The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis.

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. Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium's neurotrophic effects since Cade's original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium's neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium's neurotrophic effects in BD are an example of an old molecule acting as a new proof-of-concept agent. Continued work to decipher lithium's molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses.

[1]  R. Gainetdinov,et al.  Akt/GSK3 signaling in the action of psychotropic drugs. , 2009, Annual review of pharmacology and toxicology.

[2]  Frederick K Goodwin,et al.  Suicide risk in bipolar disorder during treatment with lithium and divalproex. , 2003, JAMA.

[3]  R. Lenox,et al.  Chronic lithium administration alters a prominent PKC substrate in rat hippocampus , 1992, Brain Research.

[4]  A. Harwood,et al.  A common mechanism of action for three mood-stabilizing drugs , 2002, Nature.

[5]  D. Kendall,et al.  Acute and chronic lithium treatments influence agonist and depolarization-stimulated inositol phospholipid hydrolysis in rat cerebral cortex. , 1987, The Journal of pharmacology and experimental therapeutics.

[6]  P. Andersen,et al.  Lithium treatment and risk of dementia. , 2008, Archives of general psychiatry.

[7]  Tadafumi Kato,et al.  Mitochondrial Dysfunction as the Molecular Basis of Bipolar Disorder , 2007, CNS Drugs.

[8]  C. W. Scott,et al.  Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Chuang,et al.  Neuroprotective effects of lithium in cultured cells and animal models of diseases. , 2002, Bipolar disorders.

[10]  G. Casadesus,et al.  Lithium Treatment Decreases Activities of Tau Kinases in a Murine Model of Senescence , 2008, Journal of neuropathology and experimental neurology.

[11]  Michael J. Berridge,et al.  Neural and developmental actions of lithium: A unifying hypothesis , 1989, Cell.

[12]  M. Casanova,et al.  Deciphering the lithium transcriptome: Microarray profiling of lithium-modulated gene expression in human neuronal cells , 2008, Neuroscience.

[13]  R. Duman,et al.  VEGF as a potential target for therapeutic intervention in depression. , 2008, Current opinion in pharmacology.

[14]  G. MacQueen,et al.  Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment , 2004, Biological Psychiatry.

[15]  Y. Okamoto,et al.  Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain , 2001, Psychopharmacology.

[16]  D. Kupfer,et al.  Reduced left anterior cingulate volumes in untreated bipolar patients , 2004, Biological Psychiatry.

[17]  M. Youdim,et al.  Prevention of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium: involvements of Bcl-2 and Bax , 2004, Neuropharmacology.

[18]  C. Bown,et al.  Attenuation of N-methyl-d-aspartate-mediated cytoplasmic vacuolization in primary rat hippocampal neurons by mood stabilizers , 2003, Neuroscience.

[19]  I. Shoulson,et al.  Neurotherapeutics, evidence-based neurology, and clinical equipoise. , 1999, Archives of neurology.

[20]  L. Young,et al.  Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate , 2007, Neuroscience.

[21]  M. A. El-Masri,et al.  Evaluation of neuroprotection by lithium and valproic acid against ouabain-induced cell damage. , 2002, Bipolar disorders.

[22]  D. Melton,et al.  A molecular mechanism for the effect of lithium on development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Ávila,et al.  Lithium inhibits Alzheimer's disease‐like tau protein phosphorylation in neurons , 1997, FEBS letters.

[24]  N. Wood,et al.  Chronic lithium chloride treatment has variable effects on motor behaviour and survival of mice transgenic for the Huntington’s disease mutation , 2003, Brain Research Bulletin.

[25]  B. Frey,et al.  Brain-derived neurotrophic factor and neuroplasticity in bipolar disorder , 2008, Expert review of neurotherapeutics.

[26]  P Leeds,et al.  Protracted lithium treatment protects against the ER stress elicited by thapsigargin in rat PC12 cells: roles of intracellular calcium, GRP78 and Bcl-2 , 2005, The Pharmacogenomics Journal.

[27]  F. Angelucci,et al.  Lithium treatment alters brain concentrations of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in a rat model of depression. , 2003, The international journal of neuropsychopharmacology.

[28]  Guang-yi Zhang,et al.  Lithium reduced N-methyl-d-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia , 2003, Neuroscience Letters.

[29]  H. Manji,et al.  Signaling: cellular insights into the pathophysiology of bipolar disorder , 2000, Biological Psychiatry.

