Chemically characterized only a decade ago, corticotropin-releasing factor (CEF)1,2 is the major physiological regulator of the hypothalamicpituitary-adrenal (HPA) axis. CRF, composed of 41 amino acids, is the primary physiological mediator of adrenocorticotropic hormone (ACTH) and β-endorphin secretion from the anterior pituitary. CRF is found not only within the hypothalamus but in extrahypothalamic brain areas, including the locus coeruleus, dorsal motor nucleus of the vagus, hippocampus, cerebral cortex, amygdala, and within several basal ganglia structures. In the hypothalamus, CRF-containing neurons project from the paraventricular nucleus to the median eminence.3 Activation of this CRF-containing neural circuit occurs in response to stress, resulting in an increase in synthesis and release of ACTH and the β-endorphin precursor, pro-opiomelanocortin (POMC), and its products.
Convergent findings suggest that dysregulation of hypothalamic and/or extrahypothalamic CRF neurons may be involved in the pathophysiology of major depression, as well as other psychiatric disorders. This paper reviews these findings and suggests areas deserving of additional investigation.
The role of CRF has been most closely investigated in major depression. A concatenation of findings implicate dysregulation of CRF in the pathogenesis of depression. These include: 1) elevated cerebrospinal fluid (CSF) CRF concentrations in drug-free depressed patients, 2) normalization of CSF CRF concentrations with recovery from major depression, 3) a blunted ACTH response to CRF in depressed patients, 4) CRF receptor downregulation in the frontal cortex of suicide victims, and 5) enlargement of both the pituitary and adrenal glands in depressed patients.
Elevated CSF CRF In Depressed Patients
Post et al4 have shown that for neuropeptides found in both CSF and plasma, there is marked dissociation between CSF and plasma concentrations. Although the source of CSF CRF remains unknown, this CSF-plasma dissociation suggests that CRF is secreted directly into CSF from central nervous system (CNS) neurons, and that CSF neuropeptide concentrations are not derived from the systemic circulation.
As noted above, CRF is widely but unevenly distributed in various areas of the brain as are its high-affinity binding sites. When administered centrally in laboratory animals, CRF produces behavioral effects resembling some symptoms of major, or melancholic, depression including decreased appetite, disturbed sleep, and psychomotor alterations.5 Elevated CSF concentrations of CRF are believed to be a reflection of increased synaptic concentrations of the peptide, likely due to central CRF hypersecretion. CRF neurons in cortical, limbic, hypothalamic, and brainstem regions are in close proximity to the ventricular system and most likely contribute to CSF CRF concentrations.
A multitude of studies have been conducted in which the CSF concentration of CRF has been measured in drug-free patients with major depression. In many of these, elevated CSF CRF concentrations have been observed. In our first study, CSF CRF concentrations were measured in 10 normal controls, 23 depressed patients, 11 schizophrenic patients, and 29 demented patients; the CSF CRF concentration was elevated in the depressed patients compared with all of the other groups. In fact, 11 of the 23 depressed patients had CSF CRF concentrations higher than the highest normal controls.6
In a second study,7 we confirmed the increased CSF CRF concentrations in depressed patients. In another study, we measured the CSF concentration of CRF in 54 depressed women, 138 neurological controls, 23 schizophrenic patients, and six manic patients; the mean CSF CRF concentration was elevated, nearly twofold, in the depressed patients 8. Patients with major depression were also reported to have higher CSF CRF concentrations than patients with chronic pain.9
More recently,. Banki et al 10 measured CSF CRF concentrations in female patients with major depression, mania, generalized anxiety, somatization disorder, and dementia, with or without concomitant major depression. CSF CRF concentrations were significantly higher in the patients with major depression and in dementia with depression as compared with neurological controls with no psychiatric disorders and with patients who had other psychiatric diagnoses. CSF CRF concentrations collected postmortem from the intracisternal space in depressed suicide victims and sudden death controls revealed markedly elevated CSF CRF concentrations in the depressed group in comparison to the controls.11
Other relevant findings include the study by Risch et al12 in which CSF CRF concentrations were elevated in depressed patients compared to controls, and the reports of Roy et al13 and Pitts et al14 of elevated CSF CRF concentrations in dexamethasone suppression test (DST) nonsuppressors.
