Which antidepressants increase GABA and How Do They Work?

October 10, 2025 •

4 min read

Dysfunction in the GABAergic system is increasingly linked to the pathophysiology of major depressive disorder, with depressed individuals often showing lower levels of $\gamma$-aminobutyric acid (GABA). This has led researchers to investigate which antidepressants increase GABA as part of their therapeutic mechanism, targeting the brain's primary inhibitory neurotransmitter.

Quick Summary

Certain antidepressants modulate GABA, the brain's main inhibitory neurotransmitter. Some SSRIs, ketamine, mirtazapine, and novel neurosteroids alter GABAergic transmission, with mechanisms ranging from indirect effects via serotonin pathways to direct potentiation of GABA-A receptors. This modulation can normalize GABA deficits associated with depression and contribute to mood-regulating effects.

Key Points

SSRIs and GABA: Long-term use of SSRIs like fluoxetine can increase cortical GABA levels, partly through direct GABA-A receptor modulation and indirect effects via serotonin signaling.
Mirtazapine's GABA-Normalizing Effect: This NaSSA has been shown in animal studies to reverse stress-induced decreases in GABA and glutamate concentrations in the hippocampus.
Ketamine's Biphasic GABA Action: Ketamine's rapid antidepressant effect is linked to an initial glutamate surge from GABAergic disinhibition, followed by a sustained increase in GABAergic function and neuroplasticity.
Neurosteroids Directly Potentiate GABA: New antidepressants like brexanolone and zuranolone act as positive allosteric modulators of GABA-A receptors, directly enhancing inhibitory neurotransmission.
Vortioxetine's Indirect GABA Modulation: This multimodal antidepressant modulates GABA indirectly, primarily by antagonizing 5-HT3 receptors on interneurons, leading to the disinhibition of glutamate release.
GABA and Depression Recovery: The normalization of cortical GABA levels is often associated with the remission of depressive symptoms following antidepressant treatment.

The Role of GABA in Mood Disorders

Gamma-aminobutyric acid (GABA) is the brain's primary inhibitory neurotransmitter, responsible for calming neural activity and maintaining a balance with excitatory neurotransmitters like glutamate. Studies using techniques like magnetic resonance spectroscopy have frequently observed reduced GABA levels in the brains of patients with major depressive disorder (MDD) compared to healthy controls. This reduction is thought to disrupt the critical balance between neural excitation and inhibition, which can lead to symptoms of depression and anxiety.

The therapeutic actions of many antidepressant drugs are not solely dependent on modulating monoamines like serotonin and norepinephrine. Growing evidence points to the importance of regulating the GABAergic system. A key finding is that clinical recovery in response to various antidepressant treatments is often associated with the normalization of cortical GABA levels. This has driven research into how different classes of antidepressants interact with GABA, whether directly or indirectly.

Antidepressants That Influence the GABAergic System

Several classes of antidepressants have been shown to modulate GABA, each using a distinct mechanism. This modulation can occur by influencing GABA release, acting directly on GABA receptors, or through downstream effects of their primary mechanisms of action.

SSRIs and their Indirect GABA Modulation

Selective serotonin reuptake inhibitors (SSRIs) primarily increase synaptic serotonin. Long-term use of SSRIs like fluoxetine and citalopram has been shown to increase cortical GABA concentrations in patients with MDD, an effect likely stemming from serotonin's interaction with GABAergic interneurons. Additionally, fluoxetine and its metabolite can directly modulate GABA-A receptors.

Mirtazapine's Modulating Role

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). Animal studies suggest mirtazapine can restore stress-induced decreases in GABA and glutamate levels in the hippocampus, indicating its antidepressant effects involve neurometabolic changes affecting the GABAergic system.

Ketamine's Rapid-Acting GABA Enhancement

Ketamine, an NMDA receptor antagonist, provides rapid antidepressant effects with a complex, biphasic influence on GABA. It initially blocks NMDA receptors on GABAergic interneurons, causing a surge of glutamate. This leads to a sustained increase in GABAergic function and synaptic plasticity, crucial for its lasting antidepressant effects.

Neurosteroids: The Direct GABA Enhancers

Neurosteroid antidepressants, such as brexanolone and zuranolone, act directly as positive allosteric modulators (PAMs) of GABA-A receptors. They enhance the receptor's function, boosting inhibitory neurotransmission rapidly and potently across both synaptic and extrasynaptic receptors.

