Lithium: Its Role in Psychiatric Research and Treatment

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This article has been cited by other articles in PMC. Abstract Although used around the world since , lithium has come into extensive use in psychiatry in the United States only within the past decade. Lithium intoxication producing chorea athetosis with recovery.

Cellular stress, atrophy, and loss in BD: therapeutic targets for lithium

The lithium treatment of maniacal psychosis. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry. Lithium in psychiatric therapy.

Lithium Treatment for Psychiatric Disorders

Are there two types of unipolar depression? Antidepressant response to tricyclics and urinary MHPG in unipolar patients. Clinical response to imipramine or amitriptyline. MHPG in the cerebrospinal fluid. Biogenic amines and affective disorders. Use of lithium carbonate in private psychiatric practice.

Therapeutic and prophylactic action of lithium against recurrent manic-depressive psychosis. Act Nerv Super Praha Nov; 9 4: Effectiveness of lithium carbonate in the treatment of manic-depressive illness. The use of lithium in the affective psychoses. A longitudinal double-blind study. A clinical trial of methysergide and lithium in mania. Controlled evaluation of lithium and chlorpromazine in the treatment of manic states: A comparison of lithium carbonate and chlorpromazine in mania.

Lithium as a prophylactic agents. Its effect against recurrent depressions and manic-depressive psychosis. Lithium prophylaxis in recurrent affective disorders. The use of lithium in affective disorders. Prophylaxis of depression in chronic recurrent affective disorder. A two-year clinical experience with lithium. Can Psychiatr Assoc J. Lithium carbonate prophylaxis failure. The current role of lithium in the treatment of affective disorders. Lithium in the treatment of depression. Lithium carbonate response in depression. Urinary MHPG excretion in primary affective disorders.

Lithium maintenance treatment of manic-melancholic patients: Lithium carbonate in affective disorders. A double-blind study of prophylaxis in unipolar recurrent depression. Methodological problems of prophylactic trials in recurrent affective disorders. Biogenic amines and emotion. Frequency of diagnoses of schizophrenia versus affective disorders from to Treatment of children of lithium-responding parents. Curr Ther Res Clin Exp. Neurotrophic factors not only increase cell survival by providing necessary trophic support, but also play an important role in inhibiting apoptosis cascades and activating cell survival pathways.

BDNF and other neurotrophic factors are essential for neuronal survival and functioning; thus, it is possible that a continuous diminution of these factors could affect neuronal viability [reviewed in 94 , 95 ]. In vitro and in vivo studies have shown that CREB and BDNF act together to mediate the neurotrophic and therapeutic effects of lithium discussed in the next section. It is therefore possible that the exact kinetics of ERK and CREB activation will ultimately determine whether the activated kinases participate in a cell survival- or death-promoting pathway.

Indeed, a number of human studies reported decreased BDNF levels in manic and depressive episodes, also considered a potential biomarker of neuronal dysfunction and chronic stress [reviewed in 97 ]. In vivo , chronic lithium increased activated ERK levels in the frontal cortex and hippocampus Postmortem studies in BD subjects have noted reduced CREB phosphorylation in lithium-treated BD subjects , , but the instability of phosphorylated proteins postmortem is well known and of concern in such reports. Also, chronic lithium treatment prevented stress-induced decreases in dendritic length, as well as stress-induced increases in CREB phosphorylation in the hippocampus Regarding other transcription factors, lithium increased the transactivation of AP-1, and also enhanced DNA binding Regarding BDNF regulation by lithium, its chronic administration increased BDNF expression in the rodent brain 99 , , particularly in the hippocampus and frontal cortex However, another study found that BDNF was not upregulated by chronic lithium treatment in therapeutically relevant doses It is important to note that recent evidence suggests that the neurotrophic effect of lithium in cortical neurons requires BDNF expression Finally, human studies have also described decreased BDNF levels in lymphoblasts from patients with BD who responded to lithium compared with matched healthy controls and their unaffected relatives Similar to BDNF, treatment with lithium for six weeks altered brain concentrations of NGF and glial cell line-derived neurotrophic factor in a rat model of depression In another study, chronic 14 days but not acute one day administration of lithium in adult rats at various doses levels of 0.

Correspondingly, lithium increased serum and hippocampal NT-3 levels in an animal model of mania VEGF, which is considered to be a neurotrophic factor, has been implicated in neuronal survival, neurotrophic effects, regeneration, growth, and differentiation. A recent study found that lithium upregulated VEGF in brain endothelial cells and astrocytes ; it also significantly attenuated the decreased expression of VEGF in the hippocampus in stressed animals The widely described presence of apoptosis in neural cells from individuals with BD occurs through diverse mechanisms.

