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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.
From its inception, international law has been closely linked to philosophy and political theory, and over time competing theoretical approaches have emerged to explain international law’s nature, form, and efficacy. Even today, we associate the most authoritative names in the discipline – whether founders such as Grotius and Vattel or more modern figures ranging from Kelsen and Lauterpacht to contemporary writers such as Chimni, Chinkin, and Koskenniemi – with specific theoretical perspectives that engage foundational questions about international law’s purpose and content.
Every generation of scholars and practitioners reshapes international legal theory as it rethinks international law and its role in international affairs. Two decades ago, the American Journal of International Law (AJIL) published a “Symposium on Methods in International Law.” The AJIL Symposium took place toward the end of the 1990s, during heady times for international law.
Over the past decades international affairs have been increasingly legalized. International law has dramatically expanded into new fields and taken on new challenges. Despite this development, there has been little in-depth scholarship on what impact these changes have had on the field of international legal theory, how it is taught, and where it is going. This volume investigates the major developments in the field and explores the core assumptions and concepts, analytical tools, and key challenges associated with different approaches. An outstanding team of legal academics provides an accessible overview of competing theoretical movements, and a more in-depth understanding of the strengths, preoccupations, insights, and limits of those schools of thought. The contributions provide an authoritative account of current thinking about the theoretical foundations of contemporary international law and will serve as an indispensable resource for students, scholars, and practitioners.