lithium-chloride and Mood-Disorders

Although lithium's serendipitous discovery as a medication for depression dates back more than 200 years, the first scientific evidence that it prevents mania and depression arose only in the 1960s. However, at that time there was a lack of knowledge about how to administer and monitor lithium therapy safely and properly. The lithium clinics in Dresden and Berlin were remarkably similar in their beginnings in the late 1960s regarding patient numbers and scientific expertise without being aware of one another due to the Iron Curtain separating Germany into a western and eastern part until 1990. In what were initially lithium-care programs run independently from one another, the lithium clinics embedded in academic settings in Dresden and Berlin represent a milestone in the history of psychopharmacological treatment of affective disorders in Germany and trailblazers for today's lithium therapy. Nowadays, lithium's clinical applications are unquestioned, such as its use in strategies to prevent mood episodes and suicide, and to treat depression. The extensively documented knowledge of lithium treatment is the fruit of more than 50 years of observing disease courses and of studying side effects and influencing factors of lithium prophylaxis. Its safe and proper administration-in determining the correct indication, baseline and follow-up examinations, recommended dosages, monitoring, or the management of side effects-is well established. Subsequently, both national and international guidelines continue recommending lithium as the gold standard in treating patients with unipolar and bipolar disorders.

Topics: Antimanic Agents; Germany; History, 20th Century; History, 21st Century; Humans; Lithium Chloride; Mood Disorders; Suicide Prevention

Lithium is considered to be the first choice mood stabilizer in recurrent mood disorders. Its widespread and large-scale use is the result of its proven efficacy. In spite of this fact, patients have been observed to show a variable response to lithium treatment: in some cases it is completely effective in preventing manic or depressive relapses, while in other cases it appears to show no influence on the disease course. The possible definition of a genetic liability profile for adverse effects and efficacy will be of great help, as lithium therapy needs at least 6 months to be effective in stabilizing mood disorders. During the last few years, a number of groups have reported possible liability genes. Lithium long-term prophylactic efficacy has been associated with serotonin transporter protein, tryptophan hydroxylase and inositol polyphosphate 1-phosphatase variants. A number of other candidate genes and anonymous markers did not yield positive associations. Therefore, even if some positive results have been reported, no unequivocal susceptibility gene for lithium efficacy has been identified. Although the available data may not currently allow a meaningful prediction of lithium response, future research is aimed at the development of individualized treament of mood disorders, including the possibility of 'pharmacological genetic counseling'.

Topics: Animals; Clinical Trials as Topic; Forecasting; Humans; Lithium Chloride; Mood Disorders; Polymorphism, Genetic

Manic depressive illness (MDI) is a common, severe, chronic and often life-threatening illness. Despite well-established genetic diatheses and extensive research, the biochemical abnormalities underlying the predisposition to, and the pathophysiology of, these disorders remain to be clearly established. Despite formidable obstacles in our attempts to understand the underlying neurobiology of this illness, there is currently considerable excitement about the progress that is being made using novel strategies to identify changes in gene expression that may have therapeutic relevance in the long-term treatment of MDI. In this paper, we describe our recent research endeavours utilizing newer technologies, including a concerted series of mRNA RT-PCR studies, which has led to the identification of novel, hitherto completely unexpected targets for the long-term actions of mood stabilizers - the major cytoprotective protein bcl-2, a human mRNA binding (and stabilizing) protein, AUH, and a Rho kinase. These results add to the growing body of data suggesting that mood stabilizers may bring about some of their long-term benefits by enhancing neuroplasticity and cellular resilience. These results are noteworthy since recent morphometric brain imaging and post-mortem studies have demonstrated that MDI is associated with the atrophy and/or loss of neurons and glia. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Cell Survival; Enoyl-CoA Hydratase; Humans; Intracellular Signaling Peptides and Proteins; Lithium Chloride; Mood Disorders; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; rho-Associated Kinases; RNA-Binding Proteins; RNA, Messenger; Transcription Factor AP-1; Valproic Acid

Heterotrimeric G proteins are a crucial point of convergence in the transmission of signals from a variety of primary messengers and their membrane receptors to downstream intracellular second messenger effector enzymes and ionic channels. Thus, these proteins have raised increasing interest in the clinical perspective of altered G protein function. This article addresses the most recent significant findings regarding the role of G proteins in the pathophysiology of mood disorders and in the molecular mechanisms underlying the treatment of these disorders, with emphasis on biochemical and genetic approaches.

