Hypothalamic–pituitary–adrenal axis dysregulation in depressed children and adolescents: A meta-analysis

doi:10.1016/j.psyneuen.2009.03.016

Psychoneuroendocrinology

Volume 34, Issue 9, October 2009, Pages 1272-1283

https://doi.org/10.1016/j.psyneuen.2009.03.016 Get rights and content

Summary

Research findings on the hypothalamic–pituitary–adrenal (HPA) axis and pediatric depression reflect a variety of methodological approaches that tap different facets of HPA-axis functions. Partly owing to the methodological heterogeneity of studies, descriptive reviews of this area have produced inconsistent conclusions. Therefore, we conducted formal meta-analyses of pertinent studies in order to advance our understanding of HPA-axis dysregulation in pediatric depression. We examined: (a) 17 published studies of HPA-axis response to the dexamethasone suppression test (DST) in depressed youth (DST; N = 926) and (b) 17 studies of basal HPA-axis functioning (N = 1332). We also examined descriptively studies that used corticotropin-releasing hormone (CRH) infusion, and those that used psychological probes of the HPA-axis. The global standardized mean effect size difference in HPA-axis response to the DST between depressed and non-depressed youth was 0.57, z = 4.18, p < 0.01. The global standardized mean difference effect size in basal HPA-axis functioning was 0.20, z = 4.53, p < 0.01. Age, sex, timing of sampling, dexamethasone dosage, or type of control group was not a significant source of variability for the DST or basal studies. In addition, when compared to non-depressed peers, depressed youth have a normative response to CRH infusion but an overactive response to psychological stressors. In conclusion, the HPA-axis system tends to be dysregulated in depressed youth, as evidenced by atypical responses to the DST, higher baseline cortisol values, and an overactive response to psychological stressors. This pattern of dysregulation suggests anomalies within the axis's negative feedback system and CRH production, but intact pituitary and adrenal sensitivity.

Section snippets

Study selection and search strategy

We restricted our search to peer-reviewed journals and sought published articles, which reported on HPA-axis functioning of depressed youth. We used PubMed, PsycINFO, and Google Scholar™ to search for studies from the earliest available date up to 15 February 2009. We searched abstracts and titles using iterations of the following search terms: depression, depressed, WITH child, children, childhood, adolescents, adolescence, WITH cortisol, HPA, CRH, and hormones. We also searched the reference

Main effects

We identified 17 studies comparing MDD and non-MDD controls on post-DST cortisol levels (total 18 samples with N = 926; see Table 1). The studies contributed a total of 49 effect sizes. Using a mixed, random effects model, the pooled effect size (k = 49) for group differences in DST response was 0.57 (z = 4.18, p < 0.01; 95% CI 0.28–0.86) indicating greater cortisol production (or less suppression) after the DST among depressed children and adolescents than among non-MDD controls. The estimate of

Discussion

Results of our meta-analyses support an association between HPA-axis dysregulation and pediatric depression. Specifically, as compared to control peers, depressed youth tend to have a dysregulated response to the dexamethasone suppression test and moderately higher cortisol levels throughout the day. However, we found no evidence of a dysregulated response to corticotropin-releasing hormone in depressed pediatric samples. Furthermore, data on HPA-axis response to psychological stressors in this

Role of funding source

This study was supported by the NIMH Program Project Grant #MH56193, HHSA, Washington, DC, USA. The NIMH had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Conflict of interest

All authors declare that there are no conflicts of interest.

Acknowledgements

We would like to thank Dr. Jutta Joormann and Dr. Delia Vazquez for their helpful comments on previous versions of this manuscript, and Dr. Anne-Marie R. Iselin for her assistance with our meta-analytic procedures. This study was supported by the NIMH Program Project Grant #MH56193, and T-32 Training Grant MH18951, HHSA, Washington, DC, USA.

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Citation Excerpt :
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REVIEWHypothalamic–pituitary–adrenal axis dysregulation in depressed children and adolescents: A meta-analysis

Summary

Section snippets

Study selection and search strategy

Main effects

Discussion

Role of funding source

Conflict of interest

Acknowledgements

Pers. Individ. Dif.

Biol. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

Psychoneuroendocrinology

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

J. Am. Acad. Child Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

Life Sci.

Biol. Psychiatry

Biol. Psychiatry

J. Affect. Disord.

Psychiatry Res.

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

J. Psychiatr. Res.

Biol. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

J. Am. Acad. Child Psychiatry

Life Sci.

Biol. Psychiatry

Biol. Psychiatry

The dexamethasone suppression test in adolescent outpatients with major depressive disorder

Am. J. Psychiatry

Biological studies in depressed children and adolescents

Int. J. Neuropsychopharmacol.

The DST in children and adolescents with major depressive disorder

Am. J. Psychiatry

The hypothalamo–pituitary–adrenal axis in major affective disorder: a review

Nord. J. Psychiat.

Cortisol secretion in adolescents with major depressive disorder

Acta Psychiat. Scand.

REVIEW
Hypothalamic–pituitary–adrenal axis dysregulation in depressed children and adolescents: A meta-analysis