PreprintPDF Available

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

Authors:
Preprints and early-stage research may not have been peer reviewed yet.

Abstract

Background Early life adversity such as childhood emotional, physical, and sexual trauma is associated with a plethora of 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 not well understood. Methods We studied patients (n=280) who were admitted to a psychiatric rehabilitation center. Self-reported histories of childhood emotional, physical, and sexual trauma history were collected. At the time of admission, we also assessed individuals’ body mass index (BMI) and collected blood samples that were used to examine levels of inflammatory marker C-reactive protein (CRP). Results The prevalence of all three types of abuse were quite 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 controlling for BMI. Limitation Our sample is relatively young, with an average age of 27.2 years, with 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, which were common overall in the sample. Future studies need to assess the causal link between childhood sexual trauma and poorer health outcomes later in life. HIGHLIGHTS - The prevalence of both childhood abuse experiences and elevations in inflammatory markers were quite high. - We found that the history and severity of childhood sexual abuse were differentially correlated with later life inflammatory status and body mass index, with childhood emotional and physical abuse not showing the same degree of correlation with inflammatory status later in early adulthood. - These results demonstrate how specific elements of environmental adversity, which, when suffered at a critical developmental period, can have lingering negative physiological consequences later in life.
1
Specific Associations Between Type of Childhood Abuse and Elevated C-Reactive Protein in Young Adult Psychiatric
Rehabilitation Participants
Mbemba M. Jabbi1, Philip D. Harvey2, Raymond J. Kotwicki3, and Charles B. Nemeroff1
1Department of Psychiatry & Behavioral Sciences, The University of Texas at Austin, Dell Medical School, Austin, TX 78738.
2Department of Psychiatry & Behavioral Sciences, The University of Miami Miller School of Medicine, Miami, FL.
3Skyland Trail, Atlanta, Georgia
Corresponding Authors: mbemba.jabbi@austin.utexas.edu [Mbemba M. Jabbi]; pharvey@med.miami.edu [Philip D. Harvey];
cnemeroff@austin.utexas.edu [Charles B. Nemeroff]
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
2
ABSTRACT
Background: Early life adversity such as childhood emotional, physical, and sexual trauma is associated with a plethora of 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 not well understood.
Methods: We studied patients (n=280) who were admitted to a psychiatric rehabilitation center. Self-reported histories of childhood
emotional, physical, and sexual trauma history were collected. At the time of admission, we also assessed individuals’ body mass
index (BMI) and collected blood samples that were used to examine levels of inflammatory marker C-reactive protein (CRP).
Results: The prevalence of all three types of abuse were quite 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 controlling for BMI.
Limitation: Our sample is relatively young, with an average age of 27.2 years, with 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, which were common overall in the sample. Future studies need to assess the causal link between childhood sexual trauma
and poorer health outcomes later in life.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
3
KEYWORDS: Child Abuse and Neglect, Sexual Abuse, Inflammation
HIGHLIGHTS
- The prevalence of both childhood abuse experiences and elevations in inflammatory markers were quite high.
- We found that the history and severity of childhood sexual abuse were differentially correlated with later life inflammatory
status and body mass index, with childhood emotional and physical abuse not showing the same degree of correlation with
inflammatory status later in early adulthood.
- These results demonstrate how specific elements of environmental adversity, which, when suffered at a critical developmental
period, can have lingering negative physiological consequences later in life.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
4
INTRODUCTION
Childhood and adolescence are pivotal developmental periods during which physical and behavioral functions develop to shape later
life adaptive functioning. Thus, traumatic environmental experiences during critical periods for a developing individual can have
profound and lasting negative consequences on developmental and later-life health outcomes (Schrepf et al., 2014; Keicolt-Glaser et
al., 2015; Petrov et al., 2016; Moraes et al., 2017; Jonker et al., 2017). For instance, previous research showed that childhood trauma
(Gould et al., 2012), including emotional, physical, and sexual abuse or other forms of maltreatment is associated with cognitive
impairments and poses long-lasting negative health consequences and significant morbidity and premature mortality (Edwards et al.,
2012; Lu et al., 2013; Matthews et al., 2014; Pereira et al. 2019; Teicher et al., 2021; Lippard & Nemeroff 2020; Lippard & Nemeroff
2021).
Although research is beginning to identify the consequences of childhood adversity in terms of the negative impacts it exerts
on central nervous system (CNS) and peripheral biomarkers, the precise linkage between childhood abuse history and later-life
physical and psychological morbidity is not fully understood. Previous research revealed that over half of all developing children or
their caregivers report at least one substantial traumatic experience before reaching 18 (Saunders & Adam 2014). Traumatic incidents
of perceived or experienced violations of bodily integrity in the forms of emotional abuse, including the threat of physical harm,
physical abuse, including actual injury resulting from violence, or the experience of sexual abuse, can have far-reaching negative
consequences on later life emotional and physical well-being, morbidity, and poorer health outcomes (Scheffers M et al., 2017;
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
5
Lippard and Nemeroff, 2020). However, whether these different childhood trauma subtypes and the severity of their occurrences can
differentially influence later life mental and physical health outcomes is not well-understood.
Early-life trauma increases the risk of several psychiatric disorders, including depression (Kiecolt-Glaser et al., 2015), anxiety
disorders, and PTSD (Choi & Sikkema 2016; Gould et al., 2021). Moreover, even in domains of severe mental illness, early life
trauma appears to be associated with an increased risk for the development of schizophrenia among individuals equally predisposed by
having a first-degree relative with the disease (Morgan & Anderson 2016). Further, individuals with early life trauma are more likely
to develop treatment-resistant mood disorders and manifest multiple features of poor disease outcomes, including suicidal behaviors
(Kiecolt-Glaser et al., 2015; Tunnard et al., 2014; Yrondi et al., 2021).
More recently, the effects of early life trauma on inflammatory responses and long-term dysregulations in immune functioning
have been demonstrated (Pace et al., 2006; Kiecolt-Glaser et al., 2015; Pitharoulli et al., 2021; Danese and Lewis, 2017). For
example, circulating C-reactive protein (CRP), an acute-phase protein of hepatic origin that rises in response to inflammation, can be
increased after early life trauma (Keicolt-Glaser 2015; Pitharoulli et al., 2021). Elevated levels of CRP are also associated with
cardiovascular disease (Kiecolt-Glaser 2015; Ananthan & Lyon 2020; Pitharoulli et al., 2021), obesity (Matthews et al., 2014), and
certain cancers (Ananthan & Lyon 2020). In addition, elevated CRP concentrations (Keicolt-Glaser 2015; Ananthan & Lyon 2020;
Pitharoulli et al., 2021) in traumatized individuals later in life can be associated with not only abuse histories but also with elevated
measures of body mass index (BMI), anxiety, as well as depressive symptoms later in life (Noll et al., 2007).
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
6
The three types of early life abuse measured with the childhood trauma questionnaire (CTQ): physical, emotional, and sexual
abuse (Bernstein et al., 1994; 1997 & 2003), may have different implications for later-life physical and mental health outcomes. For
instance, in a study of newly admitted adolescent inpatients, a history of emotional abuse, but not physical or sexual abuse, correlated
with being cyberbullied immediately before admission to an inpatient psychiatric unit (Saltz et al., 2020). Likewise, in a study of risk
for developing PTSD in the immediate aftermath of trauma (Gould et al., 2021), the total severity of early life trauma, as measured by
the total CTQ score, was associated with risk for the development of PTSD following this additional traumatic experience. In
addition, many studies have suggested that sexual abuse is particularly pernicious in risk for later life psychopathology (Kiecolt-Glaser
2015; Baumeister et al., 2016; Ananthan & Lyon 2020; Pitharoulli et al., 2021).