Normalization of CSF CRF with Recovery from Major Depression
There is evidence that the increase in CSF CRF concentrations that occurs in depression, like hypercortisolemia, normalizes upon recovery. Nine drug-free patients with major depression with psychotic features had elevated CSF CRF concentrations prior to electroconvulsive therapy (ECT). Twenty-four hours after their final ECT and associated with clinical recovery, a significant decrease in CSF CRF concentrations was observed. Thus, elevated CSF CRF concentrations, like hypercortisolemia, may represent a state, rather than a trait marker of depression.15
More recently, CSF CRF concentrations have been measured in 24 female patients with major depression, before and after antidepressant treatment. There was a significant posttreatment reduction of CSF CRF in the 15 patients who remained depression-free for at least six months after treatment, in contrast to the nine subjects who relapsed within six months. High, or even increasing, CSF CRF concentration during antidepressant treatment may indicate lack of normalization in major depression despite symptomatic improvement and may predict early relapse.16 Moreover, two recent studies are of interest. Veith et al17 reported that desipramine treatment is associated with decreased CSF CRF concentrations in normal volunteers and DeBellis et al18 reported that fluoxetine treatment in depressed patients is similarly associated with reductions in CSF CRF concentrations.
The CRF Stimulation Test in Depressed Patients
HPA axis integrity can be assessed by intravenous administration of CRF and measurement of the ACTH (or ß-endorphin) and Cortisol response. In normal subjects, using a standardized protocol of intravenous rat/ human or ovine CRF produces robust ACTH, β-endorphin, β-lipotropin, and Cortisol responses.19'20 In drug-free depressed patients, the ACTH and β-endorphin response to exogeneously administered ovine CRF (oCRF) is blunted compared to normal subjects21"27 and is state dependent, returning to normal after successful treatment of depression.28
In contrast to the blunted ACTH and β-endorphin response, the plasma Cortisol response to CRF is not different between depressed patients and normal controls,2 1^3"26,29 likely due to the adrenal gland hypertrophy observed in these patients. There is one report of a normal β-endorphin response with a blunted ACTH response to CRF in individuals with depression.30
CRF Receptor Down-regulation In Depressed Patients
Multiple hypotheses have been formulated to explain the decreased ACTH response to exogenously administered CRF. Hypercortisolemia with resultant negative feedback at various levels of the HPA axis may blunt the response of the anterior pituitary to CRF. However, this hypothesis was not supported by a study measuring the ACTH response to CRF in depressed patients following dexamethasone pretreatment. After dexamethasone pretreatment, depressed patients have higher ACTH and Cortisol responses after exogenous CRF stimulation than normal subjects.27,31 After metyrapone administration, the ACTH response to CRF is also increased in depressed patients compared to controls.32,33 Moreover, Schlaghecke et al34 reported that chronic glucocorticoid therapy had very variable effects on the ACTH response to CRF. Taken together, it would appear that hypercortisolemia alone cannot explain the blunted response of ACTH to CRF in depressed patients.
The blunted ACTH response to exogeneously administered CRF may be secondary to chronic hypersecretion of CRF from the median eminence, i.e., elevated CRF release from the hypothalamus causing downregulation of anterior pituitary CRF receptors with resultant decreased pituitary responsiveness to CRF. Such CRF-induced downregulation of CRF receptors has been demonstrated in laboratory models.35-39
To test this hypothesis, the number and affinity of CRF receptors in the frontal cortex of 26 suicide victims and 29 controls was measured.40 The suicide population consisted of 5 women and 21 men aged 36 ±18 years (mean ± SD). The control population consisted of 7 women and 22 men aged 39 ±17 years (mean ± SD) who died from myocardial infarction, motor vehicle accidents, etc. The suicide victims exhibited a marked decrease in the density of these putative CRF receptors, consistent with the hypothesis that chronic hypersecretion of the peptide produced a longlasting reduction in CRF receptor number. Awaiting further investigation is the measurement of CRF mRNA in the paraventricular nucleus (PVN) of the hypothalamus in postmortem tissue of depressed patients. If elevated levels of CRF mRNA in the PVN were found, it would directly support the hypothesis that down-regulation of CRF receptors decreases pituitary responsiveness to CRF.
