GABA_A Receptor Modulators as Emerging Therapeutic Agents for Depressive Disorders

Introduction—Medical Research and Advances in the Treatment of Depression

Overview of Depression

Depression is a prevalent chronic psychiatric disorder encountered in clinical practice and may arise from multiple etiological factors. It is primarily characterized by persistent depressed mood and anhedonia and may also present with sleep disturbances, psychomotor retardation, executive dysfunction, and impaired social functioning. In severe cases, suicidal ideation may occur.¹ Depression is associated with substantial morbidity. It not only impairs daily functioning and quality of life but is also linked to an increased risk of various comorbid medical conditions. Furthermore, depression imposes a significant socioeconomic burden.

Pathogenesis of Depression

The pathogenesis of depression is complex and multifactorial. Environmental exposures, psychological stressors, and genetic susceptibility each contribute to disease development to varying degrees. The heritability of major depressive disorder has been estimated at approximately 30%.² Although depression is widely considered to result from interactions between genetic and environmental factors, the precise underlying mechanisms remain incompletely elucidated. At the molecular and neurobiological levels, the GABAergic deficit hypothesis posits that reduced GABA levels result in depression. Such abnormal changes tend to return to normal after effective antidepressant treatment. Alongside the above hypothesis, other theories can also account for depression pathogenesis. These include the monoamine neurotransmitter and receptor hypothesis, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, impairments in neuroplasticity and brain-derived neurotrophic factor (BDNF) signaling, and the inflammation and cytokine hypothesis.

Current Treatments for Depression

A stepwise and progressive treatment strategy is generally adopted in the management of depression.³ Therapeutic interventions are implemented according to symptom severity and clinical response and may include psychological interventions, pharmacotherapy, and electroconvulsive therapy (ECT).

Pharmacological treatment options include monoamine oxidase inhibitors (MAOIs), which increase synaptic concentrations of monoamine neurotransmitters by inhibiting monoamine oxidase activity. Iproniazid is a representative non-selective, irreversible MAOI. Owing to its non-selective and irreversible inhibition, it is associated with an increased risk of hypertensive crisis. Tricyclic antidepressants (TCAs) represent another major class of antidepressants. These agents inhibit presynaptic norepinephrine and 5-hydroxytryptamine (5-HT) reuptake transporters and antagonize postsynaptic adrenergic α₁ and α₂ receptors as well as histamine H₁ receptors.^4,5 By inhibiting norepinephrine and 5-HT reuptake, TCAs increase synaptic concentrations of these neurotransmitters, thereby alleviating depressive symptoms. However, receptor antagonism contributes to a broad adverse effect profile, which may limit tolerability.^6,7

Selective serotonin reuptake inhibitors (SSRIs) were subsequently developed to improve safety and tolerability. These agents selectively inhibit 5-HT reuptake by blocking the 5-HT transporter, thereby increasing synaptic 5-HT concentrations. Compared with TCAs, SSRIs exhibit lower affinity for adrenergic α₁ and α₂ receptors, histamine H₁ receptors, muscarinic receptors, and dopamine D₂ receptors, resulting in a reduced incidence of certain adverse effects. Fluoxetine is a representative SSRI that remains widely used in the treatment of depression. Nevertheless, adverse effects such as nausea, insomnia, and sexual dysfunction may occur.⁷

More recently, esketamine has been introduced into clinical practice as a novel antidepressant agent. Ketamine was originally developed as a dissociative anesthetic; however, clinical trials have demonstrated that intravenous administration of ketamine at sub-anesthetic doses produces rapid and robust antidepressant effects.⁸

Several mechanistic hypotheses have been proposed. The disinhibition hypothesis posits that ketamine inhibits gamma-aminobutyric acid (GABA)ergic interneurons expressing N-methyl-D-aspartate receptors (NMDARs). This leads to disinhibition of glutamatergic pyramidal neurons and increases in glutamate release. Subsequent activation of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) enhances BDNF release and downstream protein synthesis. These molecular events contribute to the observed antidepressant effects.⁹

Conversely, some experimental studies indicate that ketamine may reverse depressive-like behaviors through activation of GABAergic interneurons.¹⁰ Despite its therapeutic efficacy, ketamine is associated with potential risks. Subanesthetic doses may induce transient elevations in blood pressure and heart rate, whereas higher doses are associated with an increased risk of serious cardiovascular events.¹¹ The identification of ketamine’s rapid antidepressant effects represents a significant advance in the field, facilitating the exploration of novel molecular targets and accelerating the development of next-generation rapid-acting antidepressants.