[30]  R. Rodnight,et al.  An investigation of the neuroprotective effect of lithium in organotypic slice cultures of rat hippocampus exposed to oxygen and glucose deprivation , 2001, Neuroscience Letters.

[31]  H. Manji,et al.  Mitochondrially Mediated Plasticity in the Pathophysiology and Treatment of Bipolar Disorder , 2008, Neuropsychopharmacology.

[32]  H. Manji,et al.  Lithium Decreases Membrane‐Associated Protein Kinase C in Hippocampus: Selectivity for the α Isozyme , 1993, Journal of neurochemistry.

[33]  R. Bhat,et al.  GSK3β Signalling: Casting a Wide Net in Alzheimer’s Disease , 2002, Neurosignals.

[34]  James R. Woodgett,et al.  Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signalling in intact cells , 1996, Current Biology.

[35]  Kiralee M. Hayashi,et al.  Three-Dimensional Mapping of Hippocampal Anatomy in Unmedicated and Lithium-Treated Patients with Bipolar Disorder , 2008, Neuropsychopharmacology.

[36]  O. Forlenza,et al.  Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease , 2009, European Archives of Psychiatry and Clinical Neuroscience.

[37]  D. Chuang,et al.  Long Term Lithium Treatment Suppresses p53 and Bax Expression but Increases Bcl-2 Expression , 1999, The Journal of Biological Chemistry.

[38]  H. Manji,et al.  Protein kinase C signaling in the brain: molecular transduction of mood stabilization in the treatment of manic-depressive illness , 1999, Biological Psychiatry.

[39]  H. Manji,et al.  The Mood‐Stabilizing Agents Lithium and Valproate RobustlIncrease the Levels of the Neuroprotective Protein bcl‐2 in the CNS , 1999, Journal of neurochemistry.

[40]  R. Jope.  A bimodal model of the mechanism of action of lithium , 1999, Molecular Psychiatry.

[41]  G. Casabona.  Intercellular signal modulation: A pivotal role for protein kinase C , 1997, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[42]  F. Terro,et al.  Lithium down-regulates tau in cultured cortical neurons: A possible mechanism of neuroprotection , 2008, Neuroscience Letters.

[43]  M. Raichle,et al.  Subgenual prefrontal cortex abnormalities in mood disorders , 1997, Nature.

[44]  P. Blackshear.  The MARCKS family of cellular protein kinase C substrates. , 1993, The Journal of biological chemistry.

[45]  J. Price,et al.  Glial reduction in the subgenual prefrontal cortex in mood disorders. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D. Chuang,et al.  Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats , 1998, Neuroreport.

[47]  D. Levinson,et al.  Altered platelet protein kinase C activity in bipolar affective disorder, manic episode , 1993, Biological Psychiatry.

[48]  N. Sousa,et al.  Lithium prevents stress-induced reduction of vascular endothelium growth factor levels , 2007, Neuroscience Letters.

[49]  S. Lin-Shiau,et al.  Long‐term lithium treatment prevents neurotoxic effects of β‐bungarotoxin in primary cultured neurons , 2002, Journal of neuroscience research.

[50]  E. Adalsteinsson,et al.  Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder , 1998, Biological Psychiatry.

[51]  J. Calabrese,et al.  Effects of subchronic lithium treatment on levels of BDNF, Bcl-2 and phospho-CREB in the rat hippocampus. , 2007, Basic & clinical pharmacology & toxicology.

[52]  Guang Chen,et al.  Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? , 2000, Biological Psychiatry.

[53]  J. Woodgett,et al.  Glycogen Synthase Kinase-3β Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium , 2004, The Journal of Neuroscience.

[54]  M. Alda,et al.  Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study , 2007, Psychopharmacology.

[55]  D. Chuang,et al.  Lithium Increases Transcription Factor Binding to AP‐1 and Cyclic AMP‐Responsive Element in Cultured Neurons and Rat Brain , 1997, Journal of neurochemistry.

[56]  Steven C. R. Williams,et al.  Meta-analysis, database, and meta-regression of 98 structural imaging studies in bipolar disorder. , 2008, Archives of general psychiatry.

[57]  B. Frey,et al.  Effects of lithium and valproate on serum and hippocampal neurotrophin-3 levels in an animal model of mania. , 2008, Journal of psychiatric research.

[58]  B. McEwen,et al.  Stress-induced structural remodeling in hippocampus: prevention by lithium treatment. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[59]  Tadafumi Kato,et al.  Biological predictors of lithium response in bipolar disorder , 2003, Psychiatry and clinical neurosciences.

