Full-length ArticleChildhood maltreatment severity is associated with elevated C-reactive protein and body mass index in adults with schizophrenia and bipolar diagnoses
Introduction
The immune system has been suggested to play a role in the pathophysiology of schizophrenia (SZ) and bipolar disorder (BD) (Leboyer et al., 2016, Morch et al., 2016), and we and others have shown that patients with SZ or BD show signs of an activated immune system, including increased levels of C-reactive protein (CRP) as well as more specific markers of the tumor necrosis factor (TNF), interleukin (IL)-1 and the IL-6 system (Dieset et al., 2012b, Hope et al., 2009).
Recent genome-wide association studies (GWAS) have indicated immune genes as susceptibility genes in individuals with SZ, including the major histocompatibility complex (MHC) (Schizophrenia Working Group, 2014, Ripke et al., 2009, Stefansson et al., 2009). Regions and genes within the MHC region and the HLA locus, and upregulation of the NOTCH4 gene, have been implicated in individuals with SZ and BD (Dieset et al., 2012a, Leboyer et al., 2016). Both SZ and BD are highly heritable polygenetic diseases on the opposite ends of the psychosis continuum spectrum (Craddock et al., 2009, Craddock and Owen, 2010). Beyond genes in the MHC region, genes encoding innate immune system proteins, such as the toll-like receptors TLR-4 and TLR-2, have been suggested to be central markers of immune defense against diseases (Leboyer et al., 2016).
The brain and the immune system are not fully developed at birth, and early experiences can shape the relationship between the immune system and the brain (Danese et al., 2017). In addition to genetic markers, environmental factors that affect the immune system have been associated with the development of SZ and BD, including obstetric complications, infection during pregnancy (Brown, 2011, Brown, 2015), and childhood maltreatment (Danese et al., 2008, Danese et al., 2007, Elenkov et al., 1999). Recent meta-analyses have suggested that childhood maltreatment may trigger low-grade immune activation, as reflected by increased circulating levels of CRP, TNF and IL-6 (Baumeister et al., 2015, Coelho et al., 2014). Several studies using limited sample sizes (n < 50) have investigated childhood maltreatment and inflammation in individuals with SZ, and have found higher levels of IL-6, TNF and CRP in people with childhood maltreatment (Dennison et al., 2012, Hepgul et al., 2012), thus mirroring the observations in adult individuals with SZ and BD (Dieset et al., 2012b, Hope et al., 2009).
Childhood maltreatment is more frequent in patients with severe mental illness, including SZ and BD (Aas et al., 2016, Etain et al., 2008, Larsson et al., 2013), and may contribute to disease development and disease severity at least partly through immune activation. A genetic overlap between inflammation and stress markers has been reported in patients within the psychosis spectrum (Fillman et al., 2014), thus supporting the presence of a stress-immune vulnerability in this group. Furthermore, prenatal immune stimulation in mice interacts with peripubertal stress exposure and consequently increases the likelihood of developing neuroimmunological changes later in life, thus supporting a synergistic relationship between immune activation and early life stress (Giovanoli et al., 2013).
In addition to early life stress, patients with SZ and BD present with an adverse metabolic profile, including a higher body mass index (BMI) (Coodin, 2001), which may contribute to systemic inflammation through production of inflammatory mediators by adipose tissue (Festa et al., 2001). Interestingly, a history of childhood trauma has also been associated with higher BMI via emotional eating (Danese and Tan, 2014). Together, these findings indicate that childhood maltreatment may interact with a genetic vulnerability to the disease, thus suggesting a double-hit model in which maltreatment subsequently causes elevated immune activation in individuals with SZ and BD.
First, we hypothesized that the number of childhood abuse events is associated with elevated inflammatory markers (i.e., the general inflammatory marker high-sensitivity [hs]-CRP and markers of activation of the TNF [soluble TNF receptor type 1 [sTNF-R1]] and IL-6 [gp130] system) and higher BMI levels. Second, owing to the suggested role of the immune system in the pathophysiology of SZ and BD (Leboyer et al., 2016, Morch et al., 2016), we hypothesized that patient status and the number of childhood abuse events have combined effects on the level of inflammation, such that patients who have experienced the most childhood abuse should have the most elevated inflammatory markers. Finally, owing to the roles of adipose tissue and BMI on inflammatory markers (Festa et al., 2001), we hypothesized that differences in immune activation between groups are influenced by BMI.
