Action Of Lithium Research Articles

Chronic treatment with lithium does not improve neuromuscular phenotype in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by defective levels of the survival motor neuron (SMN) protein. SMA causes spinal motoneuron (MN) loss, and progressive muscle weakness and paralysis. Currently, there is no effective therapy to cure this disease. Although different strategies focused on increasing the expression of functional SMN protein have been assayed, numerous SMN-independent therapeutic approaches have been demonstrated to have potential effectiveness in improving the SMA phenotype in mouse models and clinical trials. Recent works have shown that compounds which inhibit GSK-3β activity are effective in promoting MN survival and ameliorating lifespan in models of MN diseases including SMA. Taking into account the reported neuroprotective actions of lithium (Li) through the inhibition of GSK-3β in different studies, we tested here its potential efficiency as a therapeutic agent in a mouse model of severe SMA (SMNΔ7 mice). We show that the chronic treatment with Li initiated before the appearance of disease symptoms, although inhibited GSK-3β, did not improve the median survival, motor behavior, and spinal MN loss linked to SMA. Li administration did not either ameliorate the microglial and astroglial reaction in the spinal cord or the depletion of glutamatergic synapses on MNs observed in SMNΔ7 animals. Moreover, Li treatment did not mitigate muscle atrophy or calcitonin gene-related peptide (CGRP) downregulation in the neuromuscular junctions linked to the disease. However, a significant reduction in apoptotic cell death found in the skeletal muscle of SMA mice was observed after Li treatment.

Egr1 regulates lithium-induced transcription of the Period 2 (PER2) gene

A growing body of evidence suggests that the circadian molecular system is involved in the pathogenic and therapeutic mechanisms underlying bipolar disorders. Lithium, a representative mood stabilizer, has been reported to induce the Period2 (PER2) gene; however, the underlying molecular mechanisms require further study. We found that lithium upregulated PER2 expression at the transcriptional level in neuronally differentiated SH-SY5Y human neuroblastoma cells. Promoter reporter analyses using serial deletions of the PER2 promoter revealed that two early growth response 1 (Egr1)-binding sites (EBS) between positions −180 and −100 are required for maximal activation of the PER2 promoter by lithium. Ectopic expression of Egr1 enhanced lithium-induced PER2 promoter activity, while a point mutation in EBS abolished it. Electrophoretic mobility shift assays and chromatin immunoprecipitation indicated that Egr1 bound directly to the PER2 promoter. Stimulation of the extracellular-signal regulated kinase (ERK)1/2/Elk1 pathway by lithium was functionally linked to PER2 expression through Egr1 induction, and lithium-induced PER2 expression was strongly attenuated by depletion of Egr1 by siRNA. Lithium also upregulated the expression of Per2 and Egr1 in mouse frontal cortex. Induction of Per2 by lithium was attenuated in Egr1−/− mice. In conclusion, lithium stimulates PER2 transcription through the ERK/Elk1/Egr1 pathway in neuronal cells, indicating a connection between the ERK-Egr1 pathway and a circadian gene system in the mechanism of action of lithium.

Chronic Lithium Treatment Protects Against Liver Ischemia/Reperfusion Injury in Rats

Lithium has long been widely used in the treatment of bipolar mood disorders. Recent studies have demonstrated that lithium is able to decrease ischemia/reperfusion (I/R) injury in the brain, kidneys, and heart. Because lithium may act on a number of stress and survival pathways, it is of great interest to explore this compound also in the setting of liver I/R injury. In this study, we aimed to evaluate the effects of lithium in a model of liver I/R injury in rats. Chronic treatment with lithium (2 mmol/kg for 3 days before ischemia) decreased I/R injury, whereas acute treatment with a single dose of lithium (2 mmol/kg 1 hour before ischemia) did not confer any protection in a partial hepatic I/R model. Furthermore, rats subjected to chronic lithium treatment had a significantly better survival rate (60%) than saline-treated rats (27%) in a total hepatic I/R survival model. Chronic lithium treatment protected against liver I/R injury, as indicated by lower serum aminotransferase levels, fewer I/R-associated histopathological changes, lower hepatic inflammatory cytokine levels, less neutrophil infiltration, and lower hepatic high-mobility group box expression and serum levels. The mechanism of action of lithium appears to involve its ability to inhibit glycogen synthase kinase 3β activation, modulate mitogen-activated protein kinase activation, inhibit hepatic apoptosis, and induce autophagy. On the basis of these data, we conclude that lithium treatment may be a simple and applicable preconditioning intervention for protecting against liver I/R injury.

