Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression

Michael Raymond Binder

doi:doi:10.11648/j.ajpn.20221003.17

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Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression

Michael Raymond Binder

Published in American Journal of Psychiatry and Neuroscience (Volume 10, Issue 3)

Received: 5 August 2022 Accepted: 23 August 2022 Published: 31 August 2022

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Abstract

In 2019, after it had demonstrated rapid antidepressant effects in two placebo-controlled trials, the investigational drug brexanolone received FDA approval for the treatment of postpartum depression. Less than a year later, zuranolone, an oral formulation of the same drug, achieved similar results in patients with treatment-resistant depression. Brexanolone and zuranolone are the first in a new line of investigational drugs that act by enhancing GABA neuroinhibitory currents. The significance of this pharmacodynamic effect is that it is associated with a reduction in depressive symptoms in just 2-3 days as opposed to 2-3 weeks with antidepressants. This has naturally raised many questions about the mechanism by which these drugs exert their therapeutic effects. At the same time, an emerging hypothesis contends that psychiatric symptoms are the consequence of an inability of neurons to shut off. According to the multi-circuit neuronal hyperexcitability (MCNH) hypothesis of psychiatric disorders, psychiatric symptoms develop when symptom-related circuits in the brain fire too easily and for too long. Brexanolone and zuranolone put a brake on that firing. This article will discuss the groundbreaking success of GABAergic modulation from the perspective of the MCNH hypothesis and contrast it with the pharmacodynamic effects of standard antidepressant drugs in an effort to highlight the importance of neuronal excitability in the pathophysiology of depression and showcase the utility of the MCNH hypothesis as a guide to the assessment, treatment, and prevention of a wide range of psychiatric symptoms.

Published in	American Journal of Psychiatry and Neuroscience (Volume 10, Issue 3)
DOI	10.11648/j.ajpn.20221003.17
Page(s)	134-144
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2022. Published by Science Publishing Group

Keywords

Brexanolone, Zuranolone, GABA Modulators, GABAkines, Imidazodiazepines, Neuroregulators, Neuronal Hyperexcitability, Biomarkers of Disease

References

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Michael Raymond Binder. (2022). Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression. American Journal of Psychiatry and Neuroscience, 10(3), 134-144. https://doi.org/10.11648/j.ajpn.20221003.17

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Michael Raymond Binder. Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression. Am. J. Psychiatry Neurosci. 2022, 10(3), 134-144. doi: 10.11648/j.ajpn.20221003.17

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Michael Raymond Binder. Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression. Am J Psychiatry Neurosci. 2022;10(3):134-144. doi: 10.11648/j.ajpn.20221003.17

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@article{10.11648/j.ajpn.20221003.17,
  author = {Michael Raymond Binder},
  title = {Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression},
  journal = {American Journal of Psychiatry and Neuroscience},
  volume = {10},
  number = {3},
  pages = {134-144},
  doi = {10.11648/j.ajpn.20221003.17},
  url = {https://doi.org/10.11648/j.ajpn.20221003.17},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajpn.20221003.17},
  abstract = {In 2019, after it had demonstrated rapid antidepressant effects in two placebo-controlled trials, the investigational drug brexanolone received FDA approval for the treatment of postpartum depression. Less than a year later, zuranolone, an oral formulation of the same drug, achieved similar results in patients with treatment-resistant depression. Brexanolone and zuranolone are the first in a new line of investigational drugs that act by enhancing GABA neuroinhibitory currents. The significance of this pharmacodynamic effect is that it is associated with a reduction in depressive symptoms in just 2-3 days as opposed to 2-3 weeks with antidepressants. This has naturally raised many questions about the mechanism by which these drugs exert their therapeutic effects. At the same time, an emerging hypothesis contends that psychiatric symptoms are the consequence of an inability of neurons to shut off. According to the multi-circuit neuronal hyperexcitability (MCNH) hypothesis of psychiatric disorders, psychiatric symptoms develop when symptom-related circuits in the brain fire too easily and for too long. Brexanolone and zuranolone put a brake on that firing. This article will discuss the groundbreaking success of GABAergic modulation from the perspective of the MCNH hypothesis and contrast it with the pharmacodynamic effects of standard antidepressant drugs in an effort to highlight the importance of neuronal excitability in the pathophysiology of depression and showcase the utility of the MCNH hypothesis as a guide to the assessment, treatment, and prevention of a wide range of psychiatric symptoms.},
 year = {2022}
}

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TY  - JOUR
T1  - Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression
AU  - Michael Raymond Binder
Y1  - 2022/08/31
PY  - 2022
N1  - https://doi.org/10.11648/j.ajpn.20221003.17
DO  - 10.11648/j.ajpn.20221003.17
T2  - American Journal of Psychiatry and Neuroscience
JF  - American Journal of Psychiatry and Neuroscience
JO  - American Journal of Psychiatry and Neuroscience
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EP  - 144
PB  - Science Publishing Group
SN  - 2330-426X
UR  - https://doi.org/10.11648/j.ajpn.20221003.17
AB  - In 2019, after it had demonstrated rapid antidepressant effects in two placebo-controlled trials, the investigational drug brexanolone received FDA approval for the treatment of postpartum depression. Less than a year later, zuranolone, an oral formulation of the same drug, achieved similar results in patients with treatment-resistant depression. Brexanolone and zuranolone are the first in a new line of investigational drugs that act by enhancing GABA neuroinhibitory currents. The significance of this pharmacodynamic effect is that it is associated with a reduction in depressive symptoms in just 2-3 days as opposed to 2-3 weeks with antidepressants. This has naturally raised many questions about the mechanism by which these drugs exert their therapeutic effects. At the same time, an emerging hypothesis contends that psychiatric symptoms are the consequence of an inability of neurons to shut off. According to the multi-circuit neuronal hyperexcitability (MCNH) hypothesis of psychiatric disorders, psychiatric symptoms develop when symptom-related circuits in the brain fire too easily and for too long. Brexanolone and zuranolone put a brake on that firing. This article will discuss the groundbreaking success of GABAergic modulation from the perspective of the MCNH hypothesis and contrast it with the pharmacodynamic effects of standard antidepressant drugs in an effort to highlight the importance of neuronal excitability in the pathophysiology of depression and showcase the utility of the MCNH hypothesis as a guide to the assessment, treatment, and prevention of a wide range of psychiatric symptoms.
VL  - 10
IS  - 3
ER  -

