Action Of Lithium Research Articles

Lithium Potentiates Epithelial–Mesenchymal Transition in the Kidney through Induction of Matrix Metallopeptidase‐9

Lithium is a common therapeutic agent that is used to effectively treat patients with various mood disorders. Unfortunately there are many renal side effects of lithium therapy, including tubular atrophy and chronic interstitial fibrosis, which are not fully understood. To identify the intracellular signaling cascades that cause the proliferative action of lithium in the inner medullary collecting duct (IMCD), mIMCD3 cells were incubated with increasing concentrations of lithium chloride for 48 h. We found that lithium inhibited glycogen synthase kinase 3β (GSK‐3β) activity through serine‐9 phosphorylation in a dose responsive manner. Lithium inhibition of GSK‐3β induced ERK phosphorylation a concentration‐dependent manner. Both GSK‐3β and ERK are known to be involved in a variety of biological processes and are suggested to be key in the proliferative and antiapoptotic actions of lithium in the renal collecting duct. A reported downstream target of these kinases is matrix metallopeptidase 9 (MMP‐9), an enzyme that induces tubular cell epithelial‐mesenchymal transition (EMT) and therefore a major contributor to renal fibrosis. We found that protein abundance of MMP9 was elevated with increasing lithium concentrations in mIMCD3 cells. These results suggest that lithium inactivation of GSK‐3β potentiates EMT through ERK induction of MMP‐9 in the collecting duct.

Acute and chronic effects of lithium on BDNF and GDNF mRNA and protein levels in rat primary neuronal, astroglial and neuroastroglia cultures.

The neuroprotective effect of lithium has been attributed to its therapeutic action. However, the role of glial cells particularly astrocytes, and the possible interactions between neurons and astrocytes in neuroprotective effects of lithium have been disregarded. Thus, the aim of this study was to evaluate the direct effects of lithium on brain derived neurotrophic factor (BDNF) and glial cell line derived neurotrophic factor (GDNF) in rat primary neuronal, astrocytes, and mixed neuro-astroglial cultures to assess the possible effects of lithium on astrocytes and neuro-astroglia interactions. Rat primary astrocyte, neuronal and mixed neuro-astrocyte cultures were prepared from cortices of 18-day embryos. Cell cultures were exposed to lithium (1 mM) or vehicle for 1 day (acute) or 7 days (chronic). BDNF and GDNF mRNA and protein levels were determined by RT-PCR and ELISA, respectively. Chronic but not acute lithium treatment increased intracellular BDNF and GDNF protein levels in rat primary neuronal and astrocyte cultures, respectively (P<0.05). However, chronic lithium treatment had no significant effect on intracellular BDNF protein level in astrocyte and mixed neuron-astrocyte cultures or GDNF protein levels in mixed neuron-astrocyte culture. Furthermore, acute and chronic lithium treatment had no significant effect on mRNA and extracellular BDNF and GDNF protein levels in three studied cultures. Present study showed that chronic lithium treatment affected neurotrophins both in neurons and astrocytes in a cell-type specific manner with no effect on neuron-astrocyte interactions. The findings of this study also highlighted the importance of astrocytes as drug targets involved in the neuroprotective action of lithium.

Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics.

After decades of research, the mechanism of action of lithium in preventing recurrences of bipolar disorder remains only partially understood. Lithium research is complicated by absence of suitable animal models of bipolar disorder and by having to rely on in vitro studies of peripheral tissues. A number of distinct hypotheses emerged over the years, but none has been conclusively supported or rejected. The common theme emerging from pharmacological and genetic studies is that lithium affects multiple steps in cellular signalling, usually enhancing basal and inhibiting stimulated activities. Some of the key nodes of these regulatory networks include GSK3, CREB, and Na+-K+ ATPase. Genetic and pharmacogenetic studies are starting to generate promising findings, but remain limited by small sample sizes. As full responders to lithium seem to represent a unique clinical population, there is inherent value and need for studies of lithium responders. Such studies will be an opportunity to uncover specific effects of lithium in those individuals who clearly benefit from the treatment.

