lithium-chloride and Bipolar-Disorder

Beyond its use as an antiepileptic drug, over time valproate has been increasingly used for several other therapeutic applications. Among these, the antineoplastic effects of valproate have been assessed in several in vitro and in vivo preclinical studies, suggesting that this agent significantly inhibits cancer cell proliferation by modulating multiple signaling pathways. During the last years various clinical trials have tried to find out if valproate co-administration could enhance the antineoplastic activity of chemotherapy in glioblastoma patients and in patients suffering from brain metastases, demonstrating that the inclusion of valproate in the therapeutic schedule causes an improved median overall survival in some studies, but not in others. Thus, the effects of the use of concomitant valproate in brain cancer patients are still controversial. Similarly, lithium has been tested as an anticancer drug in several preclinical studies mainly using the unregistered formulation of lithium chloride salts. Although, there are no data showing that the anticancer effects of lithium chloride are superimposable to the registered lithium carbonate, this formulation has shown preclinical activity in glioblastoma and hepatocellular cancers. However, few but interesting clinical trials have been performed with lithium carbonate on a very small number of cancer patients. Based on published data, valproate could represent a potential complementary therapeutic approach to enhance the anticancer activity of brain cancer standard chemotherapy. Same advantageous characteristics are less convincing for lithium carbonate. Therefore, the planning of specific phase III studies is necessary to validate the repositioning of these drugs in present and future oncological research.

Topics: Antimanic Agents; Bipolar Disorder; Brain Neoplasms; Glioblastoma; Humans; Lithium; Lithium Carbonate; Lithium Chloride; Pharmaceutical Preparations; Valproic Acid

Lithium (Li) continues to be a standard small compound used for the treatment of neurological disorders. Besides neuronal cells, Li is also known to affect immune cell function. In spite of its clinical use, potential mechanisms by which Li modulates immune cells, especially macrophages and its clinical relevance in bipolar patients are not well understood. Here, we provide an overview of the literature with regard to Li's effects on monocytes and macrophages. We have also included some of our results showing that Li differentially modulates chemokine gene expression in the absence and presence of Toll-like receptor-4 stimulation in a human macrophage model. Given that Li has a wide range of intracellular targets both in macrophages as well as in other cell types, more studies are needed to further understand the mechanistic basis of Li's effect in neurological and other inflammatory diseases. These studies could undoubtedly identify new therapeutic targets for treating such diseases.

Topics: Animals; Bipolar Disorder; Chemokine CCL2; Humans; Lithium Chloride; Macrophages; Toll-Like Receptor 4

Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants.. We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants, second-generation antipsychotics, or lithium for acute major depressive episodes in patients diagnosed with type I or II bipolar disorder and applied random-effects meta-analysis to evaluate their efficacy, comparing outcomes based on standardized mean drug-placebo differences (SMD) in improvement, relative response rates (RR), and number-needed-to-treat (NNT).. We identified 24 trials of 10 treatments (lasting 7.5 weeks, with ≥ 50 collaborating sites/trial) that met eligibility criteria: lamotrigine (5 trials), quetiapine (5), valproate (4), 2 each for aripiprazole, olanzapine, ziprasidone, and 1 each for carbamazepine, lithium, lurasidone, and olanzapine-fluoxetine. Overall, pooled drug-over-placebo responder-rate superiority (RR) was moderate (29% [CI: 19-40%]), and NNT was 8.2 (CI: 6.4-11). By SMD, apparent efficacy ranked: olanzapine + fluoxetine ≥ valproate > quetiapine > lurasidone > olanzapine, aripiprazole, and carbamazepine; ziprasidone was ineffective, and lithium remains inadequately studied. Notably, drugs were superior to placebo in only 11/24 trials (5/5 with quetiapine, 2/4 with valproate), and only lamotrigine, quetiapine and valproate had > 2 trials. Treatment-associated mania-like reactions were uncommon (drugs: 3.7%; placebo: 4.7%).. Controlled trials of non-antidepressant treatments for bipolar depression remain scarce, but findings with olanzapine-fluoxetine, lurasidone, quetiapine, and perhaps carbamazepine and valproate were encouraging; lithium requires adequate testing.

Topics: Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Clinical Trials as Topic; Databases, Factual; Humans; Lithium Chloride

Lithium is a commonly prescribed treatment for bipolar disorder. Many early studies on which its use has been historically based no longer meet current research standards. A large number of studies with more modern designs have been recently published warranting a review. New research adds to the evidence for lithium's efficacy in mania and maintenance. There is also additional evidence, albeit less robust, to support its benefit in bipolar depression and mixed episodes. Meta-analyses of mainly observational data have found reduced suicidal behavior in bipolar patients taking lithium. Careful monitoring and prescribing can reduce the risk of adverse effects.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Humans; Lithium Chloride

We sought to determine whether the risk of relapse in patients with bipolar disorder is higher after discontinuation and restart of lithium treatment as compared to continuous lithium treatment in these same patients.. We conducted literature searches in the Pubmed, Embase, Cochrane, and PsycINFO databases with cross-reference checks. Relevant data were extracted and pooled for meta-analysis.. Five relevant studies were included for review, of which three studies qualified for the meta-analysis and included a total of 212 analyzed cases. Two studies found lithium to be less effective after discontinuation and reintroduction and three studies found no decreased effectiveness. The pooled odds ratio for the occurrence of one or more relapses after interruption of lithium treatment compared to continuous treatment was 1.40 (95% confidence interval: 0.85-2.31; p = 0.19).. Although studies are scarce, review and meta-analysis of the available literature does not provide convincing evidence that lithium is less effective when treatment is discontinued and restarted, compared to uninterrupted treatment.

Topics: Antimanic Agents; Bipolar Disorder; Drug Administration Schedule; Humans; Lithium Chloride; Recurrence; Treatment Outcome

All relevant guidelines recommend monotherapy as the initial treatment for manic phases of bipolar disorder (BD), with combination therapy reserved for severe cases or as a subsequent choice. However, in routine practice, monotherapy is often not sufficiently effective for acute and/or maintenance therapy. As a consequence, most patients are given combination therapies. An extensive search concerning combination treatment for manic episodes was conducted for relevant international randomized controlled studies, treatment guidelines and comprehensive reviews published since 1980. The scientific literature is sufficiently rich to validate the superiority of combination therapy over monotherapy in the manic phase in terms of efficacy and prevention of relapse; its safety profile is acceptable. Side effects are more frequent with combination therapy as a whole than with monotherapy, and discontinuation rates due to adverse events are higher. Continued administration of antipsychotics after a manic phase is controversial: drug classification, the course of the disease and the predominant polarity should all be considered before treatment is continued. Combinations including olanzapine and asenapine and to a lesser extent risperidone are associated with weight gain, those including quetiapine, haloperidol and asenapine with sedation, and those including aripiprazole with akathisia. This review of literature leads us to suggest that combination therapy including an atypical antipsychotic with lithium or valproate may be considered as a first-line approach. An appropriate algorithm for making decisions about combination treatment needs to be developed and included in future guidelines.

Topics: Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Drug Therapy, Combination; Humans; Lithium Chloride; Valproic Acid

Bipolar illness is a major psychiatric disorder that affects 1-3% of the worldwide population. Epidemiological studies have demonstrated that this illness is substantially heritable. However, the genetic characteristics remain unknown and a clear personality has not been identified for these patients. The clinical history of lithium began in mid-19th century when it was used to treat gout. In 1940, it was used as a substitute for sodium chloride in hypertensive patients. However, it was then banned, as it had major side effects. In 1949, Cade reported that lithium could be used as an effective treatment for bipolar disorder and subsequent studies confirmed this effect. Over the years, different authors have proposed many biochemical and biological effects of lithium in the brain. In this review, the main mechanisms of lithium action are summarised, including ion dysregulation; effects on neurotransmitter signalling; the interaction of lithium with the adenylyl cyclase system; inositol phosphate and protein kinase C signalling; and possible effects on arachidonic acid metabolism. However, none of the above mechanisms are definitive, and sometimes results have been contradictory. Recent advances in cellular and molecular biology have reported that lithium may represent an effective therapeutic strategy for treating neurodegenerative disorders like Alzheimer's disease, due to its effects on neuroprotective proteins like Bcl-2 and its actions on regulators of apoptosis and cellular resilience, such as GSK-3. However, results are contradictory and more specific studies into the use of lithium in therapeutic approaches for neurodegenerative diseases are required.

Topics: Animals; Antimanic Agents; Bipolar Disorder; History, 20th Century; History, 21st Century; Humans; Lithium Chloride; Neurodegenerative Diseases

Affective mixed states in bipolar disorders are a current matter of scientific debate and represent a complex clinical picture with coexisting manic and depressive symptoms. Treatment of mixed states is regarded as an important challenge. As diagnostic uncertainties complicate systematic clinical evaluations of this patient group, generally accepted clinical treatment guidelines are lacking yet. In this review the significance as well as the problems and risks of new treatment options are discussed.

Topics: Anticonvulsants; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Depression; Electroconvulsive Therapy; Humans; Lithium Chloride; Psychotherapy; Thyroid Hormones

To assess current pharmacotherapeutic options for bipolar disorder, with particular emphasis on the use of antipsychotic agents, Medline and EMBASE were searched between January 1980 and December 2005 using the keywords "schizoaffective disorder" and "bipolar disorder", combined with various antidepressants, antipsychotics, lithium or other mood stabilizers. English-language articles, review articles and original research articles were reviewed. Most data are available for the "mood stabilizers" lithium and valproate. However, these agents have important limitations regarding their tolerability and efficacy in certain groups. Newer anticonvulsants, especially lamotrigine, have demonstrated efficacy across mood-symptom domains. Antidepressants are not generally favoured as monotherapy in patients with bipolar depression or schizoaffective disorder, due to their potential to induce switching to manic states. However, data are emerging for the efficacy of selective serotonin reuptake inhibitors for bipolar depression in combination with atypical antipsychotics. Atypical antipsychotics may also be used as monotherapy or in conjunction with mood stabilizers for the treatment of acute mania and for continuing maintenance therapy. The choice of antipsychotic may be influenced by the therapeutic situation; formulations that facilitate administration in the acute scenario can provide rapid tranquillization, whereas those that enhance compliance may have a place in maintenance therapy. Our results suggest a growing role for atypical antipsychotics in the treatment of bipolar disorder and further data are anticipated.

Topics: Anticonvulsants; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Clinical Trials as Topic; Humans; Lithium Chloride

There is growing recognition that bipolar disorder frequently first presents in adolescence. Preadolescents with volatile behavior and severe mood swings also comprise a large group of patients whose difficulties may lie within the bipolar spectrum. However, the preponderance of scientific effort and clinical trials for this condition has focused on adults. This review summarizes the complexity of bipolar disorder and diagnosis of the disease among young people. It proceeds to review the principles of pharmacotherapy, assess current treatment options and to highlight areas where evidence-based guidance is lacking. Recent developments have enlarged the range of potential treatments for bipolar disorder. Nonetheless, differences in the phenomenology, course and sequelae of bipolar disorder among young people compel greater attention to the benefits and liabilities of therapy for those affected by this illness' early onset. By summarizing current research and opinion on diagnostic issues and treatment approaches, this review aims to provide an update on a clinically important yet controversial topic.

Topics: Adolescent; Anticonvulsants; Antimanic Agents; Bipolar Disorder; Child; Child, Preschool; Clinical Trials as Topic; Humans; Lithium Chloride; Practice Guidelines as Topic; Practice Patterns, Physicians'; Treatment Outcome

Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.

Topics: Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Drug Resistance; Drug Therapy, Combination; Electroconvulsive Therapy; Humans; Lithium Chloride; Psychotherapy; Reproducibility of Results; Social Adjustment

The article reviews the existing evidence and the concept of the anti-suicidal effect of lithium long-term treatment in bipolar patients. The core studies supporting the concept of a suicide preventive effect of lithium in bipolar patients come from the international research group IGSLI, from Sweden, Italy, and recently also from the U.S. Patients on lithium possess an eight- time lower suicide risk than those off lithium. The anti-suicidal effect is not necessarily coupled to lithium's episode suppressing efficacy. The great number of lives potentially saved by lithium adds to the remarkable benefits of lithium in economical terms. The evidence that lithium can effectively reduce suicide risk has been integrated into modern algorithms in order to select the optimal maintenance therapy for an individual patient.

Topics: Algorithms; Antimanic Agents; Bipolar Disorder; Drug Administration Schedule; Humans; Lithium Chloride; Suicide; Suicide Prevention

Lithium is a drug of choice for the management of bipolar disorder, a disease frequently affecting women in their childbearing years. Unfortunately, this drug has typically been contraindicated in nursing women. Data in humans are limited with respect to the use of this drug in lactating women, and early reports suggest high excretion into milk. The purpose of this report was to verify the excretion of lithium into human milk and to assess infant safety after breast-feeding. The authors found wide interpatient variability in lithium dose offered to the infant through breast milk (from 0% to 30% of maternal weight-adjusted dose), indicating that therapeutic drug monitoring of lithium in milk and/or in infant's blood, coupled with close monitoring of adverse effects, is a rational approach. Since therapeutic drug monitoring of lithium is routine, physicians caring for these women and infants should be encouraged to individualize their recommendations.

Topics: Bipolar Disorder; Breast Feeding; Confidence Intervals; Drug Monitoring; Female; Humans; Infant, Newborn; Lithium Chloride; Milk, Human; Pregnancy

Concepts in the treatment of bipolar disorder are discussed considering clinical practice.. Results of the Multicenter Study of Long-term Treatment of Affective and Schizoaffective Psychoses (MAP) study, a controlled maintenance trial, are interpreted with respect to treatment concepts.. The spectrum of patients diagnosed as bipolar has become more heterogeneous. It now comprises subtypes requiring differentiated treatment. The MAP study confirms that prophylactic efficacy of lithium seems to be specific to classic manic-depressive illness, whereas carbamazepine might be more efficacious in non-classic bipolar patients. With respect to clinical practice, treatment evaluation should also consider anti suicidal effects, inter-episodic morbidity and compliance. In these respects, results are in favour of lithium. Furthermore, data indicate that adherence to lithium clearly depends on illness concepts. This encourages efforts to supplement pharmacotherapy by psychoeducation and psychotherapy.. With the broadening of diagnostic criteria, the treatment of bipolar disorder has become more complex. Patients need an integrated approach, including differentiated mood-stabilizing pharmacotherapy and psychotherapeutic measures.

Topics: Affect; Antimanic Agents; Bipolar Disorder; Carbamazepine; Clinical Trials as Topic; Controlled Clinical Trials as Topic; Humans; Lithium Chloride; Patient Compliance; Psychotherapy; Suicide, Attempted

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

An increasing body of evidence demonstrates that lithium and valproate have a regulatory effect on signal transduction pathways. Alteration of signalling molecules triggers changes in gene expression which are thought to contribute to the therapeutic effects of these drugs on bipolar disorder. Differential-display PCR was used to identify genes in rat cerebral cortex that are regulated by chronic treatment with lithium and valproate. One novel lithium-regulated gene was identified and was characterized and studied further with 5'-RACE-PCR and library screening. We also found that valproate regulated the expression of the 78-kDa glucose-regulated protein (GRP78). Chronic treatment with valproate has also been found to increase gene transcription, mRNA and protein levels of GRP78. These results suggest novel targets for lithium and valproate that may be relevant to their mechanism of action. The data further our understanding of the mechanism of the action of mood stabilizers, and help identify new targets for genetic studies and therapeutic strategies in bipolar disorder.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Carrier Proteins; Cerebral Cortex; Endoplasmic Reticulum Chaperone BiP; Gene Expression Profiling; Gene Expression Regulation; Heat-Shock Proteins; Humans; Lithium Chloride; Molecular Chaperones; Polymerase Chain Reaction; RNA, Messenger; Valproic Acid

Lithium has been the backbone of treatment for bipolar disorder for several decades, although recent advances have identified a number of other medications that have efficacy in treating various phases of the illness. These include the antiepileptic drugs valproate semisodium (divalproex sodium) and carbamazepine and some new antiepileptic drugs (e.g. lamotrigine and topiramate), and the atypical antipsychotics (e.g. olanzapine, clozapine and risperidone). Conventional antipsychotics continue to be used frequently in bipolar disorder, although they may be somewhat less effective than other treatments. Otherwise, to date, none of these treatments have been shown to be consistently more effective than any other, so that drug adverse effects and tolerability often dictate which agents are used in an individual patient. Drugs commonly used for the treatment of bipolar disorder are generally tolerated by most patients in large samples. However, the unique adverse effect signature of a drug will often suggest that it will be less tolerable in some patients than in others. Identifying a specific treatment for a specific patient requires a careful individualised assessment of the risk of adverse effects for that patient's unique circumstances.

Topics: Animals; Anticonvulsants; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Drug Interactions; Humans; Lithium Chloride

In the actual version of the WHO diagnostic guidelines, the ICD-10, subtypes of bipolar disorder are not specified, in contrast to the American DSM-IV, where bipolar disorder has already been differentiated in bipolar I (severe manic and depressive episodes) and bipolar II disorder (depressive and hypomanic episodes). Furthermore, aspects of the longitudinal course of the illness, like rapid cycling (RC), are reflected as well. Rapid cycling is defined as four or more affective episodes within one year of the illness. It has been postulated that rapid cycling is related with a poor response to lithium, to the same extent as mixed episodes or an atypical onset (depressive episode first) of the disease. Here, the current status of alternative pharmacological and supportive therapy of rapid cycling is presented and discussed. Furthermore, the article also displays biological parameters associated with rapid cycling like higher prevalence in women, hypothyreoidism, subtype of bipolar disorder, COMT-allele, influence of sleep or risk of antidepressant induced cycling.

Topics: Animals; Anticonvulsants; Antidepressive Agents; Antimanic Agents; Bipolar Disorder; Calcium Channel Blockers; Humans; Lithium Chloride

Rapid cycling bipolar disorder (RCBD) is defined in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a type of manic-depressive illness in which the patient experiences four or more episodes of mania and/or major depression per year. It was first reported as a consequence of the reduced effectiveness of lithium carbonate in the treatment and prophylaxis of this form of bipolar disorder (BD) in contrast to those with less frequent cycling. Among the anticonvulsants, there have been reports with different degrees of controlled data concerning carbamazepine, valproate, lamotrigine, topiramate, gabapentin and primidone. There is a paucity of double-blind studies, but what is available supports the use of lamotrigine. There is open data supporting the use of carbamazepine, valproate and topiramate. Regarding other classes, nimodipine may have specific utility in ultradian- (ultra-ultra-) or ultra-RCBD and there is double-blind data regarding the specific utility of olanzapine in RCBD. Low thyroid function may be a factor in development of RCBD; therapies aimed at elevating thyroid levels, even beyond the usual range, have frequently produced benefits in open trials. More research is needed into the possible therapeutic benefits of verapamil, bupropion, choline, light therapy and electroconvulsive therapy (ECT).

Topics: Anticonvulsants; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Calcium Channel Blockers; Humans; Lithium Chloride

7Li magnetic resonance spectroscopy (MRS) has been successfully used in recent years as a new tool to measure brain tissue lithium concentrations in vivo. After demonstration of its feasibility in animal studies over a decade ago, human investigations have characterized the brain pharmacokinetics of lithium. Preliminary studies have investigated brain pharmacokinetic correlates of clinical response in the treatment of bipolar disorder patients, with indication of possible clinical relevance of 7Li MRS measures. In this paper we reviewed the accumulated literature in this area, and discuss possible directions for this research in the context of preliminary studies conducted by our group that demonstrated the feasibility of 7Li MRS at 3 T.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Brain; Humans; Isotopes; Lithium; Lithium Chloride; Magnetic Resonance Spectroscopy

To evaluate the efficacy of lithium in the treatment of acute mania.. Systematic overview of the literature and meta-analysis of randomised controlled trials. Estimation of (i) the differences in the reduction in mania severity scores, and (ii) the ratio and difference in improvement response rates.. A total of 658 patients from 12 trials were included. Treatment periods ranged from 3 to 4 weeks. The response rate ratio for lithium against placebo was 1.95 (95%CI 1.17-3.23). The mean number needed to treat was five (95%CI 3-20). Patients were twice as likely to obtain remission with lithium than with chlorpromazine (rate ratio = 1.96, 95%CI 1.02-3.77). The mean number needed to treat was four (95%CI 3-9). Neither carbamazepine nor valproate was more effective than lithium. The response rate ratios were 1.01 (95%CI 0.54-1.88) for lithium compared to carbamazepine and 1.22 (95%CI 0.91-1.64) for lithium against valproate. Haloperidol was no better than lithium on the basis of improvement based on assessment of global severity. The differences in effects between lithium and risperidone were -2.79 (95%CI -4.22 to -1.36) in favour of risperidone with respect to symptom severity improvement and -0.76 (95%CI -1.11 to -0.41) on the basis of reduction in global severity of disease. Symptom and global severity was as well controlled with lithium as with verapamil. Lithium caused more side-effects than placebo and verapamil, but no more than carbamazepine or valproate.. The clinical trial evidence suggests that lithium should remain the first line treatment for acute mania.

Topics: Acute Disease; Adolescent; Adult; Aged; Antimanic Agents; Bipolar Disorder; Female; Humans; Lithium Chloride; Male; Middle Aged; Severity of Illness Index; Treatment Outcome

Bipolar disorder is a devastating and chronic mood disorder, which can require life-long treatment. The vast majority of patients will suffer relapse of symptoms in the absence of effective therapy. Of those patients receiving treatment, compliance to medication regimens is poor. Non-compliance, when associated with lithium treatment in particular, increases the risk of recurrence of illness. Problems associated with withdrawal serve as powerful stimuli to develop alternatives to lithium monotherapy. Conventional placebo-controlled studies of treatments are difficult in patients with bipolar disorder. Large-scale, pragmatic and clinically relevant trials should be employed to assess existing and novel treatments for bipolar disorder. These can only develop out of genuine clinician and patient uncertainty and the creation of a trial culture in everyday practice.

Topics: Affect; Antimanic Agents; Bipolar Disorder; Clinical Trials as Topic; Europe; Humans; Lithium Chloride; Patient Compliance; United States

This review is based an relevant publications and addresses the following questions: Does lithium exert a recurrence-preventive, prophylactic action in manic-depressive illness? Has prophylactic treatment with anticonvulsants or antidepressants become preferable to lithium prophylaxis? Which drug or drugs should be first-choice prophylactic agent in bipolar and in unipolar manic-depressive illness?

