Ketamine modulates the neural correlates of reward processing in unmedicated patients in remission from depression

Journal article

Kotoula, Vasileia, Stringaris, Argyris, Mackes, Nuria, Mazibuko, Ndabezinhle, Hawkins, Peter C. T., Furey, Maura, Curran, H. Valerie and Mehta, Mitul A.. (2022). Ketamine modulates the neural correlates of reward processing in unmedicated patients in remission from depression. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 7(3), pp. 285-292. https://doi.org/10.1016/j.bpsc.2021.05.009
AuthorsKotoula, Vasileia, Stringaris, Argyris, Mackes, Nuria, Mazibuko, Ndabezinhle, Hawkins, Peter C. T., Furey, Maura, Curran, H. Valerie and Mehta, Mitul A.
Abstract

Background: Ketamine as an antidepressant improves anhedonia as early as 2 hours after infusion. These drug effects are thought to be exerted via actions on reward-related brain areas—yet these actions remain largely unknown. Our study investigates ketamine’s effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported.

Methods: We examined ketamine’s effects during the anticipation and receipt of expected rewards on predefined brain areas, namely, the dorsal and ventral striatum, ventral tegmental area, amygdala, and insula. We recruited 37 male and female participants with remitted depression who were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned 2 hours after drug administration in a double-blind crossover design (ketamine: 0.5 mg/kg and placebo) while performing a monetary reward task.

Results: A significant main effect of ketamine was observed across all regions of interest during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, which showed increased activation on the receipt of smaller rewards compared with neutral. The levels of (2R,6R)-hydroxynorketamine 2 hours after infusion significantly correlated with the activation observed in the ventral tegmental area for that contrast.

Conclusions: These findings demonstrate that ketamine can produce detectable changes in reward-related brain areas 2 hours after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback.

Keywords(2R,6R)-HNK; feedback; ketamine; monetary incentive delay (MID); reward-processing; VTA
Year2022
JournalBiological Psychiatry: Cognitive Neuroscience and Neuroimaging
Journal citation7 (3), pp. 285-292
PublisherElsevier Inc.
ISSN2451-9022
Digital Object Identifier (DOI)https://doi.org/10.1016/j.bpsc.2021.05.009
PubMed ID34126264
Scopus EID2-s2.0-85119366156
Open accessPublished as ‘gold’ (paid) open access
Page range285-292
FunderJohnson & Johnson
University College London
King’s College London
National Institute for Health Research (NIHR)
Biomedical Research Centre (BRC), National Institute for Health Research
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online04 Mar 2022
Publication process dates
Accepted23 May 2021
Deposited17 Mar 2025
Grant ID23034
Additional information

