Examining the developmental interface of cortisol and depression symptoms in young adolescent girls
Introduction
A substantial amount of data exists linking the functioning of the HPA-axis to depression in adults (see Plotsky et al., 1998, for a review), leading to the hypothesis that glucocorticoids play a role in the pathophysiology of depression. Moreover, developmental and sex differences in functioning of the HPA-axis mirrors those observed for depression. Sex differences in depression symptoms or disorders are generally not evident until adolescence, at which point increases in depression are evident for girls but not for boys (Keenan and Hipwell, 2005). Similar sex by age effects are observed in HPA-axis functioning. In terms of diurnal levels and awakening response, Shirtcliff et al. (2012) collected three saliva samples across the day (after awakening, in the late afternoon and before bed) from approximately 300 children every two years from ages 9 to 15 years. Girls had higher cortisol levels at awakening and steeper slopes across the day. Significant age by sex effects were observed for awakening cortisol level, which declined within individual across age, but significantly less so for girls than for boys. Platje et al. (2013) reported sex differences in the cortisol awakening response at ages 15, 16, and 17 years; girls had higher cortisol levels than boys at 30 and 60 min post-awakening, and by age 17 the CAR for girls was in a positive direction (i.e., increase in cortisol following awakening) whereas boys continued to show a decrease in cortisol following awakening.
Sex and age or pubertal effects are also found for cortisol reactivity to a stressor. Stroud et al. (2011) used a corticotropin releasing hormone (CRH) challenge in children and adolescents and reported that stage of pubertal development was associated with the pattern of response in girls, characterized primarily as a slowing of the recovery to baseline response with more advanced maturation: stage of pubertal development was not associated with cortisol response among boys.
The effects of age and puberty and sex on stress response also are evident in animal models. Pubertal female rats have prolonged corticosterone release in response to restraint stress compared to adult females (Romeo et al., 2004). Compared to controls, females rats exposed to chronic social stress during adolescence did not habituate to the stressor, showed a prolonged corticosterone response to a subsequent heterotypic stressor, and were more likely to engage in depression-like behavior during a forced swim test (e.g., less time climbing and more time immobile). Males habituated to the repeated social stressor, had an increase in corticosterone level but no difference in shape of response, and demonstrated no difference in behavior during the forced swim test as a function of social stress (Mathews et al., 2008).
The possibility that the HPA axis is maximally sensitive to experiences during adolescence has implications for psychopathology, especially for females, who demonstrate increased risk for distress disorders during adolescence (Keenan and Hipwell, 2005). Specifying the developmental interface between HPA-axis functioning and depression in humans, however, has been challenging. The use of cross sectional designs is not highly informative regarding the timing and direction of effect. Moreover, because base rates of depression symptoms and disorders are low in childhood (Son and Kirchner, 2000, Kessler et al., 2001), tests of association between cortisol levels and depression are often conducted later in adolescence. Among the few studies in which child participants were included no association between cortisol levels assessed in response to a challenge, such as CRH, and depression symptoms was observed (e.g., Birmaher et al., 1996, Puig-Antich et al., 1989).
In contrast, studies in which the association between cortisol levels and depression participants were assessed during mid- to late adolescence typically yield significant associations. Cortisol levels among depressed adolescents in response to a social stressor were elevated and slower to return to baseline compared to non-depressed adolescents (Rao et al., 2008). Higher and flatter diurnal rhythms were observed among adolescents with high depression scores (n = 9) compared to adolescents with moderate (n = 12) or low (n = 45) scores (Van den Bergh and Van Calster, 2009). Adam et al. (2010) reported that a higher baseline CAR was associated with the incidence of major depressive disorder one year later in a sample of 230 17-year olds, many of whom had a history of mood and anxiety disorders based on retrospective report.
In others studies the pattern of association between cortisol output and depression is a negative one. Results from a study on diurnal cortisol in a sample of youth whose mental health had been assessed longitudinally since childhood revealed that childhood internalizing behaviors, but not externalizing behaviors, were prospectively associated with lower morning cortisol levels in early adolescence (Ruttle et al., 2011). Measures of cortisol functioning in childhood, however, were not available for the sample. Badanes et al. (2011) also reported significant associations between low cortisol output and depression scores. In that study, cortisol levels for children in grades 3, 6, and 9 were operationalized as the average of five samples taken before and after a social stress test. Effects of age were not tested.
In summary, the pattern of association between depression symptoms, scores or disorders and cortisol reactivity, awakening response, or diurnal rhythm during adolescence is typically positive. The pattern of association involving assessment of depression in children, in contrast is inconsistent: typically no effects have been observed between depression and cortisol reactivity, and a negative association has been observed between childhood internalizing problems and cortisol levels in adolescence.
Further probing of age-related changes in the association between cortisol and depression are important for understanding the pathophysiology of depression, especially with regard to potential phenotypic differences between depression that is manifest prior to the completion of pubertal development and depression that occurs post-pubertal development. Kaufman et al. (2001) concluded from reviewing the available literature that depressed children differ from depressed adults on measures of basal cortisol secretion, and in response to a corticotropin releasing hormone (CRH) challenge. These differences along with others in neurobiology and treatment response suggested to the authors that depression in adults may be phenotypically different from childhood depression. For example, replicated findings of differences in changes in electroencephalographic (EEG) sleep associated with depression in adults and adolescents are generally not present in studies of depressed and non-depressed children (Kaufman et al., 2001). Most of the research reviewed by Kaufman and colleagues, however, was cross-sectional in design. Longitudinal research is needed to address whether associations between HPA-axis functioning and depression emerges over time.