Topics: Antimanic Agents; Genetic Predisposition to Disease; GTP-Binding Proteins; Humans; Lithium Chloride; Mood Disorders; Signal Transduction

Recent post-mortem and imaging studies provide evidence for a glial reduction in different brain areas in mood disorders. This study was aimed to test whether glial cell line-derived neurotrophic factor (GDNF), a member of transforming growth factor (TGF)-beta superfamily, in blood levels was associated with mood disorders. We measured GDNF and TGF-beta levels in whole blood in remitted patients with mood disorders [n=56; major depressive disorders (MDD) 39, bipolar disorders (BD) 17] and control subjects (n=56). GDNF and TGF-beta were assayed with the sandwich ELISA method. Total GDNF levels were significantly lower in MDD and in BD than in control subjects (MDD, p=0.0003; BD, p=0.018), while no significant difference in total TGF-beta1 or total TGF-beta2 levels was found in these groups. Our study suggests that lower GDNF levels might be involved in the pathophysiology of mood disorders, although this preliminary study has several limitations.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antidepressive Agents; Antimanic Agents; Female; Glial Cell Line-Derived Neurotrophic Factor; Humans; Lithium Chloride; Male; Middle Aged; Mood Disorders; Transforming Growth Factor beta

Novel treatments for bipolar disorder with improved efficacy and broader spectrum of activity are urgently needed. Glycogen synthase kinase 3β (GSK-3β) has been suggested to be a key player in the pathophysiology of bipolar disorder. A series of novel GSK-3β inhibitors having the common N-[(1-alkylpiperidin-4-yl)methyl]-1H-indazole-3-carboxamide scaffold were prepared taking advantage of an X-ray cocrystal structure of compound 5 with GSK-3β. We probed different substitutions at the indazole 5-position and at the piperidine-nitrogen to obtain potent ATP-competitive GSK-3β inhibitors with good cell activity. Among the compounds assessed in the in vivo PK experiments, 14i showed, after i.p. dosing, encouraging plasma PK profile and brain exposure, as well as efficacy in a mouse model of mania. Compound 14i was selected for further in vitro/in vivo pharmacological evaluation, in order to elucidate the use of ATP-competitive GSK-3β inhibitors as new tools in the development of new treatments for mood disorders.

Topics: Adenosine Triphosphate; Amphetamine; Animals; Binding, Competitive; Central Nervous System Stimulants; CHO Cells; Cricetinae; Cricetulus; Enzyme Inhibitors; Glycogen Synthase Kinase 3; High-Throughput Screening Assays; Humans; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Models, Molecular; Mood Disorders; Motor Activity; Phosphorylation; Structure-Activity Relationship; tau Proteins; X-Ray Diffraction

Topics: Adrenergic alpha-Agonists; Antimanic Agents; Antipsychotic Agents; Aripiprazole; Asthma; Attention Deficit Disorder with Hyperactivity; Cardiovascular Diseases; Chest Pain; Child; Dyskinesia, Drug-Induced; Family; Female; Guanfacine; Humans; Lithium Chloride; Male; Mood Disorders; Neuropsychological Tests; Obesity; Paroxetine; Piperazines; Polypharmacy; Pregnancy; Prenatal Exposure Delayed Effects; Psychomotor Agitation; Quinolones; Selective Serotonin Reuptake Inhibitors; Smoking; Social Environment