Characterization of Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Stimulators of Steroidogenesis

Inhibition of GSK-3β has been well documented to account for the behavioral actions of the mood stabilizer lithium in various animal models of mood disorders. Recent studies have showed that genetic or pharmacological inhibition of GSK-3β resulted in anxiolytic-like and pro-social behavior. In our ongoing efforts to develop GSK-3β inhibitors for the treatment of mood disorders, SAR studies on maleimide-based compounds were undertaken. We present herein for the first time that some of these GSK-3β inhibitors, in particular analogues 1 and 9, were able to stimulate progesterone production in the MA-10 mouse tumor Leydig cell model of steroidogenesis without any significant toxicity. These two compounds were tested in the SmartCube behavioral assay and showed anxiolytic-like signatures following daily dose administration (50 mg/kg, ip) for 13 days. Taken together, these results support the hypothesis that GSK-3β inhibition could influence neuroactive steroid production thereby mediating the modulation of anxiety-like behavior in vivo.

Lithium Inhibits Tumorigenic Potential of PDA Cells through Targeting Hedgehog-GLI Signaling Pathway

Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA) and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3β (GSK3β) that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1.

A gene trap mutagenesis screen for genes underlying cellular response to the mood stabilizer lithium

Identifying the biological pathways mediating the action of a therapeutic compound may help the development of more specific treatments while also increasing our understanding of the underlying disease pathology. Salts of the metal lithium are commonly used as a front-line mood stabilizing treatment for bipolar disorder. Lithium's action has been variously linked to inositol phosphate metabolism and the WNT/Glycogen Synthase Kinase 3β (GSK3β)/β-Catenin signalling cascade, but, to date, little is known about which of these provides the principal therapeutic benefit for patients and, more specifically, which constituent genes, through presumed sequence variation, determine differences in patient response to treatment. Here, we describe a functional screen in which SH-SY5Y neuroblastoma cells were randomly mutated through genomic integration of the pMS1 poly A ‘gene trap’ plasmid vector. Lithium normally induces differentiation of neuroblastoma cells, but a small proportion of mutated cells continued to proliferate and formed colonies. Rapid amplification of cDNA ends (RACE)-PCR was used to identify the ‘trapped’ gene in each of these lithium-resistant colonies. Heterozygous, gene trap integrations were identified within ten genes, eight of which are likely to produce loss-of-function mutations including MED10, MSI2 and three long intergenic non-coding (LINC) RNAs. Both MED10 and MSI2 have been previously linked with WNT/GSK3β/β-Catenin pathway function suggesting that this is an important mediator of lithium action in this screen. The methodology applied here provides a rapid, objective and economic approach to define the genetic contribution to drug action, but could also be readily adapted to any desired in vitro functional selection/screening paradigm.

