Pathways to inflammation in adolescence through early adversity,childhood depressive symptoms,and body mass index: A prospective longitudinal study of Chilean infants

Early adversity, depression, and obesity are associated with increases in low-grade inflammation. However, there are few prospective and longitudinal studies to elucidate how these associations unfold in children. The present study used latent growth curve models to examine pathways between family adversity in infancy, depressive symptoms in childhood, body mass index (BMI) in childhood, and inflammation in adolescence (age = 16–18). The study is an adolescent follow-up of infants from working-class communities around Santiago, Chile, who participated in a preventive trial of iron supplementation at 6 months of age. Anthropometrics, stressful life events, maternal depression, socioeconomic status, and developmental assessments were measured at 12 months, 5 years, 10 years, and adolescence. In adolescence, participants provided blood samples for high-sensitivity C-reactive protein (hsCRP) assessment. Greater exposure to early adversity in the form of interpersonal conflict stress in infancy indirectly associated with increased hsCRP through its association to increased intercept and slope of childhood BMI. Depressive symptoms at any time were not directly or indirectly associated with increased hsCRP. These findings contribute to our understanding of how early family adversity and its associations with obesity and depressive symptoms across childhood are linked to low-grade, chronic inflammation in adolescence. The model identified as best capturing the data supported the pivotal role of childhood BMI in explaining how early-life adversity is associated with inflammation in adolescence.     

A plausible model of schizophrenia must incorporate psychological and social, as well as neuro developmental, risk factors

Subtle alterations in brain development caused by genes or early environmental hazards, such as obstetric complications, play a role in projecting some individuals on a trajectory toward schizophrenia. High-risk and cohort studies demonstrate that children destined to develop schizophrenia tend to have delayed milestones and subtle neuromotor and cognitive impairments (particularly in coordination and language). These neurocognitive problems lead to difficulties in interpersonal relations, and their progressive alienation makes these at-risk children more likely to harbor odd or paranoid ideas. This cascade of increasingly deviant development may then be compounded by brain maturational changes during adolescence with a resultant lability of the dopaminergic response to stress. As a result, the individual is more susceptible to the effects of the abuse of dopamine-releasing drugs, and to other risk factors such as migration or stressful life events; social isolation may be a common pathway underlying several of the social risk factors.     

Is there a viability–vulnerability tradeoff? Sex differences in fetal programming

Objective

In this paper we evaluate the evidence for sex differences in fetal programming within the context of the proposed viability–vulnerability tradeoff.

Methods

We briefly review the literature on the factors contributing to primary and secondary sex ratios. Sex differences in fetal programming are assessed by summarizing previously published sex difference findings from our group (6 studies) and also new analyses of previously published findings in which sex differences were not reported (6 studies).

Results

The review and reanalysis of studies from our group are consistent with the overwhelming evidence of increasing risk for viability among males exposed to environmental adversity early in life. New evidence reported here support the argument that females, despite their adaptive agility, also are influenced by exposure to early adversity. Two primary conclusions are (i) female fetal exposure to psychobiological stress selectively influences fear/anxiety, and (ii) the effects of female fetal exposure to stress persist into preadolescence. These persisting effects are reflected in increased levels of anxiety, impaired executive function and neurological markers associated with these behaviors.

Conclusions

A tacit assumption is that females, with their adaptive flexibility early in gestation, escape the consequences of early life exposure to adversity. We argue that the consequences of male exposure to early adversity threaten their viability, effectively culling the weak and the frail and creating a surviving cohort of the fittest. Females adjust to early adversity with a variety of strategies, but their escape from the risk of early mortality and morbidity has a price of increased vulnerability expressed later in development.     

