid sensitivity has not been extensively explored in PTSD. Nuclear factor-κB (NF-κB) pathway activity was examined in peripheral blood mononuclear cells obtained from 12 women with childhood abuse-related PTSD and 24 healthy controls (ages 19-48) using DNA-binding ELISA. Glucocorticoid sensitivity of monocytes in whole blood was measured as the concentration of dexamethasone needed to suppress in vitro lipopolysaccharide-induced tumor necrosis factor-alpha production by 50% (DEX IC(50)). Women with PTSD displayed increased NF-κB pathway activity compared to controls (t [34]=2.45, p=0.02) that was positively correlated with PTSD severity (determined by PTSD symptom severity scale) (r(s)=0.39, p=0.02). Increased NF-κB pathway activity was associated with increased whole blood monocyte DEX IC(50) (i.e. decreased sensitivity of monocytes to glucocorticoids) across all participants (r=0.66, p<0.001). These findings suggest that enhanced inflammatory system activity in participants with childhood abuse-related PTSD is observable at the level of NF-κB, and that in general decreased immune cell glucocorticoid sensitivity may contribute to increased NF-κB pathway activity. Enhanced inflammation may contribute to co-morbid somatic disease risk in persons with childhood abuse-related PTSD.
Article
This report presents initial findings on the reliability and validity of a new retrospective measure of child abuse and neglect, the Childhood Trauma Questionnaire. Two hundred eighty-six drug- or alcohol-dependent patients were given the Childhood Trauma Questionnaire as part of a larger test battery, and 40 of these patients were given the questionnaire again after an interval of 2 to 6 months. Sixty-eight of the patients were also given a structured interview for child abuse and neglect, the Childhood Trauma Interview, that was developed by the authors. Principal-components analysis of responses on the Childhood Trauma Questionnaire yielded four rotated orthogonal factors: physical and emotional abuse, emotional neglect, sexual abuse, and physical neglect. Cronbach's alpha for the factors ranged from 0.79 to 0.94, indicating high internal consistency. The Childhood Trauma Questionnaire also demonstrated good test-retest reliability over a 2- to 6-month interval (intraclass correlation = 0.88), as well as convergence with the Childhood Trauma Interview, indicating that patients' reports of child abuse and neglect based on the Childhood Trauma Questionnaire were highly stable, both over time and across type of instruments. These findings provide strong initial support for the reliability and validity of the Childhood Trauma Questionnaire.
Article
C-reactive protein (CRP) is well characterized as one of the serum acute phase proteins, the levels of which increase dramatically after infection. CRP has been shown to be involved in multiple immunoregulatory functions. For example, it activates the classical complement cascade, opsonizes bacteria for phagocytosis, and stimulates phagocytic cells. Although CRP is predominantly produced and secreted by hepatocytes, other cells including subsets of lymphocytes, Kupffer cells, and blood monocytes have been shown to synthesize this protein as well. We hypothesized that CRP may be produced in the lung, and therefore it could function directly in pulmonary host defense. Western blot analysis showed that CRP was present in the lung tissue, lung lavage, and alveolar macrophages. This result was further confirmed by immunohistochemical staining of lung sections that showed the localization of CRP in alveolar macrophages. The CRP mRNA was detected subsequently by reverse-transcriptase PCR (RT-PCR), and a single amplified product was obtained from alveolar macrophages as well as from whole lung tissue. Both were the same size as the amplified product obtained from liver mRNA. Furthermore, in situ hybridization with CRP riboprobe demonstrated specific staining of alveolar macrophages both in lung sections and isolated cells. In addition, in situ hybridization showed that CRP mRNA levels in isolated alveolar macrophages were up-regulated by in vitro LPS stimulation. In summary, these results indicate that CRP is produced by alveolar macrophages, and suggest that CRP may be involved in the pulmonary immune response.
