Neurosteroids in depression: a review

Broekhoven, Frank van; Verkes, Robbert J.

doi:10.1007/s00213-002-1257-1

Cited by 187 publications

(127 citation statements)

References 156 publications

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“…[63][64][65] This concept was further supported, during the last decade, by studies reporting a link between GABA system and neurosteroids, which are a group of steroids synthesized de novo in the nervous system from sterol precursors. 66 Steroidogenesis occurs in glial and neuronal cells, when cholesterol is transported into the mitochondrion, and then it is converted to pregnenolone by the P450 side-chain cleavage enzyme. In turn, pregnenolone can be metabolized to pregnanes (pregnenolone sulfate, pregnanolone, allopregnanolone) and androstanes (dehydroepiandrosterone, dehydroepiandrosterone-sulfate, dihydrotestoterone metabolites).…”

Section: Gabaergic Modulation Of Neuronal Activitymentioning

confidence: 99%

“…In turn, pregnenolone can be metabolized to pregnanes (pregnenolone sulfate, pregnanolone, allopregnanolone) and androstanes (dehydroepiandrosterone, dehydroepiandrosterone-sulfate, dihydrotestoterone metabolites). 66 Although the mechanisms involved in the regulation of neurosteroids within the cells are still largely unknown, Do-Rego et al 67 have recently reported that GABA itself, acting through GABA A receptors, inhibits the activity of neurosteroidogenic enzymes. The effects of neurosteroids on GABA A receptors have been extensively investigated.…”

Section: Gabaergic Modulation Of Neuronal Activitymentioning

confidence: 99%

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GABAergic dysfunction in mood disorders

et al. 2003

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Section: Gabaergic Modulation Of Neuronal Activitymentioning

confidence: 99%

Section: Gabaergic Modulation Of Neuronal Activitymentioning

confidence: 99%

GABAergic dysfunction in mood disorders

et al. 2003

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“…Indeed, the antiglucocorticoid properties of DHEA (van Broekhoven and Verkes, 2003) may contribute to an upregulation of HPA axis responses as well as mitigate possible deleterious effects of high cortisol levels on the brain in schizophrenia subjects. This study could not show us a clear causal relationship between cortisol/DHEA(S) ratios and responsivity to antipsychotic treatment.…”

Section: Commentmentioning

confidence: 99%

Cortisol/Dehydroepiandrosterone Ratio and Responses to Antipsychotic Treatment in Schizophrenia

Ritsner

Gibel

Maayan

et al. 2005

Neuropsychopharmacol

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Dehydroepiandrosterone (DHEA) or their sulfate conjugate (DHEAS) (together abbreviated DHEA(S)) exert multiple effects in the central nervous system, and may be involved in the pathophysiological processes in schizophrenia. This prospective study aimed to investigate whether serum cortisol/DHEA(S) molar ratios are associated with response to antipsychotic treatment during the exacerbation of schizophrenia. Serum DHEA(S) and cortisol were determined at baseline, and 2 and 4 weeks later for 43 medicated schizophrenia inpatients with acute exacerbation. The patients were treated with stable doses of antipsychotic agents up to 2 weeks prior to entering the study and for the 4-week duration of the study after which they were classified as either responders or nonresponders to treatment. Findings suggest that responders had significantly higher serum cortisol levels and cortisol/DHEA(S) ratios compared with nonresponders. These differences remained significant at three time points controlling for gender, age, severity of symptoms and emotional distress, benzodiazepines, type or dosage of antipsychotic agents, and background variables. The logistic regression model shows advantages of both cortisol/DHEA(S) molar ratios vs serum cortisol and DHEA(S) concentrations for prediction of responsivity to antipsychotic treatment. No significant canonical correlations were observed between changes from baseline through end-of-study in hormonal values and severity of symptoms and emotional distress among responders and nonresponders. Thus, these data provide evidence that elevated serum cortisol and cortisol/DHEA(S) ratios may serve as markers of biological mechanisms that are involved in responsivity of schizophrenia patients to antipsychotic treatment.

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“…Elucidation of the role of neurosteroids in the pathophysiology and treatment of depression has begun recently (van Broekhoven and Verkes, 2003). Depressed patients have lower levels of plasma DHEA sulfate (DHEAS) (Barrett-Connor et al, 1999;Goodyer et al, 1998) and of saliva DHEA (Fabian et al, 2001;Takebayashi et al, 1998) than controls.…”

Section: Introductionmentioning

confidence: 99%

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

Genud

Merenlender

Gispan-Herman

et al. 2008

Neuropsychopharmacol

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Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate g-aminobutyric-acid-type-A (GABA A R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (s1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitiveline (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the d-subunit of GABA A , but not of s1R mRNA, in FSL rats compared to SD rats. The d-subunit controls the sensitivity of the GABA A R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA A agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA A ), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA A Rs in the NAc and VTA.

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Neurosteroids in depression: a review

Cited by 187 publications

References 156 publications

GABAergic dysfunction in mood disorders

GABAergic dysfunction in mood disorders

Cortisol/Dehydroepiandrosterone Ratio and Responses to Antipsychotic Treatment in Schizophrenia

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

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