Context: The mechanism and significance of diminished glucocorticoid negative feedback in schizophrenia is unknown, but is more commonly observed in schizophrenic patients with primary polydipsia. Polydipsic patients, especially those who are also hyponatremic, exhibit other neuroendocrine abnormalities that have been linked to hippocampal pathology.

Objective: To determine the effect of cortisol on plasma ACTH under conditions thought to be most sensitive to hippocampal influences.

Design: Repeated measures

Setting: Inpatient Clinical Research Center

Participants: Eight polydipsic hyponatremic, eight polydipsic normonatremic, as well as six schizophrenic patients without water imbalance. Eight healthy community volunteers matched for age and gender were also studied.

Intervention: Metyrapone (750 mg) was administered orally at 1430 and 1900 h. Beginning at 1930 h, hydrocortisone was infused over 150-min at 0.03 mg/kg/h. Blood samples and other measures were obtained at 20-min intervals from 1850 h to 2320 h.

Main Outcome Measures: Plasma ACTH and cortisol.

Results: ACTH levels did not decline significantly during the cortisol infusion in the polydipsic hyponatremic group. For any given level of cortisol, ACTH levels were higher in the hyponatremic group. While levels decline following cortisol in the other three groups, the decline was greatest in patients without water imbalance.

Conclusions: The marked impairment in glucocorticoid negative feedback in polydipsic hyponatremic schizophrenic patients is consistent with hippocampal mineralocorticoid dysfunction.