Lithium: the pharmacodynamic actions of the amazing ion

Abstract

Lithium has been used for the treatment of mood disorders for over 60 years, yet the exact mechanisms by which it exerts its therapeutic effects remain unclear. Two enzymatic chains or pathways emerge as targets for lithium: inositol monophosphatase within the phosphatidylinositol signalling pathway and the protein kinase glycogen synthase kinase 3. Lithium inhibits these enzymes through displacing the normal cofactor magnesium, a vital regulator of numerous signalling pathways. Here we provide an overview of evidence, supporting a role for the inhibition of glycogen synthase kinase 3 and inositol monophosphatase in the pharmacodynamic actions of lithium. We also explore how inhibition of these enzymes by lithium can lead to downstream effects of clinical relevance, both for mood disorders and neurodegenerative diseases. Establishing a better understanding of lithium's mechanisms of action may allow the development of more effective and more tolerable pharmacological agents for the treatment of a range of mental illnesses, and provide clearer insight into the pathophysiology of such disorders.

Cultivation of mushrooms for production of food biofortified with lithium

“…Given the popularity of the Unlike many traditional psychopharmacological compounds, Li does not bind to a cellular receptor but modifies the intracellular second messenger system. Its main postulated mechanisms of action are based on effects excreted on inositol monophosphatase (IMPase) within the phosphatidylinositol (PI) signaling pathway and the protein kinase glycogen synthase kinase 3β (GSK-3β) [12]. Calcium carbonate taken orally as pills is the most often applied form [13].…”

Temporal experience in mania

“…This enzyme, GSK3-β, blocks the inactivation/ degradation of Rev-erba. Importantly, lithium inhibits GSK3-β (Brown and Tracy 2013). Furthermore, so do other mood stabilizers, such as valproic acid and lamotrigine (Coyle 2007).…”

What Is Lithium and How Does It Work?

“…The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signaling. Unlike most other established psychopharmacological agents such as antidepressants and antipsychotics, lithium does not bind to cellular receptors; instead, it appears to exert a multitude of therapeutic actions by modifying intracellular second messenger systems downstream of metabotropic neurotransmitter receptors, via enzyme inhibition with subsequent alteration of a complex and interconnected intracellular enzymatic cascade (Brown and Tracy 2013 ). Nonetheless, when trying to dissect lithium's various mechanisms of action, two enzymatic pathways have emerged during the past decade as its targets: inositol monophosphatase (IMPase) within the phosphatidylinositol (PI) signaling pathway (Berridge and Irvine 1989 ) and the protein kinase glycogen synthase kinase-3β (GSK-3β) (Ryves and Harwood 2001 ).…”

“…Myoinositol is also the substrate for synthesis of phosphatidylinositol (PI), which is phosphorylated to form mono-, bis-, and tris-phosphatidylinositol. Lithium-induced myoinositol depletion therefore prevents the resynthesis of PIP2 and subsequent regeneration of IP3 and DAG, affecting cell signaling (Brown and Tracy 2013 ) antipsychotics, anticonvulsants, and antidepressants, lithium provides the most replicated evidence for neuroprotection in the widest range of neurodegenerative disease models (Lauterbach and Mendez 2011 ). The important question of whether lithium's intriguing pharmacodynamic properties really do translate into therapeutic neuroprotective effects in human subjects is discussed in detail in Chap.…”

“…Lithium is able to activate Akt by disrupting the formation of a protein kinase B (Akt), beta-arrestin 2(βArr2), and protein phosphatase 2A (Akt;βArr2;PP2A)-comprised signaling complex, triggered by activation of the dopamine 2 receptor (D2R) and potentially other G-proteincoupled receptors (GPCR). The Akt;βArr2;PP2A signaling complex typically leads to inactivation of Akt, preventing GSK-3 inhibition; the destabilization of this signaling complex by lithium reduces Akt dephosphorylation, enhancing Akt activity, thus indirectly inhibiting GSK-3 (Brown and Tracy 2013 ) 4.3 The Principal Pharmacodynamic Actions of Lithium monoamine neurotransmitters. Upon ingestion, lithium becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters (Juckel and Mavrogiorgou 2006 ).…”