Zobel AW, Nickel T, Sonntag A, Uhr M, Holsboer F, Ising M. Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression. A prospective study. J Psychiatr Res 35: 83-94

Max Planck Institute of Psychiatry, Kraepelinstr 2-10, 80804 Munich, Germany.
Journal of Psychiatric Research (Impact Factor: 3.96). 03/2001; 35(2):83-94. DOI: 10.1016/S0022-3956(01)00013-9
Source: PubMed


The development and course of depression is causally linked to impairment of central regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. Previous research documented that the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test identifies HPA dysfunction with high sensitivity. We evaluated the predictive validity for medium-term outcome of the cortisol response in the combined DEX/CRH test in 74 remitted patients previously suffering from major depressive disorder. Of the 74 patients, 61 remained in stable remission and 13 relapsed during the first 6 months after discharge from the hospital. Although the cortisol and ACTH responses in the DEX/CRH test did not differ between the two groups of patients on admission, the responses differed significantly just before discharge (P< 0.05). We defined two dichotomous variables as prediction rules indicating (1) the change between admission and discharge in the cortisol response to the DEX/CRH test, and (2) the effect of the CRH infusion on cortisol as compared to the baseline level in the DEX/CRH test prior to discharge only. An elevated cortisol response in the DEX/CRH test was correlated with a four- to six-fold higher risk for relapse than in individuals with a normal cortisol response. The two proposed rules for predicting relapse within the first 6 months after discharge could be optimized by including age and gender. Hence, an exaggerated cortisol response in the combined DEX/CRH test predicts the recurrence of depressive psychopathology. The test performance can be further optimized if gender and age are taken into account.

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    • "Yet, we conducted additional analysis merging the currently depressed and remitted participants and compared them to their non-affected peers, which replicated the CDI findings (results available online as a supplementary table). We decided against presenting such data given that it is unclear whether merging currently depressed and remitted participants in HPA-axis studies is appropriate (Ahrens et al., 2008; Zobel et al., 2001). Nonetheless, our results provide guidance for future studies with larger clinical samples. "
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    ABSTRACT: Given the link between youth depression and stress exposure, efforts to identify related biomarkers have involved examinations of stress regulation systems, including the hypothalamic-pituitary-adrenal (HPA) axis. Despite these vast efforts, the underlying mechanisms at play, as well as factors that may explain heterogeneity of past findings, are not well understood. In this study, we simultaneously examined separate components of the HPA-axis response (e.g. activation intensity, peak levels, recovery) to the Socially Evaluated Cold-Pressor Test in a targeted sample of 115 youth (age 9-16), recruited to overrepresent youth with elevated symptoms of depression. Among youth who displayed a cortisol response to the task, depression symptoms were associated with higher peak responses but not greater rate of activation or recovery in boys only. Among those who did not respond to the task, depression symptoms were associated with greater cortisol levels throughout the visit in boys and girls. Results suggest that depression symptoms are associated with a more prolonged activation of the axis and impaired recovery to psychosocial stressors primarily in boys. We discussed two potential mechanistic explanations of the link between depression symptoms and the duration of activation: (1) inhibitory shift (i.e. point at which the ratio of inhibitory and excitatory input into the axis shifts from greater excitatory to greater inhibitory input) or (2) inhibitory threshold (i.e. level of cortisol exposure required to activate the axis' feedback inhibition system).
    Stress (Amsterdam, Netherlands) 06/2015; 18(5):1-9. DOI:10.3109/10253890.2015.1053455 · 2.72 Impact Factor
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    • "A considerable part of acutely depressed patients shows normally regulated HPA axis activity in the DEX/CRH test already before antidepressant treatment and may nevertheless benefit from these drugs. Some researchers even found an enhanced HPA system activity at discharge in a certain proportion of depressed patients in spite of clinical recovery (Zobel et al., 2001; Schule et al., 2009). On the other hand, down-regulation of HPA axis activity in depressed patients is not necessarily followed by a favorable response (Schule et al., 2009). "
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    ABSTRACT: Background In this study, the impact of quetiapine fumarate extended release (QXR) and escitalopram (ESC) on HPA axis activity was investigated in depressed patients in relationship to antidepressant efficacy. Methods In a randomized, open-label 5-week trial 60 inpatients suffering from major depression (DSM-IV criteria) were treated for 5 weeks with either QXR (300 mg/day) or ESC (10 mg/day). The dexamethasone/CRH (DEX/CRH) test was performed before treatment, after 1, and after 5 weeks of treatment. Cortisol (COR) AUC values were used to assess HPA axis function. The Hamilton Depression Rating Scale was used weekly to estimate antidepressant efficacy. Results QXR and ESC showed comparable antidepressant effects but strongly differed in their impact on HPA axis activity. In the QXR group, a marked inhibition of COR AUC levels was observed which was most pronounced after one week of treatment but showed a partial re-increase after 5 weeks of treatment. In contrast, ESC transiently stimulated COR AUC values (week 1) whereas COR AUC levels at week 0 and week 5 were comparable. COR improvement at week 1 (defined as COR peak value reduction between DEX/CRH test 1 and 2) was significantly associated with better clinical outcome. Conclusion Apparently, different effects on HPA axis activity reflect distinct pharmacoendocrinological properties of psychotropic drugs.
    Psychoneuroendocrinology 12/2014; 39(1):141–151. DOI:10.1016/j.psyneuen.2013.10.008 · 4.94 Impact Factor
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    • "FKBP5−/− mice are more responsive to the dexamethasone suppression test, suggesting HPA axis negative feedback is accelerated in the absence of FKBP51 [6]. Normalizing the HPA axis hyperactivity observed in depressed patients may be of critical importance for treatment outcome; individuals that display persistently elevated cortisol levels following treatment have higher rates of relapse [17]–[19]. Therefore, attenuating the effect of FKBP51 on HPA axis dysregulation is an attractive therapeutic strategy for depression, especially in aged individuals. "
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in the FK506 binding protein 5 (FKBP5) gene combine with traumatic events to increase risk for post-traumatic stress and major depressive disorders (PTSD and MDD). These SNPs increase FKBP51 protein expression through a mechanism involving demethylation of the gene and altered glucocorticoid signaling. Aged animals also display elevated FKBP51 levels, which contribute to impaired resiliency to depressive-like behaviors through impaired glucocorticoid signaling, a phenotype that is abrogated in FKBP5-/- mice. But the age of onset and progressive stability of these phenotypes remain unknown. Moreover, it is unclear how FKBP5 deletion affects other glucocorticoid-dependent processes or if age-associated increases in FKBP51 expression are mediated through a similar epigenetic process caused by SNPs in the FKBP5 gene. Here, we show that FKBP51-mediated impairment in stress resiliency and glucocorticoid signaling occurs by 10 months of age and this increased over their lifespan. Surprisingly, despite these progressive changes in glucocorticoid responsiveness, FKBP5-/- mice displayed normal longevity, glucose tolerance, blood composition and cytokine profiles across lifespan, phenotypes normally associated with glucocorticoid signaling. We also found that methylation of Fkbp5 decreased with age in mice, a process that likely explains the age-associated increases in FKBP51 levels. Thus, epigenetic upregulation of FKBP51 with age can selectively impair psychological stress-resiliency, but does not affect other glucocorticoid-mediated physiological processes. This makes FKBP51 a unique and attractive therapeutic target to treat PTSD and MDD. In addition, aged wild-type mice may be a useful model for investigating the mechanisms of FKBP5 SNPs associated with these disorders.
    PLoS ONE 09/2014; 9(9):e107241. DOI:10.1371/journal.pone.0107241 · 3.23 Impact Factor
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