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Michael Raymond Binder

Department of Psychiatry, NorthShore University HealthSystem, Highland Park Hospital, Highland Park, USA

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Michael Raymond Binder. (2022). Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression. American Journal of Psychiatry and Neuroscience, 10(3), 134-144. https://doi.org/10.11648/j.ajpn.20221003.17

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ACS Style

Michael Raymond Binder. Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression. Am. J. Psychiatry Neurosci. 2022, 10(3), 134-144. doi: 10.11648/j.ajpn.20221003.17

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Michael Raymond Binder. Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression. Am J Psychiatry Neurosci. 2022;10(3):134-144. doi: 10.11648/j.ajpn.20221003.17

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@article{10.11648/j.ajpn.20221003.17,
  author = {Michael Raymond Binder},
  title = {Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression},
  journal = {American Journal of Psychiatry and Neuroscience},
  volume = {10},
  number = {3},
  pages = {134-144},
  doi = {10.11648/j.ajpn.20221003.17},
  url = {https://doi.org/10.11648/j.ajpn.20221003.17},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ajpn.20221003.17},
  abstract = {In 2019, after it had demonstrated rapid antidepressant effects in two placebo-controlled trials, the investigational drug brexanolone received FDA approval for the treatment of postpartum depression. Less than a year later, zuranolone, an oral formulation of the same drug, achieved similar results in patients with treatment-resistant depression. Brexanolone and zuranolone are the first in a new line of investigational drugs that act by enhancing GABA neuroinhibitory currents. The significance of this pharmacodynamic effect is that it is associated with a reduction in depressive symptoms in just 2-3 days as opposed to 2-3 weeks with antidepressants. This has naturally raised many questions about the mechanism by which these drugs exert their therapeutic effects. At the same time, an emerging hypothesis contends that psychiatric symptoms are the consequence of an inability of neurons to shut off. According to the multi-circuit neuronal hyperexcitability (MCNH) hypothesis of psychiatric disorders, psychiatric symptoms develop when symptom-related circuits in the brain fire too easily and for too long. Brexanolone and zuranolone put a brake on that firing. This article will discuss the groundbreaking success of GABAergic modulation from the perspective of the MCNH hypothesis and contrast it with the pharmacodynamic effects of standard antidepressant drugs in an effort to highlight the importance of neuronal excitability in the pathophysiology of depression and showcase the utility of the MCNH hypothesis as a guide to the assessment, treatment, and prevention of a wide range of psychiatric symptoms.},
 year = {2022}
}

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TY  - JOUR
T1  - Emergent Success of GABA Modulators Links Neuronal Hyperexcitability to the Pathophysiology of Depression
AU  - Michael Raymond Binder
Y1  - 2022/08/31
PY  - 2022
N1  - https://doi.org/10.11648/j.ajpn.20221003.17
DO  - 10.11648/j.ajpn.20221003.17
T2  - American Journal of Psychiatry and Neuroscience
JF  - American Journal of Psychiatry and Neuroscience
JO  - American Journal of Psychiatry and Neuroscience
SP  - 134
EP  - 144
PB  - Science Publishing Group
SN  - 2330-426X
UR  - https://doi.org/10.11648/j.ajpn.20221003.17
AB  - In 2019, after it had demonstrated rapid antidepressant effects in two placebo-controlled trials, the investigational drug brexanolone received FDA approval for the treatment of postpartum depression. Less than a year later, zuranolone, an oral formulation of the same drug, achieved similar results in patients with treatment-resistant depression. Brexanolone and zuranolone are the first in a new line of investigational drugs that act by enhancing GABA neuroinhibitory currents. The significance of this pharmacodynamic effect is that it is associated with a reduction in depressive symptoms in just 2-3 days as opposed to 2-3 weeks with antidepressants. This has naturally raised many questions about the mechanism by which these drugs exert their therapeutic effects. At the same time, an emerging hypothesis contends that psychiatric symptoms are the consequence of an inability of neurons to shut off. According to the multi-circuit neuronal hyperexcitability (MCNH) hypothesis of psychiatric disorders, psychiatric symptoms develop when symptom-related circuits in the brain fire too easily and for too long. Brexanolone and zuranolone put a brake on that firing. This article will discuss the groundbreaking success of GABAergic modulation from the perspective of the MCNH hypothesis and contrast it with the pharmacodynamic effects of standard antidepressant drugs in an effort to highlight the importance of neuronal excitability in the pathophysiology of depression and showcase the utility of the MCNH hypothesis as a guide to the assessment, treatment, and prevention of a wide range of psychiatric symptoms.
VL  - 10
IS  - 3
ER  -

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