The Effects of Childhood Trauma on Adult Psychopathology: A Review
Introduction
Although psychiatric disorders have existed in populations for throughout history, science has yet to irrefutably lay blame to a single cause. The debate between nature and nurture on development persists and influences many different domains within the biological sciences to believe differing, and often opposing, theories. The purpose of this narrative review is to assess the link that childhood trauma has on development of adult psychiatric disease. This link has been identified and confirmed through many different research studies, however the precise mechanisms by which the experience of trauma relates to adult disease is unclear. There are differing hypotheses on these mechanisms, including inflammatory processes, alterations in the hypothalamic-pituitary-adrenal axis (HPA axis), structural brain changes and epigenetic changes. Identifying the exact causative agent would strongly influence the methods through which these diseases are treated or offer alternative research pathways into finding novel pharmaceuticals. Furthermore, the current gold standard for treatment of early childhood traumas is early intervention, which intervenes in disease development during the critical period to reverse any potential damage done.
Although childhood trauma is a large contributor to adult psychiatric disease, it is important to note that not all psychiatric disease is caused by trauma, either in childhood or adulthood. Therefore, recognizing the differences between trauma-mediated psychopathology and “organic” psychopathology is necessary. That said, a large study conducted using WHO data on childhood adversities determined that approximately 30% of all adult psychiatric illness is attributable to childhood adversity (Kessler et al., 2010). This number is staggering and shows the obvious need for further research in this area.
Methods
This review was conducted with the use of Penn State’s online library access and Google Scholar. Searches included key words such as: “childhood trauma”, “adult psychiatric disease”, “HPA axis”, “inflammation”, “early life trauma”, “antidepressants”, “treatment of psychiatric disease” and “epigenetics”. Articles that referenced acute physical trauma, such as car accidents, or that were not in English were excluded from this review.
Trauma’s Effects on the Brain
Inflammation
Inflammatory pathways in adults with psychiatric disease are altered in many ways as opposed to healthy controls. A basic understanding of the immune system and its functions is necessary to recognize the differences between healthy and dysfunctional immune systems. The primary immune components that are altered in psychiatric disorders include cytokines and T-cells. Cytokines are protein markers produced by immune system cells which assist the immune system in cell activation, cellular death or immune system mobilization. Cytokines include interleukins (IL) and tumor necrosis factor (TNF) among many others. T-cells are cells that circulate in the blood stream and search for antigens (Parkin & Cohen, 2001).
The presence of multiple inflammatory biomarkers proves that the immune system is chronically activated in those with psychiatric disease. For instance, Wilson et al. (1999) note that in patients diagnosed with PTSD, there is a significant increase in the index of activation of the immune system (that is, the ratio of CD45RO:CD45RA T-cells) as opposed to healthy controls. This increase in the presence of T-cells is attributable to an overall increase in immune function, as the production and proliferation of these cells follows higher levels of interleukins in the body, which are produced in response to antigens (Berard & Tough, 2002). However, with the presence of psychiatric disease, there is not an antigen present and this immune dysregulation must be due to another variable shared by most, if not all, psychiatric patients.
The higher prevalence of T-cells is not the only dysregulated immune function, however. Dennison et al. (2012) conducted empirical research on the presence of other inflammatory biomarkers in a cohort of schizophrenia patients that all reported a history of childhood abuse. Namely, this study investigated the presence of IL-1β, IL-6, IL-8 and TNF-α. All the analyzed cytokines are considered pro-inflammatory markers, as opposed to some cytokines, which reduce overall immune response. Results showed that pro-inflammatory markers IL-6 and TNF-α in particular were at increased levels only in schizophrenia patients with a history of childhood trauma. However, this study had significant limitations, including that some patients were actively taking psychiatric medications and these medications have a noted effect of altering levels of cytokines in the body. Furthermore, the patients with schizophrenia had an overall higher BMI than healthy controls, and increased body weight is also strongly correlated to increased overall cytokine activation. Nevertheless, after controlling for these BMI differences, the significance of increased cytokine presence persisted (Dennison et al., 2012).
