Elsevier

Biological Psychiatry

Volume 67, Issue 5, 1 March 2010, Pages 458-464
Biological Psychiatry

Archival Report
Evidence of Cortical Inhibitory Deficits in Major Depressive Disorder

https://doi.org/10.1016/j.biopsych.2009.09.025Get rights and content

Background

Several lines of evidence suggest that major depressive disorder is associated with deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission. Transcranial magnetic stimulation represents a noninvasive technique to measure cortical inhibition. In this study, we endeavored to measure cortical inhibition in medicated patients with treatment resistant major depressive disorder (TRD), unmedicated patients with major depressive disorder, and medicated euthymic patients with a history of major depressive disorder and compare them with healthy subjects.

Methods

Twenty-five patients with TRD, 16 unmedicated patients with major depressive disorder, 19 medicated euthymic patients with previous major depressive disorder (i.e., 17-item Hamilton Rating Scale for Depression < 8), and 25 healthy subjects were enrolled. Cortical inhibition was measured with transcranial magnetic stimulation paradigms known as short-interval cortical inhibition and the cortical silent period, which index GABAA and GABAB receptor-mediated inhibitory neurotransmission, respectively.

Results

All major depressive disorder patient groups demonstrated significant cortical silent period deficits compared with healthy subjects. By contrast, only TRD patients demonstrated significant deficits in short-interval cortical inhibition compared with healthy subjects, medicated euthymic major depressive disorder patients, and unmedicated major depressive disorder patients. The TRD patients also demonstrated a significantly greater resting motor threshold compared with all other clinical subgroups and healthy subjects, suggesting that TRD was also associated with hypoexcitability of the frontal cortex.

Conclusions

Our findings suggest that GABAB neurophysiological deficits are closely related to pathophysiology of major depressive disorder. Our findings also suggest that more severe illness is selectively associated with GABAA receptor-mediated inhibitory deficits.

Section snippets

Subjects

This study included 60 right-handed patients (mean age = 47.17 years ± 11.20 years, 22 men and 38 women) with a DSM-IV diagnosis of MDD confirmed by the Structured Clinical Interview for DSM-IV (SCID) (18) and 25 healthy right-handed volunteers (mean age = 43.84 years ± 8.95 years, 12 men and 13 women). Healthy subjects were screened for psychopathology with a modified SCID (18). Exclusion criteria included a self-reported comorbid medical or neurological illness, a history of drug or alcohol

Results

Across all four groups of patients with MDD and healthy control subjects, there was no significant difference in the percentage of male subjects (χ2 = 2.65, p = .10) or in age [ANOVA: F(84) = 1.30, p = .28] (Table 1). Vis-à-vis psychiatric symptoms, group-wise comparisons among TRD and unmedicated MDD patients did not reveal significant differences in HAMD17 scores [t(39) = 1.53, p = .13]; however, as anticipated, there were significant differences between TRD patients and unmedicated MDD

Discussion

Our results suggest that all patients with MDD, regardless of symptom or medication state, demonstrated significant CSP deficits compared with healthy subjects. By contrast, only TRD patients demonstrated SICI deficits. Taken together these data suggest that MDD is associated with deficits in neurophysiological indexes of GABAB receptor-mediated inhibitory neurotransmission, whereas patients with TRD demonstrated deficits in neurophysiological indexes of both GABAB and GABAA receptor-mediated

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