Do Antidepressants Increase GABA? A Pharmacological Deep Dive

October 10, 2025 •

3 min read

Studies show that about 50 out of 100 people taking antidepressants notice an improvement in symptoms [1.10.2]. While often associated with serotonin, the question remains: Do antidepressants increase GABA, the brain's main calming neurotransmitter? The answer is more complex than a simple yes or no.

Quick Summary

Evidence suggests that while traditional antidepressants like SSRIs don't directly target GABA receptors, their long-term use is associated with increased GABA concentrations in the brain, potentially normalizing deficits found in depression [1.2.2, 1.4.1].

Key Points

Indirect Action: Traditional antidepressants like SSRIs don't directly target GABA receptors but have been shown to increase brain GABA concentrations over time [1.4.1].
Normalization Effect: SSRI treatment can normalize the low GABA levels commonly observed in patients with major depression [1.4.1, 1.9.4].
GABA and Depression: Low levels of GABA, the brain's main inhibitory neurotransmitter, are strongly associated with major depressive disorder [1.6.1].
Different from Benzodiazepines: Unlike benzodiazepines that enhance GABA's effects directly and rapidly, antidepressants cause a slow, indirect modulation of the GABA system [1.8.1, 1.2.1].
Long-Term Changes: Chronic antidepressant use can alter the expression and function of GABAB receptors, suggesting a fundamental remodeling of the GABA system [1.9.1].
New Drug Targets: The link between GABA and depression has led to the development of new drugs, like neuroactive steroids, that directly target GABA receptors [1.5.4].
Delayed Onset Explained: The indirect effect on the GABA system may help explain why antidepressants often take several weeks to become fully effective [1.2.1].

The Role of GABA in Mental Health

Gamma-aminobutyric acid, or GABA, is the primary inhibitory neurotransmitter in the central nervous system [1.8.1]. Its main function is to decrease neuronal excitability, producing a calming effect [1.6.1]. Research has consistently shown that individuals with major depressive disorder (MDD) and anxiety disorders often have lower levels of GABA in their brains [1.6.1, 1.6.5]. This deficit is linked to the hyperactivity in certain brain regions and contributes to symptoms of depression, anxiety, and stress [1.6.2]. The GABAergic system's role in mood regulation has made it a significant area of interest for developing new antidepressant therapies [1.6.3].

How Do Traditional Antidepressants Work?

Most mainstream antidepressants, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), are designed to work by increasing the levels of monoamine neurotransmitters like serotonin in the brain [1.8.2]. They block the reabsorption (reuptake) of serotonin into neurons, making more of it available to improve communication between them. While this is their primary mechanism, their therapeutic effects often take weeks to manifest, suggesting a more complex, indirect downstream process is at play [1.2.1]. It is this delayed action that has led researchers to investigate their effects on other neurotransmitter systems, including GABA.

The Indirect Link: Do Antidepressants Increase GABA?

The direct answer is that most common antidepressants, like SSRIs, do not directly bind to or agonize GABA receptors in the same way that drugs like benzodiazepines do [1.8.2]. However, the evidence strongly points to an indirect and significant long-term effect. Multiple studies have shown that chronic treatment with antidepressants leads to changes in the GABA system.

Increased GABA Concentrations: A key study using magnetic resonance spectroscopy (MRS) found a significant increase in occipital cortex GABA concentrations in depressed patients after an average of two months of SSRI treatment [1.4.1, 1.9.4]. This effect appears to normalize the low pretreatment GABA levels often seen in depression [1.4.1]. Another study confirmed this, showing that even acute administration of an SSRI could increase brain GABA concentrations, suggesting the effect is a direct action of the drug, not just a secondary consequence of mood improvement [1.4.2].
Changes in Receptor Function: Long-term administration of various classes of antidepressants has been shown to increase the expression of specific GABAB receptor subunits in the hippocampus [1.9.1]. This enhancement suggests that a core component of antidepressant response involves modifying and potentially repairing the GABA system [1.9.1]. The current hypothesis is that antidepressants ultimately act by enhancing the function of GABA-releasing interneurons, helping to restore a healthy balance of brain activity [1.2.1].

