Brexanolone, a neurosteroid antidepressant, vindicates the gabaergic deficit hypothesis of depression and may foster resilience [version 1; peer review

4 approved]

Bernhard Luscher, Hanns Möhler

Research output: Contribution to journalReview article

Abstract

The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABAA receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.

Original languageEnglish (US)
Article number751
JournalF1000Research
Volume8
DOIs
StatePublished - Jan 1 2019

Fingerprint

Pregnanolone
Peer Review
Antidepressive Agents
Neurotransmitter Agents
Depression
GABA-A Receptors
Central Nervous System Agents
Postpartum Depression
Foster Home Care
Serotonin Uptake Inhibitors
Ketamine
gamma-Aminobutyric Acid
Ligands
Networks (circuits)

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

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title = "Brexanolone, a neurosteroid antidepressant, vindicates the gabaergic deficit hypothesis of depression and may foster resilience [version 1; peer review: 4 approved]",
abstract = "The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABAA receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.",
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N2 - The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABAA receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABAA receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.

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