Neural signaling mechanisms in depression: bridging classical monoamine hypotheses, animal models, and emerging antidepressant strategies

Major depressive disorder affects many people across their lives, but its biological causes are still not fully understood. Older theories focused on imbalances in monoamine neurotransmitters like serotonin, leading to common antidepressants such as selective serotonin reuptake inhibitors. These drugs can take weeks to work, must be taken continuously, and fail to help about one-third of patients, while also carrying risks like increased suicidal thoughts in some groups. Newer findings show that ketamine and psychedelic compounds can produce rapid antidepressant effects by acting on glutamate signaling, synaptic plasticity, and immune-brain interactions, challenging the older models. This review covers both historical and emerging views on antidepressant development, describes major animal models of depression, and discusses recent translational research that is reshaping treatment approaches.

Study at a glance

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.