Telomerase dysregulation in the hippocampus of a rat model of depression: normalization by lithium.

Background:Telomeres are protective DNA-protein complexes at the ends of each chromosome, maintained primarily by the enzyme telomerase. Shortening of the blood leukocyte telomeres is associated with aging, several chronic diseases, and stress, eg, major depression. Hippocampus is pivotal in the regulation of cognition and mood and the main brain region of telomerase activity. Whether there is telomere dysfunction in the hippocampus of depressed subjects is unknown. Lithium, used in the treatment and relapse prevention of mood disorders, was found to protect against leukocyte telomere shortening in humans, but the mechanism has not been elucidated. To answer the questions whether telomeres are shortened and the telomerase activity changed in the hippocampus and whether lithium could reverse the process, we used a genetic model of depression, the Flinders Sensitive Line rat, and treated the animals with lithium.Methods:Telomere length, telomerase reverse transcriptase (Tert) expression, telomerase activity, and putative mediators of telomerase activity were investigated in the hippocampus of these animals.Results:The naïve Flinders Sensitive Line had shorter telomere length, downregulated Tert expression, reduced brain-derived neurotrophic factor levels, and reduced telomerase activity compared with the Flinders Resistant Line controls. Lithium treatment normalized the Tert expression and telomerase activity in the Flinders Sensitive Line and upregulated β-catenin.Conclusion:This is the first report showing telomere dysregulation in hippocampus of a well-defined depression model and restorative effects of lithium treatment. If replicated in other models of mood disorder, the findings will contribute to understanding both the telomere function and the mechanism of lithium action in hippocampus of depressed patients.

Lithium-induced neuroprotection is associated with epigenetic modification of specific BDNF gene promoter and altered expression of apoptotic-regulatory proteins.

Bipolar disorder (BD), one of the most debilitating mental disorders, is associated with increased morbidity and mortality. Lithium is the first line of treatment option for BD and is often used for maintenance therapy. Recently, the neuroprotective action of lithium has gained tremendous attention, given that BD is associated with structural and functional abnormalities of the brain. However, the precise molecular mechanism by which lithium exerts its neuroprotective action is not clearly understood. In hippocampal neurons, the effects of lithium (1 and 2 mM) on neuronal viability against glutamate-induced cytotoxicity, dendritic length and number, and expression and methylation of BDNF promoter exons and expression of apoptotic regulatory genes were studied. In rat hippocampal neurons, lithium not only increased dendritic length and number, but also neuronal viability against glutamate-induced cytotoxicity. While lithium increased the expression of BDNF as well as genes associated with neuroprotection such as Bcl2 and Bcl-XL, it decreased the expression of pro-apoptotic genes Bax, Bad, and caspases 3. Interestingly, lithium activated transcription of specific exon IV to induce BDNF gene expression. This was accompanied by hypomethylation of BDNF exon IV promoter. This study delineates mechanisms by which lithium mediates its effects in protecting neurons.

Cytoskeleton involvement in lithium-induced SH-SY5Y neuritogenesis and the role of glycogen synthase kinase 3β.