Indeed, the primary function of IP 3 is the release of calcium from the ER. The release of calcium from the ER is an important signaling event in all cells 63 , In this context, it is important to note that altered calcium dynamics has been the most reproducible biological measure in the pathophysiology of BD [for an excellent review, see ].

A large movement of calcium into the mitochondria will exceed mitochondrial capacity to export protons, potentially interrupting adenosine triphosphate ATP synthesis and the activation of the permeability transition pore with release of cytochrome c, thus initiating cellular apoptosis. In addition, excessive production of reactive oxygen species ROS, or free radicals triggered by mitochondrial dysfunction whether or not this is related to lower antioxidant capacity may lead to oxidative stress.

Glutathione is the main antioxidant substrate in all tissues, and its production is rate-limited by its precursor, cysteine; notably, glutathione alterations have been reported in BD , Furthermore, a recent study evaluated oxidative stress parameters in unmedicated and treated BD subjects during an initial manic episode; the investigators found that the end products of lipid peroxidation, thiobarbituric acid reactive substances TBARS and antioxidant enzyme activity [superoxide dismutase SOD and catalase CAT ] were increased in unmedicated manic patients compared to healthy controls With regard to Bcl-2, it has been shown to attenuate cell death in the ER and mitochondria by limiting calcium overload and cytochrome c release, sequestering proforms of death-inducing caspase enzymes, and controlling mitochondrial calcium release.

In addition, stress significantly worsened the size of the infarct area in control mice, but not in transgenic mice that constitutively express increased Bcl-2, which appears to be a neuronal neurotrophic factor. In another study, lithium also enhanced the expression of ER chaperones proteins GRP78, GRP94, and calreticulin, thus protecting against the deleterious effects of malfolded proteins Interestingly, depletion of neuronal IP 3 located in the ER represents a direct effect by lithium and other mood stabilizers to increase neuronal growth-cone area, and was reversed by inositol Chronic treatment with lithium also inhibited reactive oxygen metabolite H 2 O 2 -induced cell death and increased glutathione levels in primary cultured rat cerebral cortical cells Chronic lithium treatment directly inhibited oxidative damage to lipids and proteins The authors concluded that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses, which may be related to energy metabolism and neuroplasticity pathway dysfunction Bcl-2 levels were robustly increased in frontal cortex after lithium treatment, particularly in layers II and III Also, long-term, but not acute, treatment with lithium of cultured cerebellar granule cells induced concentration-dependent decreases in mRNA of p53 and protein levels of Bax both of which are pro-apoptotic ; conversely, Bcl-2 mRNA and protein levels increased considerably.

In addition, chronic treatment with lithium in drinking water prevented the aluminum-induced translocation of cytochrome c, upregulating Bcl-2 and Bcl-X L , and thus reducing DNA damage. Because of its neuroprotective effects against a variety of insults, lithium has garnered considerable interest as a neuroprotective drug for a broad range of central nervous system disorders.

Over a decade ago, Nonaka and colleagues reported that chronic, but not acute, lithium treatment at therapeutic doses robustly protected neurons against glutamate excitotoxicity by inhibiting N-methyl-D-aspartate NMDA receptor-mediated calcium influx. Pretreatment with lithium blocked glutamate-induced effects and apoptosis in rat cerebellar granule cells by preventing the rapid activation of c-Jun N-terminal kinase and p38 kinase, and by increasing AP-1 binding.

Additional studies have demonstrated that chronic treatment with lithium at therapeutically relevant concentrations attenuated NMDA-mediated cytoplasmic vacuolization in primary rat hippocampal neurons Similarly, lithium in combination with a GSK inhibitor and VPA blocked against glutamate-induced cell excitotoxicity in aging cerebellar granule cells High doses of lithium 5 mM had neuroprotective effects against C 2 -ceramide N-acetyl-sphingosine -induced apoptosis in primary cultures of cerebellar granule neurons , presumably by blocking the dephosphorylation of both protein kinase B PKB and GSK ; however, the doses used in this study would be toxic for humans.

In cultures exposed to oxygen and glucose deprivation in a model of ischemia, lithium treatment 0. In another model of excitotoxicity using ouabain a potent inhibitor of sodium-potassium adenosine triphosphatase , lithium pretreatment in human neuroblastoma SH-SY5Y cells at 1 mM diminished ouabain-induced lactate dehydrogenase LDH, a measure of cellular damage Lithium also prevented colchicine-induced apoptosis in rat cerebellar granule neurons Finally, in another cell culture model of neurotoxicity, therapeutically relevant concentrations of lithium 1.