Commentary on the special issue on the adolescent brain: Adolescence,trajectories, and the importance of prevention

Adolescence as highlighted in this special issue is a period of tremendous growth, synaptic exuberance, and plasticity, but also a period for the emergence of mental illness and addiction. This commentary aims to stimulate research on prevention science to reduce the impact of early life events that often manifest during adolescence. By promoting a better understanding of what creates a normal and abnormal trajectory, the reviews by van Duijvenvoorde et al., Kilford et al., Lichenstein et al., and Tottenham and Galvan in this special issue comprehensively describe how the adolescent brain develops under typical conditions and how this process can go awry in humans. Preclinical reviews also within this issue describe how adolescents have prolonged extinction periods to maximize learning about their environment (Baker et al.), whereas Schulz and Sisk focus on the importance of puberty and how it interacts with stress (Romeo). Caballero and Tseng then set the stage of describing the neural circuitry that is often central to these changes and psychopathology. Factors that affect the mis-wiring of the brain for illness, including prenatal exposure to anti-mitotic agents (Gomes et al.) and early life stress and inflammation (Schwarz and Brenhouse), are included as examples of how exposure to early adversity manifests. These reviews are synthesized and show how information from the maturational stages that precede or occur during adolescence is likely to hold the key towards optimizing development to produce an adolescent and adult that is resilient and well adapted to their environment.     

Early Childhood Environment and Genetic Interactions: the Diathesis for Suicidal Behavior

Adverse childhood experiences are associated with higher risk for suicide and suicidal behavior later in life. There are known associations between childhood trauma, particularly sexual abuse, and higher rates of suicide, non-lethal suicide attempts, and non-suicidal self-injurious behaviors in adolescence and adulthood. Emotional abuse/neglect, disrupted parental attachment, and cumulative effect of multiple forms of maltreatment, also increase risk. Yet, the causal relationship remains unclear. The diathesis-stress model provides a framework for understanding how early life adverse experiences contribute to suicide vulnerability. Current findings from the fields of biology, neurology, and genetics shed new light on mediating variables and possible causal links between early childhood trauma and suicide. In this paper, we review recent advances, particularly regarding the interaction of early life environmental adverse events with genetics factors, that increase the diathesis for psychological traits are associated with subsequent deliberate self-harm behaviors.     

Sensitive periods of substance abuse: Early risk for the transition to dependence

Early adolescent substance use dramatically increases the risk of lifelong substance use disorder (SUD). An adolescent sensitive period evolved to allow the development of risk-taking traits that aid in survival; today these may manifest as a vulnerability to drugs of abuse. Early substance use interferes with ongoing neurodevelopment to induce neurobiological changes that further augment SUD risk. Although many individuals use drugs recreationally, only a small percentage transition to SUD. Current theories on the etiology of addiction can lend insights into the risk factors that increase vulnerability from early recreational use to addiction. Building on the work of others, we suggest individual risk for SUD emerges from an immature PFC combined with hyper-reactivity of reward salience, habit, and stress systems. Early identification of risk factors is critical to reducing the occurrence of SUD. We suggest preventative interventions for SUD that can be either tailored to individual risk profiles and/or implemented broadly, prior to the sensitive adolescent period, to maximize resilience to developing substance dependence. Recommendations for future research include a focus on the juvenile and adolescent periods as well as on sex differences to better understand early risk and identify the most efficacious preventions for SUD.     

Unravelling the Link Between Prenatal Stress,Dopamine and Substance Use Disorder

Substance use disorder (SUD) refers to the detrimental use of psychoactive substances and it is related to a cluster of behavioural, cognitive and physiological dysfunctions indicating that the individual continues using the substance despite significant substance-related problems. Although it is one of the most prevalent neuropsychiatric diseases affecting society worldwide, the mechanism underlying the vulnerability of certain individuals is not well understood yet. It is now widely accepted that, in addition to genetic factors, environmental adversities during critical stages of development of an organism could also be considered as risk factors that contribute to SUD. It has been suggested that prenatal stress (PS) could play an important role in the causal mechanisms of SUD, since it was shown that PS leads individuals to poor stress management and behavioural problems, both of which increase the risk of SUD. It is widely accepted that gestational stress exposure in rats interferes with the correct progeny development. In particular, research in this field points out that the development of the mesocorticolimbic dopaminergic (DA) system is sensitive to disruption by exposure to early stressors. Interestingly, PS induces behavioural abnormalities that are similar to those observed in individuals that present SUD. Since dysfunction of mesocorticolimbic DA pathway has been reported in both prenatally stressed and SUD individuals, in this review we will summarise the current knowledge supporting that PS may serve as a strong candidate to explain the vulnerability of certain individuals to develop SUD following repeated drug exposure. We will also propose a mechanistic hypothesis to explain PS-induced changes on mesocorticolimbic DA system.     