Lithium modulates signals impacting on the cytoskeleton, a dynamic system contributing to neural plasticity at multiple levels. In this study, SH-SY5Y human neuronal cells were cultured in the absence (C) or in presence (Li) of a 0.5 mM Li2CO3 (i.e. 1 mM lithium ion) for 25-50 weeks. We investigated the effect of this treatment on (1) morphological changes of cells observed using Hemalun eosin staining assay, (2) cytoskeletal changes by indirect immunofluorescence (IIF) staining of microtubules (α-tubulin) and heavy neurofilaments subunits (NF-H) and by measuring the expression rate changes of genes coding for receptor for activated C kinase (RACK1), casein kinase2 (CK2) and thymosine beta-10 using cDNA arrays technology, (3) cell adhesion properties by IIF staining of β-catenin protein. Besides, we have tried to understand the molecular mechanism of lithium action that triggers changes in cytoskeleton and neurites outgrowth. Thus, we examined the effect of this treatment on glycogen synthase kinase 3 (GSK3) expression and activity using western blotting of GSK3 and phosphorylated β-catenin, a downstream GSK3 target protein. Our results showed that lithium treatment reduces axon length, increases axonal spreading, enhances neurites growth and neurites branching with an increase of growth cone size. Moreover, genes coding for CK2 and thymosine beta-10 were significantly up-regulated, however, that coding for RACK1 was down-regulated. The most interesting result in this work is that mechanism underlying lithium action was not related to the inhibition of GSK3 activity. In fact, neither expression rate nor activity of this protein was changed.

A gedanken experiment to find a neuroanatomical model for post-traumatic stress disorder

Post-traumatic stress disorder is a persistent stress syndrome in which abnormal brain physiology persists long after cessation of the acute psychological event that causes it. Normal physiological homeostasis depends on equilibria. The basic unit of equilibrium is the negative feedback loop (NFL) and the simplest way to disrupt homeostasis would be to break an NFL. The resulting model requires two nuclei in the brain reciprocally-connected in an NFL, one of which, in response to the perception of overwhelming threats or demands, generates rapid pacemaker firing which leads to excitotoxic cell death in the other. The injured nucleus must also be able to undergo neurogenesis, which would explain clinical recovery. The relevant site of neurogenesis is the hippocampus, which is reciprocally connected with the dorsal raphe nucleus (DRN), a serotonergic pacemaker nucleus which has been shown to light up on PET scan (i.e. undergo burst firing) in response to stress. The model postulates that the DRN delivers an excitotoxic blow to the hippocampus. Then, via a second pathway, it promotes neurogenesis. The model incorporates potential sites of action for several psychoactive drugs, including anti-depressants and lithium, which promote neurogenesis; and valproate and atypical anti-psychotics, which block excitotoxicity. The theory has the advantage of being formulated in terms of how the brain actually works, i.e. through the interaction between pacemakers and processed sensory input from the outside world. It also directs pharmacological thinking to the role played by pacemakers and pacemaker currents.

Lithium and the application of its compounds in different fields of medicine

Although lithium has not been classified as an essential element for humans, it can influ ence numerous metabolic processes and exert diverse effects in the human body, both positive and negative ones. Its actions enable the use of lithium compounds in therapy of different illnesses. It is mostly used for cure of psychiatric disorders: as a mood stabilizer and for intensifying the action of antidepressants. However, its compounds have been also tried in other fields of medicine: as an adjuvant in patients with thyroid diseases undergoing radioiodine therapy, in dermatology, in cure of neurodegenerative and ophthalmic illnesses as well as in tumour therapy. Lithium displays beneficial action only within a determined range of its serum concentration and an overrun of the safe threshold can cause side effects. Due to this fact, the Li serum level as well as many other factors, e.g.: body weight, creatinine, renal and thyroid functions should be monitored during the whole therapy. Many studies were undertaken to clarify the mechanism by which lithium affects organisms but the results still remain unsatisfactory. Nevertheless, some interesting aspects of lithium action have been revealed, including its effect on the enzymatic activity, neurodegenerative processes, apoptosis, formation of cytokines as well as neurotransmission and oxidant balance.

