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Inhibition of glycogen synthase kinase 3 (GSK3) by lithium. Lithium directly inhibits GSK3 by competitive binding for magnesium (Mg²⁺), disrupting the catalytic functioning of GSK3. Lithium also indirectly inhibits GSK3 by increasing serine phosphorylation, through P13K-mediated phosphorylation/activation of Akt. 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 signalling complex, triggered by activation of the dopamine 2 receptor (D2R) and potentially other G-protein coupled receptors (GPCR). The Akt;βArr2;PP2A signalling complex typically leads to inactivation of Akt, preventing GSK3 inhibition; the destabilisation of this signalling complex by lithium reduces Akt dephosphorylation, enhancing Akt activity, thus indirectly inhibiting GSK3.
Source publication
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...
Similar publications
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...
Citations
... 14 Improvement with medications such as lithium is consistent with the literature. 15 Similarly, side effects of medication were also an important contributor to their distress. 16 However, adherence to medications is reported to be associated with fewer health problems, better coping with stress, and a stronger belief in the controllability of their health. ...
Background
Individuals with bipolar disorder (BD) experience considerable difficulty in functioning during remission as well. The actual lived experience of individuals with BD with respect to their functioning is not understood in the cultural context.
Methods
A qualitative approach in the form of interviews was taken from 11 participants who were diagnosed with BD in remission from a tertiary care hospital. The interviews were audio recorded and coded. Thematic analysis was carried out using a grounded theory approach to bring out relevant themes surrounding their inter-episodic functional limitations.
Results
The thematic analysis resulted in nine themes associated with the functioning, namely illness issues, treatment as an antidote, impact on self, relationship issues, coping strategies, disturbed cognitive functioning, stigma, occupational consequences, and dubious future.
Conclusions
The qualitative interview analysis provides a comprehensive picture of the experiences undergone by patients with BD. The themes and the sub-themes that came up in the analysis are reflective of the experiences of these individuals. The findings of the study can be utilized in planning effective interventions for remitted patients in the future so that functional limitations can be effectively addressed.
... Notably, many eventually converged toward the lithium inhibition of GSK-3β and PI, the mechanisms postulated in the 1980s/1990s. In 2013, Brown and Tracy assumed these mechanisms to be the most important for lithium action at the cellular level [163], and in 2016, Malhi and Outhred simply stated that the research in the 21st century cemented GSK-3β inhibition as a key mechanism underpinning the effects of lithium [164]. In a recent review of the biological bases and treatment strategies in BD, the inhibition of the PI system and GSK-3β as the main mechanisms for lithium action are also underscored [165]. ...
Despite lithium's presence in modern psychiatry for three-quarters of a century, the mechanisms of its therapeutic action have not been fully elucidated. This article presents the evolution of the views on these mechanisms, and both the old and new findings are discussed. Among the old mechanisms, lithium's effect on the purinergic system; electrolyte metabolism; membrane transport; and second messenger systems, namely, cyclic nucleotide and phosphatidylinositol (PI), glycogen synthase kinase-3beta (GSK-3β), brain-derived neurotrophic factor, and neurotransmitters, are discussed. The new data were obtained from in vitro studies, molecular biology, and genetic research. They showed the effects of lithium on the immune system, biological rhythms, telomere functions, and mitochondria. In this article, each lithium mechanism is considered in the light of its association with the pathogenesis of bipolar disorder or/and as a marker of the lithium response. Although not exhaustive, this review elucidates the multiple potential mechanisms of lithium action. It was also observed that many seemingly "old" mechanisms have experienced a resurgence in research conducted during the 21st century. Additionally, many studies converged on the previously postulated mechanisms of lithium inhibiting GSK-3β and PI.
... Notably, many eventually converged toward the lithium inhibition of GSK-3β and PI, the mechanisms postulated in the 1980s/1990s. In 2013, Brown and Tracy assumed these mechanisms to be the most important for lithium action at the cellular level [163], and in 2016, Malhi and Outhred simply stated that the research in the 21st century cemented GSK-3β inhibition as a key mechanism underpinning the effects of lithium [164]. In a recent review of the biological bases and treatment strategies in BD, the inhibition of the PI system and GSK-3β as the main mechanisms for lithium action are also underscored [165]. ...