Differential antidepressant-like response to lithium treatment between mouse strains: effects of sex, maternal care, and mixed genetic background

Lithium is a mood stabilizer with both antidepressant and antimanic properties, however its mechanism of action is unclear. Identifying the genetic factors that influence lithium's therapeutic actions will be an important step to assist in identifying such mechanisms. We previously reported that lithium treatment of male mice has antidepressant-like effects in the C57BL/6J strain but that such effects were absent in the BALB/cJ strain. This study aimed to assess the roles of both genetic and non-genetic factors such as sex and non-shared environmental conditions that may mediate differential behavioral responses to lithium. Mice were treated with lithium for 10 days and then tested in the forced swim test followed by lithium discontinuation and retesting to assess effects of lithium withdrawal. We also assessed effects of sex and cross-fostering on lithium response between the C57BL/6J and BALB/cJ strains, and antidepressant-like effects of lithium in the hybrid CB6F1/J strain that is derived from C57BL/6J and BALB/cJ parental strains. Neither sex nor maternal care significantly influenced the differential antidepressant-like response to lithium. Withdrawal from lithium treatment reversed antidepressant-like effects in the C57BL/6J strain but had no effects in BALB/cJ mice. Lithium treatment did not result in antidepressant-like effects in the CB6F1/J strain. Genetic factors are likely primarily responsible for differential antidepressant-like effects of lithium in the C57BL/6J and BALB/cJ strains. Future studies identifying such genetic factors may help to elucidate the neurobiological mechanisms of lithium's therapeutic actions.

An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors

Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania, however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium’s effectiveness on these mice remain unclear. Here we find that Cholecystokinin(Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knock-down of Cck expression via RNA interference (RNAi) in the VTA of wild type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective anti-manic agent.

Genetic Influences on Response to Mood Stabilizers in Bipolar Disorder

Mood stabilizers form a cornerstone in the long-term treatment of bipolar disorder. The first representative of their family was lithium, still considered a prototype drug for the prevention of manic and depressive recurrences in bipolar disorder. Along with carbamazepine and valproates, lithium belongs to the first generation of mood stabilizers, which appeared in psychiatric treatment in the 1960s. Atypical antipsychotics with mood-stabilizing properties and lamotrigine, which were introduced in the mid-1990s, form the second generation of such drugs. The response of patients with bipolar disorder to mood stabilizers has different levels of magnitude. About one-third of lithium-treated patients are excellent responders, showing total prevention of the episodes, and these patients are clinically characterized by an episodic clinical course, complete remission, a bipolar family history, low psychiatric co-morbidity and a hyperthymic temperament. It has been suggested that responders to carbamazepine or lamotrigine may differ clinically from responders to lithium. The main phenotype of the response to mood stabilizers is a degree of prevention against recurrences of manic and depressive episodes during long-term treatment. The most specific scale in this respect is the so-called Alda scale, where retrospective assessment of lithium response is scored on a 0–10 scale. The vast majority of data on genetic influences on the response to mood stabilizers has been gathered in relation to lithium. The studies on the mechanisms of action of lithium and on the neurobiology of bipolar disorder have led to the identification of a number of candidate genes. The genes studied for their association with lithium response have been those connected with neurotransmitters (serotonin, dopamine and glutamate), second messengers (phosphatidyl inositol [PI], cyclic adenosine-monophosphate [cAMP] and protein kinase C [PKC] pathways), substances involved in neuroprotection (brain-derived neurotrophic factor [BDNF] and glycogen synthase kinase 3-β [GSK-3β]) and a number of other miscellaneous genes. There are no published pharmacogenomic studies of mood stabilizers other than lithium, except for one study of the X-box binding protein 1 (XBP1) gene in relation to the efficacy of valproate. In recent years, a number of genome-wide association studies (GWAS) in bipolar disorders have been performed and some of those have also focused on lithium response. They suggest roles for the glutamatergic receptor AMPA (GRIA2) gene and the amiloride-sensitive cation channel 1 neuronal (ACCN1) gene in long-term lithium response. A promise for better elucidating the genetics of lithium response has been created by the formation of the Consortium on Lithium Genetics (ConLiGen) to establish the largest sample, to date, for the GWAS of lithium response in bipolar disorder. The sample currently comprises more than 1,200 patients, characterized by their response to lithium treatment according to the Alda scale. Preliminary results from this international study suggest a possible involvement of the sodium bicarbonate transporter (SLC4A10) gene in lithium response. It is concluded that the pharmacogenetics of response to mood stabilizers has recently become a growing field of research, especially so far as the pharmacogenetics of the response to lithium is concerned. Clearly, the ConLiGen project is a highly significant step in this research. Although the results of pharmacogenetic studies are of significant scientific value, their possible practical implications are yet to be seen.