Bipolar disorder (BP) is a debilitating psychiatric disorder, affecting ∼2% of the worldwide population, for which the etiological basis, pathogenesis, and neurocircuitry remain poorly understood. Individuals with BP suffer from recurrent episodes of mania and depression, which are commonly treated with the mood stabilizer lithium. However, nearly half of BP patients do not respond adequately to lithium therapy and the clinically relevant mechanisms of lithium for mood stabilization remain elusive. Here, we modeled lithium responsiveness using cellular assays of glycogen synthase kinase 3 (GSK-3) signaling and mood-related behavioral assays in inbred strains of mice that differ in their response to lithium. We found that activating AKT through phosphosrylation of a key regulatory site (Thr308) was associated with lithium response-activation of signaling pathways downstream of GSK-3 in cells and attenuation of mood-related behaviors in mice-and this response was attenuated by selective and direct inhibition of AKT kinase activity. Conversely, the expression of constitutively active AKT1 in both the cellular and behavioral assays conferred lithium sensitivity. In contrast, selective and direct GSK-3 inhibition by the ATP-competitive inhibitor CHIR99021 bypassed the requirement for AKT activation and modulated behavior in both lithium-responsive and non-responsive mouse strains. These results distinguish the mechanism of action of lithium from direct GSK-3 inhibition both in vivo and in vitro, and highlight the therapeutic potential for selective GSK-3 inhibitors in BP treatment.

Topics: Amphetamine; Analysis of Variance; Animals; Antimanic Agents; Cell Line, Transformed; Corpus Striatum; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Drug Interactions; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Humans; Lithium Chloride; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mood Disorders; Proto-Oncogene Proteins c-akt; Signal Transduction; Transfection

Besides their role in desensitization, beta-arrestin 1 and 2 promote the formation of signaling complexes allowing G protein-coupled receptors (GPCR) to signal independently from G proteins. Here we show that lithium, a pharmacological agent used for the management of psychiatric disorders such as bipolar disorder, schizophrenia, and depression, regulates Akt/glycogen synthase kinase 3 (GSK3) signaling and related behaviors in mice by disrupting a signaling complex composed of Akt, beta-arrestin 2, and protein phosphatase 2A. When administered to beta-arrestin 2 knockout mice, lithium fails to affect Akt/GSK3 signaling and induce behavioral changes associated with GSK3 inhibition as it does in normal animals. These results point toward a pharmacological approach to modulating GPCR function that affects the formation of beta-arrestin-mediated signaling complexes.

Topics: Animals; Antimanic Agents; Arrestins; Behavior, Animal; beta-Arrestin 1; beta-Arrestin 2; beta-Arrestins; Brain; Cell Line; Down-Regulation; Glycogen Synthase Kinase 3; Humans; Lithium Chloride; Mice; Mice, Knockout; Mood Disorders; Motor Activity; Protein Phosphatase 2; Proto-Oncogene Proteins c-akt; Receptors, G-Protein-Coupled; Signal Transduction

Inositol is a simple polyol precursor in a second messenger system important in brain myo-insitol, the natural isomer, which has been found to be therapeutically effective in depression, panic disorder, and obsessive-compulsive disorder in double-blind controlled trials. Recently, epi-inositol, an unnatural stereoisomer of myo-inositol, was found to have effects similar to those of myo-inositol to reverse lithium-pilocarpine seizures. We measured the behavior of rats in an elevated plus maze model of anxiety after chronic treatment of 11 daily intraperitoneal injections of epi-inositol, myo-inositol, or control solution. Epi-inositol reduced anxiety levels of rats compared with controls, and its effect was stronger than that of myo- inositol. Lithium has been hypothesized to alleviate mania by reducing brain inositol levels. Inositol in brain derives from the second messenger cycle, from new synthesis, or from diet via transport across the blood brain barrier. Because the first two are inhibited by lithium, we propose that an inositol-free diet will augment lithium action in mania by enhancing restriction of inositol.

Topics: Animals; Antimanic Agents; Blood-Brain Barrier; Brain Chemistry; Diet; Disease Models, Animal; Humans; Inositol; Lithium Chloride; Male; Mood Disorders; Rats; Rats, Sprague-Dawley