Inhibition by lithium of glycogen synthase kinase-3 (GSK-3): Possible mechanism of therapeutic action of lithium

Lithium ion (Li+) is used as mood stabilizer in mood disorder for more than 60 years, but its mode of action remains largely obscure. Due to similarities with Mg2+, Li+ affects many biological processes dependent on Mg2+. During the past 10 years, a body of evidence has highlighted the inhibition of glycogen synthase kinase-3 (GSK-3) as a possible mechanism of therapeutic action of Li+. GSK-3 corresponds to two kinase-type enzymes (GSK-3α and GSK-3β), able to phosphorylate many proteins in neuronal and non-neuronal cells and, thereby, to exert a regulatory role in many cellular functions. GSK-3 itself is negatively regulated by phosphorylation produced by several enzymes, including Akt. It is currently believed that direct inhibition of GSK-3 by Li+ has no therapeutic relevance since only observed with Li+ concentrations toxic in humans. In contrast, Li+ concentrations consistent with therapeutic action in human activate Akt and, thereby, strongly inhibit the activity of GSK-3 [1]. Experimental animal studies have shown that the inhibitory effects of Li+ on responses to psychostimulants are related to an action on GSK-3 [2]. These behavioral responses can be compared to manic episodes and these results suggest that the antimanic effect of Li+ is mediated through GSK-3 inhibition. Several other studies suggest that antidepressant-like responses of Li+, assessed by behavioral tests in animal, depend on the GSK-3 inhibition [3]. Altogether, these preclinical data tend to attribute to the GSK-3 inhibition both antimanic and antidepressant effects, and perhaps a mood stabilizing effect. However, in the absence of clear understanding of mood disorder etiology, evaluating the exact contribution of GSK-3 inhibition to clinical effects of Li+ remains a complex issue.

P.3.b.014 Investigation of Heschl gyrus and planum temporale in patients with schizophrenia and bipolar disorder: a 1H MRS study

Increasing numbers of youth are presenting for psychiatric evaluation with markedly irritable mood plus “hyperarousal” symptoms. Diagnostically homeless in current nosology, the syndrome (as well as its underlying neurobiology) is little understood. To address this problem, we conducted an exploratory proton magnetic resonance spectroscopy (MRS) study in a large sample of youth with chronic, functionally disabling irritability accompanied by hyperarousal, a clinical syndrome known as “severe mood dysregulation” (SMD), which may represent a broad phenotype of pediatric bipolar disorder. Medication-free SMD youth (N = 36) and controls (N = 48) underwent 1.5 Tesla MRS in four regions of interest. The following three neurometabolites, relative to creatine (Cr), were quantified with LCModel Software: (a) myo-inositol (mI), a marker of intra-cellular second messengers linked to the neurobiology of bipolar disorder; (b) glutamate/glutamine (GLX), a marker of the major excitatory neurotransmitter glutamate; and (c) N-acetyl aspartate (NAA), a marker of neuronal energetics. SMD subjects had significantly lower temporal mI/Cr versus controls. However, this difference did not survive correction for multiple comparisons. Given studies implicating mI in lithium's action in BD adults and youth, further work is necessary to determine potential therapeutic implications of our present finding and how SMD youth differ pathophysiologically from those with strictly defined BD.

Lithium efficacy in bipolar depression with flexible dosing: A six-week, open-label, proof-of-concept study.

Lithium has a narrow therapeutic index with a subtle balance between effectiveness and adverse effects. Current guidelines recommend the use of lithium as a treatment for acute bipolar depression; however, the therapeutic range for the treatment has not been fully defined. Recently, the adjunctive lower lithium dose in bipolar depression has revealed potential efficacy; however, no study has investigated it predominantly in monotherapy. In this open-label, proof-of-concept study, 31 individuals with bipolar disorder during a depressive episode were randomized and 29 were followed up for six weeks with flexible lithium dosing. All subjects had a 21-item Hamilton Rating Scale for Depression (HAM-D) score of ≥18 at baseline. Subjects were divided into two groups, with higher (Li ≥0.5 mEq/l) or lower (Li <0.5 mEq/l) blood lithium levels. Response and remission rates were evaluated using the HAM-D scores. Following 6 weeks of lithium treatment, the remission rate for all patients was 62.0%. The plasma lithium levels did not impact the clinical response. However, subjects with higher blood lithium levels had an increased prevalence of nausea, restlessness, headaches and cognitive complaints. The results indicate that the lithium dose for the treatment of bipolar depression in an individual should be based on the clinical efficacy and side-effects. In the context of personalized psychiatric treatments, it is necessary to evaluate the therapeutic action of lithium with individual regimens in order to develop more tolerable and effective treatment approaches.