Another relevant inflammatory biomarker is C-reactive protein (CRP). This protein is produced in response to inflammation; however, it is non-specific and is present whenever inflammation occurs in the body, regardless of source. Coelho et al. (2013) note that increased CRP levels are associated with depression in adults, however after controlling for the presence of childhood trauma, this association was no longer significant. Furthermore, in patients with schizophrenia, CRP levels were much higher in those that reported childhood trauma as opposed to those who had schizophrenia without trauma and healthy controls. These higher levels of inflammatory markers existed at baseline, but also increased more significantly in patients with disease than controls when confronted with psychosocial stress (Coelho et al., 2013).
The interrelatedness of all inflammatory markers makes it difficult to determine the root cause of immune activation in psychiatric disease, as all biomarkers can affect the production of others, as all biomarkers provide feedback to the immune system. It is also relevant that the levels of these cytokines and other related inflammatory markers were increased in these psychiatric diseases, but in a different manner than is seen in other inflammatory diseases, such as rheumatoid arthritis (Coelho et al., 2013). This lends credence to the idea that these increases were relevant to the psychiatric diseases themselves and not to other confounding infections or comorbid disease.
HPA Axis
Another significant alteration that is seen across multiple studies is an alteration in the HPA axis. This pathway functions as a biological response to stressors by secreting a variety of different hormones. The result is an increase in blood serum levels of cortisol, coined “the stress hormone”. In normal individuals, cortisol release occurs as a result of exposure to stressful environmental stimuli, however cortisol has a short half-life in the blood, meaning that after the stressor ends, blood cortisol levels can return to baseline relatively quickly (Mckay & Cidlowski, 2003). However, as levels of cortisol increase in the blood, these half-lives become longer. The HPA axis also has a negative feedback mechanism, meaning that as cortisol levels increase in the blood, the initiation mechanism turns off to termination secretion of hormones (Spencer & Deak, 2017).
This pathway is often implicated in the “fight-or-flight” response that humans exhibit in response to stressors. However, this pathway is still developing in childhood and adverse childhood experiences can significantly change the strength or frequency with which this axis operates and therefore affect subsequent adult life trajectory (Gonzalez, 2013). For instance, the negative feedback mechanism may become ineffective, resulting in constant stimulation of hormones, or the entire system may become exhausted, resulting in relative system dysfunction and failure.
In particular, the cortisol levels of those who have experienced childhood maltreatment are often reduced, especially upon waking, as opposed to healthy controls. These diurnal measures of cortisol, in healthy persons, typically peak approximately 30 minutes after waking and then gradually decrease throughout the day (Tarullo & Gunnar, 2006). However, among children that have experienced abuse or maltreatment, diurnal measures of cortisol showed no increase upon waking and no significant changes throughout the day, meaning that the mechanisms within the HPA axes of these children were somehow damaged.
The evidence for cortisol levels in response to psychosocial stress is mixed. Some studies have found that cortisol levels were reduced in response to stress, whereas others have found marked increases in response to psychosocial stress, especially among women (Gonzalez, 2013). However, in young children, when exposed to situations that measure attachment styles, those that have secure attachments do not experience increased levels of cortisol after being tested, however children with disorganized attachment styles do show significant increases in cortisol levels (Tarullo & Gunnar, 2006). Disorganized attachment styles in early childhood are often linked to development of adult psychopathology.
Structural Brain Changes
There is research to suggest that the presence or absence of particular brain structures may encourage or discourage psychiatric disease. As the brain develops throughout childhood, it is possible that adverse childhood experiences may contribute to structural changes that encourage the likelihood of psychiatric disease. Hostinar et al. (2017) conducted an empirical study that analyzed the effects of front-right-sided brain bias on the presence of adult psychopathology. Front-right-sided bias has been implicated in certain behaviors that may encourage development of psychiatric disease, such as withdrawal and negative affect. This study also analyzed the effects that inflammation and childhood maltreatment may have on frontal-right-side bias and psychopathology. Results found that front-right-side bias was significantly associated with chronic inflammation and childhood maltreatment, but only when childhood maltreatment was considered moderate to severe. However, childhood maltreatment was not proven to be a direct indicator of front-right-side bias. Thus, it is more likely that front-right-side bias proves as a risk factor for development of adult psychopathology and childhood maltreatment compounds that risk (Hostinar et al., 2017).
