It is known that early life experiences have a profound effect on the developing brain. 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 ,cannabid vertical grow racks 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, 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 .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.Although research on levels of inflammatory plasma analytes in FEP subjects has been more prolific, it is also more inconsistent. A recent systematic review aggregated 59 studies of cytokine levels in early psychosis subjects,commercial marijuana vertical growing reporting evidence for significantly higher levels of circulating cytokines, IL-6, IL-1b, IL-2, IL-4, IL-10, TNF-α, and IL-8, in FEP as compared to HC groups. However, these results were not consistent across studies, with additional evidence from several studies demonstrating these findings only in drug naive subjects, no significant differences or suppression of analytes in FEP compared to HC subjects . As will be discussed, the effect of antipsychotic medication on inflammatory analytes is an important variable that has been inconsistently examined in current inflammatory research. Additionally, there have been few studies investigating levels of chemokines between FEP and HC subjects, with only one study examining MCP-1 in FEP subjects . Martínez-Cengotitabengoa et al. examined the associationbetween MCP-1 and cognition in FEP subjects, reporting that MCP-1 was strongly associated with learning and memory, consistent with findings that MCP-1 is associated with cognitive deficits in Alzheimer disease and HIV dementia . More research is needed to explore the role of chemokines in early psychosis, particularly if these analytes are associated with cognitive decline and other relevant impairments in psychotic illness. More consistently, levels of BDNF have been reported to be significantly reduced in drug naïve FEP subjects, as compared to HC subjects . Importantly, Toll and Mane discuss that studies reporting reductions in FEP levels of BDNF compared to HC subjects have been predominantly conducted in drug-naïve FEP patients as compared to studies reporting no alterations in FEP levels of BDNF compared to HC subjects have been conducted in medicated patients. These results are consistent with previous meta-analyses in drug-naïve schizophrenia groups , as well as subsequent studies, which additionally report that levels of BDNF are generally reduced in drugnaïve FEP patients and appear to be associated with learning capacity and cognition ; however, reductions in BDNF have not been reported to be associated with psychotic symptom severity nor predictive of conversion to psychosis . Despite inconsistent findings, several studies have demonstrated the clinical relevance of inflammatory plasma analytes in psychosis groups, through successful development of blood based protein biomarker multiplexed immuno assays that either discriminate individuals with a psychotic disorder from HC subjects or reliably predict which CHR individuals will go on to develop a psychotic disorder.
In unmedicated FEP subjects, Schwarz et al. identified inflammatory, oxidative stress, and HPA signaling serum proteins that were uniquely altered in FEP subjects. Chan et al. established a biomarker panel with high discriminatory power to differentiate CHR individuals who would later be diagnosed with schizophrenia versus a diagnosis of bipolar disorder.Associations between inflammatory plasma analytes, psychotic symptoms severity, and functioning has been well studied in patients with chronic psychosis , but less extensively in FEP and CHR subjects. In schizophrenia groups, higher levels of pro-inflammatory cytokines TNF-α and IL-6 have been associated with higher levels of depressive symptoms, greater physical comorbidities, such as arthritis, reduced executive functioning, and lower self-rated mental well-being, suggesting that these markers are clinically relevant . Similarly, plasma levels of chemokines MCP-1, MIP-1β, Eotaxin-1, and MDC have been observed to not only be higher in patients with schizophrenia compared to healthy controls, but also significantly associated with increased levels of sub-clinical depressive symptoms, worse self-rated mental well-being, and greater overall severity of typically mild medical illnesses . Very few studies have evaluated the effect of childhood trauma on inflammation in psychosis. In a sample of individuals with chronic schizophrenia subjects, Dennison, McKernan, Cryan, and Dinan provide evidence that individuals with a history of childhood trauma show significantly higher levels of TNF-a and IL-6 as compared to subjects without a history of trauma and healthy controls. In fact, both Dennison et al. and Di Nicola et al. demonstrated that levels of TNF-a were correlated with history of childhood trauma, specificallyseverity of the trauma in psychosis subjects. Hepgul et al. , reports that levels of CRP were significantly higher in first episode psychosis subjects with a history of childhood trauma as compared to those without a history of childhood trauma and healthy controls. Chase et al. demonstrated that childhood trauma, through its effects on IL6, may be a risk factor for schizophrenia. This is consistent with the meta-analysis conducted by Baumeister, Akhtar, Ciufolini, Pariante, and Mondelli , demonstrating that CRP, IL-6, and TNF-a were markedly elevated in individuals with a history of childhood trauma versus those without. Finally, Mondelli et al. conducted research on cortisol awakening response in first episode psychosis and established that history of childhood sexual trauma is associated with blunted cortisol awakening response. Authors purport that this finding helps to explain the association between HPA-axis abnormalities and excess psychological stress in first episode psychosis subjects. Importantly, no studies to our knowledge have sought to examine the relationship between childhood trauma, inflammation, and clinical outcomes in CHR subjects.However, results from the North American Prodrome Longitudinal Study 2 have established several important findings regarding the relationship between childhood trauma and inflammation independently on clinical outcomes in CHR subjects. Firstly, Addington et al. evaluated the relationship between childhood trauma and clinical outcomes in CHR subjects.