- At least one third of individuals with major depressive disorder (MDD) remain treatment-refractory after receiving currently available antidepressants underscoring the urgent need for new antidepressant therapies. Of the novel pharmacotherapeutic strategies seeking to rapidly alleviate depressive symptoms, glutamatergic modulators have emerged as promising potential targets. The present study sought to examine the potassium (KATP) channel activator diazoxide as a possible treatment for MDD. Diazoxide increases glutamate uptake from the synaptic cleft by activating the KATP channel to chronically increase expression of the excitatory amino acid transporter (EAAT)-2 system in glial cells. Diazoxide is FDA-approved for the treatment of sulfonylurea-induced hypoglycemia, hypoglycemia due to hyperinsulinemia, and hypertension.