Lithium potentiates GSK-3β activity by inhibiting phosphoinositide 3-kinase-mediated Akt phosphorylation

Accumulating evidence has pointed to the direct inhibitory action of lithium, an anti-depressant, on GSK-3β. The present study investigated further insight into lithium signaling pathways. In the cell-free assay Li2CO3 significantly inhibited phosphoinositide 3-kinase (PI3K)-mediated phosphorylation of Akt1 at Ser473, but Li2CO3 did not affect PI3K-mediated PI(3,4,5)P3 production and 3-phosphoinositide-dependent protein kinase 1 (PDK1)-mediated phosphorylation of Akt1 at Thr308. This indicates that lithium could enhance GSK-3β activity by suppressing Akt-mediated Ser9 phosphorylation of GSK-3β in association with inhibition of PI3K-mediated Akt activation. There was no direct effect of Li2CO3 on Akt1-induced phosphorylation of GSK-3β at Ser9, but otherwise Li2CO3 significantly reduced GSK-3β-mediated phosphorylation of β-catenin at Ser33/37 and Thr41. This indicates that lithium directly inhibits GSK-3β in an Akt-independent manner. In rat hippocampal slices Li2CO3 significantly inhibited phosphorylation of Akt1/2 at Ser473/474, GSK-3β at Ser9, and β-catenin at Ser33/37 and Thr41. Taken together, these results indicate that lithium exerts its potentiating and inhibiting bidirectional actions on GSK-3β activity.

Lithium and the other mood stabilizers effective in bipolar disorder target the rat brain arachidonic acid cascade.

This Review evaluates the arachidonic acid (AA, 20:4n-6) cascade hypothesis for the actions of lithium and other FDA-approved mood stabilizers in bipolar disorder (BD). The hypothesis is based on evidence in unanesthetized rats that chronically administered lithium, carbamazepine, valproate, or lamotrigine each downregulated brain AA metabolism, and it is consistent with reported upregulated AA cascade markers in post-mortem BD brain. In the rats, each mood stabilizer reduced AA turnover in brain phospholipids, cyclooxygenase-2 expression, and prostaglandin E2 concentration. Lithium and carbamazepine also reduced expression of cytosolic phospholipase A2 (cPLA2) IVA, which releases AA from membrane phospholipids, whereas valproate uncompetitively inhibited in vitro acyl-CoA synthetase-4, which recycles AA into phospholipid. Topiramate and gabapentin, proven ineffective in BD, changed rat brain AA metabolism minimally. On the other hand, the atypical antipsychotics olanzapine and clozapine, which show efficacy in BD, decreased rat brain AA metabolism by reducing plasma AA availability. Each of the four approved mood stabilizers also dampened brain AA signaling during glutamatergic NMDA and dopaminergic D2 receptor activation, while lithium enhanced the signal during cholinergic muscarinic receptor activation. In BD patients, such signaling effects might normalize the neurotransmission imbalance proposed to cause disease symptoms. Additionally, the antidepressants fluoxetine and imipramine, which tend to switch BD depression to mania, each increased AA turnover and cPLA2 IVA expression in rat brain, suggesting that brain AA metabolism is higher in BD mania than depression. The AA hypothesis for mood stabilizer action is consistent with reports that low-dose aspirin reduced morbidity in patients taking lithium, and that high n-3 and/or low n-6 polyunsaturated fatty acid diets, which in rats reduce brain AA metabolism, were effective in BD and migraine patients.