Topics: Antidepressive Agents; Antimanic Agents; Bipolar Disorder; Humans; Lithium Chloride; Secondary Prevention

This paper describes the development and use of the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making. The Bipolar Trials Network developed and implemented the MRTF in a comparative effectiveness study for bipolar disorder (LiTMUS). The MRTF was used to assess the frequency, types, and reasons for medication adjustments. Changes in treatment were operationalized by the metric Necessary Clinical Adjustments (NCA), defined as medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. Randomized treatment groups did not differ in rates of NCAs, however, responders had significantly fewer NCAs than non-responders. Patients who had more NCAs during their previous visit had significantly lower odds of responding at the current visit. For each one-unit increase in previous CGI-BP depression score and CGI-BP overall severity score, patients had an increased NCA rate of 13% and 15%, respectively at the present visit. Ten-unit increases in previous Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores resulted in an 18% and 14% increase in rates of NCAs, respectively. Patients with fewer NCAs had increased quality of life and decreased functional impairment. The MRTF standardizes the reporting and rationale for medication adjustments and provides an innovative metric for clinical effectiveness. As the first tool in psychiatry to track the types and reasons for medication changes, it has important implications for training new clinicians and examining clinical decision making. (ClinicalTrials.gov number NCT00667745).

Topics: Adolescent; Adult; Antimanic Agents; Bipolar Disorder; Comparative Effectiveness Research; Decision Making; Female; Humans; Lithium Chloride; Male; Middle Aged; Patient Identification Systems; Prescription Drugs; Psychiatric Status Rating Scales; Surveys and Questionnaires; Treatment Outcome; Young Adult

The aim of the present study was to assess the effect of aspirin on lithium-related sexual dysfunction in men with stable bipolar affective disorder (BAD).. In a randomized, double-blind, placebo-controlled study, 32 men with stable BAD who had been on lithium maintenance therapy randomly received aspirin (240 mg/day) or placebo for six weeks. The International Index for Erectile Function (IIEF) was used to assess sexual symptoms at baseline, Week 3, and Week 6. Depressive and mania symptoms and plasma lithium concentrations were assessed at baseline and Week 6. Side effects were assessed using a checklist.. Thirty patients (15/group) completed the study. Baseline and endpoint lithium concentrations and mania and depressive symptoms did not differ significantly between the two groups. Significant effects of time × treatment interaction were observed for total score [Greenhouse-Geisser: F(1.410,39.466) = 6.084, p = 0.010] and erectile function [Greenhouse-Geisser: F(1.629,45.602) = 7.250, p = 0.003]. By Week 6, patients in the aspirin group showed significantly greater improvement in the total (63.9% improvement from the baseline) and erectile function domain (85.4% improvement from the baseline) scores than the placebo group (14.4% and 19.7% improvement from the baseline, p-values = 0.002 and 0.001, respectively). By Week 6, 12 (80%) patients in the aspirin group and three (20%) patients in the placebo group met the criteria of minimal clinically important change [χ(2) (1) = 10.800, p = 0.001]. Other IIEF domains also showed significant improvement at the end of the trial. The frequency of side effects was similar between the two groups.. Aspirin effectively improves lithium-related sexual dysfunction in men with stable BAD.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Bipolar Disorder; Double-Blind Method; Humans; Lithium Chloride; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Sexual Dysfunction, Physiological; Treatment Outcome; Young Adult

There is no robust proof that the efficacy of lithium in the prevention of manic and depressive episodes in bipolar disorder depends on its plasma level. This analysis aimed to compare the effect of lithium within the presumed therapeutic range of 0.6-1.2 mEq/L and below 0.6 mEq/L with that of placebo.. We carried out a post hoc analysis of a double-blind trial in which patients aged ≥18 years with bipolar I disorder (DSM-IV) who had achieved stabilization from a manic, depressive, or mixed episode during open-label treatment with quetiapine were randomized to continue quetiapine or to switch to lithium or placebo for up to 104 weeks. Of patients randomized to lithium, 201 obtained median lithium levels between 0.6 and 1.2 mEq/L, and 137 obtained median lithium levels <0.6 mEq/L. Their outcomes were compared with those of patients receiving placebo (n = 404). The primary outcome was time to recurrence of any mood event; additional outcomes included time to recurrence of a manic or depressive event.. Times to recurrence of any mood event as well as a manic or depressive event were significantly longer for the lithium 0.6-1.2 mEq/L group versus placebo and versus lithium <0.6 mEq/L, with no differences between lithium <0.6 mEq/L and placebo..   The results support and expand previous findings that lithium should be dosed high enough to achieve plasma levels ≥0.6 mEq/L in order to achieve an effect in the prevention of both manic and depressive recurrences of bipolar I disorder. A major limitation is that the composition of the two lithium groups was not based on randomization.

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Dibenzothiazepines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Substitution; Female; Humans; International Cooperation; Lithium Chloride; Male; Middle Aged; Outcome Assessment, Health Care; Psychiatric Status Rating Scales; Quetiapine Fumarate; Statistics, Nonparametric; Time Factors

This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP+MS (n=127) vs. placebo+MS (n=113). At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p<0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had similar weight and metabolic profiles compared to the placebo+MS group across visits. These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes.

Topics: Adjuvants, Immunologic; Antipsychotic Agents; Bipolar Disorder; Body Weight; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Longitudinal Studies; Male; Metabolic Diseases; Metabolome; Piperazines; Psychiatric Status Rating Scales; Thiazoles; Valproic Acid

A substantial portion of the morbidity associated with rapid-cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add-on therapy for rapid-cycling bipolar depression non-responsive to the combination of lithium plus divalproex.. During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18-65 years with DSM-IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double-blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed-models analysis..   During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non-adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double-blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was -8.5 ± 1.7 points for lamotrigine and -9.1 ± 1.5 points for placebo (p = not significant; mixed-models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo.. The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double-blind treatment.

Topics: Adolescent; Adult; Aged; Antimanic Agents; Bipolar Disorder; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lamotrigine; Lithium Chloride; Male; Middle Aged; Psychiatric Status Rating Scales; Retrospective Studies; Triazines; Valproic Acid; Young Adult

Preclinical studies suggest that lithium may exert neurotrophic effects that counteract pathological processes in the brain of patients with bipolar disorder (BD). To describe and compare the course and magnitude of gray matter volume changes in patients with BD who are treated with lithium or valproic acid (VPA) compared to healthy comparison subjects, and to assess clinical relationships to gray matter volume changes induced by lithium in patients with BD, we conducted longitudinal brain imaging and clinical evaluations of treatment response in 22 mood-stabilizing and antipsychotic medications-naive patients with BD who were randomly assigned to either lithium or VPA treatment after baseline assessment. Fourteen healthy comparison subjects did not take any psychotropic medications during follow-up. Longitudinal data analyses of 93 serial magnetic resonance images revealed lithium-induced increases in gray matter volume, which peaked at week 10-12 and were maintained through 16 weeks of treatment. This increase was associated with positive clinical response. In contrast, VPA-treated patients with BD or healthy comparison subjects did not show gray matter volume changes over time. Results suggest that lithium induces sustained increases in cerebral gray matter volume in patients with BD and that these changes are related to the therapeutic efficacy of lithium.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Brain; Brain Mapping; Female; Humans; Image Processing, Computer-Assisted; Lithium Chloride; Longitudinal Studies; Magnetic Resonance Imaging; Male; Time Factors; Valproic Acid; Young Adult

To assess the association between mood state and the prevalence and the severity of lithium adverse drug reactions (ADRs).. A 26-year follow-up study was conducted among patients > or =18 years treated at the outpatient lithium clinic of the University Medical Center Groningen, The Netherlands, between November 1973 and December 2000. At each monthly scheduled visit, patients were questioned by a research nurse in a standardized manner about the presence and the severity of nine specific ADRs that frequently occur as a consequence of lithium treatment and that can be identified by the patients themselves. In addition, lithium serum level was measured and mood state was rated at each visit.. A total of 186 patients participated and the median duration of follow-up was 5.7 years (interquartile range 2.2-11.8 years). We observed an increased prevalence and severity of ADRs with increased lithium serum level (p < 0.05), also when adjusting for mood state. The prevalence and the severity of ADRs increased with decreasing mood state into the depressive range and decreased with mood state increasing into the manic range (p < 0.05), also when adjusting for lithium serum level. Taking into account the intraindividual dependency of the data resulted in a statistically significant (p < 0.001) association between, respectively, lithium serum level, mood state, and the prevalence and severity of ADRs.. Both physicians and researchers need to be aware that lithium serum level and mood state are independently associated with patient reporting and severity scoring of ADRs, which may complicate objective assessment of ADRs.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Affect; Aged; Antimanic Agents; Bipolar Disorder; Blood Chemical Analysis; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Lithium Chloride; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Retrospective Studies; Young Adult

Neuropsychological studies of bipolar disorder reveal deficits in a variety of domains, including affective processing, memory, and sustained attention. These findings are difficult to interpret due to the potential confounding effects of mood-stabilizing medications. The present study aims to compare the cognitive performance of medicated and unmedicated subjects with bipolar depression to healthy control subjects.. Unmedicated subjects with bipolar depression (UBD, n = 32), subjects with bipolar depression on therapeutic doses of lithium or valproic acid (MBD, n = 33), and healthy control subjects (HC, n = 52) performed neuropsychological tasks measuring affective processing, visual memory, and sustained attention. Performance measures were covaried with age and mood ratings, where applicable.. With regard to affective processing, the MBD group exhibited greater response latency than the UBD and HC groups. For the same task, the MBD group made more omission errors during the happy condition than in the sad condition. On a task of sustained attention, the MBD group made more errors than the HC group. There were no significant group differences on measures of visual memory.. Deficits in affective processing were found in the medicated group, while unmedicated subjects appear to be unaffected. In particular, the MBD group made more errors during happy conditions, indicating a potential attentional bias in subjects with bipolar depression on mood-stabilizing medications. The present study also implicates impairment in sustained attention for medicated subjects with bipolar disorder, particularly those with the type II variety.

Topics: Adult; Affect; Analysis of Variance; Antimanic Agents; Bipolar Disorder; Cognition; Female; Humans; Lithium Chloride; Male; Middle Aged; Neuropsychological Tests; Valproic Acid; Young Adult

We evaluated the prophylactic efficacy and the long-term tolerability of oxcarbazepine administration in the treatment of bipolar I and II disorder as an adjunctive therapy to lithium. We conducted a 52-wk, double-blind, randomized, placebo-controlled, parallel-group, multicentre, clinical trial. Bipolar I and II DSM-IV outpatients, having had two or more episodes in the last year, but currently being in remission, were randomly assigned on a 1:1 ratio to oxcarbazepine (n=26) or placebo (n=29) as adjuncts to ongoing treatment with lithium. The primary efficacy variable was the length of the remission period assessed by means of the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS). Other assessments were the Clinical Global Impression (CGI-BP-M), functional activity (GAF), anxiety (HAMA) and impulsiveness (BIS-11). The average time until first recurrence of any type was 19.2+/-13.9 wk and 18.6+/-17.0 wk for oxcarbazepine and placebo respectively (p=0.315). Ten (38.46%) patients had a recurrence of any kind in the oxcarbazepine group vs. 17 (58.62%) in the placebo group (p=0.1354). There was a trend for depressive episodes being less likely in the oxcarbazepine group compared to the placebo group (11.54% and 31.03% respectively, p=0.085), and for better functionality with the GAF (p=0.074). Impulsivity was significantly better prevented by oxcarbazepine (p=0.0443). Overall, oxcarbazepine was well tolerated. This pilot, randomized clinical trial, suggests that oxcarbazepine might have some prophylactic efficacy with regards to impulsivity and perhaps mood episodes in patients taking lithium, although further, adequately powered controlled trials are needed to confirm these findings.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Carbamazepine; Double-Blind Method; Drug Therapy, Combination; Female; GABA Modulators; Humans; Impulsive Behavior; Lithium Chloride; Long-Term Care; Lorazepam; Male; Oxcarbazepine; Pilot Projects; Psychiatric Status Rating Scales; Reproducibility of Results; Sample Size; Secondary Prevention; Survival Analysis

Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder (BD). This study evaluates plasma levels of the oxidative/energy metabolism markers, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and neuron-specific enolase (NSE) during initial episodes of mania compared to controls in 75 subjects. Two groups of manic subjects (unmedicated n=30, and lithium-treated n=15) were age/gender matched with healthy controls (n=30). TBARS and antioxidant enzymes activity (SOD and CAT) were increased in unmedicated manic patients compared to controls. Conversely, plasma NSE levels were lower during mania than in the controls. In contrast, acute treatment with lithium showed a significant reduction in both SOD/CAT ratio and TBARS levels. These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses, which may be related to dysfunctions on energy metabolism and neuroplasticity pathways. Antioxidant effects using lithium in mania were shown, and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of BD.

Topics: Adult; Analysis of Variance; Bipolar Disorder; Case-Control Studies; Catalase; Female; Humans; Lithium Chloride; Male; Neuroprotective Agents; Oxidative Stress; Phosphopyruvate Hydratase; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances

Dysregulated protein kinase C (PKC) distribution and activation, and abnormal receptor-G protein coupling, have been implicated in the pathophysiology of bipolar affective disorder (BD). The therapeutic effectiveness of lithium has also been correlated with its ability to reduce PKC activation and G protein-mediated signaling. We examine the cellular distribution and activation of PKC and receptor-G protein coupling in blood platelets from normal controls, patients with BD mania or schizophrenia during treatment-free state, and after lithium or valproic acid administration. PKC activity was measured under basal and 50 nM phorbol 12-myristate, 13-acetate (PMA), 1 microM serotonin or 0.5 U/ml thrombin-stimulated conditions. The coupling of G proteins to serotonin or thrombin receptors were assessed by serotonin or thrombin-mediated [35S]GTPgammaS binding to membrane Galpha proteins. The results demonstrate that membrane-associated PKC activity and stimulus-induced PKC translocation are increased in BD manic, whereas stimulus-elicited PKC translocation is attenuated in schizophrenic patients. Lithium and valproic acid treatments attenuated the stimulus-induced PKC translocations to a similar degree and decreased PKC activity in both cytosolic and membranous fractions after two weeks of drug administration. An increase in 5-HT or thrombin stimulated [35S]GTPgammaS binding to Galpha proteins was detected in BD manic but not in schizophrenic patients although basal [35S]GTPgammaS binding was not different across the diagnostic groups. Lithium and valproic acid treatments similarly reduced receptor-G protein coupling with comparable time courses. Thus, increased membrane-associated PKC, cytosol to membrane PKC translocation and receptor-G protein coupling in platelets of BD manic patients were alleviated by lithium or valproic acid treatments.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Blood Platelets; Enzyme Activation; Female; GTP-Binding Proteins; Humans; Lithium Chloride; Male; Protein Kinase C; Schizophrenia; Signal Transduction; Valproic Acid

There are no published placebo-controlled studies of any agent in the treatment of acute mania in children or adolescents. This is the first placebo-controlled study of lithium's efficacy in the treatment of acute mania in adolescents.. In this discontinuation study, participants received open treatment with lithium at therapeutic serum levels (mean 0.99 mEq/L) for at least 4 weeks. Responders were randomly assigned to continue or discontinue lithium during a 2-week double-blind, placebo-controlled phase. This study had 80% power to detect a 40% difference in exacerbation rates between groups (10% on lithium versus 50% on placebo).. Twenty-three of 40 protocol participants (57.5%) experienced a clinically significant symptom exacerbation during the 2-week double-blind phase. However, the slightly lower exacerbation rate in the group maintained on lithium (10/19 or 52.6%) versus the group switched to placebo (13/21 or 61.9%) did not reach statistical significance.. This study does not support a large effect for lithium continuation treatment of adolescents with acute mania, mostly due to the unexpectedly high rate of exacerbations in the group that continued on lithium. Further studies are warranted to clarify whether acute mania in adolescents is lithium responsive.

Topics: Acute Disease; Adolescent; Aggression; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Brief Psychiatric Rating Scale; Comorbidity; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Psychotic Disorders; Recurrence; Risperidone; Treatment Outcome

The objective of this study was to determine the clinical and quality of life outcomes associated with adjunctive treatment of olanzapine added to either lithium or valproic acid/divalproex sodium in patients with bipolar disorder.. Patients with bipolar I disorder, were randomized to receive either olanzapine (5-20 mg) added to mood stabilizer therapy (n=224), or placebo added to mood stabilizer therapy (n=112) for 6 weeks. Changes in clinical outcomes over 6 weeks were measured by the Young Mania Rating Scale (Y-MRS) and the Hamilton Rating Scale for Depression (HAM-D). Quality of life was measured by the Lehman Brief Quality of Life Interview (QLI).. Patients treated with olanzapine added to mood stabilizers, experienced significantly greater mean clinical improvements from baseline on both the Y-MRS and the HAM-D compared to those treated with placebo added to mood stabilizers. Over 6 weeks, patients treated with olanzapine added to mood stabilizers had significantly greater mean improvements from baseline on five of the nine subjective scales on the QLI, compared to patients treated with placebo added to mood stabilizers. Changes in scores on the subjective scales of the QLI were more strongly correlated to changes in depressive symptomatology measured by the HAM-D, than to changes in symptoms of mania measured by the Y-MRS.. The results of this study demonstrate that patients receiving adjunctive treatment have significantly greater improvements in both clinical and quality of life outcomes compared to monotherapy with mood stabilizers.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Olanzapine; Placebos; Quality of Life; Treatment Outcome; Valproic Acid

This study investigated the impact of latency (the time between illness onset and initiation of prophylactic treatment) on the outcome of prophylaxis in bipolar disorders.. The effect of prophylaxis delay (latency) on the course of illness was assessed in 147 patients. Dependent variables were: reduction of days spent in the hospital (prior to vs. during prophylaxis), time to first recurrence, and Morbidity-Index during prophylaxis (lithium or carbamazepine). Latency and other independent variables were tested using a multivariate approach.. Latency (9.3 years on average) had no significant effect on the subsequent response. Illness severity prior to prophylaxis, however, did predict the relative response. The course of illness during treatment could not be predicted by any one factor.. The delay in initiating prophylaxis appears to have no influence on prophylaxis outcome. Instead, those whose illness was more severe were treated earlier and these patients subsequently showed a relatively greater response. If severity is not controlled for as part of the analysis, latency may be mistaken as an important predictor for response.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Carbamazepine; Disease Progression; Drug Administration Schedule; Female; Humans; Lithium Chloride; Male; Middle Aged; Severity of Illness Index; Time Factors

This study investigated the relationship between psychotherapeutic interventions and pharmacologic measures of pharmacotherapy treatment adherence in patients with bipolar I disorder, as well as the relationship between these measures and treatment outcome. Subjects were participating in an ongoing maintenance treatment study. Audiotaped therapy sessions were rated for frequency of psychotherapeutic interventions related to pharmacotherapy treatment adherence. Pharmacologic measures of medication adherence were compared to the tape ratings as well as to treatment outcome. Variability in log erythrocyte (RBC) lithium-a marker of probable nonadherence to the pharmacotherapy regimen-for individual patients correlated significantly with treatment adherence interventions scale ratings. This marker of nonadherence was significantly related to maintenance treatment outcome, as was variability of the serum lithium level/dose (L/D) ratio; however, no relationship was found between treatment adherence interventions scale ratings and outcome.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Erythrocytes; Female; Humans; Lithium Chloride; Male; Middle Aged; Patient Compliance; Statistics, Nonparametric; Treatment Outcome

The possible relationship between deep white matter hyperintensity (WMHI) lesions detected by magnetic resonance imaging and response to lithium was examined in 16 patients with bipolar disorder who had been under maintenance treatment with lithium for more than 1 year. Bipolar patients who had higher scores of WMHI responded significantly better to lithium (r = 0.57, P < 0.05) than did those who had lower scores. This preliminary result suggests that the presence of WMHI may be associated with a better response to lithium.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Brain; Female; Humans; Lithium Chloride; Magnetic Resonance Imaging; Male; Middle Aged; Severity of Illness Index; Treatment Outcome

This study's purpose was to clarify the appropriate treatment of bipolar depression by comparing the addition of an antidepressant versus a second mood stabilizer for inpatients being treated with lithium carbonate or divalproex sodium.. Twenty-seven patients were randomly assigned to groups that received double-blind treatment with paroxetine or a second mood stabilizer (lithium carbonate or divalproex sodium) for 6 weeks.. Both groups showed significant improvement in depressive symptoms during the 6-week trial. There were significantly more noncompleters in the group being treated with the two mood stabilizers than in the group being treated with a mood stabilizer and paroxetine.. Both treatments appeared to be effective; however, the addition of an antidepressant may have greater clinical utility in the treatment of bipolar depression.

Topics: Adult; Antidepressive Agents, Second-Generation; Antimanic Agents; Bipolar Disorder; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Hospitalization; Humans; Lithium Chloride; Male; Paroxetine; Patient Dropouts; Psychiatric Status Rating Scales; Treatment Outcome; Valproic Acid

Choline-containing compounds (Cho) were examined by proton magnetic resonance spectroscopy (1H-MRS) in the left subcortical region, including basal ganglia, in 19 euthymic patients with bipolar disorder and 19 age-matched normal controls. Ten of the patients were treated with lithium; the remaining 9 were not treated with lithium for at least 30 d. The Cho to creatine + phosphocreatine (Cr) peak ratio in the bipolar patients (0.75 +/- 0.38 [mean +/- SD]) was higher than that in the normal controls (0.52 +/- 0.26, P < 0.05). There was no significant difference in the Cho:Cr peak ratio between patients treated with lithium (0.63 +/- 0.36) and without lithium (0.89 +/- 0.35). These results do not support the hypothesis that lithium increases the brain choline-containing compounds, but rather imply that membrane breakdown may occur in the basal ganglia of patients with bipolar disorder.

Topics: Adult; Antimanic Agents; Basal Ganglia; Bipolar Disorder; Choline; Female; Humans; Lithium Chloride; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male

This study examined choline augmentation of lithium for rapid-cycling bipolar disorder. Choline bitartrate was given openly to 6 consecutive lithium-treated outpatients with rapid-cycling bipolar disorder. Five patients also underwent brain proton magnetic resonance spectroscopy. Five of 6 rapid-cycling patients had a substantial reduction in manic symptoms, and 4 patients had a marked reduction in all mood symptoms during choline therapy. The patients who responded to choline all exhibited a substantial rise in the basal ganglia concentration of choline-containing compounds. Choline was well tolerated in all cases. Choline, in the presence of lithium, was a safe and effective treatment for 4 of 6 rapid-cycling patients in our series. A hypothesis is suggested to explain both lithium refractoriness in patients with bipolar disorder and the action of choline in mania, which involves the interaction between phosphatidylinositol and phosphatidylcholine second-messenger systems.

