Evidence of cortical inhibitory deficits in major depressive disorder.
BACKGROUND
Several lines of evidence suggest that major depressive disorder is associated with deficits in gamma-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 GABA(A) and GABA(B) 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 GABA(B) neurophysiological deficits are closely related to pathophysiology of major depressive disorder. Our findings also suggest that more severe illness is selectively associated with GABA(A) receptor-mediated inhibitory deficits.
Levinson
Andrea J
AJ
Centre for Addiction and Mental Health, University of Toronto, Toronto, ON ONM5T 1R8, Canada.
Fitzgerald
Paul B
PB
Favalli
Gabriela
G
Blumberger
Daniel M
DM
Daigle
Melissa
M
Daskalakis
Zafiris J
ZJ
D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology*; D003865:Major Depressive Disorder / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D004576:Electromyography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000294:innervation; D009433:Neural Inhibition / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D011795:Surveys and Questionnaires; D009435:Synaptic Transmission / Q000502:physiology; D050781:Transcranial Magnetic Stimulation
D011963:Receptors, GABA-A; D017367:Selective Serotonin Reuptake Inhibitors