Matthews and colleagues examined the relationship between CRP levels and childhood sexual, emotional, and physical abuse
and neglect in a cohort of mid-life women (Matthews et al., 2014). They found that sexual and emotional abuse history, history of
emotional and physical neglect, and the total number of recorded incidents of childhood abuse were associated with elevated CRP
levels over a 7-year period. These findings of correlations between childhood abuse history and number of abuses with later life CRP
levels were found to be moderated by BMI (Matthews et al., 2014). All participants were female, and all were outpatients. In addition,
recent integrative reviews and meta-analyses examining the relationship between the history of childhood adversity and later life
measures of CRP, including measures of interleukin family of inflammatory factors, and tumor necrosis factor-α (TNF-α), have found
differential relationships between the type of trauma and later life inflammatory measures, but the results of these meta-analyses were
not clear-cut (Shrepf et al. 2014; Baumeister et al. 2016; Pereira et al. 2019; Brown et al. 2021).
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
7
In the present study, we examined young (Mean age=27) females and males, varying in their lifetime trauma history, at the
time of admission to a psychiatric rehabilitation facility. We assessed the presence and severity of early life trauma by documenting
the history of a) emotional abuse, b) physical abuse, and c) sexual abuse using the CTQ (Bernstein et al., 1994; 1997 & 2003). Our
study design affords a potentially reliable assessment of childhood trauma by assessing a young adult sample with limited chronicity
of psychiatric and medical conditions and more proximal experiences of childhood trauma. Obtaining BMI and CRP data at the time
of admission during the first physical examination, precluded treatment-related changes in CRP or BMI from influencing the results.
These assessments at the time of admission allowed for the exclusion of individuals with chronic medical conditions that could cause
elevations in inflammatory markers. We specifically examined the relationship between emotional, physical, and sexual trauma
history (particularly meeting criteria for a definite history of abuse), and a) levels of CRP, and b) body mass index (BMI)/obesity.
Previous studies have indicated that sexual abuse may be particularly pernicious both for later effects on functioning and with
elevations in BMI (Moraes et al., 2017). In addition, previous studies in depression have highlighted the relationship between CRP
levels and obesity (Pitharouli et al., 2021). Since elevated CRP and BMI have both been implicated as biophysical consequences of
abuse (Matthews et al., 2014; Kiecolt-Glaser 2015; Ananthan & Lyon 2020; Pitharoulli et al., 2021; Noll et al., 2007), we examined
the independent association of BMI and CRP with each of the three types of early-life abuse measured by the CTQ.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
8
METHODS
Participants.
This study comprised patients admitted to Skyland Trail, a non-profit residential and ambulatory psychiatric rehabilitation facility in
Atlanta, GA. The center has a continuum of care in the context of a recovery model, where more symptomatic individuals were
initially placed in residential facilities with planned transitions into day treatment, intensive outpatient, and transitional treatment
tracks as symptomology improves. Therefore, less symptomatic individuals were directly entered into day treatment or intensive
outpatient tracks. Individuals with chronic physical illnesses cannot be managed at Skyland Trail and are not admitted to residential
services. Patients were included in the current analyses if they were admitted between April 2019 and December 2020 and completed
the Childhood Trauma Questionnaire (CTQ), had a physical examination with a BMI score, and a blood sample collected at admission
and assayed for CRP (n = 280). Diagnostic information was collected with the Mini-International Neuropsychiatric Inventory (MINI).
Diagnoses using DSM-5 criteria were generated at admission with a consensus process involving a) trained clinicians who
administered the structured rating scale and b) an attending psychiatrist who reviewed all available records and the clinician
impressions. These diagnoses were collected at admission using a structured procedure on which we had previously published the
methods (Kotwicki and Harvey, 2013).
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
9
The Institutional Review Board at the University of Miami Miller School of Medicine evaluated this project. That IRB determined
that since all data were obtained for clinical purposes and were examined on a completely de-identified basis, the project is exempt
from IRB review. See this determination in supplemental materials.
Assessments.
After admission and during their entire rehabilitation stay, patients at the center received biweekly clinical assessments tailored to
their primary treatment targets. Participants with a diagnosis of major depression from the MINI interview were assessed with the
Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). Participants with a
MINI diagnosis of bipolar disorder were also evaluated with the MADRS and the Young Mania Rating Scale (YMRS). The Brief
Psychiatric Rating Scale (BPRS) was used to assess all cases with psychotic symptoms, including participants with major depression
or bipolar disorder with psychotic features. Ratings were performed by raters who were not the primary clinicians. Thus, not all
participants were rated with the same clinical assessment scales, for which we created an aggregate for use in statistical analyses as
described below.
Childhood Trauma Questionnaire: The CTQ is a widely used 28-item self-report questionnaire that asks about experiences of
abuse or neglect in childhood (Bernstein et al., 1994). It consists of five subscales measuring emotional, physical, or sexual abuse and
emotional or physical neglect (Bernstein et al., 1994; 1997 & 2003). It has good internal consistency, and each subscale has items
assessing minimization and denial, with all CTQ items reported on a 5 point scale ranging from Never True to Very Often True. The
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
10
scale requires approximately a 6th-grade reading level to complete. We used the total scores for the CTQ and the three abuse
subscales measuring a history of emotional, physical, or sexual abuse for our analyses. For our primary analyses, we generated
present/absent ratings based on the criteria of Walker et al. (1999). These cutoffs include scores of 8 or more on sexual and physical
abuse and 10 or more on emotional abuse.
C-Reactive Protein. Blood samples were collected at the time of admission during the physical examination from the antecubital
vein, and CRP levels were measured at a commercial laboratory using the high sensitivity assay for CRP. For CRP, we used the total
score and generated three different subclassifications of blood levels of CRP: <1.0 mg/L; 1.0 mg/L to 3.0 mg/L; and >3.0 mg/L. For
reference, any CRP levels above the 0-3 mg/L are considered to reflect abnormally high/disease-related levels of peripheral
inflammation (Pepys & Hirschfield 2003).
Body Mass Index (BMI) We calculated BMI from height and weight measured during the admission physical examination when the
blood sample for measurement of the CRP was also collected. As with the other variables, we collected BMI as a continuous variable
and divided subjects into low or normal weight (BMI<24.9), overweight (BMI 25-29.9), and obese (BMI 30 or more) categories.
Data Analyses.
Several analyses were performed. We examined the categorical associations between present absent ratings on the three CTA
variables and the three classes of BMI and CRP measures. As a secondary analysis, we computed intercorrelations between the full
range of raw scores on the three different abuse subscales and total scores on the CTQ and the full range of scores on BMI and CRP,
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
11
using nonparametric Spearman Rank correlations. Finally, in the event of significant correlations between BMI and CRP and any of
the categorical variables of abuse, we planned to use linear regression analysis to determine whether the associations between CRP
and BMI and abuse were independent or if elevations in CRP were to some degree explained by increased body mass index. We also
examined group differences in all four clinical rating scales with t-tests for the three abuse subtypes on a present/absent basis. We also
created a composite clinical severity scale by standardizing all the scales and creating an aggregate score based on the average of the z
scores for symptom severity for the individual scales.
We performed a power analysis to identify the size of correlations that could be detected meaningfully. Using the power
analysis module of SPSS version 28 (IBM Corporation, 2021), we determined that a Pearson correlation of r=.17 could be detected
with our sample size of 280, at p<.05, power=.80. Further, in terms of regression analyses, the power analysis suggested that we could
detect an overall regression partial correlation of .18, at p<.05, power>.80. Thus, we had enough power to detect correlations that
share a 3% variance between variables and would be at the lowest range of possible clinical significance.