[60]  R. Traystman,et al.  Social stress exacerbates stroke outcome by suppressing Bcl-2 expression , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[61]  G. Moore,et al.  Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants. , 1999, Psychosomatic medicine.

[62]  Gabriele Siciliano,et al.  Lithium delays progression of amyotrophic lateral sclerosis , 2008, Proceedings of the National Academy of Sciences.

[63]  H. Manji,et al.  The Mood Stabilizer Valproic Acid Activates Mitogen-activated Protein Kinases and Promotes Neurite Growth* , 2001, The Journal of Biological Chemistry.

[64]  M. Alda,et al.  BDNF protein levels are decreased in transformed lymphoblasts from lithium-responsive patients with bipolar disorder. , 2008, Journal of psychiatry & neuroscience : JPN.

[65]  R. Jope,et al.  Mood stabilizers, glycogen synthase kinase-3β and cell survival , 2002, Molecular Psychiatry.

[66]  H. Manji,et al.  Chronic Sodium Valproate Selectively Decreases Protein Kinase C α and ε In Vitro , 1994 .

[67]  J. Ávila,et al.  Lithium protects cultured neurons against β‐amyloid‐induced neurodegeneration , 1999 .

[68]  J. Ávila,et al.  Regulation of tau phosphorylation and protection against beta-amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer's disease. , 2002, Bipolar disorders.

[69]  D. Hallahan,et al.  Lithium treatment prevents neurocognitive deficit resulting from cranial irradiation. , 2006, Cancer research.

[70]  Y. Yonekura,et al.  Neuroprotective effect of chronic lithium treatment against hypoxia in specific brain regions with upregulation of cAMP response element binding protein and brain-derived neurotrophic factor but not nerve growth factor: comparison with acute lithium treatment. , 2008, Bipolar disorders.

[71]  J. Cade.  Lithium salts in the treatment of psychotic excitement. , 1949, The Medical journal of Australia.

[72]  H. Manji,et al.  Signaling networks in the pathophysiology and treatment of mood disorders. , 2002, Journal of psychosomatic research.

[73]  D. Ankerst,et al.  Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: A systematic review of the in vivo proton magnetic resonance spectroscopy findings , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[74]  E. Masliah,et al.  Lithium Ameliorates HIV-gp120-Mediated Neurotoxicity , 2002, Molecular and Cellular Neuroscience.

[75]  A. Serretti,et al.  A glycogen synthase kinase 3-β promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression , 2004, Neuroscience Letters.

[76]  D. Chuang,et al.  Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington's disease , 2004, Molecular Psychiatry.

[77]  J. Kasahara,et al.  Reduced CREB phosphorylation after chronic lithium treatment is associated with down-regulation of CaM kinase IV in rat hippocampus. , 2007, The international journal of neuropsychopharmacology.

[78]  Xiujun Sun,et al.  Mood stabilizing drug lithium increases expression of endoplasmic reticulum stress proteins in primary cultured rat cerebral cortical cells. , 2006, Life sciences.

[79]  R. Frozza,et al.  Lithium and Valproate Protect Hippocampal Slices Against ATP-induced Cell Death , 2007, Neurochemical Research.

[80]  J. Warsh,et al.  Role of intracellular calcium signaling in the pathophysiology and pharmacotherapy of bipolar disorder: current status , 2004, Clinical Neuroscience Research.

[81]  H. Manji,et al.  Does long-term medication with lithium, clozapine or antidepressants prevent or attenuate dementia in bipolar and depressed patients? , 2007, International journal of psychiatry in clinical practice.

[82]  Shuxin Li,et al.  Inactivation of Glycogen Synthase Kinase 3 Promotes Axonal Growth and Recovery in the CNS , 2008, The Journal of Neuroscience.

[83]  J. Alonso,et al.  Different dependence of lithium and valproate on PI3K/PKB pathway. , 2002, Bipolar disorders.

[84]  Hoau Yan Wang,et al.  Enhanced protein kinase C activity and translocation in bipolar affective disorder brains , 1996, Biological Psychiatry.

[85]  H. Manji,et al.  AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test. , 2004, The international journal of neuropsychopharmacology.

[86]  M. Berridge.  Inositol Trisphosphate, Calcium, Lithium, and Cell Signaling , 1989 .

[87]  P. C. Chin,et al.  Inhibition of GSK3beta is a common event in neuroprotection by different survival factors. , 2005, Brain research. Molecular brain research.

[88]  R. Kessler,et al.  Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. , 2007, Archives of general psychiatry.

