ETIOLOGY OF CHILDHOOD AND ADOLESCENT DEPRESSION

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The development of depression in children and adolescents involves a complex, multifactorial model. No single risk factor accounts for all or even most of the variance. Rather, it is more likely that the accumulation, and/or interaction among multiple risk factors will lead to depression

Family-Genetic Factors

There is clear evidence of familial transmission of depression. These data, however, cannot distinguish environmental from genetic causes of transmission . Family, twin and adoption studies documented effects of both genetic and environmental factors for unipolar depression . In a large study of adolescent female twins, genetic factors accounted for 40.4% of the variance in risk for major 96 Uma Rao and Li-Ann Chen depression. Non-shared environmental effects accounted for the remaining portion of the variance. Similarly, large-scale studies indicate that exposure to early adverse situations (e.g., parental loss, chaotic family environment, childhood abuse) account for over 50% of the attributable risk for depression. Most importantly, genes and early experiences interact. For example, Caspi et al. found that exposure to severe childhood maltreatment doubled the risk of major depression in individuals with two copies of the short allele in the promoter region of the gene encoding serotonin transporter (5-HTT). In contrast, childhood maltreatment was not associated with increased risk for depression in individuals with two copies of the long allele of the 5-HTT gene.
Genetic and environmental influences have been found to vary with age and sex. Shared environmental influences may be more important in younger children, and these influences may be replaced by new genetic and unique environmental influences as children grow older . In one study, the increased heritability effect in adolescents was found only for girls, and not boys . In summary, many cases of depression might arise from the confluence of genetic predisposition interacting with experiential factors that occur during a specific window of vulnerability. This, in turn, leads to a cascade of events that unfold over the course of maturation.

Neurobiology

Neurobiological studies of childhood and adolescent depression have employed methods used in adult studies and attempted to replicate those observations. Most of the studies focused on sleep architecture and neuroendocrine systems . There also is emerging literature on structural and functional neuroimaging techniques . It is important to note that the sample sizes in many of these neurobiological studies are modest.

Sleep Architecture and Electrophysiological Studies

In adults, the most reliable sleep architecture changes associated with major depression include sleep continuity disturbances, shorter latency to rapid eye movement (REM) sleep, increased phasic REM sleep and diminished slow-wave sleep . Sleep architecture measures have shown considerable variability with regard to group differences between depressed youngsters and matched controls . The findings vary as function of age, gender, familial risk, severity of illness and clinical course  . Depressed adolescents seem to have relatively more frequent disturbances in circadian rest-activity rhythms, sleep architecture and electroencephalographic (EEG) rhythms during sleep compared with depressed children . Changes in sleep architecture and sleeprelated EEG rhythms also were documented in healthy adolescents at high-risk for depression based on family history, and these changes were associated with vulnerability for depression during prospective follow-up . Additionally, baseline sleep architecture patterns differed between depressed adolescents who subsequently had a recurrent unipolar course versus those who developed bipolar illness; adolescents with unipolar course had predominantly REM sleep changes while adolescents with bipolar course manifested nonREM sleep changes . In the same study, adolescents who subsequently developed substance use disorders had relatively normal EEG sleep patterns .

The observed variability in sleep architecture changes in depressed youngsters may reflect, at least in part,
heterogeneity in the longitudinal clinical course of these disorders.

Electrophysiological studies also documented reduced left frontal electrical activity in infant and adolescent offspring of depressed mothers , and in adolescents with major depressive disorder . Deceased left frontal EEG activity probably reflects an under-activation of the approach system and reduced positive emotional expression, which also might be a vulnerability marker for depression.

Neuroendocrine Studies

Among the neuroendocrine markers of pediatric depression, there has been considerable interest in the HPA system, consistent with the hypothesis that depression is linked to altered responses to stress. Numerous studies documented HPA dysregulation in adult depression including higher basal corticotropin-releasing hormone (CRH) and cortisol secretion, nonsuppression of cortisol in response to dexamethasone administration, and blunted corticotropin response to CRH adminsitration [170, 171]. Findings from HPA studies in depressed children and adolescents have been inconsistent [150, 151]. Specifically, depressed children did not display changes in 24-hour cortisol patterns compared to matched controls without a psychiatric disorder. Few differences in basal cortisol secretion have been observed between depressed adolescents and controls, and when group differences were detected, they tend to be subtle alterations in normal diurnal patterns. These subtle changes, however, were relatively robust in predicting the longitudinal clinical course; higher cortisol secretion in the evening or during sleep, a time when the HPA axis is relatively quiescent, was associated with a longer time to recovery from the depressive episode , a propensity for recurrence, and suicide attempts [174]. Higher cortisol secretion also was detected in at-risk youth who subsequently developed depression [157, 175, 176]. In cross-sectional studies, HPA activity varied as a function of exposure to stressful experiences in depressed children and adolescents, with increased activity specifically in youth with adverse experiences.

