Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections
Dialogues in Clinical Neuroscience March 31, 2014 DOI: 10.31887/dcns.2014.16.1/rduman (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression |
| Keywords | Glutamate receptor Antidepressant Glutamatergic Neurotransmission Nmda receptor Neurotrophic factors Hippocampus Synapse Brain-derived neurotrophic factor |
| Citations | 248 |
| Key findings | Ketamine and scopolamine rapidly increase spine synapses in the prefrontal cortex and reverse stress-induced synaptic deficits through glutamate transmission and BDNF signaling. |
Abstract
Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.
Comparable studies
Other narrative reviews on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets | 2012 | Review | |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse | 2003 | 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 | |
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Sudarshan Kriya Yogic Breathing in the Treatment of Stress, Anxiety, and Depression: Part II—Clinical Applications and Guidelines | 2005 | Review |
Citations in the library
Cited by 35
- The neuropsychopharmacology of cannabis: A review of human imaging studies Pharmacology & Therapeutics October 20, 2018
- Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants The Annual Review of Pharmacology and Toxicology October 9, 2018
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants Translational Psychiatry September 20, 2016
- The Effects of Ketamine on Cognition in Treatment-Resistant Depression: A Systematic Review and Priority Avenues for Future Research. Neuroscience & Biobehavioral Reviews November 23, 2020
and 30 more in the library
Cites 13
- 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
- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
- Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase Science December 6, 2007
- Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects Molecular Psychiatry October 15, 2013
and 8 more in the library