Neural excitation/inhibition imbalance and the treatment of severe depression

An influential hypothesis holds that depression is related to a neural excitation/inhibition imbalance, but its role in the treatment of depression remains unclear. Here, we show that unmedicated patients with severe depression demonstrated reduced inhibition of brain-wide resting-state networks relative to healthy controls. Patients using antidepressants showed inhibition that was higher than unmedicated patients and comparable to controls, but they still suffered from severe depression. Subsequent treatment with electroconvulsive therapy (ECT) reduced depressive symptoms, but its effectiveness did not depend on changes in network inhibition. Concomitant pharmacotherapy increased the effectiveness of ECT, but only when the strength of neural inhibition before ECT was within the normal range and not when inhibition was excessive. These findings suggest that reversing the excitation/inhibition imbalance may not be sufficient nor necessary for the effective treatment of severe depression, and that brain-state informed pharmacotherapy management may enhance the effectiveness of ECT.