Enlargement of Pituitary and Adrenal Glands in Depressed Patients
Laboratory animal studies have revealed that chronic CRF administration can cause an increase in the number and volume of corticotrophs.41,42 In humans, using magnetic resonance imaging, the pituitary gland has been shown to be enlarged in depressed patients in comparison to age- and sex-matched controls.43 We have now confirmed these findings and found a significant correlation between pituitary gland enlargement and postdexamethasone Cortisol concentrations.44
Zis and Zis45 reported that individuals who committed suicide had increased postmortem adrenal gland weights compared to controls. Enlargement of adrenal gland size in depressed patients was recently reported by Nemeroff et al.46 In that study, 38 depressed patients had significantly increased adrenal gland volumes as assessed by computed tomography in comparison to age- and sexmatched normal controls. Enlargement of the adrenal gland is most likely due to adrenocortical enlargement rather than adrenomedullary enlargement because: (a) the adrenal medulla constitutes less than 10% of the gland mass, (b) adrenal medullary cells are not known to increase in size or multiply, except when neoplastic, and (c) adrenocortical cells are capable of both hypertrophy and hyperplasia. Adrenal gland size, however, did not correlate with dexamethasone suppression test results, patient age, or severity or duration of the depressive episode.
CRF hypersecretion in depressed patients most likely contributes to pituitary gland enlargement and ultimately to adrenal gland hypertrophy. Recently, the enlargement of adrenal gland size in depressed patients was confirmed by Rubin and colleagues,47 who obtained evidence that these changes may be state dependent. The literature awaits a subsequent study in which CRF stimulation tests and CSF CRF concentrations are obtained concurrently with pituitary and adrenal gland size in depressed patients.
There is evidence that in addition to major depression, CRF hypersecretion occurs in anorexia nervosa (AN). Indeed, many patients with AN also exhibit comorbid depressive symptoms. As in individuals with depression, patients with AN exhibit elevated plasma Cortisol levels, increased secretion of urinary free Cortisol, and DST nonsuppression.48 These findings, including CRF hypersecretion, indicate HPA axis hyperactivity in both these disorders.
In AN, the following have been observed: (a) elevated CSF CRF concentrations, (b) normalization of CSF CRF concentrations with recovery of weight loss, and (c) a blunted ACTH response to CRF in underweight anorexic patients.
Elevated CSF CRF concentrations have been reported in patients with AN.49,50 Normalized pituitary-adrenal function and CSF CRF concentrations occur upon weight recovery.50 In addition, Kaye and colleagues reported that CSF concentrations of CRF are significantly correlated with depression severity ratings in the patients with weight correction.
As in major depression, underweight anorexic patients exhibit a blunted ACTH response after intravenous CRF administration.49,51 ACTH responses to CRF normalize after weight gain. Hotta and colleagues49 report that this normalization occurs immediately after correction of weight loss. However, the ACTH response to CRF has also been reported to normalize only after six months following weight gain.49 Further research will seek to elucidate the role of CRF in AN and determine whether it is associated with the frequent concomitant major depression.
Studies evaluating the integrity of the HPA axis using CRF have also been conducted in patients diagnosed with schizophrenia. Normal CSF CRF concentrations are usually found in schizophrenic patients.6,8 ACTH and Cortisol responses to CRF are also normal in schizophrenic patients.52
CSF CRF concentration levels have been investigated in a variety of other psychiatric disorders, including mania, panic disorder, somatization disorders, and Alzheimer's disease. Although limited numbers of patients have been used, in general, no major alterations of CSF CRF concentrations have been found in comparison to nonpsychiatric controls.8,10,53,54
Alterations in CRF neuronal function have been most extensively studied in patients with major depression. Dysregulation of the HPA axis may occur, at least in part, via hypersecretion of CRF as reflected by elevated CSF CRF concentrations. Both the elevated CSF concentrations of CRF and the blunted ACTH response to a standard CRF stimulation test, like hypercortisolemia, return to normal after successful treatment of depression. These neuroendocrine abnormalities appear to represent a state rather than a trait marker of depression.
The blunted ACTH response to exogeneously administered CRF may be secondary to chronic CRF hypersecretion causing down-regulation (decreased number) of anterior pituitary CRF receptors. This CRF hypersecretion most likely contributes to pituitary gland enlargement and ultimately to adrenal gland hypertrophy in depressed patients. CRF receptor antagonists may represent a novel class of antidepressant agent.
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