Adolescent vulnerability to cardiovascular consequences of chronic emotional stress: Review and perspectives for future research

Emotional stress has been recognized as a modifiable risk factor for cardiovascular diseases. Adolescence has been proposed as a developmental period of vulnerability to stress. This idea has been mainly supported by experimental research in animals demonstrating a higher impact of chronic emotional stress in adolescents compared with adults. Adolescent vulnerability is also based on evidence that stress during this developmental period affects development, so that enduring changes are found in adult animals that experienced stress during adolescence. The purpose of the present review is to discuss experimental research in rodent models that investigated the impact of long-term exposure to stressful events during adolescence on cardiovascular function. The development of cardiovascular function and autonomic activity in rodents is initially reviewed. Then, a discussion of an adolescent vulnerability to cardiovascular effects of chronic stress is presented. From the reviewed literature, perspective for future research is proposed to better elucidate adolescent vulnerability to cardiovascular complications evoked by chronic emotional stress.     

Sex differences in resilience: Experiential factors and their mechanisms

Adverse life events can lead to stable changes in brain structure and function and are considered primary sources of risk for post‐traumatic stress disorder, depression and other neuropsychiatric disorders. However, most individuals do not develop these conditions following exposure to traumatic experiences, and research efforts have identified a number of experiential factors associated with an individual's ability to withstand, adapt to and facilitate recovery from adversity. While multiple animal models of stress resilience exist, so that the detailed biological mechanisms can be explored, studies have been disproportionately conducted in male subjects even though the prevalence and presentation of stress‐linked disorders differ between sexes. This review focuses on (a) the mechanisms by which experiential factors (behavioral control over a stressor, exercise) reduce the impact of adverse events as studied in males; (b) whether other manipulations (ketamine) that buffer against stress‐induced sequelae engage the same circuit features; and (c) whether these processes operate similarly in females. We argue that investigation of experiential factors that produce resistance/resilience rather than vulnerability to adversity will generate a unique set of biological mechanisms that potentially underlie sex differences in mood disorders.     

Stress in adolescence as a first hit in stress-related disease development: Timing and context are crucial

The two-hit stress model predicts that exposure to stress at two different time-points in life may increase or decrease the risk of developing stress-related disorders later in life. Most studies based on the two-hit stress model have investigated early postnatal stress as the first hit with adult stress as the second hit. Adolescence, however, represents another highly sensitive developmental window during which exposure to stressful events may affect programming outcomes following exposure to stress in adulthood. Here, we discuss the programming effects of different types of stressors (social and nonsocial) occurring during adolescence (first hit) and how such stressors affect the responsiveness toward an additional stressor occurring during adulthood (second hit) in rodents. We then provide a comprehensive overview of the potential mechanisms underlying interindividual and sex differences in the resilience/susceptibility to developing stress-related disorders later in life when stress is experienced in two different life stages.     

Correlates of adverse childhood events among adults with schizophrenia spectrum disorders

OBJECTIVE: Multiple studies have found that childhood adversity is related to a range of poor mental health, substance abuse, poor physical health, and poor social functioning outcomes in the general population of adults. However, despite the high rates of childhood adversity in schizophrenia, the clinical correlates of these events have not been systematically evaluated. This study evaluated the relationship between adverse experiences in childhood and functional, clinical, and health outcomes among adults with schizophrenia. METHODS: The authors surveyed 569 adults with schizophrenia regarding adverse childhood events (including physical abuse, sexual abuse, parental mental illnesses, loss of a parent, parental separation or divorce, witnessing domestic violence, and foster or kinship care). The relationships between cumulative exposure to these events and psychiatric, physical, and functional outcomes were evaluated. RESULTS: Increased exposure to adverse childhood events was strongly related to psychiatric problems (suicidal thinking, hospitalizations, distress, and posttraumatic stress disorder), substance abuse, physical health problems (HIV infection), medical service utilization (physician visits), and poor social functioning (homelessness or criminal justice involvement). CONCLUSIONS: The findings extend the results of research in the general population by suggesting that childhood adversity contributes to worse mental health, substance abuse, worse physical health, and poor functional outcomes in schizophrenia.     