RESULTS
Descriptive information on the patient population is presented in Table 1. Participants were evenly divided between males and
females (with an average age of 27.2) and the sample was largely white. Most were single and never married, and the principal
diagnoses were in the mood disorders category. In addition, 46% had comorbid substance abuse, 42% were of average weight, and
28% were obese, with the high CRPs in the > 3.0 range being present in 26% of the participants.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
12
Table 2 presents the means and standard deviations for the severity scores for abuse categories and the clinical variables and
yes/no classifications based on our classification strategy; 53% were positive for emotional abuse, 27% for physical abuse, and 21%
for sexual abuse. Furthermore, 27 of 280 cases (9.6%) were positive for all three forms of abuse. In comparison, both sexual abuse
and emotional abuse (but not physical abuse) were positive for 17 of the 280 cases (6%), and both sexual abuse and physical abuse
(but not emotional abuse) were present in only 2 cases (<1.0%).
Table 3 presents the categorical analyses of the abuse subtypes yes/no classification and BMI and CRP groupings. As seen in
the table, for sexual abuse, but not emotional or physical abuse, there was a significantly higher number of participants with very high-
level CRP scores, >3.0 mg/L. Obesity was not associated with the presence of any of the three types of abuse.
We also examined
other possible patient characteristics associated with the three different forms of abuse. We found that sex was not associated with any
of the three abuse subtypes, all X2 (1)<1.91, all p>.39, and total scores on the CTQ did not differ as a function of sex, t(278)=.35,
p=.73, and neither did length of stay did not correlate with CTQ total scores, ρ=-.07, p=.314. The occurrence of a substance abuse
diagnosis did not differ as a function of the presence of any of the three types of abuse, all at X2 (1)<2.10, all p>.15.
Table 4 presents intercorrelations between the CTQ variables and their correlations with BMI and CRP and group differences
(Abuse present/Absent) in the four clinical variables. All abuse variables were significantly intercorrelated with Spearman’s rank
correlation. We found associations between childhood abuse type and CRP to be significant only for sexual abuse severity-CRP
correlations (ρ=.168, p=0.005), consistent with the analyses presented above regarding present/absent status for sexual abuse and
being in the most elevated group for CRP. In contrast, and consistent with the group-based analyses, we did not find any significant
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
13
correlations between CRP and emotional (ρ=0.038, p=.530) or physical (ρ=-.036, p=.549) abuse severity. BMI did not correlate with
a history of emotional abuse (ρ=0.02, p=.252), physical abuse (ρ =0.02), or sexual abuse, ρ=0.13, p=.07. Furthermore, group
differences based on presence/absence of childhood abuse subtype in relation to symptom ratings were observed only for Hamilton
Anxiety scores, wherein physical and sexual abuse history, but not the history of emotional abuse, were associated with significantly
higher baseline scores of anxiety. Depression, mania, and psychotic symptoms as indexed by the BPRS did not differ significantly
between the different abuse groups, and the composite score of BPRS did not vary as a function of abuse history either. Finally, the
presence of PTSD comorbidity (which was found in 84 of the 280 participants, with 58 comorbid for MDD and PTSD), was
significantly associated with total CTQ scores. Those with comorbid PTSD had higher scores on the total CTQ (p=0.016,
t(278)=2,42), as well as emotional (p<0.001,t(278)=4.12), physical (p=0.003, t(278)=3.03) and sexual abuse (p<0.001, t(278)=5.32).
However, PTSD comorbidity was not related with either CRP levels (p=.47, t(278)=.49) or BMI (p=.12, t(278)=.73).
The severity of sexual abuse was associated with CRP on both dichotomous and continuous analyses, so, despite the lack of
correlation between BMI and CRP, we used a regression analysis to evaluate whether the relationships between CRP, BMI, and sexual
abuse were overlapping. We predicted CRP scores in the entire sample, entering BMI in the first block of regression analysis and then
entering the three abuse severity scores in the second block, in a stepwise model. The overall regression analysis was significant at
F(2,277)=10.80, p<.001. Specifically, the BMI scores entered first in the regression accounting for 5% of the variance in CRP scores
(partial correlation: r=.22, t=2.75, p<.001), while the severity of sexual abuse accounted for an additional 3% of the variance (Partial
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
14
correlation: r=.17, t=2.09, p=.031). Physical and emotional abuse history did not predict CRP levels after the entry of BMI and sexual
abuse in the regression model: both t<1.51, p>.13.
DISCUSSION
In this study, we examined the relationship between the childhood trauma subtypes and later-life peripheral inflammation as assessed
with CRP levels and found a significant\influence of childhood sexual trauma on inflammatory markers. On a present/absent basis,
53%, 27%, and 21% of the participants reported childhood experiences of emotional, physical, and sexual abuse, respectively. These
results underscore the high prevalence of early life trauma in individuals receiving treatment for psychiatric disorders. Furthermore, as
this was a rehabilitation facility and all participants were previously treated without recovery, these individuals comprising the current
study sample presented, with more refractory disease.
We found that higher levels of CRP correlated significantly with only the presence of a history of sexual abuse. This observed
relationship between sexual abuse and CRP scores could not be explained by our measures of acute mood and psychotic symptoms, as
the severity of depression, mania, and psychotic symptoms did not differ between childhood trauma subtypes. In addition, the severity
of anxiety at the time of admission was also found to be elevated in participants with a physical or sexual abuse history, but not
emotional abuse.
Of interest, the presence of a history of sexual abuse was not as strongly related to obesity or general mental illness diagnoses.
Notably, except for childhood sexual abuse history, childhood abuse did not show a significant relationship, on either a continuous or
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
15
dichotomous basis, with later life circulatory CRP levels. Our current finding aligns in part with a previous study showing a trend
towards a statistically significant link between childhood sexual and emotional but not physical trauma abuse with indices of
physiological health in a middle-aged female-only cohort (Matthews et al., 2014). Our findings also support another recent
longitudinal study that followed children and their parents from when the children are ages 9-18 and then sampled their inflammatory
CRP levels between ages 18-23, finding that a history of childhood sexual abuse and bullying victimization were the only two abuse
types associated with later life elevated CRP levels (Lob et al. 2022). Our results also lend credence to the suggestion that the
traumatic nature of childhood sexual abuse renders it a far-reaching negative risk factor for later life poor health outcomes (Matthews
et al., 20214; Kiecolt-Glaser 2015; Baumeister et al., 2016; Scheffers M et al., 2017; Ananthan & Lyon 2020; Lippard & Nemeroff
2020; Pitharoulli et al., 2021). Together, our results suggest that, possibly more than emotional and physical abuse, childhood sexual
trauma may have an enduring influence on later life inflammation.
Of the 280 patients whose data were examined, 84 had comorbid PTSD of which 58 were diagnosed with primary MDD, and
20 had bipolar disorder. It may seem surprising that primary diagnoses of PTSD were not more common in our sample given the
pervasive history of childhood trauma, which was present in 65.26% of our participants. As noted above, childhood abuse combined
with recent traumatic experiences appears to increase risk of the near-term development of PTSD. However, trauma exposure in
childhood is also clearly linked to mood disorders (Lippard & Nemeroff 2022), especially MDD (Gordon, Nemeroff & Felitti 2020;
Teicher, Gordon & Nemeroff 2021) and bipolar disorder (Gordon, Nemeroff & Felitti 2020; Teicher, Gordon & Nemeroff 2021),
leading some to suggest that the field of psychiatry needs to include childhood trauma-induced disorder as a special diagnostic
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
16
category (Gordon, Nemeroff & Felitti 2020; Teicher, Gordon & Nemeroff 2021), much like proposals for transdiagnostic
consideration of suicidal ideation and behavior.