Response to Lithium in Bipolar Disorder: Clinical and Genetic Findings

The use of lithium is a cornerstone for preventing recurrences in bipolar disorder (BD). The response of patients with bipolar disorder to lithium has different levels of magnitude. About one-third of lithium-treated patients are excellent lithium responders (ELR), showing total prevention of the episodes. A number of clinical characteristics were delineated in patients with favorable response to lithium as regards to clinical course, family history of mood disorders, and psychiatric comorbidity. We have also demonstrated that temperamental features of hypomania (a hyperthymic temperament) and a lack of cognitive disorganization predict the best results of lithium prophylaxis. A degree of prevention against manic and depressive episodes has been regarded as an endophenotype for pharmacogenetic studies. The majority of data have been gathered from so-called "candidate" gene studies. The candidates were selected on the basis of neurobiology of bipolar disorder and mechanisms of lithium action including, among others, neurotransmission, intracellular signaling, neuroprotection or circadian rhythms. We demonstrated that response to lithium has been connected with the genotype of BDNF gene and serum BDNF levels and have shown that ELR have normal cognitive functions and serum BDNF levels, even after long-term duration of the illness. A number of genome-wide association studies (GWAS) of BD have been also performed in recent years, some of which also focused on lithium response. The Consortium on Lithium Genetics (ConLiGen) has established the large sample for performing the genome-wide association study (GWAS) of lithium response in BD, and the first results have already been published.

Variabilité de la réponse au lithium

Bipolar disorder (2% of the general population) is a major affective disorder associated with considerable burden and costs. Lithium (Li) is the leading treatment for relapse prevention in bipolar disorders with many patients who remain asymptomatic for several years (even decades). In addition, it is the only psychoactive drug that has demonstrated efficacy in suicide prevention. However a large proportion of patients is experiencing very high relapse rates (overall between 70 and 80% relapse, two years after a major episode). The management of Li treatment is complicated by several uncertainties: (i) the pharmacodynamic and therapeutic mechanism of action of lithium (Li) remains widely unknown, (ii) no recent pharmacokinetic studies using modern modeling approaches is available, (iii) finally, data are dramatically lacking for the extended release form of lithium that is used nowadays in a large majority of patients. Transport mechanisms of Li transport through the blood-brain barrier (BBB) remain unknown and very little is also known on the effect of Li chronic exposure on the expression of some BBB biomarkers especially those involved in transport and metabolism of drugs. The BBB is likely to play an important role in lithium efficacy. Very little is known about the correlation between brain and blood lithium levels and mechanisms involved in the lithium transport at the BBB remain largely unexplored. PK parameters and PK-PD relationships of plasma and intra-erythrocyte lithium levels (using lithium extended release) of lithium extended release are also lacking. In this article, we review the potential developments of research on lithium response variability.

Imagerie cérébrale et lithium

ObjectivesRecent neuroimaging techniques like MRI, allow a better understanding of the mechanism of action of lithium. In this article, we summarize the main results about neuroimaging and lithium in bipolar disorder. MethodsWe selected relevant literature about brain imaging and lithium action in bipolar disorder. Results and conclusionsBrain imaging studies bring evidence that lithium therapeutic effect is associated with a neurotrophic effect, especially in the grey matter and the hippocampus. They also raise hopes that we may in the future use brain imaging to measure directly brain lithium concentrations with spectroscopy and to help the clinician predict the response to lithium.