Antidepressant Effects of GABA_A Receptor Modulators

Stress- and Depression-Induced Neuronal Atrophy and Synapse Loss—Restoration of the GABAergic System as a Potential Novel Approach for Depression

Neuroimaging studies and postmortem analyses have demonstrated that individuals with major depressive disorder exhibit reduced brain volume and decreased neuronal density in the dorsolateral prefrontal cortex (dlPFC), findings that indicate a reduction in synaptic number and functional connectivity within this region.^12,13 Chronic stress has been shown to induce synaptic instability, dendritic atrophy characterized by reduced dendritic length and branching, and decreased dendritic spine density and strength.¹⁴ In addition, chronic stress impairs hippocampal and prefrontal cortex (PFC) function and reduces the expression of AMPARs and NMDARs.¹⁵ These alterations contribute to disruption of the excitatory–inhibitory balance within neural circuits. Consequently, therapeutic strategies for depression have evolved from approaches primarily aimed at modulating neurotransmitter concentrations to interventions focused on restoring synaptic structure and functional plasticity.

Research on ketamine has further emphasized that modulation of excitatory–inhibitory circuit dynamics may represent a promising therapeutic direction. The GABAergic system constitutes the principal inhibitory neurotransmitter system in the human brain. In depressive disorders, reductions in central GABA concentrations have been observed, accompanied by decreased expression of enzymes and proteins involved in GABA synthesis.¹⁶ Restoration of GABAergic neurotransmission may therefore represent a viable therapeutic strategy for the treatment of depression.

GABA Neurotransmission and the Synaptic Restorative Role of BDNF

GABA Neurotransmission

GABA is synthesized through a metabolic pathway commonly referred to as the GABA shunt. In this process, GABA is produced from glutamate derived from the tricarboxylic acid cycle. A portion of the synthesized GABA is released into the synaptic cleft to exert inhibitory neurotransmission, whereas the remaining fraction is converted into succinate and re-enters the tricarboxylic acid cycle.^17,18 Following synaptic release, GABA binds to GABA_ARs and GABABRs located on postsynaptic membranes. Activation of GABA_ARs increases chloride ion conductance, leading to membrane hyperpolarization and reduced neuronal excitability.¹⁸ GABABR activation mediates slower inhibitory signaling through G-protein–coupled mechanisms. Extracellular GABA is subsequently metabolized by GABA transaminase (GABA-T) to succinic semialdehyde, which re-enters the tricarboxylic acid cycle. In addition, GABA undergoes reuptake via specific transporters for reuse. A proportion is taken up by glial cells, where it is metabolized or recycled and subsequently transported back to neurons, thereby re-entering the GABA shunt for resynthesis (Figure 1).^19,20 This tightly regulated cycle maintains inhibitory neurotransmission and excitatory–inhibitory balance within neural circuits.

Figure 1 Synaptic release, receptor activation, reuptake, and metabolic recycling of GABA.

Role of BDNF in Stress and Depression

BDNF-Mediated Neuronal Plasticity and Therapeutic Effects

Neuronal plasticity refers to the capacity of the nervous system to reorganize its structural and functional properties in response to internal or external stimuli.²¹ Depression has been associated with structural and functional abnormalities in neural networks. Structural remodeling and restoration of synaptic connectivity are therefore considered critical for the recovery of normal neural circuit function.²² BDNF exerts its biological effects through two principal receptor systems: the low-affinity p75 neurotrophin receptor and the high-affinity tropomyosin receptor kinase B (TrkB). TrkB receptors exist in multiple isoforms, including the full-length TrkB-FL and the truncated TrkB-T1. Binding of BDNF to TrkB-FL induces receptor phosphorylation and activates three major intracellular signaling cascades: the MAPK/ERK pathway, the PI3K-Akt pathway, and the PLCγ–Ca²⁺ pathway.²³ These pathways collectively regulate synaptic plasticity and excitatory–inhibitory balance (Figure 2).