Topics: Adult; Affect; Antimanic Agents; Basal Ganglia; Bipolar Disorder; Choline; Drug Resistance; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Magnetic Resonance Spectroscopy; Male; Middle Aged; Nootropic Agents; Psychiatric Status Rating Scales

Most previous studies of long-term maintenance therapy for bipolar illness simply compared proportions of patients experiencing recurrences. This method is inadequate because the length of time until a recurrence is not taken into account and because data from patients who withdraw prematurely from the study without a recurrence are either ignored or analyzed improperly. More appropriate survival analytic techniques were applied to the data from the National Institute of Mental Health Collaborative Study of bipolar patients treated with lithium carbonate, imipramine hydrochloride, or both. An interaction between treatment and the nature of the index episode (the episode that brought the patients into the study) was found. In patients with manic index episodes, both lithium and the combination were superior to imipramine. In patients with depressive index episodes, the combination was significantly superior to imipramine, whereas lithium was indistinguishable from imipramine. The latter finding differs from the original analysis, which found the combination to be no different from the other two treatments for patients with a depressive index episode.

Topics: Actuarial Analysis; Bipolar Disorder; Chlorides; Depressive Disorder; Drug Therapy, Combination; Female; Humans; Imipramine; Lithium; Lithium Chloride; Male; Models, Statistical; Multicenter Studies as Topic; Outcome and Process Assessment, Health Care; Patient Dropouts; Recurrence; Regression Analysis

Three separate lithium chloride doses, calculated according to body weight, and a placebo were administered under double-blind conditions to 68 manic inpatients. The relationship of lithium chloride treatment dose to steady-state serum lithium levels (day 7 to 10 of treatment) and clinical response were examined. High (0.72 mEq/kg/day) and medium (0.5 mEq/kg/day) lithium chloride doses were more efficacious than placebo (P<.001 and P<.05, respectively), as determined by decrements in global mania ratings (day 7 to 10 of treatment). A low dose (0.24 mEq/kg/day) was not found to be more efficacious than placebo. The proportion of patients with improved manic ratings increased markedly as a function of increased steady-state serum lithium level(chi-squared for trend in proportions, 17.91; P<.001).

Topics: Acute Disease; Adolescent; Adult; Aged; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Body Weight; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Middle Aged; Patient Dropouts; Placebos; Psychiatric Status Rating Scales; Treatment Outcome

It has been suggested that bipolar disorder (BD) is associated with clinical and biological features of accelerated aging. In our previous studies, we showed that long-term lithium treatment was correlated with longer leukocyte telomere length (LTL) in BD patients. A recent study explored the role of TL in BD using patients-derived lymphoblastoid cell lines (LCLs), showing that baseline TL was shorter in BD compared to controls and that lithium in vitro increased TL but only in BD. Here, we used the same cell system (LCLs) to explore if a 7-day treatment protocol with lithium chloride (LiCl) 1 mM was able to highlight differences in TL between BD patients clinically responders (Li-R; n = 15) or non-responders (Li-NR; n = 15) to lithium, and if BD differed from non-psychiatric controls (HC; n = 15).. There was no difference in TL between BD patients and HC. Moreover, LiCl did not influence TL in the overall sample, and there was no difference between diagnostic or clinical response groups. Likewise, LiCl did not affect TL in neural precursor cells from healthy donors.. Our findings suggest that a 7-day lithium treatment protocol and the use of LCLs might not represent a suitable approach to deepen our understanding on the role of altered telomere dynamics in BD as previously suggested by studies in vivo.

Topics: Bipolar Disorder; Cell Line; Humans; Lithium; Lithium Chloride; Lithium Compounds; Neural Stem Cells; Telomere

LiCl is widely prescribed for bipolar disorder but adversely associated with a higher incidence of increased body weight. Here, we investigated effects and underlying mechanisms of LiCl on lipid accumulation. LiCl induced dose-dependent lipid accumulation in HepG2 and RAW264.7 cells under normal as well as high glucose conditions. LiCl exposure additionally promoted lipid accumulation in livers of zebrafish. SB216763, a specific GSK-3β inhibitor, did not affect lipid accumulation in HepG2 cells. Expression of key lipogenic enzymes, such as FAS and aP2, as well as SR-B1 were increased in RAW264.7 cells. LiCl enhanced FAS, ACC and SCD-1 mRNA levels while suppressing CPT-1 in HepG2 cells. LiCl stimulated DNA binding activities of SREBP-1c and ChREBP. LiCl activated AMPK phosphorylation but the AMPK inhibitor, AICAR, did not suppress LiCl-induced lipid accumulation in RAW264.7. LiCl, but not SB216763, induced a significant increase in ROS in RAW264.7 and HepG2 cells. NOX activity was dose-dependently enhanced by LiCl. Furthermore, NOX-1, NOX-2 and DUOX-1 mRNA levels were upregulated at an early stage of LiCl stimulation. LiCl-induced lipid accumulation was suppressed by the antioxidant, NAC, and inhibitors of NOX, DPI and APO. Phosphorylation and transcriptional activity of CREB were enhanced by LiCl. The cell-permeable cAMP analog, di-butyryl cAMP, not only promoted lipid accumulation itself but also LiCl-induced lipid accumulation in RAW264.7 cells. H-89, a PKA inhibitor, suppressed CREB activation, lipid accumulation and NOX activity in RAW264.7 cells. Our results indicate that LiCl stimulates lipid accumulation in hepatocyte and macrophage cells potentially through increased PKA-dependent ROS production.

Topics: AMP-Activated Protein Kinases; Animals; Antimanic Agents; Bipolar Disorder; Glycogen Synthase Kinase 3 beta; Hep G2 Cells; Humans; Indoles; Isoquinolines; Lipid Metabolism; Lithium Chloride; Liver; Maleimides; Mice; RAW 264.7 Cells; Reactive Oxygen Species; Sulfonamides; Weight Gain; Zebrafish

For decades, lithium chloride (LiCl) has been used as a treatment option for those living with bipolar disorder (BD). As a result, many studies have been conducted to examine its mode of action, toxicity, and downstream cellular responses. We know that LiCl is able to affect cell signaling and signaling transduction pathways through protein kinase C and glycogen synthase kinase-3, which are considered to be important in regulating gene expression at the translational level. However, additional downstream effects require further investigation, especially in translation pathway. In yeast, LiCl treatment affects the expression, and thus the activity, of

Topics: 5' Untranslated Regions; Amino Acyl-tRNA Synthetases; Antimanic Agents; Bipolar Disorder; Gene Expression Regulation; Gene Knockout Techniques; Lithium Chloride; Organisms, Genetically Modified; Phosphoglucomutase; Protein Biosynthesis; RNA Helicases; RNA, Messenger; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction

Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium Chloride; Male; Middle Aged; Movement Disorders; Posture; Video Recording

Lithium (Li) and valproate (VPA) are used in the treatment of bipolar disorder (BD), with narrow therapeutic window requiring periodic control of serum levels. This prevents intoxication, lack of efficacy due to low serum concentrations, and allows monitoring adherence. We aimed at evaluating the bioequivalence of salivary and blood levels of LI or VPA in a sample of adult BD patients. Secondarily, lithium bioequivalence was evaluated across different patients' lifespans. BD patients treated with either Li or VPA underwent contemporary standard serum and salivary measurements. Blood levels of both drugs were taken according to standard procedures. Li salivary levels were performed by an adapted potentiometric method on the AVL9180 electrolyte analyzer. VPA salivary levels were taken with an immune-assay method with turbidimetric inhibition. A total of 50 patients (38 on Li, 12 on VPA) were enrolled. Blood-saliva bioequivalence for VPA was not found due to a high variability in salivary measures. Li measures resulted in a high correlation (r=0.767, p<0.001), showing no partial correlation with age (r=0.147, p=0.380). Li salivary test is a reliable method of measuring Li availability and is equivalent to serum levels. Potential advantages of Li salivary testing are its non-invasive nature and the possibility of doing the test during the usual appointment with the psychiatrist.

Topics: Adult; Antidepressive Agents; Bipolar Disorder; Female; Humans; Lithium Chloride; Male; Middle Aged; Psychiatric Status Rating Scales; Saliva; Therapeutic Equivalency; Valproic Acid

Lithium continues to be the treatment of choice for bipolar disorder. Acute lithium poisoning is a potentially serious event. We present a retrospective observational significative study of episodes of acute lithium poisoning during a 52- month period. Poisoning was defined by a blood lithium concentration of 1.5 mEq/L or higher. We analyzed treatment and epidemiologic and clinical characteristics of 70 episodes were identified (incidence density among treated patients, 1.76 per 100 patient-years). The most frequent cause of lithium poisoning was a concurrent medical condition (46%). Most poisonings were mild (74.2%), but neurologic involvement was identified in 40.3%. Electrocardiographic abnormalities were found in 8 cases. Acute renal failure, found in 23 patients (37.1%), was mild in most cases, although 11 patients required hemodialysis. We concluded that acute lithium poisoning is an uncommon complication, but risk needs to be lowered. Patients should be warned to avoid dosage errors and to take special care during concurrent illnesses and while taking other medications.. El litio sigue siendo el tratamiento de elección en el trastorno bipolar. La intoxicación aguda por litio (IAL) es un cuadro potencialmente grave. Se presenta un estudio observacional, retrospectivo de las IAL observadas durante un periodo de 52 meses. Se definió como IAL cuando se registró una concentración de litio en sangre 1,5 mEq/L. Se analizaron sus características clínicas, epidemiológicas y su tratamiento de 70 episodios de IAL (densidad de incidencia: 1,76 IAL por cada 100 pacientes tratados-año). La causa más frecuente de IAL fue un proceso patológico intercurrente (46%). La mayoría fueron de carácter leve (74,2 %), con sintomatología neurológica en el 40,3%. En 8 IAL hubo alteraciones electrocardiográficas, 23 IAL (37,1%) se asociaron con fracaso renal agudo, la mayoría de carácter leve y 11 precisaron hemodiálisis. Se concluye que la IAL es una complicación infrecuente, pero es necesario disminuir su riesgo advirtiendo al paciente ante la existencia de procesos intercurrentes, errores en la posología o polimedicación.

Topics: Acute Disease; Acute Kidney Injury; Aged; Antidepressive Agents; Bipolar Disorder; Comorbidity; Female; Humans; Lithium Chloride; Male; Middle Aged; Nervous System Diseases; Poisoning; Renal Dialysis; Retrospective Studies

Hitherto literature indicates that mood stabilizers exert variable effects on oxidative and antioxidative systems, which are involved in the pathogenesis of Bipolar Disorder. Herein we primarily sought to characterize markers of peripheral oxidative stress during euthymia in adults with Bipolar Disorder under current intake of different mood stabilizers (lithium, anticonvulsants and atypical antipsychotics/AAPs).. Peripheral oxidative stress parameters (TBARS/Thiobarbituric acid-reactive-substances, MDA/ malondialdehyde and carbonyl proteins) and antioxidative markers (SOD/Cu/Zn superoxide dismutase, GST/glutathione Stransferase and TAC/total antioxidative capacity) were measured in serum of 115 euthymic bipolar individuals (50 females, 65 males; HAMD<11 and YMRS<8). Differences in (anti)oxidative markers between bipolar participants treated with different mood stabilizing medication were tested with MANCOVAS and ANCOVAS with SPSS.21.. Bipolar individuals taking lithium had significantly lower oxidative parameters than test persons without lithium (multivariate effect for MDA and TBARS: F(2/182)= 3.956, p= 0.021; univariate effect for MDA: F(2/182)= 7.880, p= 0.006, Partial η2= 0.041). Subjects with AAPs had significantly higher MDA and TBARS levels compared to participants without AAPs (multivariate effect F(2/182)= 3.122, p= 0.046, Partial η2= 0.033). Patients taking anticonvulsants had significantly lower GST levels than patients without antiepileptic medication (F(1/165)= 4.501, p= 0.035, Partial η2= 0.027).. Lithium taking participants had the lowest MDA and TBARS levels, while AAP taking test persons had high oxidative stress markers. The observed effects on oxidative markers may provide a mechanistic basis for understanding lithium's neuroprotective effects.

Topics: Adult; Analysis of Variance; Anticonvulsants; Antioxidants; Antipsychotic Agents; Austria; Bipolar Disorder; Female; Humans; Lithium Chloride; Male; Middle Aged; Oxidative Stress; Reactive Oxygen Species; Treatment Outcome

Topics: Aged; Antimanic Agents; Bipolar Disorder; Humans; Lithium Chloride; Male; Nystagmus, Pathologic

Bipolar disorder is a chronic disease characterized by recurring episodes of mania and depression that can lead to disability. This study investigates the protective effects of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a drug with well-known antioxidant properties, in a model of mania induced by ketamine in rats. Locomotor activity was assessed in the open-field test. Superoxide dismutase (SOD), catalase (CAT) and thiobarbituric acid reactive substances (TBARS) levels were measured in order to evaluate oxidative damage in the rat hippocampus and prefrontal cortex. Increased locomotor activity (hyperlocomotion) was observed at the open-field test with ketamine treatment (25 mg/kg, i.p., 8 days). Edaravone (18 mg/kg) treatment did not prevent hyperlocomotion in the mania model induced with ketamine in rats, but lithium chloride (47.5 mg/kg, i.p., positive control) did prevent hyperlocomotion. Edaravone and lithium chloride treatments were found to reduce the increase in SOD and CAT activity following ketamine administration in a non-significant manner but caused no change in TBARS levels.

Topics: Analysis of Variance; Animals; Antimanic Agents; Antipyrine; Bipolar Disorder; Brain; Catalase; Disease Models, Animal; Drug Administration Schedule; Edaravone; Excitatory Amino Acid Antagonists; Exploratory Behavior; Female; Ketamine; Lithium Chloride; Locomotion; Malondialdehyde; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Bipolar disorder (BD) has been associated with diverse abnormalities in neural plasticity and cellular resilience. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) support synaptic neuronal survival and differentiation. NT-3 and NT-4/5 levels were found to be altered in BD, potentially representing a physiological response against cellular stress. However, the use of psychopharmacological agents and heterogeneous mood states may constitute important biases in such studies. Thus, we aimed to assess NT-3 and NT-4/5 levels in medication-free BD type I or II individuals in a current depressive episode, before and after 6 weeks of lithium monotherapy and matched with healthy controls.. Twenty-three patients with BD type I or II during a depressive episode and 28 healthy controls were studied. Patients were required to have a 21-item Hamilton Depression Rating Scale score ≥18 and had not undergone any psychopharmacological treatment for at least 6 weeks prior to study entry. Patients were treated with lithium for 6 weeks and plasma NT-3 and NT-4/5 levels were determined at baseline and endpoint using ELISA method.. Baseline plasma levels of both NT-3 and NT-4/5 were significantly increased in acutely depressed BD subjects in comparison to healthy controls (p=0.040 and 0.039, respectively). The NT-3 and NT-4/5 levels did not significantly change after lithium treatment. NT-3 and NT-4/5 levels were positively correlated to illness duration in BD (p=0.032 and 0.034, respectively).. Our findings suggest that NT-3 and NT-4/5 levels are increased in the depressive phase of BD, which seems directly associated with illness duration. The increased levels of NT-3 and NT-4/5 may underlie a biological response to cellular stress associated with the course of BD.

Topics: Adolescent; Adult; Analysis of Variance; Antimanic Agents; Bipolar Disorder; Female; Humans; Lithium Chloride; Male; Middle Aged; Nerve Growth Factors; Neurotrophin 3; Retrospective Studies; Young Adult

Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT1 and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders.

Topics: Adolescent; Adult; Antimanic Agents; bcl-Associated Death Protein; Bipolar Disorder; Female; Gene Expression Regulation; Gene Regulatory Networks; Humans; Lithium Chloride; Male; Middle Aged; NADH Dehydrogenase; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Signal Transduction; Statistics, Nonparametric; TOR Serine-Threonine Kinases; Young Adult

Black Swiss (BS) mice were shown to be an advantageous strain to model behavioral domains of mania, but to date only male mice were tested, whereas bipolar disorder (BPD) is equally prevalent in women and men. This study was therefore designed to examine the possibility of using both male and female BS mice in future studies. Groups of male and female BS mice were compared with each other, with or without lithium treatment, in tests for domains of mania-like behavior including activity in an open field, sweet solution preference, elevated plus maze, forced swim and amphetamine-induced hyperactivity. The results indicate mostly a similarity between female and male BS mice, both naïve and after chronic lithium treatment. The results are discussed in the context of the deficiency in utilizing female mice in animal models research and suggest that both male and female BS mice can be used to model domains of mania-like behavior.

Topics: Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Bipolar Disorder; Disease Models, Animal; Female; Lithium Chloride; Male; Mice; Species Specificity

The aim of the present study was to assess differences and correlations between the hippocampal volumes (HCVs), serum nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) levels in adolescents with bipolar disorder (BP) compared to healthy controls.. Using structural magnetic resonance imaging, we compared HCVs of 30 patients with euthymic BP who were already enrolled in a naturalistic clinical follow-up. For comparison, we enrolled 23 healthy controls between the ages of 13 and 19. The boundaries of the hippocampus were outlined manually. The BDNF and NGF serum levels were measured with the sandwich ELISA.. The groups did not differ in the right or left HCVs or in the NGF or BDNF serum levels. However, negative correlations were found between the right HCVs and the duration of the disorder and medication and positive correlations were found between the duration of the medications and the NGF and BDNF levels in the patient group. Additionally, positive correlations were found between the follow-up period and left normalized HCVs in both the BP and lithium-treated groups.. The right HCVs may vary with illness duration and the medication used to treat BP; NGF and BDNF levels may be affected by long-term usage. Further research is needed to determine whether these variables and their structural correlates are associated with clinical or functional differences between adolescents with BP and healthy controls.

Topics: Adolescent; Antidepressive Agents; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Disease Progression; Female; Functional Laterality; Hippocampus; Humans; Lithium Chloride; Magnetic Resonance Imaging; Male; Nerve Growth Factor; Statistics as Topic; Valproic Acid; Young Adult

Disturbances of circadian rhythms occur in all episodes of bipolar disorder (BD). Lithium, as gold-standard in the maintenance treatment of BD, is known to influence circadian processes.. In a pilot study lymphoblastoid cell lines (LCLs) were generated from 8 BD patients and 6 healthy controls. The LCLs were treated with lithiumchloride (LiCl) for 3 weeks. Cell cycles were then synchronized and expressional analysis by quantitative Real Time PCR was done.. BD and controls differed in the period length regarding DBP (albumin D-box binding protein) expression and DBP expression was also influenced by lithium treatment. Furthermore, baseline DBP expression was significantly different between non-treated BD and healthy controls. None of the other analyzed circadian genes showed to be influenced by chronic lithium treatment or to be differentially regulated due to the diagnosis.. We here show that chronic lithium treatment of LCLs leads to decreased expression of the clock gene DBP, rendering DBP a lithium-regulated gene. We could confirm the role of the circadian clock as well in lithium mode of action as in the pathomechanisms of BD although future studies with a greater number of participants and cell lines are needed.

Topics: Antimanic Agents; Bipolar Disorder; Cell Line; Circadian Clocks; DNA-Binding Proteins; Female; Gene Expression; Humans; Lithium Chloride; Male; Pilot Projects; Transcription Factors

Mutations in cathepsin D (CTSD), an aspartic protease in the endosomal-lysosomal system, underlie congenital neuronal ceroid-lipofuscinosis (cNCL, also known as CLN10), a devastating neurodegenerative disease. CLN10 patients die within the first few days of life, and in the few patients who live into adulthood psychopathological symptoms have not been reported. Extensive neuropathology and altered neurotransmission have been reported in CTSD-deficient mice; however signs of neuropsychiatric behavior in these mice are not well characterized due to the severe movement disorder and premature death of the animal. In the present study, we show that heterozygous CTSD-deficient (CTSD HET) mice display an overall behavioral profile that is similar to human mania, including hyperlocomotion, d-amphetamine-induced hyperactivity, sleep-disturbance, and reduced anxiety-like behavior. However, under stressful conditions CTSD HET mice manifest depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. Chronic administration of lithium chloride or valproic acid, two clinically effective mood stabilizers, reverses the majority of these behavioral abnormalities. In addition, CTSD HET mice display stress-induced hypersecretion of corticosterone. These findings suggest an important role for CTSD in the regulation of mood stabilization.

Topics: Adaptation, Ocular; Animals; Antidepressive Agents; Bipolar Disorder; Cathepsin D; Corticosterone; Depression; Dextroamphetamine; Disease Models, Animal; Exploratory Behavior; Female; Food Preferences; Hyperkinesis; Lithium Chloride; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuronal Ceroid-Lipofuscinoses; Sleep Wake Disorders; Swimming; Valproic Acid

Mutations that reduce expression or give rise to a Thr85Ser (T85S) mutation of Ca(2+)-CaM-dependent protein kinase kinase-2 (CaMKK2) have been implicated in behavioural disorders such as anxiety, bipolar and schizophrenia in humans. Here we report that Thr85 is an autophosphorylation site that endows CaMKK2 with a molecular memory that enables sustained autonomous activation following an initial, transient Ca(2+) signal. Conversely, autophosphorylation of Ser85 in the T85S mutant fails to generate autonomous activity but instead causes a partial loss of CaMKK2 activity. The loss of autonomous activity in the mutant can be rescued by blocking glycogen synthase kinase-3 (GSK3) phosphorylation of CaMKK2 with the anti-mania drug lithium. Furthermore, CaMKK2 null mice representing a loss of function model the human behavioural phenotypes, displaying anxiety and manic-like behavioural disturbances. Our data provide a novel insight into CaMKK2 regulation and its perturbation by a mutation associated with behavioural disorders.