© 2021 Society of Biological Psychiatry. Published by Elsevier Inc.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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J.B. Stroud, Tom P. Freeman, Robert Leech, Chandni Hindocha, Will Lawn, D.J. Nutt, H. V. Curran and R. L. Carhart-Harris. (2018). Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression. Psychopharmacology. 235(2), pp. 459-466. https://doi.org/10.1007/s00213-017-4754-y
Psilocybin with psychological support for treatment-resistant depression: six-month follow-up
R. L. Carhart-Harris, M. Bolstridge, C.M.J. Day, J. Rucker, R. Watts, David Erritzoe, M. Kaelen, B. Giribaldi, M. A P Bloomfield, S. Pilling, J.A. Rickard, B. Forbes, A. Feilding, D. Taylor, H. V. Curran and D.J. Nutt. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology. 235(2), pp. 399-408. https://doi.org/10.1007/s00213-017-4771-x
Non-dependent and dependent daily cannabis users differ in mental health but not prospective memory ability
Ruth Braidwood, Samantha Mansell, Jon Waldron, Peter Rendell, Sunjeev Kamboj and H. Valerie Curran. (2018). Non-dependent and dependent daily cannabis users differ in mental health but not prospective memory ability. Frontiers in Psychiatry. 9(97), pp. 1-9. https://doi.org/10.3389/fpsyt.2018.00097
Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function
Celia Morgan, Tom P. Freeman, Chandni Hindocha, Grainne Schafer, Chelsea Gardner and H. Valerie Curran. (2018). Individual and combined effects of acute delta-9-tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function. Translational Psychiatry (online). 8(1), pp. 1-10. https://doi.org/10.1038/s41398-018-0191-x
Cannabis Dampens the Effects of Music in Brain Regions Sensitive to Reward and Emotion
Tom P. Freeman, Rebecca A. Pope, Matthew B. Wall, James A. Bisby, Maartje Luijten, Chandni Hindocha, Claire Mokrysz, Will Lawn, Abigail Moss, Michael A. P. Bloomfield, Celia J. A. Morgan, David J. Nutt and H. Valerie Curran. (2018). Cannabis Dampens the Effects of Music in Brain Regions Sensitive to Reward and Emotion. International Journal of Neuropsychopharmacology. 21(1), pp. 21-32. https://doi.org/10.1093/ijnp/pyx082
Cannabidiol reverses attentional bias to cigarette cues in a human experimental model of tobacco withdrawal
Chandni Hindocha, Tom P. Freeman, Meryem Grabsk, Jack B. Stroud, Holly Crudgington, Alan C. Davies, Ravi K. Das, William Lawn, Celia Morgan and H. Valerie Curran. (2018). Cannabidiol reverses attentional bias to cigarette cues in a human experimental model of tobacco withdrawal. Addiction. 113(9), pp. 1696-1705. https://doi.org/10.1111/add.14243
Amisulpride for very late-onset schizophrenia-like psychosis: The ATLAS three-arm RCT
Howard, Robert, Cort, Elizabeth, Bradley, Rosie, Harper, Emma, Kelly, Linda, Bentham, Peter, Ritchie, Craig, Reeves, Suzanne, Fawzi, Waleed, Livingston, Gill, Sommerlad, Andrew, Oomman, Sabu, Nazir, Ejaz, Nilforooshan, Ramin, Barber, Robert, Fox, Chris, Macharouthu, Ajay, Ramachandra, Pranathi, Pattan, Vivek, ... Gray, Richard. (2018). Amisulpride for very late-onset schizophrenia-like psychosis: The ATLAS three-arm RCT. Health Technology Assessment. 22(67), pp. 1 - 60. https://doi.org/10.3310/hta22670
Ketamine treatment for depression : Opportunities for clinical innovation and ethical foresight
Singh, Ilina, Morgan, Celia, Curran, Valerie, Nutt, David, Schlag, Anne and McShane, Rupert. (2017). Ketamine treatment for depression : Opportunities for clinical innovation and ethical foresight. The Lancet Psychiatry. 4(5), pp. 419-426. https://doi.org/10.1016/S2215-0366(17)30102-5
Anatomy of a Joint: Comparing Self-Reported and Actual Dose of Cannabis and Tobacco in a Joint, and How These Are Influenced by Controlled Acute Administration
Chandni Hindocha, Tom P. Freeman and H. Valerie Curran. (2017). Anatomy of a Joint: Comparing Self-Reported and Actual Dose of Cannabis and Tobacco in a Joint, and How These Are Influenced by Controlled Acute Administration. Cannabis and Cannabinoid Research. 2(1), pp. 217-223. https://doi.org/10.1089/can.2017.0024
Acute memory and psychotomimetic effects of cannabis and tobacco both 'joint' and individually: A placebo-controlled trial
Hindocha, Chandni, Freeman, T. P., Xia, J. X., Shaban, Natacha D. C. and Curran, Helen V.. (2017). Acute memory and psychotomimetic effects of cannabis and tobacco both 'joint' and individually: A placebo-controlled trial. Psychological Medicine. 47(15), pp. 2708 - 2719. https://doi.org/10.1017/S0033291717001222