Developmental neurobiology of childhood stress and trauma.

Severe early stress and maltreatment produces a cascade of events that have the potential to alter brain development. The first stage of the cascade involves the stress-induced programming of the glucocorticoid, noradrenergic, and vasopressin-oxytocin stress response systems to augment stress responses. These neurohumors then produce effects on neurogenesis, synaptic overproduction and pruning, and myelination during specific sensitive periods. Major consequences include reduced size of the mid-portions of the corpus callosum; attenuated development of the left neocortex, hippocampus, and amygdala along with abnormal frontotemporal electrical activity; and reduced functional activity of the cerebellar vermis. These alterations, in turn, provide the neurobiological framework through which early abuse increases the risk of developing post-traumatic stress disorder (PTSD), depression, symptoms of attention-deficit/hyperactivity, borderline personality disorder, dissociative identity disorder, and substance abuse.     

Emotion dysregulation mediates the relationship between lifetime cumulative adversity and depressive symptomatology

Repeated exposure to stressful events across the lifespan, referred to as cumulative adversity, is a potent risk factor for depression. Research indicates that cumulative adversity detrimentally affects emotion regulation processes, which may represent a pathway linking cumulative adversity to vulnerability to depression. However, empirical evidence that emotion dysregulation mediates the relationship between cumulative adversity and depression is limited, particularly in adult populations. We examined the direct and indirect effects of cumulative adversity on depressive symptomatology in a large community sample of adults (n = 745) who were further characterized by risk status: never-depressed (n = 638) and “at-risk” remitted mood-disordered (n = 107). All participants completed the Cumulative Adversity Inventory (CAI), the Difficulties in Emotion Regulation Scale (DERS), and the Center for Epidemiologic Studies Depression Scale (CES-D). Bootstrapped confidence intervals were computed to estimate the indirect effect of emotion dysregulation on the relationship between cumulative adversity and depressive symptomatology and to test whether this indirect effect was moderated by risk status. Emotion dysregulation partially and significantly mediated the relationship between cumulative adversity and depressive symptomatology independent of risk status. Overall, cumulative adversity and emotion dysregulation accounted for 50% of the variance in depressive symptomatology. These findings support the hypothesis that disruption of adaptive emotion regulation processes associated with repeated exposure to stressful life events represents an intrapersonal mechanism linking the experience of adverse events to depression. Our results support the utility of interventions that simultaneously emphasize stress reduction and emotion regulation to treat and prevent depressive vulnerability and pathology.     

The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression

OBJECTIVE: Three potent risk factors for major depression are female sex, the personality trait of neuroticism, and adversity resulting from exposure to stressful life events. Little is known about how they interrelate in the etiology of depressive illness. METHOD: In over 7,500 individual twins from a population-based sample, the authors used a Cox proportional hazard model to predict onsets of episodes of DSM-III-R major depression in the year before the latest interviews on the basis of previously assessed neuroticism, sex, and adversity during the past year; adversity was operationalized as the long-term contextual threat scored from 15 life event categories. RESULTS: In the best-fit Cox model for prediction of depressive onsets, neuroticism, female sex, and greater adversity all strongly increased risk for major depression. An interaction was seen between neuroticism and adversity such that individuals with high neuroticism were at greater overall risk for major depression and were more sensitive to the depressogenic effects of adversity. An interaction was also seen between adversity and sex, as the excess risk for major depression in women was confined to individuals with low stress exposure. CONCLUSIONS: Psychosocial adversity interacts both with neuroticism and with sex in the etiology of major depression. The impact of neuroticism on illness risk is greater at high than at low levels of adversity, while the effect of sex on probability of onset is the opposite--greater at low than at high levels of stress. Complete etiologic models for major depression should incorporate interactions between risk factor classes.     