Role of Lithium Augmentation in the Management of Major Depressive Disorder

The high rate of non-responders to initial treatment with antidepressants requires subsequent treatment strategies such as augmentation of antidepressants. Clinical guidelines recommend lithium augmentation as a first-line treatment strategy for non-responding depressed patients. The objectives of this review were to discuss the current place of lithium augmentation in the management of treatment-resistant depression and to review novel findings concerning lithium's mechanisms of action. We conducted a comprehensive and critical review of randomized, placebo-controlled trials, controlled and naturalistic comparator studies, and continuation-phase and discontinuation studies of lithium augmentation in major depression. The outcomes of interest were efficacy, factors allowing outcome prediction and results from preclinical studies investigating molecular mechanisms of lithium action. Substantial efficacy of lithium augmentation in the acute treatment of major depression has been demonstrated in more than 30 open-label studies and 10 placebo-controlled trials. In a meta-analysis addressing the efficacy of lithium in 10 randomized, controlled trials, it had a significant positive effect versus placebo, with an odds ratio of 3.11 corresponding to a number-needed-to-treat (NNT) of 5 and a mean response rate of 41.2% (versus 14.4% in the placebo group). The main limitations of these studies were the relatively small numbers of study participants and the fact that most studies included augmentation of tricyclic antidepressants, which are not in widespread use anymore. Evidence from continuation-phase studies is sparse but suggests that lithium augmentation should be maintained in the lithium-antidepressant combination for at least 1 year to prevent early relapses. Concerning outcome prediction, single studies have reported associations of better outcome rates with more severe depressive symptomatology, significant weight loss, psychomotor retardation, a history of more than three major depressive episodes and a family history of major depression. Additionally, one study suggested a predictive role of the -50T/C single nucleotide polymorphism of the glycogen synthase kinase 3 beta (GSK3B) gene in the probability of response to lithium augmentation. With regard to novel mechanisms of action, GABAergic, neurotrophic and genetic effects might explain the effects of lithium augmentation. In conclusion, augmentation of antidepressants with lithium remains a first-line, evidence-based management option for patients with major depression who have not responded adequately to antidepressants. While the mechanisms of action are currently widely studied, further clinical research on the role of lithium potentiation of the current generation of antidepressants is warranted to reinforce its role as a gold-standard treatment for patients who respond inadequately to antidepressants.

Les indications actuelles du lithium : la prévention du risque suicidaire

Affective disorders are associated with an increased risk of suicidal behavior. For instance, 18% of bipolar males having a past history of suicide attempt die by suicide. In comparison to untreated patients, those receiving a continuous pharmacological treatment for bipolar disorder have a reduced surmortality, including by suicide (Angst et al., 2002). Evidence shows that lithium has specific antisuicidal properties. Meta-analyses including long-term randomized controlled trials have shown a 80% decrease of suicidal behaviors in patients receiving lithium for 18months or more. In a recent meta-analysis including controlled studies comparing lithium vs. placebo or active drugs in both unipolar and bipolar disorders, Cipriani et al., 2013 have shown significant reduction of suicide mortality in patients on lithium. In addition, lithium is more efficient than anticonvulsants to prevent suicidal behaviors. In a large Danish study (Sondergard et al., 2009), although the rate of suicide was higher during periods when patients purchased anticonvulsants than during periods with lithium, the suicide rate decreased with the number of prescriptions in a rather similar way for patients first treated with lithium and patients first treated with anticonvulsants. But switch to or augmentation with lithium to patients initiated on anticonvulsants was associated with a significantly reduced rate of suicide whereas a switch to or augmentation with anticonvulsants to patients first started on lithium showed no additional effect on the suicide rate. Antisuicidal effect of lithium is now admitted in bipolar disorder as well as in unipolar depression and seems to be independent of the effect on mood. Ahrens et al., 2001, have investigated a group of high-risk patients with recurrent affective disorders who had committed suicide attempts before the start of lithium. According to their recurrence-related response to long-term lithium prophylaxis, nearly 50% of poor responders did not exhibit any further suicidal behavior during lithium treatment. Khan et al., 2011, have conducted an exploratory proof of concept-randomized trial comparing suicidality in depressed patients assigned to citalopram+lithium or to citalopram+placebo for 4weeks. Lithium when used in therapeutic doses (>0.5mEq/L) was associated with prevention of suicidal thoughts and behaviors. It is important to know that lithium has to be discontinuated very slowly (by 10% a month). After the discontinuation of lithium, suicidal acts are more frequent in the first year than at later times or before start of lithium treatment (Tondo et al., 1998). The mechanism of action of lithium remains poorly understood. It may be due to an action of lithium on suicidal physiopathology. Indeed, lithium reduces aggressive and impulsive behaviors in both humans and animals, and possibly modulates suicidal vulnerability traits. Indeed, decision-making alterations are associated with suicidal phenotype and rely on orbitofrontal cortex dysfunction. In euthymic bipolar patients, decision-making performances have been correlated with lithium dose (Adida et al., submitted). In addition, main molecular targets of lithium, Wnt - GSK3 – β-catenin and IP-3 pathways, have been involved in suicidal vulnerability through post-mortem and genetic studies. In addition, SAT-1 pathway could be involved in antisuicidal effect of lithium. To summarize, for a therapeutic dose, lithium has well demonstrated preventive effect on suicide behaviours in mood disorders, independently of its action on mood. It improves clinical dimensions associated with suicidal risk (impulsivity, aggression), raising the question of dimensional prescription. Finally, further studies are needed to elucidate the antisuicidal mechanism of action of lithium. However, it could be suggested that lithium acts on suicidal vulnerability factors at a macroscopic level (decision-making, cerebral volumes) as well as microscopic level (molecular pathways).

