Acute Ketamine Modulated Functional Brain Coupling and Dissociative and Affective States in Human Subjects: Interim Analyses
Laura M Hack, Katherine G. Warthen, Xue Zhang, Boris D. Heifets, Trisha Suppes, Peter J van Roessel, Carolyn I. Rodríguez, Brian Knutson, Leanne M Williams
bioRxiv Preprint Server September 20, 2021 preprint DOI: 10.1101/2021.09.20.460992 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blinded, placebo-controlled, within-subjects mechanistic trial |
|---|---|
| Sample size | 7 |
| Population | Healthy adult subjects |
| Intervention | subanesthetic racemic intravenous (IV) ketamine |
| Dose | two fixed doses of subanesthetic racemic IV ketamine |
| Topics | Anxiety Ketamine Esketamine |
| Keywords | Drug Dissociative Brain function Brain connectivity Neural circuits Neurobiology Brain pathways Mental health Mood Emotions Stress Dissociation Therapeutic potential Treatment Perception Mental states |
| Citations | 2 |
| Key findings | Ketamine induces dose-dependent dissociation and intoxication, alters affective states, and changes functional brain connectivity, with specific coupling patterns correlating with dissociative, affective, and stress responses. |
Abstract
Ketamine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor that is both a drug of abuse and an FDA-approved anesthetic used off-label for treatment-resistant depression. Despite its growing clinical use for depression and pain, the relationships between the acute dissociative and affective effects of ketamine that contribute to its abuse liability and therapeutic potential, along with the neural mechanisms underlying these effects, are not well established. To address this need, we have implemented a randomized, double-blinded, placebo-controlled, within-subjects mechanistic trial. Healthy adult subjects undergo infusion with two fixed doses of subanesthetic racemic intravenous (IV) ketamine and placebo and their acute responses are assessed with self-report questionnaires, behavioral measures, hormone levels, and neuroimaging. As planned in our analysis strategy, we present interim results for the first 7 subjects of our study, focusing on dissociative and affective states and resting functional brain coupling signatures of these states. The first key finding was that ketamine induced dose-dependent increases in dissociation and related intoxication. Ketamine also altered affective states, reducing emotional insensitivity but increasing stress assessed by cortisol. Second, ketamine had an effect on altering brain connectivity, particularly for specific connections between regions of the reward and negative affect circuits and involving thalamic sub-regions. Third, regarding brain-response associations, ketamine-induced increases in amygdala-anteroventral thalamus coupling were correlated with greater dissociation and intoxication, whereas decreases in the coupling of the anteromedial thalamus and posterior parietal thalamus were correlated with increased sensory aspects of reward responsiveness. Additional specific correlations were observed between affective measures relevant to reward responsiveness or its absence and drug-altered changes in localized functional connections involving the nucleus accumbens (NAcc), amygdala, and thalamic sub-regions. We also discovered a consistent profile of negative associations between ketamine altered connectivity involving the NAcc and specific thalamic sub-regions and effects of anxiety. Further, drug-altered increases in the coupling of the amygdala and anteroventral thalamus were associated with increases in cortisol, an indicator of biochemical stress. The findings highlight the utility of integrating self-reports, objective measures, and functional neuroimaging to disentangle the brain states underlying specific acute responses induced by ketamine. With the likely continued expansion of FDA indications for ketamine, understanding acute responses and underlying neural mechanisms is important for maximizing the therapeutic potential of ketamine while minimizing the risk of promoting misuse or abuse of this substance.
Comparable studies
Other randomized controlled trials on ketamine for anxiety, most cited first.