The investigators hypothesized that the neuroprotective effects of lithium were due to its ability to attenuate intracellular calcium overload Indeed, one study suggested that lithium selectively prevents apoptosis in cortical neurons by increasing calcium through activation of PI3-K and PLC Treatment with therapeutic doses of lithium was also neuroprotective against ATP-induced cell death in hippocampal slices of adult rats In this section, we review the neuroprotective effects of lithium in a series of models of brain ischemia, injury especially spinal cord and optic nerve injury , infection, irradiation, neurodegeneration, and neuroinflammation [e.

Nonaka and Chuang examined the effects of chronic lithium pretreatment 16 days on neurological deficits and brain infarcts induced by left middle cerebral artery occlusion MCAO, a model of brain ischemia in rats. Another study similarly showed that neurological deficits resulting from cerebral ischemia induced by MCAO were decreased in rats treated with lithium 25 and 48 h after ischemia; reduced infarct volume, ischemia-induced caspase-3 immunoreactivity, and AP-1 protein expression were also observed after lithium administration.

Chronic lithium treatment also protected against hypoxia in frontal cortex, caudate putamen, hippocampus, and cerebellum; expression of BDNF and phospho-CREB were higher in the frontal cortex Lithium also reduced ischemia-induced hippocampal CA1 damage and behavioral deficits memory impairment in gerbils. These behavioral benefits were associated with an increase in viable cells associated with downregulation of pro-apoptotic p53 in the CA1, and upregulation of anti-apoptotic Bcl-2 and HSP in the ischemic brain Exposure of cultured cortical neurons to lithium decreased tau protein levels, a decrease associated with reduced tau mRNA levels While lithium has obvious neuroprotective properties, it is not clear whether it also reduces or prevents the risk of dementia.

One recent study found that chronic lithium attenuated dementia risk More recently, a large, observational study evaluating subjects with dementia in Denmark between and found that, while individuals who had used lithium at least once had an increased rate of dementia compared to those not exposed to lithium, individuals who used lithium continuously had similar rates of dementia to the general population Chronic lithium significantly reduced the size of quinolinic acid-induced striatal lesions, potentially associated with increased Bcl-2 protein levels Correspondingly, Senatorov and colleagues proposed that the neuroprotective properties of lithium are not only due to its ability to inhibit apoptosis but also its ability to stimulate neuronal and astroglial progenitor proliferation in the quinolinic acid-injected striatum.

Also, lithium reduced striatal neurodegeneration induced in rats by 3-nitropropionic acid 3-NP by inhibiting calpain and cdk5 activation, and consequent cellular death Lithium treatment also reduced the intracellular increase in calcium induced by 3-NP MPTP depletes striatal dopamine and its metabolites in mice. Because lithium treatment prevented reduction of striatal Bcl-2 in MPTP-treated mice, but the opposite effect was seen with Bax, this effect was hypothesized to be mediated by Bcl-2 and Bax Recently, Feng and colleagues investigated the effects of lithium and VPA on symptom onset, survival time, and neurological deficits in copper zinc superoxide dismutase SOD1 G93A mutant mice, a model of ALS; they observed delayed onset and decreased neurological deficit after treatment.

In a parallel study of G93A mice, lithium also delayed disease onset and duration and augmented life span Notably, there is also clinical evidence to support the neuroprotective properties of lithium in ALS. Furthermore, disease progression was markedly attenuated in the lithium-treated group A study investigating the neuroprotective effects of lithium pretreatment against HIV-gpmediated toxicity in SY5Y neuronal cells found that lithium pretreatment significantly reduced gpassociated neurotoxicity However, post-treatment with lithium had minimal neuroprotective effects against gp, both in vivo and in vitro.

These encouraging preclinical findings were extended to humans. Spinocerebellar ataxia type 1 SCA1 is a dominantly inherited neurodegenerative disorder characterized by progressive motor and cognitive dysfunction.

Lithium Treatment for Psychiatric Disorders

In a SCA1 mouse model, chronic administration of lithium had a positive effect on multiple behavioral measures and hippocampal neuropathology Another type of brain injury, cranial irradiation, results in lifelong neurocognitive deficiency in cancer survivors, in part due to radiation-induced apoptosis and decreased neurogenesis in the subgranular zone of the hippocampus. A recent investigation examined whether lithium treatment protects irradiated hippocampal neurons from apoptosis and improves the cognitive performance of irradiated mice.

These effects were sustained when cells were treated with lithium combined with ionizing radiation.

Lithium treatment before cranial irradiation also improved performance in the Morris water maze paradigm, suggesting that lithium attenuates the cognitive deficits that result from cranial irradiation Treatment with GSK-3 inhibitors, including lithium to rats with thoracic spinal cord lesion or contusion injuries, induced significant sprouting in the caudal spinal cord and promoted locomotor functional recovery Similarly, in a rat model of optic nerve injury, chronic treatment with lithium protected retinal ganglion cell survival and axon regeneration; an increase in Bcl-2 immunoreactivity was seen with lithium treatment in retinal ganglion cells , Finally, a recent study reported that chronic treatment with lithium upregulated brain arachidonic acid AA metabolism in an animal model of neuroinflammation; thus, lithium could possibly be considered in the treatment of human brain diseases associated with neuroinflammation [for a good review, see ].

