Neural signaling mechanisms in depression: bridging classical monoamine hypotheses, animal models, and emerging antidepressant strategies
Mizuki Yamamoto, Haruka Hirakata, Koji Toda
Frontiers in Cell and Developmental Biology March 25, 2026 DOI: 10.3389/fcell.2026.1777975 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | General depression |
| Topics | Depression Serotonin |
| Keywords | Monoaminergic Antidepressant Monoamine neurotransmitter Reuptake inhibitor Fluoxetine Glutamatergic Neurotransmission Neurotransmitter systems Translational research Animal studies Adverse effect Schizophrenia object-oriented programming Animal model Pharmacology |
| Citations | 5 |
| Key findings | Recent discoveries of rapid-acting antidepressant effects of ketamine and psychedelic compounds have challenged traditional monoaminergic models and highlighted alternative mechanisms involving glutamatergic signaling, synaptic plasticity, and immune-brain interactions. |
Abstract
Major depressive disorder is a highly prevalent psychiatric condition that can affect individuals across the lifespan, yet its pathophysiology remains incompletely understood. Classical hypotheses, informed by preclinical and clinical studies, emphasized dysregulated monoaminergic neurotransmission and guided the development of widely prescribed antidepressants, including selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors. Although these agents improved treatment outcomes, they typically require weeks to achieve therapeutic effects, must be taken continuously, and fail to produce adequate responses in nearly one-third of patients. In addition, adverse effects, such as increased suicidal ideation in some populations, highlight the need for safer and more effective therapies. Recent discoveries of rapid-acting antidepressant effects of ketamine and psychedelic compounds have challenged traditional monoaminergic models and highlighted alternative mechanisms involving glutamatergic signaling, synaptic plasticity, and immune-brain interactions. At the same time, long-standing assumptions about neurotransmitter abnormalities are being re-examined, reinvigorating interest in mechanistic and circuit-level models. This review summarizes historical and emerging perspectives on antidepressant development, outlines major animal models of depression, and highlights recent advances in translational research that are redefining therapeutic strategies.
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
Cites 29
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology November 8, 2017
and 24 more in the library