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antiglucocorticoids in depression (abstracts)

Posted by Elizabeth on May 29, 2001, at 22:05:45

J Clin Psychopharmacol 1991 Apr;11(2):121-6
Response to steroid suppression in major depression resistant to antidepressant therapy.
Murphy BE, Dhar V, Ghadirian AM, Chouinard G, Keller R.
Reproductive Physiology Unit, Montreal General Hospital, Quebec, Canada.

Because of the similarities in the psychiatric symptoms of Cushing's syndrome and those of major depression, and because the former generally remits when the hyperadrenalism is alleviated, an open clinical trial of the effect of steroid suppression in major depression was undertaken. Ten patients satisfying the DSM-III-R criteria for major depression, and classified as treatment-resistant, were included. Eight patients completed the study, which consisted of discontinuation of other psychotropic drugs and 2 months' treatment with one or more steroid suppressive agent (aminoglutethimide, ketoconazole and/or metyrapone). Six were classified as responders, and two as partial responders. In six, the improvement has been sustained for longer than 5 months after withdrawing the drugs. Side effects were mild to moderate. These results provide some evidence that steroids are involved in the maintenance of major depression, and that their suppression may lead to a readjustment of the hypothalamic-pituitary-adrenal axis with remission of the depression.

J Steroid Biochem Mol Biol 1991 Aug;39(2):239-44
Treatment of major depression with steroid suppressive drugs.
Murphy BE.
Department of Medicine, McGill University, Montreal, Canada.

The hypercorticism frequently observed in major depression, unaccompanied by signs of Cushing's syndrome, is still poorly understood. One suicidal young woman, with very high cortisol levels and unusual resistance to dexamethasone suppression, is described. She was successfully treated with steroid suppressive drugs (aminoglutethimide, metyrapone), had a prompt and complete remission and has remained well for more than two years on no medication. This success prompted an on-going clinical trial of this therapy. The available drugs and a working hypothesis of their action are discussed.

Am J Psychiatry 1993 May;150(5):810-2
Ketoconazole administration in hypercortisolemic depression.
Wolkowitz OM, Reus VI, Manfredi F, Ingbar J, Brizendine L, Weingartner H.
Department of Psychiatry, University of California, San Francisco.

Ketoconazole, an antiglucocorticoid drug, was administered to 10 hypercortisolemic depressed patients for up to 6 weeks. Three patients dropped out because of side effects or intercurrent illness. The remaining seven had significant ketoconazole-associated decreases in serum cortisol levels and in depression ratings. Antiglucocorticoid agents may be useful probes for investigating the sequelae of hypercortisolemia in patients with major depression.

Biol Psychiatry 1995 Mar 15;37(6):369-75
The psychotropic effects of inhibitors of steroid biosynthesis in depressed patients refractory to treatment.
Ghadirian AM, Engelsmann F, Dhar V, Filipini D, Keller R, Chouinard G, Murphy BE.
Department of Psychiatry, McGill University, Montreal, Canada.

Twenty patients, diagnosed as suffering from treatment-resistant major depression, were treated with one or more drugs that decrease corticosteroid biosynthesis. Nine were psychotic, 11 nonpsychotic. Seventeen completed the treatment (8 psychotic, 9 nonpsychotic); 13 responded (5 psychotic, 8 nonpsychotic; 11 responded completely (i.e., a drop in the Hamilton Depression Scale of at least 50%, to < or = 15), and 2 responded partially. The mean age of the responders (45.2 +/- 12.6 years) did not differ significantly from that of the nonresponders (48.7 +/- 12/3). Data were analyzed in the following categories; (1) the presence or absence of psychosis, (2) response or nonresponse to treatment, and (3) the drug(s) used (aminoglutethimide, ketoconazole, or a combination of either of these with metyrapone). The patients improved over time on the Hamilton Depression Scale independent of the medication used. Responders demonstrated improvement in mood, insomnia, anxiety, diurnal variation, paranoia and obsessive compulsiveness. Nonpsychotics responded better than psychotics.

Biol Psychiatry 1995 Mar 15;37(6):364-8
Cortisol synthesis inhibition: a new treatment strategy for the clinical and endocrine manifestations of depression.
Thakore JH, Dinan TG.
Dept. of Psychological Medicine, St. Batholomew's Hospital, West Smithfield, London, UK.

Evidence exists that oversecretion of cortisol may be responsible for the clinical manifestations and serotonergic abnormality in depressive illness. Using the cortisol synthesis inhibitor ketoconazole, we investigated the effects of directly lowering cortisol on the symptoms and the response of prolactin (PRL) to d-fenfluramine in eight patients suffering from major depression. Prolactin responses to d-fenfluramine were measured, and patients were treated with 400-600 mg of ketoconazole for 4 weeks, after which they were retested. Five patients treated with ketoconazole recovered from their depression, while the other three had decreases in their Hamilton Depression Rating Scale (HAMD) scores of < or = 50% and were deemed partial responders. Posttreatment prolactin responses to d-fenfluramine were higher than pretreatment values. Ketoconazole normalizes the blunted prolactin responses to d-fenfluramine and may be an effective method by which to treat depression. This implies that hypercortisolemia may be responsible for the clinical features and serotonergic subsensitivity observed in depression.

Nihon Shinkei Seishin Yakurigaku Zasshi 1996 Feb;16(1):33-6
Clinical effects of cortisol synthesis inhibition on treatment-resistant depression. [Article in Japanese]
Iizuka H, Kishimoto A, Nakamura J, Mizukawa R.
Department of Neuro-Psychiatry, Faculty of Medicine, Tottori University, Yonago, Japan.

