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Letters to the Editor
Published Online: 22 June 2021

Comment on “Understanding the Clinical Effects and Mechanisms of Action of Neurosteroids”

To the Editor: We read with interest the commentary “Understanding the Clinical Effects and Mechanisms of Action of Neurosteroids” by Kleinman and Schatzberg, published in the March 2021 issue of the Journal (1). We welcome the opportunity to provide additional commentary based on pharmacological and clinical data.
The authors correctly point out that the neuroactive steroids brexanolone and zuranolone are thought to exert activity primarily through positive allosteric modulation of the GABAA receptor. However, it is inaccurate to characterize the antidepressant activity of these molecules as analogous to that of benzodiazepines. We encourage readers to review for themselves the literature detailing the unique pharmacology, receptor trafficking activity, receptor signaling, and physiology of neuroactive steroids (26). Briefly, benzodiazepines act only at gamma subunit–containing synaptic GABAA receptors (7). In contrast, neuroactive steroids are positive allosteric modulators at both synaptic and extrasynaptic GABAA receptors, potentiating both phasic and tonic currents, respectively (24, 811). In vitro, zuranolone potentiated phasic GABAA currents synergistically with diazepam, consistent with the noncompetitive activity and distinct binding sites of the two compound classes (4). Neuroactive steroids can also enhance GABAergic signaling by increasing the surface expression of GABAA receptors (4, 1214), unlike the decreased GABAA receptor surface expression reported with benzodiazepines (15). Finally, antidepressant-like actions of a neurosteroid tool compound (SGE-516) were not observed with a benzodiazepine in animal studies (6). Moreover, as an important clarification, data do not suggest that postpartum depression is caused by abnormal hormone levels. As such, neuroactive steroids do not correct a hormonal deficiency in postpartum depression but instead may act by stabilizing dysregulated hyperexcitable neuronal networks (4, 6, 10).
The authors also question the durability of response with neuroactive steroids. Following a rapid onset of action, separating from placebo within 2–3 days of dosing, sustained responses were observed with brexanolone in patients with postpartum depression for up to 30 days (16, 17). With a similarly rapid onset, sustained efficacy responses were observed for patients with postpartum depression and major depressive disorder treated with zuranolone (1820). In addition, interim open-label data indicate that approximately 70% of patients receiving 30 mg of zuranolone required only one or two 14-day treatments through a 1-year follow-up (20).
Finally, the authors speculate on how tolerance or withdrawal could potentially interact with clinical outcomes and call for understanding the human abuse potential of neurosteroids (especially for zuranolone, which is in late-stage clinical development). We agree that comprehensive assessments for tolerance and dependence are necessary. These important assessments are being closely monitored throughout the zuranolone clinical development program. In an ongoing uncontrolled study of patients with major depression over a 1-year period, tolerance and withdrawal have not emerged clinically when using 30 mg of zuranolone for 14-day periods in retreatment; additional data on the use of 50 mg of zuranolone are currently being collected (20).
In conclusion, we hope our description of some of the important differences between benzodiazepines and neuroactive steroids is helpful. We appreciate the opportunity to respond, and we encourage readers to review the extensive literature on neuroactive steroids, benzodiazepines, and other GABAergic agents so that clinicians are fully informed about potential therapeutic options.