It is important to note that, although our findings are based on a sample of well-characterized psychiatric patients in a
relatively controlled environment, the following limitations deserve mention. First, our sample size of 280 participants is not large,
and minorities are under-represented, making our study sample not representative of the US population. The average sample age of
27.2 years is also relatively young. Second, seventy-five percent of the participants were either single or never married at the time of
the study, which is not surprising given the relatively young age range of the sample. Third, psychiatric diagnoses were unevenly
distributed, with major depression predominating and psychosis being relatively rare. Fourth, there were no sex differences in the
prevalence of different types of abuse. Still, all participants were receiving treatment for persistent psychiatric morbidities, which
might be associated with a lack of difference in the prevalence of the abuse types. Fifth, the CRP measures could be impacted by
medication use. Still, because our currently reported CRP data were collected at baseline (i.e., at the time of admission), we could not
fully control for prior medication. A lack of reliable data on medication use before admission means the possible effects of
medication use before admission to the facility could not be accounted for. However, the specific correlation between CRP and only
one of the three abuse subtypes argues against generic effects of medication treatment or other systemic illness because it is not clear
how this bias could be related to a single type of early childhood abuse. Fifth, forty-six percent of our sample had a history of
comorbid substance use even though none of these clinical variables, including sex, showed any significant relationship with CRP or
BMI status. Finally, while our focus on CRP measures from peripheral blood has yielded important findings, the interpretations of
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
17
our results showing selective inflammatory CRP correlates for sexual abuse are limited by the lack of interactive biomarkers such as
brain imaging measures (Sheffield et al. 2013), or glucocorticoid metrics of the HPA-axis responses (Stein et al. 1997; Sapolsky et al.
2000), and transcription factor activity such as nuclear factor-
κ
B (NF-
κ
B) pathway responses (Pace et al. 2012). Considering our
findings of an interaction between sexual abuse history and CRP levels, additional measures of glucocorticoid levels such as cortisol at
admission could reveal further mechanistic insights given the role of glucocorticoids as transcription factors that mediate
immune/inflammatory responses, and in influencing both carbohydrate and blood glucose metabolic functions during stressful and
traumatic life events (Sapolsky et al. 2000).
Future studies need to recruit more representative samples across a wider age range spanning socioeconomic and racial groups,
including younger individuals, where the abuse may have been even more proximal, and older participants to examine the lifelong
persistence of these effects. Finally, the relationship between treatment response and measures of inflammation is an important issue
that needs to be addressed with follow-up data, which is now being collected at this research site.
Conclusion
The high prevalence rate of childhood trauma in this psychiatric population and the link between abuse history and later life negative
consequences was supported by our findings of a specific association between childhood sexual abuse and early-adulthood
inflammatory status. This finding is a compelling example of how childhood environmental adversity, at a critical developmental
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
18
period, can have lingering negative physiological consequences. Future studies need to include more representative samples and
further examine the mechanism by which early-life sexual trauma can have negative implications for physical health outcomes.
Acknowledgements:
The authors thank the patients and family members for the data used in this study. The authors further thank Lokavya Marreddy for
help with the preparation of this manuscript.
Declaration of potential conflicts:
M Jabbi.
None.
PD Harvey Dr. Harvey has received consulting fees or travel reimbursements from Alkermes, ANeuroTech (division of Anima BV),
Bio Excel, Boehringer Ingelheim, Karuna Pharma, Minerva Pharma, and Sunovion Pharma during the past year. In addition, he
receives royalties from the Brief Assessment of Cognition in Schizophrenia (Owned by Verasci, Inc). He is Chief Scientific Officer of
i-Function, Inc.
RJ. Kotwicki.
None.
CB Nemeroff.
Research/Grants: National Institutes of Health (NIH)
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
19
Consulting (last 12 months): ANeuroTech (division of Anima BV), Signant Health, Sunovion Pharmaceuticals, Inc., Janssen Research
& Development LLC, Magstim, Inc., Navitor Pharmaceuticals, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Acadia
Pharmaceuticals, Axsome, Sage, BioXcel Therapeutics, Silo Pharma, XW Pharma, Neuritek, Engrail Therapeutics, Corcept
Therapeutics Pharmaceuticals Company
Stockholder: Xhale, Seattle Genetics, Antares, BI Gen Holdings, Inc., Corcept Therapeutics Pharmaceuticals Company, EMA
Wellness, TRUUST Neuroimaging
Scientific Advisory Boards: ANeuroTech (division of Anima BV), Brain and Behavior Research Foundation (BBRF), Anxiety and
Depression Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc.,
Magnolia CNS, Heading Health, TRUUST Neuroimaging
Board of Directors: Gratitude America, ADAA, Xhale Smart, Inc.
Patents:
- Method and devices for transdermal delivery of lithium (US 6,375,990B1)
- Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US
7,148,027B2)
Speakers Bureau:
None
Author Statement
Contributors: M Jabbi, P Harvey, R Kotwicki and C Nemeroff. P Harvey, R Kotwicki and C Nemeroff conceived and designed the
study. R Kotwicki acquired the data. P Harvey and M Jabbi performed the data analysis. P Harvey, M Jabbi, R Kotwicki, and C
Nemeroff wrote the paper. There was no external funding for this work.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
20
REFERENCES
Ananthan, K., & Lyon, A.R. (2020). The Role of Biomarkers in Cardio-Oncology. Journal of Cardiovascular Translational
Research, 13(3), 431-450. https://doi.org/10.1007/s12265-020-10042-3
Arasappan D, Eickhoff SB, Nemeroff CB, Hofmann HA, Jabbi M. (2021). Transcription Factor Motifs Associated with Anterior
Insula Gene Expression Underlying Mood Disorder Phenotypes. Mol Neurobiol, 58(5):1978-1989. http://doi.org/10.1007/s12035-020-
02195-8
Baumeister, D., Akhtar, R., Ciufolini, S., Pariante, C.M., & Mondelli, V. (2016). Childhood
trauma
and adulthood
inflammation: a
meta-analysis of peripheral
C-reactive
protein, interleukin-6 and tumour necrosis factor-alpha. Molecular Psychiatry, 21(5), 642-
9. https://doi.org/10.1038/mp.2015.67
Bernstein, D.P., Ahluvalia, T., Pogge, D., & Handelsman, L. (1997). Validity of the Childhood Trauma Questionnaire in an adolescent
psychiatric population. Journal of the American Academy of Child & Adolescent Psychiatry, 36(3), 340-
8. https://doi.org/10.1097/00004583-199703000-00012
Bernstein, D.P., Fink, L., Handelsman, L., Foote, J., Lovejoy, M., Wenzel, K., Sapareto, E., Ruggiero, J. (1994). Initial reliability and
validity of a new retrospective measure of child
abuse
and neglect. American Journal of Psychiatry, 151(8), 1132-
6. https://doi.org/10.1176/ajp.151.8.1132
Bernstein, D.P., Stein, J.A., Newcomb, M.D., Walker, E., Pogge, D., Ahluvalia, T., Stokes, J., Handelsman, L., Medrano, M.,
Desmond, D., & Zule, W. (2003). Development and validation of a brief screening version of the Childhood Trauma
Questionnaire. Child Abuse & Neglect, 27(2), 169-90. https://doi.org/10.1016/S0145-2134(02)00541-0
Choi, K.W., & Sikkema, K.J. (2016). Childhood Maltreatment and Perinatal Mood and
Anxiety
Disorders: A Systematic
Review. Trauma, Violence, & Abuse, 17(5), 427-453. https://doi.org/10.1177/1524838015584369
Danese, A., & J Lewis, S. (2017). Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood
Trauma? Neuropsychopharmacology, 42(1), 99-114. https://doi.org/10.1038/npp.2016.198
Dong, Q., & Wright, J.R. (1996). Expression of C-reactive protein by alveolar macrophages. Journal of Immunology, 156, 4815–
4820.
