Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia

Samantha V. Abram, Brian J. Roach, Susanna L. Fryer, Vince D. Calhoun, Adrian Preda, Theo G.M. van Erp, Juan R. Bustillo, Kelvin O. Lim, Rachel L. Loewy, Barbara K. Stuart, John H. Krystal, Judith M. Ford, Daniel H. Mathalon

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI) studies demonstrate a thalamic dysconnectivity pattern in schizophrenia involving excessive connectivity with sensory regions and deficient connectivity with frontal, cerebellar, and thalamic regions. The NMDAR antagonist ketamine, when administered at sub-anesthetic doses to healthy volunteers, induces transient schizophrenia-like symptoms and alters rsfMRI thalamic connectivity. However, the extent to which ketamine-induced thalamic dysconnectivity resembles schizophrenia thalamic dysconnectivity has not been directly tested. The current double-blind, placebo-controlled study derived an NMDAR hypofunction model of thalamic dysconnectivity from healthy volunteers undergoing ketamine infusions during rsfMRI. To assess whether ketamine-induced thalamic dysconnectivity was mediated by excess glutamate release, we tested whether pre-treatment with lamotrigine, a glutamate release inhibitor, attenuated ketamine’s effects. Ketamine produced robust thalamo-cortical hyper-connectivity with sensory and motor regions that was not reduced by lamotrigine pre-treatment. To test whether the ketamine thalamic dysconnectivity pattern resembled the schizophrenia pattern, a whole-brain template representing ketamine’s thalamic dysconnectivity effect was correlated with individual participant rsfMRI thalamic dysconnectivity maps, generating “ketamine similarity coefficients” for people with chronic (SZ) and early illness (ESZ) schizophrenia, individuals at clinical high-risk for psychosis (CHR-P), and healthy controls (HC). Similarity coefficients were higher in SZ and ESZ than in HC, with CHR-P showing an intermediate trend. Higher ketamine similarity coefficients correlated with greater hallucination severity in SZ. Thus, NMDAR hypofunction, modeled with ketamine, reproduces the thalamic hyper-connectivity observed in schizophrenia across its illness course, including the CHR-P period preceding psychosis onset, and may contribute to hallucination severity.

Original languageEnglish (US)
Pages (from-to)2448-2456
Number of pages9
JournalMolecular psychiatry
Issue number5
StatePublished - May 2022

Bibliographical note

Funding Information:
DHM consults for Boehringer Ingelheim International, Cadent Therapeutics, Syndesi Therapeutics, Recognify Life Sciences, and Gilgamesh Pharmaceuticals. JHK consults for AstraZeneca Pharmaceuticals, Biogen Idec, Biomedisyn, Bionomics Ltd., Boehringer Ingelheim International, COMPASS Pathways Ltd., Concert Pharmaceuticals, Inc., Epiodyne, Inc., EpiVario, Inc., Heptares Therapeutics Ltd., Janssen Research & Development, Otsuka America Pharmaceutical, Inc., Perception Neuroscience Holdings, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc., Takeda Industries, and Taisho Pharmaceutical Co., Ltd.; is a scientific advisor of Bioasis Technologies, Inc., Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), BlackThorn Therapeutics, Inc., Cadent Therapeutics (Clinical Advisory Board), Cerevel Therapeutics, LLC, EpiVario, Inc., Lohocla Research Corporation, Novartis Pharmaceuticals Corporation, and PsychoGenics, Inc.; is a member of the board of directors of Inheris Biopharma, Inc.; holds stock or stock options with Biohaven Pharmaceuticals, Sage Pharmaceuticals, Spring Care, Inc., BlackThorn Therapeutics, Inc., EpiVario, Inc., and Terra Life Sciences; and is editor of Biological Psychiatry. JHK was also awarded the following patents: (i) Seibyl JP, Krystal JH, Charney DS. Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia. U.S. Patent No. 5447948. September 5, 1995; (ii) Vladimir C, Krystal JH, Sanacora G. Glutamate Modulating Agents in the Treatment of Mental Disorders. U.S. Patent No. 8778979 B2. Patent Issue Date July 15, 2014. U.S. Patent Application No. 15/695,164. Filing Date September 5, 2017; (iii) Charney D, Krystal JH, Manji H, Matthew S, Zarate C. Intranasal Administration of Ketamine to Treat Depression. U.S. Patent Application No. 14/197767 filed on March 5, 2014. U.S. Application or Patent Cooperation Treaty International Application No. 14/306382 filed on June 17, 2014; (iv) Zarate C, Charney DS, Manji HK, Mathew SJ, Krystal JH, Department of Veterans Affairs. Methods for Treating Suicidal Ideation. Patent Application No. 14/197767 filed on March 5, 2014, by Yale University Office of Cooperative Research; (v) Arias A, Petrakis I, Krystal JH. Composition and Methods to Treat Addiction. Provisional Use Patent Application No. 61/973/961. April 2, 2014. Filed by Yale University Office of Cooperative Research; (vi) Chekroud A, Gueorguieva R, Krystal JH. Treatment Selection for Major Depressive Disorder. U.S. Patent and Trademark Office Docket No. Y0087.70116US00. Filed June 3, 2016. Provisional patent submission by Yale University; (vii) Gihyun Y, Petrakis I, Krystal JH. Compounds, Compositions, and Methods for Treating or Preventing Depression and Other Diseases. U.S. Provisional Patent Application No. 62/444552. Filed on January 10, 2017 by Yale University Office of Cooperative Research OCR 7088 US01; (viii) Abdallah C, Krystal JH, Duman R, Sanacora G. Combination Therapy for Treating or Preventing Depression or Other Mood Diseases. U.S. Provisional Patent Application No. 62/719935. Filed on August 20, 2018, by Yale University Office of Cooperative Research OCR 7451 US01. AstraZeneca Pharmaceuticals provides the drug saracatinib for research related to JHK’s work supported by the National Institute on Alcohol Abuse and Alcoholism grant Center for Translational Neuroscience of Alcoholism (CTNA-4). The other authors have nothing to disclose. SVA, SLF, JMF, and DHM are United States Government employees. The Department of Veterans Affairs had no role in the study design, collection, analysis, interpretation of the data, writing the manuscript, or the decision to submit the paper for publication. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

Funding Information:
Funding was provided by the Veterans Affairs Research Career Development Award (to DHM), GlaxoSmithKline for an investigator-initiated study (to DHM), the National Institute of Mental Health (R01 MH076989 to DHM), and from the National Center for Research Resources at the National Institutes of Health (Function Biomedical Informatics Research Network: NIH 1 U24 RR021992; Biomedical Informatics Research Network Coordinating Center: NIH 1 U24 RR025736-01). The funding sources had no role in study design, data collection, analysis, or data interpretation. Manuscript writing by SVA was supported by the Department of Veterans Affairs Sierra-Pacific Mental Illness Research, Education, and Clinical Center (MIRECC). JMF is supported by a Veterans Affairs Senior Research Career Scientist award.

Publisher Copyright:
© 2022, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

PubMed: MeSH publication types

  • Journal Article
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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