PUBLISHED VERSION: 10.3390/ph18040467
Despite lithium's presence in modern psychiatry for three quarters of a century, the mechanisms of its therapeutic action have not been fully elucidated. In the article, the evolution of the views on these mechanisms is presented, and both the old and new findings are discussed. Among the old mechanisms, lithium effect on the purinergic system, electrolyte metabolism and membrane transport, second messenger systems: cyclic nucleotide and phosphatidylinositol (PI), glycogen synthase kinase-3beta (GSK-3β), brain-derived neurotrophic factor, and neurotransmitters, are discussed. The new data have been obtained from in vitro studies, molecular biology and genetic researches. They also showed the effect of lithium on the immune system, biological rhythms, and telomere functions. In the article, each lithium mechanism is considered in the light of its association with the pathogenesis of bipolar disorder or/and as a marker of lithium response. This review, although not complete, shows that the possible mechanisms of lithium action are multifold. It turned out that many apparent “old” mechanisms had their revival in research performed in the 21st century. Additionally, many studies eventually converged on the mechanisms postulated in the 1980s/1990s of inhibitiing GSK-3β and PI by lithium.
... These and other factors were tested for their role in LiCl-directed regulation of PGC-1α (Fig. 4E). LiCl is not a specific GSK3β inhibitor 33 , so to directly test for GSK3β regulation of PGC-1α, neurons were treated with a specific inhibitor called inhibitor VIII. Treatment with inhibitor VIII phenocopied the effects of LiCl on PGC-1α4 (activated) and on B1E2 (repressed) but not on PGC-1α1 that only responded to LiCl and not inhibitor VIII (Fig. 4F). ...
The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cell-type specific promotors, repressed with aging, and integral in coordinating metabolism and growth signaling. Transcriptional and proteomic profiles of cortex from male adult, middle age, and advanced age mice reveal an aging metabolic signature linked to PGC-1α. In primary culture, a neuron-exclusive promoter produces the functionally dominant isoform of PGC-1α. Using growth repression as a challenge, we find that PGC-1α is regulated downstream of GSK3β independently across promoters. Broad cellular metabolic consequences of growth inhibition observed in vitro are mirrored in vivo, including activation of PGC-1α directed programs and suppression of aging pathways. These data place PGC-1α centrally in a growth and metabolism network directly relevant to brain aging.
... Lithium's mechanism of action has not yet been fully unraveled but data show that it involves multifaceted interactions within the central nervous system. Among other described effects, it inhibits the enzyme inositol monophosphatase 1 (IMPA1) in its therapeutic levels [8,9], leading to decreased levels in the two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG) [10][11][12]. This disruption in inositol signaling cascades can influence neurotransmission, cellular signaling, synaptic plasticity and autophagy [10,[13][14][15], possibly contributing to its mood-stabilizing effects [16,17]. ...
... In addition, lithium has garnered attention for its potential anti-inflammatory effects. Another target suggested as lithium's mechanism of action is the enzyme glycogen synthase kinase-3 2 of 10 (GSK-3), also claimed to be lithium-inhibitable, impacting various intracellular signaling pathways implicated in mood regulation [11,15,18,19]. This inhibition is claimed to modulate neurotransmitter signaling, particularly involving serotonin and dopamine, which are crucial for mood stabilization [20,21], and to dampen inflammatory signaling pathways [22]. ...
This narrative review examines lithium’s effects on immune function, inflammation and cell survival, particularly in bipolar disorder (BD) in in vitro studies, animal models and clinical studies. In vitro studies show that high lithium concentrations (5 mM, beyond the therapeutic window) reduce interleukin (IL)-1β production in monocytes and enhance T-lymphocyte resistance, suggesting a protective role against cell death. Lithium modulates oxidative stress in lipopolysaccharide (LPS)-activated macrophages by inhibiting nuclear factor (NF)-ƙB activity and reducing nitric oxide production. At therapeutically relevant levels, lithium increased both pro-inflammatory [interferon (INF)-γ, IL-8 and tumor necrosis factor (TNF)-α)] and anti-inflammatory (IL-10) cytokines on whole blood supernatant culture in healthy volunteers, influencing the balance of pro- and anti-inflammatory responses. Animal models reveal lithium’s potential to alleviate inflammatory diseases by reducing pro-inflammatory cytokines and enhancing anti-inflammatory responses. It also induces selective macrophage death in atherosclerotic plaques without harming other cells. In primary rat cerebellum cultures (ex vivo), lithium prevents neuronal loss and inhibits astroglial growth, impacting astrocytes and microglia. Clinical studies show that lithium alters cytokine profiles and reduces neuroinflammatory markers in BD patients. Chronic treatment decreases IL-2, IL-6, IL-10 and IFN-γ secretion from peripheral blood leukocytes. Lithium response correlates with TNF-α levels, with poor responders showing higher TNF-α. Overall, these findings elucidate lithium’s diverse mechanisms in modulating immune responses, reducing inflammation and promoting cell survival, with significant implications for managing BD and other inflammation-related conditions. Yet, to better understand the drug’s impact in BD and other inflammatory/neuroinflammatory conditions, further research is warranted to appreciate lithium’s therapeutic potential and its role in immune regulation.