Section snippets
Participants
The participants were recruited consecutively from psychiatric units (outpatient and inpatient) in 4 major hospitals in Oslo, as part of the Thematically Organized Psychosis (TOP) Study. A total of 483 participants (with schizophrenia [n = 148] or bipolar disorder [n = 123]), and healthy individuals [n = 212]) were recruited. Inclusion criteria for the healthy controls were the following: living in the same district as the patients, being between 18 and 65 years and having no lifetime diagnosis of any
Sample characteristics
Sample demographics and clinical characteristics are shown in Table 1. One hundred ninety-one (70.5%) patients were taking at least one type of antipsychotic medication; eighty (29.5%) patients used antidepressants. The mean age of the patients was 30.3 ± 10.6 years, and 51% of the patients were males. Patients with SZ were younger than both patients with BD and the control group (Table 1). A significant difference among the three groups was also found for sex distribution (P = 0.002): the BD group
Discussion
Our study is, to our knowledge, the largest study to show an association between childhood abuse and activation of immune markers in patients with SZ or BD (measured as one group) and HCs. Our study demonstrates combined effects of the level/severity of childhood maltreatment and a psychosis spectrum diagnosis on elevated immune activation. Participants who reported more types of childhood abuse were also more likely to be obese, contributing to the elevated hs-CRP in the patient group. Our
Financial disclosure
This study was funded by grants from the University of Oslo, South-Eastern Norway Health Authority (#2013088) and the Research Council of Norway and the KG Jebsen Foundation. There are no potential conflicts of interest.
Acknowledgments
We thank the patients who took part in the study and the NORMENT center which contributed to the data collection.
References (50)
- et al.
Interplay between childhood trauma and BDNF val66met variants on blood BDNF mRNA levels and on hippocampus subfields volumes in schizophrenia spectrum and bipolar disorders
J. Psychiatr. Res.
(2014) - et al.
The blood-brain barrier and immune function and dysfunction
Neurobiol. Dis.
(2010) The environment and susceptibility to schizophrenia
Prog. Neurobiol.
(2011)- et al.
Cardiovascular risk factors during second generation antipsychotic treatment are associated with increased C-reactive protein
Schizophr. Res.
(2012) - et al.
Causes of decreased life expectancy over the life span in bipolar disorder
J. Affect. Disord.
(2015) - et al.
High prevalence of childhood trauma in patients with schizophrenia spectrum and affective disorder
Compr. Psychiatry
(2013) - et al.
Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression
Biol. Psychiatry
(2009) - et al.
Abnormal cortisol levels during the day and cortisol awakening response in first-episode psychosis: the role of stress and of antipsychotic treatment
Schizophr. Res.
(2010) - et al.
Inflammatory evidence for the psychosis continuum model
Psychoneuroendocrinology
(2016) - et al.
Body mass index is directly associated with biomarkers of angiogenesis and inflammation in children and adolescents
Nutrition
(2012)
Additive effects of childhood abuse and cannabis abuse on clinical expressions of bipolar disorders
Psychol. Med.
A history of childhood trauma is associated with slower improvement rates: findings from a one-year follow-up study of patients with a first-episode psychosis
BMC. Psychiatry
Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha
Mol. Psychiatry
Initial reliability and validity of a new retrospective measure of child abuse and neglect
Am. J. Psychiatry
The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes
J. Leukoc. Biol.
The Kraepelinian dichotomy from the perspective of prenatal infectious and immunologic insults
Schizophr. Bull.
Childhood maltreatment and inflammatory markers: a systematic review
Acta Psychiatr. Scand.
Statistical Power Analysis for the Behavioral Sciences
Body mass index in persons with schizophrenia
Can. J. Psychiatry
The Kraepelinian dichotomy - going, going… but still not gone
Br. J. Psychiatry
Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or “schizoaffective”) psychoses
Schizophr. Bull.
Childhood maltreatment and obesity: systematic review and meta-analysis
Mol. Psychiatry
Childhood maltreatment predicts adult inflammation in a life-course study
Proc. Natl. Acad. Sci. U. S. A
Elevated inflammation levels in depressed adults with a history of childhood maltreatment
Arch. Gen. Psychiatry
Psychoneuroimmunology of early-life stress: the hidden wounds of childhood trauma?
Neuropsychopharmacology.
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