Although most research implicates early life stressors and related brain alterations as negative consequences of adversity, some researchers believe that these alterations in brain structure and function instead serve as protective mutations to negative experience. That is, as children experience maltreatment, their brains alter functionality in order to encourage survival under adverse circumstances. Teicher et al. (2016) support this idea through their review of evidence involving differing brain changes based on types of trauma experienced. For instance, those that experienced verbal abuse in childhood had reduced grey matter in the auditory cortex. Those that experienced, and more specifically saw, inter-parental violence had reductions in the visual cortex while women who experienced sexual abuse as children had reductions in somatosensory regions of the brain that control for genitalia. These clear correlations support the theory that brain changes in response to adversity serve as protective factors (Teicher et al., 2016). Unfortunately, once removed from these adversities, these structural changes persist and can ultimately develop into maladaptive behaviors and disease.
Other brain structures have been implicated in adult psychopathology as well. One of the most relevant brain structures is the hippocampus. This structure is responsible for memory and is highly susceptible to the effects of glucocorticoids, such as cortisol. Patients with psychiatric disease often show reduction in hippocampal volume, particularly in those with major depressive disorder (Teicher et al., 2016). Similarly, the amygdala is highly susceptible to stress and glucocorticoids, however this brain region is responsible for understanding emotional stimuli, such as facial expressions and threats. Studies show that volume change in the amygdala is not directly related to childhood trauma, but instead the amygdala is overly sensitized by childhood trauma and subsequent traumatic events can influence the increase or decrease in volume size (Teicher et al., 2016). Some studies have also shown reduced white and grey matter in multiple brain regions, including the orbitofrontal cortex, prefrontal cortex and anterior cingulate cortex, in those who have experienced maltreatment (Teicher et al., 2016).
There is another factor that must be considered in the analysis of brain structure, and that is the strong evidence that some individuals who experienced maltreatment show structural changes that mimic those with psychiatric disease, however these individuals do not develop disease (Teicher et al., 2016). Thus, there must be some factor that allows for alteration in brain structure but protects from disease.
Epigenetics
Genetic differences can account for many aspects of psychopathology, particularly with regard to resilience factors. Not all individuals exposed to the same stressors develop disease, however there may also be factors beyond DNA sequencing that can account for the way in which genes are expressed and resilience is either encouraged or absent. These alterations in genetic expression can be attributed to epigenetic changes and differences between individuals. These changes can occur in childhood and particularly in response to stress or trauma.
Epigenetic changes result from different sources, such as histone modification, non-coding RNA sequences and DNA methylation. DNA methylation is of particular importance in psychiatric research as it can inhibit transcription of genes throughout the genome, which can encourage or discourage disease. This methylation occurs as a result of methyl groups attaching to DNA sequences and creating a physical block against transcription proteins (Ozben, 2019).
Weder et al. (2014) conducted an empirical research study to analyze the effect that childhood trauma had on epigenetic changes, particularly in those with adult psychopathology. Epigenetic alterations at three genes were strongly associated with the presence of disorder, particularly depression. These genes included ID3, GRIN1 and TPPP. These genes are responsible for pituitary regulation and production of cortisol, neural plasticity influenced by glutamate and NMDA receptors, and myelination in white matter areas of the brain, respectively (Weder et al., 2014). Interestingly, epigenetic profiles of depressed patients with a history of childhood trauma and those without are different, which has implications for potential treatments (Weder et al., 2014).
The precise origins of these epigenetic changes are not well understood, however various theories exist. The level of maternal care in infancy, prenatal stress, adolescent drug use and levels of environmental enrichment have all been implicated in having effects on epigenetic changes and likelihood of developing psychiatric disease in adulthood. Furthermore, all of these factors have a dose-dependent relationship on development of disease (Dudley et al., 2011).
In particular, the effect of maternal habits on children during infancy can be seen through a study conducted by Weaver et al. (2004). This study analyzed the epigenetic alterations in mice pups based on the frequency of grooming received from the mother in the first week of life. Results showed that increased maternal grooming altered the glucocorticoid receptor gene expression and thus led to more healthy HPA axis function. These changes were present as early as the first postnatal day, which underscores the importance of maternal intimacy immediately after birth and consistently throughout childhood (Weaver et al., 2004).
