Rachael L Sumner1, Rebecca McMillan2, Meg J Spriggs3, Doug Campbell4, Gemma Malpas4, Elizabeth Maxwell4, Carolyn Deng4, John Hay4, Rhys Ponton2, Ian J Kirk5, Frederick Sundram6, Suresh D Muthukumaraswamy2. 1. School of Pharmacy, University of Auckland, Auckland, New Zealand. Electronic address: rsum009@aucklanduni.ac.nz. 2. School of Pharmacy, University of Auckland, Auckland, New Zealand. 3. School of Psychology, University of Auckland, Auckland, New Zealand; Brain Research New Zealand, Aukland, New Zealand; Centre for Psychedelic Research, Department of Medicine, Imperial College London, London, United Kingdom. 4. Department of Anaesthesia and Perioperative Medicine, Auckland District Health Board, Auckland, New Zealand. 5. School of Psychology, University of Auckland, Auckland, New Zealand; Brain Research New Zealand, Aukland, New Zealand. 6. Department of Psychological Medicine, University of Auckland, Auckland, New Zealand.
Abstract
BACKGROUND: The rapid-acting clinical effects of ketamine as a novel treatment for depression along with its complex pharmacology have made it a growing research area. One of the key mechanistic hypotheses for how ketamine works to alleviate depression is by enhancing long-term potentiation (LTP)-mediated neural plasticity. METHODS: The objective of this study was to investigate the plasticity hypothesis in 30 patients with depression noninvasively using visual LTP as an index of neural plasticity. In a double-blind, active placebo-controlled crossover trial, electroencephalography-based LTP was recorded approximately 3 to 4 hours following a single 0.44-mg/kg intravenous dose of ketamine or active placebo (1.7 ng/mL remifentanil) in 30 patients. Montgomery-Åsberg Depression Rating Scale scores were used to measure clinical symptoms. Visual LTP was measured as a change in the visually evoked potential following high-frequency visual stimulation. Dynamic causal modeling investigated the underlying neural architecture of visual LTP and the contribution of ketamine. RESULTS:Montgomery-Åsberg Depression Rating Scale scores revealed that 70% of participants experienced 50% or greater reduction in their depression symptoms within 1 day of receiving ketamine. LTP was demonstrated in the N1 (p = .00002) and P2 (p = 2.31 × 10-11) visually evoked components. Ketamine specifically enhanced P2 potentiation compared with placebo (p = .017). Dynamic causal modeling replicated the recruitment of forward and intrinsic connections for visual LTP and showed complementary effects of ketamine indicative of downstream and proplasticity modulation. CONCLUSIONS: This study provides evidence that LTP-based neural plasticity increases within the time frame of the antidepressant effects of ketamine in humans and supports the hypothesis that changes to neural plasticity may be key to the antidepressant properties of ketamine.
RCT Entities:
BACKGROUND: The rapid-acting clinical effects of ketamine as a novel treatment for depression along with its complex pharmacology have made it a growing research area. One of the key mechanistic hypotheses for how ketamine works to alleviate depression is by enhancing long-term potentiation (LTP)-mediated neural plasticity. METHODS: The objective of this study was to investigate the plasticity hypothesis in 30 patients with depression noninvasively using visual LTP as an index of neural plasticity. In a double-blind, active placebo-controlled crossover trial, electroencephalography-based LTP was recorded approximately 3 to 4 hours following a single 0.44-mg/kg intravenous dose of ketamine or active placebo (1.7 ng/mL remifentanil) in 30 patients. Montgomery-Åsberg Depression Rating Scale scores were used to measure clinical symptoms. Visual LTP was measured as a change in the visually evoked potential following high-frequency visual stimulation. Dynamic causal modeling investigated the underlying neural architecture of visual LTP and the contribution of ketamine. RESULTS: Montgomery-Åsberg Depression Rating Scale scores revealed that 70% of participants experienced 50% or greater reduction in their depression symptoms within 1 day of receiving ketamine. LTP was demonstrated in the N1 (p = .00002) and P2 (p = 2.31 × 10-11) visually evoked components. Ketamine specifically enhanced P2 potentiation compared with placebo (p = .017). Dynamic causal modeling replicated the recruitment of forward and intrinsic connections for visual LTP and showed complementary effects of ketamine indicative of downstream and proplasticity modulation. CONCLUSIONS: This study provides evidence that LTP-based neural plasticity increases within the time frame of the antidepressant effects of ketamine in humans and supports the hypothesis that changes to neural plasticity may be key to the antidepressant properties of ketamine.
Authors: Rebecca B Price; Nicholas Kissel; Andrew Baumeister; Rebecca Rohac; Mary L Woody; Elizabeth D Ballard; Carlos A Zarate; William Deakin; Chadi G Abdallah; Adriana Feder; Dennis S Charney; Michael F Grunebaum; J John Mann; Sanjay J Mathew; Bronagh Gallagher; Declan M McLoughlin; James W Murrough; Suresh Muthukumaraswamy; Rebecca McMillan; Rachael Sumner; George Papakostas; Maurizio Fava; Rebecca Hock; Jennifer L Phillips; Pierre Blier; Paulo Shiroma; Peter Šóš; Tung-Ping Su; Mu-Hong Chen; Mikael Tiger; Johan Lundberg; Samuel T Wilkinson; Meredith L Wallace Journal: Mol Psychiatry Date: 2022-09-07 Impact factor: 13.437
Authors: Michael S Jacob; Brian J Roach; Holly K Hamilton; Ricardo E Carrión; Aysenil Belger; Erica Duncan; Jason Johannesen; Matcheri Keshavan; Sandra Loo; Margaret Niznikiewicz; Jean Addington; Carrie E Bearden; Kristin S Cadenhead; Tyrone D Cannon; Barbara A Cornblatt; Thomas H McGlashan; Diana O Perkins; William Stone; Ming Tsuang; Elaine F Walker; Scott W Woods; Daniel H Mathalon Journal: Schizophr Res Date: 2021-03-02 Impact factor: 4.939