Is GABA (Gamma-Aminobutyric Acid) dysfunction associated with the pathophysiology of bipolar disorder?

GABA Dysregulation in Bipolar Disorder

Yes, GABA (gamma-aminobutyric acid) dysregulation is strongly associated with the pathophysiology of bipolar disorder, with multiple lines of evidence demonstrating both elevated brain GABA levels and altered GABA receptor expression in affected individuals.

Evidence for GABA Abnormalities

Elevated Brain GABA Levels

• Euthymic bipolar patients demonstrate significantly elevated GABA/creatine ratios compared to healthy controls, with a 25.1% elevation in the anterior cingulate cortex and 14.6% elevation in the parieto-occipital cortex 1
• These elevations are more pronounced in bipolar patients not taking GABA-modulating medications, suggesting that mood stabilizers may partially normalize these abnormalities 1
• The elevated GABA levels appear to reflect GABAergic dysfunction rather than enhanced inhibitory tone, potentially contributing to impaired neural oscillations during cognitive processing 1

Peripheral GABA Markers

• Low plasma GABA is found in 30-40% of bipolar patients during both manic and depressed phases, indicating this is a trait marker rather than state-dependent 2
• Plasma GABA serves as an index of brain GABA activity and represents a shared biological correlate between bipolar and unipolar mood disorders 2

GABA Receptor Alterations

• Multiple GABA receptor subunits show significant dysregulation in bipolar disorder, including altered protein expression of GABAA receptor subunits (α1, α2, α6, β1, β3, δ, ε, π) and GABAB receptor subunits (R1, R2) in the superior frontal cortex 3
• The lateral cerebellum shows significantly altered expression of GABAA α2-, β1-, and ε-receptor subunits in bipolar patients 4
• These alterations in receptor stoichiometry can result in abnormal ligand binding, transmission, and pharmacology of GABA receptors 3

Clinical Implications

Impact on Symptoms

• Impaired GABAergic transmission may contribute to anxiety, panic symptoms, and disrupted learning and information processing commonly seen in bipolar disorder 3
• The GABAergic dysfunction likely contributes to impaired gamma oscillations that normally occur during cognitive processing 3

Treatment Considerations

• GABA-modulating medications (such as valproate and other mood stabilizers) appear to reduce elevated brain GABA levels in bipolar disorder 1
• The American Academy of Child and Adolescent Psychiatry recommends mood stabilizers (lithium, valproate, lamotrigine) and atypical antipsychotics as first-line treatments for bipolar disorder, many of which have GABAergic effects 5
• Neurosteroids that promote GABA modulation represent potential future therapeutic avenues for addressing GABAergic dysfunction 4

Important Caveats

• One study found no significant differences in whole brain GABA levels between bipolar patients and controls, though this may reflect methodological differences or the effects of medication status 6
• The relationship between elevated brain GABA and low plasma GABA remains incompletely understood, suggesting complex compartmentalization or regulatory mechanisms 1, 2
• Most research has been conducted in medicated patients, making it difficult to separate primary disease pathology from medication effects 1