title: Comparing the actions of lanicemine and ketamine in depression: key role of the anterior cingulate.
abstract: Intravenous infusion of lanicemine (formerly AZD6765), a low trapping non-selective N-methyl-D-aspartate (NMDA) receptor antagonist, induces antidepressant effects with a similar time course to ketamine. We investigated whether a single dose lanicemine infusion would reproduce the previously reported decrease in subgenual anterior cingulate cortex (sgACC) activity evoked by ketamine, a potential mechanism of antidepressant efficacy. Sixty un-medicated adults meeting the criteria for major depressive disorder were randomly assigned to receive constant intravenous infusions of ketamine, lanicemine or saline during a 60min pharmacological magnetic resonance imaging (phMRI) scan. Both ketamine and lanicemine gradually increased the blood oxygen level dependent signal in sgACC and rostral ACC as the primary outcome measure. No decreases in signal were seen in any region. Interviewer-rated psychotic and dissociative symptoms were minimal following administration of lanicemine. There was no significant antidepressant effect of either infusion compared to saline. The previously reported deactivation of sgACC after ketamine probably reflects the rapid and pronounced subjective effects evoked by the bolus-infusion method used in the previous study. Activation of the ACC was observed following two different NMDA compounds in both Manchester and Oxford using different 3T MRI scanners, and this effect predicted improvement in mood 1 and 7 days post-infusion. These findings suggest that the initial site of antidepressant action for NMDA antagonists may be the ACC (NCT01046630. A Phase I, Multi-centre, Double-blind, Placebo-controlled Parallel Group Study to Assess the pharmacoMRI Effects of AZD6765 in Male and Female Subjects Fulfilling the Criteria for Major Depressive Disorder; http://clinicaltrials.gov/show/NCT01046630).
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Darragh
authors.initials: D
authors.lastname: Downey
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Arpan
authors.initials: A
authors.lastname: Dutta
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McKie
authors.affiliation: P1vital Ltd, Wallingford, UK.
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Dawson
authors.affiliation: P1vital Ltd, Wallingford, UK.
authors.forename: Colin T
authors.initials: CT
authors.lastname: Dourish
authors.affiliation: P1vital Ltd, Wallingford, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Craig
authors.affiliation: AstraZeneca Pharmaceuticals LP, R&D, Wilmington, DE 18950, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: AstraZeneca Pharmaceuticals LP, R&D, Wilmington, DE 18950, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: McCarthy
authors.affiliation: University Department of Psychiatry, Oxford, UK.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Harmer
authors.affiliation: University Department of Psychiatry, Oxford, UK.
authors.forename: Guy M
authors.initials: GM
authors.lastname: Goodwin
authors.affiliation: University of Manchester, Manchester, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Williams
authors.affiliation: University of Manchester, Manchester, UK; Manchester Mental Health and Social Care Trust, UK.
authors.forename: J F William
authors.initials: JF
authors.lastname: Deakin
mesh_terms: D000293:Adolescent; D000328:Adult; D000339:Affect; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006179:Gyrus Cinguli / Q000187:drug effects*; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010627:Phenethylamines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C585977:AZD6765; D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D010627:Phenethylamines; D011725:Pyridines; D007649:Ketamine
keywords: Anterior cingulate; Antidepressant; Ketamine; Lanicemine; Major depressive disorder; fMRI