title: An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression.
abstract: Amino-acid neurotransmitter system dysfunction plays a major role in the pathophysiology of major depressive disorder (MDD). We used proton magnetic resonance spectroscopy (¹H-MRS) to investigate whether prefrontal levels of amino-acid neurotransmitters predict antidepressant response to a single intravenous infusion of the N-methyl-D-aspartate (NMDA) antagonist ketamine in MDD patients. Fourteen drug-free patients with MDD were scanned 1-3 d before receiving a single intravenous infusion of ketamine (0.5 mg/kg). We measured gamma aminobutyric acid (GABA), glutamate, and Glx/glutamate ratio (a surrogate marker of glutamine) in the ventromedial prefrontal cortex (VM-PFC) and the dorsomedial/dorsal anterolateral prefrontal cortex (DM/DA-PFC). Correlation analyses were conducted to determine whether pretreatment GABA, glutamate, or Glx/glutamate ratio predicted change in depressive and anxiety symptoms 230 min after ketamine administration. Pretreatment GABA or glutamate did not correlate with improved depressive symptoms in either of the two regions of interest (p>0.1); pretreatment Glx/glutamate ratio in the DM/DA-PFC was negatively correlated with improvement in depressive symptoms [r s(11)=-0.57, p<0.05]. Pretreatment glutamate levels in the VM-PFC were positively correlated with improvement in anxiety symptoms [r s(11)=0.57, p<0.05]. The findings suggest an association between lower Glx/glutamate ratio and greater improvement in response to ketamine treatment. Because glutamine is mainly contained in glia, the decreased Glx/glutamate ratio observed in this study may reflect the reduction in glial cells found in the same regions in post-mortem studies of individuals with MDD, and suggests that the presence of this neuropathological construct may be associated with antidepressant responsiveness to ketamine.
authors: Experimental Therapeutics and Pathophysiology Branch, Division of Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors: Giacomo
authors: G
authors: Salvadore
authors: Jan Willem
authors: JW
authors: van der Veen
authors: Yan
authors: Y
authors: Zhang
authors: Stefano
authors: S
authors: Marenco
authors: Rodrigo
authors: R
authors: Machado-Vieira
authors: Jacqueline
authors: J
authors: Baumann
authors: Lobna A
authors: LA
authors: Ibrahim
authors: David A
authors: DA
authors: Luckenbaugh
authors: Jun
authors: J
authors: Shen
authors: Wayne C
authors: WC
authors: Drevets
authors: Carlos A
authors: CA
authors: Zarate
mesh_terms: D000328:Adult; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011237:Predictive Value of Tests; D011569:Psychiatric Status Rating Scales; D012189:Retrospective Studies; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D005973:Glutamine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine