Rhythms of mood: Bidirectional regulation of molecular clocks and neurotransmission in affective disorders

Mood disorders, primarily major depressive and bipolar disorder, are characterized by significant neurochemical dysregulation and disturbances in biological rhythms. Recent evidence suggests for a complex, bidirectional interplay between the molecular circadian clock and major neurotransmitter systems, including monoamines (dopamine, serotonin, and norepinephrine), glutamate and GABA. While the suprachiasmatic nucleus acts as the master pacemaker, local clocks in limbic regions—such as the prefrontal cortex, hippocampus, ventral tegmental area and nucleus accumbens—maintain semi-autonomous oscillations that can decouple under stress, contributing to mood dysregulation. This review synthesizes findings from animal models and clinical research demonstrating how core clock genes directly regulate neural networks controlling reward, stress responses and synaptic plasticity. Conversely, neurotransmitter signaling provides critical feedback to entrain or disrupt these local molecular rhythms. By combining circadian modulation with neurotransmission, this review provides a framework for understanding mood disorders pathophysiology and identifying novel therapeutic approaches. These insights might facilitate the development of precision chronotherapies and interventions for treatment, highlighting the essential role of circadian clock in psychiatry. • Circadian mechanisms and neurotransmitter systems exert bidirectional regulation fundamental for the pathogenesis and treatment of mood disorders • Core clock genes modulate mood by regulating region- and cell type-specific brain networks that control monoaminergic signaling and glutamatergic plasticity • Local clocks in limbic brain regions like the PFC and hippocampus can decouple from the master pacemaker during stress, leading to dysregulated plasticity and mood • Neurotransmitters such as dopamine, serotonin and noradrenaline provide essential feedback to entrain or disrupt molecular oscillations • Integrating circadian modulation with neurotransmission offers a powerful framework for developing novel chronotherapies and precision interventions for treatment-resistant MDD and BD