IMPORTANCE A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. OBJECTIVE To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. DESIGN, SETTING, AND PARTICIPANTS This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal.

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using 1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.

Higher serotonin-1A (5-HT) receptor binding potential (BP) has been found in major depressive disorder (MDD) during and between major depressive episodes. We investigated whether higher 5-HT binding is a biologic trait transmitted to healthy high risk (HR) offspring of MDD probands. Data were collected contemporaneously from: nine HR, 30 depressed not-recently medicated (NRM) MDD, 18 remitted NRM MDD, 51 healthy volunteer (HV) subjects. Subjects underwent positron emission tomography (PET) using [C]WAY100635 to quantify 5-HT BP, estimated using metabolite, free fraction-corrected arterial input function and cerebellar white matter as reference region. Multivoxel pattern analyses (MVPA) of PET data evaluated group status classification of individuals. When tested across 13 regions of interest, an effect of diagnosis is found on BP which remains significant after correction for sex, age, injected mass and dose: HR have higher BP than HV (84.3% higher in midbrain raphe, 40.8% higher in hippocampus, mean BP across all 13 brain regions is 49.9% ± 11.8% higher). Voxel-level BP maps distinguish HR vs. HV. Elevated 5-HT BP appears to be a familially transmitted trait abnormality. Future studies are needed to replicate this finding in a larger cohort and demonstrate the link to the familial transmission of mood disorders.