Article
To present initial findings on the validity of a recently developed maltreatment inventory, the Childhood Trauma Questionnaire (CTQ), in a sample of adolescent psychiatric patients. Three hundred ninety-eight male and female adolescents (aged 12 to 17 years) admitted to the inpatient service of a private psychiatric hospital were given the CTQ as part of a larger test battery. Structured interviews were also conducted with the primary therapists of 190 of the patients to obtain ratings of abuse and neglect based on all available data, including clinical interviews with patients and their relatives and information from referring clinicians and agencies. Principal-components analysis of the CTQ items yielded five rotated factors-emotional abuse, emotional neglect, sexual abuse, physical abuse, and physical neglect-closely replicating the factor structure in an earlier study of adult patients. The internal consistency of the CTQ factors was extremely high both in the entire sample and in every subgroup examined. When CTQ factor scores were compared with therapists' ratings in a series of logistic regression analyses, relationships between the two sets of variables were highly specific, supporting the convergent and discriminant validity of the CTQ. Finally, when therapists' ratings were used as the validity criterion, the CTQ exhibited good sensitivity for all forms of maltreatment, and satisfactory or better levels of specificity. These initial findings suggest that the CTQ is a sensitive and valid screening questionnaire for childhood trauma in an adolescent psychiatric inpatient setting.
Article
A study was undertaken to determine if female survivors of childhood and/or adolescent sexual abuse (CSA) would exhibit hypothalamic-pituitary-adrenal (HPA) axis abnormalities characteristic of patients with combat-related posttraumatic stress disorder (PTSD)--i.e., enhanced cortisol suppression to low-dose dexamethasone and increased density of lymphocyte glucocorticoid receptors. Nineteen women who reported experiencing severe CSA and 21 nonvictimized women participated in a low-dose (0.5 mg) dexamethasone suppression test and donated blood for measurement of lymphocyte glucocorticoid receptor binding. Women with CSA had significantly enhanced suppression of plasma cortisol in response to 0.5 mg dexamethasone compared to the nonvictimized women. These observations are consistent with findings in male veterans with combat-related PTSD. They suggest that this pattern of HPA axis dysfunction may be a characteristic sequel of psychiatric disorders that occur following a range of traumatic experiences. This HPA axis profile is different than that associated with acute stress or with major depressive disorder.
Article
Early childhood maltreatment has been associated with adverse adult health outcomes, but little is known about the magnitude of adult health care use and costs that accompany maltreatment. We examined differences in annual health care use and costs in women with and without histories of childhood sexual, emotional, or physical abuse or neglect. A random sample of 1225 women members of a health maintenance organization completed a 22-page questionnaire inquiring into childhood maltreatment experiences as measured by the Childhood Trauma Questionnaire. Health care costs and use data were obtained from the automated cost-accounting system of the health maintenance organization, including total costs, outpatient and primary care costs, and emergency department visits. Women who reported any abuse or neglect had median annual health care costs that were $97 (95% confidence interval, $0.47-$188.26) greater than women who did not report maltreatment. Women who reported sexual abuse had median annual health care costs that were $245 (95% confidence interval, $132.32-$381.93) greater than costs among women who did not report abuse. Women with sexual abuse histories had significantly higher primary care and outpatient costs and more frequent emergency department visits than women without these histories. Although the absolute cost differences per year per woman were relatively modest, the large number of women in the population with these experiences suggests that the total costs to society are substantial.
Article
The stress system coordinates the adaptive responses of the organism to stressors of any kind.(1). The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing "low turnover" osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.
Article
The goal of this study was to develop and validate a short form of the Childhood Trauma Questionnaire (the CTQ-SF) as a screening measure for maltreatment histories in both clinical and nonreferred groups. Exploratory and confirmatory factor analyses of the 70 original CTQ items were used to create a 28-item version of the scale (25 clinical items and three validity items) and test the measurement invariance of the 25 clinical items across four samples: 378 adult substance abusing patients from New York City, 396 adolescent psychiatric inpatients, 625 substance abusing individuals from southwest Texas, and 579 individuals from a normative community sample (combined N=1978). Results showed that the CTQ-SF's items held essentially the same meaning across all four samples (i.e., measurement invariance). Moreover, the scale demonstrated good criterion-related validity in a subsample of adolescents on whom corroborative data were available. These findings support the viability of the CTQ-SF across diverse clinical and nonreferred populations.