Figure 2 Intracellular signaling pathways activated by BDNF–TrkB receptor interaction.

(1) PI3K-Akt pathway: Activation of PI3K-Akt signaling interacts with mammalian target of rapamycin and downstream effectors to promote protein synthesis, cellular growth, and survival.²⁴ Antidepressant-like effects of liquiritin have been associated with modulation of this pathway.²⁵ Furthermore, BDNF-induced PI3K-Akt activation enhances dendritic translocation of postsynaptic density protein 95 following NMDA receptor activation, linking this pathway to activity-dependent synaptic potentiation.^26,27

(2) MAPK pathway: TrkB activation initiates a kinase cascade that stimulates the MAPK signaling pathway and produces ERK, which plays a regulatory role in cell proliferation and differentiation.²⁸ BDNF-mediated MAPK signaling has also been shown to regulate AMPA receptor trafficking and dendritic spine delivery in a bidirectional manner.^29,30

(3) PLC pathway: The PLCγ pathway contributes to multiple BDNF-mediated processes, including neuronal differentiation and survival, neurite outgrowth of dopaminergic neurons, phosphorylation of NMDARs and AMPARs, transcriptional regulation of GABA receptors, and facilitation of hippocampal integration and synaptic plasticity.^31–36

TrkB-T1 functions primarily as a dominant-negative receptor by forming heterodimers with TrkB-FL, thereby attenuating canonical BDNF signaling.³⁷ In addition to this inhibitory role, TrkB-T1 has been implicated in BDNF sequestration and intracellular trafficking, neurite outgrowth, cytoskeletal regulation in astrocytes and glioma cells, modulation of Rho GTPase activity, and potential activation of PLCγ and MAPK pathways.^38,39

BDNF exerts neuroprotective and pro-survival effects, including inhibition of apoptosis and promotion of cell survival.⁴⁰ It also plays a central role in synaptic maintenance and function. BDNF enhances excitatory transmission by increasing the amplitude of AMPA receptor-mediated miniature excitatory postsynaptic currents and strengthens inhibitory transmission by increasing the frequency of miniature inhibitory postsynaptic currents and enlarging GABAergic presynaptic terminals.⁴¹ In addition, BDNF promotes dendritic growth and branching, increases synapse number and density, and facilitates synaptic plasticity through modulation of intracellular calcium dynamics, regulation of AMPAR trafficking, facilitation of retrograde signaling, and enhancement of long-term potentiation in the hippocampus and dentate gyrus.^29,42–46 Collectively, these mechanisms support the role of BDNF as a critical mediator of synaptic restoration and plasticity in depressive disorders and highlight its potential as a disease-modifying therapeutic target.

Antidepressant Effects of GABA_A Receptor Modulators

Pharmacological Actions of GABA_A Receptor Modulators

GABA_A Receptors

GABA_A receptors (GABA_ARs) are ligand-gated ion channel receptors activated by GABA. Structurally, GABA_ARs are pentameric ligand-gated ion channels composed of five subunits arranged around a central chloride-conducting pore. These receptors are encoded by a family of 19 homologous genes, categorized into subunit classes based on sequence homology: α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–3. Most native GABA_ARs are assembled from two α subunits, two β subunits, and either one γ or one δ subunit, forming heteropentameric receptor subtypes.^17,47 The regional distribution, synaptic versus extrasynaptic localization, pharmacological profile, and physiological properties of GABA_ARs are determined by their specific subunit composition (see Table 1).^48–65 Variations in subunit assembly contribute to functional heterogeneity across brain regions.

Table 1 Subunit Composition, Functional Diversity, and Regional Distribution of GABAAR Subtypes

Function of GABA_ARs and Their Relationship with Depression

The GABAergic deficit hypothesis of depression posits that reduced inhibitory neurotransmission contributes to the pathophysiology of depressive disorders and that restoration of GABAergic function is associated with therapeutic improvement.