Microarray analysis of global gene expression in leukocytes following lithium treatment

To elucidate the molecular effects of lithium, we studied global gene expression changes induced by lithium in leukocytes from healthy subjects.Eight healthy male subjects participated in this study. Lithium was prescribed for weeks to reach a therapeutic serum concentration. Leukocyte counts and serum lithium concentrations were determined at baseline (before medication), after 1 and 2 weeks of medication and at 2 weeks after stopping medication. Gene expression profiling was performed at each time point using Agilent G4112F Whole Human Genome arrays (The Agilent Technologies, Santa Clara, CA, USA). Expression of some candidate genes was also assessed by real-time polymerase chain reaction (PCR).Gene ontology analysis revealed that the cellular and immune responses to stimulus and stress indeed played a major role in the cellular response to lithium treatment. Pathway analysis revealed that the interleukin 6 pathway, the inhibitor of differentiation pathway, and the methane metabolism pathway were regulated by lithium. Using real-time PCR, we also confirmed that five candidate genes in these pathways were significantly changed, including suppressor of cytokine signaling 3 and myeloperoxidase.Our investigation suggests that the molecular action of lithium is mediated in part by its effects on the cellular and immune response to stimulus and stress followed by the interleukin 6, inhibitor of differentiation, and methane metabolism pathways.

Polymorphism of circadian clock genes and prophylactic lithium response

The therapeutic action of lithium in bipolar mood disorder may be connected with its effect on biological rhythms. In the present study, an attempt was made to investigate an association between multiple single nucleotide polymorphisms (SNPs) and their haplotypes pertaining to four genes involved in regulation of biological rhythms [circadian locomotor output cycle kaput (CLOCK), aryl hydrocarbon receptor nuclear translocator-like (ARNTL), timeless circadian clock (TIMELESS), period circadian clock 3 (PER 3)], and the efficacy of lithium prophylaxis. The study was performed on 115 patients with bipolar mood disorder (45 males, 70 females) with a mean age of 52 ± 12 years, with lithium prophylaxis for 22 ± 8 years, recruited from the outpatients in the Department of Psychiatry, Poznan University of Medical Sciences. The assessment of the lithium prophylactic response was made retrospectively using the Alda scale. Genotyping was done for nine SNPs of the CLOCK gene, 18 SNPs of the ARNTL gene, six SNPs of the timeless circadian clock (TIM) gene, and nine SNPs of the PER3 gene. An association with the degree of lithium prophylaxis was found for six SNPs and three haplotype blocks of the ARNTL gene, and two SNPs and one haplotype block of the TIM gene. No association with SNPs or haplotypes of the CLOCK and PER3 genes was observed. The results suggest that the ARNTL and TIM genes may be associated with the lithium prophylactic response in bipolar illness. This association may be related to the role of these genes in the predisposition to bipolar mood disorder. Of special interest may be polymorphisms of these genes involved both in the predisposition to bipolar mood disorder and the lithium response.