... Despite its long history of use, the mechanism of action of lithium is not yet fully understood. However, two main mechanisms of action have been postulated: by blocking inositol phosphatases involved in intracellular signal transduction and by inhibiting glycogen synthase kinase 3 [110,111]. In addition, it increases GABA-based inhibitory neurotransmission, which is of particular importance in the treatment of mania [112]. ...
The effectiveness of available neuropsychiatric drugs in the era of an increasing number of patients is not sufficient, and the complexity of neuropsychiatric disease entities that are difficult to diagnose and therapeutically is increasing. Also, discoveries about the pathophysiology of neuropsychiatric diseases are promising, including those initiating a new round of innovations in the role of oxidative stress in the etiology of neuropsychiatric diseases. Oxidative stress is highly related to mental disorders, in the treatment of which the most frequently used are first- and second-generation antipsychotics, mood stabilizers, and antidepressants. Literature reports on the effect of neuropsychiatric drugs on oxidative stress are divergent. They are starting with those proving their protective effect and ending with those confirming disturbances in the oxidation–reduction balance. The presented publication reviews the state of knowledge on the role of oxidative stress in the most frequently used therapies for neuropsychiatric diseases using first- and second-generation antipsychotic drugs, i.e., haloperidol, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole, mood stabilizers: lithium, carbamazepine, valproic acid, oxcarbazepine, and antidepressants: citalopram, sertraline, and venlafaxine, along with a brief pharmacological characteristic, preclinical and clinical studies effects.
... Unknown provided an overview of the evidence supporting one of the most widely accepted models by Berridge and Irvine -The Inositol Depletion Theory. 15 This model proposed that lithium inhibited inositol phosphate-phosphatase (IMPase) and glycogen synthase kinase 3 (GSK3), which led to a confusional state. This model was further supported by data from the authors demonstrating that the level of inhibition is increased in people with bipolar disorder. ...
Objective: Lithium carbonate is a mood stabilizer used in the treatment of bipolar disorder. However, its narrow therapeutic index (normal = 0.6-1.2 mmol/L) predisposes patients to toxic effects. This study aimed to identify case reports and review the evidence on the frequency, mechanism, risk factors and guidelines associated with a lithium-induced confusional state in patients with bipolar disorder. Methods: All Databases from the National Center for Biotechnology Information (NCBI) were used to search for lithium AND “confusional state” AND “case report” published in English between 2015 and 2020. This search engine was also used to search for lithium AND “confusional state” AND frequency OR mechanism OR “risk factor” OR guideline published in English. Results: Case reports showed (1) all patients were treated with lithium for bipolar disorder and hospitalized for a confusional state, (2) most patients took concomitant therapies and recovered after lithium withdrawal, (3) some patients were female and old-aged (65+ years old), and (4) no ethnicities, causality assessments and dose patterns were reported. Other scientific literature showed (1) frequencies of a lithium-induced confusional state varied from very common (>10%) to rare (<0.01%), (2) inhibition of inositol phosphate-phosphatase (IMPase) and glycogen synthase kinase-3 (GSK3) might result in a lithium-induced confusional state, (3) ageing, diseases and concomitant therapies increased the risk of a lithium-induced confusional state, and (4) patients should complete lab tests and diagnostic procedures to monitor and/or prevent a lithium-induced confusional state. Conclusion: Case reports and other scientific literature elucidated the relationship between lithium and a confusional state.
... It is well established that lithium inhibits various phosphoinositol phosphates that function in inositol phosphate metabolism, such as IMPase and inositol polyphosphatase 1-phosphatase, which influence DAG turnover (Berridge et al., 1989;Brown & Tracy, 2013). Lithium's ability to deplete inositol was suggested to be crucial for its therapeutic outcome (Harwood, 2005;Sade et al., 2016). ...