BD is a disorder that entails mood episodes as well as considerable structural impairment, potentially secondary to changes in cellular plasticity and resilience. Indeed, a recent meta-analysis and meta-regression of 98 structural studies in BD showed a robust change in brain structure in BD, as well as evidence that lithium increases gray matter volume Overall, lithium seems to be an exogenous support that activates adaptive mechanisms in the brain. Future effective treatments for BD possessing neurotrophic properties are expected to be at least partially lithium-mimetic agents.

Neuroprotection is the most consistent biological outcome associated with lithium treatment in both preclinical and clinical models of BD. Paradoxically, lithium is a simple metal with a complex mechanism of action. It is a monovalent cation that is also a very light, reactive, wide-spread, and unstable alkali metal, and thus it has outstanding and unique penetration in most tissues and cells. Its ability to be potentially omnipresent explains its high sensitivity and low specificity for biological effects targeting at neurotrophic pathways, as well as its potentially wide range of clinical indications and undesirable side effects profile.

Studies showing that lithium has neurotrophic effects at doses that are extremely toxic even lethal for humans are not uncommon, but these cannot be reliably translated to human diseases, especially BD. Although not addressed by the present review, the study of lithium-responsive gene networks related to neurotrophic effects are promising and may improve our understanding of critical nuclear downstream targets expressing key proteins and peptides.

Also, given that lithium has a narrow therapeutic margin and well-known side effects, and that good response rates are observed in only about half of patients, the search for biological predictors of better lithium response has begun [see ], although such work needs further replication. Overall, lithium has been associated with significant neurotrophic properties not only in BD but also in a wide range of models for other brain and neurological disorders.

We are optimistic that recent novel insights into the mechanisms of action of lithium will ultimately lead to a better understanding of clinically relevant pathophysiological targets, and the consequent development of improved treatments for those who suffer from BD and other devastating disorders. Ioline Henter provided outstanding editorial assistance. The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manuscript. National Center for Biotechnology Information , U. Author manuscript; available in PMC Jan 1.

Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available at Bipolar Disord. See other articles in PMC that cite the published article. Abstract Lithium has been and continues to be the mainstay of bipolar disorder BD pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention.

Cellular stress, atrophy, and loss in BD: Direct targets of lithium involving neuroprotection: Open in a separate window. Neurotrophic signaling cascades General aspects of neurotrophic signaling cascades: Mitochondrial and ER regulation of oxidative stress and apoptosis: Conclusions and perspectives BD is a disorder that entails mood episodes as well as considerable structural impairment, potentially secondary to changes in cellular plasticity and resilience. Footnotes The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manuscript.

Lifetime and month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Impairments of neuroplasticity and cellular resilience in severe mood disorders: Suicide risk in bipolar disorder during treatment with lithium and divalproex. Decreased risk of suicides and attempts during long-term lithium treatment: Lithium salts in the treatment of psychotic excitement.

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Lithium-induced increase in human brain grey matter. Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients. Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness. A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression.

Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes. Annu Rev Pharmacol Toxicol. Glycogen synthase kinase-3 GSK3 in psychiatric diseases and therapeutic interventions. Inhibition of GSK3beta is a common event in neuroprotection by different survival factors.

Brain Res Mol Brain Res. Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. A bimodal model of the mechanism of action of lithium. In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase Mood stabilizers, glycogen synthase kinase-3beta and cell survival. A molecular mechanism for the effect of lithium on development. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells.

Glycogen synthase kinase-3beta haploinsufficiency mimics the behavioral and molecular effects of lithium. Lithium reduces Gsk3b mRNA levels: Eur Arch Psychiatry Clin Neurosci. AR-A, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. Beta-catenin overexpression in the mouse brain phenocopies lithium-sensitive behaviors. Kaidanovich O, Eldar-Finkelman H. The role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. Expert Opin Ther Targets. Regulation of tau phosphorylation and protection against beta-amyloid-induced neurodegeneration by lithium.

Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Neuroprotective effects of lithium in cultured cells and animal models of diseases. Regulation and localization of tyrosine phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. Deletion of GSK-3beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation.

Signaling networks in the pathophysiology and treatment of mood disorders. Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Tanaka C, Nishizuka Y. The protein kinase C family for neuronal signaling. Preclinical and clinical development of novel agents that target the protein kinase C family.

Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Wang HY, Friedman E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Chronic lithium administration alters a prominent PKC substrate in rat hippocampus.

Lithium and myo-inositol homeostasis.

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