New Advances in the Pharmacology and Toxicology of Lithium: A Neurobiologically Oriented Overview

Abstract

Over the last six decades, lithium has been considered the gold standard treatment for the long-term management of bipolar disorder due to its efficacy in preventing both manic and depressive episodes as well as suicidal behaviors. Nevertheless, despite numerous observed effects on various cellular pathways and biologic systems, the precise mechanism through which lithium stabilizes mood remains elusive. Furthermore, there is recent support for the therapeutic potential of lithium in other brain diseases. This review offers a comprehensive examination of contemporary understanding and predominant theories concerning the diverse mechanisms underlying lithium's effects. These findings are based on investigations utilizing cellular and animal models of neurodegenerative and psychiatric disorders. Recent studies have provided additional support for the significance of glycogen synthase kinase-3 (GSK3) inhibition as a crucial mechanism. Furthermore, research has shed more light on the interconnections between GSK3-mediated neuroprotective, antioxidant, and neuroplasticity processes. Moreover, recent advancements in animal and human models have provided valuable insights into how lithium-induced modifications at the homeostatic synaptic plasticity level may play a pivotal role in its clinical effectiveness. We focused on findings from translational studies suggesting that lithium may interface with microRNA expression. Finally, we are exploring the repurposing potential of lithium beyond bipolar disorder. These recent findings on the therapeutic mechanisms of lithium have provided important clues toward developing predictive models of response to lithium treatment and identifying new biologic targets. SIGNIFICANCE STATEMENT: Lithium is the drug of choice for the treatment of bipolar disorder, but its mechanism of action in stabilizing mood remains elusive. This review presents the latest evidence on lithium's various mechanisms of action. Recent evidence has strengthened glycogen synthase kinase-3 (GSK3) inhibition, changes at the level of homeostatic synaptic plasticity, and regulation of microRNA expression as key mechanisms, providing an intriguing perspective that may help bridge the mechanistic gap between molecular functions and its clinical efficacy as a mood stabilizer.

Fig. 1

Lithium (Li⁺) modulates a number of cellular pathways in the brain involved in neuroplasticity and neuroprotection. Inhibition of GSK3 is clearly central to its therapeutic mechanisms. Recent research has elucidated the direct and indirect effects of lithium on neurotrophic response, ER stress, UPR, autophagy, oxidative stress, inflammation, and mitochondrial function, mechanisms modulated by lithium that facilitate cell viability. Lithium elicits homeostatic synaptic plasticity that is dependent on AMPAR expression on the cell surface and requires BDNF/TrkB signaling. Structural imaging studies indicate that lithium may lead to neuroprotection by increasing gray matter volumes in the amygdala, hippocampus, and prefrontal cortex. Conversely, findings from neuropsychological and functional magnetic resonance imaging studies suggest that the overall influence of lithium on cognition leans toward potential cognitive impairment. Different biologic pathways might be targeted during affective episodes: neurotransmitter modulation, inhibition of GSK-3 and dopamine regulation in mania, enhancement of neuroplasticity and neurotransmitter modulation in depression and cAMP signaling, and glutamate and GABA regulation during maintenance phases. MARCKS, myristoylated alanine-rich C kinase substrate.

Fig. 2

Representative scheme of the main molecular and cellular targets modulated directly and indirectly by lithium (Li⁺). Lithium inhibits IMPase (A), including inositol polyphosphate 1-phosphatase (IPPase), fructose 1,6-bisphosphatase (FBPase), and bisphosphate nucleotidases (BPntase). These enzymes are part of the phosphatidylinositol 4,5-bisphosphate (PIP2) cycle, one of the signaling pathways underlying many cellular functions, such as G-coupled neurotransmitter receptors (GPCR) signaling, cytokinesis, endocytosis, and apoptosis. Phospholipase C (PLC) mediates the hydrolysis of PIP2 to the secondary messengers diacylglycerol (DAG) and IP3, which, in turn, activate downstream signaling pathways, including PKC and IP3 receptor (IP3R)/ER stress/ UPR. Therefore, lithium inhibits ER stress (ERS), altered UPR signaling, and increased intracellular Ca²⁺ levels through depletion of free inositol (B) and subsequent lower IP3 levels and IP3R activation (C). ERS and abnormal UPR result in the buildup of misfolded or unfolded proteins, faulty autophagy, and cell death via apoptosis. Lithium acts to counter these effects through the IP3/IP3R mechanism (C). Lithium directly inhibits GSK3 and facilitates the phosphorylation of GSK3 at the N-terminal serine (D). Lithium also acts by inhibiting PKC (D) through an intricate myristoylated alanine-rich C kinase substrate (MARCKS) pathway initiated by its inhibition of GSK3 (D). Inhibition of PKC and GSK3 by lithium prevents the potentially harmful effects of downstream activation of these pathways. These include 1) oxidative stress pathway (E) due to accumulation of reactive oxygen species (ROS) scavenged from damaged mitochondria and downregulation of the transcriptional nuclear factor (erythroid-derived 2)-like 2 (Nrf2); 2) impaired transcription of neurotrophic, neuroprotective, and antioxidant genes (F), such as BDNF, vascular endothelial growth neurotrophic (VEGF), IGF, Bcl-2, and Nrf2, which is reversed by lithium through inhibition of GSK3 (D) and activation of the CREB transcription factor placed downstream of GPCRs (F); 3) activation of the inflammasome, production of proinflammatory cytokines underlying activation of the STAT/interferon-γ (INFγ)/NF-kB pathway (G); and 4) accumulation of hyperphosphorylated τ, which is concurrent to cytoskeletal alterations and autophagy impairment (H). The anti-inflammatory effects of lithium are also produced by suppressing TLR4 signaling (G). Lithium also modifies the expression of miRNAs and their targeted mRNA, suggesting that they could play a role in modulating lithium’s clinical efficacy (I). Modified from Puglisi-Allegra et al. (2021). eIF2α, eukaryotic translation initiation factor 2α.

Fig. 3

Positive feedback mechanisms regulating GSK3. (A) GSK3 is phosphorylated and inhibited by AKT in response to upstream signals. PP1 dephosphorylates and activates GSK3. GSK-3 inhibits AKT and activates PP1, thereby potentiating its activity. (B) Lithium, directly and indirectly, inhibits GSK3 and disrupts both feedback loops. Disruption of these feedback loops by lithium may leave an increased response of endogenous ligands (e.g., neurotransmitters such as glutamate, dopamine, and serotonin) that signal through AKT and whose synaptic levels are affected in BD. Modified from Snitow et al. (2021).