The poet W.B Yeats wrote that "All that is personal soon rots, it must be packed in ice or salt". Here we show that in Caenorhabditis elegans nematodes, simple animals with just 302 neurons, memories are preserved on ice and in lithium salt.
C. elegans nematodes can form associative memories, which are typically forgotten quickly. We discovered that when placed on ice, worms delay forgetting of specific olfactory memories by at least 8-fold. Delayed forgetting was canceled completely when the worms were gradually adapted to low temperatures, owing to a genetically-encoded program that turns acclimated worms cold-tolerant. RNA-seq, mutant analyses, and pharmacological assays revealed that regulation of membrane properties switches cold-induced delayed forgetting ON and OFF, and, remarkably, that lithium delays forgetting only in cold-sensitive but not cold-tolerant worms. We found that downregulation of the diacylglycerol pathway in the AWC sensory neurons is essential for lithium-mediated delayed forgetting, and using neuronal activity recordings located the memory trace to the downstream AIY interneurons. We suggest that the awesome genetic tractability of C. elegans might be harnessed to study the effects of lithium and cold temperatures on the brain, why it influences psychiatric disorders, and even more fundamentally how memory is stored and lost.
... Central to the PI3K pathway is the PI-cycle, which is another of the most researched mechanisms in bipolar disorder [23]. For several decades PI-cycle inhibition has been a target of substantial interest to pharmaceutical research and has been considered a competing hypothesis to GSK3β inhibition for the primary mechanism of action of Lithium. ...
Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature of bipolar disorder pathophysiology. In this paper, we propose that mania represents a condition of heightened cerebral energy metabolism facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Glycolysis in astrocytes fuels the formation of denovo glutamate, which can be used as a mitochondrial fuel source in neurons via transamination to alpha-ketoglutarate and subsequent reductive carboxylation to replenish tricarboxylic acid cycle intermediates. Upregulation of glycolysis and glutaminolysis in this manner causes the brain to enter a state of heightened metabolism and excitatory activity which we propose to underlie the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, when recruited in the long term to counteract impaired oxidative metabolism it may become a pathological process. In this article, we develop these ideas in detail, present supporting evidence and propose this as a novel avenue of investigation to understand the biological basis for mania.
... In this study, we examined the expression levels of enzyme proteins Interestingly, Li affects the synthesis of PI(4,5)P2 and subsequent generation of IP3 and DAG. 24 In addition, the impairment of the PLC-mediated pathway is known to be associated with BD. [25][26][27] Several GWASs have identified PLC signaling as a pathway contributing to BD risk, 28 among which mirR-144 is widely expressed in the brain and is upregulated by Li, and its target is considered to be the PTEN pathway. 42 In addition, mood stabilizers, including Li, have been suggested to potentially alter the DNA methylation status 43 in many regions, which were also altered in the postmortem brains of patients with BD in this study, suggesting that Li may affect the expression of several genes involved in BD's pathology by altering their DNA methylation. ...
Aim
The etiology of bipolar disorder (BD) remains unknown; however, lipid abnormalities in BD have received increasing attention in recent years. In this study, we examined the expression levels of enzyme proteins associated with the metabolic pathway of phosphoinositides (PIs) and their downstream effectors, protein kinase B (Akt1) and glycogen synthase kinase 3β (GSK3β), which have been assumed to be the targets of mood stabilizers such as lithium, in the postmortem brains of patients with BD.
Methods
The protein expression levels of phosphatidylinositol 4‐phosphate 5‐kinase type‐1 gamma (PIP5K1C), phosphatidylinositol 4‐kinase alpha (PIK4CA), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), Akt1, and GSK3β were measured using enzyme‐linked immunosorbent assays and multiplex fluorescent bead‐based immunoassays in the prefrontal cortex (PFC). Specifically, PTEN, Akt1, GSK3β, and PIP5K1C were measured in seven BD patients and 48 controls. Additionally, PIK4CA was analyzed in 10 cases and 34 controls.
Results
PTEN expression levels were markedly decreased in the PFCs of patients with BD, whereas those of Akt and GSK3β were prominently elevated. Moreover, patients medicated with lithium exhibited higher Akt1 expression levels and lower PTEN expression levels in comparison with the untreated group.
Conclusion
Our results suggest that the expression levels of Akt1/GSK3β and its upstream regulator PTEN are considerably altered.
