title: A review of ketamine in affective disorders: current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action.
abstract: BACKGROUND
  Recent research has seen low-dose ketamine emerge as a novel, rapid-acting antidepressant. Ketamine, an N-methy-d-aspartate (NMDA) receptor antagonist, leads to effects on the glutamatergic system and abnormalities in this neurotransmittor system are present in depression. This article aims to (1) review the clinical literature on low-dose ketamine as a rapid-acting antidepressant in affective disorders, (2) provide a critical overview of the limitations of ketamine and research attempts to overcome these (3) discuss the proposed mechanisms of action of ketamine and (4) point towards future research directions.
  
  
  METHODS
  The electronic database Pubmed, Web of Science and sciencedirect were searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, electroconvulsive therapy, mechanism of action.
  
  
  RESULTS
  The literature demonstrates evidence supporting a rapid-acting antidepressant effect of low-dose intravenous ketamine in major depressive disorder, in bipolar depression and in depression with suicidal ideation. There are mixed results as to whether ketamine leads to a reduction in time to remission in patients undergoing electroconvulsive therapy (ECT). Efforts to unravel ketamine's therapeutic mechanism of action have implicated the mammalian target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen synthase kinase (GSK-3). Ketamine's limiting factors are the transient nature of its antidepressant effect and concerns regarding abuse, and research efforts to overcome these are reviewed.
  
  
  CONCLUSIONS
  Current and future research studies are using ketamine as a promising tool to evaluate the glutamatergic neurotransmittor system to learn more about the pathophysiology of depression and develop more specific rapid-acting antidepressant treatments.
authors.affiliation: Department of Psychiatry, University College Cork, Western Road, Cork City, Cork, Ireland. Electronic address: marienaughton@beaumont.ie.
authors.forename: Marie
authors.initials: M
authors.lastname: Naughton
authors.affiliation: Department of Psychiatry, University College Cork, Western Road, Cork City, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Electronic address: g.clarke@ucc.ie.
authors.forename: Gerard
authors.initials: G
authors.lastname: Clarke
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. Electronic address: o.oleary@ucc.ie.
authors.forename: Olivia F
authors.initials: OF
authors.lastname: O'Leary
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland. Electronic address: j.cryan@ucc.ie.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.affiliation: Department of Psychiatry, University College Cork, Western Road, Cork City, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Electronic address: t.dinan@ucc.ie.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy; D003131:Combined Modality Therapy; D003863:Depression / Q000188:drug therapy; D003865:Major Depressive Disorder / Q000188:drug therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D004565:Electroconvulsive Therapy; D006801:Humans; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D059020:Suicidal Ideation; D009435:Synaptic Transmission / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Bipolar depression; Ketamine; N-Methyl-d-aspartate receptor antagonist; Rapid-acting antidepressant; Suicidal ideation; Treatment-resistant depression