Treatment of Disease
Inflammation Pathways
Although inflammation has become an area of interest in recent years with regarding to psychiatric disease, it is important to note that not all psychiatric diseases present with increased inflammation. However, the presence of certain biomarkers offers a good predictor for whether anti-inflammatory therapy may be appropriate for a particular individual. C-reactive protein offers one of the most relevant markers for response to these types of therapies (Miller & Raison, 2015). Anti-inflammatory drugs therefore offer a novel approach to psychiatric treatment, particularly for those who do not respond to traditional treatments.
In an analysis by Strawbridge et al. (2015), inflammatory biomarkers were assessed to determine their predictive power for treatment response in depressed patients. The biomarkers analyzed included IL-6, TNF-α and CRP. Results were interesting with respect to those who did and did not respond to treatment. IL-6 levels were reduced across all populations regardless of response to treatment and conversely, CRP levels remained at a constant level across all populations regardless of response to treatment. However, TNF-α levels were able to predict who would and would not respond to anti-inflammatory treatment. With the use of infliximab, an anti-inflammatory TNF-α antagonist, patients who began the study with high levels of TNF-α responded with remarkable success to infliximab to treat depression, whereas those who began with low levels of TNF-α did not respond at all. It is also notable that those who began with high levels of TNF-α also represented individuals with a higher likelihood of treatment resistance with the use of traditional pharmaceutical methods (Strawbridge et al., 2015).
It is relevant to note that SSRI treatment, the first-line treatment for many depressive disorders, can have some effect on inflammatory markers as well. Although not statistically significant for TNF-α or IL-6, SSRI treatments were able to reduce IL-1β levels, although the reduction was minimal. TNF-α also did not respond to therapy with bupropion, an atypical antidepressant, however bupropion was a more effect treatment choice to those who did not respond to SSRI therapy (Hannestad et al., 2011).
Epigenetics
Although genetic traits are typically seen as immutable, epigenetic traits have the potential to be modified throughout the lifespan. Epigenetic changes incurred in childhood are typically more difficult to alter, however Weaver et al. (2005) offers a theory that would allow for these changes to occur. Following the previously discussed study by Weaver et al. in which infant mice developed alterations in their epigenome from maternal attention or neglect, the mice that suffered neglect and subsequent over-activation of the HPA axis due to methylation at the glucocorticoid receptor (GR) gene region, were able to have these methyl tags altered within their genome. Weaver et al. accomplished this through infusion of methionine, an amino acid, for 7 days. After the infusion, rats that previously had hypo-methylated regions of the GR gene had increased methylation in these regions, which correlated to a more healthy response of the HPA axis to stress (Weaver et al., 2005).
The most notable and obvious risk to treatments such as these is the lack of specificity when intravenously injecting methionine and hoping for methylation in the target DNA region. Nonetheless, Weaver et al. reported that DNA analysis of the treated rats showed that methylation only occurred in approximately 300 other regions, representing less than 1% of the entire genome. Remarkably, this treatment was able to also treat the target area without direction (Weaver et al., 2005).
Currently Available Treatments
There are a variety of treatments currently available that can treat psychiatric disorders with relative success. The exact pathways of each of these therapies are not entirely understood, but the basic mechanisms can be deduced. Cognitive-behavioral therapy (CBT) is one of the most effective treatments for psychiatric disorders, as it can permanently alter the way in which an individual processes external stimuli and stores memory and emotion. Furthermore, CBT focuses on behavioral routine and maintenance of regular activity, while in some cases combatting compulsive behaviors, in order to treat psychiatric disease (Goldapple et al., 2004). With respect to the exact mechanisms at play in CBT, Goldapple et al. (2004) performed a neuroimaging study that analyzed the brains of 17 depressed patients after 15–20 sessions of CBT and compared to a 6-week treatment with paroxetine, an SSRI antidepressant drug. Markedly different brain regions showed changes depending on which treatment was used. CBT produced unique effects including alterations in the dorsal midcingulate, ventromedial frontal and posterior cingulate regions. Conversely, paroxetine treatment exclusively showed changes in subgenual cingulate, insula, brainstem and cerebellum. There was some crossover between treatment, including the dorsolateral prefrontal cortex, inferior parietal cortex and hippocampus, however these changes were seen in an inverse pattern for each of the treatments (Goldapple et al., 2004).
