3 results
Zuranolone, a Positive Allosteric Modulator of the GABAA Receptor: Hypothesized Mechanism of Action in Major Depressive Disorder
- Stephen M. Stahl, Rebecca Hammond, Manny Garcia, Simon Kyaga, Mona Kotecha, Mark Pollack, James Doherty
-
- Journal:
- CNS Spectrums / Volume 28 / Issue 2 / April 2023
- Published online by Cambridge University Press:
- 14 April 2023, pp. 260-261
-
- Article
-
- You have access Access
- Export citation
-
Major depressive disorder (MDD) is a heterogeneous condition characterized by depressed mood and/or loss of interest/pleasure in activities, among other symptoms. Most currently available treatments for depression were developed on the hypothesis that depressive symptoms arise from a depletion of monoamines within the central nervous system (CNS). However, clinical understanding has advanced to identify brain network dysregulation as the primary driver of depression, with monoamines playing a lesser role. Prolonged inability to regulate brain networks may lead to the core symptoms and clinical presentation of MDD. Depression has been linked to impaired neuronal activity in brain networks (e.g., central executive network [CEN], default mode network [DMN], and salience network [SN]). It is hypothesized that improvement in depressive symptoms may result from restoring balance in brain networks governing mood.
γ-aminobutyric acid (GABA) is critical for maintaining and restoring excitatory-inhibitory balance in the brain and regulating brain networks. Approximately one-third of neurons in the CNS are GABAergic, regulating network activity throughout the brain, including regions involved in mood, sleep, and cognition. GABA activates GABAA receptors (GABAAR), inhibiting neuronal activity through phasic (via synaptic GABAAR) and tonic (via extrasynaptic GABAAR) currents. Tonic GABA currents may play a particularly important role in regulating network activity, since they produce a large net inhibitory effect and are also involved in controlling the excitability of inhibitory interneurons, the key regulators of rhythmic brain network activity.
Zuranolone is an investigational oral GABAAR positive allosteric modulator and neuroactive steroid. In clinical trials, treatment with zuranolone has shown significant improvement over placebo in depressive symptoms in adults with MDD or postpartum depression, with a generally well-tolerated and consistent safety profile.
The hypothesized mechanism of zuranolone differs from monoamine-based antidepressants and from benzodiazepines. Unlike benzodiazepines, which bind to the α/γ subunit interface in synaptic GABAAR and enhance phasic inhibitory currents, zuranolone binds to the α/β subunit interface present in nearly all GABAAR, leading to enhanced phasic (synaptic) and tonic (extrasynaptic) inhibitory currents. Furthermore, in vitro evidence suggests that whereas benzodiazepines are associated with GABAAR downregulation, zuranolone upregulates the surface expression of GABAAR.
In conclusion, by upregulating GABAAR expression and increasing phasic and tonic inhibitory GABAergic signaling, zuranolone may rapidly restore and maintain excitatory-inhibitory balance in brain networks, thus allowing the brain to potentially respond appropriately to internal and external stimuli.
FundingSage Therapeutics, Inc., and Biogen Inc.
Digital health technologies and major depressive disorder
- Roger S. McIntyre, Walter Greenleaf, Grzegorz Bulaj, Steven T. Taylor, Georgia Mitsi, Dylan Saliu, Andy Czysz, Greg Silvesti, Manny Garcia, Rakesh Jain
-
- Journal:
- CNS Spectrums / Volume 28 / Issue 6 / December 2023
- Published online by Cambridge University Press:
- 12 April 2023, pp. 662-673
-
- Article
-
- You have access Access
- Open access
- HTML
- Export citation
-
There is an urgent need to improve the clinical management of major depressive disorder (MDD), which has become increasingly prevalent over the past two decades. Several gaps and challenges in the awareness, detection, treatment, and monitoring of MDD remain to be addressed. Digital health technologies have demonstrated utility in relation to various health conditions, including MDD. Factors related to the COVID-19 pandemic have accelerated the development of telemedicine, mobile medical apps, and virtual reality apps and have continued to introduce new possibilities across mental health care. Growing access to and acceptance of digital health technologies present opportunities to expand the scope of care and to close gaps in the management of MDD. Digital health technology is rapidly evolving the options for nonclinical support and clinical care for patients with MDD. Iterative efforts to validate and optimize such digital health technologies, including digital therapeutics and digital biomarkers, continue to improve access to and quality of personalized detection, treatment, and monitoring of MDD. The aim of this review is to highlight the existing gaps and challenges in depression management and discuss the current and future landscape of digital health technology as it applies to the challenges faced by patients with MDD and their healthcare providers.
Contributors
-
- By Masoud Azodi, Patricia Baetens, Steven Bayer, Joel Bernstein, Jonathan D. Black, Christophe Blockeel, Carolien M. Boomsma, Birgit Borgström, Mark Bowman, Nicholas Brook, Elisabeth Carlsen, Peter Carne, Ying Cheong, Jen-Ruei Chen, Erin Clark, S. Alberto Dávila Garza, Sunita De Sousa, Michel De Vos, Leo Doherty, Patricio Donoso, Cindy M. P. Duke, Human M. Fatemi, Alison Fernbach, Juan A. Garcia-Velasco, Elizabeth S. Ginsburg, Dorothy A. Greenfeld, William M. Hague, Daniel Hajioff, Tristan Hardy, Catherine Henry, Outi Hovatta, John Hutton, Gordana Ivanovic, Sameer Jatkar, Shilpa Jesudason, Theo Joseph, Amanda Kallen, Sonal Karia, Bala Karunakaran, Jenneke C. Kasius, Ben Kroon, Dimitra Kyrou, Robert Lahoud, Jennifer M Levine, Inge Liebaers, Shane T. Lipskind, Derek Lok, Nick S. Macklon, Manveen (Manny) Mangat, Tom P. Manolitsas, S. McDowell, Cherise Mooy, Mark R. Morton, Andrew Murray, Robert J. Norman, Sara Ornaghi, Israel Ortega, Michael J. Paidas, Evaggelos Papanikolaou, Pasquale Patrizio, Sofie Piessens, Biljana Popovic Todorovic, Luk Rombauts, Katrina Rowan, Denny Sakkas, P. Sanhueza, Kirsten Tryde Schmidt, Mark Teoh, Hammed A. Tijani, Jelena Todorovic, Saioa Torrealday, Herman Tournaye, Geoffrey Trew, W. Verpoest, Veerle Vloeberghs, A. Yazdani
- Edited by Nick S. Macklon, University of Southampton, Human M. Fatemi, Robert J. Norman, University of Adelaide, Pasquale Patrizio
-
- Book:
- Case Studies in Assisted Reproduction
- Published online:
- 05 February 2015
- Print publication:
- 22 January 2015, pp ix-xiv
-
- Chapter
- Export citation