Antiglucocorticoid treatment of depression: double-blind ketoconazole

Wolkowitz, Owen M.; Reus, Victor I.; Chan, Trevor; Manfredi, Francesca; Raum, William J.; Johnson, Ron J.; Canick, Jonathan

doi:10.1016/s0006-3223(98)00267-4

Cited by 157 publications

(84 citation statements)

References 19 publications

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“…Ketokonazole, in addition to blocking adrenal steroid synthesis, inhibits cytochrome P450-dependent enzymes (11-hydroxylase, 17-hydroxylase, C17,20 lyase) similar to aminogluthetimide and has direct inhibitory effects on other anterior pituitary cells than corticotrophs (Stalla et al 1989) thus, for example, affecting gonadal steroid secretion. Consistent with predictions from open label studies (e.g., Murphy 1991; Thakore and Dinan 1995), a recent double blind placebo-controlled study suggested that ketokonazole is superior to placebo among hypercortisolemic depressed patients (Wolkowitz et al 1999). Here again, it is difficult to dissociate the effects of ketokonazole from the effects of other adrenal steroids which are produced at much higher rates because of the enzyme blockade.…”

Section: Cortisol Synthesis Inhibitorsmentioning

confidence: 84%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

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Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

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Section: Cortisol Synthesis Inhibitorsmentioning

confidence: 84%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,982

1,228

View full text Add to dashboard Cite

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“…Elevated cortisol levels in depressed patients usually return to normal following successful antidepressant treatment (Wolkowitz et al, 1993(Wolkowitz et al, , 1999. Previous studies have demonstrated that classical benzodiazepines decrease HPA cortex axis activity (Mikkelsen et al, 2005) and a low serum corticosterone levels could be associated with reduced anxiety (Ferguson et al, 2004;Smith et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Reduced Anxiety and Depression-Like Behaviors in Mice Lacking GABA Transporter Subtype 1

Liu

Cai

et al. 2006

Neuropsychopharmacol

117

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g-Aminobutyric acid (GABA) transporter subtype 1 (GAT1), which transports extracellular GABA into presynaptic neurons, plays an important regulatory role in the function of GABAergic systems. However, the contributions of the GAT1 in regulating mental status are not fully understood. In this paper, we observed the behavioral alterations of GAT1 knockout (GAT1 À/À ) mice using several depressionand anxiety-related models (eg, the forced-swimming test and the tail-suspension test for testing depression-related behaviors; the openfield test, the dark-light exploration test, the emergence test, and the elevated plus maze (EPM) test for anxiety-related behaviors). Here we found that GAT1 À/À mice showed a lower level of depression-and anxiety-like behaviors in comparison to wild-type mice. Furthermore, GAT1 À/À mice exhibited measurable insensitivity to selected antidepressants and anxiolytics such as fluoxetine, amitriptyline, buspirone, diazepam, and tiagabine in the tail-suspension test and/or the EPM test. Moreover, the basal level of corticosterone was found to be significantly lower in GAT1 À/À mice. These results showed that the absence of GAT1 affects mental status through enhancing the GABAergic system, as well as modifying the serotonergic system and the hypothalamic-pituitary-adrenal (HPA) activity in mice.

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“…Since numerous clinical investigations point to hypercorticism as an important factor in the pathogenesis of depression, treating depression with GR antagonists or steroid synthesis inhibitors could be a promising strategy (Murphy et al, 1998;Wolkowitz et al, 1999;Belanoff et al, 2001;Reus and Wolkowitz, 2001). Administration of the GR antagonist RU 38486 clearly increased HPA axis drive in human subjects (Laue et al, 1989;Kawai et al, 1987) and rats Van Haarst et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Effect of Chronic Administration of Selective Glucocorticoid Receptor Antagonists on the Rat Hypothalamic–Pituitary–Adrenocortical Axis

Bachmann

Linthorst

Holsboer

et al. 2002

Neuropsychopharmacol

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The effects of the selective glucocorticoid receptor (GR) antagonists ORG 34850, ORG 34116, and ORG 34517 on the rat hypothalamic-pituitary-adrenocortical (HPA) system were investigated. To assess the potency of the compounds to occupy GR in the brain and pituitary, we applied a single acute subcutaneous (s.c.) injection (10 mg/kg). ORG 34517 was most potent to occupy GR in the anterior pituitary and distinct brain areas, whereas all compounds were unable to occupy mineralocorticoid receptor (MR). Chronic administration of ORG 34850, ORG 34116, and ORG 34517 (20 mg/kg/day) for 1, 3, and 5 weeks resulted only in minor changes in brain GR levels. However, profound increases of hippocampal MR were observed virtually at all time points. Treatment with ORG 34850 and ORG 34116 elicited episodic increases in HPA axis activity, whereas ORG 34517 did not cause any changes in HPA activity. Thus, the GR antagonists exert distinct effects on the HPA axis, which may be pertinent for the proposed antidepressant activity of these compounds.

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Antiglucocorticoid treatment of depression: double-blind ketoconazole

Cited by 157 publications

References 19 publications

The Corticosteroid Receptor Hypothesis of Depression

The Corticosteroid Receptor Hypothesis of Depression

Reduced Anxiety and Depression-Like Behaviors in Mice Lacking GABA Transporter Subtype 1

Effect of Chronic Administration of Selective Glucocorticoid Receptor Antagonists on the Rat Hypothalamic–Pituitary–Adrenocortical Axis

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