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
21
Edwards, V.J., Freyd, J.J., Dube, S.R., Anda, R.F., Felitti, V.J. (2012). Health Outcomes by Closeness of Sexual Abuse Perpetrator: A
Test of Betrayal Trauma Theory. Journal of Aggression, Maltreatment & Trauma, 21:133–148.
Gabay, C., & Kushner, I. (1999). Acute-phase proteins and other systemic responses to inflammation. New England Journal of
Medicine, 340, 448–454. https://doi.org/10.1056/nejm199902113400607
Gordon JB, Nemeroff CB, Felitti V. (2020). Screening for Adverse Childhood Experiences.
JAMA,, 324(17):1789. https://
doi.org/10.1001/jama.2020.16449
Gould, F., Harvey, P.D., Hodgins, G., Jones, M.T., Michopoulos, V., Maples-Keller, J., Rothbaum, B.O., Rothbaum, A.O., Ressler,
K.J., Nemeroff, C.B. (2021). Prior trauma-related experiences predict the development of post-traumatic stress disorder after a new
traumatic event.
Depression and Anxiety, 38(1), 40-47. https://doi.org/10.1002/da.23084
Herisson, F., Frodermann, V., Courties, G., Rohde, D., Sun, Y., Vandoorne, K., Wojtkiewicz, G.R., Masson, G.S., Vinegoni, C., Kim,
J., Kim, D.E., Weissleder, R., Swirski, F.K., Moskowitz, M.A., & Nahrendorf, M. (2018). Direct vascular channels connect skull bone
marrow and the brain surface enabling myeloid cell migration. Nature Neuroscience, 21(9), 1209-
1217. https://doi.org/10.1038/s41593-018-0213-2
Jabbi M, Arasappan D, Eickhoff SB, Strakowski SM, Nemeroff CB, Hofmann HA. (2020). Neuro-transcriptomic signatures for mood
disorder morbidity and suicide mortality. J Psychiatr Res, 127:62-74. https://doi.org/10.1016/j.jpsychires.2020.05.013
Jonker, I., Rosmalen, J.G.M., & Schoevers, R.A. (2017).
Childhood life events, immune activation and the development of mood and
anxiety disorders: the TRAILS study. Translational Psychiatry, 7(5), e1112. https://doi.org/10.1038/tp.2017.62
Kiecolt-Glaser, J.K., Derry, H.M., & Fagundes, C.P.
(2015). Inflammation: depression fans the flames and feasts on the
heat.
America Journal of Psychiatry, 172(11), 1075-91. https://doi.org/10.1176/appi.ajp.2015.15020152
Kotwicki, R., Harvey, P.D. (2013). Systematic Study of Structured Diagnostic Procedures in Outpatient Psychiatric Rehabilitation: A
Three-year, Three-cohort Study of the Stability of Psychiatric Diagnoses. Innov. Clin. Neurosci;10(5-6):14-19.
Lippard, E.T.C., & Nemeroff, C.B. (2020). The Devastating Clinical Consequences of Child Abuse and Neglect: Increased Disease
Vulnerability and Poor Treatment Response in Mood Disorders. American Journal of Psychiatry, 177(1), 20-
36. https://doi.org/10.1176/appi.ajp.2019.19010020
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
22
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.
Lippard ETC, Nemeroff CB. (2022). Going beyond risk factor: Childhood maltreatment and associated modifiable targets to improve
life-long outcomes in mood disorders. Pharmacol Biochem Behav, 215:173361. https://
doi.org/10.1016/j.pbb.2022.173361
Liu T, Zhang L, Joo D, Sun SC. (2017). NF-
κ
B signaling in inflammation.
Signal Transduct Target Ther, 2:17023-. https://doi.org/10.1038/sigtrans.2017.23
Lob E, Lacey R, Giunchiglia V, Steptoe A. (2022). Adverse childhood experiences and severity levels of inflammation and depression
from childhood to young adulthood: a longitudinal cohort study. Mol Psychiatry. (In press). https://doi.org/10.1038/s41380-022-
01478-x
Lu, S., Peng, H., Wang, L., Vasish, S., Zhang, Y., Gao, W., Wu, W., Liao, M., Wang, M.,Tang, H., Li, W., Li, W., Li, Z., Zhou, J.,
Zhang, Z., Li, L. (2013). Elevated specific peripheral cytokines found in major depressive disorder patients with childhood trauma
exposure: A cytokine antibody array analysis. Comprehensive Psychiatry, 54( 7), 953-961.
Matthews, K.A., Chang, Y.F., Thurston, R.C., & Bromberger, J.T. (2014). Child abuse is related to
inflammation
in mid-
life
women: role of obesity. Brain, Behavior, and Immunity, 36, 29-34. https://doi.org/10.1016/j.bbi.2013.09.013
Moraes, J.B., Maes, M., Barbosa, D.S., Ferrari, T.Z., Uehara, M.K.S., Carvalho, A.F., & Nunes, S.O.V. (2017).
Elevated C-reactive
Protein Levels in Women with Bipolar Disorder may be Explained by a History of Childhood Trauma, Especially Sexual Abuse, Body
Mass Index and Age. CNS & Neurological Disorders Drug Targets, 16(4), 514-
521. https://doi.org/10.2174/1871527316666170407151514
Morgan, C., & Gayer-Anderson, C. (2016). Childhood adversities and psychosis: evidence, challenges, implications.
World
Psychiatry, 15(2), 93-102. https://doi.org/10.1002/wps.20330
Noll, J.G., Zeller, M.H., Trickett, P.K., & Putnam, F.W. (2007). Obesity risk for female victims of childhood sexual abuse: a
prospective study.
Pediatrics, 120(1), e61-e67. https://doi.org/10.1542/peds.2006-3058
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
23
Pace, T.W., Mletzko, T.C., Alagbe, O., Musselman, D.L., Nemeroff, C.B., Miller, A.H., & Heim, C.M. (2006). Increased stress-
induced inflammatory responses in male patients with major depression and increased early life stress. American Journal of
Psychiatry, 163(9), 1630-3. https://doi.org/10.1176/ajp.2006.163.9.1630
Pace TW, Wingenfeld K, Schmidt I, Meinlschmidt G, Hellhammer DH, Heim CM. (2012). Increased peripheral NF-
κ
B pathway
activity in women with childhood abuse-related posttraumatic stress disorder. Brain Behav Immun, 26(1):13-7.
https://doi.org/10.1016/j.bbi.2011.07.232
Pepys, M.B., & Hirschfield, G.M. (2003). C-reactive
protein: a
critical
update. Journal of Clinical Investigation, 111(12), 1805-
12. https://doi.org/10.1172/jci18921
Petrov, M.E., Davis, M.C., Belyea, M.J., & Zautra, A.J. (2016).
Linking childhood abuse and hypertension: sleep disturbance and
inflammation as mediators.