Preclinical studies provide supporting evidence for this hypothesis. Deletion of the γ2 subunit in mice induces depressive-like phenotypes. Heterozygous (γ2⁺/⁻) mice exhibit anxiety- and depression-like behaviors in behavioral paradigms, accompanied by hyperactivity of the HPA axis.⁶⁶ Elevated glucocorticoid levels associated with HPA axis activation further reduce GABA_AR expression in forebrain regions, particularly in the frontal cortex and ventral hippocampus.^67,68

Chronic stress has been shown to induce loss of hippocampal interneurons, and γ2 subunit deficiency exacerbates this process. This interaction establishes a reciprocal cycle of GABAergic dysfunction and HPA axis hyperactivity, resulting in progressive impairment of hippocampal function. Moreover, increased HPA axis activity may influence responsiveness to antidepressant treatment. γ2⁺/⁻ mice demonstrate a significantly attenuated response to fluoxetine compared with desipramine, indicating that altered GABA_AR function may modulate pharmacological sensitivity.^66,69

Deletion of the γ2 subunit also markedly reduces hippocampal neurogenesis, neuronal maturation, differentiation, and survival, thereby increasing vulnerability to anxiety- and mood-related phenotypes and reducing resilience under conditions of chronic stress.^70,71 Importantly, the γ2 subunit constitutes a critical binding site for benzodiazepines (BZDs). Its deletion substantially decreases benzodiazepine binding site availability, thereby directly influencing the pharmacodynamic efficacy of BZD-related agents.⁷²

Specific α subunits of GABA_ARs have been implicated in the regulation of depression-related behaviors. The α3 subunit is expressed in monoaminergic neurons and primarily mediates GABAergic inhibition of dopaminergic, serotonergic (5-HT), and noradrenergic systems.⁷³ Mice with complete deletion of the α3 subunit (α3⁻/⁻) demonstrate increased active swimming time in the forced swim test (FST), a finding generally interpreted as reflecting reduced behavioral despair.⁷⁴ GABA_ARs containing the α2 subunit are considered to play a critical role in affective regulation, as these receptors are highly expressed in limbic regions, including the amygdala, hippocampus, and nucleus accumbens,^75,76 which are central to emotional processing and implicated in the pathophysiology of depression.^77,78

Studies using α2 heterozygous (α2⁺/⁻) and homozygous knockout (α2⁻/⁻) mice and comparing their behavior with wild-type littermates in the novelty suppressed feeding test, FST, and tail suspension test have demonstrated that α2⁻/⁻ mice exhibit increased behavioral despair, indicating that the α2 subunit serves as an important regulator of anxiety- and depression-related behaviors within the GABAergic system.⁷⁷ The α5 subunit primarily contributes to synaptic plasticity, cognition, and memory and has been associated with depression, aging, and cognitive impairment; it is also a key determinant of dendritic inhibition.⁷⁹ α5-containing GABA_ARs are localized on the dendrites of pyramidal neurons apposed to somatostatin-expressing interneurons (SST interneurons), predominantly within the middle and deep layers of the hippocampus and frontal cortex.⁸⁰

Reduced expression of SST and related markers has been reported in postmortem brain tissue from individuals with depression, schizophrenia, bipolar disorder, and Alzheimer’s disease. Notably, the affected regions overlap with those enriched in α5-containing GABA_ARs.^81,82 Experimental evidence further demonstrates that decreased SST expression or impaired SST interneuron function induces anxiety- and depression-like phenotypes as well as cognitive deficits,^83–85 whereas enhancement of SST interneuron activity produces antidepressant-like effects.^86,87 These findings suggest that the α5 subunit may represent a potential therapeutic target for depression.

Moreover, the α5 subunit interacts with multiple other GABA_AR subunits; for example, the β3 subunit frequently co-assembles with α5, and regions exhibiting high β3 expression in the hippocampus also demonstrate elevated α5 expression.⁸⁸ α5-containing GABA_ARs may also form heteropentameric assemblies with α1 and α2 subunits. In mixed α subunit-containing receptors, preferential assembly of α5 with γ2 has been observed, generating benzodiazepine binding sites characterized by α5-specific pharmacological properties. Therefore, pharmacological modulation of the α5 subunit may exert antidepressant effects through subunit-specific interactions and the pharmacological modulation of α5-containing GABA_ARs using selective positive or negative allosteric modulators.^79,89

The β subunits play a critical role in the assembly and functional regulation of GABA_ARs and are essential for conferring receptor biological activity.⁸⁹ Among these, the β3 subunit is of particular importance.

