Zuranolone, a Positive Allosteric Modulator of the GABAA Receptor: Hypothesized Mechanism of Action in Major Depressive Disorder. (April 2023)

• Record Type: Journal Article
• Authors: Stahl, Stephen M.; Hammond, Rebecca; Garcia, Manny; Kyaga, Simon; Kotecha, Mona; Pollack, Mark; Doherty, James
• Is Part Of: CNS spectrums. Volume 28:Number 2(2023)
• Page Start: 260
• Page End: 261
• Publication Date: 2023-04
• Subjects: Neuropsychiatry -- Periodicals; Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1017/S1092852923002092
• Languages: English
• ISSNs: 1092-8529

Abstract

Abstract: : 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 (GABAA R), inhibiting neuronal activity through phasic (via synaptic GABAA R) and tonic (via extrasynaptic GABAA R) 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 GABAA R 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 GABAA R and enhance phasic inhibitory currents, zuranolone binds to the α/β subunit interface present in nearly all GABAA R, leading to enhanced phasic (synaptic) and tonic (extrasynaptic) inhibitory currents. Furthermore, in vitro evidence suggests that whereas benzodiazepines are associated with GABAA R downregulation, zuranolone upregulates the surface expression of GABAA R. In conclusion, by upregulating GABAA R 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. Funding: Sage Therapeutics, Inc., and Biogen Inc.