LiteratureReview/Previous Research            Clinical studies have found abnormallevels of glutamate in MDD. For example, one of the earliest study done by the departmentof clinical psychiatry, University of Milan in Italy found that levels ofglutamate plasma were higher in patients with mood disorders (Altamura, Moro etal.,1993)4. Another study conducted in 2009 that looked into the relationshipbetween plasma Glx levels and MDD in diagnosed subjects found that glutamateand glutamine play an influential role in depression (Saygin et al.

, 2009)5,19,16.A more direct methods of evaluating glutamate dysfunction in the brain has beendone using MRS. For instance, proton MRS showed a reduction ofglutamate/glutamine levels in the hippocampus (Block, Von Widdern et al., 2009)6.Additional MRS studies of brain area around the prefrontal cortex decided thatdepressed patients showed diminishing Glx levels in ROIs (Hasler, Tumonis etal., 2007)6.

Moreover, postmortem studies have found changes in theexpression of NMDA receptor subunits in MDD patients. for example, a studyconducted in 2014 by the Department of Psychiatry, University of Pittsburgh,found Abnormal glutamate receptor expression in the medial temporal lobe inpatients with MDD and mood disorders (Szebeni, Crawford et al., 2014)7,11,16. Recent studies focusing on the NMDAreceptor and its antagonists, ketamine, have showed a rapid antidepressanteffect.

Also, low-dose I.V infusion of ketamine produces fast and sustained therapyfor MDD patients (Hao X, Zhu X et al,. 2016)8,2,13,17.