Psychiatric illnesses that begin during adolescence and disrupt successful transition into adulthood represent one such category of mental disorders for which primary prevention is key, but therapeutic targets meeting the goal of prevention are lacking. This study seeks to provide rationale for and test the hypothesis that immune system dysregulation may serve as a biological mediator between the experience of childhood trauma and vulnerability for developing psychosis by evaluating associations between childhood trauma, inflammation, and clinical outcomes in a sample of subjects at clinical high risk for psychosis . Childhood trauma is defined as the experience of severe and/or chronic interpersonal stress including abuse or neglect . In the development of a validated childhood trauma assessment tool, the Childhood Trauma Questionnaire , Bernstein et al. defined subcategories of childhood trauma as follows: 1) sexual abuse is defined as sexual activity between a minor child and an adult or older person ; 2) Physical abuse is defined as bodily assault imposed upon a minor by an adult, which resulted in risk or experience of injury; 3) Emotional abuse is defined as verbal assaults on an individual’s sense of worth or well-being, including verbal humiliation, intimidation, or demeaning behavior directed towards a minor by an adult; 4) Physical neglect is defined as the failure of caretakers to provide for a child’s basic physical needs, including food, clothing, shelter, safety, and health care,drying rack for weed as well as poor parental supervision if such behavior places a minor’s safety in jeopardy; and 5) Emotional neglect is defined as a failure for a caretaker to provide a minor with appropriate emotional support or validation.
Sub-types of trauma differ in prevalence. The United States Department of Health and Human Services Administration for Children and Families report that the national number of children receiving a child protective services investigation response increased 10.0% percent from 2013 to 2017 , with the national rounded number of victims in 2017 approximated at 674,000 children. Three-quarters of these victims experienced neglect, 18.3 percent physical abuse, and 8.6 percent sexual abuse . However, prevention of childhood trauma extends far beyond mere desire to protect children, as research has established that the consequences of childhood trauma are severe and long-lasting. Firstly, experience of childhood trauma increases risk for medical illnesses such as lung disease, arthritic disorders, cardiac disease, diabetes, and autoimmune disorders . Moreover, the development of medical disorders is found to be directly proportional to the number and magnitude of childhood traumas experienced . Secondly, experience of childhood trauma is associated with significantly increased lifetime risk for developing serious mental illnesses, such as major depressive disorder , bipolar disorder , post-traumatic stress disorder , schizophrenia , as well as personality disorders and substance use disorders . Research on sub-types of childhood trauma and early life stress reveal that physical abuse, sexual abuse, and neglect are associated with the development of mood disorders and anxiety disorders, while emotional abuse is associated with development of personality disorders and schizophrenia . Other studies have identified sub-types of emotional abuse and neglect to be among the most significant predictors of developing a mood disorder in adulthood . Experience of multiple childhood traumas is a significant predictor of increased chronicity of depression, increased suicidal behavior, as well as poor response to antidepressant or combined psychosocial and pharmacological treatment .
History of childhood trauma is also highly prevalent in patients diagnosed with BD . Incidence of childhood trauma is a significant predictor for severity of manic and depressive symptoms, psychotic symptoms, rapid cycling, greater number of depressive episodes, and increased risk of suicide attempts in individuals diagnosed with BD Importantly, childhood trauma has been reliably shown to be associated with increased risk for developing psychosis later in life . Research on the relationship between childhood adversity and psychosis not only links childhood abuse and neglect to psychotic symptoms, specifically hallucinations, but also indicates that the relationship is causal, with a dose-effect . A large cohort study by , demonstrated that youth who experienced trauma in the first 17 years of life were 2.91 times more likely to have psychotic symptoms at 18 years of age, and those who experienced 3 or more types of childhood trauma were 4.7 times more likely to have psychotic symptoms. Exposure to trauma during childhood is associated with increased emotional and psychotic reactivity to stress in patients diagnosed with psychotic disorders . This increased stress reactivity may represent both an expressed genetic liability, as well as an acquired vulnerability due to exposure to traumatic events. Exposure to childhood trauma may actually sensitize patients with psychosis liability for the later exposure to daily life stress . In fact, Varese et al. , argues the relationship between childhood trauma and psychosis is so significant, that removing childhood trauma from the population would yield a 33% decrease in number of individuals with psychosis. While studies have repeatedly shown that experience of childhood trauma is associated with an increased risk for developing both physical and mental illnesses later in life, the biological mechanisms by which this risk manifests are less explicit .Optimal development of some brain functions is actually experience-dependent, meaning that input from external stimuli during critical periods of neural development are essential for appropriate neurological development and absence of sufficient input can have deleterious effects .
