ABSTRACT
Use of antipsychotic medications has been associated consistently with weight gain and metabolic disturbances, and a subsequent increased risk for diabetes and cardiovascular disease. Two experiments tested whether CORT 108297, a newly identified selective glucocorticoid antagonist could (i) reduce and (ii) prevent olanzapine-induced weight gain in rats. In the first experiment, rats dosed only with olanzapine gained a statistically significant amount of weight. When vehicle was added to their olanzapine dose, they continued to gain weight; when CORT 108297 was added to their regimen, they lost a significant amount of weight. Rats administered CORT 108297 plus olanzapine had significantly less abdominal fat than those who received olanzapine alone. In the second experiment, rats receiving olanzapine plus CORT 108297 gained significantly less weight than rats receiving only olanzapine. Increasing doses of CORT 108297 were associated with less weight gain.
Subject(s)
Antipsychotic Agents/adverse effects , Aza Compounds/pharmacology , Benzodiazepines/adverse effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Receptors, Glucocorticoid/antagonists & inhibitors , Weight Gain/drug effects , Animals , Body Weight , Female , Olanzapine , RatsABSTRACT
OBJECTIVE: The theory that psychotic major depression is a distinct syndrome is supported by reports of statistically significant differences between psychotic and nonpsychotic major depression in presenting features, biological measures, familial transmission, course and outcome, and response to treatment. This study examined differences in performance on a verbal memory test and in cortisol levels between patients with psychotic and nonpsychotic major depression and healthy volunteers. METHOD: Ten patients with psychotic major depression, 17 patients with nonpsychotic major depression, and 10 healthy volunteers were administered the Wallach Memory Recognition Test and had blood drawn at half-hour intervals over the course of an afternoon to assay cortisol levels. RESULTS: Subjects with psychotic major depression had a higher rate of errors of commission on the verbal memory test (incorrectly identified distracters as targets) than did subjects with nonpsychotic major depression or healthy volunteers; errors of omission were similar among the three groups. Subjects with psychotic major depression had higher cortisol levels throughout the afternoon than subjects with nonpsychotic major depression or healthy volunteers. This effect became even more pronounced later in the afternoon. CONCLUSIONS: Psychotic major depression is endocrinologically different from nonpsychotic major depression and produces cognitive changes distinct from those seen in nonpsychotic major depression.
Subject(s)
Affective Disorders, Psychotic/diagnosis , Cognition Disorders/diagnosis , Depressive Disorder/diagnosis , Hydrocortisone/blood , Neuropsychological Tests/statistics & numerical data , Adult , Affective Disorders, Psychotic/blood , Affective Disorders, Psychotic/physiopathology , Aged , Circadian Rhythm/physiology , Cognition Disorders/blood , Depressive Disorder/blood , Depressive Disorder/physiopathology , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Prefrontal Cortex/physiology , Verbal Learning/physiology , Wechsler Scales/statistics & numerical dataABSTRACT
The rationale for treating psychotic major depression with glucocorticoid receptor (GR) antagonists is reviewed. Five patients with psychotic major depression were given 600 mg of mifepristone in a 4-day, double-blind, placebo-controlled crossover study. All the patients completed the protocol and adverse effects were not observed or reported. All of the five patients showed substantial improvements in their Hamilton Rating Scale for Depression scores while they were receiving mifepristone, and four of the five patients showed substantial improvement in their Brief Psychiatric Rating Scale scores. Little, if any, improvement was seen with placebo. These preliminary results suggest that short-term use of GR antagonists may be effective in the treatment of psychotic major depression and that additional study, perhaps using higher doses or more treatment days, seems warranted.
Subject(s)
Depressive Disorder, Major/drug therapy , Hormone Antagonists/therapeutic use , Mifepristone/therapeutic use , Psychotic Disorders/drug therapy , Adolescent , Adrenocorticotropic Hormone/blood , Adult , Aged , Brief Psychiatric Rating Scale , Cross-Over Studies , Depressive Disorder, Major/blood , Double-Blind Method , Female , Humans , Hydrocortisone/blood , Male , Middle Aged , Psychotic Disorders/blood , Time FactorsABSTRACT
The brain is a major target organ for corticosteroids. It has been observed that excessive circulatory levels of endogenous and exogenous corticosteroids are frequently associated with cognitive impairment in a wide variety of clinical disease states. Cognition and low levels of corticosteroids have been less well studied. In this paper we review the literature on glucocorticosteroid effects on cognition and delineate specific functions that appear to be causally affected. We draw a possible connection to specific areas of brain perturbation, including the hippocampus and frontal lobe regions. The possibility that cognitive dysfunction caused by glucocorticoids can be pharmacologically managed is introduced.