Potential Mechanisms of Action of Lithium in Bipolar Disorder

Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood stabilizer, and has a wealth of empirical evidence supporting its efficacy in this role. Despite this, the specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood. Given the inherently complex nature of the pathophysiology of bipolar disorder, this paper aims to capture what is known about the actions of lithium ranging from macroscopic changes in mood, cognition and brain structure, to its effects at the microscopic level on neurotransmission and intracellular and molecular pathways. A comprehensive literature search of databases including MEDLINE, EMBASE and PsycINFO was conducted using relevant keywords and the findings from the literature were then reviewed and synthesized. Numerous studies report that lithium is effective in the treatment of acute mania and for the long-term maintenance of mood and prophylaxis; in comparison, evidence for its efficacy in depression is modest. However, lithium possesses unique anti-suicidal properties that set it apart from other agents. With respect to cognition, studies suggest that lithium may reduce cognitive decline in patients; however, these findings require further investigation using both neuropsychological and functional neuroimaging probes. Interestingly, lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects. At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes. For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission. For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission. In addition to these many putative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to its therapeutic actions. In this regard, lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression. Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3 and autophagy. Overall, it is clear that the processes which underpin the therapeutic actions of lithium are sophisticated and most likely inter-related.

The Pathology of Lithium Induced Nephropathy: A Case Report and Review, with Emphasis on the Demonstration of Mast Cells

Lithium is a psychotropic agent which is widely employed in the psychiatric practice throughout the world. The therapeutic index of lithium is low and an acute intoxication may appear, which may lead to death or a permanent disability. A frequent side effect of lithium is renal toxicity. The collecting tubules have been identified as the site of action of lithium, due to the down regulation of Acquaporin-2. The mast cells have been associated with a wide range of human renal diseases. They have been documented to be associated with interstitial fibrosis and an impaired renal function. We are reporting a case of a 42 year old male who was admitted with a history of an altered sensorium of short duration. He had bipolar disorder and was on lithium. Investigations revealed a severely compromised renal function. The patient's condition worsened and he expired. A necropsy was performed. The kidneys and the lungs were subjected to a histopathological examination. The kidneys showed a significant Chronic Tubulointerstitial Nephropathy [CTIN] and a considerable glomerular pathology. Toludine blue [1%] staining demonstrated mast cells in the interstitium and the connective tissue of the renal pelvis. This appears to be the first time that mast cells were demonstrated in a case of lithium induced nephropathy in humans. It may be hypothesized that mast cells may possibly play a role in lithium induced nephropathy as a concurrent mechanism.

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

The mood stabilizers lithium and valproic acid (VPA) are traditionally used to treat bipolar disorder (BD), a severe mental illness arising from complex interactions between genes and environment that drive deficits in cellular plasticity and resiliency. The therapeutic potential of these drugs in other central nervous system diseases is also gaining support. This article reviews the various mechanisms of action of lithium and VPA gleaned from cellular and animal models of neurologic, neurodegenerative, and neuropsychiatric disorders. Clinical evidence is included when available to provide a comprehensive perspective of the field and to acknowledge some of the limitations of these treatments. First, the review describes how action at these drugs' primary targets--glycogen synthase kinase-3 for lithium and histone deacetylases for VPA--induces the transcription and expression of neurotrophic, angiogenic, and neuroprotective proteins. Cell survival signaling cascades, oxidative stress pathways, and protein quality control mechanisms may further underlie lithium and VPA's beneficial actions. The ability of cotreatment to augment neuroprotection and enhance stem cell homing and migration is also discussed, as are microRNAs as new therapeutic targets. Finally, preclinical findings have shown that the neuroprotective benefits of these agents facilitate anti-inflammation, angiogenesis, neurogenesis, blood-brain barrier integrity, and disease-specific neuroprotection. These mechanisms can be compared with dysregulated disease mechanisms to suggest core cellular and molecular disturbances identifiable by specific risk biomarkers. Future clinical endeavors are warranted to determine the therapeutic potential of lithium and VPA across the spectrum of central nervous system diseases, with particular emphasis on a personalized medicine approach toward treating these disorders.

Lithium: the pharmacodynamic actions of the amazing ion.

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.

Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action

Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3β through a β-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)- and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/β-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3β in regulating DA- or lithium-sensitive behaviors, we generated conditional knockouts of GSK3β, where GSK3β was deleted in either DA D1- or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3β in D2 (D2GSK3β(-/-)) but not D1 (D1GSK3β(-/-)) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3β(-/-) or D1GSK3β(-/-) mice compared with control mice. Interestingly, genetic stabilization of β-catenin, a downstream target of GSK3β, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3β(-/-) or D1GSK3β(-/-) mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be β-arrestin2- and GSK3β-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3β but not stabilization of β-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.

Use of Lithium for Sexual Obsessions in Asperger’s Disorder

Back to table of contents Previous article Next article LettersFull AccessUse of Lithium for Sexual Obsessions in Asperger’s DisorderLokesh Shahani, M.D.Lokesh ShahaniDept. of Internal MedicineSIU School of MedicineSpringfield, ILSearch for more papers by this author, M.D.Published Online:1 Oct 2012https://doi.org/10.1176/appi.neuropsych.11090232AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Obsessional/repetitive behaviors are a core feature of autistic-spectrum disorders. Symptoms suggesting a DSM-IV diagnosis of obsessive compulsive disorder have been reported in 37% of the children with autism.1 Sexual obsessions have been commonly reported in these patients.2We report on a 17-year-old young man with a diagnosis of Asperger’s disorder who complained of having intrusive sexual thoughts and urges. He was masturbating 25–30 times per day, resulting in penile ulcers. These symptoms were associated with severe anxiety and frustration, leading to suicidal thoughts and self-injurious behavior, including stabbing his penis with tweezers. The patient denied any concomitant mood or psychotic symptoms. He denied any substance use, and his urine toxicology screen was negative. The patient was currently on sertraline 200 mg, clomipramine 225 mg, and aripiprazole 10 mg daily. He has had previous failed trials on citalopram, fluvoxamine, fluoxetine, clonazepam, quetiapine, and risperidone.Low serotonin levels have been associated with impulsive and aggressive behaviors,3 and enhancement of central serotonin neurotransmission could ameliorate heightened sexual desire and compulsivity associated with such sexual behaviors.4 Lithium has been shown to have some efficacy in similar behaviors associated with obsessive-compulsive features, such as pathological gambling.5 Hence, a trial of lithium was considered in this patient, and the dose was titrated up to 600 mg twice daily, with a lithium level of 0.56 mEq/L. The patient showed significant improvement in his sexual obsessions. He has not had a relapse in his obsessive symptoms and participates in cognitive-behavioral therapy to help with sustained remission.Lithium is known to increase serotonin levels in the cerebrospinal fluid by inducing serotonin synthesis.6 The particular pro-serotonergic action of lithium could be helpful in reducing the heightened sexual obsession and compulsive behavior. Further double-blind, placebo-controlled studies are needed to confirm the role of lithium as an augmentation agent for treatment of obsessive sexual behaviors.Dept. of Internal MedicineSIU School of MedicineSpringfield, ILCorrespondence: e-mail: [email protected]comReferences1 Leyfer OT, Folstein SE, Bacalman S, et al.: Comorbid psychiatric disorders in children with autism: interview development and rates of disorders. J Autism Dev Disord 2006; 36:849–861Crossref, Medline, Google Scholar2 Zandt F, Prior M, Kyrios M: Repetitive behaviour in children with high-functioning autism and obsessive-compulsive disorder. J Autism Dev Disord 2007; 37:251–259Crossref, Medline, Google Scholar3 Cocarro EF, Kavoussi RJ: Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Arch Gen Psychiatry 1998; 54:1081–1088Crossref, Google Scholar4 Stein DJ, Hollander E, Anthony DT, et al.: Serotonergic medications for sexual obsessions, sexual addictions, and paraphilias. J Clin Psychiatry 1992; 53:267–271Medline, Google Scholar5 Pallanti S, Quercioli L, Sood E, et al.: Lithium and valproate treatment of pathological gambling: a randomized, single-blind study. J Clin Psychiatry 2002; 63:559–564Crossref, Medline, Google Scholar6 Lenox RH, Hahn CG: Overview of the mechanism of action of lithium in the brain: fifty-year update. J Clin Psychiatry 2000; 61(Suppl 9):5–15Medline, Google Scholar FiguresReferencesCited byDetailsCited byThe World Federation of Societies of Biological Psychiatry guidelines on the assessment and pharmacological treatment of compulsive sexual behaviour disorder17 November 2022 | Dialogues in Clinical Neuroscience, Vol. 24, No. 1Sexuality in autism: hypersexual and paraphilic behavior in women and men with high-functioning autism spectrum disorder1 April 2022 | Dialogues in Clinical Neuroscience, Vol. 19, No. 4 Volume 24Issue 4 Fall 2012Pages E17-E17 Metrics PDF download History Published online 1 October 2012 Published in print 1 October 2012