Journal of Behavioral Medicine, 39(4), 716-26. https://doi.org/10.1007/s10865-016-9742-x
Pitharouli, M.C., Hagenaars, S.P., Glanville, K.P., Coleman, J.R.I., Hotopf, M., Lewis, C.M., & Pariante, C.M. (2021). Elevated C-
Reactive Protein in Patients With
Depression, Independent of Genetic, Health, and Psychosocial Factors: Results From the UK
Biobank. American Journal of Psychiatry, 178(6), 522-529. https://doi.org/10.1176/appi.ajp.2020.20060947
Reid, B., & Danese, A. (2020). Challenges in researching the immune pathways between
early
life
adversity and
psychopathology. Development and Psychopathology, 32(5), 1597-1624. https://doi.org/10.1017/S0954579420001157
Saltz, S.B., Rozon, M., Pogge, D.L., & Harvey, P.D. (2020). Cyberbullying and Its Relationship to Current Symptoms and History of
Early Life Trauma: A Study of Adolescents in an Acute Inpatient Psychiatric Unit.
Journal of Clinical Psychiatry, 81(1),
18m12170. https://doi.org/10.4088/jcp.18m12170
Sapolsky RM, Romero LM, Munck AU. (2000). How do glucocorticoids influence stress responses? Integrating permissive,
suppressive, stimulatory, and preparative actions.
Endocr Rev, 21(1):55-89. https://doi.org/10.1210/edrv.21.1.0389
Saunders, B.E., & Adams, Z.W. (2014). Epidemiology of traumatic experiences in childhood.
Child and Adolescent Psychiatric Clinics of North America, 23(2), 167-84, vii. https://doi.org/10.1016/j.chc.2013.12.003
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
24
Scheffers, M., Hoek, M., Bosscher, R.J., van Duijn, M.A.J., Schoevers, R.A., van Busschbach, J.T. (2017). Negative body experience
in women with early childhood trauma: associations with trauma severity
and dissociation. European Journal of Psychotraumatology, 8(1), 1322892. https://doi.org/10.1080/20008198.2017.1322892
Schrepf, A., Markon, K., & Lutgendorf, S.K. (2014).
From childhood trauma to elevated C-reactive protein in adulthood: the role of
anxiety and emotional eating. Psychosomatic Medicine, 76(5), 327-36. https://doi.org/10.1097/psy.0000000000000072
Sheffield JM, Williams LE, Woodward ND, Heckers S. (2013). Reduced gray matter volume in psychotic disorder patients with
a history of childhood sexual abuse. Schizophr Res, 143(1):185-91. https://doi.org/10.1016/j.schres.2012.10.032
Stein MB, Yehuda R, Koverola C, Hanna C. (1997). Enhanced dexamethasone suppression of plasma cortisol in adult women
traumatized by childhood sexual abuse. Biol Psychiatry, 42(8):680-6. https://doi.org/10.1016/s0006-3223(96)00489-1
Teicher, M.H., Gordon, J.B., & Nemeroff, C.B. (In Press). Recognizing the importance of childhood maltreatment as a critical factor
in psychiatric diagnoses, treatment, research, prevention, and education. Molecular Psychiatry.
Tunnard, C., Rane, L.J., Wooderson, S.C., Markopoulou, K., Poon, L., Fekadu, A., Juruena, M., & Cleare, A.J. (2014). The impact of
childhood adversity on suicidality and clinical course in
treatment-resistant
depression. Journal of Affective Disorders, 152-
154, 122-30. https://doi.org/10.1016/j.jad.2013.06.037
Walker, E.A., Unutzer, J., Rutter, C., Gelfand, A., Saunders, K., Vonkorff, M., Koss, M.P., & Katon, W. (1999). Costs of Health Care
Use by Women HMO Members with a History of Childhood Abuse and Neglect. JAMA Psychiatry, 56, 609-
613. https://doi.org/10.1001/archpsyc.56.7.609
Yrondi, A., Vaiva, G., Walter, M., D Amato, T., Bellivier, F., Bennabi, D., Bougerol, T., Camus, V., Doumy, O., Genty, J.B., Haffen,
E., Holtzmann, J., Horn, M., Lançon, C., Leboyer, M., Llorca, P.M., Maruani, J., Moirand, R., Molière, F., Petrucci, J., Richieri,
R., Samalin, L., Schmitt, L., Stephan, F.; FondaMental Advanced Centers of Expertise in Resistant Depression (FACE-
DR), Courtet, P., El-Hage, W., Aouizerate, B.; List of FondaMental Advanced Centre of Expertise (FACE-DR) collaborators;
& FACE-DR Clinical Sites and Principal Collaborators in France. (2021). Childhood
Trauma
increases suicidal behaviour in
a
treatment-resistant
depression
population: a FACE-DR report. J Psychiatric Research, 135, 20-
27. https://doi.org/10.1016/j.jpsychires.2020.12.055
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
25
TABLES
Table 1a
Demographic Information on Participants (N=280)
Values
Mean
Standard
Deviation
Age 27.24 10.12
Body Mass Index 27.45 6.86
Length of Stay (Days) 67.59 31.94
CRP 3.18 4.94
Table 1b
BMI categories (%)
Count
Normal/Under 42
Overweight 30
Obese 28
CRP Categories (%)
Count
<1.0 50
1-3.0 24
3.1 or more 26
Sex (%)
Count
Male 47
Female 53
Racial Status (%)
Count
White 84
Black 6
Asian 4
Mixed 6
Marital Status (%)
Count
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
26
Single, Never Married 75
Married 20
Divorced or separated 5
Primary Diagnosis at Admission (%)
Count
Major depression 59
Bipolar Disorder 25
Generalized Anxiety Disorder 13
PTSD 84
Psychosis 11
Psychotic Disorders
31 cases in total
Schizophrenia: 11
Schizoaffective: 18
Schizophreniform: 2
Substance Abuse
Percentage
Substance Abuse 46%
Substance abuse subtypes
129 cases in
total
Alcohol 45
Cannabis 50
Cocaine 9
Hallucinogens 5
Opiates 4
Stimulants 4
Sedatives 7
Solvents 6
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
27
Table 2
Childhood Trauma and Clinical Symptom Scores
Sample
Size/N Mean (% abuse history in sample) Standard Deviation
CTQ Total 280 65.26 18.53
Physical Abuse 280 7.37 (27) 4.53
Emotional Abuse 280 11.78 (53) 6.33
Sexual Abuse 280 7.43 (21) 5.75
Montgomery-Asberg Depression 187 22.78 8.63
Hamilton Anxiety Rating Scale 172 19.31 8.21
Brief Psychiatric Rating Scale 40 46.8 11.89
Young Mania Rating Scale 33 8.58 6.99
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
28
Table 3
Associations between abuse types and BMI and CRP classifications
BMI Group
%
Abuse History Average Overweight Obese X
2
p-value
Emotional Abuse
Yes 40 30 30 0.034 0.99
No 40 30 30
Physical
Abuse
Yes 47 28 26 1.13 0.57
No 38 31 31
Sexual Abuse
Yes 32 24 44 5.19 0.075
No 43 32 26
CRP Group
%
Abuse History <1.0 1.0-3.0 >3.0 X
2
p-value
Emotional Abuse
Yes 48 27 25 2.17 0.5
No 54 20 26
Physical
Abuse
Yes 51 25 24 0.24 0.89
No 50 26 24
Sexual Abuse
Yes 42 20 38 6.37 0.04
No 53 25 22
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
29
Table 4
Associations of CTQ Scores, Clinical Variables, CRP, and Body Mass
Index Based on Spearman Correlations
Emotional
Abuse Physical
Abuse Sexual
Abuse CRP BMI
CTQ Total .59** .83** .77** -0.02 0.04
Emotional Abuse - - .66** .40** -0.06 0.02
Physical Abuse - - - - .56** -0.07 0.04
Sexual Abuse - - .17* 0.13
CRP - - . .52**
Note. *p<.01; **p<.001
Group Differences in Clinical Variables as a Function of Abuse Status
Emotional
Abuse
Physical
Abuse
Sexual
Abuse
Clinical Variable
t-value p-value t-value p-
value t-value p-value
Montgomery-Asberg Depression 0.91 0.36 1.46 0.07 0.21 0.82
Hamilton Anxiety Rating Scale 1.92 0.06 2.57 0.01 2.53 0.01
Brief Psychiatric Rating Scale 0.93 0.36 1.67 0.1 1.12 0.26
Young Mania Rating Scale 1.29 0.2 1.08 0.28 0.6 0.53
Composite Score 1.41 0.16 0.69 0.49 1.67 0.1
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
30
Figure 1
Figure 1 Caption. Illustrates the association between abuse history and BMI to predict CRP values across individuals. The stepwise
regression indicated that only sexual abuse was correlated with CRP values.