[89]  Guang Chen,et al.  Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? , 1999, Biological Psychiatry.

[90]  D. Chuang,et al.  Regulation of c‐Jun N‐terminal kinase, p38 kinase and AP‐1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection , 2003, Journal of neurochemistry.

[91]  J. Hauser,et al.  Prophylactic lithium response and polymorphism of the brain-derived neurotrophic factor gene. , 2005, Pharmacopsychiatry.

[92]  Christina A. Wilson,et al.  GSK-3α regulates production of Alzheimer's disease amyloid-β peptides , 2003, Nature.

[93]  E. Raymond,et al.  Preclinical and clinical development of novel agents that target the protein kinase C family. , 2006, Seminars in oncology.

[94]  J. M. Fuentes,et al.  Partial lithium‐associated protection against apoptosis induced by C2‐ceramide in cerebellar granule neurons , 1998, Neuroreport.

[95]  D. Kupfer,et al.  Medication effects in neuroimaging studies of bipolar disorder. , 2008, The American journal of psychiatry.

[96]  H. Manji,et al.  The Role of the Extracellular Signal-Regulated Kinase Signaling Pathway in Mood Modulation , 2003, The Journal of Neuroscience.

[97]  H. Kang,et al.  Calcium-dependent prevention of neuronal apoptosis by lithium ion: essential role of phosphoinositide 3-kinase and phospholipase Cgamma. , 2003, Molecular pharmacology.

[98]  C. Hanstock,et al.  Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients , 2003, International clinical psychopharmacology.

[99]  A. Takashima,et al.  Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100 , 2002, Neuroscience Letters.

[100]  D. Kupfer,et al.  Increased gray matter volume in lithium-treated bipolar disorder patients , 2002, Neuroscience Letters.

[101]  D. Chuang,et al.  Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[102]  I. Shoulson.  Neuroprotective clinical strategies for Parkinson's disease , 1992, Annals of neurology.

[103]  H. Manji,et al.  Support of retinal ganglion cell survival and axon regeneration by lithium through a Bcl-2-dependent mechanism. , 2003, Investigative ophthalmology & visual science.

[104]  J. Bramham,et al.  Lithium and myo-inositol homeostasis. , 1993, Biochimica et biophysica acta.

[105]  J. Woodgett,et al.  Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes. , 1992, The Journal of biological chemistry.

[106]  R. Lenox,et al.  Sodium valproate down-regulates the myristoylated alanine-rich C kinase substrate (MARCKS) in immortalized hippocampal cells: a property of protein kinase C-mediated mood stabilizers. , 1998, The Journal of pharmacology and experimental therapeutics.

[107]  E. Zrenner,et al.  Citicoline and lithium rescue retinal ganglion cells following partial optic nerve crush in the rat. , 2006, Experimental eye research.

[108]  J. Parrish,et al.  Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness. , 1999, The American journal of psychiatry.

[109]  Y. Nishizuka.  Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. , 1992, Science.

[110]  C. Hahn,et al.  Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. , 1999, Bipolar disorders.

[111]  G. Moore,et al.  Lithium-induced increase in human brain grey matter , 2000, The Lancet.

[112]  J. Greer,et al.  Phosphoinositide deficiency due to inositol depletion is not a mechanism of lithium action in brain. , 2004, Molecular genetics and metabolism.

[113]  S. Rapoport,et al.  Mode of action of mood stabilizers: is the arachidonic acid cascade a common target? , 2008, Molecular Psychiatry.

[114]  R. Machado-Vieira,et al.  Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: A possible role for lithium antioxidant effects , 2007, Neuroscience Letters.

[115]  J. D. den Boer,et al.  Selective chronic stress‐induced in vivo ERK1/2 hyperphosphorylation in medial prefrontocortical dendrites: implications for stress‐related cortical pathology? , 2002, The European journal of neuroscience.

[116]  W. Drevets,et al.  A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. , 2009, The Journal of clinical psychiatry.

[117]  R. Jope.  Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. , 2003, Trends in pharmacological sciences.

[118]  P. Silverstone,et al.  Bipolar disorder and myo-inositol: a review of the magnetic resonance spectroscopy findings. , 2005, Bipolar disorders.

[119]  H. Eldar-Finkelman,et al.  The role of glycogen synthase kinase-3 in insulin resistance and Type 2 diabetes , 2002, Expert opinion on therapeutic targets.

[120]  F. Liu,et al.  Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. , 2004, Biochemistry.