First, β3 is required for the assembly of functional GABA_ARs and serves as a key determinant of inhibitory transmission in the hippocampus; deletion of the β3 subunit markedly reduces inhibitory synaptic function, whereas deletion of β1 or β2 produces no significant alterations.

Second, the β3 subunit preferentially co-assembles with α2 and α3 subunits, thereby contributing to the modulation of anxiety- and depression-related behaviors.^89–91 Experimental evidence indicates that propofol selectively targets β3-containing GABA_ARs and attenuates anxiety-like behaviors by inhibiting corticotropin-releasing hormone neuron activity within the paraventricular nucleus of the hypothalamus.⁹²

These findings indicate an association between the β3 subunit and anxiety-related phenotypes and suggest that pharmacological targeting of β3-containing GABA_ARs to enhance GABAergic transmission may mitigate anxiety symptoms.

GABA_ARs containing the δ subunit and postpartum depression: GABA_ARs containing the δ subunit have been implicated in the pathophysiology of postpartum depression. Mice lacking the δ subunit display postpartum depression–like behaviors, whereas wild-type mice exhibit either no significant behavioral alterations or comparatively milder depressive-like phenotypes following parturition.⁹³ It has been proposed that these behavioral changes are associated with fluctuations in central neurosteroid concentrations occurring before and after delivery.⁹⁴ Collectively, these findings support a significant association between δ subunit–containing GABA_ARs and vulnerability to postpartum depression.

Positive Allosteric Modulators of GABA_ARs

Positive allosteric modulators (PAMs) of GABA_ARs comprise a class of agents that enhance receptor activity in the presence of GABA. This group includes BZDs, barbiturates, neuroactive steroids, and general anesthetics such as etomidate. The selectivity, efficacy, and pharmacodynamic properties of PAMs are closely influenced by the specific GABA_AR subunits to which they bind. As presented in Table 2, different GABA_AR modulators interact with distinct receptor interfaces, resulting in diverse pharmacological effects.^90,95–103 Figure 3 presents the binding sites of commonly used modulators.

Table 2 Receptor Binding Interfaces and Pharmacodynamic Profiles of GABAAR Agonists

Figure 3 Subunit-specific binding sites and allosteric modulation of GABAAR modulators.

Effects of GABA_ARs and Their Modulators in Patients with Depression

The functional properties of GABA_ARs are highly dependent on receptor subtype composition.¹⁰⁴ Distinct subtypes are associated with different therapeutic profiles in depression. Accordingly, GABA_AR modulators are categorized in this review based on subtype selectivity, and representative agents from each category are discussed.

Modulators Targeting α Subunits—BZD and Others

BZDs are GABA_AR PAMs that bind at the α⁺/γ⁻ subunit interface, with the γ subunit being essential for binding and subtype selectivity.¹⁷ As the γ2 subunit is widely expressed across GABA_AR subtypes, BZDs generally exhibit limited subtype selectivity. Clinically, BZDs are widely used as anxiolytics but are not typically regarded as primary antidepressant agents.⁹⁴ However, certain BZDs, such as alprazolam and adinazolam, have demonstrated antidepressant-like effects comparable to or exceeding those of conventional antidepressants, potentially through preferential modulation of α2-containing GABA_ARs.⁹⁴

Current evidence indicates that BZDs enhance chloride ion conductance by binding to the α⁺/γ⁻ interface, thereby potentiating GABA-mediated inhibitory neurotransmission.¹⁰⁵ Nevertheless, several limitations restrict their use. BZDs require the presence of GABA for activity and are ineffective in its absence. In addition, long-term use is associated with adverse effects, including cognitive impairment tolerance, dependence, and withdrawal symptoms.^106,107 Consequently, BZDs are infrequently used as primary antidepressant therapies.

α2 subunit–selective modulator—TPA023: Activates targeting α2-containing GABA_ARs are of particular interest given the established association between the α2 subunit and affective regulation. Although no agent demonstrates complete subtype specificity, compounds with relative selectivity may offer therapeutic advantages. TPA023 is a selective modulator with preferential activity at α2/α3 subtypes. Its modulation of α2/α3-containing receptors mediates anxiolytic effects, while its low intrinsic activity at α1-containing receptors minimizes sedative effects and reduces the risk of α1-associated adverse outcomes, including dependence liability.^102,108,109 The favorable pharmacological profile and relatively mild adverse effect spectrum of TPA023 suggest potential utility as a novel antidepressant candidate.