However, this dynamic and synergistic process, while critical for development, also leaves the developing brain vulnerable to influence by negative external stimuli. Thus, the experience of stressful life events, such as childhood trauma, during critical periods of development has been shown to influence the development of neural systems, specifically those involved in response to stress/threat . Yet, the experience of stress does not unequivocally lead to maladaptive consequences, as we know that not all individuals who experience childhood trauma go on to develop physical or mental illnesses. However, the experience of early life stress may uncover biological vulnerabilities in some individuals causing modulation of typical neurobiological stress response, creating life-long patterns of emotionality, behavioral, and physiological responding . While this review will not discuss the role of epigenetics in development of mood disorders, it is important to briefly reference findings from animal model research which demonstrate that experience of early life stressful events, such as maternal separation or neglect, differentially affects neuronal development , mRNA expression and even cortisol reactivity due to differential expression of underlying epigenetic vulnerabilities . One neurological system is critical to the understanding of how environmental stimuli impact biological stress response: the hypothalamic-pituitary-adrenal axis. The HPA-axisis responsible for the release of glucocorticoids in the brain that signal activation of coordinated autonomic, neuroendocrine, metabolic, and immune system responses . Importantly, the HPA axis is highly responsive to environmental adversities both in childhood and in adulthood . Experience of early life stress is implicated in modulation of HPA-axis functioning , with experience of trauma affecting not only the expression of stress induced hormones , but also increasing reactivity to acute stress, and decreasing recovery of cortisol following acute stress . The responsiveness of the HPA-axis is determined by the ability of glucocorticoids to regulate the release of additional stress hormones,trimming cannabis providing return to homeostasis once the perceived stress or threat has subsided . Findings are inconsistent as to whether childhood trauma or early life stress leads to exclusively hyper-activation versus hypo-activation of HPAaxis glucocorticoid release , but nonetheless, dysregulation of HPA- axis has been associated with the development of both mental and physical illnesses, including increased risk for cardiac disease, diabetes, obesity, and autoimmune disorders . In fact, the overlap between physical and mental illness resulting from exposure to childhood trauma and HPA-axis dysregulation , has led to the exploration of the role of the immune system as an underlying mechanism in psychopathology, as inflammation is involved in the pathogenesis of many of the aforementioned medical disorders associated with childhood trauma and HPA-axis dysregulation .Research on the impact of childhood trauma on inflammation has established a dosedependent relationship between number of childhood traumas and elevations/reductions in levels of many inflammatory markers, including IL-6 and Creactive protein . Moreover, cytokines and other markers of inflammation are known to be potent activators of the central HPA-axis stress response . Inflammatory cytokines, including tumor necrosis factor-α , interleukin-1β and interleukin-6 can stimulate the HPA-axis independently, or in combination . Further, IL-6 plays a major role in the immune stimulation of the HPA-axis, particularly in times of chronic inflammatory stress.
Replicated studies have demonstrated that cytokines such as IL-1, IL-6, TNF-α and IFN-α, activate the HPA-axis by increasing levels of corticotrophin releasing hormone , adrenocorticotropic hormone and cortisol . The influence of inflammation on the HPA-axis stress response is well-established . Thus, the HPA-axis is not only modulated by childhood trauma, but it is a powerful modulator of inflammatory activity, and is in turn modulated by inflammatory processes. Both inflammation and HPA-axis activation are mechanisms by which the body protects itself from threat. The immune system plays a critical role in the body’s response to injury and infection as it simultaneously prevents the proliferation of pathogens, while also promoting tissue survival, repair, and recovery through regulated circulation of inflammatory markers . Relevant to the discussion of mood disorders, immune system response is associated with behavioral alterations in mood, sleep, energy, cognition, and motivation. Animal models provide evidence that induction of a “pro-inflammatory state” leads to patterns of behaviors in mice, termed “sickness behaviors” that resemble depressive symptomatology and include: lethargy, decreased appetite, decreased interest in exploring, decreased sexual activity, and increased time spent sleeping . In humans, increases in depressive symptoms have been observed in conjunction with administration of immuno-therapies, such as vaccinations , lipopolysaccharides , interferon , and interleukin-2 . Further, an increased prevalence of mood symptoms is present in a variety of inflammatory conditions including auto-immune diseases, cardiovascular diseases, diabetes, obesity, and metabolic syndrome, as well as benign inflammatory conditions including asthma and allergies . As a result of these associations, there has been an increased interest in exploring the relationship between inflammation and development of various forms of psychopathology. Research on inflammation in individuals diagnosed with MDD has repeatedly shown increased incidence of mood symptoms and episodes associated with elevated levels of Creactive protein , TNF-α, IL-1β, IL-2 and IL-6, in peripheral blood . Further, increased severity of depressive symptoms has been associated with higher levels of inflammatory markers in a dose-dependent manner. Similarly, research on inflammation in individuals diagnosed with BD has repeatedly shown increased incidence of mood symptoms and episodes associated with elevated levels of CRP, TNF-α, IL-1β, IL-2 and IL-6, and decreased BDNF . Acute elevations in inflammatory markers have also been shown to occur during depressive and manic episodes, with marker concentrations peaking during mood episodes and dropping during euthymic periods .Impairment of HPA-axis functioning has been shown to occur within the CHR population . A limited number of studies have explored differences in levels of plasma inflammatory analytes between CHR and HC groups, as the primary study aim . Stojanovic et al. reported that levels of plasma IL-6 were significantly higher in CHR subjects as compared to HC subjects. Zeni-Graiff et al. later replicated the IL-6 results, additionally reporting that levels of IL-17 were significantly lower in CHR subjects as compared to HC subjects. Karanikas et al. report significantly higher levels of IL-4 in CHR as compared to HC subjects. Focking et al. report that individuals identified to be at “ultra-high risk” for developing a psychotic disorder, demonstrate elevations in baseline levels of plasma IL12/23p40 compared to healthy controls and that elevations of this marker were associated with transition to a psychotic disorder. Finally, Yee, Lee, and Lee report significantly higher levels of serum BDNF in CHR subjects as compared to healthy controls, although the elevation was not predictive of transition to psychosis. Thus, there appears to be evidence of increased levels of several inflammatory analytes in individuals at heightened risk for psychosis, but how these elevations compare to elevations of inflammatory analytes across later phases of psychotic illness remains unclear. Further, CHR groups tend to be rather heterogenous, with 20–35% of CHR individuals developing full psychotic symptoms over a 2-year period , so it is unclear whether these early finding are specific to psychosis risk or general psychopathology and environmental factors.