Understanding where in the brain treatments function is essential, but even more important is to understand what these regions of the brain represent and how alterations in these areas can affect behavior and cognition. With respect to CBT, all of the areas modulated by this therapy involve processes such as working memory, cognitive ruminations and emotional processing tasks. Furthermore, although this particular study focused on major depressive disorder, other studies have analyzed CBT therapy for other disorders such as social phobia and obsessive-compulsive disorder, with success (Goldapple et al., 2004). Notably, therapies to treat other disorders ultimately cause changes in other areas of the brain, seemingly to treat the exact areas in the brain that are malfunctioning with respect to specific disorders (Goldapple et al., 2004).
The second most common treatment for psychiatric disorders involves pharmacotherapy. Depending on the disorder that is being treated, this could involve drugs from different classes, such as selective-serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics, benzodiazepines, monoamine oxidase inhibitors (MAOIs) and a variety of atypical-action drugs. When treating depressive disorders, anxiety disorders and obsessive-compulsive disorders, the first line of treatment typically involves antidepressant therapies such as SSRIs and SNRIs. Although the mechanism of action for each of these therapies is seemingly obvious, the exact way in which these drugs produce effects is not well understood. Increased levels of monoamines such as serotonin and norepinephrine are seen, however, the effects of these drugs typically take four to six weeks to reach full effect, while the increase in monoamine concentration occurs immediately after administration. There is clearly another mechanism at play.
Castren and Rantamaki (2010) propose that this alternative mechanism may be an increase in neural plasticity, effectively allowing the brain to heal itself, with the use of these medications. Development of new neurons, neurogenesis, persists throughout the lifetime, however there is reason to believe that psychiatric disorders can inhibit this action and ultimately cause neurodegeneration, which can affect many different brain structures and cause the cognitive distortions seen in psychiatric disorders. In order to combat this degeneration, antidepressant drugs may raise levels of brain-derived neurotrophic factor (BDNF) to reinvigorate neurogenesis and help the brain recover. There is strong evidence to show that BDNF levels are raised after treatment with antidepressant drugs and this mechanism also accounts for the lag in treatment response seen with many antidepressant drugs. During this lag time, BDNF is circulating throughout the body and brain and aiding in creation of new neurons and brain pathways, however this process takes time. Interestingly, electroconvulsive therapy (ECT) has exhibited the same mechanism of action, via BDNF increase, in patients with severe depression (Castren & Rantamaki, 2010).
A particularly remarkable finding by Ventencourt et al. (2008) encourages this idea of increased neuronal plasticity due to antidepressant drugs. This study induced amblyopia (monocular deprivation, “lazy eye”) in a rat model during the critical period of development. Due to the deprivation of sight in one eye, the brains of these rats shifted neuronal control in the visual cortex from both eyes to a single eye. After reaching adulthood, the rats were then allowed to use both eyes, but the damage to the visual cortex was seemingly permanent. However, after administration of fluoxetine (SSRI), the visual cortex of these rats was able to reach child-like plasticity, reengage the previously ignored area of the visual cortex and completely restore vision to the blind eye. Although these findings may not translate into other brain regions, they offer incredible insight into the abilities of brains to recover, even well beyond the critical period (Ventencourt et al., 2008).
Another interesting phenomenon in psychiatric treatment involves the high levels of placebo response during clinical trials. Typical placebo response rates in clinical trials involving depression are around 30–40% (Sonawalla & Rosenbaum, 2002). In a study conducted by Leuchter et al. (2002), the way in which the placebo effect elucidates a response was analyzed. The study found that although the changes incurred by the placebo response were different than those provided by pharmaceutical treatment, there were notable changes in brain function as seen via PET scan. In fact, many of the brain changes resulting from placebo treatment were the inverse of changes seen by medication treatment (Leuchter et al., 2002). Exactly why this is true is unclear, however placebo treatments may offer an interesting alternative view into treatments overall.
The Gold Standard: Early Intervention
The ideal method for child maltreatment and abuse is early intervention, both to interfere with abusive patterns and to provide treatments to children that have incurred abuse as soon as possible. There are different theories as to why speed of treatment is so essential, however the idea of critical periods is widely accepted.
