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 Peer reviewed DOI: 10.3389/fcell.2026.1777975 via OpenAlex
Summary
Major depressive disorder is common but not fully understood, with traditional treatments like selective serotonin reuptake inhibitors often taking weeks to work and being ineffective for about one-third of patients. New rapid-acting treatments such as ketamine and psychedelics are shifting the focus from monoamines to glutamatergic signaling and other mechanisms. This review discusses both historical and new perspectives on antidepressant development and highlights advances in animal models and translational research.
Study at a glance
| Design | review |
|---|---|
| Key finding | Traditional antidepressants often take weeks to show effects and are ineffective for nearly one-third of patients, prompting exploration of rapid-acting alternatives. |
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.