title: Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression.
abstract: BACKGROUND
  Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine.
  
  
  METHODS
  Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores.
  
  
  RESULTS
  Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders.
  
  
  CONCLUSIONS
  These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.
authors.affiliation: Section on Neurobiology of Fear and Anxiety, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. cornwellb@mail.nih.gov
authors.forename: Brian R
authors.initials: BR
authors.lastname: Cornwell
authors.forename: Giacomo
authors.initials: G
authors.lastname: Salvadore
authors.forename: Maura
authors.initials: M
authors.lastname: Furey
authors.forename: Craig A
authors.initials: CA
authors.lastname: Marquardt
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Brutsche
authors.forename: Christian
authors.initials: C
authors.lastname: Grillon
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D001931:Brain Mapping; D002540:Cerebral Cortex / Q000187:drug effects* / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy / Q000473:pathology; D004558:Electric Stimulation; D005260:Female; D005385:Fingers / Q000294:innervation; D007839:Functional Laterality; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D015225:Magnetoencephalography; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D011930:Reaction Time / Q000187:drug effects; D055366:Synaptic Potentials / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine; C033419:norketamine