Clinical trial with a steroid suppressive agent, metyrapone, was carried out in 6 patients with treatment-resistant depression (3 patients with major depression and 3 with bipolar disorder). Up to 2,000 mg/day of metyrapone was administered for 4 weeks, and 10 trials of the therapy were done in these patients. Most patients completed the therapy without remarkable side effects. As a result, three patients (6 trials) showed remission within 4 weeks and one patient (one trial) showed a partial response. In the remitted patients, plasma cortisol levels were suppressed below 10 micrograms/dl during the therapy and plasma ACTH levels were elevated. These results indicate that "hypercortisolemia-induced depression" similar to Cushing's disease may be present in patients with treatment-resistant depression.

Can J Psychiatry 1998 Apr;43(3):279-86
Neuroendocrine responses to inhibitors of steroid biosynthesis in patients with major depression resistant to antidepressant therapy.
Murphy BE, Ghadirian AM, Dhar V.
McGill University, Montreal, Quebec.

OBJECTIVE: Patients with major depression frequently have high cortisol levels and resistance to dexamethasone. We sought to determine to what extent major depression might be influenced by inhibitors of steroid biosynthesis and to study the endocrine changes produced. METHOD: After drug washout, 20 treatment-resistant patients with major depression were given aminoglutethimide, metyrapone, and/or ketoconazole, along with a small dose of cortisol for 8 weeks. Hamilton Depression Rating Scale (HDRS) ratings, 8:00 AM cortisol dehydroepiandrosterone sulfate (DHAS), adrenocorticotropin (ACTH), and testosterone levels were followed weekly or oftener. A dexamethasone suppression test (DST) was conducted before and after treatment. RESULTS: Seventeen patients (85%) completed the course of treatment, and a significant mean drop (P < or = 0.0001) of 50% in the HDRS score occurred by 7 weeks of treatment. Cortisol levels fluctuated widely and were often still high after the patient had improved clinically. Dehydroepiandrosterone sulfate levels fell more uniformly and were found to be a useful indicator of compliance and, to some extent, efficacy with aminoglutethimide and ketoconazole therapy. The correlation between DHAS and HDRS (r = 0.94) was significant (P = 0.02). Testosterone levels in men fell with ketoconazole but returned promptly to normal at the end of treatment. Adrenocorticotropin levels were normal or elevated, depending on the assay used, and rose (P = 0.07; n = 13) in most subject during therapy. Of the 6 responders who had nonsuppressor DSTs before starting therapy, 5 had reverted to normal 1 to 2 weeks following cessation of therapy (P = 0.0006). CONCLUSIONS: Abnormal metabolism of adrenocortical steroids may perpetuate depression, and alterations of synthesis or metabolism of these steroids may lead to a remission.

Psychosom Med 1999 Sep-Oct;61(5):698-711
Treatment of depression with antiglucocorticoid drugs.
Wolkowitz OM, Reus VI.
Department of Psychiatry, University of California, San Francisco, School of Medicine 94143-0984, USA.

OBJECTIVE: The theoretical and empirical rationales for the potential therapeutic use of antiglucocorticoid agents in the treatment of depression are reviewed. METHOD: Individual case reports, case series, open-label, and double-blind, controlled trials of the usage of cortisol-lowering treatments in Cushing's syndrome and major depression are evaluated and critiqued. RESULTS: In each of the 28 reports of antiglucocorticoid treatment of Cushing's syndrome, antidepressant effects were noted in some patients; the largest two series document a response rate of 70% to 73%. Full response, however, was at times erratic and delayed. Across the 11 studies of antiglucocorticoid treatment of major depression, some degree of antidepressant response was noted in 67% to 77% of patients. Antidepressant or antiobsessional effects of antiglucocorticoid augmentation of other psychotropic medications have also been noted in small studies of patients with treatment-resistant depression, obsessive-compulsive disorder, and schizoaffective disorder or schizophrenia. CONCLUSIONS: These promising results with antiglucocorticoid treatment must be interpreted cautiously because of the small sample sizes and heterogeneity of the studies reviewed, the bias favoring publication of positive results, and the open-label nature of most of the studies. Although definitive controlled trials remain to be conducted, there is a consistent body of evidence indicating that cortisol-lowering treatments may be of clinical benefit in select individuals with major depression and other hypercortisolemic conditions.

Biol Psychiatry 1999 Apr 15;45(8):1070-4
Antiglucocorticoid treatment of depression: double-blind ketoconazole.
Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W, Johnson R, Canick J.
Department of Psychiatry, University of California at San Francisco Medical Center, USA.

BACKGROUND: Hypercortisolemia is frequently observed in major depression but its pathophysiologic significance is unknown. In patients in whom hypercortisolism contributes to depressive symptomatology, antiglucocorticoid agents should have antidepressant effects. METHODS: Twenty medication-free depressed patients (eight of whom were hypercortisolemic and twelve of whom were not) received either the cortisol biosynthesis inhibitor, ketoconazole (400-800 mg/d p.o.) or placebo for 4 weeks in a double-blind manner, and behavioral ratings were performed weekly. RESULTS: Ketoconazole, compared to placebo, was associated with improvements in depression ratings in the hypercortisolemic, but not in the non-hypercortisolemic patients. The hormonal changes seen (decreased dehydroepiandrosterone and testosterone levels and increased pregnenolone and pregnenolone-sulfate levels) are consistent with enzymatic blockade of C17,20-lyase, 11-hydroxylase, and 17-hydroxylase. Ketoconazole was generally well tolerated with no occurrence of significant side effects or laboratory abnormalities. CONCLUSIONS: This small-scale double-blind study suggests that antiglucocorticoids have antidepressant activity in hypercortisolemic depressed patients. The data are consistent with a causal role of adrenocortical dysfunction in some depressed patients and suggest the need for larger-scale trials.




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