Topics: Amino Acid Sequence; Animals; Anxiety; Bipolar Disorder; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Cell Line; Chlorocebus aethiops; COS Cells; Glycogen Synthase Kinase 3; Humans; Ionomycin; Lithium Chloride; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Phosphorylation; Reflex, Startle; Sequence Alignment

Topics: Aged; Athetosis; Bipolar Disorder; Chorea; Cognition Disorders; Diagnosis, Differential; Female; Humans; Lithium Chloride; Long-Term Care

Previous studies have provided evidence of subtle thyroid hormone metabolism abnormalities in patients with mood disorders. Although these studies are informative, the precise role of the hypothalamic-pituitary-thyroid axis in bipolar disorder, especially in women, remains unclear. We sought to further corroborate thyroid function in patients with bipolar disorder in comparison to patients with other psychiatric, as well as non-psychiatric, diagnoses.. In this retrospective, cross-sectional, naturalistic study, serum thyroid-stimulating hormone (TSH) levels in a total sample of 3,204 patients were compared. The study sample included patients with bipolar disorder (n = 469), unipolar depression (n = 615), and other psychiatric diagnoses (n = 999), patients from endocrinology clinics (n = 645), and patients from dermatology clinics (n = 476). Analyses were completed using two different normal ranges for TDH: a high normal range (0.4-5.0 μIU/mL) and a low normal range (0.3-3.0 μIU/mL).. Patients with bipolar disorder showed significantly higher serum TSH levels compared to all other groups. In women, the rate of above normal range TSH was highest in patients with bipolar disorder for both high (5.0 μIU/mL; 12.1%) and low (3.0 μIU/mL; 30.4%) upper normal limits. In patients with bipolar disorder, serum TSH levels did not differ significantly between different mood states. In the lithium-treated patients (n = 240), a significantly lower percentage of women (55.9%) compared to men (71.2%) fell within the 0.3-3.0 μIU/mL normal TSH window (p = 0.016). For the high normal range (0.4-5.0 μIU/mL), serum lithium levels above 0.8 mmol/L were associated with a significantly lower proportion of female patients (59.2%) falling within the normal range than male patients (88.9%). Non-lithium treatment was not associated with a gender difference.. Our findings show a higher rate of TSH abnormality in patients with bipolar disorder, particularly those taking lithium, compared to those with other psychiatric and medical conditions. Lithium-associated thyroid dysregulation occurs more frequently in female patients. Using the low normal range TSH values at follow-up can increase sensitivity in recognizing hyperthyroidism in lithium-treated female patients, and help in preventing the development of subclinical hypothyroidism and an adverse course of illness.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antimanic Agents; Bipolar Disorder; Cross-Sectional Studies; Female; Humans; Lithium Chloride; Male; Middle Aged; Retrospective Studies; Thyroid Diseases; Thyrotropin; Young Adult

Lithium is often the mood stabilizer of choice for the treatment of type I bipolar disorder. However, side effects as well as the narrow therapeutic dosing range often complicate its use. Lithium toxicity can be fatal and its serum level needs to be closely monitored, especially at the time of introduction and titration, or whenever combined with potentially interacting drugs, such as inhibitors of angiotensin-converting enzyme (ACE-I) or angiotensin receptor 1 (AT1 ) blockers. ACE-I and AT1 blockers can increase serum lithium levels, leading to acute lithium toxicity upon their introduction or titration.. Here, we report a case of lithium toxicity during concomitant treatment with valsartan, an AT1 blocker, in a patient who previously displayed a stable serum lithium level. The patient was observed for a few weeks and the serum lithium concentration was measured regularly.. In contrast to previous reports, the toxicity in our patient occurred not upon introduction or titration of lithium or valsartan but after subtle modifications in daily dosing schedule for lithium. Just before the onset of toxicity, lithium had been split into two doses, whereby half of the lithium daily dose was administrated concomitantly with valsartan. We presumed that this combination had led to simultaneous concentration peaks of valsartan and lithium, promoting lithium retention within a sharp time window.. Our observation points to the need for caution not only during the introduction and titration of ACE-I/AT1 blockers in lithium-treated patients, but also whenever the temporal pattern of drug administration is modified.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Antimanic Agents; Bipolar Disorder; Creatinine; Drug Synergism; Female; Humans; Lithium Chloride; Tetrazoles; Valine; Valsartan

Cognitive dysfunction in bipolar disorder has been well-established in cross-sectional studies; however, there are few data regarding the longitudinal course of cognitive performance in bipolar disorder. The aim of this study was to examine the course of cognitive function in a sample of euthymic patients with bipolar disorder during a five-year follow-up period.. Eighty euthymic outpatients with a DSM-IV diagnosis of bipolar disorder and 40 healthy control comparison subjects were neuropsychologically assessed at baseline (T1) and then at follow-up of five years (T2). A neurocognitive battery including the main cognitive domains of speed of processing, working memory, attention, verbal memory, visual memory, and executive function was used to evaluate cognitive performance.. Repeated-measures multivariate analyses showed that progression of cognitive dysfunction in patients was not different to that of control subjects in any of the six cognitive domains examined. Only a measure from the verbal memory domain, delayed free recall, worsened more in patients with bipolar disorder. Additionally, it was found that clinical course during the follow-up period did not influence the course of cognitive dysfunction.. Cognitive dysfunction that is characteristic of bipolar disorder is persistent and stable over time. Only dysfunction in verbal recall was found to show a progressive course that cannot be explained by clinical or treatment variables.

Topics: Adult; Analysis of Variance; Anticonvulsants; Antimanic Agents; Bipolar Disorder; Cognition Disorders; Cross-Sectional Studies; Female; Humans; Lithium Chloride; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Psychiatric Status Rating Scales; Statistics as Topic

This study was designed to investigate the protective effect of melatonin in a preclinical animal model of mania induced by ouabain (OUA). Male Wistar rats were pretreated with melatonin (5 or 20mg/kg; intraperitoneal, i.p.) for seven days or with the mood stabilizer lithium chloride (positive control) (45 mg/kg, per oral, p.o.). One day after the last dose, animals received an intracerebroventricular (i.c.v.) injection of OUA (5μl, 10(-5)M), a Na(+)K(+)ATPase-inhibiting compound. Locomotor activity was assessed in the open-field test (OFT). The levels of reactive species (RS), protein carbonyl (PC) and non-protein thiols (NPSH), as well as the activities of the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured in the cerebral cortex and hippocampus of rats. OUA markedly increased the locomotor activity in the OFT, and the pretreatment with melatonin or lithium chloride prevented this effect. Melatonin treatment (similar to lithium) was also effective in preventing the following alterations elicited by OUA: increase of RS and PC levels; depletion of NPSH levels; increase of SOD activity; and inhibition of CAT and GPx activities. Moreover, we found that brain oxidative stress and behavioural alterations elicited by OUA were significantly correlated. Our study showed that Melatonin, similarly to lithium, protected against OUA-induced brain oxidative stress and hyperlocomotion in rats. Thus, our findings reinforce the notion that oxidative stress may play an important role in the manic-like behavioural. Therefore, we indicate that melatonin has antimanic-like action, suggesting a potential role for this substance in the pharmacological management of Bipolar disorder.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Catalase; Cerebral Cortex; Disease Models, Animal; Glutathione Peroxidase; Hippocampus; Lithium Chloride; Locomotion; Male; Melatonin; Motor Activity; Neuroprotective Agents; Ouabain; Oxidative Stress; Protein Carbonylation; Rats; Rats, Wistar; Superoxide Dismutase

Recent studies revealed that bipolar disorder may be associated with deficits of neuroplasticity. Additionally, accumulating evidence has implicated alterations of the intracellular signaling molecule protein kinase C (PKC) in mania.. Using sleep deprivation (SD) as an animal model of mania, this study aimed to examine the possible relationship between PKC and neuroplasticity in mania. Rats were subjected to SD for 72 h and tested behaviorally. In parallel, SD-induced changes in hippocampal cell proliferation were evaluated with bromodeoxyuridine (BrdU) labeling. We then examined the effects of the mood stabilizer lithium, the antipsychotic agent aripiprazole, and the PKC inhibitors chelerythrine and tamoxifen on both behavioral and cell proliferation impairments induced by SD. The antidepressant fluoxetine was used as a negative control.. We found that SD triggered the manic-like behaviors such as hyperlocomotion and increased sleep latency, and reduced hippocampal cell proliferation. These alterations were counteracted by an acute administration of lithium and aripiprazole but not of fluoxetine, and only a single administration of aripiprazole increased cell proliferation on its own. Importantly, SD rats exhibited increased levels of phosphorylated synaptosomal-associated protein 25 (SNAP-25) in the hippocampus and prefrontal cortex, suggesting PKC overactivity. Moreover, PKC inhibitors attenuated manic-like behaviors and rescued cell proliferation deficits induced by SD.. Our findings confirm the relevance of SD as a model of mania, and provide evidence that antimanic agents are also able to prevent SD-induced decrease of hippocampal cell proliferation. Furthermore, they emphasize the therapeutic potential of PKC inhibitors, as revealed by their antimanic-like and pro-proliferative properties.

Topics: Animals; Antidepressive Agents, Second-Generation; Antimanic Agents; Antipsychotic Agents; Aripiprazole; Benzophenanthridines; Bipolar Disorder; Cell Proliferation; Disease Models, Animal; Fluoxetine; Hippocampus; Lithium Chloride; Male; Piperazines; Prefrontal Cortex; Protein Kinase C; Protein Kinase Inhibitors; Quinolones; Rats, Sprague-Dawley; Sleep Deprivation; Tamoxifen

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

Topics: Animals; Behavior, Animal; Bipolar Disorder; Cholecystokinin; CLOCK Proteins; Gene Knockdown Techniques; Histone-Lysine N-Methyltransferase; Humans; Lithium Chloride; Male; Mice; Mutation; Myeloid-Lymphoid Leukemia Protein; Ventral Tegmental Area

Topics: Animals; Ankyrins; Anxiety Disorders; Bipolar Disorder; Lithium Chloride; Male; Stress, Psychological

An altered polyamine system has been suggested to play a key role in mood disorders and suicide, a hypothesis corroborated by the evidence that lithium inhibits the polyamine mediated stress response in the rat brain. Recent post-mortem studies have shown that spermidine/spermine N1-acetyltransferase (SAT1), the key regulator of cellular polyamine content, is under-expressed in brains from suicide victims compared to controls. In our study we tested the effect of in vitro lithium treatment on SAT1 gene and protein expression in B lymphoblastoid cell lines (BLCLs) from bipolar disorder (BD) patients who committed suicide (and for which BLCLs were collected prior to their death), BD patients with high and low risk of suicide and a sample of non-psychiatric controls. Baseline mRNA levels were similar in the four groups of subjects (p > 0.05). Lithium had no effect in suicide completers (p > 0.05) while it significantly increased SAT1 expression in the high risk (p < 0.001) and low risk (p < 0.01) groups as well as in controls (p < 0.001). Protein and mRNA levels were not correlated; lithium significantly reduced protein levels only in the control sample (p < 0.05). Our findings suggest that SAT1 transcription is influenced by lithium and that this effect is altered in BD patients who completed suicide, further supporting a role for polyamines in suicide.

Topics: Acetyltransferases; Adult; Antimanic Agents; B-Lymphocytes; Bipolar Disorder; Canada; Case-Control Studies; Cell Line; Female; Gene Expression Regulation, Enzymologic; Humans; Italy; Lithium Chloride; Male; Middle Aged; RNA, Messenger; Suicidal Ideation; Suicide; Suicide, Attempted; Young Adult

Bipolar disorder (BD) has been associated with persistent low-grade inflammation and premature cell senescence, as shown by reduced telomere length (TL). The human cytomegalovirus (CMV) has increasingly been implicated in accelerated immunosenescence in aging studies. Here, we compared CMV serology and its relationships with cell senescence markers, including TL and lymphocyte subsets, in patients with type I BD and healthy controls.. Twenty-two euthymic female patients with BD type I and 17 age-matched healthy controls were selected for the study. A sample of blood was collected and mononuclear cells and DNA were isolated and TL measured. CMV immunoglobulin M (IgM) and IgG titers were measured using chemiluminescent assays. Lymphocyte subsets [T, natural killer (NK) and NKT] were phenotyped by flow cytometry.. Individuals with BD had shorter TLs but higher CMV IgG levels than controls (both p < 0.01). CMV IgG level was inversely correlated with TL. None of the subjects showed IgM reactivity for CMV, excluding acute viral infection. CMV IgG level was associated with expansion of senescent CD8+CD28- T cells and NK cells, which are involved in viral control.. These data support the hypothesis of accelerated aging in BD, as shown by shortened telomeres, higher seropositivity for CMV, and expansion of senescent T cells.

Topics: Adult; Aging; Analysis of Variance; Antigens, CD; Antimanic Agents; Bipolar Disorder; Case-Control Studies; Cytomegalovirus; Female; Flow Cytometry; Humans; Immunoglobulins; Lithium Chloride; Lymphocytes; Middle Aged; Statistics, Nonparametric; Telomere

Abnormalities of signal transduction are considered among the susceptibility factors for bipolar disorder (BD). These include changes in G-protein-mediated signaling and subsequent modification of gene expression via transcription factors such as cAMP response element-binding protein (CREB).. We investigated levels of CREB in lymphoblasts from patients with BD, all responders to lithium prophylaxis (n = 13), and healthy control subjects (n = 15). Phosphorylated CREB (pCREB) was measured by immunoblotting in subjects with BD (n = 15) as well as in their affected (n = 17) and unaffected (n = 18) relatives, and healthy controls (n = 16).. Basal CREB levels were comparable in patients and control subjects and were not changed by lithium treatment. pCREB levels were increased in both patients and their relatives compared to controls (p = 0.003). Forskolin stimulation led to a 24% increase in pCREB levels in cells from healthy subjects (p = 0.002) but not in the other three groups. When using basal and stimulated pCREB levels as a biochemical phenotype in a preliminary linkage study, we found the strongest support for linkage in regions largely overlapping with those showing linkage with the clinical phenotype (3p, 6p, 16p, 17q, 19q, and 21q).. Abnormal pCREB signaling could be considered a biochemical phenotype for lithium-responsive BD.

Topics: Adjuvants, Immunologic; Adult; Antimanic Agents; B-Lymphocytes; Bipolar Disorder; Cells, Cultured; Colforsin; Cyclic AMP Response Element-Binding Protein; Family; Female; Genotype; Humans; Lithium Chloride; Longitudinal Studies; Male; Middle Aged; Phosphorylation

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750,000 high-quality genetic markers on a combined sample of ∼14,000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17,700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10(-11) level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63,000 case-control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

Topics: Ankyrins; Antidepressive Agents; Asian People; Bipolar Disorder; Cell Line, Transformed; Cytokines; Dose-Response Relationship, Drug; Female; Gene Expression Regulation; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Lectins; Lithium Chloride; Male; Membrane Transport Proteins; Meta-Analysis as Topic; Polymorphism, Single Nucleotide; Receptors, Prostaglandin; RNA, Messenger; Time Factors; Valproic Acid; White People

We present the case of a male patient with a family history of both bipolar disorder (BD) and Wilson's disease (WD). Wilson's disease was diagnosed for this patient in 2008, at the age of 28 years, and shortly thereafter his bipolar illness began with depressive episodes. The patient has been treated with zinc sulphate for WD and with antidepressants for depression. In 2009, lithium was added, and in 2010 antidepressants were discontinued. During treatment with zinc sulphate, a gradual improvement of hepatic indices and a decrease of mandibulofacial dystonia was noted. In 2011, a hypomanic state occurred which subsided with an increase of the lithium dose. Since then, the patient has been mostly in a euthymic mood with subclinical hypomanic periods. We suggest that lithium may be a viable option for treating bipolar illness in patients with Wilson's disease.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Hepatolenticular Degeneration; Humans; Lithium Chloride; Male

Ankyrin 3 (ANK3) has been strongly implicated as a risk gene for bipolar disorder (BD) by recent genome-wide association studies of patient populations. However, the genetic variants of ANK3 contributing to BD risk and their pathological function are unknown.. To gain insight into the potential disease relevance of ANK3, we examined the function of mouse Ank3 in the regulation of psychiatric-related behaviors using genetic, neurobiological, pharmacological, and gene-environment interaction (G×E) approaches. Ank3 expression was reduced in mouse brain either by viral-mediated RNA interference or through disruption of brain-specific Ank3 in a heterozygous knockout mouse.. RNA interference of Ank3 in hippocampus dentate gyrus induced a highly specific and consistent phenotype marked by decreased anxiety-related behaviors and increased activity during the light phase, which were attenuated by chronic treatment with the mood stabilizer lithium. Similar behavioral alterations of reduced anxiety and increased motivation for reward were also exhibited by Ank3+/- heterozygous mice compared with wild-type Ank3+/+ mice. Remarkably, the behavioral traits of Ank3+/- mice transitioned to depression-related features after chronic stress, a trigger of mood episodes in BD. Ank3+/- mice also exhibited elevated serum corticosterone, suggesting that reduced Ank3 expression is associated with elevated stress reactivity.. This study defines a new role for Ank3 in the regulation of psychiatric-related behaviors and stress reactivity that lends support for its involvement in BD and establishes a general framework for determining the disease relevance of genes implicated by patient genome-wide association studies.

Topics: Animals; Ankyrins; Anxiety Disorders; Bipolar Disorder; Corticosterone; Dentate Gyrus; Lithium Chloride; Male; Mice; Mice, Knockout; Mice, Transgenic; Stress, Psychological

In this study, we investigated serum protein levels of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in patients with bipolar disorder.. Over a 2-year period, 26 patients with bipolar I disorder (manic episode) and 56 healthy controls were recruited. The Young Mania Rating Scale scores of patients with bipolar mania were >26. Serum BDNF and TrkB protein levels were measured with ELISA kits.. Using ANCOVA with age adjustment, we found that there were no significant differences in serum BDNF protein levels between patients with bipolar mania and healthy controls (p = 0.582). In contrast, the serum TrkB protein level was significantly higher in bipolar mania patients than in healthy controls (p = 0.001), especially in women (p = 0.001). Of 26 patients with bipolar mania, 21 underwent a second measurement of serum BDNF and TrkB protein levels after a 4-week treatment with mood stabilizers. There were no significant changes in serum BDNF or TrkB protein levels.. These findings suggest that serum TrkB protein levels may play an important role in the psychopathology of bipolar mania. However, a larger sample size is needed to confirm these results.

Topics: Adult; Analysis of Variance; Antimanic Agents; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Female; Humans; Lithium Chloride; Male; Middle Aged; Protein Kinases; Retrospective Studies; Valproic Acid; Young Adult

Bipolar disorder and schizophrenia share common pathophysiological processes and may have similar perceptual abnormalities. Mismatch negativity (MMN) and P3a - event-related potentials associated with auditory preattentional processing - have been extensively studied in schizophrenia, but rarely in bipolar disorder. Furthermore, MMN and P3a have not been examined between diagnostic subgroups of patients with bipolar disorder. We evaluated MMN and P3a in patients with bipolar disorder compared to patients with schizophrenia and healthy controls.. MMN and P3a were assessed in 52 bipolar disorder patients, 30 schizophrenia patients, and 27 healthy control subjects during a duration-deviant auditory oddball paradigm.. Significant MMN and P3a amplitude reductions were present in patients with bipolar disorder and schizophrenia relative to controls. The MMN reduction was more prominent in patients with schizophrenia than bipolar disorder, at a trend level. P3a did not differ significantly between patient groups. There were no MMN or P3a differences between patients with bipolar I (n = 34) and bipolar II (n = 18) disorder. Patients with bipolar I disorder failed to show lateralized MMN, in contrast to the other groups. No MMN or P3a differences were found between patients with bipolar disorder taking (n = 12) and not taking (n = 40) lithium, as well as between those taking (n = 30) and not taking (n = 22) antipsychotic medications.. Patients with bipolar disorder showed deficits in preattentive auditory processing, including MMN deficits that are less severe and P3a deficits that are slightly more pronounced, than those seen in schizophrenia.

Topics: Acoustic Stimulation; Adult; Analysis of Variance; Bipolar Disorder; Brain Mapping; Contingent Negative Variation; Electroencephalography; Event-Related Potentials, P300; Female; Functional Laterality; Humans; Lithium Chloride; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

Hippocampal volume decrease associated with illness burden is among the most replicated findings in unipolar depression. The absence of hippocampal volume changes in most studies of individuals with bipolar disorder (BD) may reflect neuroprotective effects of lithium (Li).. We recruited 17 BD patients from specialized Li clinics, with at least two years of regularly monitored Li treatment (Li group), and compared them to 12 BD participants with < 3 months of lifetime Li exposure and no Li treatment within two years prior to the scanning (non-Li group) and 11 healthy controls. All BD patients had at least 10 years of illness and five episodes. We also recruited 13 Li-naïve, young BD participants (15-30 years of age) and 18 sex- and age-matched healthy controls. We compared hippocampal volumes obtained from 1.5-T magnetic resonance imaging (MRI) scans using optimized voxel-based morphometry with small volume correction.. The non-Li group had smaller left hippocampal volumes than controls (corrected p < 0.05), with a trend for lower volumes than the Li group (corrected p < 0.1), which did not differ from controls. Young, Li-naïve BD patients close to the typical age of onset had comparable hippocampal volumes to controls.. Whereas patients with limited lifetime Li exposure had significantly lower hippocampal volumes than controls, patients with comparable illness burden, but with over two years of Li treatment, or young Li-naïve BD patients, showed hippocampal volumes comparable to controls. These results provide indirect support for neuroprotective effects of Li and negative effects of illness burden on hippocampal volumes in bipolar disorders.

Topics: Adult; Analysis of Variance; Antimanic Agents; Bipolar Disorder; Canada; Cost of Illness; Czech Republic; Female; Hippocampus; Humans; Lithium Chloride; Magnetic Resonance Imaging; Male; Middle Aged; Psychiatric Status Rating Scales; Young Adult

Topics: Antipsychotic Agents; Bipolar Disorder; Contraindications; Decision Making; Female; Humans; Lithium Chloride; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Risk

Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha-lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine-induced model of mania.. In the reversal protocol, adult mice were first given d-amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open-field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid-reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain-derived neurotrophic factor (BDNF) levels were measured in the HC.. ALA and Li prevented and reversed the AMPH-induced increase in locomotor activity. PREVENTION MODEL: ALA and Li co-administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. REVERSAL MODEL: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH-induced decreases in BDNF and GSH in the HC.. Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA's possible antimanic effect.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Brain; Brain-Derived Neurotrophic Factor; Central Nervous System Stimulants; Dextroamphetamine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Glutathione; Lipid Peroxidation; Lithium Chloride; Male; Malondialdehyde; Mice; Motor Activity; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Thioctic Acid

In this study, we assessed the oxidative stress parameters in rats submitted to an animal model of mania induced by ouabain (OUA), which included the use of lithium (Li) and valproate (VPA). Li and VPA treatment reversed and prevented the OUA-induced damage in these structures, however, this effect varies depending on the brain region and treatment regimen. Moreover, the activity of the antioxidant enzymes, namely, superoxide dismutase (SOD) and catalase (CAT) was found to be increased and decreased, respectively, in the brain of OUA-administered rats. Li and VPA modulated SOD and CAT activities in OUA-subjected rats in both experimental models. Our results support the notion that Li and VPA exert antioxidant-like properties in the brain of rats submitted to animal model of mania induced by ouabain.

