The effects of lithium: from mood stabilization to disease-modifying effects in neurological and psychiatric disorders

Lithium (Li⁺) remains a foundational treatment in psychiatry, particularly for bipolar disorder, manic episodes, and suicide prevention in major depressive disorder and other mood disorders. Although clinically used for decades, its molecular and systems-level mechanisms are not fully resolved. Beyond its psychiatric indications, lithium is increasingly recognized as a regulator of neuronal resilience, with emerging relevance for aging and neurodegenerative disease.Despite the serendipitous discovery of additional mood stabilizers, lithium's efficacy remains unmatched and extends beyond mood disorders potentially offering therapeutic effects in neurological and other brain-related conditions. Its long-term actions are thought to involve multiple interacting mechanisms of action, that, although increasingly characterised, remain not fully defined and require further investigation.At the cellular level, lithium modulates maturation processes within the central and peripheral nervous systems, neurogenesis, synaptic plasticity, intracellular trafficking, and organelle function and dynamics, involving mitochondria and lysosomes and trans-Golgi network derived structures. A key mechanism involves regulation of GSK3β signaling, with downstream effects on inflammation, cytoskeletal stability, and neuronal survival. Recent evidence indicates that endogenous lithium is dynamically regulated in the brain and may contribute to cognitive preservation during aging. Brain lithium levels are reduced in mild cognitive impairment and further diminished in Alzheimer’s disease (AD), potentially due to amyloid sequestration as suggested by recent findings. Experimental lithium depletion accelerates amyloid-β and tau pathology, neuroinflammation, synaptic loss, and cognitive decline, accompanied by transcriptomic changes overlapping with AD signatures. Together, these findings suggest that disruption of lithium homeostasis may represent an early contributor to neurodegenerative vulnerability.This Research Topic aims to integrate molecular mechanisms with behavioral outcomes across psychiatric and neurodegenerative disorders, providing a comprehensive and mechanistically grounded overview of lithium’s modulatory actions. We seek contributions that clarify how lithium modifies disease trajectories in mood disorders, preserves synaptic and circuit integrity, and may act as a disease-modifying intervention in AD. Particular attention will be given to long-term effects on cognitive, affective, and motor domains, including relevance to Parkinson’s disease (PD), as well as the epigenetic and transcriptomic consequences of lithium deficiency or chronic treatment.We welcome preclinical and translational studies addressing:• Cellular and molecular mechanisms underlying lithium’s modulation of psychiatric disease trajectories.• Long-term effects of lithium on brain circuits governing affective and cognitive behavior.• Regulation and physiological roles of endogenous brain lithium in ageing and cognitive resilience.• Disruption of lithium homeostasis in mild cognitive impairment and AD.• Lithium as a disease-modifying strategy in AD: preclinical and clinical evidence.• Lithium–amyloid interactions and strategies to enhance brain lithium bioavailability.• Effects of lithium on synaptic integrity, neuroinflammation, myelination, and neural circuit stability.• Molecular and morphological bases of lithium-induced motor and behavioral plasticity, including relevance to PD.• Epigenetic and transcriptomic consequences of lithium deficiency and long-term administration.• Development of lithium-mimetic compounds and novel lithium-based pharmacological strategies.This Research Topic positions lithium as both a therapeutic agent and a physiological regulator of brain integrity, bridging psychiatry, aging biology, and neurodegeneration within a unified mechanistic framework. Topic editors: Galila Agam, Francesco Fornai, Gabriele Sani Source: https://www.frontiersin.org/research-topics/78797/the-effects-of-lithium-from-mood-stabilization-to-disease-modifying-effects-in-neurological-and-psychiatric-disorders