Intranasal (R)-ketamine modulates depression symptom and neurotransmitters-associated human brain connectivity.

Racemic (R,S)-ketamine exerts rapid antidepressant effects, and growing evidence suggests its R-isomer may offer sustained efficacy with fewer side effects. However, the neurobiological mechanisms underlying (R)-ketamine's action in the human brain are largely unknown. To address this, we acquired resting-state fMRI data from 32 healthy volunteers 24 ​h before and after intranasal administration of (R)-ketamine (n ​= ​24) or placebo (n ​= ​8). We primarily assessed changes in long-range functional synchrony using degree centrality (DC) and elucidated the sources of these changes with functional connectivity (FC) analysis. (R)-ketamine significantly decreased DC in a key cognitive-motor integration hub: the supplementary motor area/middle cingulate cortex (SMA/MCC, cluster-corrected P ​< ​0.05). Critically, the reduction of DC was absent under the placebo condition, yielding a significant group-by-time interaction (P ​= ​0.01). The reduction in long-range synchrony of the SMA/MCC was primarily driven by attenuated FC with both the dorsal medial prefrontal cortex/dorsal anterior cingulate cortex (dMPFC/dACC) and the cerebellum, and was spatially correlated with serotonin, norepinephrine, and acetylcholine neurotransmitter profiles. More importantly, the clinical relevance of the neuroimaging phenotypes was established in an independent Major Depressive Disorder (MDD) cohort, where FC between the SMA/MCC and dMPFC/dACC significantly correlated with depressive symptom severity (HAMD score, P ​= ​0.019). This study provides novel, system-level evidence that intranasal (R)-ketamine modulates specific human brain networks by attenuating long-range synchrony in the SMA/MCC. The link between the neuroimaging phenotype, depression-relevant neurotransmitter profiles, and clinical symptom severity may offer a plausible therapeutic mechanism of (R)-ketamine.

• Publication year

  2025

• Venue

  Neurotherapeutics

• Publication date

  2025-11-01

• Fields of study

  Medicine, Psychology

• Identifiers
  DOI 10.1016/j.neurot.2025.e00790PMID 41224612PMCID PMC12976523
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The brain’s action-mode network

  2025cited by this paper
• Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms

  2024cited by this paper
• Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder

  2024cited by this paper
• The role of pre‐supplementary motor cortex in action control with emotional stimuli: A repetitive transcranial magnetic stimulation study

  2024cited by this paper
• Frontostriatal salience network expansion in individuals in depression

  2024cited by this paper
• The neural signature of psychomotor disturbance in depression

  2023cited by this paper
• A somato-cognitive action network alternates with effector regions in motor cortex

  2023cited by this paper
• White matter dysfunction in psychiatric disorders is associated with neurotransmitter and genetic profiles

  2023cited by this paper
• TMS over the pre-SMA enhances semantic cognition via remote network effects on task-based activity and connectivity

  2023cited by this paper
• Toward coordinate-based cognition dictionaries: A brainmap and neurosynth demo.

  2022cited by this paper
• The serotonin theory of depression: a systematic umbrella review of the evidence

  2022cited by this paper
• PhiPipe: A multi‐modal MRI data processing pipeline with test–retest reliability and predicative validity assessments

  2022cited by this paper
• The middle cingulate cortex and dorso-central insula: A mirror circuit encoding observation and execution of vitality forms

  2021cited by this paper
• Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability

  2021cited by this paper
• Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

  2021cited by this paper
• Intravenous arketamine for treatment-resistant depression: open-label pilot study

  2020cited by this paper
• Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals

  2020cited by this paper
• Reduced default mode network functional connectivity in patients with recurrent major depressive disorder

  2019cited by this paper
• Intrinsic connectomes are a predictive biomarker of remission in major depressive disorder

  2019cited by this paper
• (R)‐ and (S)‐ketamine induce differential fMRI responses in conscious rats

  2019cited by this paper
• (R)‐Ketamine exerts antidepressant actions partly via conversion to (2R,6R)‐hydroxynorketamine, while causing adverse effects at sub‐anaesthetic doses

  2019cited by this paper
• Resting-state brain network features associated with short-term skill learning ability in humans and the influence of N-methyl-d-aspartate receptor antagonism

  2018cited by this paper
• (2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice

  2018cited by this paper
• Cholinergic Regulation of Mood: From Basic and Clinical Studies to Emerging Therapeutics

  2018cited by this paper
• The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis.

  2017cited by this paper
• Ketamine Treatment and Global Brain Connectivity in Major Depression

  2017cited by this paper
• Local-Global Parcellation of the Human Cerebral Cortex From Intrinsic Functional Connectivity MRI

  2017cited by this paper
• Ketamine Has Distinct Electrophysiological and Behavioral Effects in Depressed and Healthy Subjects

  2017cited by this paper
• Test-retest reliability of functional connectivity networks during naturalistic fMRI paradigms

  2016cited by this paper
• The effects of low‐dose ketamine on the prefrontal cortex and amygdala in treatment‐resistant depression: A randomized controlled study

  2016cited by this paper
• Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs.

  2015cited by this paper
• Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial

  2015cited by this paper
• Metabolic connectivity mapping reveals effective connectivity in the resting human brain

  2015cited by this paper
• R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects

  2015cited by this paper
• Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism

  2015cited by this paper
• R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine.

  2014cited by this paper
• Functional and Structural Alterations in the Cingulate Motor Area Relate to Decreased Fronto-Striatal Coupling in Major Depressive Disorder with Psychomotor Disturbances

  2014cited by this paper
• Disrupting SMA activity modulates explicit and implicit emotional responses: an rTMS study.

  2014cited by this paper
• Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels

  2013cited by this paper
• The role of the midcingulate cortex in monitoring others' decisions

  2013cited by this paper
• Network centrality in the human functional connectome.

  2012cited by this paper
• The organization of the human cerebral cortex estimated by intrinsic functional connectivity.

  2011cited by this paper
• The importance of norepinephrine in depression

  2011cited by this paper
• The oscillating brain: Complex and reliable

  2010cited by this paper
• Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport

  2009cited by this paper
• Energy-Efficient Action Potentials in Hippocampal Mossy Fibers

  2009cited by this paper
• Functional role of the supplementary and pre-supplementary motor areas

  2008cited by this paper
• Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI.

  2007cited by this paper
• Meta-analysis of the factor structures of four depression questionnaires: Beck, CES-D, Hamilton, and Zung.

  2006cited by this paper
• A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.

  2006cited by this paper
• Regional homogeneity approach to fMRI data analysis

  2004cited by this paper
• Mapping context and content: the BrainMap model

  2002cited by this paper
• Antidepressant effects of ketamine in depressed patients.

  2000cited by this paper
• Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET).

  1997cited by this paper
• New concepts of the supplementary motor area.

  1996cited by this paper

• No citing papers are available for this paper.