Lithium enhances CRTC oligomer formation and the interaction between the CREB coactivators CRTC and CBP — Implications for CREB-dependent gene transcription

Lithium salts are important drugs to treat bipolar disorder. Previous work showed that lithium by enforcing the interaction between the transcription factor CREB and its coactivator CRTC1 enhanced cAMP-stimulated CREB-dependent gene transcription. Both CREB and CRTC have been implicated in neuronal adaptation, which might underlie lithium's therapeutic action. In the present study the mechanisms of lithium action on cAMP-induced CREB-dependent gene transcription were further elucidated. Transient transfection assays revealed that all three CRTC isoforms conferred lithium responsiveness to CREB whereas their intrinsic transcriptional activities remained unchanged by lithium, suggesting a conformational change of CREB or CRTC by lithium. In in vitro protein–protein interaction assays lithium enhanced the interaction between CREB and both coactivators CRTC and CBP. Furthermore, lithium enforced the oligomerization of CRTC, a prerequisite for CREB interaction. For further evaluation it was investigated whether lithium competes with magnesium, which coordinates the conformation of the CREB basic region leucine zipper (bZip). Mutational analysis of the magnesium coordinating lysine-290 within the bZip, in vitro and intracellular interaction assays and luciferase reporter-gene assays revealed that the effect of lithium on the CREB–CRTC interaction or on the transcriptional activity, respectively, was not affected by the mutation, thus excluding a magnesium–lithium competition. However, the CREB–CRTC interaction was strongly increased in lysine-290-mutants thereby extending the CRTC–CREB interaction domain. Taken together the results exclude a competition between lithium and magnesium at the bZip, but suggest that lithium by enforcing the CRTC-oligomer formation and the interaction of CREB–CBP–CRTC enhances cAMP-induced CREB-dependent gene transcription.

