A continuum hypothesis of psychotomimetic rapid antidepressants.
Joost Haarsma, Catherine J Harmer, Sandra Tamm
Brain and Neuroscience Advances 2021 DOI: 10.1177/23982128211007772 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine classical psychedelics sleep deprivation |
| Topics | Ketamine |
| Keywords | Sleep deprivation Predictive coding Psychedelics Rapid antidepressants Psychotomimetics |
| Key findings | The authors propose that ketamine, classical psychedelics, and sleep deprivation are acute antidepressants partly through the same mechanisms that produce their psychotomimetic effects, and hypothesize that these interventions share a common mechanism of increasing the flexibility of prior expectations within a hierarchical predictive coding framework. |
Abstract
Ketamine, classical psychedelics and sleep deprivation are associated with rapid effects on depression. Interestingly, these interventions also have common psychotomimetic actions, mirroring aspects of psychosis such as an altered sense of self, perceptual distortions and distorted thinking. This raises the question whether these interventions might be acute antidepressants through the same mechanisms that underlie some of their psychotomimetic effects. That is, perhaps some symptoms of depression can be understood as occupying the opposite end of a spectrum where elements of psychosis can be found on the other side. This review aims at reviewing the evidence underlying a proposed continuum hypothesis of psychotomimetic rapid antidepressants, suggesting that a range of psychotomimetic interventions are also acute antidepressants as well as trying to explain these common features in a hierarchical predictive coding framework, where we hypothesise that these interventions share a common mechanism by increasing the flexibility of prior expectations. Neurobiological mechanisms at play and the role of different neuromodulatory systems affected by these interventions and their role in controlling the precision of prior expectations and new sensory evidence will be reviewed. The proposed hypothesis will also be discussed in relation to other existing theories of antidepressants. We also suggest a number of novel experiments to test the hypothesis and highlight research areas that could provide further insights, in the hope to better understand the acute antidepressant properties of these interventions.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 7
- Toward Synergies of Ketamine and Psychotherapy Frontiers in Psychology March 25, 2022
- Reconsidering "dissociation" as a predictor of antidepressant efficacy for esketamine. Psychopharmacology April 1, 2023
- Efficacy of Ketamine with and without Lamotrigine in Treatment-Resistant Depression: A Preliminary Report Pharmaceuticals August 1, 2023
- Neurocognitive effects of psilocybin: A systematic and comprehensive review of neuroimaging studies in humans. Neuroscience & Biobehavioral Reviews August 1, 2025
- Psychotomimetic compensation versus sensitization. Pharmacology Research & Perspectives August 1, 2024
and 2 more in the library
Cites 53
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
and 48 more in the library