In the present study, we provide data that expands and extends the existing research by examining the interrelations among depression symptoms and cortisol levels in the same individuals at ages 10 and 12 years. We test concurrent and longitudinal associations between depression symptoms and cortisol to provide support for the hypothesis that there are age related changes in depression-cortisol associations. In addition, we explore whether dysregulation of the HPA-axis occurs after an extended period of exposure to depressive symptoms by examining depression symptoms measured over four years, from ages 9 to 12 years, as a function of cortisol levels and changes in cortisol output from ages 10 to 12 years.
Section snippets
Sampling of participants
Participants for the present study were recruited from the Pittsburgh Girls Study (PGS) (Keenan et al., 2010). The PGS sample was formed following an enumeration of households in the city of Pittsburgh. Of the 2992 eligible families 2451 (85%) were successfully re-contacted and agreed to participate in a longitudinal study with annual in-home interviews. Girls selected for participation in the emotions sub-study (PGS-E) were from the youngest participants in the PGS who either screened high on
Descriptive statistics
Descriptive statistics for DSM-IV depression symptoms and cortisol levels at ages 10 and 12 are presented in Table 1. On average girls reported approximately 2 symptoms of depression at each age. The pattern of cortisol levels was characterized by a decrease over the course of the administration of the CPT, as one would expect in the later afternoon. Thus, the CPT as a stimulus did not, for the most part elicit a cortisol response (i.e., increase). Area under the curve with respect to ground (
Discussion
The data from the present study add to the building evidence that developmental changes in the sensitivity of HPA-axis functioning occur during adolescence, and that such changes are likely relevant for the pathophysiology of depression. Controlling for pubertal stage and time of day of saliva collection, concurrent and earlier symptoms of depression were significantly associated with cortisol levels measured at age 12. In contrast, cortisol levels obtained at age 10 were unrelated with
Role of funding source
This study was supported by NIMH grants R01 MH66167 and R03 MH084073 to Dr. Keenan.
Conflict of interest statement
None of the authors report conflicts of interest with the data presented in this paper.
Acknowledgements
This study was supported by NIMH grants R01 MH66167 and R03 MH084073 to Dr. Keenan. We thank the families participating in the Learning about Girls’ Emotions Study.
References (54)
- et al.
Prospective prediction of major depressive disorder from cortisol awakening responses in adolescence
Psychoneuroendocrinology
(2010) - et al.
Adrenocortical and hemodynamic predictors of pain perception in men and women
Pain
(2002) - et al.
Sex differences in the association between cortisol concentrations and laboratory pain responses in healthy children
Gender Med.
(2009) - et al.
Corticotropin-releasing hormone challenge in prepubertal major depression
Biol. Psychiatry
(1996) - et al.
Contemporary use of the cold pressor task in pediatric pain research: a systematic review of methods
J. Pain
(2012) - et al.
Pubarche as well as thelarche may be a marker for the onset of puberty
J. Pediatr. Adolesc. Gynecol.
(2008) - et al.
Chronicity of depressive problems and the cortisol response to psychosocial stress in adolescents: the TRAILS study
Psychoneuroendocrinology
(2013) - et al.
Major depression in late life is associated with both hypo- and hypercortisolemia
Biol. Psychiatry
(2007) - et al.
Prevalence and co-occurrence of self-rated pain and perceived health in school-children: age and gender differences
Eur. J. Pain
(2007) - et al.
An evaluation of sex differences in psychological and physiological responses to experimentally-induced pain: a path analytic description
Pain
(2004)
Somatic complaints and psychopathology in children and adolescents: stomach aches, musculoskeletal pains, and headaches
J. Am. Acad. Child. Adolesc. Psychiatry
A new view on hypocortisolism
Psychoneuroendocrinology
Are child-, adolescent-, and adult-onset depression one and the same disorder?
Biol. Psychiatry
Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version K-SADS-PL: initial reliability and validity data
J. Am. Acad. Child. Adolesc. Psychiatry
Subthreshold symptoms of depression in girls are stable and predictive of depressive disorders
J Am. Acad. Child. Adolesc. Psychiatry
Mood disorders in children and adolescents: an epidemiologic perspective
Biol. Psychiatry
Relationship of pain and symptoms to pubertal development in adolescents
Pain
Investigations of HPA function and the enduring consequences of stressors in adolescence in animal models
Brain Cogn.
Increased depressive behaviour in females and heightened corticosterone release in males to swim stress after adolescent social stress in rats
Behav. Brain Res.
The HPA axis in major depression: classical theories and new developments
Trends Neurosci.
Long-term stability of the cortisol awakening response over adolescence
Psychoneuroendocrinology
Psychoneuroendocrinology of depression: hypothalamic–pituitary–adrenal axis
Psychiatr. Clin. North Am.
Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change
Psychoneuroendocrinology
Effects of early and recent adverse experiences on adrenal response to psychosocial stress in depressed adolescents
Biol. Psychiatry
Disentangling psychobiological mechanisms underlying internalizing and externalizing behaviors in youth: longitudinal and concurrent associations with cortisol
Horm. Behav.
Back to the future: the organizational–activational hypothesis adapted to puberty and adolescence
Horm. Behav.
Long-lasting changes in behavioural and neuroendocrine indices in the rat following neonatal maternal separation: gender-dependent effects
Brain Res.
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