Topics: Analysis of Variance; Animals; Antimanic Agents; Bipolar Disorder; Brain; Catalase; Disease Models, Animal; Drug Interactions; Gene Expression Regulation, Enzymologic; Injections, Intraventricular; Lithium Chloride; Male; Ouabain; Protein Carbonylation; Rats; Rats, Wistar; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Valproic Acid

Memantine, a selective antagonist of the N-methyl-D-aspartate receptor, is approved for the treatment of moderate to severe Alzheimer's disease. Ion dysregulation is thought to be involved in the pathophysiology of bipolar illness, suggesting that memantine may be effective in treating bipolar manic and/or depressive episodes. We utilized two preclinical models of mania that mimic pathophysiologic changes seen in bipolar illness to examine the potential efficacy of memantine in the treatment of this disorder. Locomotor hyperactivity of male Sprague-Dawley rats in an open field was induced with intracerebroventricular (ICV) administration of 10(-3) M ouabain. Memantine (2.5, 5 or 7.5mg/kg), lithium (6.75 mEq/kg), or vehicle were administered acutely via intraperitoneal injection immediately prior to ouabain, then chronically for 7 days (oral memantine 20, 30, and 40 mg/kg/day in water; lithium 2.4 g/kg food). In a second model of bipolar disorder, cycling between population spikes and epileptiform bursts was investigated in rat hippocampal slices treated with ouabain (3.3 μM) alone or in combination with memantine (0.5, 1.0, and 5.0 μM). Ouabain-induced hyperlocomotion was normalized with acute and chronic lithium and chronic use of memantine. Memantine delayed the onset of ouabain-induced-cycling in hippocampal slices. Memantine may have antimanic properties.

Topics: Action Potentials; Animals; Antimanic Agents; Bipolar Disorder; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Exploratory Behavior; Hippocampus; In Vitro Techniques; Lithium Chloride; Male; Memantine; Ouabain; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Time Factors

Topics: Adult; Antidepressive Agents; Antimanic Agents; Bipolar Disorder; Depressive Disorder; Female; Humans; Lithium Chloride; Treatment Outcome

Bipolar disorder (BPD) is a devastating long-term disease for which a significant symptom is mania. Rodent models for mania include psychostimulant-induced hyperactivity and single gene alterations, such as in the Clock or DAT genes, but there is still a pressing need for additional models. Recently, our lab isolated a line of mice, termed Madison (MSN), that exhibit behavioral characteristics that may be analogous to symptoms of mania. In this study we quantified possible traits for mania and tested the response to common anti-BPD drugs in altering the behavioral profiles observed in this strain. Relative to other mouse lines, MSN mice showed significant elevations of in-cage hyperactivity levels, significant decreases in daytime sleep, and significant increases in time swimming in the forced swim test. In terms of sexual behavior, the MSN mice showed significantly higher number of mounts and a trend toward higher time mounting. In separate studies, olanzapine and lithium (or respective controls) were administered to MSN mice for at least 2weeks and response to treatments was evaluated. Olanzapine (1mg/kg/day) significantly decreased in-cage hyperactivity and significantly increased time sleeping. Lithium (0.2-0.4% in food) significantly decreased in-cage hyperactivity. Given the behavioral phenotypes and the response to anti-BPD treatments, we propose that MSN mice may provide a possible new model for understanding the neural and genetic basis of phenotypes related to mania and for developing pharmaceutical treatments.

Topics: Animals; Antimanic Agents; Behavior, Animal; Benzodiazepines; Bipolar Disorder; Body Weight; Dark Adaptation; Disease Models, Animal; Exploratory Behavior; Lithium Chloride; Mice; Olanzapine; Sexual Behavior, Animal; Sleep; Swimming

Lithium has been used extensively for mood stabilization, and it is particularly efficacious in the treatment of bipolar mania. Like other drugs used in the treatment of psychiatric diseases, it has little effect on the mood of healthy individuals. Our previous studies found that mice with a mutation in the Clock gene (ClockΔ19) have a complete behavioral profile that is very similar to human mania, which can be reversed with chronic lithium treatment. However, the cellular and physiological effects that underlie its targeted therapeutic efficacy remain unknown. Here we find that ClockΔ19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA), and that lithium treatment selectively reduces the firing rate in the mutant mice with no effect on activity in wild-type mice. Furthermore, lithium treatment reduces nucleus accumbens (NAc) dopamine levels selectively in the mutant mice. The increased dopaminergic activity in the Clock mutants is associated with cell volume changes in dopamine neurons, which are also rescued by lithium treatment. To determine the role of dopaminergic activity and morphological changes in dopamine neurons in manic-like behavior, we manipulated the excitability of these neurons by overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of ClockΔ19 mice and wild-type mice using viral-mediated gene transfer. Introduction of this channel mimics the effects of lithium treatment on the firing rate of dopamine neurons in ClockΔ19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in ClockΔ19 animals results in a normalization of locomotor- and anxiety-related behavior that is very similar to lithium treatment; however, it is not sufficient to reverse depression-related behavior. These results suggest that abnormalities in dopamine cell firing and associated morphology underlie alterations in anxiety-related behavior in bipolar mania, and that the therapeutic effects of lithium come from a reversal of these abnormal phenotypes.

Topics: Action Potentials; Analysis of Variance; Animals; Anxiety; Bipolar Disorder; Cell Count; Chromatography, High Pressure Liquid; CLOCK Proteins; Dark Adaptation; Depression; Disease Models, Animal; Dopamine; Green Fluorescent Proteins; Helplessness, Learned; Histones; In Vitro Techniques; Lithium Chloride; Locomotion; Male; Maze Learning; Mice; Mice, Inbred BALB C; Mice, Knockout; Mutation; Neurons; Patch-Clamp Techniques; Swimming; Tyrosine 3-Monooxygenase; Ventral Tegmental Area

Lithium has long been recognised for its mood-stabilizing effects in the management of bipolar disorder (BD) but in practice its use has been limited because of real and 'imagined' concerns. This article addresses the need for lithium to be measured with respect to its clinical and functional effects. It introduces a visual scale, termed lithiumeter, which captures the optimal lithium plasma levels for the treatment of BD..   Key words pertaining to lithium's administration, dosing, and side effects as well as its efficacy in acute and long-term treatment of BD were used to conduct an electronic search of the literature. Relevant articles were identified by the authors and reviewed.. This paper outlines the considerations necessary prior to initiating lithium therapy and provides a guide to monitoring lithium plasma levels. Current recommendations for optimal plasma lithium levels in the management of BD are then discussed with respect to indications for use in the acute phases of the illness and maintenance therapy. The risks associated with lithium treatment are also discussed.. The lithiumeter provides a practical guide of optimal lithium levels for the clinical management of BD.

Topics: Antimanic Agents; Bipolar Disorder; Databases, Factual; Guidelines as Topic; Humans; Lithium Chloride; Outcome Assessment, Health Care

Repeated unavoidable stress induces in rats decreased reactivity to avoidable stressors and an anhedonia-like condition that are reverted by long-term antidepressant treatments and regarded as models of core symptoms of depression. Morphine-sensitized rats present resilience to stress-induced behavioral deficits and, if hyporeactivity to stress models a depressive symptom, stress resistance can be regarded as a manic symptom. This hypothesis is supported by the observation that long-term lithium administration reinstates sensitivity to stress in sensitized rats. The first aim of the study was to examine the effects of carbamazepine, a standard antimanic treatment, on the stress resilience of sensitized rats, to further characterize morphine sensitization as a model of manic symptom. Carbamazepine administration abolished stress resilience but did not interfere with the expression of sensitization. The second aim of the study was to assess whether repeated carbamazepine treatment affected the dopaminergic and behavioral responses to a natural reward, a palatable food (vanilla sugar, VS), in non food-deprived sensitized and control rats and compare these possible effects with those of repeated lithium administration. Control and sensitized rats showed increased extraneuronal dopamine levels in the nucleus accumbens shell after VS consumption and competence to acquire an instrumental VS-sustained appetitive behavior (VAB). Repeated carbamazepine treatment abolished the dopaminergic response to VS consumption and disrupted the competence to acquire VAB in control rats. Lithium-treated rats showed a dopaminergic response to VS and easily acquired the appetitive behavior. In sensitized rats, neither carbamazepine nor lithium administration interfered with the dopaminergic response to VS and the acquisition of VAB. In summary, the effect of carbamazepine on the stress resilience of sensitized rats further supported the hypothesis that morphine sensitization might model some symptoms of mania. Moreover, in control rats carbamazepine treatment elicited an anhedonia-like condition that clearly distinguished the effects of this drug from those of lithium.

Topics: Analgesics, Opioid; Animals; Anticonvulsants; Antimanic Agents; Appetitive Behavior; Bipolar Disorder; Brain Chemistry; Carbamazepine; Central Nervous System Sensitization; Choice Behavior; Dopamine; Escape Reaction; Food; Lithium Chloride; Male; Microdialysis; Morphine; Nucleus Accumbens; Rats; Rats, Sprague-Dawley; Resilience, Psychological; Stress, Psychological

Irregularities of intracellular calcium (Ca2+) homeostasis have been implicated in the pathophysiology of bipolar disorder (BD). Findings that chronic ex-vivo treatment with lithium modifies lysophosphatidic acid (LPA)-stimulated Ca2+ responses in B lymphoblast cell lines (BLCLs) from BD-I patients and healthy controls, and differentially decreases levels of the type-3 canonical transient receptor potential Ca2+-permeable channel in BLCLs from BD-I patients, support the view that the amelioration of these abnormalities is important in the therapeutic action of lithium. To determine whether other clinically efficacious mood stabilizers share these effects, LPA (100 mum)- and thapsigargin (TG, 200 nm)-stimulated Ca2+ responses were determined in BLCLs from BD-I patients and healthy controls treated acutely (24 h) and chronically (7 d) ex vivo with therapeutically relevant concentrations of lithium (0.75 mm), valproate (0.5 mm), lamotrigine (15 mum) or respective vehicles. Chronic treatment with valproate significantly attenuated LPA-stimulated Ca2+ responses ([downward arrow]8%: F's=9.1-9.4, d.f.=1, 9, p's<0.05) compared to vehicle in BLCLs from BD-I patients and healthy controls, similar to chronic lithium treatment ([downward arrow]8%: F=6.2, d.f.=1, 21, p<0.05), but also attenuated TG-evoked Ca2+ responses ([downward arrow]10% to [downward arrow]19%: F's=5.5-15.5, d.f.=1, 12, p's<0.05). However, chronic lamotrigine treatment did not affect LPA- or TG-stimulated Ca2+ responses. These results suggest that chronic lithium and valproate treatments act differently from lamotrigine in respect of modulation of receptor- and/or capacitance-mediated Ca2+ flux. These differential effects on Ca2+ responses may be relevant to the distinctive clinical profiles of these mood stabilizers.

Topics: Adult; Antimanic Agents; B-Lymphocytes; Bipolar Disorder; Calcium; Cell Line, Transformed; Drug Interactions; Enzyme Inhibitors; Female; Humans; Intracellular Fluid; Lipopolysaccharides; Lithium Chloride; Male; Middle Aged; Thapsigargin; Valproic Acid

Topics: Adult; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Clozapine; Dyskinesia, Drug-Induced; Humans; Lithium Chloride; Male

Retigabine is a novel compound with anticonvulsant efficacy. Preclinical studies have indicated that the compound, like other anticonvulsants may also have antimanic efficacy. Bipolar disorder is characterized by episodes of depression and mania, which show a progressively faster recurrence and an increase in severity with time. Recurrence of episodes in bipolar disorders is suggested to reflect a process of sensitization. Repeated intermittent administration of amphetamine in rodents gives rise to a behavioral sensitization phenomena argued to have similarities to the sensitization found in humans. The aims were therefore to explore the predictive validity of the amphetamine sensitization model as a behavioral model of mania by testing the effect of a range of antimanic drugs and to evaluate the effect of retigabine on the sensitized amphetamine response. Furthermore, since withdrawal from prolonged use of amphetamine in humans can result in depression symptoms it was explored if a state of anhedonia could be assessed by testing saccharine preference before and during the withdrawal period of the model. The tested antimanic drugs (lithium, valproate, carbamazepine and lamotrigine) all attenuated the sensitized locomotor activity induced and with the exception of valproate the found effects seemed not to be due to sedation. Interestingly, retigabine also attenuated the induced locomotor activity with a lowest effective dose at 1.0mg/kg, whereas basal locomotor activity was only reduced at 8.0mg/kg, suggesting a genuine calming and antimanic-like efficacy of the compound. In addition, saccharine preference data suggest that withdrawal from the d-amphetamine pre-treatment regimen may induce depression-like behavior indicating that both manic and depression-like behavior is expressed in this mouse model.

Topics: Amphetamine; Analysis of Variance; Animals; Anticonvulsants; Antimanic Agents; Behavior, Animal; Bipolar Disorder; Carbamates; Disease Models, Animal; Dose-Response Relationship, Drug; Food Preferences; Lithium Chloride; Male; Mice; Motor Activity; Phenylenediamines; Saccharin; Treatment Outcome

There is a body of evidence suggesting that BDNF is involved in bipolar disorder (BD) pathogenesis. Intracerebroventricular (ICV) injection of ouabain (OUA), a specific Na(+)/K(+) ATPase inhibitor, induces hyperlocomotion in rats, and has been used as an animal model of mania. The present study aims to investigate the effects of the lithium (Li) and valproate (VPT) in an animal model of mania induced by ouabain. In the reversal model, animals received a single ICV injection of OUA or cerebrospinal fluid (aCSF). From the day following the ICV injection, the rats were treated for 6 days with intraperitoneal (IP) injections of saline (SAL), Li or VPT twice a day. In the maintenance treatment (prevention model), the rats received IP injections of Li, VPT, or SAL twice a day for 12 days. In the 7th day of treatment the animals received a single ICV injection of either OUA or aCSF. After the ICV injection, the treatment with the mood stabilizers continued for more 6 days. Locomotor activity was measured using the open-field test and BDNF levels were measured in rat hippocampus and amygdala by sandwich-ELISA. Li and VPT reversed OUA-related hyperactive behavior in the open-field test in both experiments. OUA decreased BDNF levels in first and second experiments in hippocampus and amygdala and Li treatment, but not VPT reversed and prevented the impairment in BDNF expression after OUA administration in these cerebral areas. Our results suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania.

Topics: Amygdala; Analysis of Variance; Animals; Antimanic Agents; Bipolar Disorder; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Drug Interactions; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Hippocampus; Lithium Chloride; Male; Motor Activity; Ouabain; Rats; Rats, Wistar; Valproic Acid

There are several hypotheses on functional neuronal networks that modulate mood states and which might form the neuroanatomical basis of bipolar disorder. The thalamus has been reported to be a key structure within the circuits that modulate mood states and might thus play an important role within the aetiology of the bipolar affective disorder. Nevertheless, structural brain imaging studies on the thalamus volume of bipolar patients have shown heterogeneous results. Using structural MRI scanning, we compared the thalamus volume of 41 euthymic bipolar patients to the thalamus volume of 41 well-matched healthy controls. Taking the concomitant medication as a co-variable within the patient group, the analysis of variance revealed a significantly smaller relative volume of the right thalamus in patients not treated with lithium when compared with healthy controls. In contrast, there are no significant differences concerning the thalamus volume between all euthymic bipolar patients and healthy controls. The study only shows findings of a transverse section. No longitudinal analysis was performed. More detailed information on patients' pharmacological histories could not be obtained. In conclusion, this result may be interpreted as an indication of the impact of the thalamus in the pathogenesis of the bipolar I disorder and emphasises the need for further longitudinal studies in bipolar patients with special attention paid to the concomitant medication, in particular to the role of lithium.

Topics: Adult; Analysis of Variance; Antimanic Agents; Bipolar Disorder; Female; Humans; Lithium Chloride; Magnetic Resonance Imaging; Male; Middle Aged; Thalamus

To investigate whether treatment with lithium in patients with mania or bipolar disorder is associated with a decreased rate of subsequent dementia.. Linkage of register data on prescribed lithium in all patients discharged from psychiatric health care service with a diagnosis of mania or bipolar disorder and subsequent diagnoses of dementia in Denmark during a period from 1995 to 2005.. A total of 4,856 patients with a diagnosis of a manic or mixed episode or bipolar disorder at their first psychiatric contact were included in the study. Among these patients, 2,449 were exposed to lithium (50.4%), 1,781 to anticonvulsants (36.7%), 4,280 to antidepressants (88.1%), and 3,901 to antipsychotics (80.3%) during the study period. A total of 216 patients received a diagnosis of dementia during follow-up (103.6/10,000 person-years). During the period following the second prescription of lithium, the rate of dementia was decreased compared to the period following the first prescription. In contrast, the rates of dementia during multiple prescription periods with anticonvulsants, antidepressants, or antipsychotics, respectively, were not significantly decreased compared to the rate of dementia during the period with one prescription of these drugs.. Continued treatment with lithium was associated with a reduced rate of dementia in patients with bipolar disorder in contrast to continued treatment with anticonvulsants, antidepressants, or antipsychotics. Methodological reasons for these findings cannot be excluded due to the nonrandomized nature of the data.

Topics: Adult; Aged; Antidepressive Agents; Antimanic Agents; Antipsychotic Agents; Bipolar Disorder; Dementia; Denmark; Evidence-Based Medicine; Female; Follow-Up Studies; Humans; Lithium Chloride; Male; Middle Aged; Registries; Regression Analysis; Retrospective Studies

This study reports on the naturalistic pharmacotherapy of 266 youths with bipolar disorder (BP), manic or hypomanic episode (158 males and 108 females, 13.8+/-2.8 years), first treated with monotherapy on valproic acid (VPA) (n=158, 59.4%), lithium (n=90, 33.8%) or atypical antipsychotics (n=18, 6.8%). Among the patients receiving mood stabilizers, 59.5% of those treated with VPA and 47.8% of those receiving lithium did not need other antimanic agents (mood stabilizers and/or atypical antipsychotics). Lower severity was associated with a greater persistence of both VPA and lithium monotherapy. Factors associated with greater persistence of VPA monotherapy were BP II and co-occurring generalized anxiety disorder, separation anxiety disorder and simple phobias. On the contrary, BP I and co-occurring psychotic symptoms and/or conduct disorder were associated with a lower persistence of VPA monotherapy. Factors associated with lower persistence of lithium monotherapy were younger age and the association with attention deficit hyper-activity disorder (ADHD). Type of BP and presence of psychotic symptoms and conduct disorder did not affect the lithium monotherapy. Overall, predictors of non-response (multiple stepwise logistic regression) in both VPA and lithium groups were baseline Clinical Global Impression (CGI) Severity score and comorbid conduct disorder; while psychotic symptoms and absence of comorbid generalized anxiety disorder were predictors of poorer treatment response only in the VPA group, and chronic course, comorbid ADHD and absence of comorbid panic disorder were predictors only in the lithium group. Such naturalistic data from an ordinary clinical setting have relevance to clinical practice.

Topics: Adolescent; Age Factors; Antimanic Agents; Bipolar Disorder; Child; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Psychiatric Status Rating Scales; Retrospective Studies; Severity of Illness Index; Statistics, Nonparametric; Treatment Outcome; Valproic Acid

Recent studies demonstrate that the neuropeptide VGF (nonacronymic) is regulated in the hippocampus by antidepressant therapies and animal models of depression and that acute VGF treatment has antidepressant-like activity in animal paradigms. However, the role of VGF in human psychiatric disorders is unknown. We now demonstrate using in situ hybridization that VGF is downregulated in bipolar disorder in the CA region of the hippocampus and Brodmann's area 9 of the prefrontal cortex. The mechanism of VGF in relation to LiCl was explored. Both LiCl intraperitoneally and VGF intracerebroventricularly reduced latency to drink in novelty-induced hypophagia, and LiCl was not effective in VGF(+/-) mice, suggesting that VGF may contribute to the effects of LiCl in this behavioral procedure that responds to chronic antidepressant treatment. VGF by intrahippocampal injection also had novel activity in an amphetamine-induced hyperlocomotion assay, thus mimicking the actions of LiCl injected intraperitoneally in a system that phenocopies manic-like behavior. Moreover, VGF(+/-) mice exhibited increased locomotion after amphetamine treatment and did not respond to LiCl, suggesting that VGF is required for the effects of LiCl in curbing the response to amphetamine. Finally, VGF delivered intracerebroventricularly in vivo activated the same signaling pathways as LiCl and is necessary for the induction of mitogen-activated protein kinase and Akt by LiCl, thus lending insight into the molecular mechanisms underlying the actions of VGF. The dysregulation of VGF in bipolar disorder as well as the behavioral effects of the neuropeptide similar to LiCl suggests that VGF may underlie the pathophysiology of bipolar disorder.

Topics: Analysis of Variance; Animals; Antimanic Agents; Bipolar Disorder; Blotting, Western; Down-Regulation; Hippocampus; Humans; In Situ Hybridization; Lithium Chloride; MAP Kinase Signaling System; Mice; Mice, Transgenic; Motor Activity; Neurons; Neuropeptides; Prefrontal Cortex; Proto-Oncogene Proteins c-akt; RNA, Messenger

Bipolar disorder (BD) is a chronic, prevalent, and highly debilitating psychiatric illness. Folic acid has been shown to have antidepressant-like effects in preclinical and clinical studies and has also been suggested to play a role in BD. The present work investigates the therapeutic value of folic acid supplementation in a preclinical animal model of mania induced by ouabain.. Male Wistar rats were treated twice daily for seven days with folic acid (10, 50, and 100 mg/kg, p.o.) or the mood stabilizer lithium chloride (LiCl) (45 mg/kg, p.o.). One day after the last dose was given, the animals received an i.c.v. injection of ouabain (10 microM), a Na(+),K(+)-ATPase-inhibiting compound. Locomotor activity was assessed in the open-field test. Thiobarbituric acid-reactive substance (TBARS) levels, glutathione peroxidase (GPx), and glutathione reductase (GR) activities were measured in the cerebral cortex and hippocampus.. Ouabain (10 microM, i.c.v.) significantly increased motor activity in the open-field test, and seven days of pretreatment with folic acid (50 mg/kg, p.o.) or LiCl (45 mg/kg, p.o.) completely prevented this effect. Ouabain treatment elicited lipid peroxidation (increased TBARS levels) and reduced GPx activity in the hippocampus. GR activity was decreased in the cerebral cortex and hippocampus. These effects were prevented by pretreatment with folic acid and LiCl.. Our results show that folic acid, similarly to LiCl, produces a clear antimanic action and prevents the neurochemical alterations indicative of oxidative stress in an animal model of mania.

