Gamma-aminobutyric acid (GABA) and glutamate are implicated in the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS), though findings from magnetic resonance spectroscopy (MRS) are inconsistent. Furthermore, the relationship between GABAA-receptor availability and rTMS outcomes remains largely unexplored. In this study, GABA and glutamate levels in the dorsal anterior cingulate cortex (dACC) were measured using a 1H-MRS MEGA-PRESS sequence in 42 patients with bipolar or unipolar depression, both before and after a sham-controlled, double-blind clinical trial involving intermittent theta-burst stimulation (iTBS) over the dorsomedial prefrontal cortex. A subset of 28 patients also underwent [11C]flumazenil positron emission tomography (PET) to measure whole-brain GABAA-receptor availability and mean receptor availability in the nucleus accumbens and dACC. Depressive symptoms were assessed using the self-rated Montgomery Åsberg Depression Rating Scale (MADRS-S). The results indicated no significant changes in neurotransmitter levels or GABAA-receptor availability post-iTBS in either the active or sham conditions. However, changes in MADRS-S scores after active iTBS were positively correlated with changes in GABA levels in the dACC (r(13) = 0.54, p = 0.04) and baseline GABAA-receptor availability in the nucleus accumbens (r(11) = 0.66, p = 0.02). These correlations were absent in the sham group. The findings suggest that a reduction in GABA within targeted frontostriatal circuits can be part of the antidepressant mechanism of iTBS, challenging previous research. Additionally, they indicate a potential predictive role for frontostriatal GABAA-receptor availability in the treatment of depression using dorsomedial prefrontal iTBS.

Altered cortical excitability is reported in schizophrenia and depression, but findings are inconsistent. Prefrontal repetitive transcranial magnetic stimulation (TMS) induces short-term motor cortex excitability changes in healthy individuals, but its effect in schizophrenia and depression remains unexplored. Prefrontal intermittent theta burst stimulation (iTBS) improves negative symptoms in depression. Cortical excitability is a suggested biomarker for prefrontal iTBS response. We investigated if prefrontal iTBS affects motor cortex excitability in schizophrenia or depression. Secondary aims were to examine motor cortex excitability as a predictor of iTBS effect on negative symptoms in depression and to compare excitability between groups with schizophrenia, depression and healthy controls. TMS indices of cortical excitability − resting motor threshold, short-interval intracortical inhibition, intracortical facilitation and long-interval intracortical inhibition (LICI) − were pooled from previous studies, including an RCT evaluating iTBS for negative symptoms. The dataset comprised 44 patients with schizophrenia, 52 with depression, and 62 healthy controls. Regression models indicated no effect of active versus sham iTBS on any TMS index (all p ≥ .61). No baseline TMS index predicted negative symptom changes after iTBS in depression (all p ≥ .44). Patients with schizophrenia exhibited more pronounced LICI inhibition than the other groups (Mann-Whitney U = 1670, p < .001). LICI correlated with antipsychotic dose (Spearman's ρ = −0.28, p = .04). Prefrontal iTBS does not modify cortical excitability in schizophrenia or depression, nor does cortical excitability predict prefrontal iTBS effects on negative symptoms. The more pronounced LICI inhibition in schizophrenia may be related to the illness or medication.

INTRODUCTION: Gamma-aminobutyric acid (GABA) deficiency is suggested in depressive disorders, along with alterations in cortical excitability. However, whether these excitability changes are related to GABAA receptor availability is largely unknown. Our aim was to assess the correlation between these measures in depressed patients and healthy controls.

METHODS: Twenty-eight patients with a major depressive episode, measured before and after participating in a clinical trial with repetitive transcranial magnetic stimulation (TMS), and 15 controls underwent [11C]flumazenil positron emission tomography to assess GABAA receptor availability and paired pulse TMS (ppTMS) to evaluate cortical excitability. Both whole-brain voxel-wise GABAA receptor availability and mean values from left hand motor cortex and left paracentral lobule were correlated to the ppTMS outcomes: short-interval intracortical inhibition reflecting GABAA receptor activity, long-interval intracortical inhibition representing GABAB receptor activity, intracortical facilitation reflecting glutamate N-methyl-D-aspartate-receptor activity, as well as the resting motor threshold (rMT), considered a global measure of corticospinal excitability.

RESULTS: No significant differences in baseline GABAA receptor availability or cortical excitability were found between patients and controls. Additionally, no correlations were observed between baseline measurements of GABAA receptor availability and TMS outcomes. Changes in GABAA receptor availability in the hand motor cortex, between pre- and post-assessments, were inversely related to pre-post changes in hand rMT.

CONCLUSION: We found that a change in GABAA receptor availability was inversely related to a change in rMT, suggesting a link between GABA deficiency and increased rMT previously observed in depressive episodes. The results highlight the complex mechanisms governing cortical excitability measures and offer new insight into their properties during the depressive state.