Effects of NMDA-receptor blockade by ketamine on mentalizing and its neural correlates in humans: a randomized control trial.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Ketamine*/pharmacology ; Mentalization*; Humans ; Receptors, N-Methyl-D-Aspartate ; N-Methylaspartate ; Glutamates

Schizophrenia is associated with various deficits in social cognition that remain relatively unaltered by antipsychotic treatment. While faulty glutamate signaling has been associated with general cognitive deficits as well as negative symptoms of schizophrenia, no direct link between manipulation of glutamate signaling and deficits in mentalizing has been demonstrated thus far. Here, we experimentally investigated whether ketamine, an uncompetitive N-methyl-D-aspartate receptor antagonist known to induce psychotomimetic effects, influences mentalizing and its neural correlates. In a randomized, placebo-controlled between-subjects experiment, we intravenously administered ketamine or placebo to healthy participants performing a video-based social cognition task during functional magnetic resonance imaging. Psychotomimetic effects of ketamine were assessed using the Positive and Negative Syndrome Scale. Compared to placebo, ketamine led to significantly more psychotic symptoms and reduced mentalizing performance (more "no mentalizing" errors). Ketamine also influenced blood oxygen level dependent (BOLD) response during mentalizing compared to placebo. Specifically, ketamine increased BOLD in right posterior superior temporal sulcus (pSTS) and increased connectivity between pSTS and anterior precuneus. These increases may reflect a dysfunctional shift of attention induced by ketamine that leads to mentalizing deficits. Our findings show that a psychotomimetic dose of ketamine impairs mentalizing and influences its neural correlates, a result compatible with the notion that deficient glutamate signaling may contribute to deficits in mentalizing in schizophrenia. The results also support efforts to seek novel psychopharmacological treatments for psychosis and schizophrenia targeting glutamatergic transmission.
(© 2023. Springer Nature Limited.)