[121]  C. Ragan,et al.  Reduced inositol polyphosphate accumulation and inositol supply induced by lithium in stimulated cerebral cortex slices. , 1990, The Biochemical journal.

[122]  Chelsea T. Finn,et al.  Brain lithium, N-acetyl aspartate and myo-inositol levels in older adults with bipolar disorder treated with lithium: a lithium-7 and proton magnetic resonance spectroscopy study. , 2008, Bipolar disorders.

[123]  M. Tricklebank,et al.  Evidence that a proconvulsant action of lithium is mediated by inhibition of myo-inositol phosphatase in mouse brain , 1991, Brain Research.

[124]  D. Kupfer,et al.  1H magnetic resonance spectroscopy investigation of the dorsolateral prefrontal cortex in bipolar disorder patients. , 2005, Journal of affective disorders.

[125]  Kiralee M. Hayashi,et al.  Greater Cortical Gray Matter Density in Lithium-Treated Patients with Bipolar Disorder , 2007, Biological Psychiatry.

[126]  H. Canatan,et al.  Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder , 2002, Cell biochemistry and function.

[127]  D. Chuang,et al.  Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model , 2008, Neuroscience.

[128]  M. Pallàs,et al.  Lithium prevents colchicine-induced apoptosis in rat cerebellar granule neurons. , 2004, Bipolar disorders.

[129]  Jun-Feng Wang,et al.  Chronic Treatment with Mood Stabilizers Lithium and Valproate Prevents Excitotoxicity by Inhibiting Oxidative Stress in Rat Cerebral Cortical Cells , 2005, Biological Psychiatry.

[130]  J. Alonso,et al.  Lithium blocks the PKB and GSK3 dephosphorylation induced by ceramide through protein phosphatase-2A. , 2002, Cellular signalling.

[131]  S. Brecht,et al.  Chronic Treatment With a Low Dose of Lithium Protects the Brain Against Ischemic Injury by Reducing Apoptotic Death , 2003, Stroke.

[132]  E. Masliah,et al.  Lithium improves HIV-associated neurocognitive impairment , 2006, AIDS.

[133]  R. Jope,et al.  Glycogen Synthase Kinase-3β Facilitates Staurosporine- and Heat Shock-induced Apoptosis , 2000, The Journal of Biological Chemistry.

[134]  M. Pallàs,et al.  Evaluation of acute antiapoptotic effects of Li+ in neuronal cell cultures , 2006, Journal of Neural Transmission.

[135]  H. Gurling,et al.  A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder , 2007, Pharmacogenetics and genomics.

[136]  P. Renshaw,et al.  Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research , 2005, Molecular Psychiatry.

[137]  B. Doble,et al.  Deletion of GSK-3beta in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation. , 2008, The Journal of clinical investigation.

[138]  L. Young,et al.  The effect of mood stabilizer lithium on expression and activity of glutathione s-transferase isoenzymes , 2008, Neuroscience.

[139]  S. Nahorski,et al.  Lithium Reduqes the Accumulation or Inositol Polyphosphate Second Messengers Following Cholinergic Stimulation of Cerebral Cortex Slices , 1989 .

[140]  A. Reith,et al.  Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. , 2001 .

[141]  M. Roh,et al.  Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions. , 2006, Current drug targets.

[142]  D. Chuang,et al.  Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity , 2002, Neuropharmacology.

[143]  A. Mørk,et al.  The effect of escitalopram, desipramine, electroconvulsive seizures and lithium on brain-derived neurotrophic factor mRNA and protein expression in the rat brain and the correlation to 5-HT and 5-HIAA levels , 2004, Brain Research.

[144]  Guang Chen,et al.  In Vivo Evidence in the Brain for Lithium Inhibition of Glycogen Synthase Kinase-3 , 2004, Neuropsychopharmacology.

[145]  T. Sotnikova,et al.  Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[146]  P. Renshaw,et al.  Effect of lithium on phosphoinositide metabolism in human brain: a proton decoupled 31P magnetic resonance spectroscopy study , 2001, Biological Psychiatry.

[147]  R. Lenox,et al.  Chronic Lithium‐Induced Down‐Regulation of MARCKS in Immortalized Hippocampal Cells: Potentiation by Muscarinic Receptor Activation , 1996, Journal of neurochemistry.

[148]  S. Skaper.  The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. , 2008, CNS & neurological disorders drug targets.

[149]  H. Xiong,et al.  Neuroprotective Mechanisms of Lithium in Murine Human Immunodeficiency Virus-1 Encephalitis , 2005, The Journal of Neuroscience.

