Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression
J. Siegel, Ben J Palanca, Beau M Ances, E. Kharasch, J. Schweiger, Michael D Yingling, Abraham Z. Snyder, Ginger E. Nicol, Eric J Lenze, Nuri B Farber
Psychopharmacology January 22, 2021 DOI: 10.1007/s00213-021-05762-6 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Open-label, proof-of-principle study Peer reviewed |
|---|---|
| Sample size | 23 |
| Population | Adults with treatment-resistant depression |
| Interventions | Ketamine Clonidine |
| Dose | 0.15 mg/kg/h titrated toward 0.6 mg/kg/h |
| Duration | 96-hour infusion, 8-week follow-up |
| Topics | Depression Esketamine Ketamine |
| Citations | 53 |
| Registration | NCT01179009 |
| Key points | A single prolonged ketamine infusion provides a tolerated, rapid, and sustained antidepressant response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. |
Abstract
Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov: Treatment Resistant Depression (Pilot), NCT01179009.
Comparable studies
Other non-randomized and open-label trials on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder Subjects with DSM-IV-diagnosed treatment-resistant major depressive disorder | 2010 | Open-label trial | n = 33 |
| Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression Adults (≥ 18 years) with treatment-resistant depression | 2020 | Phase 3, open-label, multicenter, long-term study | n = 802 |
| Intravenous arketamine for treatment-resistant depression: open-label pilot study Humans with treatment-resistant depression | 2020 | Open-label pilot trial | n = 7 |
| A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide. Hospitalized patients with Major Depressive Disorder and acute suicidal ideation and... | 2024 | Open label study | n = 17 |
| Ketamine Safety and Tolerability in Clinical Trials for Treatment-Resistant Depression Participants with DSM-IV-defined major depressive disorder and treatment-resistant... | 2014 | Pooled analysis of three clinical trials | n = 97 |
Citations in the library
Cited by 24
- Psilocybin desynchronizes the human brain. Nature August 1, 2024
- The anterior cingulate cortex as a key locus of ketamine’s antidepressant action Neuroscience & Biobehavioral Reviews May 10, 2021
- Ketamine as a therapeutic agent for depression and pain: mechanisms and evidence. Journal of Neurological Sciences 2022
- Brain-based correlates of antidepressant response to ketamine: a comprehensive systematic review of neuroimaging studies. The Lancet Psychiatry October 1, 2023
- Intrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review Frontiers in Psychiatry May 26, 2022
and 19 more in the library
Cites 17
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
- Ketamine for chronic pain: risks and benefits British Journal of Clinical Pharmacology February 21, 2013
and 12 more in the library