Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depression
IntroductionKetamine demonstrates robust and rapidly occurring antidepressant effects in patients with difficult-to-treat major depressive disorder. Ketamine’s antidepressant effects and its impact on functional networks in non-resistant forms of major depressive disorder are expected to provide val...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2025.1531375/full |
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| author | Kasper Recourt Joop Van Gerven Joop Van Gerven Nadieh Drenth Jeroen van der Grond Kantaro Nishigori Nic J. Van Der Wee Gabriël E. Jacobs Gabriël E. Jacobs |
| author_facet | Kasper Recourt Joop Van Gerven Joop Van Gerven Nadieh Drenth Jeroen van der Grond Kantaro Nishigori Nic J. Van Der Wee Gabriël E. Jacobs Gabriël E. Jacobs |
| author_sort | Kasper Recourt |
| collection | DOAJ |
| description | IntroductionKetamine demonstrates robust and rapidly occurring antidepressant effects in patients with difficult-to-treat major depressive disorder. Ketamine’s antidepressant effects and its impact on functional networks in non-resistant forms of major depressive disorder are expected to provide valuable insight into ketamine’s mechanism of action related to depression.MethodsThis study employs an existing network model of major depressive disorder to investigate the effects of ketamine on resting state connectivity in a therapy-non-resistant major depressive disorder population. In a randomized, double-blind, placebo-controlled, cross-over study, 0.5 mg/kg racemic ketamine or 0.9%NaCl was administered intravenously in 16 MDD patients. We applied resting-state functional magnetic resonance imaging (rs-fMRI) to explore changes in functional brain connectivity directly at 50, 80 and 165 min (acute) and 24 h (delayed) following ketamine administration. A clinician-rated 10-item scale (MADRS) was administered at 165 min and 24 h after ketamine administration. Connections-of-interest (COIs) were based on the previously published corticolimbic-insular-striatalpallidal-thalamic (CLIPST) circuitry model of major depressive disorder.ResultsCompared with placebo, ketamine significantly (p < 0.0014) reduced the mean (SD) MADRS total score from 21.2 (5.9) pre-dose to 10.3 (4.6) 24 h post-dose. At both acute (p < 0.0172) and delayed (p < 0.0488) time points, significant rs-fMRI connectivity changes occurred only in MDD-related COIs as proposed by the CLIPST model. No changes in functional connectivity were found in non-CLIPST connections.DiscussionThis study demonstrates that ketamine specifically affects depression-related circuitry. Analyzing functional connectivity based on a neurocircuitry model of a specific CNS disease and drug action may be an effective approach that could result in a more targeted analysis in future pharmaco-fMRI studies in CNS drug development. |
| format | Article |
| id | doaj-art-c5a9b1de06b74133882e008cb14da3f7 |
| institution | Kabale University |
| issn | 1662-453X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj-art-c5a9b1de06b74133882e008cb14da3f72025-02-03T06:33:52ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2025-02-011910.3389/fnins.2025.15313751531375Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depressionKasper Recourt0Joop Van Gerven1Joop Van Gerven2Nadieh Drenth3Jeroen van der Grond4Kantaro Nishigori5Nic J. Van Der Wee6Gabriël E. Jacobs7Gabriël E. Jacobs8Department of Psychiatry, Centre for Human Drug Research, Leiden, NetherlandsDepartment of Psychiatry, Centre for Human Drug Research, Leiden, NetherlandsDepartment of Psychiatry, Leiden University Medical Center, Leiden, NetherlandsDepartment of Radiology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Radiology, Leiden University Medical Center, Leiden, NetherlandsSumitomo Pharma Co., Ltd., Tokyo, JapanDepartment of Psychiatry, Leiden University Medical Center, Leiden, NetherlandsDepartment of Psychiatry, Centre for Human Drug Research, Leiden, NetherlandsDepartment of Psychiatry, Leiden University Medical Center, Leiden, NetherlandsIntroductionKetamine demonstrates robust and rapidly occurring antidepressant effects in patients with difficult-to-treat major depressive disorder. Ketamine’s antidepressant effects and its impact on functional networks in non-resistant forms of major depressive disorder are expected to provide valuable insight into ketamine’s mechanism of action related to depression.MethodsThis study employs an existing network model of major depressive disorder to investigate the effects of ketamine on resting state connectivity in a therapy-non-resistant major depressive disorder population. In a randomized, double-blind, placebo-controlled, cross-over study, 0.5 mg/kg racemic ketamine or 0.9%NaCl was administered intravenously in 16 MDD patients. We applied resting-state functional magnetic resonance imaging (rs-fMRI) to explore changes in functional brain connectivity directly at 50, 80 and 165 min (acute) and 24 h (delayed) following ketamine administration. A clinician-rated 10-item scale (MADRS) was administered at 165 min and 24 h after ketamine administration. Connections-of-interest (COIs) were based on the previously published corticolimbic-insular-striatalpallidal-thalamic (CLIPST) circuitry model of major depressive disorder.ResultsCompared with placebo, ketamine significantly (p < 0.0014) reduced the mean (SD) MADRS total score from 21.2 (5.9) pre-dose to 10.3 (4.6) 24 h post-dose. At both acute (p < 0.0172) and delayed (p < 0.0488) time points, significant rs-fMRI connectivity changes occurred only in MDD-related COIs as proposed by the CLIPST model. No changes in functional connectivity were found in non-CLIPST connections.DiscussionThis study demonstrates that ketamine specifically affects depression-related circuitry. Analyzing functional connectivity based on a neurocircuitry model of a specific CNS disease and drug action may be an effective approach that could result in a more targeted analysis in future pharmaco-fMRI studies in CNS drug development.https://www.frontiersin.org/articles/10.3389/fnins.2025.1531375/fullhypothesis-driven analysismajor depressive disorderketaminefunctional MRIglutamatergic modulatorNMDA receptor |
| spellingShingle | Kasper Recourt Joop Van Gerven Joop Van Gerven Nadieh Drenth Jeroen van der Grond Kantaro Nishigori Nic J. Van Der Wee Gabriël E. Jacobs Gabriël E. Jacobs Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depression Frontiers in Neuroscience hypothesis-driven analysis major depressive disorder ketamine functional MRI glutamatergic modulator NMDA receptor |
| title | Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depression |
| title_full | Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depression |
| title_fullStr | Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depression |
| title_full_unstemmed | Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depression |
| title_short | Ketamine effects on resting state functional brain connectivity in major depressive disorder patients: a hypothesis-driven analysis based on a network model of depression |
| title_sort | ketamine effects on resting state functional brain connectivity in major depressive disorder patients a hypothesis driven analysis based on a network model of depression |
| topic | hypothesis-driven analysis major depressive disorder ketamine functional MRI glutamatergic modulator NMDA receptor |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2025.1531375/full |
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