Bidirectional pharmacological modulation of α5-GABA_ARs for antidepressant effects: Selective targeting of α5-containing GABA_ARs has also demonstrated antidepressant potential. α5-selective PAMs, such as GL-II-73, retain anxiolytic properties similar to those of BZDs while additionally exhibiting pro-cognitive effects in models of acute stress, chronic stress, and aging-related memory impairment.^79,110 Conversely, α5-selective negative allosteric modulators (NAMs) have also demonstrated antidepressant-like effects. The proposed mechanism appears to involve modulation of glutamatergic neurotransmission, in a manner analogous to that of ketamine.¹¹¹

Modulators Targeting β Subunits—Etomidate and Propofol

Numerous anesthetic agents enhance GABA_AR-mediated inhibitory neurotransmission through direct interaction with receptor subunits, particularly intravenous anesthetics such as etomidate and propofol, as well as neuroactive steroid anesthetics.^112–114

Etomidate and propofol function as GABA_AR positive allosteric modulators with preferential activity at receptors containing the β3 subunit. Etomidate selectively modulates GABA_ARs incorporating β2 or β3 subunits, thereby enhancing inhibitory synaptic transmission.^47,100 In addition, etomidate exerts suppressive effects on HPA axis activity. The β subunits are essential for GABAAR assembly and stability, and the β3 subunit plays a central role in maintaining inhibitory transmission within the hippocampus, a region closely implicated in the pathophysiology of depression.

Although direct antidepressant effects of etomidate alone have not been extensively reported, propofol has demonstrated antidepressant-like properties in preclinical models. Its mechanism of action is pharmacologically similar to that of etomidate. In mice exposed to chronic unpredictable mild stress, propofol administration reduces depressive-like behaviors, supporting its antidepressant potential.¹¹⁵ Both etomidate and propofol are widely used as anesthetic agents for induction during ECT. Comparative studies indicate that etomidate may provide superior therapeutic outcomes compared with propofol in the context of ECT, potentially due to distinct pharmacodynamic characteristics.^{100,116–118}

Evidence indicates that etomidate may enhance the therapeutic efficacy of ECT through modulation of BDNF. BDNF regulates the expression of nuclear factor erythroid 2–related factor 2 (Nrf2) in astrocytes.¹¹⁹ Experimental findings demonstrate that ECT alleviates depressive-like behaviors in chronic unpredictable mild stress (CUMS) models by activating the BDNF/Nrf2 signaling pathway, thereby reducing ferroptosis in hippocampal neurons. Etomidate has been demonstrated to augment the antidepressant effects of ECT by upregulating BDNF/Nrf2 signaling and inhibiting hippocampal neuronal ferroptosis.¹¹⁷ These observations suggest that etomidate may exert adjunctive antidepressant effects through modulation of BDNF-dependent neuroprotective pathways.

Modulators Targeting Multiple Subunits—Neurosteroids

Neurosteroids are steroids synthesized within the central nervous system that regulate neuronal excitability through rapid, non-genomic mechanisms.¹²⁰ They are primarily produced locally in the hippocampus and other brain regions. Based on structural characteristics, neurosteroids are broadly classified into pregnane neurosteroids (eg., allopregnanolone, APα) and sulfated neurosteroids (Table 3). These compounds have long been recognized for their sedative, anesthetic, and anticonvulsant properties in both animal models and humans. Their biological effects involve multiple mechanisms, including modulation of GABAARs, regulation of glutamatergic neurotransmission, and influence on synaptic plasticity.¹²¹

Table 3 Molecular Targets and Pharmacological Actions of Neurosteroids in the Central Nervous System

With respect to GABA_ARs, neurosteroids may function as either positive or negative allosteric modulators, depending on their molecular structure. Pregnane neurosteroids such as APα act as potent positive modulators of GABA_ARs, whereas sulfated neurosteroids generally function as negative modulators.^103,122 The magnitude and direction of neurosteroid effects are influenced by GABA_AR subunit composition; specific α and γ subunits modulate efficacy and potency, and receptors containing the δ subunit demonstrate particular sensitivity to neurosteroid-induced potentiation of GABA responses.^123–125

