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Patient-Specific Considerations, the GABA Pathway, and New Clinical Trial Data on Neuroactive Steroids in MDD and PPD
Overview
Studies evaluating neuroactive steroid GABAA receptor positive allosteric modulators demonstrate promising results for the treatment of MDD and PPD.
Learning Objectives
After completing this educational activity, you should be able to:
- Highlight the inadequacies of suboptimal depression treatment related to adherence, adverse effects, persistent symptoms/lack of efficacy, polypharmacy, and treatment resistance
- Outline the underlying neurobiology of major depression and postpartum depression, with a focus on the GABAergic system
- Review the clinical trial data for approved and investigational GABAergic neuroactive steroid treatments
Target Audience
Psychiatrists and Psychiatry NP/PAs
Program Description
Major depressive disorder (MDD) and major depressive episode with peripartum onset, commonly referred to as postpartum depression (PPD), are among the most common psychiatric illnesses and are leading contributors to disability and suicide. Standard of care antidepressants are the cornerstone of MDD treatment; however, nonadherence to antidepressants has been widely recognized as one of the reasons for treatment failure in MDD. Delayed response in current therapies can take up to 4 or even 8 weeks for patients to experience therapeutic benefits. Low treatment response rates are seen in a considerable amount of patients, with early-stage treatment-resistant depression (TRD) affecting 50% of patients receiving first-line treatments and 30% developing into substantive TRD. Given these treatment gaps, there is an urgent need to develop novel antidepressants with a faster onset of action and shorter treatment course, which could improve adherence and treatment response rates. The neurobiology of depression is multifactorial, with different pathways converging on the development of the neurocircuit dysfunction characteristic of depression. Neuroactive steroids play an important role in modulating acute and chronic stress via their phasic and tonic inhibitory effects on select GABAA receptors, ultimately modulating neurocircuit function. With clinical recognition of the importance of neurosteroids in the modulation of GABAA signaling pathways, researchers have developed novel neuroactive steroid–based pharmacotherapies that have been tested in clinical studies. Given their rapid onset of action and shorter treatment course, these novel antidepressants have the potential to change the treatment paradigm for MDD and PPD.
J Clin Psychiatry 2023;84(suppl 1):JCP.SG22045SU1C
To cite: Deligiannidis KM, Clayton AH. Patient-specific considerations, the GABA pathway, and new clinical trial data on neuroactive steroids in MDD and PPD. J Clin Psychiatry. 2023;84(suppl 1):JCP.SG22045SU1C
To share: https://doi.org/10.4088/JCP.SG22045SU1C
© Copyright 2023 Physicians Postgraduate Press, Inc.
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Support Statement
Supported by an educational grant from Sage Therapeutics, Inc. and Biogen Inc.
Learning Objective
After completing this educational activity, you should be able to:
- Highlight the inadequacies of suboptimal depression treatment related to adherence, adverse effects, persistent symptoms/lack of efficacy, polypharmacy, and treatment resistance
- Outline the underlying neurobiology of major depression and postpartum depression, with a focus on the GABAergic system
- Review the clinical trial data for approved and investigational GABAergic neuroactive steroid treatments
Release, Review, and Expiration Dates
This CME activity was published in March 2023 and is eligible for AMA PRA Category 1 Credit™ through March 31, 2024.
Statement of Need and Purpose
There is a need to understand the current gaps in care related to major depressive disorder and postpartum depression. The current treatment armamentarium has created nuanced gaps in care that need to be addressed. There is a significant lack of achieved remission in patients who switch from common modality to common modality (SNRI, SSRI, etc.). Older patients who face polypharmacy considerations creates an issue for those prescribed more than one antidepressant medication. In clinical practice, only 60% to 70% of patients receiving treatment for depression ultimately achieve remission following treatment. Moreover, half of patients fail to respond adequately to initial treatment with first-line selective serotonin reuptake inhibitor (SSRI) therapy, and nearly two-thirds do not report adequate remission of depressive symptom. New research related to the GABA pathway has provided compelling evidence that this modality may show promise in treating MDD. There are currently 4 GABA-targeting therapeutics either approved or in development whose data needs to be shared with clinicians.
Unlabeled and Investigational Usage
The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use.
No endorsement of unapproved products or uses is made or implied by coverage of these products or uses.
Please refer to the official prescribing information for each product for discussion of approved indicators, contraindications and warnings.
Review Process
The faculty members agreed to provide a balanced and evidence-based presentation and discussed the topics and CME objectives during the planning sessions. The faculty’s submitted content was validated by CME Institute staff, and the activity was evaluated for accuracy, use of evidence, and fair balance by the Chair and a peer reviewer who is without conflict of interest.
The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.
© Copyright 2023 Physicians Postgraduate Press, Inc.
Faculty Affiliation
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Financial Disclosure
The CME Institute adheres to the Standards for Integrity and Independence in Accredited Continuing Education of the Accreditation Council for Continuing Medical Education (ACCME). Any individuals in a position to control the content of a continuing education activity, including faculty, content developers, reviewers, staff, and others, are required to disclose to learners the presence or absence of any relevant financial relationships with an ACCME-defined ineligible company within the preceding 24 months of the activity. The ACCME defines an “ineligible company” as one whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.
The CME Institute has mitigated all relevant conflicts of interest prior to the commencement of the activity. None of the individuals involved in the content have relevant financial relationships with ineligible companies except the following:
Kristina M. Deligiannidis, MD has received consulting fees from Sage Therapeutics, Brii Biosciences, GH Research Ireland, Neuroscience Software Inc., and Guidepoint; has received grant/research support from Sage Therapeutics and Vorso Corporation; has received honoraria for speaking/teaching with Platform Q Health Education CME and Peer View Institute for Medical Education; and has received travel expenses from Biogen; Anita H. Clayton, MD has stock options with Euthymics and S1 Biopharma and equity interest/stocks in Mediflix LLC.
Marlene P. Freeman, MD, Editor in Chief, Boston, MA, has received research funding from JayMac and Sage; has been a member of the Independent Data Safety and Monitoring Committee for Janssen (Johnson & Johnson), Novartis, and Neurocrine; and has served on advisory boards for Eliem and Sage. As an employee of Massachusetts General Hospital (MGH), Dr Freeman works with the MGH National Pregnancy Registry, which receives funding from Alkermes, Aurobindo, AuroMedics, Johnson & Johnson/Janssen, Otsuka, Sage, Sunovion, Supernus, and Teva, and works with the MGH Clinical Trials Network and Institute, which receives research funding from multiple pharmaceutical companies and the National Institute of Mental Health. Dr Freeman has also received royalties through MGH for the Massachusetts General Hospital Female Reproductive Lifecycle and Hormones Questionnaire.
None of the other planners, reviewers, and CME Institute staff for this educational activity have relevant financial relationships with ineligible companies to disclose. All relevant financial relationships have been mitigated.
Accreditation Statement
The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Credit Designation
The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 1.50 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Note: The American Nurses Credentialing Center (ANCC) and the American Academy of Physician Assistants (AAPA) accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.
To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.
Available Credit
- 1.50 AMA PRA Category 1 Credit™
- 1.50 Participation