Venlafaxine Augmentation With Lithium Leading to Serotonin Syndrome

Back to table of contents Previous article Next article LettersFull AccessVenlafaxine Augmentation With Lithium Leading to Serotonin SyndromeLokesh ShahaniLokesh ShahaniDepartment on Internal Medicine, SIU School of Medicine, Springfield, Ill.Search for more papers by this authorPublished Online:1 Jul 2012https://doi.org/10.1176/appi.neuropsych.11080196AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Serotonin syndrome is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. The serotonin syndrome is often described as a clinical triad of mental-status changes, autonomic hyperactivity, and neuromuscular abnormalities, and is actually a spectrum of clinical findings ranging from benign to lethal.Case ReportMs. A was a 42-year-old Caucasian female admitted to the psychiatric unit with worsening depressive symptoms and suicidal ideations. The patient was diagnosed with major depressive disorder in her early twenties and has had relapses on various antidepressants in the past. Currently she was on venlafaxine 225 mg extended release tablet for the past 7 months with good response. She denied any medical comorbidity and was not on any other medications. She denied any recent concomitant substance use and her urine toxicology was negative. Her physical examination and routine laboratory investigation on admission were unremarkable.Considering the patient’s past history and failure to respond to various antidepressants in the past, augmentation with lithium was considered at this time. Lithium carbonate was started at dose of 300 mg/day and increase to 600 mg/day on day 4 of admission. On day 5 the patient developed confusion, fever and hyper-reflexia including clonus in her ankle. Serotonin syndrome was considered and the patient was moved to an intensive care unit for close monitoring. Lithium levels were 0.2 mEq/L and lithium toxicity was ruled out. Patient did demonstrate leucocytosis and elevated creatine phosphokinase in her laboratory investigations.Her psychotropic medications were discontinued and supportive care was provided. Patient has some intermittent agitation which was treated with lorazepam. The patient’s condition improved over the next 4 days and was moved back to the psychiatric unit. She was reintroduced to venlafaxine again and later augmented with aripiprazole and had a good response to the same.DiscussionSerotonin toxicity has been traditionally seen with high doses of serotonergic antidepressants or their combination. Recently various pro-serotonergic drugs have been implicated in serotonin syndrome if used along with antidepressants. Lithium and venlafaxine combination has been previously described to cause serotonin syndrome,1–3 however the mechanism is unclear. Lithium is known to increase serotonin levels in the cerebrospinal fluid by inducing serotonin synthesis4 and is supported by animal studies where is enhances the serotonin toxicity.5 Pharmacokinetic interaction where lithium reduces the renal excretion of venlafaxine has not found to be clinically significant.6 This mechanism is less likely in our case as the patient maintained adequate renal function reflected in her laboratory investigation.Physicians should be aware and educate the patients on the risk of serotonin toxicity when various pro- serotonergic agents are used in patients previously stable on their antidepressant regimen.Department on Internal Medicine, SIU School of Medicine, Springfield, Ill.References1 Adan-Manes J, Novalbos J, López-Rodríguez R, et al.: Lithium and venlafaxine interaction: a case of serotonin syndrome. J Clin Pharm Ther 2006; 31:397–400Crossref, Medline, Google Scholar2 Mekler G, Woggon B: A case of serotonin syndrome caused by venlafaxine and lithium. Pharmacopsychiatry 1997; 30:272–273Crossref, Medline, Google Scholar3 Torre LE, Menon R, Power BM: Prolonged serotonin toxicity with proserotonergic drugs in the intensive care unit. Crit Care Resusc 2009; 11:272–275Medline, Google Scholar4 Lenox RH, Hahn CG: Overview of the mechanism of action of lithium in the brain: fifty-year update. J Clin Psychiatry 2000; 61(Suppl 9):5–15Medline, Google Scholar5 Wood AJ, Goodwin GM: A review of the biochemical and neuropharmacological actions of lithium. Psychol Med 1987; 17:579–600Crossref, Medline, Google Scholar6 Troy SM, Parker VD, Hicks DR, et al.: Pharmacokinetic interaction between multiple-dose venlafaxine and single-dose lithium. J Clin Pharmacol 1996; 36:175–181Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByManagement of severe arterial hypertension associated with serotonin syndrome: a case report analysis based on systematic review techniques11 March 2019 | Therapeutic Advances in Psychopharmacology, Vol. 9Clinical drug-drug interactions: focus on venlafaxineDrug Metabolism and Personalized Therapy, Vol. 30, No. 1Reactions Weekly, Vol. 1432, No. 1 Volume 24Issue 3 Summer 2012Pages E47-E47 Metrics PDF download History Published online 1 July 2012 Published in print 1 July 2012

Polymerization of butadiene under the action of lithium containing initiating system

Polymerization of butadiene under the action of n-butyl lithium modified by of alkali and alkaline earth metal alkoxides was researched. Microstructure and molecular characteristics of the samples of polybutadiene synthesized were determined. The influence of polymerization conditions on the properties of the resulting polymer was examined.

