Anxiety in Major Depression and Cerebrospinal Fluid Free Gamma-Aminobutyric Acid

Abstract

Background Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems. Methods and Materials Patients with a DSM-IV major depressive episode (N = 167: 130 major depressive disorder; 37 bipolar disorder) and healthy volunteers (N = 38) had CSF free GABA measured by gas chromatography mass spectroscopy. Monoamine metabolites were assayed by high performance liquid chromatography. Symptomatology was assessed by Hamilton depression rating scale. Results Psychic anxiety severity increased with age and correlated with lower CSF free GABA, controlling for age. CSF free GABA declined with age but was not related to depression severity. Other monoamine metabolites correlated positively with CSF GABA but not with psychic anxiety or depression severity. CSF free GABA was lower in MDD compared with bipolar disorder and healthy volunteers. GABA levels did not differ based on a suicide attempt history in mood disorders. Recent exposure to benzodiazepines, but not alcohol or past alcoholism, was associated with a statistical trend for more severe anxiety and lower CSF GABA. Conclusions Lower CSF GABA may explain increasing severity of psychic anxiety in major depression with increasing age. This relationship is not seen with monoamine metabolites, suggesting treatments targeting the GABAergic system should be evaluated in treatment-resistant anxious major depression and in older patients.

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

“…The observed increase in GABA was also seen in nonresponders, suggesting that GABA increase may contribute to the antidepressant mechanism of TMS, but this association was not causal. Levels of GABA are low in the depressed brain, supported by convergent evidence from CSF samples, 25 GABAergic neuronal density 26 and GAD67 expression 27 in postmortem brains. Prior MRS studies revealed GABA reductions in depressed individuals compared with healthy controls, 11,28 with more pronounced MPFC reductions in a treatment-refractory subgroup.…”

Meta-analysis of central and peripheral γ-aminobutyric acid levels in patients with unipolar and bipolar depression

“…Our search identified 45 studies: 26 studies for the comparison of patients with current MDE versus healthy controls, [8][9][10][11][12][13][14][15][16][17][18]30,[33][34][35][36][37][38][39][40][41][42][43][44][45][46] 12 studies for the comparison of patients with current MDE before treatment versus after treatment, 12,20,23,25,26,28,36,43,[47][48][49][50] and 11 for the comparison of euthymic patients and controls. 18,[21][22][23]27,29,38,[51][52][53][54] Figure 1 depicts the study selection proce...…”

Rare variants in neuronal excitability genes influence risk for bipolar disorder

“…GABA A receptors are widely distributed in the brain and are the primary channels through which GABA inhibits the excitability of neurons in the central nervous system (24,25). Abnormalities in GABA function have been postulated for many years in bipolar disorder and are supported by the observation of decreased CSF GABA in bipolar patients (26), as well as alterations in GABA subunit ratios in the postmortem brain (27). Positive allosteric modulators of GABA A receptors (benzodiazepines) are used adjunctively in the treatment of mania, a key aspect of BD.…”