Increased early life stress and depressive symptoms in patients with comorbid substance abuse and schizophrenia

Early adverse events have been associated with increased rates of substance abuse and depression. To investigate the association between early adverse events and comorbid substance abuse in schizophrenia patients, early life stress, depressive symptoms, positive and negative symptoms, anxiety, and cognitive function were measured in an age-, sex-, and race-matched sample of 40 schizophrenia patients with and without comorbid substance abuse. Compared to patients without substance abuse, patients with schizophrenia and a history of substance abuse had a significantly higher incidence of early life trauma, as well as significantly higher scores on the Modified Hamilton Rating Scale for Depression and the Psychiatric Epidemiology Research Interview Life Events Scale. No differences between groups were found in positive or negative symptoms, anxiety, or cognitive function. The results emphasize the importance of early life stress and affective symptoms and their potential relationship to substance abuse disorders in schizophrenia patients.     

The neurobiology of the stress cascade and its potential relevance for schizophrenia

This review explores the neurobiology of stress and its possible role in the etiology of schizophrenia. Major life events may play a role in onset and relapse in schizophrenia. Other data suggest that early stress exposure increases schizophrenia risk, especially in individuals with latent vulnerability. Animal research has led to an elucidation of the mechanisms by which stress and cortisol are toxic to the hippocampus and impair cognition. Associations among these factors have been found in a variety of human conditions, including psychiatric illness and normal aging. These mechanisms are plausible in schizophrenia, which is characterized by a degree of cortisol dysregulation, hippocampal abnormality, and cognitive impairment. Characterization of the role of the stress cascade in schizophrenia has implications for novel pharmacologic and other treatment, especially for cognitive symptoms, which are debilitating and largely refractory to treatment.     

Developmental influences on stress response systems: Implications for psychopathology vulnerability in adolescence

The adolescent transition is marked by increases in stress exposure and significant maturation of neural and hormonal stress processing systems. Variability in the development of these systems during adolescence may influence the risk for stress-related psychopathology. This paper aims to review the developmental maturation of the HPA axis and related stress regulation systems, and demonstrate how interference in this adaptive developmental process may increase the risk for negative outcomes. We argue that the developmental maturation of the HPA axis aims to improve the regulatory capacity of the axis in order to more adaptively respond to these increases in stress reactivity. Additionally, we review evidence that sex differences in the development of the HPA and related axes may contribute to sex differences in the risk for stress-related psychopathology. Finally, we discuss how contextual factors, such as early trauma and obesity may alter the development of HPA axis during the adolescence transition and how alterations of normative development increase the risk for stress-related disorders.     

Impulsivity and adolescent substance use: rashly dismissed as "all-bad"?

The initial use of illicit drugs and alcohol typically occurs during adolescence. Individual differences in impulsivity and related constructs are consistently identified as key factors in the initiation and later problematic use of substances. Consequently, impulsivity is generally regarded as a negative trait; one that conveys only risk. However, what is often overlooked in addiction science is the positive role facets of trait impulsivity can play in everyday life and adaptive functioning. The following review aims to summarize recent advances in the psychobiology of impulsivity, including current perspectives on how it can convey risk for substance misuse. The review will also consider the importance of adolescence as a phase of life characterized by substantial neurodevelopment and natural increases in impulsivity. Uniquely, the review aims to reframe thinking on adolescent impulsivity to include the positive with the negative, and discuss how such thinking can benefit efforts for early intervention and future research.     

Childhood adversity and vulnerability to mood and anxiety disorders

Based upon epidemiological surveys, adverse childhood events are proposed to be risk factors for adult depressive and anxiety disorders. However, the extent to which these events are seen in clinical patient populations is less clear. We examined the prevalence of a number of proposed risk factors for depression in 650 patients with mood and anxiety disorders at the time of presentation for treatment in an outpatient subspecialty clinic. Emotional abuse, physical abuse, or sexual abuse (childhood adversity) was found in approximately 35% of patients with major depression and panic disorder, was more common in women than men, and was associated with an earlier onset of symptoms. Childhood adversity was also strongly associated with marital discord/divorce, and psychopathology in a parent, suggesting family discord predisposes to childhood abuse. Furthermore, the association of childhood abuse with parental mental illness suggests that genetic and environmental factors are difficult to separate as etiological factors in vulnerability. Depression and Anxiety 5:66–72, 1997. © 1997 Wiley-Liss, Inc