Enhanced Lithium-Induced Brain Recovery Following Cranial Irradiation Is Not Impeded by Inflammation

Radiation-induced brain injury occurs in many patients receiving cranial radiation therapy, and these deleterious effects are most profound in younger patients. Impaired neurocognitive functions in both humans and rodents are associated with inflammation, demyelination, and neural stem cell dysfunction. Here we evaluated the utility of lithium and a synthetic retinoid receptor agonist in reducing damage in a model of brain-focused irradiation in juvenile mice. We found that lithium stimulated brain progenitor cell proliferation and differentiation following cranial irradiation while also preventing oligodendrocyte loss in the dentate gyrus of juvenile mice. In response to inflammation induced by radiation, which may have encumbered the optimal reparative action of lithium, we used the anti-inflammatory synthetic retinoid Am80 that is in clinical use in the treatment of acute promyelocytic leukemia. Although Am80 reduced the number of cyclooxygenase-2-positive microglial cells following radiation treatment, it did not enhance lithium-induced neurogenesis recovery, and this alone was not significantly different from the effect of lithium on this proinflammatory response. Similarly, lithium was superior to Am80 in supporting the restoration of new doublecortin-positive neurons following irradiation. These data suggest that lithium is superior in its restorative effects to blocking inflammation alone, at least in the case of Am80. Because lithium has been in routine clinical practice for 60 years, these preclinical studies indicate that this drug might be beneficial in reducing post-therapy late effects in patients receiving cranial radiotherapy and that blocking inflammation in this context may not be as advantageous as previously suggested.

Lithium: A switch from LTD- to LTP-like plasticity in human cortex

Lithium, a simple cation, is the mainstay treatment of bipolar disorder. Deficient synaptic plasticity is considered one important mechanism of this disease. Lithium inhibits glycogen synthase kinase-3beta (GSK-3β), which is involved in the regulation of synaptic plasticity. In animal preparations, inhibition of GSK-3β by lithium up-regulated long-term potentiation (LTP) of excitatory synapses but down-regulated long-term depression (LTD). The effects of lithium on plasticity in the human brain are unexplored. We tested the effects of a single oral dose of 900 mg of lithium on LTP-/LTD-like plasticity in human motor cortex induced by established paired associative transcranial magnetic stimulation (PASLTP, PASLTD) protocols. We studied 10 healthy adults in a placebo-controlled double-blind randomized crossover design. PAS-induced plasticity was indexed by change in motor evoked potential amplitude recorded in a hand muscle. In the placebo session, subjects were stratified, according to the known variability of the PASLTP response, into PASLTP ‘LTP responders’ and PASLTP ‘LTD responders’ (n = 5 each). Lithium did not affect the PASLTP-induced LTP-like plasticity in the ‘LTP responders’, but switched the PASLTP-induced LTD-like plasticity in the ‘LTD responders’ to LTP-like plasticity. In contrast, lithium had no effect on the PASLTD-induced LTD-like plasticity in the ‘LTD responders’. We provide first-time evidence that lithium significantly modulates brain stimulation induced plasticity in human cortex. The switch from LTD- to LTP-like plasticity is best explained by the inhibitory action of lithium on GSK-3β. This conclusion is necessarily circumstantial because GSK-3β activity was not directly measured. We discuss that other important plasticity-related modes actions of lithium cannot explain our findings.