Mitchel A. Kling a , David R. Rubinow b , Allen R. Doran c , Alec Roy c , Candace L. Davis b , Joseph R. Calabrese a , Lynnette K. Nieman d , Robert M. Post b , George P. Chrousos d , Philip W. Gold a
08 April 2008
To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushing’s disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushing’s disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 ± 2.9 vs. 37.4 ± 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 ± 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushing’s disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r<sup>2</sup> = 0.90; d.f. = 22; p < 0.001). In the depressed patients, the CSF SRIF levels also showed an inverted quadratic relationship with urinary free cortisol excretion (r<sup>2</sup> = 0.87; d.f. = 16; p < 0.001). These findings, together with those from recent preclinical and human volunteer studies, suggest that CRH is a positive modulator of central SRIF release under physiological conditions, while glucocorticoid excess tends to suppress SRIF. These data are of interest in the light of evidence suggesting an involvement of SRIF in functions such as mood regulation, learning, and memory which are disturbed in both Cushing’s disease and major depression.