Another neuroendocrine marker possibly related to depression is growth hormone, which is secreted by the anterior pituitary and follows a circadian pattern with increased secretion during slow-wave sleep. Although the precise role of growth hormone secretion in depression is not known, it appears to be a marker of central noradrenergic and 5-HT systems [179].
Reduced growth hormone secretion during sleep has been observed in adult depression [180], but findings in children and adolescents have been variable [150, 151]. One study found that depressed children with stressful life events had increased growth hormone secretion compared to their counterparts who did not experience recent stress, suggesting that environmental factors have a moderating influence [181]. In another investigation, depressed adolescents who subsequently exhibited suicidal behavior had increased growth hormone secretion during sleep, and when this group was separated, depressed adolescents manifested blunted growth hormone secretion compared with controls [182]. In contrast to the findings in basal secretion, pharmacological challenge studies documented blunted growth hormone response to a variety of pharmacological agents in depressed children, similar to those reported in depressed adults [179]. In contrast, data in adolescents were predominantly
negative. Although the sample sizes were modest in these adolescent studies, pubertal changes and gender might account for some variability among child, adolescent and adult samples

Neuroimaging Studies

Studies using various neuroimaging techniques provided converging lines of evidence supporting prefrontal cortical-striatal and medial temporolimbic dysfunction in adult depression . There is preliminary evidence of anatomic and functional differences in the brains of depressed and at-risk youth compared to matched controls without disorder. Reduced left frontal volume was documented, particularly in youngsters with
familial depression. Alterations in amygdala and hippocamplal volumes also were found , although the effects may be moderated by anxiety symptoms . Moreover, amygdala responses to emotional tasks have been documented in normal and depressed youngsters . In neurochemical studies, reduced glutamate and creatinine/phosphocreatinine concentrations in the anterior cingulate, and increased choline concentrations in the left dorsolateral prefrontal cortex, were documented in children and adolescents with depression.

Summary of Neurobiological Research

Neurobiological research in pediatric depression suggests that neurobiological factors change during the course of development, and developmentally-influenced neurobiological processes may become disrupted during depressive episodes. Longitudinal studies that account for familial and clinical variability allude to this possibility. These data also indicate that pediatric depressive disorders may not necessarily result from the same etiological
processes, and the specific subtype with familial loading or depressive disorder with a recurrent unipolar course may be associated with neurobiological changes typically observed in adult unipolar depression. Experiential factors also appear to influence neurobiological findings. Future longitudinal investigations with large sample sizes should examine genetic, developmental and socio-cultural influences on neurobiological factors associated with the onset and clinical course of depression in children and adolescents.

Temperament and Personality

Temperament is broadly defined as individual differences in emotional and behavioral style that appear early in life, are consistent over time and across situations, and presumed to have a genetic/biological basis . It is however, important to note that experience and learning, particularly within the social context, also can influence the development and expression of temperament . The trait that is associated with most emotional disorders has been given various labels by different theorists, including behavioral inhibition, harm avoidance , negative affectivity , neurotism, and trait anxiety, although there is a significant overlap among these constructs both from conceptual and empirical perspectives.

Negative affectivity is the propensity to experience negative emotions, and it reflects sensitivity to negative stimuli, increased wariness, vigilance, physiological arousal and emotional distress. In contrast, positive affectivity is characterized by sensitivity to reward cues, sociability and adventurousness  . Depression is characterized by high levels of negative affectivity and low levels of positive affectivity , and these features also have been found in depressed children  . A higher frequency of behavioral inhibition also has been observed in laboratory tasks with young offspring of depressed parents . Moreover, some longitudinal studies have shown that children with inhibited, socially-reticent and easily-upset temperament in early childhood had higher rates of depressive disorders during adolescence and/or early adulthood than those who did not demonstrate these characteristics  . Also, difficult temperament, characterized by inflexibility, low positive mood ithdrawal, and poor concentration correlated with depressive symptoms both concurrently and prospectively in adolescents and adults . There is also evidence that the effects of temperament on depression may be mediated by other factors, including cognitive and contextual variables . Some of these factors will be discussed in subsequent sections.
The relation between temperament and depression may vary with age. In one study, neurotic-like symptoms predicted the first episode of depression in 31-41-year-old individuals but this was not the case for 17-30-year-olds  . Similarly, adult participants who experienced a first episode of depression had exhibited elevated levels of dependent traits 2-3 years earlier . However, no differences were found with regard to such dependent traits between adolescents who later developed depression and those who did not develop the
disorder  . Gender also might influence the relationship between temperament and depression. In a prospective study, females with higher levels of chronic depression during young adulthood were described as shy and withdrawn at 3-4 years of age, whereas males with chronic depression exhibited higher levels of under-controlled behavior as young children .

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