Pa
rti
al
Co
rre
lat
io
n
wi
th
C
RP
Va
lue
s
30
. CC-BY-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 11, 2022. ; https://doi.org/10.1101/2022.04.04.22273426doi: medRxiv preprint
ResearchGate has not been able to resolve any citations for this publication.
Article
Full-text available
Childhood maltreatment is the most important preventable risk factor for psychiatric disorders. Maltreated individuals typically develop psychiatric disorders at an earlier age, have a more pernicious course, more comorbidities, greater symptom severity, and respond less favorably to treatments than non-maltreated individuals with the same primary DSM-5 diagnosis. Furthermore, maltreated individuals have alterations in stress-susceptible brain regions, hypothalamic-pituitary-adrenal response, and inflammatory marker levels not discernible in their non-maltreated counterparts. Hence, maltreated and non-maltreated individuals with the same primary DSM-5 diagnoses appear to be clinically and neurobiologically distinct. The failure to embody this distinction in DSM-5 has interfered with our ability to discover novel treatments, to recommend currently available treatments most likely to be efficacious, and has been a largely unrecognized confound that has thwarted our ability to identify the biological basis for major psychiatric disorders. Incorporating this distinction into DSM will help transform this sign and symptom-based classification system to a more etiologically informed nosology. We discuss several diagnostic alternatives and recommend the inclusion of a Developmental Trauma Disorder diagnosis for severely dysregulated individuals, of all ages, with numerous comorbidities, who experienced interpersonal victimization and disruptions in attachment, such as emotional maltreatment or neglect. For less severely affected maltreated individuals, we suggest using conventional diagnostic categories, such as major depression, but with an essential modifier indicating a history of childhood maltreatment, or early life stress, to delineate the ecophenotypic variant. Implementing this strategy should improve our ability to effectively diagnose and treat individuals with psychiatric disorders and to accelerate discovery.
Article
Full-text available
Exposure to childhood adversity is a critical risk factor for the development of psychopathology. A growing field of research examines how exposure to childhood adversity is translated into biological risk for psychopathology through alterations in immune system functioning, most notably heightened levels of inflammation biomarkers. Though our knowledge about how childhood adversity can instantiate biological risk for psychopathology is growing, there remain many challenges and gaps in the field to understand how inflammation from childhood adversity contributes to psychopathology. This paper reviews research on the inflammatory outcomes arising from childhood adversity and presents four major challenges that future research must address: (a) the measurement of childhood adversity, (b) the measurement of inflammation, (c) the identification of mediators between childhood adversity and inflammation, and (d) the identification of moderators of inflammatory outcomes following childhood adversity. We discuss synergies and inconsistencies in the literature to summarize the current understanding of the association between childhood adversity, a proinflammatory phenotype, and the biological risk for psychopathology. We discuss the clinical implications of the inflammatory links between childhood adversity and psychopathology, including possibilities for intervention. Finally, this review conclude by delineates future directions for research, including issues of how best to detect, prevent, and understand these “hidden wounds” of childhood adversity.
Article
Full-text available
Mood disorders represent a major cause of morbidity and mortality worldwide but the brain-related molecular pathophysiology in mood disorders remains largely undefined. Because the anterior insula is reduced in volume in patients with mood disorders, RNA was extracted from the anterior insula postmortem anterior insula of mood disorder samples and compared with unaffected controls for RNA-sequencing identification of differentially expressed genes (DEGs) in (a) bipolar disorder (BD; n = 37) versus (vs.) controls (n = 33), and (b) major depressive disorder (MDD n = 30) vs. controls, and (c) low vs. high axis I comorbidity (a measure of cumulative psychiatric disease burden). Given the regulatory role of transcription factors (TFs) in gene expression via specific-DNA-binding domains (motifs), we used JASPAR TF binding database to identify TF-motifs. We found that DEGs in BD vs. controls, MDD vs. controls, and high vs. low axis I comorbidity were associated with TF-motifs that are known to regulate expression of toll-like receptor genes, cellular homeostatic-control genes, and genes involved in embryonic, cellular/organ, and brain development. Robust imaging-guided transcriptomics by using meta-analytic imaging results to guide independent postmortem dissection for RNA-sequencing was applied by targeting the gray matter volume reduction in the anterior insula in mood disorders, to guide independent postmortem identification of TF motifs regulating DEG. Our findings of TF-motifs that regulate the expression of immune, cellular homeostatic-control, and developmental genes provide novel information about the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate underlying neuroanatomical phenotypes in mood disorders.
Article
Full-text available
In the field of cardio-oncology, it is well recognised that despite the benefits of chemotherapy in treating and possibly curing cancer, it can cause catastrophic damage to bystander tissues resulting in a range of potentially of life-threatening cardiovascular toxicities, and leading to a number of damaging side effects including heart failure and myocardial infarction. Cardiotoxicity is responsible for significant morbidity and mortality in the long-term in oncology patients, specifically due to left ventricular dysfunction. There is increasing emphasis on the early use of biomarkers in order to detect the cardiotoxicity at a stage before it becomes irreversible. The most important markers of cardiac injury are cardiac troponin and natriuretic peptides, whilst markers of inflammation such as interleukin-6, C-reactive protein, myeloperoxidase, Galectin-3, growth differentiation factor-15 are under investigation for their use in detecting cardiotoxicity early. In addition, microRNAs, genome-wide association studies and proteomics are being studied as novel markers of cardiovascular injury or inflammation. The aim of this literature review is to discuss the evidence base behind the use of these biomarkers for the detection of cardiotoxicity.
Article
Full-text available
Background: A crucial but often overlooked impact of early life exposure to trauma is its far-reaching effect on a person’s relationship with their body. Several domains of body experience may be negatively influenced or damaged as a result of early childhood trauma. Objective: The aim of this study was to investigate disturbances in three domains of body experience: body attitude, body satisfaction, and body awareness. Furthermore, associations between domains of body experience and severity of trauma symptoms as well as frequency of dissociation were evaluated. Method: Body attitude was measured with the Dresden Body Image Questionnaire, body satisfaction with the Body Cathexis Scale, and body awareness with the Somatic Awareness Questionnaire in 50 female patients with complex trauma and compared with scores in a non-clinical female sample (n = 216). Patients in the clinical sample also filled out the Davidson Trauma Scale and the Dissociation Experience Scale. Results: In all measured domains, body experience was severely affected in patients with early childhood trauma. Compared with scores in the non-clinical group, effect sizes in Cohen’s d were 2.7 for body attitude, 1.7 for body satisfaction, and 0.8 for body awareness. Associations between domains of body experience and severity of trauma symptoms were low, as were the associations with frequency of dissociative symptoms. Conclusions: Early childhood trauma in women is associated with impairments in self-reported body experience that warrant careful assessment in the treatment of women with psychiatric disorders.