Article
The authors sought to determine innate immune system activation following psychosocial stress in patients with major depression and increased early life stress. Plasma interleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells were compared in medically healthy male subjects with current major depression and increased early life stress (N=14) versus nondepressed male comparison subjects (N=14) before and after completion of the Trier Social Stress Test. Trier Social Stress Test-induced increases in IL-6 and NF-kappaB DNA-binding were greater in major depression patients with increased early life stress and independently correlated with depression severity, but not early life stress. Natural killer (NK) cell percentages also increased following stress. However, there were no differences between groups and no correlation between NK cell percentage and stress-induced NF-kappaB DNA-binding or IL-6. Male major depression patients with increased early life stress exhibit enhanced inflammatory responsiveness to psychosocial stress, providing preliminary indication of a link between major depression, early life stress and adverse health outcomes in diseases associated with inflammation.
Article
The role of cytokines in bipolar disorder is still controversial. Although a few studies have found alterations of cytokines in bipolar disorder, their findings were inconsistent. The aim of this study was to determine whether the cytokines are involved in the pathophysiology of bipolar disorder. A total of 37 manic patients with bipolar disorder and 74 control subjects were recruited. The mitogen-induced production of tumor necrosis factor (TNF)-alpha, interleukin-6 (IL-6), IL-4, interferon (IFN)-gamma, and IL-2 was measured using quantitative sandwich ELISA at the time of admission and 6 weeks after mood stabilizer treatment. IL-6 and TNF-alpha production of bipolar manic patients was significantly higher than those of normal controls, while IL-4 values of the patients were significantly lower than normal controls. IL-6/IL-4, TNF-alpha/IL-4, IL-2/IL-4, and IFN-gamma/IL-4 ratios were significantly higher in bipolar manic patients than in normal controls. After 6 weeks of treatment, the levels of IL-6 significantly decreased compared with baseline. The effect of various types of mood stabilizers on cytokine production should be considered. These findings suggest that the increased activity of pro-inflammatory cytokines and an imbalance between pro-inflammatory and anti-inflammatory cytokines may play a role in the pathophysiology of bipolar disorder.
Article
Efforts are under way to articulate environmental, psychosocial, and biological conditions that may predispose the development and maintenance of obesity. There is increasing evidence that adverse childhood experiences such as childhood abuse may be implicated in the development of obesity. Given the dearth of prospective evidence for this link, the objective of this study was to track body mass across development (from childhood, through adolescence, and into young adulthood [ie, ages 6-27]) in a prospective, longitudinal study of abused and nonabused female subjects. Height and weight were obtained for 84 female subjects with substantiated childhood sexual abuse and 89 demographically similar comparison female subjects at 6 points during development. Obesity status was examined at various stages during development, and body-mass growth trajectories were contrasted across the 2 groups. It was hypothesized that, in comparison with their nonabused peers, abused female subjects would be more likely to (1) manifest obesity by early adulthood and (2) manifest high-risk growth trajectories throughout development. Obesity rates were not different across groups in childhood or adolescence. By young adulthood (ages 20-27), abused female subjects were significantly more likely to be obese (42.25%) than were comparison female subjects (28.40%). Hierarchical linear modeling growth-trajectory analyses indicated that abused female subjects, on average, acquired body mass at a significantly steeper rate from childhood through young adulthood than did comparison female subjects after controlling for minority status and parity. Psychosocial difficulties (eg, depression) and psychobiological conditions (eg, hypothalamic-pituitary-adrenal axis dysregulation) that have been shown to be related to both childhood abuse and obesity may help to explain these results. The identification of high-risk growth trajectories may improve health outcomes for victims. Systematic study of the mechanistic pathways and mediating processes that would help to explain the connection between childhood sexual abuse and later obesity is encouraged.
Chapter in: Childhood Maltreatment and Mood Disorders
  • E T C Lippard
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Lippard, E.T.C., & Nemeroff, C.B. (2020). Chapter in: Childhood Maltreatment and Mood Disorders. APA Textbook of Mood Disorders Second Edition. By C.B. Nemeroff, S.M. Strakowski, N. Rasgon, and A.F. Schatzberg, Eds.
C-reactive protein: a critical update.
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Pepys, M.B., & Hirschfield, G.M. (2003). C-reactive protein: a critical update. J. Clinical Investig, 111(12), 1805-12. https://doi.org/10.1172/jci18921
Adverse childhood experiences and severity levels of inflammation and depression from childhood to young adulthood: a longitudinal cohort study.
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Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress.
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