REFERENCES

1.
Kleinman RA, Schatzberg AF: Understanding the clinical effects and mechanisms of action of neurosteroids. Am J Psychiatry 2021; 178:221–223
2.
Reddy DS, Estes WA: Clinical potential of neurosteroids for CNS disorders. Trends Pharmacol Sci 2016; 37:543–561
3.
Maguire J: Neuroactive steroids and GABAergic involvement in the neuroendocrine dysfunction associated with major depressive disorder and postpartum depression. Front Cell Neurosci 2019; 13:83
4.
Althaus AL, Ackley MA, Belfort GM, et al: Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator. Neuropharmacology 2020; 181:108333
5.
Martinez Botella G, Salituro FG, Harrison BL, et al: Neuroactive steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): a clinical next generation neuroactive steroid positive allosteric modulator of the (γ-aminobutyric acid)A receptor. J Med Chem 2017; 60:7810–7819
6.
Melón L, Hammond R, Lewis M, et al: A novel, synthetic, neuroactive steroid is effective at decreasing depression-like behaviors and improving maternal care in preclinical models of postpartum depression. Front Endocrinol (Lausanne) 2018; 9:703
7.
Farrant M, Nusser Z: Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci 2005; 6:215–229
8.
Jacob TC: Neurobiology and therapeutic potential of α5-GABA type A receptors. Front Mol Neurosci 2019; 12:179
9.
Luscher B, Shen Q, Sahir N: The GABAergic deficit hypothesis of major depressive disorder. Mol Psychiatry 2011; 16:383–406
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Lee V, Maguire J: The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits 2014; 8:3
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Zorumski CF, Paul SM, Covey DF, et al: Neurosteroids as novel antidepressants and anxiolytics: GABA-A receptors and beyond. Neurobiol Stress 2019; 11:100196
12.
Abramian AM, Comenencia-Ortiz E, Modgil A, et al: Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors. Proc Natl Acad Sci USA 2014; 111:7132–7137
13.
Modgil A, Parakala ML, Ackley MA, et al: Endogenous and synthetic neuroactive steroids evoke sustained increases in the efficacy of GABAergic inhibition via a protein kinase C-dependent mechanism. Neuropharmacology 2017; 113(Pt A):314–322
14.
Parakala ML, Zhang Y, Modgil A, et al: Metabotropic, but not allosteric, effects of neurosteroids on GABAergic inhibition depend on the phosphorylation of GABAA receptors. J Biol Chem 2019; 294:12220–12230
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Jacob TC, Michels G, Silayeva L, et al: Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition. Proc Natl Acad Sci USA 2012; 109:18595–18600
16.
Meltzer-Brody S, Colquhoun H, Riesenberg R, et al: Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet 2018; 392:1058–1070
17.
Kanes S, Colquhoun H, Gunduz-Bruce H, et al: Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet 2017; 390:480–489
18.
Gunduz-Bruce H, Silber C, Kaul I, et al: Trial of SAGE-217 in patients with major depressive disorder. N Engl J Med 2019; 381:903–911
19.
Deligiannids KM: Brexanolone and zuranolone clinical data in patients with postpartum depression. Presented at the 28th European Virtual Congress of Psychiatry. European Psychiatry Association; July 4–7, 2020
20.
Sage Therapeutics: Sage Therapeutics announces positive interim, topline zuranolone safety and tolerability data from open-label SHORELINE study in patients with MDD. 2020 (https://investor.sagerx.com/news-releases/news-release-details/sage-therapeutics-announces-positive-interim-topline-zuranolone)

Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 572 - 573

History

Accepted: 1 February 2021
Published in print: June 2021
Published online: 22 June 2021

Keywords

  1. Depressive Disorders
  2. Major Depressive Disorder
  3. Pre/Peri/Postnatal Issues
  4. Mood Disorders-Postpartum
  5. Pharmacotherapy
  6. Drugs-New

Authors

Details

David R. Rubinow, M.D. [email protected]
University of North Carolina School of Medicine, Chapel Hill (Rubinow); Sage Therapeutics, Cambridge, Mass. (Lasser, Kanes).
Robert Lasser, M.D., M.B.A.
University of North Carolina School of Medicine, Chapel Hill (Rubinow); Sage Therapeutics, Cambridge, Mass. (Lasser, Kanes).
Stephen J. Kanes, M.D., Ph.D.
University of North Carolina School of Medicine, Chapel Hill (Rubinow); Sage Therapeutics, Cambridge, Mass. (Lasser, Kanes).

Notes

Send correspondence to Dr. Rubinow ([email protected]).

Competing Interests

Dr. Rubinow has received consulting fees and stock options from Sage. Dr. Lasser and Dr. Kanes are full-time employees of Sage and may hold stock or stock options.

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