Leveraging Neuroplasticity to Enhance Adaptive Learning: The Potential for Synergistic Somatic-Behavioral Treatment Combinations to Improve Clinical Outcomes in Depression.
Samuel T. Wilkinson, Paul E. Holtzheimer, Shan Gao, David S Kirwin, Rebecca B Price
Biological Psychiatry September 20, 2018 DOI: 10.1016/j.biopsych.2018.09.004 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine D-cycloserine Electroconvulsive therapy Transcranial brain stimulation |
| Topics | Depression Ketamine Neuroplasticity |
| Keywords | Humans Antidepressive agents Combined modality therapy Electroconvulsive therapy Behavior therapy Neuronal plasticity Transcranial magnetic stimulation Neuromodulation |
| Key findings | The authors argue that plasticity-enhancing biological treatments (ketamine, D-cycloserine, electroconvulsive therapy, transcranial brain stimulation) reduce depressive symptoms but relapse often occurs after discontinuation. They propose that combining these treatments with cognitive or behavioral interventions during a window of enhanced neuroplasticity could yield synergistic, longer-lasting clinical improvements, though key evidence is still missing. |
Abstract
Until recently, therapeutic development in psychiatry was targeted solely toward symptom reduction. While this is a worthwhile goal, it has yielded little progress in improved therapeutics in the last several decades in the field of mood disorders. Recent advancements in our understanding of pathophysiology suggests that an impairment of neuroplasticity may be a critical part of the development of neuropsychiatric disorders. Interventions that enhance or modulate neuroplasticity often reduce depressive symptoms when applied as stand-alone treatments. Unfortunately, when treatments are discontinued, the disease state often returns as patients relapse. However, treatments that enhance or modulate plasticity not only reduce symptom burden, but also may provide an opportune window wherein cognitive or behavioral interventions could be introduced to harness a state of enhanced neuroplasticity and lead to improved longer-term clinical outcomes. Here, we review the potential of synergistically combining plasticity-enhancing and behavioral therapies to develop novel translational treatment approaches for depression. After reviewing relevant neuroplasticity deficits in depression, we survey biological treatments that appear to reverse such deficits in humans, including N-methyl-D-aspartate receptor modulators (ketamine, D-cycloserine), electroconvulsive therapy, and transcranial brain stimulation. We then review evidence that either directly or indirectly supports the hypothesis that a robust enhancement of neuroplasticity through these methods might promote the uptake of cognitive and behavioral interventions to enhance longer-term treatment outcomes through a synergistic effect. We identify key missing pieces of evidence and discuss future directions to enhance this emerging line of research.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| 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: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cited by 21
- Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial Psychotherapy and Psychosomatics 2021
- Psilocybin's lasting action requires pyramidal cell types and 5-HT2A receptors. Nature June 1, 2025
- The Psychedelic Future of Post-Traumatic Stress Disorder Treatment Current Neuropharmacology January 5, 2024
- At-home, sublingual ketamine telehealth is a safe and effective treatment for moderate to severe anxiety and depression: Findings from a large, prospective, open-label effectiveness trial. Journal of Affective Disorders July 1, 2022
- Toward Synergies of Ketamine and Psychotherapy Frontiers in Psychology March 25, 2022
and 16 more in the library
Cites 13
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine use: a review Addiction July 21, 2011
- Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression American Journal of Psychiatry October 1, 2015
- Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics Annual Review of Medicine October 23, 2014
and 8 more in the library