Alterations in stress cortisol reactivity in depressed preschoolers relative to psychiatric and no-disorder comparison groups.

BACKGROUND: Despite the robust and widely replicated finding of elevated hypothalamic-pituitary-adrenal (HPA) axis reactivity in depressed adults, studies of depressed children have yielded ambiguous findings. Animal models of early depression and studies of children experiencing early psychosocial deprivation have suggested that alterations in HPA axis reactivity are evident in early "depressive-like" conditions. The current study is, to our knowledge, the first investigation of HPA axis reactivity in very young children with a clinical depressive syndrome for which content validity has been established. METHODS: Depressed, psychiatric, and no-disorder comparison children aged 3 through 5.6 years were studied for HPA axis reactivity in response to experimental psychosocial stressors. The children were diagnosed using a developmentally appropriate, structured psychiatric interview. Salivary cortisol was obtained at 3 time points during a laboratory assessment before and after stressors involving separation from the parent and frustrating tasks. RESULTS: Repeated measures of multivariate analysis of variance revealed a significant interaction between the diagnostic group and 2 cortisol percent change scores. Depressed preschoolers displayed a pattern of increasing cortisol levels throughout the assessment in response to both separation and frustration stressors. In contrast, both comparison groups showed decreasing cortisol levels in response to the separation stressor. All groups displayed increasing cortisol levels in response to frustrating tasks. Preschoolers with a presumptive melancholic depressive subtype displayed these alterations at a greater magnitude relative to comparison groups. CONCLUSIONS: To our knowledge, these findings are the first to demonstrate altered HPA axis reactivity in depressed preschoolers. These alterations are consistent with those described in depressed adults and in animal models of early depression. These findings provide evidence for possible continuity of HPA axis alterations in depressive disorders across the lifespan and are discussed in the context of prior studies of HPA axis reactivity in clinically depressed children and adolescents, suggesting that younger age and inpatient status are features associated with altered HPA axis reactivity.

Characteristics of depressed preschoolers with and without anhedonia: evidence for a melancholic depressive subtype in young children.

OBJECTIVE: This study investigated whether a melancholic subtype similar to that established in depressed adults can be identified in depressed preschool children. METHOD: A final group total of 156 preschool children between the ages of 3.0 and 5.6 years and their caregivers underwent a comprehensive psychiatric assessment that included a structured psychiatric interview modified for young children. The clinical characteristics of four study groups (N=156) were compared: depressed preschoolers with anhedonia, depressed preschoolers without anhedonia ("hedonic"), a psychiatric comparison group with DSM-IV attention deficit hyperactivity disorder and/or oppositional defiant disorder, and a healthy comparison group. RESULTS: Fifty-four depressed preschoolers were identified, and 57% of this depressed group was anhedonic, a symptom deemed to be highly developmentally and clinically significant when arising in the preschool period. The anhedonic depressed subgroup identified was characterized by greater depression severity, alterations in stress cortisol reactivity, increased family history of major depressive disorder, and increased frequency of psychomotor retardation as well as other melancholic symptoms, such as a lack of brightening in response to joyful events. CONCLUSIONS: The clinical characteristics of this depressed subgroup are consistent with those described in melancholic depressed adults and suggest that a melancholic depressed subtype can be manifest in children as young as age 3.

Stress-system genes and life stress predict cortisol levels and amygdala and hippocampal volumes in children.

Depression has been linked to increased cortisol reactivity and differences in limbic brain volumes, yet the mechanisms underlying these alterations are unclear. One main hypothesis is that stress causes these effects. This is supported by animal studies showing that chronic stress or glucocorticoid administration can lead to alterations in hippocampal and amygdala structures. Relatedly, life stress is cited as one of the major risk factors for depression and candidate gene studies have related variation in stress-system genes to increased prevalence and severity of depression. The present study tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four stress-system genes (CRHR1, NR3C2, NR3C1, and FKBP5) and early life stress would predict increases in cortisol levels during laboratory stressors in 120 preschool-age children (3-5 years old), as well as hippocampal and amygdala volumes assessed with MRI in these same children at school age (7-12 years old). We found that stress-system genetic profile scores positively predicted cortisol levels while the number of stressful/traumatic life events experienced by 3-5 years old negatively predicted cortisol levels. The interaction of genetic profile scores and early life stress predicted left hippocampal and left amygdala volumes. Cortisol partially mediated the effects of genetic variation and life stress on limbic brain volumes, particularly on left amygdala volume. These results suggest that stress-related genetic and early environmental factors contribute to variation in stress cortisol reactivity and limbic brain volumes in children, phenotypes associated with depression in adulthood.