Topics: Animals; Antimanic Agents; Biomarkers; Bipolar Disorder; Disease Models, Animal; Folic Acid; Hippocampus; Injections, Intraventricular; Lithium Chloride; Male; Motor Activity; Ouabain; Oxidative Stress; Rats; Rats, Wistar

Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium Chloride; Male; Middle Aged; Neurotoxicity Syndromes; Psychomotor Performance; Valproic Acid

Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium Chloride

Bipolar disorder is a debilitating psychiatric illness presenting with recurrent mania and depression. The pathophysiology of bipolar disorder is poorly understood, and molecular targets in the treatment of bipolar disorder remain to be identified. Preclinical studies have suggested that glycogen synthase kinase-3 (GSK3) is a potential therapeutic target in bipolar disorder, but evidence of abnormal GSK3 in human bipolar disorder and its response to treatment is still lacking.. This study was conducted in acutely ill type I bipolar disorder subjects who were hospitalized for a manic episode. The protein level and the inhibitory serine phosphorylation of GSK3 in peripheral blood mononuclear cells of bipolar manic and healthy control subjects were compared, and the response of GSK3 to antimanic treatment was evaluated.. The levels of GSK3α and GSK3β in this group of bipolar manic subjects were higher than healthy controls. Symptom improvement during an eight-week antimanic treatment with lithium, valproate, and atypical antipsychotics was accompanied by a significant increase in the inhibitory serine phosphorylation of GSK3, but not the total level of GSK3, whereas concomitant electroconvulsive therapy treatment during a manic episode appeared to dampen the response of GSK3 to pharmacological treatment.. Results of this study suggest that GSK3 can be modified during the treatment of bipolar mania. This finding in human bipolar disorder is in agreement with preclinical data suggesting that inhibition of GSK3 by increasing serine phosphorylation is a response of GSK3 to psychotropics used in bipolar disorder, supporting the notion that GSK3 is a promising molecular target in the pharmacological treatment of bipolar disorder.

Topics: Adult; Aged; Analysis of Variance; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Electroshock; Female; Gene Expression Regulation, Enzymologic; Glycogen Synthase Kinase 3; Humans; Lithium Chloride; Male; Middle Aged; Olanzapine; Retrospective Studies; Serine; Young Adult

Topics: Anticonvulsants; Bipolar Disorder; Humans; Lithium Chloride; Randomized Controlled Trials as Topic; Valproic Acid

Topics: Antimanic Agents; Bipolar Disorder; Diagnostic and Statistical Manual of Mental Disorders; Humans; Lithium Chloride; Randomized Controlled Trials as Topic

Topics: Anticonvulsants; Bipolar Disorder; Drug Therapy, Combination; Humans; Lithium Chloride; Valproic Acid

Topics: Anticonvulsants; Bipolar Disorder; Clinical Trials as Topic; Humans; Lithium Chloride; Testosterone

Considerable biochemical evidence suggests that the protein kinase C (PKC) signaling cascade may be a convergent point for the actions of anti-manic agents, and that excessive PKC activation can disrupt prefrontal cortical regulation of thinking and behavior. To date, however, brain protein targets of PKC's anti-manic effects have not been fully identified. Here we showed that PKC activity was enhanced in the prefrontal cortex of animals treated with the psychostimulant amphetamine. Phosphorylation of MARCKS, a marker of PKC activity, was increased in the prefrontal cortex of animals treated with the psychostimulant amphetamine, as well as in sleep-deprived animals (another animal model of mania), but decreased in lithium-treated animals. The antidepressant imipramine, which shows pro-manic properties in patients with bipolar disorder (BPD), also enhanced phospho-MARCKS in prefrontal cortex in vivo. We further explored the functional targets of PKC in mania-associated behaviors. Neurogranin is a brain-specific, postsynaptically located PKC substrate. PKC phosphorylation of neurogranin was robustly increased by pro-manic manipulations and decreased by anti-manic agents. PKC phosphorylation of the NMDA receptor site GluN1S896 and the AMPA receptor site GluA1T840 was also enhanced in the prefrontal cortex of animals treated with the antidepressant imipramine, as well as in behaviorally sleep-deprived animals, in striking contrast to the reduced activity seen in lithium-treated animals. These results suggest that PKC may play an important role in regulating NMDA and AMPA receptor functions. The biochemical profile of the PKC pathway thus encompasses both pro- and anti-manic effects on behavior. These results suggest that PKC modulators or their intracellular targets may ultimately represent novel avenues for the development of new therapeutics for mood disorders.

Topics: Amphetamine; Animals; Antidepressive Agents, Tricyclic; Bipolar Disorder; Cell Membrane; Central Nervous System Stimulants; Disease Models, Animal; Imipramine; Intracellular Signaling Peptides and Proteins; Lithium Chloride; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Myristoylated Alanine-Rich C Kinase Substrate; Neurogranin; Phosphorylation; Prefrontal Cortex; Protein Kinase C; Rats; Rats, Inbred WKY; Receptors, Glutamate; Sleep Deprivation

Several studies have suggested mitochondrial abnormality in bipolar disorder (BD) and schizophrenia (SZ). We have previously reported the decreased expression of mitochondrial complex I subunit gene, NDUFV2 at 18p11, in lymphoblastoid cell lines (LCLs) from Japanese patients with bipolar I disorder (BDI). Recently it was reported that no differences were found in NDUFV2 mRNA levels in LCLs of Caucasian BDI patients compared with controls. In this study, we tested the altered expression of NDUFV2 in extended Japanese LCLs and LCLs from different ethnic groups. Similar tendency was found in the current study compared with our previous study, since decreased expression of NDUFV2 in LCLs from Japanese patients with BDI was found (p=0.03). We also found that the expressions of NDUFV2 were up-regulated in those from patients with Japanese bipolar II disorder (p=0.001) and the mRNA levels of this gene were down-regulated in Caucasian SZ (p=0.000001) compared with controls. Furthermore, we revealed that the mRNA expression of NDUFV2 in LCLs cultured with valproate, one of mood stabilizers, were significantly increased compared with controls (p=0.02). Our study presented the further evidence of biological significance of NDUFV2 in BD and SZ.

Topics: Adult; Aged; Aged, 80 and over; Antimanic Agents; Bipolar Disorder; Cell Line, Transformed; Female; Gene Expression; Genotype; Humans; Lithium Chloride; Lymphocytes; Male; Middle Aged; NADH Dehydrogenase; RNA, Messenger; Schizophrenia; Statistics, Nonparametric; Up-Regulation; Valproic Acid

Previously, we have found an association between the -48 A/G polymorphism of the dopamine receptor D1 (DRD1) gene and bipolar disorder. The aim of the present study was to investigate a possible association of this polymorphism with the quality of the prophylactic lithium response in bipolar patients.. Ninety-two patients (39 male, 53 female), aged 30-77 (mean: 54 years) were studied. They have received lithium for prophylactic purposes for 5-27 years (mean: 15 years). Twenty-four patients were identified as excellent lithium responders (ER), 48 patients as partial responders (PR), and 20 patients were non-responders (NR). They all were genotyped for -48 A/G polymorphism of the DRD1 gene.. The frequency of G/G genotype in ER, PR, and NR patients was 21%, 48%, and 60%, respectively, and the frequency of G allele was 58%, 76%, and 80%, respectively.. The results obtained suggest that the higher frequency of G allele, and G/G genotype, which has been associated with a predisposition to bipolar illness, is also connected with a poorer prophylactic effect of lithium.

Topics: Adult; Aged; Antimanic Agents; Bipolar Disorder; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Lithium Chloride; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Receptors, Dopamine D1

Lithium (Li) is commonly used in the treatment of bipolar disorder (BD). However, the molecular mechanism of its action is not completely understood. MicroRNAs (miRNAs), a class of small RNA species are recognized as important regulators in post-transcription gene expression. To explore the role of miRNAs in Li's action, we quantitatively analysed the expression patterns of 13 miRNAs in 20 lymphoblastoid cell lines (LCLs) with or without Li treatment in culture. Using paired t statistics in the analysis, we identified significant changes in seven of the 13 miRNAs tested in LCLs sampled at treatment day 4 (p<0.05). Four of the seven significant miRNAs, miR-34a, miR-152, miR-155, and miR-221 consistently changed expression in the same LCLs at a longer treatment time-point, day 16 (Bonferroni p<0.05). Interestingly, miR-221 and miR-34a also changed expression in rat hippocampus in response to Li treatment (Zhou et al. 2008), although in the opposite direction. We focused on the predicted target mRNAs of miR-221 and miR-34a, and identified 29 and ten targets that were strongly and inversely correlated to expression with the two miRNAs, respectively. Our results suggest that miRNAs are excellent candidates for the study of the molecular basis of Li's treatment action in cell systems such as lymphocytes given limited access to the human brain.

Topics: Antimanic Agents; Bipolar Disorder; Case-Control Studies; Cell Line; Gene Expression Regulation; Humans; Lithium Chloride; Lymphocytes; Michigan; MicroRNAs; Reverse Transcriptase Polymerase Chain Reaction; Time Factors

Little is known regarding the relationship between treatment adherence and residual cognitive dysfunction in euthymic bipolar disorder patients. This study aimed to investigate whether poor treatment adherence is associated with cognitive impairment in euthymic bipolar patients and whether other factors may be associated with both adherence and cognitive functioning.. Euthymic DSM-IV bipolar I or II disorder patients (N = 103: 61 with high levels of treatment adherence and 42 with poor treatment adherence) were assessed using a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions and compared with 35 healthy controls of similar age, sex distribution, and education. Data were collected from September 2005 to June 2007.. Bipolar patients with poor treatment adherence had more hospitalizations than those with high adherence. After controlling for age, gender, estimated IQ score, and Young Mania Rating Scale and 17-item Hamilton Rating Scale for Depression scores, non-treatment-adherent patients performed less well than normal controls in verbal learning and some executive functions. Among treatment-adherent and poorly adherent bipolar disorder patients, performance was similar in attention tasks and short-term and long-term verbal recall, but non-treatment-adherent patients were more impaired in ability to inhibit interferences and in spatial working memory. Poorer treatment adherence also was associated with the bipolar I subtype and with greater illness severity, as indicated by number of manic episodes and hospitalizations and history of psychosis. Pharmacologic factors, such as treatment with lithium, may also influence the relationship between neurocognition and adherence.. There is a close relationship between poor treatment adherence and cognitive impairment, but the causal inferences of these findings are uncertain. Poor treatment adherence may worsen the course of bipolar disorder and so indirectly worsen cognitive performance, or cognitive impairment may contribute to poor treatment adherence and reflect more severe illness.

Topics: Adult; Bipolar Disorder; Cognition Disorders; Comorbidity; Diagnostic and Statistical Manual of Mental Disorders; Female; Humans; Lithium Chloride; Male; Memory; Neuropsychological Tests; Patient Compliance; Psychiatric Status Rating Scales; Psychomotor Performance; Severity of Illness Index; Verbal Learning

We assessed performance on the Wisconsin Card Sorting Test (WCST), measuring executive functions, in 30 patients showing different prophylactic effect of lithium (excellent lithium responders-ER, partial responders-PR and non-responders-NR), and in fifty persons of their offspring (12 of ER, 26 of PR, and 12 of NR). Age- and gender head-to-head matched population consisted of 30 subjects for lithium group and 50 subjects for the offspring of lithium patients. In lithium patients, NR had significantly worse results compared to the remaining groups and to control subjects on perseverative errors (WCST-P) and conceptual responses (WCST-%conc). No differences were observed in the offspring of patients with different effect of lithium, however, they showed an impairment on WCST-P and WCST-%conc compared to matched healthy controls. Therefore, the favorable effect of lithium prophylaxis may be associated with a preservation of executive cognitive functions and the offspring of bipolar patients shows an impairment of such functions.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antimanic Agents; Bipolar Disorder; Cognition Disorders; Executive Function; Female; Humans; Lithium Chloride; Longitudinal Studies; Male; Middle Aged; Neuropsychological Tests; Young Adult

Lithium, which is approved for treating patients with bipolar disorder, is reported to inhibit 3'(2')-phosphoadenosine-5'-phosphate (PAP) phosphatase activity. In yeast, deletion of PAP phosphatase results in elevated PAP levels and in inhibition of sulfation and of growth. The effect of lithium on PAP phosphatase is remarkable for the low Ki (approximately 0.2 mM), suggesting that this system would be almost completely shut down in vivo with therapeutic levels of 1 mM lithium, thereby elevating PAP levels. To test the hypothesis that lithium inhibition of PAP phosphatase is pharmacologically relevant to bipolar disorder, we fed rats LiCl for 6 weeks, and assayed brain PAP levels after subjecting the brain to high-energy microwaving. We also measured PAP phosphatase mRNA and protein levels in frozen brain tissue of lithium-treated mice. Brain adenosine phosphates were extracted by trichloroacetic acid and assayed by HPLC with a gradient system of two phases. PAP phosphatase mRNA was measured by RT-PCR, and PAP phosphatase protein was measured by Western blotting. Brain PAP levels were below detection limit of 2 nmol/g wet weight, even following lithium treatment. Lithium treatment also did not significantly change brain PAP phosphatase mRNA or protein levels. These results question the relevance of PAP phosphatase to the therapeutic mechanism of lithium. A statistically significant 25% reduced brain ADP/ATP ratio was found following lithium treatment in line with lithium's suggested neuroprotective effects.

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adenosine Triphosphate; Animals; Antimanic Agents; Bipolar Disorder; Brain; Brain Chemistry; Lithium Chloride; Lithium Compounds; Male; Neuroprotective Agents; Phosphoric Monoester Hydrolases; Rats; Rats, Inbred F344; RNA, Messenger

While an excess of glucocorticoids is associated with hippocampal pathology in mood disorders, lithium exerts robust neuroprotective and neurotrophic effects. Here, 21 stably remitted bipolar I patients who had been on chronic lithium maintenance therapy, on average, for more than a decade, and 19 carefully matched healthy controls were studied using 3 T (1)H-magnetic resonance spectroscopy of left and right hippocampus. Salivary cortisol samples were obtained to assess activity of the hypothalamus-pituitary-adrenal system. Absolute concentrations of N-acetylaspartate (NAA), choline-containing compounds and total creatine were similar in euthymic bipolar patients and healthy controls. Hippocampal glutamate concentrations were significantly increased as an effect of patient status (patients>controls) and laterality (left hippocampus>right hippocampus). Hippocampal glutamate content (Glu) was strongly correlated with NAA. Across groups and within the patient group, diurnal saliva cortisol levels showed a significant inverse relationship with both Glu and NAA. Taken together, these results add to the concept of bipolar disorder as an illness involving disturbed hippocampal structural plasticity under the opposing influences of lithium and glucocorticoids.

Topics: Adult; Aged; Antimanic Agents; Aspartic Acid; Bipolar Disorder; Case-Control Studies; Choline; Circadian Rhythm; Creatine; Female; Glutamic Acid; Hippocampus; Humans; Hydrocortisone; Linear Models; Lithium Chloride; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neuronal Plasticity; Saliva

Topics: Antimanic Agents; Bipolar Disorder; Contrast Media; Depression; Female; Humans; Iodine; Lithium Chloride; Middle Aged; Thyrotoxicosis

Lithium has been successfully employed to treat bipolar disorder for decades, and recently, was shown to attenuate the symptoms of other pathologies such as Alzheimer's disease, Down's syndrome, ischemic processes, and glutamate-mediated excitotoxicity. However, lithium's narrow therapeutic range limits its broader use. Therefore, the development of methods to better predict its dose becomes essential to an ideal therapy.. the performance of adult Wistar rats was evaluated at the open field and elevated plus maze after a six weeks treatment with chow supplemented with 0.255%, or 0.383% of lithium chloride, or normal feed. Thereafter, blood samples were collected to measure the serum lithium concentration.. Animals fed with 0.255% lithium chloride supplemented chow presented a higher rearing frequency at the open field, and higher frequency of arms entrance at the elevated plus maze than animals fed with a 50% higher lithium dose presented. Nevertheless, both groups presented similar lithium plasmatic concentration.. different behaviors induced by both lithium doses suggest that these animals had different lithium distribution in their brains that was not detected by lithium serum measurement.. serum lithium concentration measurements do not seem to provide sufficient precision to support its use as predictive of behaviors.

Topics: Analysis of Variance; Animals; Antimanic Agents; Bipolar Disorder; Brain; Female; Lithium Chloride; Male; Maze Learning; Rats; Rats, Wistar

Recent studies have suggested that oxidative stress and DNA damage may play a role in the pathophysiology of bipolar disorder (BD). We investigated the effects of the mood stabilizers lithium and valproate on amphetamine-induced DNA damage in an animal model of mania and their correlation with oxidative stress markers.. In the first experiment (reversal model), we treated adult male Wistar rats with D-amphetamine (AMPH) or saline for 14 days; between the 8th and 14th days, rats also received lithium, valproate or saline. In the second experiment (prevention model), rats received either lithium, valproate or saline for 14 days; between the 8th and 14th days, we added AMPH or saline. We evaluated DNA damage using single-cell gel electrophoresis (comet assay), and we assessed the mutagenic potential using the micronucleus test. We assessed oxidative stress levels by lipid peroxidation levels (TBARS) and antioxidant enzyme activities (superoxide dismutase and catalase). We assessed DNA damage and oxidative stress markers in blood/plasma and hippocampal samples. We evaluated mutagenesis in fresh lymphocytes.. In both models, we found that AMPH increased peripheral and hippocampal DNA damage. The index of DNA damage correlated positively with lipid peroxidation, whereas lithium and valproate were able to modulate the oxidative balance and prevent recent damage to the DNA. However, lithium and valproate were not able to prevent micronucleus formation.. Our results support the notion that lithium and valproate exert central and peripheral antioxidant-like properties. In addition, the protection to the integrity of DNA conferred by lithium seems to be limited to transient DNA damage and does not alter micronuclei formation.

Topics: Amphetamine; Animals; Antimanic Agents; Antioxidants; Bipolar Disorder; Central Nervous System Stimulants; Comet Assay; DNA Damage; Hippocampus; Lipid Peroxidation; Lithium Chloride; Male; Micronucleus Tests; Motor Activity; Oxidative Stress; Rats; Rats, Wistar; Valproic Acid

To report on a patient with Hashimoto's encephalopathy induced by lithium. PATIENT AND INTERVENTIONS: A 61-year-old woman with a type II bipolar disorder and a history of lithium-induced thyrotoxicosis associated with silent thyroiditis was hospitalized to treat a severe major depressive episode. Given long-term treatment with levothyroxine for hypothyroidism that had resulted from silent thyroiditis, endogenous hormone in thyroid follicles was assumed to be minimized by the negative feedback, decreasing risk of recurrent thyrotoxicosis if lithium were restarted.. Lithium clearly relieved the patient's depressive symptoms, but after 40 days encephalopathy developed. Thyrotoxicosis was ruled out, and serum antithyroid antibody titers were elevated. In the cerebrospinal fluid, protein content was substantially elevated and antithyroid antibodies were detected. Encephalopathy resolved dramatically after course of intravenous pulse therapy with methylprednisolone.. We believe that autoantibodies against antigens shared by the thyroid gland and the brain were induced by exposure to lithium, causing the patient to develop Hashimoto's encephalopathy.

Topics: Antimanic Agents; Bipolar Disorder; Female; Hashimoto Disease; Humans; Lithium Chloride; Middle Aged

Topics: Adolescent; Antimanic Agents; Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Female; Hepatolenticular Degeneration; Humans; Lithium Chloride; Male; Olanzapine; Psychiatric Status Rating Scales; Young Adult

Emerging data suggests that omega-3 fatty acid deficiency may be a risk factor for bipolar disorder. In the present study, we determined the effects of chronic dietary-induced omega-3 fatty acid deficiency and/or concomitant chronic lithium chloride (LiCl) treatment on amphetamine (AMPH)-induced behavioral sensitization, a phenomenon that may recruit neuroplastic mechanisms relevant to the pathophysiology of bipolar disorder.. Adult male C57BL/6J mice were randomly assigned to one four diets: Control (alpha-linolenic-fortified), Control+LiCl (0.255%), alpha-linolenic-Deficient, or Deficient+LiCl (0.255%), and behavioral testing initiated 65 days later. Locomotor activity was determined following 3 intermittent (separated by 7d) injections of amphetamine (AMPH) (1mg/kg). After behavioral testing, red blood cell (RBC) and regional brain (prefrontal cortex, hippocampus, ventral striatum) fatty acid composition was determined by gas chromatography.. Each diet group exhibited comparable locomotor activity following acute AMPH treatment. However, the development of sensitization following repeated AMPH treatment was significantly augmented in Deficient mice relative to controls, and this augmented response was prevented by chronic LiCl treatment. Relative to controls, Deficient mice exhibited deficits in RBC and regional brain docosahexaenoic acid (DHA, 22:6n-3) composition, reciprocal elevations in vaccenic acid (18:1n-7), arachidonic acid (AA, 20:4n-6), and docosapentaenoic acid (DPA, 22:5n-6) compositions, and elevations in AA:DHA, oleic acid:DHA, and DPA:DHA ratios. The fatty acid abnormalities in Deficient mice were not altered by concurrent chronic lithium treatment. Mice fed the Control+LiCl diet exhibited a significant increase in AA composition in RBC and all brain regions, and an elevated AA:DHA ratio in the prefrontal cortex and hippocampus, relative to Controls. Fatty acid composition in RBC and different brain regions were predominantly positively correlated. Within the ventral striatum, DHA composition was inversely correlated, and AA:DHA and oleic acid:DHA ratios positively correlated, with total distance traveled following the final AMPH treatment.. These data indicate that alterations in fatty acid composition resulting from dietary-induced omega-3 fatty acid deficiency augment the development of AMPH-induced behavioral sensitization in a manner that is prevented by chronic lithium treatment. The implications of these findings for understanding the contribution of omega-3 fatty acid deficiency to the pathophysiology and progression of bipolar disorder are discussed.

