Elsevier

Biological Psychiatry

Volume 44, Issue 1, 1 July 1998, Pages 15-20
Biological Psychiatry

Original Articles
Plasma corticotropin-releasing factor in depressive disorders

https://doi.org/10.1016/S0006-3223(97)00539-8Get rights and content

Abstract

Background: The aim of this work was to investigate alterations of plasma corticotropin-releasing factor (CRF) levels in depressive states. We have also measured plasma cortisol and corticotropin (ACTH) concentrations and examined their correlation with the peripheral CRF values.

Methods: Thirty-six outpatients from the psychiatric department of a Barcelona hospital who were diagnosed as having major depressive disorder (n = 26) and dysthymic depressive disorder (n = 10) were studied. Among the major depressed patients, 10 suffered from severe depressive disorder and 16 from mild or moderate depressive disorder. The comparison group consisted of 17 healthy volunteers. Cortisol, ACTH, and CRF concentrations were determined by iodine-125 radioimmunoassay; CRF measurements were performed on C18 extracted samples.

Results: CRF and cortisol plasma concentrations were significantly higher in major depression and dysthymia than in the comparison group. The major depressed patients did not show significantly different CRF and cortisol levels than the dysthymic. Severe major depressive disorder exhibited significantly higher CRF plasma levels than the mild or moderate episodes. Plasma cortisol and CRF concentrations correlated significantly.

Conclusions: The results obtained indicate that plasma CRF values are altered in depressive disorders and suggest that these determinations could be important for understanding the pathophysiology in affective illness.

Introduction

In recent years, a great deal of work in neurobiology has been dedicated to investigating the role of corticotropin-releasing factor (CRF) in the pathophysiology of certain affective disorders. CRF, a 41-amino acid peptide secreted by neurons in the paraventricular nucleus of the hypothalamus, is the most potent adrenocorticotropic hormone (ACTH) secretagogue and the major physiological regulator of the hypothalamic–pituitary–adrenal (HPA) axis. Studies in the past 15 years have shown a broader role for CRF than the well-known coordination of the endocrine response to stress. Immunoreactive CRF (I-CRF) has been demonstrated to be present in several extrahypothalamic brain areas, including parts of the limbic system, and in the brain stem nuclei, where it is involved in behavior and in the central autonomic response to stress, respectively (Nemeroff 1992).

Peripheral consequences of disturbances in the HPA axis have been largely described in depressed patients and cause a peripheral profile that includes mainly increased secretion of plasma or urine cortisol and insensitivity to glucocorticoid feedback. Accumulated data based on the pituitary–adrenal response to ovine CRF suggest that abnormalities of the HPA axis reflect a primary central nervous system (CNS) defect resulting in excessive activation of CRF secretion via central mechanisms (Licinio and Gold 1991). To elucidate this hypothesis, several authors have measured CRF in the cerebrospinal fluid (CSF) of depressed patients. Most of these studies report higher than normal CSF CRF levels Nemeroff et al 1984, Banki et al 1987, Arato et al 1989, France et al 1988, Widerlow et al 1988. Others describe unchanged CSF CRF values in the total group of depressed patients Roy et al 1987, Pitts et al 1995, although nonsuppressors showed higher CRF values (Roy et al 1987) and suppressors lower values (Pitts et al 1995). One report even found decreased CSF CRF levels in depression (Geracioti et al 1992). The contradictory results from these works are probably due to several factors affecting the analytic methods used for CRF measurement or to the status of patient medication at the time of the study.

Reports on immunoreactive CRF distribution demonstrate its presence in tissues outside the brain (Suda et al 1984). CRF has been measured in peripheral plasma in several diseases, stress situations, and HPA disorders. These studies have not clarified whether the real origin of plasma CRF is central or peripheral. Some authors suggest that the major component of plasma CRF has a hypothalamic source, whereas others conclude that plasma CRF is derived mainly from extrahypothalamic tissues Suda et al 1987, Cunnah et al 1987, Ellis et al 1990, Wittert et al 1991, Wittert et al 1993, Donald et al 1994. It may be that discrepancies regarding the real origin of plasma CRF, or the technical difficulties caused mainly by its low plasma levels, have discouraged authors from evaluating CRF plasma alterations in depressive disorders. Very few works have investigated the plasma levels of this neuropeptide in major depression Widerlov et al 1986, Charlton et al 1986.

In this study we examine possible variations in plasma CRF concentrations in patients affected with major depression and dysthymic disorder, as compared with healthy subjects. To assess HPA axis activity and investigate its correlation with peripheral CRF values, we measured plasma ACTH and cortisol concentrations in the same subject population.

Section snippets

Patients

After receiving approval from the Valle Hebrón Teaching Hospital Health Board Ethics Committee, informed consent was obtained from all participating patients. Thirty-six outpatients, between 24 and 79 years old (mean age 49), receiving care at the Psychiatric Unit of our hospital, were classified according to the ICD-10 Classification of Mental and Behavioral Disorders (World Health Organization 1992). The three groups studied included: 1) severe depressive disorder, single (F.32.2) or

Results

The demographic data of the 53 subjects in the study are shown in Table 1. We found that the frequency distribution of patient medication was similar in the three diagnostic categories (p = .93), and that sex was similar in the four groups studied (p = .54).

Figure 1 shows the individual cortisol (nmol/L), CRF (pmol/L), and ACTH (pg/mL) plasma levels found in our subjects.

Table 2summarizes the cortisol, CRF, and ACTH plasma levels (mean ± SEM), and the significance levels obtained in the four

Discussion

Consistent with earlier studies, as well as with our own previous findings, major depression (severe and mild or moderate episode) was accompanied by significantly increased basal cortisol levels and unchanged basal plasma ACTH levels Licinio and Gold 1991, Galard et al 1991. In reference to plasma CRF levels in major depression, we obtained highly significant (p < .0001) increased values when compared with healthy subjects. These results agree with a previous study (Widerlöv et al 1986) that

Acknowledgements

This work was supported by a grant PR(HG) 106/97 from the Hospital General Universitari Vall d’Hebron, Barcelona, Spain.

We express our gratitude to the nursing staff of the Hormone Laboratory for their technical assistance and Celine Cavallo for her English language support.

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