Psychol Med. 2004 Apr;34(3):385-9. (PMID: 15259823)
Mol Psychiatry. 2012 Jul;17(7):664-5. (PMID: 22212598)
Soc Cogn Affect Neurosci. 2009 Jun;4(2):166-76. (PMID: 19287044)
Soc Cogn Affect Neurosci. 2016 Nov;11(11):1741-1751. (PMID: 27496338)
Autism. 2020 Feb;24(2):364-373. (PMID: 31339349)
Neurosci Biobehav Rev. 2019 Oct;105:212-219. (PMID: 31415864)
Metab Brain Dis. 2018 Jun;33(3):843-854. (PMID: 29397522)
Psychopharmacology (Berl). 2018 Dec;235(12):3479-3493. (PMID: 30426183)
ACS Chem Neurosci. 2017 Jun 21;8(6):1122-1134. (PMID: 28418641)
Psychol Bull. 2021 Mar;147(3):293-327. (PMID: 33151703)
Neuroreport. 2003 Mar 3;14(3):387-91. (PMID: 12634489)
Psychopharmacology (Berl). 2018 Dec;235(12):3559-3571. (PMID: 30357437)
Br J Psychiatry. 2011 Jun;198(6):448-56. (PMID: 21628707)
Psychol Med. 2007 Apr;37(4):595-601. (PMID: 17094815)
Schizophr Bull. 2020 Apr 10;46(3):464-470. (PMID: 32133507)
Neuroimage. 2011 Apr 15;55(4):1899-911. (PMID: 21172444)
Neurosci Conscious. 2021 Feb 10;2021(1):niaa028. (PMID: 33747545)
J Autism Dev Disord. 2006 Jul;36(5):623-36. (PMID: 16755332)
Neuropsychopharmacology. 2018 May;43(6):1324-1333. (PMID: 29105665)
Schizophr Bull. 2012 Jun;38(4):854-64. (PMID: 21345917)
Nat Neurosci. 2012 Apr 15;15(5):663-8. (PMID: 22504349)
Int J Mol Sci. 2021 Jul 12;22(14):. (PMID: 34299076)
CNS Drugs. 2013 May;27(5):335-43. (PMID: 23533009)
Neuroimage. 2015 Mar;108:396-409. (PMID: 25554429)
Eur Arch Psychiatry Clin Neurosci. 2012 Apr;262(3):217-26. (PMID: 21892777)
Front Cell Neurosci. 2013 Mar 27;7:31. (PMID: 23543703)
Soc Cogn Affect Neurosci. 2006 Jun;1(1):56-64. (PMID: 18574518)
Schizophr Res. 2017 Jul;185:161-166. (PMID: 28089135)
Am J Psychiatry. 2005 Feb;162(2):394-6. (PMID: 15677610)
Cogn Affect Behav Neurosci. 2016 Dec;16(6):991-1002. (PMID: 27444935)
Schizophr Bull. 1987;13(2):261-76. (PMID: 3616518)
Neuroimage Clin. 2013 Nov 27;4:154-63. (PMID: 24371798)
Pharmacol Ther. 2010 Dec;128(3):419-32. (PMID: 20705091)
Psychopharmacology (Berl). 2017 Sep;234(18):2707-2725. (PMID: 28612134)
Pharmacol Rev. 2018 Jul;70(3):621-660. (PMID: 29945898)
Br J Addict. 1991 Sep;86(9):1119-27. (PMID: 1932883)
Neurobiol Dis. 2019 Nov;131:104315. (PMID: 30391541)
Schizophr Res. 2005 Nov 15;79(2-3):231-8. (PMID: 15982856)
Harv Rev Psychiatry. 2018 Nov/Dec;26(6):320-339. (PMID: 29465479)
Psychopharmacology (Berl). 2013 Jan;225(1):227-39. (PMID: 22836372)
Brain Connect. 2012;2(3):125-41. (PMID: 22642651)
Front Behav Neurosci. 2017 Jun 06;11:106. (PMID: 28634445)
J Neurosci. 1997 Apr 15;17(8):2921-7. (PMID: 9092613)
World J Biol Psychiatry. 2018;19(sup3):S86-S96. (PMID: 28449613)
J Magn Reson Imaging. 2011 Jul;34(1):173-83. (PMID: 21618334)
Psychol Med. 2010 Oct;40(10):1607-17. (PMID: 20056024)
Arch Gen Psychiatry. 2000 Dec;57(12):1139-47. (PMID: 11115327)
J Cogn Neurosci. 2017 Feb;29(2):221-234. (PMID: 27991030)
Neuroimage Clin. 2017 Jul 24;16:125-131. (PMID: 28794973)
Trends Neurosci. 2016 Sep;39(9):587-596. (PMID: 27477199)
Neuroimage. 2010 Jan 1;49(1):894-904. (PMID: 19733672)
J Psychopharmacol. 2012 Sep;26(9):1211-7. (PMID: 22389244)
Neurosci Biobehav Rev. 2011 Jan;35(3):573-88. (PMID: 20620163)
Psychiatry Res. 2011 Apr 30;186(2-3):203-9. (PMID: 20947175)
Neuropsychologia. 1971 Mar;9(1):97-113. (PMID: 5146491)
Sci Rep. 2019 Feb 14;9(1):2116. (PMID: 30765822)
Soc Neurosci. 2011;6(5-6):569-81. (PMID: 22050432)
Neuroimage. 2016 Jan 1;124(Pt A):8-15. (PMID: 26348558)
Neuroimage. 2003 May;19(1):200-7. (PMID: 12781739)
Ann N Y Acad Sci. 2003 Nov;1003:131-7. (PMID: 14684441)
Neuroimage. 2016 May 15;132:373-389. (PMID: 26921716)
Hum Brain Mapp. 2017 Aug;38(8):3791-3803. (PMID: 28556306)
Arch Gen Psychiatry. 1994 Mar;51(3):199-214. (PMID: 8122957)
Neuropsychopharmacology. 2020 Jul;45(8):1346-1352. (PMID: 32059228)
Neuroimage Clin. 2020;28:102444. (PMID: 33039973)
Front Hum Neurosci. 2014 Oct 16;8:818. (PMID: 25360101)
Hum Brain Mapp. 2017 Sep;38(9):4788-4805. (PMID: 28608647)
Sci Rep. 2020 Feb 13;10(1):2616. (PMID: 32054907)
Neuropsychopharmacology. 2019 Jun;44(7):1239-1246. (PMID: 30758327)
Schizophr Res. 2011 Aug;130(1-3):170-5. (PMID: 21620681)
Neuropsychopharmacology. 1996 May;14(5):301-7. (PMID: 8703299)
Conscious Cogn. 2013 Jun;22(2):479-85. (PMID: 23518233)
Schizophr Res. 2015 Mar;162(1-3):42-6. (PMID: 25623602)
Cereb Cortex. 2015 Nov;25(11):4596-609. (PMID: 26048954)
Nat Rev Neurosci. 2015 Oct;16(10):620-31. (PMID: 26373471)
Schizophr Res. 2013 Mar;144(1-3):31-6. (PMID: 23347949)
PLoS One. 2008;3(12):e3890. (PMID: 19060949)
J Psychiatry Neurosci. 2012 Sep;37(5):297-304. (PMID: 22498076)

690G0D6V8H (Ketamine)
0 (Receptors, N-Methyl-D-Aspartate)
6384-92-5 (N-Methylaspartate)
0 (Glutamates)

Date Created: 20231011 Date Completed: 20231102 Latest Revision: 20231123

20250114

PMC10567921

10.1038/s41598-023-44443-6

37821513