Topics: Amphetamine; Animals; Antimanic Agents; Bipolar Disorder; Central Nervous System Stimulants; Disease Models, Animal; Drug Administration Schedule; Drug Hypersensitivity; Fatty Acid Desaturases; Hippocampus; Hypothalamus; Lithium Chloride; Locomotion; Male; Mice; Mice, Inbred C57BL; Random Allocation

Bipolar spectrum disorders are severe chronic mood disorders that are characterized by episodes of mania or hypomania and depression. Because patients with manic symptoms often experience clinical benefit from treatment with anticonvulsant drugs, it was hypothesized that retigabine, a novel compound with anticonvulsant efficacy, may also possess antimanic activity. The amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity model has been proposed as a suitable model for studying antimanic-like activity of novel compounds in mice and rats. The aims of the present study in rats were therefore (1) to confirm previous findings with lithium and lamotrigine, and (2) to evaluate the effect of the novel compound retigabine on AMPH+CDP-induced hyperactivity in rats. In all experiments, co-administration of AMPH and CDP induced a significant increase (191-295%) in locomotor activity. Lithium chloride (0.9 mg/kg) and lamotrigine (20 mg/kg), which are known to effectively stabilize mood in humans, both significantly decreased AMPH+CDP-induced locomotor activity without affecting basal locomotor activity. The results furthermore indicate that retigabine, like lithium and lamotrigine, significantly and dose-dependently attenuates the induced hyperactivity at a lowest effective dose of 1.0 mg/kg, whereas basal locomotor activity is reduced only at doses 4.0 mg/kg. In conclusion, retigabine was found to have an antimanic-like effect in the AMPH+CDP-induced hyperactivity model, suggesting a potential role for retigabine in the treatment of mania and possibly in the management of bipolar disorder.

Topics: Amphetamine; Animals; Anticonvulsants; Behavior, Animal; Bipolar Disorder; Carbamates; Chlordiazepoxide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Lamotrigine; Lithium Chloride; Male; Motor Activity; Phenylenediamines; Rats; Rats, Wistar; Triazines

Many bipolar affective disorder (BD) susceptibility loci have been identified but the molecular mechanisms responsible for the disease remain to be elucidated. In the locus 4p16, several candidate genes were identified but none of them was definitively shown to be associated with BD. In this region, the PPP2R2C gene encodes the Bgamma-regulatory subunit of the protein phosphatase 2A (PP2A-Bgamma). First, we identified, in two different populations, single nucleotide polymorphisms and risk haplotypes for this gene that are associated to BD. Then, we used the Bgamma subunit as bait to screen a human brain cDNA library with the yeast two-hybrid technique. This led us to two new splice variants of KCNQ2 channels and to the KCNQ2 channel itself. This unusual K+ channel has particularly interesting functional properties and belongs to a channel family that is already known to be implicated in several other monogenic diseases. In one of the BD populations, we also found a genetic association between the KCNQ2 gene and BD. We show that KCNQ2 splice variants differ from native channels by their shortened C-terminal sequences and are unique as they are active and exert a dominant-negative effect on KCNQ2 wild-type (wt) channel activity. We also show that the PP2A-Bgamma subunit significantly increases the current generated by KCNQ2wt, a channel normally inhibited by phosphorylation. The kinase glycogen synthase kinase 3 beta (GSK3beta) is considered as an interesting target of lithium, the classical drug used in BD. GSK3beta phosphorylates the KCNQ2 channel and this phosphorylation is decreased by Li+.

Topics: Animals; Antimanic Agents; Argentina; Bipolar Disorder; Case-Control Studies; Chlorocebus aethiops; COS Cells; Enzyme Inhibitors; Gene Frequency; Genetic Predisposition to Disease; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Haplotypes; Humans; KCNQ2 Potassium Channel; Linkage Disequilibrium; Lithium Chloride; Membrane Potentials; Odds Ratio; Phosphoprotein Phosphatases; Phosphorylation; Polymorphism, Single Nucleotide; Protein Isoforms; Protein Phosphatase 2; Risk Assessment; Risk Factors; Thalamus; Transfection; United Kingdom

Bipolar disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3beta (GSK3beta). The mood stabilizer lithium inhibits GSK3beta in vitro and in mouse brain, and this is currently the strongest known potential therapeutic target of lithium. We tested whether lithium modified GSK3beta in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects.. The PBMCs were obtained from 23 healthy control subjects, 9 bipolar subjects currently treated with lithium, and 13 lithium-free bipolar subjects. Immunoblot analyses were used to measure the inhibited, serine9-phosphorylated GSK3beta.. The level of phospho-Ser9-GSK3beta in PBMCs was regulated by agents that modified kinases and phosphatases acting on GSK3beta and was increased by in vitro lithium treatment. More important, phospho-Ser9-GSK3beta levels were eightfold higher in PBMCs from lithium-treated bipolar than healthy control subjects.. Signaling pathways regulating serine9-phosphorylation of GSK3beta can be studied in human PBMCs. Both in vitro and in vivo therapeutic lithium treatment is associated with a large increase in phospho-Ser9-GSK3beta in PBMCs. Therefore, the inhibitory serine9-phosphorylation of GSK3beta in human PBMCs may provide a biochemical marker to evaluate the association between GSK3beta inhibition and therapeutic responses to lithium treatment.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Brain; Cytoskeletal Proteins; Female; Humans; In Vitro Techniques; Lithium Chloride; Male; Middle Aged; Monocytes; Neuronal Plasticity; Nuclear Proteins; Phosphorylation; Phosphoserine; Signal Transduction

Lithium is an effective mood stabilizer for bipolar disorder patients and its therapeutic effect may involve inhibition of inositol monophosphatase activity. In humans, the enzyme is encoded by two genes, IMPA1 and IMPA2. IMPA2 maps to 18p11.2, a genomic interval for which evidence of linkage to bipolar disorder has been supported by several reports. We performed a genetic association study in Japanese cohorts (496 patients with bipolar disorder and 543 control subjects). Interestingly, we observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder, the identical SNPs reported previously in a different population. In vitro promoter assay and genetic haplotype analysis showed that the combination of (-461C)-(-207T)-(-185A) drove enhanced transcription and the haplotypes containing (-461C)-(-207T)-(-185A) contributed to risk for bipolar disorder. Expression study on post-mortem brains revealed increased transcription from the IMPA2 allele that harbored (-461C)-(-207T)-(-185A) in the frontal cortex of bipolar disorder patients. The examination of allele-specific expressions in post-mortem brains did not support genomic imprinting of IMPA2, which was suggested nearby genomic locus. Contrasting to a prior report, therapeutic concentrations of lithium could not suppress the transcription of IMPA2 mRNA, and the mood-stabilizing effect of lithium is, if IMPA2 was one of the targets of lithium, deemed to be generated via inhibition of enzymatic reaction rather than transcriptional suppression. In conclusion, the present study suggests that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA2 levels in the brain, albeit the genetic effect varies among populations.

Topics: Adult; Bipolar Disorder; Cell Line, Tumor; Cells, Cultured; Chromosomes, Human, Pair 18; Female; Gene Expression Regulation; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Lithium Chloride; Male; Middle Aged; Neuroblastoma; Phosphoric Monoester Hydrolases; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Risk; Transcription, Genetic; Transfection

Topics: Adult; Antimanic Agents; Bipolar Disorder; Female; Humans; Lithium; Lithium Chloride; Metrorrhagia

Topics: Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Antimanic Agents; Bipolar Disorder; Female; Humans; Lithium Chloride; Middle Aged; Tetrazoles; Valine; Valsartan

Some studies suggest that mitochondrial dysfunction may be related to the pathophysiology of bipolar disorder. In this work, we evaluated the activity of citrate synthase in rats, and the effects of the treatment with mood stabilizers (lithium and valproate) on the enzyme activity. In the first experiment (reversal treatment), amphetamine or saline were administered to rats for 14 days, and between day 8 and 14, rats were treated with either lithium, valproate or saline. In the second experiment (prevention treatment), rats were pretreated with lithium, valproate or saline, and between day 8 and 14, rats were administered amphetamine or saline. In reversal and prevention models, amphetamine administration significantly inhibited citrate synthase activity in rat hippocampus. In amphetamine-pretreated animals, valproate administration reversed citrate synthase activity inhibition induced by amphetamine. In the prevention model, pretreatment with lithium prevented amphetamine-induced citrate synthase inhibition. Our results showed that amphetamine inhibited citrate synthase activity and that valproate reversed and lithium prevented the enzyme inhibition.

Topics: Amphetamine; Analysis of Variance; Animals; Antimanic Agents; Bipolar Disorder; Citrate (si)-Synthase; Disease Models, Animal; Drug Interactions; Hippocampus; Lithium Chloride; Male; Rats; Rats, Wistar; Valproic Acid

Patients with bipolar disorder have been reported to have neurocognitive deficits; however, it is not known whether the cognitive dysfunctions are state-dependent or a stable trait. Lithium and valproate, 2 of the most widely used mood stabilizers in the treatment of bipolar disorder, have also been associated with cognitive impairment. However, the degree and pattern of neurocognitive impairment in euthymic bipolar patients on either monotherapy with lithium or valproate have not been compared before in depth.. We compared 17 euthymic outpatients with bipolar disorder (BD) on lithium monotherapy to 11 euthymic outpatients with BD on valproate monotherapy and 29 comparison subjects using tests measuring immediate verbal memory and executive functions in addition to 3 subtests of the Wechsler Adult Intelligence Scale Revised. The groups were similar in terms of level of education, duration and severity of illness, and gender distribution. Patients on lithium monotherapy were older than patients on valproate and healthy controls. Mood symptoms as assessed by standardized scales were mild to non-existent in both patient groups.. Immediate verbal memory was impaired in both patient groups compared to controls, where the main effect of age was not significant. No significant differences could be found on the other cognitive measures.. Both lithium and valproate may be associated with immediate verbal memory impairment, sparing other cognitive functions. Presence of a similar verbal memory deficit in the lithium and valproate groups suggests that this deficit might be intrinsic to BD or that the 2 medications influence immediate verbal memory similarly. Larger samples of remitted bipolar patients on monotherapy should be studied for more precise conclusions.

Topics: Adolescent; Adult; Antimanic Agents; Bipolar Disorder; Cognition Disorders; Diagnostic and Statistical Manual of Mental Disorders; Evaluation Studies as Topic; Female; Humans; Intelligence Tests; Lithium Chloride; Male; Memory; Middle Aged; Multivariate Analysis; Neuropsychological Tests; Problem Solving; Valproic Acid; Verbal Learning

To study the ex vivo interleukin (IL)-1beta and IL-6 production of monocytes in bipolar disorder (BD) patients in the absence/presence of lithium.. Monocytes of outpatients with DSM-IV BD (n=80, of whom 64 were lithium-treated) and of healthy control subjects (n=59) were cultured in vitro and exposed (24 h) or not exposed to lipopolysaccharide (LPS) and/or graded concentrations of lithium chloride (LiCl). IL-1beta and IL-6 production was assessed by enzyme-linked immunosorbent assay (ELISA) (supernatants).. Monocytes stimulated by LPS from non-lithium-treated bipolar patients were characterized by an abnormal IL-1beta/IL-6 production ratio, i.e., low IL-1beta and high IL-6 production. Lithium treatment increased IL-1beta and decreased IL-6 production and thus restored the aberrant ratio. In vitro exposure of monocytes to LiCl did not have the same effects as lithium treatment: the procedure decreased IL-1beta production and had minimal effects on IL-6 production.. Blood monocytes have an altered proinflammatory status in BD. Lithium treatment restores this altered status. Short-term in vitro exposure of monocytes to lithium has other effects than lithium treatment.

Topics: Adult; Ambulatory Care; Bipolar Disorder; Cells, Cultured; Diagnostic and Statistical Manual of Mental Disorders; Enzyme-Linked Immunosorbent Assay; Female; Humans; In Vitro Techniques; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lithium Chloride; Lithium Compounds; Male; Middle Aged; Monocytes; Psychiatric Status Rating Scales; Psychotropic Drugs

Dendritic cells (DC) are key regulators of the immune system, which is compromised in patients with bipolar disorder. We sought to study monocyte-derived DC in bipolar disorder.. Monocytes purified from blood collected from DSM-IV bipolar disorder outpatients (n = 53, 12 without lithium treatment) and healthy individuals (n = 34) were differentiated into DC via standard granulocyte-macrophpage colony-stimulating factor/interleukin-4 culture (with/without 1, 5, and 10 mmol/L lithium chloride). The DC were analyzed for DC-specific and functional markers and for T-cell stimulatory potency.. Monocytes of bipolar patients showed a mild hampering in their differentiation into fully active DC, showing a weak residual expression of the monocyte marker CD14 and a relatively low potency to stimulate autologous T cells. Lithium treatment abolished this mild defect, and monocyte-derived DC of treated bipolar patients showed signs of activation (i.e., an up-regulated potency to stimulate autologous T cells and a higher expression of the DC-specific marker CD1a). This activated phenotype contrasted with the suppressed phenotype of monocyte-derived DC exposed to lithium in vitro (10 mmol/L) during culture.. Dendritic cells show mild aberrancies in bipolar disorder that are fully restored to even activation after in vivo lithium treatment.

Topics: Adult; Antigens, CD; Antigens, CD1; Antimanic Agents; Autoantibodies; Bipolar Disorder; CD83 Antigen; Cell Differentiation; Cell Lineage; Coculture Techniques; Dendritic Cells; Female; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunoglobulins; Interleukin-4; Lithium Chloride; Male; Membrane Glycoproteins; Middle Aged; Monocytes; T-Lymphocytes

Phosphoglucomutase catalyses the reversible conversion of glucose-6-P and glucose-1-P. Lithium is a potent inhibitor of phosphoglucomutase in vitro, however, it is not known if phosphoglucomutase was significantly inhibited by Li+ in Li+-treated bipolar patients. Here, we demonstrate that phosphoglucomutase inhibition by chronic Li+ treatment causes alterations of glucose-phosphate levels in various tissues of rats. Also, phosphoglucomutase inhibition results in compensatory elevation of phosphoglucomutase activity in rat tissues and in leukocytes isolated from Li+-treated bipolar patients. The increase of uninhibited phosphoglucomutase activity in leukocytes of Li+-treated bipolar patients is due to the increased expression of the PGM1 gene.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Brain; Calcium; Glucose-6-Phosphate; Glucosephosphates; Humans; Leukocytes; Lithium Chloride; Liver; Magnesium; Male; Muscle, Skeletal; Myocardium; Phosphoglucomutase; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Antidepressive Agents; Antimanic Agents; Bipolar Disorder; Humans; Lithium Carbonate; Lithium Chloride; Suicide; Suicide, Attempted

To evaluate the effectiveness of lithium augmentation of topiramate on mood symptoms, binge eating behavior, and body weight in obese bipolar patients with binge eating disorder (BED) seeking weight management.. We conducted a naturalistic study of 12 consecutive outpatients with bipolar disorders, BED, and obesity who received lithium augmentation for mood instability during the course of topiramate-based pharmacotherapy for obesity and BED. Lithium was added to topiramate (mean dose 514 mg i.d.) and titrated to a mean dose of 1009 mg i.d. (mean plasma concentration 0.7 mmol/L). Treatment response was assessed by comparing changes in clinical severity scales for mood and eating disorders, weekly binge eating frequency, and weight for the 2 months before and the first 2 months during lithium treatment.. A statistically significant improvement in global severity of mood symptoms was observed after as compared to before lithium augmentation. Statistically insignificant reductions in weight and in binge frequency and severity were also observed after lithium addition.. Optimal weight loss treatment in obese patients with comorbid bipolar and BEDs may require stabilization of mood. The combination of lithium and topiramate may have a role in the management of this difficult-to-treat population.

Topics: Adult; Anti-Obesity Agents; Antimanic Agents; Bipolar Disorder; Body Mass Index; Body Weight; Bulimia Nervosa; Comorbidity; Drug Interactions; Female; Follow-Up Studies; Fructose; Humans; Lithium Chloride; Male; Middle Aged; Obesity; Severity of Illness Index; Statistics, Nonparametric; Surveys and Questionnaires; Topiramate

Lithium inhibits inositol monophosphatase at therapeutically effective concentrations, and it has been hypothesized that depletion of brain inositol levels is an important chemical alteration for lithium's therapeutic efficacy in bipolar disorder. We have employed adult rat cortical slices as a model to investigate the gene regulatory consequences of inositol depletion effected by lithium using cytidine diphosphoryl-diacylglycerol as a functionally relevant biochemical marker to define treatment conditions. Genes coding for the neuropeptide hormone pituitary adenylate cyclase activating polypeptide (PACAP) and the enzyme that processes PACAP's precursor to the mature form, peptidylglycine alpha-amidating monooxygenase, were upregulated by inositol depletion. Previous work has shown that PACAP can increase tyrosine hydroxylase (TH) activity and dopamine release, and we found that the gene for GTP cyclohydrolase, which effectively regulates TH through synthesis of tetrahydrobiopterin, was also upregulated by inositol depletion. We propose that modulation of brain PACAP signaling might represent a new opportunity in the treatment of bipolar disorder.

Topics: Animals; Antimanic Agents; Biomarkers; Biopterins; Bipolar Disorder; Cerebral Cortex; Cytidine Diphosphate Diglycerides; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation; GTP Cyclohydrolase; Inositol; Lithium Chloride; Male; Mixed Function Oxygenases; Multienzyme Complexes; Nerve Growth Factors; Neuropeptides; Neurotransmitter Agents; Oligonucleotide Array Sequence Analysis; Organ Culture Techniques; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Rats, Sprague-Dawley; Tyrosine 3-Monooxygenase; Up-Regulation

Topics: Abortion, Eugenic; Adult; Anencephaly; Antimanic Agents; Bipolar Disorder; Female; Humans; Lithium Chloride; Pregnancy; Pregnancy Trimester, First; Treatment Refusal; Ultrasonography, Prenatal

Although the existence of mood disorders was identified centuries ago, the present state of knowledge is unsatisfactory. This special issue of Archives of Suicide Research (ASR), the official journal of the International Academy for Suicide Research, presents the state of the science and collects new empirical data. Different aspects of suicidality in bipolar and bipolar spectrum disorders are outlined and the prophylactic aspects of pharmacotherapy are noted, especially the anti-suicide effect of lithium. A call for further study is, however, necessary.

Topics: Antimanic Agents; Bipolar Disorder; Humans; Lithium Chloride; Risk Factors; Suicide

Topics: Antipsychotic Agents; Bipolar Disorder; Female; Humans; Interleukin-1; Interleukin-6; Lithium Chloride; Male; Middle Aged; Psoriasis; Tumor Necrosis Factor-alpha

This case report describes a patient who developed a seizure with single-pulse transcranial magnetic stimulation during motor threshold estimation. The patient had no history of seizures in the past and no gross neurologic deficits. The only possible seizure-provoking factors were modest doses of lithium and chlorpromazine, which the patient was on, and family history of seizure in a brother. This report aims to highlight the fact that single-pulse transcranial magnetic stimulation may provoke a seizure even in the absence of gross neurologic abnormality.

Topics: Adult; Bipolar Disorder; Chlorpromazine; Electromagnetic Fields; Humans; Lithium Chloride; Male; Seizures

The characteristic ECG pattern of ST-segment elevation in V1 and V2 in the Brugada syndrome is dynamic; it is often intermittently present in affected individuals and can be unmasked by sodium channel blockers, including antiarrhythmic drugs and tricyclic antidepressants. We report here 2 patients who developed the Brugada ECG pattern after administration of lithium, a commonly used drug not previously reported to block cardiac sodium channels.. Lithium induced transient ST-segment elevation (type 1 Brugada pattern) in right precordial leads at therapeutic concentrations in 2 patients with bipolar disorder. Lithium withdrawal in the patients resulted in reversion to type 2 or 3 Brugada patterns or resolution of ST-T abnormalities. In Chinese hamster ovary cells transfected with SCN5A, which encodes the cardiac sodium channel, lithium chloride caused concentration-dependent block of peak INa at levels well below the therapeutic range (IC50 of 6.8+/-0.4 micromol/L).. The widely used drug lithium is a potent blocker of cardiac sodium channels and may unmask patients with the Brugada syndrome.

Topics: Adult; Aged; Animals; Antimanic Agents; Bipolar Disorder; Bundle-Branch Block; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Electrophysiology; Female; Humans; Ion Channel Gating; Lithium Chloride; Male; Muscle Proteins; NAV1.5 Voltage-Gated Sodium Channel; Ovary; Patch-Clamp Techniques; Sodium Channels; Transfection

Topics: Antimanic Agents; Bipolar Disorder; Carbamazepine; Confounding Factors, Epidemiologic; Female; Humans; Length of Stay; Lithium Chloride; Male; Middle Aged; Severity of Illness Index; Time Factors

Our knowledge concerning immune functioning in bipolar affective disorder (BAD) is limited, while lithium's immunomodulatory effects seem multiple and conflicting. Our aim was to evaluate cytokine production and lithium's effect on it in BAD patients, using ELISPOT technique as a sensitive tool.. Cytokine (IL-2, IL-6, IL-10 and IFN-gamma) production from isolated peripheral blood lymphocytes (PBLs) was evaluated (ELISPOT technique) in 40 euthymic BAD patients under chronic lithium treatment, in 20 healthy volunteers, and in 10 never medicated BAD patients before and after the introduction of lithium therapy. In all cases, cytokine plasma levels were also measured using ELISA.. BAD patients under chronic lithium treatment had significantly lower numbers of IL-2, IL-6, IL-10 and IFN-gamma secreting cells compared to healthy volunteers. The number of cytokine secreting cells decreased in never medicated patients after 3 months of lithium treatment. In vitro stimulation of PBLs with lithium did not affect the number of cytokine secreting cells either in the patients or in the healthy volunteers.. The significantly lower number of PBLs producing cytokines (IL-2, IL-6, IL-10 and IFN-gamma) in euthymic BAD patients under chronic lithium treatment result from the long-term (over 3 months) lithium administration. In vitro stimulation of PBLs with lithium did not change the number of cytokine producing cells. Our findings may be useful in elucidating possible downregulatory effects of lithium in humans.