The Multifaceted Action of Vortioxetine

Vortioxetine's effects on GABA are indirect and complex, involving its impact on serotonin receptors. As a 5-HT3 receptor antagonist, it inhibits GABA release from certain interneurons, leading to a "disinhibition" of glutamatergic neurons and increased glutamate release. This modulation contributes to vortioxetine's effects on cognition and plasticity.

Comparison of Antidepressant Effects on GABA


Antidepressant Class	Primary Mechanism of Action	How it Modulates GABA	Speed of GABA Modulation	Role in Antidepressant Effect
SSRIs (e.g., Fluoxetine, Citalopram)	Increase synaptic serotonin	Indirectly, via serotonin's action on GABA interneurons and direct GABAA receptor modulation (fluoxetine)	Gradual (weeks to months)	Normalizes GABA levels in depressed patients; contributes to therapeutic effects
Mirtazapine (NaSSA)	Blocks $\alpha_2$-adrenergic autoreceptors, blocks 5-HT2 and 5-HT3 receptors	Normalizes stress-induced GABA deficits through neurometabolic changes	Variable; animal studies show effects after chronic stress	Reverses neurochemical changes in chronic stress models
Ketamine (NMDA Antagonist)	Blocks NMDA receptors, primarily on GABA interneurons	Causes initial transient GABA decrease, followed by sustained GABAergic increase	Rapid (within hours), with sustained effects	Sustained increase in GABAergic plasticity is crucial for therapeutic action
Neurosteroids (e.g., Zuranolone, Brexanolone)	Positive Allosteric Modulator of GABA-A receptors	Directly enhances GABA-A receptor function	Rapid (within hours)	Rapidly enhances inhibitory neurotransmission to alleviate symptoms
Vortioxetine (Multimodal)	Serotonin reuptake inhibition, 5-HT receptor modulation	Inhibits GABA release via 5-HT3 antagonism, causing disinhibition	Complex; part of its overall multimodal action	Contributes to effects on cognition and synaptic plasticity

The Future of GABA-Targeted Antidepressants

Targeting GABA directly with neurosteroids represents a significant advance in depression pharmacology, offering potentially rapid and effective treatment options, particularly for severe cases. Ongoing research continues to explore the intricate relationships between neurotransmitters and how time-dependent and circuit-specific effects of antidepressants influence GABAergic transmission. The goal is to develop more targeted therapies by refining our understanding of depression's neurobiological basis. Further research is key to translating these insights into improved clinical outcomes.

Conclusion

The role of GABAergic dysfunction in depression is increasingly recognized. Various antidepressants, including SSRIs, ketamine, mirtazapine, and neurosteroids, modulate GABAergic activity through distinct mechanisms. Whether indirectly via serotonin pathways, by restoring neurometabolic balance, through a biphasic process, or by directly potentiating GABA-A receptors, influencing GABA is a crucial part of their therapeutic effect. Continued research into the GABAergic system holds promise for developing more targeted and effective depression treatments.

Frequently Asked Questions

GABA is the brain's primary inhibitory neurotransmitter, responsible for calming neural activity. An imbalance in GABA, often manifesting as reduced levels in depression, can disrupt the brain's excitatory-inhibitory balance, leading to symptoms like anxiety and low mood.

No, not all antidepressants increase GABA. The relationship is complex and depends on the specific drug and its mechanism. Some, like certain SSRIs, increase GABA levels, while others, like vortioxetine, can modulate it differently, such as inhibiting GABA release from specific interneurons.

The mechanism is not fully understood but appears to be both indirect and direct. Long-term treatment with SSRIs can increase overall cortical GABA levels. In some cases, such as with fluoxetine, there is evidence for a direct positive modulation of GABA-A receptors.

Ketamine has a biphasic effect. It initially blocks NMDA receptors on GABAergic interneurons, causing a burst of excitatory glutamate. This, in turn, leads to a compensatory and sustained increase in GABAergic function, which is critical for its long-term antidepressant action.

Neurosteroid antidepressants are a new class of medication, including brexanolone and zuranolone, that act as positive allosteric modulators of GABA-A receptors. This means they directly enhance the function of these receptors, boosting inhibitory signaling in the brain to provide rapid antidepressant effects.

Mirtazapine's effect on GABA is considered indirect. Animal studies show it can restore GABA levels that were reduced by chronic stress. This is thought to be a downstream effect of its complex mechanism of action, which involves modulating various neurotransmitter receptors.

The apparent contradiction highlights the complexity of neural circuits. While some antidepressants aim to normalize low GABA levels, others target specific interneuron circuits. For example, vortioxetine's inhibition of GABA release from certain interneurons leads to a disinhibition of excitatory glutamate neurons, contributing to its cognitive-enhancing and mood-regulating effects.