Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trialResearch in context
Summary: Background: Intravenous (IV) ketamine has emerged as a rapid and effective treatment for TRD. However, the specific neural mechanisms of ketamine's effects in humans remains unclear. Although neuroplasticity is implicated as a mechanism of action in animal models, relatively few rando...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423004681 |
| _version_ | 1797377875882541056 |
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| author | Manivel Rengasamy Sanjay Mathew Robert Howland Angela Griffo Benjamin Panny Rebecca Price |
| author_facet | Manivel Rengasamy Sanjay Mathew Robert Howland Angela Griffo Benjamin Panny Rebecca Price |
| author_sort | Manivel Rengasamy |
| collection | DOAJ |
| description | Summary: Background: Intravenous (IV) ketamine has emerged as a rapid and effective treatment for TRD. However, the specific neural mechanisms of ketamine's effects in humans remains unclear. Although neuroplasticity is implicated as a mechanism of action in animal models, relatively few randomized controlled trials (RCTs) in TRD patients have examined ketamine's impact on functional connectivity, a posited functional marker of neuroplasticity—particularly in the context of a mood-induction paradigm (termed miFC). Methods: 152 adults with TRD (63% female; 37% male) were randomly allocated to receive a single infusion of ketamine or saline in a 2:1 ratio. We examined changes in connectivity (from baseline to 24-h post-infusion) that differed by treatment, and whether clinical treatment response at 24-h post-infusion was uniquely related (among patients allocated to ketamine relative to saline) to (1) pre-treatment connectivity and (2) changes in connectivity. We examined both miFC and rsFC, using prefrontal cortex and limbic seed regions. We also conducted a multiverse analysis to examine findings most robust against analytic decisions. Findings: Across both miFC and rsFC, ketamine was associated with greater in prefrontal/limbic connectivity compared to saline, and lower baseline connectivity of limbic and prefrontal regions predicted greater treatment response in patients receiving ketamine. Greater connectivity increases in participants receiving ketamine was uniquely related to greater treatment response. In addition, certain findings were identified as being reproducible against different analytic decisions in multiverse analyses. Interpretation: Our findings identify specific neural connectivity patterns impacted by ketamine and were uniquely related to outcomes following ketamine (relative to saline). These findings generally support prominent neuroplasticity models of ketamine's therapeutic efficacy. These findings lay new groundwork for understanding how to enhance and optimize ketamine treatments and develop novel rapid-acting treatments for depression. Funding: This research was supported by NIH grant R01MH113857 and by the Clinical and Translational Sciences Institute at the University of Pittsburgh (UL1-TR-001857). |
| first_indexed | 2024-03-08T19:59:40Z |
| format | Article |
| id | doaj.art-ee45826318594abdacce204e8d462dda |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-03-08T19:59:40Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-ee45826318594abdacce204e8d462dda2023-12-24T04:45:51ZengElsevierEBioMedicine2352-39642024-01-0199104902Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trialResearch in contextManivel Rengasamy0Sanjay Mathew1Robert Howland2Angela Griffo3Benjamin Panny4Rebecca Price5Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Corresponding author. Department of Psychiatry, Western Psychiatric Hospital, Pittsburgh, PA.Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA; Michael E. Debakey VA Medical Center, Houston, TX, USA; The Menninger Clinic, Houston, TX, USADepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USADepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USADepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USADepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USASummary: Background: Intravenous (IV) ketamine has emerged as a rapid and effective treatment for TRD. However, the specific neural mechanisms of ketamine's effects in humans remains unclear. Although neuroplasticity is implicated as a mechanism of action in animal models, relatively few randomized controlled trials (RCTs) in TRD patients have examined ketamine's impact on functional connectivity, a posited functional marker of neuroplasticity—particularly in the context of a mood-induction paradigm (termed miFC). Methods: 152 adults with TRD (63% female; 37% male) were randomly allocated to receive a single infusion of ketamine or saline in a 2:1 ratio. We examined changes in connectivity (from baseline to 24-h post-infusion) that differed by treatment, and whether clinical treatment response at 24-h post-infusion was uniquely related (among patients allocated to ketamine relative to saline) to (1) pre-treatment connectivity and (2) changes in connectivity. We examined both miFC and rsFC, using prefrontal cortex and limbic seed regions. We also conducted a multiverse analysis to examine findings most robust against analytic decisions. Findings: Across both miFC and rsFC, ketamine was associated with greater in prefrontal/limbic connectivity compared to saline, and lower baseline connectivity of limbic and prefrontal regions predicted greater treatment response in patients receiving ketamine. Greater connectivity increases in participants receiving ketamine was uniquely related to greater treatment response. In addition, certain findings were identified as being reproducible against different analytic decisions in multiverse analyses. Interpretation: Our findings identify specific neural connectivity patterns impacted by ketamine and were uniquely related to outcomes following ketamine (relative to saline). These findings generally support prominent neuroplasticity models of ketamine's therapeutic efficacy. These findings lay new groundwork for understanding how to enhance and optimize ketamine treatments and develop novel rapid-acting treatments for depression. Funding: This research was supported by NIH grant R01MH113857 and by the Clinical and Translational Sciences Institute at the University of Pittsburgh (UL1-TR-001857).http://www.sciencedirect.com/science/article/pii/S2352396423004681KetamineNeural connectivityRCTResting-statePositive mood induction |
| spellingShingle | Manivel Rengasamy Sanjay Mathew Robert Howland Angela Griffo Benjamin Panny Rebecca Price Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trialResearch in context EBioMedicine Ketamine Neural connectivity RCT Resting-state Positive mood induction |
| title | Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trialResearch in context |
| title_full | Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trialResearch in context |
| title_fullStr | Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trialResearch in context |
| title_full_unstemmed | Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trialResearch in context |
| title_short | Neural connectivity moderators and mechanisms of ketamine treatment among treatment-resistant depressed patients: a randomized controlled trialResearch in context |
| title_sort | neural connectivity moderators and mechanisms of ketamine treatment among treatment resistant depressed patients a randomized controlled trialresearch in context |
| topic | Ketamine Neural connectivity RCT Resting-state Positive mood induction |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423004681 |
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