Article
Full-text available
The indirect association of childhood abuse with prevalent hypertension in adulthood through sleep disturbance and pro-inflammatory biomarkers was investigated in 589 community-dwelling, middle-aged adults. Participants completed the Childhood Trauma Questionnaire and self-reported current sleep disturbance and medical diagnoses including hypertension. Blood pressure was taken and blood samples were analyzed for C-reactive protein, interleukin-6, and fibrinogen. Hypertension was present in 41.3 % of the sample. In the full multiple mediation model, tested using structural equation modeling, all hypothesized pathways were significant (p's < 0.05). Childhood abuse was significantly related to both body mass index and sleep disturbance, which, both in turn, were significantly associated with inflammation, which was subsequently associated with hypertension status. The model demonstrated good fit [χ(2) (122) = 352.0, p < 0.001, CFI = 0.918, RMSEA = 0.057] and the indirect effect of all mediators was significant (indirect effect: 0.02, 95 % CI 0.005-0.03, p = 0.001). Sleep disturbance, body mass, and inflammation may be independent, intermediate steps between childhood abuse and subsequent hypertension that may be amenable to biobehavioral interventions.
Article
Full-text available
Childhood trauma confers higher risk of adulthood physical and mental illness; however, the biological mechanism mediating this association remains largely unknown. Recent research has suggested dysregulation of the immune system as a possible biological mediator. The present paper conducted a meta-analysis to establish whether early-life adversity contributes to potentially pathogenic pro-inflammatory phenotypes in adult individuals. A systematic search of Pubmed, PsycINFO, EMBASE, Scopus and Medline identified 25 articles for the meta-analysis, including 18 studies encompassing a sample of 16 870 individuals for C-reactive protein (CRP), 15 studies including 3751 individuals for interleukin-6 (IL-6) and 10 studies including 881 individuals for tumour necrosis factor-α (TNF-α). Random-effects meta-analysis showed that individuals exposed to childhood trauma had significantly elevated baseline peripheral levels of CRP (Fisher's z=0.10, 95% confidence interval (CI)=0.05-0.14), IL-6 (z=0.08, 95% CI=0.03-0.14) and TNF-α (z=0.23, 95% CI=0.14-0.32). Subgroup analyses for specific types of trauma (sexual, physical or emotional abuse) revealed that these impact differentially the single inflammatory markers. Moreover, meta-regression revealed greater effect sizes in clinical samples for the association between childhood trauma and CRP but not for IL-6 or TNF-α. Age, body mass index (BMI) and gender had no moderating effects. The analysis demonstrates that childhood trauma contributes to a pro-inflammatory state in adulthood, with specific inflammatory profiles depending on the specific type of trauma.Molecular Psychiatry advance online publication, 2 June 2015; doi:10.1038/mp.2015.67.
Article
Objective: The authors investigated the pathways (genetic, environmental, lifestyle, medical) leading to inflammation in major depressive disorder using C-reactive protein (CRP), genetic, and phenotypic data from the UK Biobank. Methods: This was a case-control study of 26,894 participants with a lifetime diagnosis of major depressive disorder from the Composite International Diagnostic Interview and 59,001 control subjects who reported no mental disorder and had not reported taking any antidepressant medication. Linear regression models of log CRP level were fitted to regress out the effects of age, sex, body mass index (BMI), and smoking and to test whether the polygenic risk score (PRS) for major depression was associated with log CRP level and whether the association between log CRP level and major depression remained after adjusting for early-life trauma, socioeconomic status, and self-reported health status. Results: CRP levels were significantly higher in patients with depression relative to control subjects (2.4 mg/L compared with 2.1 mg/L, respectively), and more case than control subjects had CRP levels >3 mg/L (21.2% compared with 16.8%, respectively), indicating low-grade inflammation. The PRS for depression was positively and significantly associated with log CRP levels, but this association was no longer significant after adjustment for BMI and smoking. The association between depression and increased log CRP level was substantially reduced, but still remained significant, after adjustment for the aforementioned clinical and sociodemographic factors. Conclusions: The data indicate that the "genetic" contribution to increased inflammation in depression is due to regulation of eating and smoking habits rather than an "autoimmune" genetic predisposition. Moreover, the association between depression and increased inflammation even after full adjustment indicates either the presence of yet unknown or unmeasured psychosocial and clinical confounding factors or that a core biological association between depression and increased inflammation exists independently from confounders.
Article
Background: Cyberbullying has received wide media attention and appears to be linked to frequent adverse consequences, with multiple suicides reported. This study examined the prevalence of cyberbullying among adolescent psychiatric inpatients and related it to social media usage, current levels of symptoms, and histories of adverse early life experience. Methods: Data on the prevalence of social media utilization and cyberbullying victimization were collected from adolescent psychiatric inpatients aged 13 to 17 years from September 2016 to April 2017. Fifty adolescent psychiatric inpatients completed 2 surveys assessing childhood trauma (the Trauma Symptom Checklist for Children and the Childhood Trauma Questionnaire) and the Cyberbullying Questionnaire. Results: Twenty percent of participants (10/50) had been victimized by cyberbullying. Access to and engagement in social media or Internet-based communication was extremely common, with most participants engaging on a daily basis or more frequently in at least 1 social media activity. Those who had been bullied endorsed significantly higher scores on posttraumatic stress disorder (PTSD), depression, anger, and fantasy dissociation scales than those who were not bullied (all P values < .05). Subjects who reported having been victims of cyberbullying endorsed significantly higher levels of lifetime emotional abuse on the Childhood Trauma Questionnaire than those who were not bullied (P = .013); however, they did not report a significantly higher level of the other types of trauma (physical abuse, sexual abuse, emotional neglect, or physical neglect). More bullied than nonbullied subjects had clinically and statisticallysignificant elevations in hyperresponse, PTSD, and depression scale scores (P < .05). Conclusions: Being cyberbullied was associated with greater psychiatric symptom severity. Further, histories of emotional abuse were correlated with recent cyberbullying. These data suggest that individuals with histories of childhood trauma also seem vulnerable to continued adverse experiences during adolescence.
Article
The brain and the immune system are not fully formed at birth but rather continue to mature in response to the postnatal environment. The two-way interaction between brain and immune system makes it possible for childhood psychosocial stressors to affect immune system development, which in turn can affect brain development and its long-term functioning. Drawing from experimental animal models and observational human studies, we propose that the psychoneuroimmunology of early-life stress can offer an innovative framework to understand and treat psychopathology linked to childhood trauma. Early-life stress predicts later inflammation, and there are striking analogies between the neurobiological correlates of early-life stress and of inflammation. Furthermore, there are overlapping trans-diagnostic patterns of association between childhood trauma or inflammation and clinical outcomes. These findings suggest new strategies to remediate the effect of childhood trauma before the onset of clinical symptoms, such as anti-inflammatory interventions and potentiation of the adaptive immunity. Similar strategies might be used to ameliorate the unfavourable treatment response described in psychiatric patients with a history of childhood trauma.Neuropsychopharmacology Reviews 2016; 0:000-000; doi:10.1038/npp.2016.198.