[150]  S. Cichon,et al.  A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder , 2008, Molecular Psychiatry.

[151]  Wei-Hua Lee,et al.  Lithium: a novel treatment for Alzheimer's disease? , 2007, Expert opinion on drug safety.

[152]  C. Shaw,et al.  Lithium Therapy Improves Neurological Function and Hippocampal Dendritic Arborization in a Spinocerebellar Ataxia Type 1 Mouse Model , 2007, PLoS Medicine.

[153]  M. Pallàs,et al.  Evidence of calpain/cdk5 pathway inhibition by lithium in 3-nitropropionic acid toxicity in vivo and in vitro , 2009, Neuropharmacology.

[154]  C. Gottfried,et al.  Serum S100B and antioxidant enzymes in bipolar patients. , 2007, Journal of psychiatric research.

[155]  H. Manji,et al.  Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. , 2001, Psychopharmacology bulletin.

[156]  G. MacQueen,et al.  Abnormalities in the cAMP signaling pathway in post-mortem brain tissue from the Stanley Neuropathology Consortium , 2001, Brain Research Bulletin.

[157]  M. Stewart,et al.  Reduced brain inositol in lithium-treated rats. , 1971, Nature: New biology.

[158]  M. Herman,et al.  Lithium inhibits aluminum‐induced apoptosis in rabbit hippocampus, by preventing cytochrome c translocation, Bcl‐2 decrease, Bax elevation and caspase‐3 activation , 2002, Journal of neurochemistry.

[159]  G. Rajkowska.  Cell pathology in bipolar disorder. , 2002, Bipolar disorders.

[160]  R. Belmaker,et al.  Myo-inositol attenuates two specific behavioral effects of acute lithium in rats. , 1991, Psychopharmacology bulletin.

[161]  Y. Nishizuka,et al.  The protein kinase C family for neuronal signaling. , 1994, Annual review of neuroscience.

[162]  F. Goodwin,et al.  Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. , 2006, Bipolar disorders.

[163]  G. Rajkowska,et al.  Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells , 2000, Biological Psychiatry.

[164]  E. Masliah,et al.  Neuroprotective Effects of Regulators of the Glycogen Synthase Kinase-3β Signaling Pathway in a Transgenic Model of Alzheimer's Disease Are Associated with Reduced Amyloid Precursor Protein Phosphorylation , 2007, The Journal of Neuroscience.

[165]  H. Manji,et al.  β-Catenin Overexpression in the Mouse Brain Phenocopies Lithium-Sensitive Behaviors , 2007, Neuropsychopharmacology.

[166]  Jiang-Ning Zhou,et al.  Lithium regulates hippocampal neurogenesis by ERK pathway and facilitates recovery of spatial learning and memory in rats after transient global cerebral ischemia , 2007, Neuropharmacology.

[167]  S. Kennedy,et al.  Neuroimaging approaches in mood disorders: technique and clinical implications. , 2007, Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists.

[168]  H. Manji,et al.  Glycogen synthase kinase-3: a target for novel bipolar disorder treatments. , 2004 .

[169]  D. Chuang,et al.  Lithium suppresses excitotoxicity-induced striatal lesions in a rat model of Huntington’s disease , 2001, Neuroscience.

[170]  J. McCracken,et al.  Decreased Anterior Cingulate Myo-inositol/Creatine Spectroscopy Resonance with Lithium Treatment in Children with Bipolar Disorder , 2001, Neuropsychopharmacology.

[171]  Z. Marinova,et al.  The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons , 2009, Molecular Psychiatry.

[172]  Takanobu Nakazawa,et al.  Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation , 2002, Journal of neurochemistry.

[173]  B. Frey,et al.  Lithium increases nerve growth factor levels in the rat hippocampus in an animal model of mania , 2006, Behavioural pharmacology.

[174]  Sophia Frangou,et al.  New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings , 2004, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[175]  Z. Marinova,et al.  Synergistic Neuroprotective Effects of Lithium and Valproic Acid or Other Histone Deacetylase Inhibitors in Neurons: Roles of Glycogen Synthase Kinase-3 Inhibition , 2008, The Journal of Neuroscience.

[176]  D. Chuang,et al.  Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[177]  D. Chuang,et al.  Lithium reduces ischemia-induced hippocampal CA1 damage and behavioral deficits in gerbils , 2007, Brain Research.

[178]  R. Hellweg,et al.  Subchronic treatment with lithium increases nerve growth factor content in distinct brain regions of adult rats , 2002, Molecular Psychiatry.