Editorial : Reporting guidelines for psychopharmacology
Steckler, Thomas, Curran, H. Valerie, de Wit, Harriet, Howes, Oliver, Hoyer, Daniel, Lucki, Irwin, Miczek, Klaus A., Morrow, A. Leslie, Price, Lawrence H. and Robbins, Trevor W.. (2016). Editorial : Reporting guidelines for psychopharmacology. Psychopharmacology. 233(7), pp. 1131-1134. https://doi.org/10.1007/s00213-016-4252-7
AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers
Morgan, Celia J. A., Freeman, T. P., Powell, J. and Curran, Helen V.. (2016). AKT1 genotype moderates the acute psychotomimetic effects of naturalistically smoked cannabis in young cannabis smokers. Translational Psychiatry. 6(2), pp. 1 - 6. https://doi.org/10.1038/tp.2015.219
Deconstructing the nature of episodic foresight deficits associated with chronic opiate use
Mercuri, Kimberly, Terrett, Gill, Bailey, Phoebe E., Henry, Julie D., Curran, Helen Valerie and Rendell, Peter G.. (2016). Deconstructing the nature of episodic foresight deficits associated with chronic opiate use. British Journal of Clinical Psychology. 55(4), pp. 401 - 413. https://doi.org/10.1111/bjc.12110
Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males
Mokrysz, Claire, Freeman, Tom P., Korkki, S., Griffiths, K. and Curran, Helen V.. (2016). Are adolescents more vulnerable to the harmful effects of cannabis than adults? A placebo-controlled study in human males. Translational Psychiatry. 6(11), pp. 1 - 10. https://doi.org/10.1038/tp.2016.225
LSD enhances the emotional response to music
Kaelen, M., Barrett, F. S., Roseman, L., Lorenz, R., Family, N., Bolstridge, M., Curran, Helen V., Feilding, A., Nutt, David J. and Carhart-Harris, R. L.. (2015). LSD enhances the emotional response to music. Psychopharmacology. 232(19), pp. 3607 - 3614. https://doi.org/10.1007/s00213-015-4014-y
Effects of immediate-release opioid on memory functioning: A randomized-controlled study in patients receiving sustained-release opioids
Kamboj, S. K., Conroy, L., Tookman, A., Carroll, E., Jones, L. and Curran, H.. (2014). Effects of immediate-release opioid on memory functioning: A randomized-controlled study in patients receiving sustained-release opioids. European Journal of Pain. 18(10), pp. 1376 - 1384. https://doi.org/10.1002/j.1532-2149.2014.498.x
Effects of ecstasy on cooperative behaviour and perception of trustworthiness: A naturalistic study
Stewart, L. H., Ferguson, B., Morgan, C. J. A., Swaboda, N., Jones, L., Fenton, R., Wall, M. B. and Curran, H.. (2014). Effects of ecstasy on cooperative behaviour and perception of trustworthiness: A naturalistic study. Journal of Psychopharmacology. 28(11), pp. 1001 - 1008. https://doi.org/10.1177/0269881114544775
Prospective memory impairment in long-term opiate users
Terrett, Gillian, McLennan, Skye, Henry, Julie, Biernacki, Kathryn, Mercuri, Kimberly, Curran, Valerie and Rendell, Peter. (2014). Prospective memory impairment in long-term opiate users. Psychopharmacology. 231(13), pp. 2623 - 2632. https://doi.org/10.1007/s00213-014-3432-6
Benzodiazepines: Risks and benefits. A reconsideration
Baldwin, David S., Aitchison, Katherine, Bateson, Alan, Curran, H. Valerie, Davies, Simon, Leonard, Brian, Nutt, David J., Stephens, David N. and Wilson, Sue. (2013). Benzodiazepines: Risks and benefits. A reconsideration. Journal of Psychopharmacology. 27(11), pp. 967 - 971. https://doi.org/10.1177/0269881113503509
Prospective memory and future event simulation in individuals with alcohol dependence
Griffiths, Alison, Hill, Robert, Morgan, Celia, Rendell, Peter Gregory, Karimi, Khashayar, Wanagaratne, Shamil and Curran, Valerie. (2012). Prospective memory and future event simulation in individuals with alcohol dependence. Addiction. 107(10), pp. 1809 - 1816. https://doi.org/10.1111/j.1360-0443.2012.03941.x
Neurocognitive function and schizophrenia-proneness in individuals dependent on ketamine, on high potency cannabis (skunk) or on cocaine
Morgan, Celia, Duffin, S., Hunt, S., Monaghan, L., Mason, O. and Curran, Helen. (2012). Neurocognitive function and schizophrenia-proneness in individuals dependent on ketamine, on high potency cannabis (skunk) or on cocaine. Pharmacopsychiatry. 45(7), pp. 269 - 274. https://doi.org/10.1055/s-0032-1306310