Although the δ subunit does not constitute part of the canonical neurosteroid binding site, its presence enhances functional responses following ligand binding. Certain neurosteroids, including pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), also positively modulate NMDA-type glutamate receptors.¹²⁶

Neurosteroids have demonstrated significant antidepressant effects through mechanisms involving modulation of the GABAergic and glutamatergic systems, regulation of BDNF signaling, anti-inflammatory activity, and normalization of HPA axis dysregulation. Direct administration of APα alleviates depressive-like behaviors in animal models of depression, and PS and DHEAS have demonstrated antidepressant effects in both preclinical and clinical studies.^127–130

Neurosteroids exhibit particularly pronounced therapeutic effects in postpartum depression, likely related to their modulation of δ subunit–containing GABA_ARs, which are strongly implicated in this condition. Neurosteroid-based therapeutics, including brexanolone and zuranolone, have been developed and approved for the treatment of postpartum depression.¹³¹ Although mechanistic investigations have largely focused on GABA_AR and NMDAR modulation, increasing evidence indicates that synaptic plasticity is a critical mediator of their antidepressant efficacy.

Neurosteroids regulate BDNF expression and contribute to neuronal protection and regeneration.¹³² Experimental findings indicate that APα increases BDNF levels in the hippocampus and amygdala, potentially through GABA_AR-dependent mechanisms¹³³ (Figure 4). In immature neurons, APα induces depolarization via GABA_AR-mediated activation of voltage-gated L-type Ca²⁺ channels, resulting in altered chloride flux and increased intracellular Ca²⁺ signaling. Elevated Ca²⁺ levels may activate and phosphorylate calcium/calmodulin-dependent protein kinase II (CaMKII), thereby promoting transcription factor activation and increasing BDNF expression, ultimately supporting synaptic plasticity.^134–136

Figure 4 Molecular mechanisms underlying the antidepressant effects of allopregnanolone (APα).

Additional evidence indicates that estradiol enhances BDNF expression in the mouse brain, promoting synaptogenesis and neuronal plasticity.¹³⁷ Administration of progesterone has also been demonstrated to produce antidepressant-like effects; however, inhibition of its conversion to APα markedly attenuates these effects, indicating that APα mediates the primary antidepressant activity. The anti-inflammatory properties of neurosteroids further contribute to their effects on synaptic function.¹³²

Exogenous APα inhibits lipopolysaccharide (LPS)-induced pro-inflammatory responses by preventing activation of Toll-like receptor 4 (TLR4) and suppressing signaling through MyD88-dependent TLR pathways, including TLR7 and TLR2.^138,139 These actions preserve hippocampal neuronal viability and reduce inflammation-associated neural injury.¹⁴⁰ Moreover, APα suppresses HPA axis hyperactivity, thereby facilitating regulation of acute stress responses, stabilizing BDNF expression, and protecting hippocampal neurons.^121,141 Collectively, the multifaceted mechanisms of neurosteroids underscore their therapeutic potential as novel and broadly applicable antidepressant agents.

Summary and Perspectives

With the continued advancement of research on depression, therapeutic approaches have progressively shifted toward precision medicine. This review has examined the therapeutic potential of GABA_AR modulators in depressive disorders. Owing to their complex pentameric structure and diverse subunit composition, GABA_ARs exhibit substantial functional heterogeneity. Conventional GABA_AR modulators generally lack subunit selectivity, which may contribute to a broad spectrum of adverse effects. Accordingly, the development of subunit-selective GABA_AR modulators represents a promising strategy for next-generation antidepressant therapies. Several representative selective GABA_AR modulators have been discussed, and their pharmacological mechanisms and therapeutic profiles have been summarized.

Although neurosteroid-based agents have already been used in the treatment of postpartum depression, the broader clinical application of GABA_AR-targeting compounds in depressive disorders remains an area of considerable potential. Furthermore, investigation of GABA_AR modulators should extend beyond receptor-level mechanisms alone. Multiple agents, including etomidate and neurosteroid-based compounds, have been demonstrated to regulate BDNF expression.¹¹⁷ Given the functional interplay between the GABAergic system and BDNF signaling, pharmacological agents with multimodal mechanisms may offer a rational and promising direction for the development of future rapid-acting antidepressants.