These critical periods highlight different timepoints throughout development when certain areas of the brain are the most susceptible to change, particularly changes induced by stress. This critical period encompasses all of childhood and most of adolescence, during which time the brain is undergoing massive development. In psychiatric disease, the alteration of glutamate, GABA and dopamine neurons in the brain can account for a large impact on the development of adult psychopathology (Lockhart et al., 2018). Furthermore, development of the prefrontal cortex, which functions in fear and anxiety response as well as high-level cognitive functioning, is ongoing throughout childhood and adolescence. All of these developments are highly susceptible to glucocorticoids, such as those produced through the HPA axis in response to stress. Proposed theories as to the origins of these alterations include epigenetic mechanisms as well as overall developmental alterations (Lockhart et al., 2018).
Other investigations have analyzed the structural changes that occur alongside these developmental periods. Martin et al. (2011) report that after age 12, the development of grey matter within the brain is complete. However, other areas of the brain such as the temporal lobe increase until age 18. After these critical periods of development, the neuronal structure within the brain becomes essentially permanent (Martin et al., 2011). Therefore, harnessing the plasticity of these regions that have not finished developing is essential during these critical periods in order to potentially prevent persistent adult psychopathology.
Conclusion
Providing intervention for all children that have experienced trauma or maltreatment is a daunting task, however the health and wellbeing of our society depend upon it. Using different biobehavioral methods to determine exactly how and why certain early life experiences affect the future trajectory of the lives of children is essential to accomplish this task. Some research even shows that childhood adversity may be able to transcend generations, creating a compounding problem. These changes are theorized to be heritable through the epigenome, passing down the burden of environmental stimuli and trauma (Burton & Metcalfe, 2014).
The ideal treatment for early childhood adversity is a combination of biological and behavioral modifications. Instilling healthy coping mechanisms along with repairing potentially damaged pathways prior to the termination of the critical period can allow for these coping skills and alternative thought pathways to be utilized well into adulthood. Although early intervention with pharmaceutical methods has not been well established, it stands to reason that with the high degree of neural plasticity during childhood, pharmaceuticals may not be necessary if the alternative intervention is provided within the critical period.
Unfortunately, a large percentage of children leave the critical period without having received treatment and go on to develop adult psychiatric disease. However, there are proven methods to mitigate these diseases and new technologies and methodologies are being discovered all the time. Currently, research suggests that CBT may offer alterations in thought and emotion pathways that allow for healthy behaviors to overcome the presence of disease. Furthermore, antidepressant pharmaceutical therapies, which have existed for decades, may have all the while been eliciting effects through unknown mechanisms, allowing for an expansion of neural plasticity to near-child-like levels. This discovery could reach into other domains as well, allowing for damaged brains across the spectrum to recover from disease.
Some of the more novel theories involve an immune and genetic investigations into these diseases. The role that immune function and inflammation play in psychiatric disease is not well understood, however there are clear correlations between inflammatory biomarkers and psychiatric disease. It is also apparent that individuals with higher initial levels of inflammation respond more appropriately and aggressively to anti-inflammatory treatments.
Alternatively, when looking at the genetic basis of psychiatric disease, there are many different facets. It is understood that psychiatric disease is a directly heritable trait, with those having close relatives with disease being more likely to develop diseases themselves. However, beyond the DNA code, there is another portion of the genome, the epigenome, which is highly susceptible to environmental influence and therefore can be changed when individuals are exposed to stress. This epigenome is partially responsible for turning genes on and off and therefore can encourage or discourage development of disease due to stress.
Future directions in research in this area involve developing a deeper understanding of the role that inflammation has on disease. Current research is developing theories regarding the connection between the gut microbiome and the brain, leading to a holistic and integrated approach to treating mental health. Creating different and more specific treatments that target the exact mechanisms that are defective in individuals with disease will allow for significantly more treatment success. The changes in brain and body function between different psychiatric diseases, and even within diseases, vary greatly making targeted treatment essential for recovery.
Furthermore, another interesting and elusive piece of psychiatric research involves individuals exposed to adversity who do not go on to develop disease. The protective factors that these individuals possess could unlock extremely beneficial treatment protocols for those who do develop disease. Identifying how and why some people have resilient personality types while others do not could significantly impact psychiatric treatment. Cognitive-behavioral therapy attempts to teach certain resilience factors, however innate resilience seems to have an even greater effect on outcomes (Happer et al., 2017).
Childhood adversities can completely alter and derail an individual’s life. Finding the mechanisms through which these adversities affect childhood development and how those children go on to develop disease will significantly alter the course of psychiatry and psychiatric disease around the globe.
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