Comparison: Antidepressants vs. Benzodiazepines

While both medication classes can be used in treating conditions with GABA deficits, their mechanisms and effects are distinct.


Feature	Antidepressants (SSRIs/SNRIs)	Benzodiazepines
Primary Target	Primarily affect serotonin and/or norepinephrine reuptake [1.8.2].	Act as positive allosteric modulators at GABA-A receptors [1.8.1].
Effect on GABA	Indirectly increase GABA concentrations and alter receptor function over time [1.4.1, 1.9.1].	Directly enhance the effect of GABA, providing immediate calming [1.8.1].
Onset of Action	Slow, typically takes several weeks for full therapeutic effect [1.2.1].	Rapid, improving anxiety symptoms quickly [1.8.1].
Long-Term Use	Considered first-line for chronic treatment of depression and anxiety [1.8.2].	Not recommended for long-term use due to risks of dependence, tolerance, and withdrawal [1.8.1].
Primary Use Case	Major Depressive Disorder, Anxiety Disorders [1.10.4].	Short-term management of severe anxiety, panic attacks, insomnia [1.8.1, 1.8.2].

Newer and Emerging GABA-Centric Treatments

Recognizing the GABA deficit in depression has spurred the development of new drugs that target this system more directly. Neuroactive steroids (NASs) that act as positive allosteric modulators (PAMs) of GABAA receptors are a promising new class of treatment [1.3.3]. For instance, brexanolone is an intravenous NAS approved for postpartum depression, and other oral medications like zuranolone are in development for MDD [1.5.4]. These treatments represent a shift toward directly addressing the underlying GABAergic dysfunction in depression [1.6.3].

Conclusion

While traditional antidepressants do not directly and immediately boost GABA in the way benzodiazepines do, extensive research demonstrates that they do increase GABA concentrations and improve GABAergic function over the long term [1.4.1, 1.9.1]. This effect appears to be a crucial part of their therapeutic mechanism, helping to normalize the GABA deficits found in people with depression [1.3.4, 1.4.1]. The prevailing theory is that by modulating serotonin, these drugs trigger a cascade of downstream effects that ultimately repair and enhance the brain's primary inhibitory system. As our understanding evolves, a new generation of antidepressants is emerging that targets the GABA system directly, offering new hope for treating major depressive disorder. For more in-depth scientific information, see the Nature article on the mechanism of neuroactive steroids.

Frequently Asked Questions

Studies show that SSRI treatment is associated with a significant increase in GABA concentrations in the brain, particularly in the occipital cortex. This appears to normalize the lower levels often found in individuals with depression [1.4.1, 1.2.2].

Most common antidepressants (like SSRIs) do not work directly on GABA receptors. However, their long-term use influences the GABA system indirectly [1.2.1]. Newer treatments for depression, such as Brexanolone and Zuranolone, are designed to work directly as positive allosteric modulators of GABAA receptors [1.5.4].

Benzodiazepines directly bind to GABA-A receptors to enhance GABA's inhibitory effects, leading to rapid calming [1.8.1]. Most antidepressants do not act on GABA receptors directly; instead, they slowly and indirectly cause an increase in brain GABA levels over weeks of treatment [1.2.1, 1.4.1].

Research suggests a strong connection. Deficits in the GABA system and reduced GABA levels are considered a core part of the pathophysiology of major depressive disorder, contributing to an imbalance of brain activity [1.6.1, 1.3.4].

Certain activities and foods may help support GABA production. Practices like yoga and meditation have been shown to increase GABA levels [1.7.3]. Foods rich in GABA or its precursors include fermented foods, spinach, tomatoes, mushrooms, and green tea [1.7.2].

While some studies show changes after acute administration [1.4.2], significant increases in GABA concentrations that correlate with therapeutic effects are typically observed after several weeks to two months of consistent treatment [1.4.1].

Yes, studies indicate that fluoxetine, an SSRI, interacts with the GABA system. Chronic treatment can modify GABA receptor function and expression [1.9.1]. At certain concentrations, it can enhance GABA-stimulated chloride uptake, though its primary mechanism remains serotonin reuptake inhibition [1.5.5].