Topics: Adult; Anticonvulsants; Antimanic Agents; Bipolar Disorder; Carbamazepine; Cytokines; Down-Regulation; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Lithium Chloride; Long-Term Care; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Recurrence; Valproic Acid

Lithium's neurotrophic effects have been reported in several in vitro and ex vivo studies. Preliminary human studies with magnetic resonance imaging (MRI) and spectroscopy have recently provided evidence of lithium-induced increases in gray matter volumes and N-acetyl-aspartate levels. In order to further examine the hypothesis that lithium treatment would relate to detectable increases in gray matter brain content, we blindly measured gray and white matter volumes in MRI images of 12 untreated and 17 lithium-treated bipolar patients and 46 healthy controls. Using multivariate analysis of covariance with age and gender as covariates, we found that total gray matter volumes were significantly increased in lithium-treated (747.9 +/- 69.8 cm(3)) compared with untreated patients (639.2 +/- 91.2 cm(3); F = 10.6; d.f. = 1, 25; P = 0.003) and healthy individuals (675.8 +/- 61.8 cm(3); F = 17.4; d.f. = 1, 59; P < 0.001), suggesting in vivo effects of lithium on gray matter, which could possibly reflect lithium's neurotrophic effects.

Topics: Analysis of Variance; Bipolar Disorder; Brain; Chi-Square Distribution; Cross-Sectional Studies; Female; Humans; Lithium Chloride; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Statistics, Nonparametric

The present paper describes a case of serotonin syndrome (SS), which developed in a patient with bipolar affective disorder after the addition of olanzapine to her regimen of lithium and citalopram. This appears to be the first report that implicates olanzapine with SS. Clinicians should be aware of the risk of SS when adding atypical antipsychotics, such as olanzapine, to serotonergic agents.

Topics: Antipsychotic Agents; Benzodiazepines; Bipolar Disorder; Citalopram; Female; Humans; Lithium Chloride; Middle Aged; Olanzapine; Pirenzepine; Risk Factors; Selective Serotonin Reuptake Inhibitors; Serotonin Syndrome

The relationship between electroencephalogram (EEG) finding and lithium response was retrospectively examined in 58 patients with bipolar disorder. All necessary information was obtained from the clinical charts. The patients were categorized into two groups (responder or nonresponder) with regard to the lithium response and into three groups (normal, borderline, or abnormal) concerning the EEG finding. The information both on EEG and lithium response could be obtained from 27 patients. Only five cases were classified as lithium responders. None of these five responders had abnormal EEG finding, while all of five patients with abnormal EEG finding were categorized into nonresponder. No statistically significant interaction was detected between EEG finding and lithium response. This retrospective study suggests that epileptiform EEG abnormality is worth studying further as a possible predictor of lithium resistance in bipolar disorder.

Topics: Bipolar Disorder; Chi-Square Distribution; Drug Resistance; Electroencephalography; Female; Humans; Lithium Chloride; Male; Retrospective Studies

To study the effectiveness of adding lamotrigine to the treatment of inpatient geriatric patients with bipolar disorder (BD) who were in the depressed phase and had been on lithium and valproate for at least 3 months.. Lamotrigine was started at 25 mg given at bedtime, with weekly incremental increases of 12.5 mg daily until a total dosage of either 75 mg or 100 mg was obtained. Improvement was measured by clinical interview and Hamilton Depression Rating Scale (HDRS) scores. Patients were reassessed at 6 weeks, and if their HDRS score had decreased by at least 50%, they were considered to have improved.. The study group comprised 5 women with an average age of 71.5 years (range 65 to 85). Four had rapid-cycling BD, and 1 had mixed BD. All patients had early age of onset, as judged by their first contact with a psychiatrist or their first hospitalization. The average initial HDRS score was 27 (range 20 to 35). Of the patients, 3 out of the 5 had remission of symptoms, as judged by clinical interview and reduction of their HDRS score by 50%. At 3 months follow-up, these 3 patients had not required rehospitalization and were doing well. Lamotrigine was well tolerated, and none of the patients developed a rash. One patient did develop coarse hand tremor that improved when the lamotrigine dosage was decreased.. Lamotrigine in conjunction with lithium and valproate may be effective in treating geriatric patients with BD and depression.

Topics: Aged; Aged, 80 and over; Antimanic Agents; Bipolar Disorder; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Lamotrigine; Lithium Chloride; Male; Triazines; Valproic Acid

Topics: Adult; Anticonvulsants; Antimanic Agents; Bipolar Disorder; Drug Interactions; Female; Fructose; Humans; Lithium Chloride; Topiramate

The eukaryotic initiation factor-2B (eIF-2B) can regulate translation and protein synthesis. We used Western blot analysis to quantify the protein level of the catalytic epsilon (epsilon) subunit of eIF-2B in brains of rats fed lithium chloride (LiCl) for 6 weeks so as to produce a brain lithium concentration that is therapeutically effective in bipolar disorder. The ratio of eIF-2B (epsilon) to actin protein was significantly reduced (P<0.01) in LiCl-fed rats, 0.86+/-0.06 (SE) compared to 1.2+/-0.07 in control rats. These results suggest that a therapeutic level of lithium may downregulate the synthesis of proteins whose translation depends on eIF-2B.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Brain; Brain Chemistry; Eukaryotic Initiation Factor-2B; Lithium Chloride; Male; Protein Biosynthesis; Rats; Rats, Inbred F344

To determine whether genetic differences could contribute to the pharmacological sensitivity of lithium chloride (LiCl) to reverse amphetamine-associated changes in behavior C57BL/6nCrlBR and C3H/HenCrlBR male mice were tested for the ability of an acute dose of LiCl to reverse the locomotor enhancing effects of an acute dose of amphetamine. A series of experiments were conducted that compared dose response of LiCl, chamber lighting conditions, and chamber shape on amphetamine-induced activity in two strains of mice with different genetic backgrounds. Acute amphetamine (3 mg/kg) increased locomotor activity in C57BL/6nCrlBR mice and LiCl (1-4 mEq/kg) blocked this effect. LiCl-induced changes in baseline activity seen at high doses of LiCl were not seen for the low doses. The dark condition reduced time resting but chamber shape did not appear to alter results. In C3H/HenCrlBR mice, amphetamine did not significantly increase levels of activity but did decrease rearing behavior which suggests that genetic difference between C57BL/6nCrlBR and C3H/HenCrlBR mice may contribute to sensitivity to amphetamine. In sum, the ability of LiCl to reverse amphetamine-induced changes in locomotor activity in C57BL/6nCrlBR mice may provide a useful model to study genetic and pharmacological aspects of psychiatric illnesses such as bipolar disorder.

Topics: Amphetamines; Analysis of Variance; Animals; Antimanic Agents; Bipolar Disorder; Central Nervous System Stimulants; Disease Models, Animal; Drug Evaluation; Lithium Chloride; Male; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Motor Activity

The aim of this study was to give further support to the available evidence that mood stabilizers can reduce the risk of antidepressant-induced maniform switch phenomena in bipolar I depressed patients.. Medical records of 158 patients with bipolar I depression were analysed for the incidence of switch phenomena from depression to maniform states (mania and hypomania). The impact of mood stabilizers on reducing the risk of switching was analyzed using logistic regression analyses.. Maniform switches during inpatient treatment were observed in 39 (25%) patients out of the total of 158 patients. Results indicate that especially patients receiving tricyclic antidepressants are at risk of switching to maniform states. This risk was shown to be significantly less when patients also received a mood stabilising medication (lithium, carbamazepine or valproic acid).. This was a retrospective study with patients receiving naturalistic treatment. A prospective, double-blind design would probably lead to more conclusive findings.. Treatment with mood stabilizers may be a potent strategy to reduce the risk of antidepressant-induced maniform switches in bipolar I depressed patients.

Topics: Adult; Aged; Antidepressive Agents, Tricyclic; Antimanic Agents; Bipolar Disorder; Carbamazepine; Depressive Disorder; Female; Humans; Lithium Chloride; Male; Middle Aged; Retrospective Studies; Risk Factors; Treatment Outcome; Valproic Acid

A series of studies from independent laboratories have found increased levels of G(s)alpha in bipolar disorder in postmortem brain and peripheral blood cells. Long-term lithium administration blunts G-protein coupled cAMP signaling and may regulate G(s)alpha levels.. We measured G(s)alpha in transformed lymphoblasts obtained from subjects with bipolar disorder and compared the findings with 23 age- and sex-matched controls. To reduce patient heterogeneity, we included only patients with an excellent response to lithium prophylaxis.. We found no differences in G(s)alpha protein levels measured with immunoblotting. G(s)alpha levels did not correlate with age, age of onset or duration of lithium therapy.. This study made use of transformed lymphoblasts, which may not fully represent changes that occur in regionalized brain tissue. Furthermore, the transformed lymphoblasts used in this study were acquired from a select group of bipolar disorder subjects that responded to lithium treatment. Lastly, consideration has to be given to the small sample size of the study.. These results are consistent with recent observations suggesting that mood state and treatment effects may account at least in part for increased G(s)alpha levels in bipolar disorder.. This study suggests a need to further characterize biological phenotypes in subjects with mood disorders to enhance genetic studies.

Topics: Adult; Aged; Antimanic Agents; Bipolar Disorder; Cyclic AMP; Female; Heterotrimeric GTP-Binding Proteins; Humans; Lithium Chloride; Lymphocyte Activation; Male; Middle Aged; Phenotype; Signal Transduction

Inositol uptake was measured at concentrations of 25, 40 and 50 microM in human astrocytoma cell cultures treated for 1-3 weeks with pharmacologically relevant concentrations of LiCl, valproic acid or carbamazepine as well as in control cultures that had not been treated with any drug. After at least 2 weeks of treatment, each of these 3 conventional anti-bipolar drugs increased the uptake significantly at 25 microM inositol, had no effect at 40 microM, and decreased it at 50 microM inositol. Reduction of the drug concentrations by 50% abolished the stimulation of uptake at 25 microM inositol by lithium and valproic acid and reduced that by carbamazepine. These findings may contribute to an understanding of the mechanisms of action for anti-bipolar medication, and explain the controversy in the literature whether or not brain inositol is reduced after chronic administration of lithium.

Topics: Antimanic Agents; Astrocytoma; Bipolar Disorder; Brain; Brain Neoplasms; Carbamazepine; Dose-Response Relationship, Drug; Humans; Inositol; Lithium Chloride; Signal Transduction; Tritium; Tumor Cells, Cultured; Valproic Acid

We report on three cases of acutely manic prepubertal children diagnosed with bipolar disorder who were treated with olanzapine in addition to their existing mood stabilizer regimens. All three had marked improvement of their manic symptoms within 3-5 days of beginning olanzapine therapy as measured by clinician-rated instruments. Adverse effects included sedation and weight gain. These results suggest that olanzapine may have an antimanic or mood stabilizing effect in acutely manic children with bipolar disorder.

Topics: Antimanic Agents; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Benzodiazepines; Bipolar Disorder; Child; Drug Therapy, Combination; Humans; Lithium Chloride; Male; Olanzapine; Pirenzepine; Sleep Stages; Valproic Acid; Weight Gain

Physical, cognitive, and social factors play a central role in the lithium compliance of people with bipolar disorder. However, studies provide only a partial understanding of this phenomenon and there is currently no nursing model that takes into consideration a combination of factors. This study, based on Pender's preventive health beliefs model, was intended to identify the psychosocial determinants of lithium compliance. A random sample (n = 149) of outpatients at a large Montreal psychiatric hospital was used to measure lithium compliance on the basis of 5 criteria: compliance according to the nurse and according to the patient, appointment compliance, and compliance according to two criteria related to hyperuricemia. Polytomous logistic regression analyses were computed by regressing a composite of these criteria on sociodemographic variables and on the variables of the Pender model: susceptibility, seriousness, control over health, motivation to be healthy, perceived benefits and obstacles, and triggering factors. It appears that being female, being elderly, living with a partner, and perceived treatment benefits and obstacles are determining factors in lithium compliance. These results are all the more important in light of Quebec's newly implemented drug insurance plan, which could increase the obstacles to medication. Nurses will have to be increasingly vigilant with respect to these new obstacles and will have to adjust their interventions accordingly.

Topics: Adult; Antimanic Agents; Bipolar Disorder; Female; Health Knowledge, Attitudes, Practice; Hospitals, Psychiatric; Humans; Lithium Chloride; Logistic Models; Male; Models, Psychological; Outpatients; Patient Compliance; Quebec; Risk Factors; Socioeconomic Factors; Surveys and Questionnaires

Topics: Adult; Antimanic Agents; Bipolar Disorder; Diet, Reducing; Female; Humans; Hyponatremia; Lithium Chloride

The beta 2-Mg (beta 2-microglobulin) and GAG (glycosaminogyclan) excretions in 107 patients with bipolar disorder who had been on lithium treatment for 1-15 years were compared with 29 matched psychiatric control patients. 24-h urine volume, urine beta 2-Mg, GAG values were significantly higher, and maximal urinary osmolality was significantly lower in patients on lithium than in controls. No relationship was found between creatinine clearances and duration of illness, duration of lithium treatment and daily lithium dosages. Duration of lithium treatment was not related to the concentrating capacity. The beta 2-Mg excretion rates were significantly higher in patients with manifest polyuria and with severe concentration defect.

Topics: Adult; Basement Membrane; beta 2-Microglobulin; Bipolar Disorder; Creatinine; Female; Glomerular Filtration Rate; Glycosaminoglycans; Humans; Kidney Concentrating Ability; Kidney Function Tests; Kidney Glomerulus; Kidney Tubules, Proximal; Lithium Chloride; Long-Term Care; Male; Middle Aged; Polyuria

Both mania and bipolar depression have been associated with decrements in the activity of the sodium and potassium-activated adenosine triphosphatase (Na,K-ATPase) membrane pump. Although the role of this observation in the pathophysiology of bipolar illness is unclear, it has been proposed that this defect could be central to the pathogenesis of the illness. In an effort to test this hypothesis, the authors examined the efficacy of lithium pretreatment in attenuating behavioral changes secondary to acute administration of a single intracerebroventricular (i.c.v.) dose of the Na,K-ATPase-inhibiting compound, ouabain, in the Sprague-Dawley rat. Ouabain (10(-3)M) significantly decreased motor activity in automated activity monitors. Lithium pretreatment for 7 d totally prevented this effect. These preliminary data suggest that i.c.v. ouabain administration in the rat may prove to be a viable animal model for bipolar illness.

Topics: Animals; Antimanic Agents; Bipolar Disorder; Enzyme Inhibitors; Exploratory Behavior; Injections, Intraventricular; Lithium Chloride; Male; Ouabain; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase

A random sample of patients (n = 43) had been investigated to detect any difference in response of bright light therapy in lithium-treated inpatients (n = 18) suffering from depression. Only 27% of the lithium-based inpatients respond to bright light therapy, but 73% of patients respond who were not treated with lithium. We conclude that lithium therapy reduces the chance of achieving t remission of depression by bright light therapy.

Topics: Adult; Antidepressive Agents; Bipolar Disorder; Combined Modality Therapy; Depressive Disorder; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Middle Aged; Phototherapy; Treatment Outcome

Twenty-two patients affected by bipolar or schizoaffective disorder, in whom carbamazepine was added to lithium after recurrence when on maintenance with lithium alone, were followed up prospectively for 2 to 13 years. The number of episodes, hospitalizations, and cumulative affective morbidity was markedly reduced after carbamazepine augmentation. Seventeen patients presented a better course during combined treatment than during lithium alone, and of these 15 had no further recurrences. Four patients did not appear to improve after carbamazepine augmentation, whereas one featured reemergence of affective episodes after having derived satisfactory benefit from combination for 7 years (delayed tolerance). Carbamazepine augmentation was associated with a reduction of lithium doses in some patients, including a subgroup who had not tolerated lithium at usual therapeutic levels. Carbamazepine significantly reduced serum thyrotropin concentrations, which were abnormally high in approximately one half of patients when on lithium alone. Total serum thyroxine concentrations were also decreased after carbamazepine augmentation, but free thyroid hormone concentrations did not change. Other significant carbamazepine-induced changes in laboratory tests included increases in total cholesterol concentrations and decreases in white blood cell counts.

Topics: Adolescent; Adult; Antimanic Agents; Bipolar Disorder; Carbamazepine; Drug Therapy, Combination; Female; Humans; Lithium Chloride; Male; Middle Aged; Prospective Studies; Psychotic Disorders; Statistics, Nonparametric

Lithium remains a first-line treatment for the acute and prophylactic management of bipolar illness. Previous studies in our laboratory have demonstrated that chronic, but not acute, exposure to therapeutic concentrations of lithium significantly reduces the expression of the protein kinase C (PKC) substrate MARCKS (myristoylated alanine-rich C kinase substrate) in the rat hippocampus and an immortalized hippocampal cell line (HN33). The anticonvulsant drugs valproate and carbamazepine are emerging as efficacious alternative and adjunctive treatments for bipolar disorder. In the present study, we sought to determine the effects of valproate and carbamazepine on MARCKS protein levels by using our hippocampal cell model.. HN33 immortalized hippocampal cells were exposed acutely or chronically to sodium valproate 1 mM, carbamazepine 100 microM, lithium chloride 5 mM, or lithium chloride 5 mM + sodium valproate 1 mM. Additionally, cells were exposed to lithium chloride 5 mM in the absence or presence of inositol 5 microM, or sodium valproate 1 mM in the absence or presence of inositol 40 microM. After drug exposure, cells were collected, separated into soluble and membrane fractions, and MARCKS protein assayed by Western blot analysis using polyclonal rabbit antibody. Immunoreactive bands were quantitated by densitometric analysis.. We report that chronic exposure of HN33 cells to either lithium or valproate produced a time-dependent down-regulation of MARCKS protein. Maximal reduction in MARCKS levels were observed after 3 days of exposure to valproate and after 7 days of exposure to lithium. The reduction of MARCKS produced by lithium and valproate alone were additive when the two drugs were combined. The reduction in MARCKS produced by lithium was reversed by the addition of inositol to the media, whereas the reduction produced by valproate was unaffected by the addition of inositol. Carbamazepine failed to affect MARCKS protein levels at each dose and time tested.. These data provide evidence that, like lithium, chronic exposure to valproate produces a significant time-dependent down-regulation of the PKC substrate MARCKS, whereas carbamazepine is without effect. The MARCKS reduction produced by valproate appears to occur independently of inositol concentrations yet is additive with the reduction produced by lithium, which is inositol-reversible. Valproate- and lithium-induced regulation of MARCKS expression appears to be mediated by different mechanisms that may utilize PKC, and may be associated with the clinical profile of these mood stabilizers. Regulation of MARCKS expression may be associated with the prophylactic efficacy of lithium in the long-term stabilization of the recurrent affective episodes in bipolar disorder, and valproate may share this property.

Topics: Animals; Bipolar Disorder; Blotting, Western; Carbamazepine; Cell Line; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Gene Expression; Hippocampus; Humans; Inositol; Intracellular Signaling Peptides and Proteins; Lithium Chloride; Membrane Proteins; Myristoylated Alanine-Rich C Kinase Substrate; Neurons; Protein Biosynthesis; Protein Kinase C; Proteins; Rabbits; Rats; Valproic Acid

Patients with manic depressive disorder (DSM-III-R bipolar disorder) have an abnormality of the Na+,K(+)-ATPase pumps in their lymphocytes: the pump numbers do not upregulate to stimulation with lithium and ethacrynate. We have now investigated the in vitro adaptive responses of lymphocyte Na+,K(+)-ATPase pumps in the first-degree unaffected relatives of patients with a clear history of manic depressive disorder. The lymphocytes of the healthy relatives upregulated their Na+,K(+)-ATPase pumps normally, suggesting that the abnormal response that we have previously observed in patients with the disorder reflects a complex relation between the biochemical phenotype and the development of clinical symptoms.

Topics: Bipolar Disorder; Cells, Cultured; Ethacrynic Acid; Humans; Lithium Chloride; Lymphocytes; Sodium-Potassium-Exchanging ATPase; Up-Regulation

We have recently reported a study of beta-adrenergic receptor binding characteristics in lymphoblast cell lines derived from patients with bipolar disorder (BD) and healthy, matched control subjects. In the present study we have investigated the effects of incubating cells from the same subjects with lithium chloride (1 mM) for 7 days prior to assay. There was no difference in beta-adrenergic receptor number between control and BD cell lines and incubation with lithium had no effect on receptor number in either group. Exposure of the cells to isoprenaline (1 nM) for 24 h immediately prior to assay caused significantly less down-regulation in BD cells (15 +/- 5%) than control cells (39 +/- 4%), as described previously. Incubation with lithium significantly increased the down-regulation response to isoprenaline in BD cells (39 +/- 6%) but not in control cells (30 +/- 7%). After lithium, the agonist-induced decrease in beta-AR number in BD cells was no longer significantly different from that in control cells. We conclude that lithium selectively enhanced the agonist down-regulation of beta-adrenergic receptors in cells derived from patients with bipolar disorder. The functional significance of this result and the potential biochemical mechanisms responsible for this effect are discussed.

Topics: Adult; Aged; Bipolar Disorder; Cell Line, Transformed; Down-Regulation; Female; Humans; Iodocyanopindolol; Isoproterenol; Lithium Chloride; Lymphocytes; Male; Middle Aged; Pindolol; Radioligand Assay; Receptors, Adrenergic, beta

Topics: Aged; Bipolar Disorder; Chlorides; Female; Humans; Hypertrophy; Lithium; Lithium Chloride; Oculomotor Muscles; Orbital Diseases; Ultrasonography

When lithium serum levels were within the (human) therapeutic range, young and old adult male and female rats (housed singly or in groups) all displayed faster limbic seizure onset times in response to a muscarinic cholinergic agonist (pilocarpine 20 mg/kg) if a single systemic dosage of chlorpromazine was injected 24 hours previously. The effect was comparable to injecting an additional 10 mg/kg of pilocarpine. These results strongly suggest that cholinergic rebound from chlorpromazine administrations during lithium treatment could facilitate subclinical electrical lability and very localized neuronal necrosis within the limbic system of clinical patients, resulting in normalization of psychiatric symptoms.

Topics: Animals; Bipolar Disorder; Chlorides; Chlorpromazine; Drug Therapy, Combination; Female; Limbic System; Lithium; Lithium Chloride; Male; Neurons; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Seizures

1. This study examines the effects of chronic lithium administration on changes induced by amphetamine administration and withdrawal on open field locomotor activity of rats, and considered as an animal model of behaviors displayed in bipolar disorders. 2. For 21 days, rats were administered either single daily intraperitoneal injections (IP) of 0.9% saline, 0.15 mEq/kg, or 1.5 mEq/kg lithium chloride (LiCl). From day 7 to day 16, half of the animals in each group consisting of 12 rats were administered twice daily IP injections of either 1.5 mg/kg d-amphetamine or 0.9% saline. From day 17 to 21, d-amphetamine was withdrawn. 3. Neither dose of LiCl significantly altered the increases in activity levels produced by amphetamine. The withdrawal of amphetamine lead to an immediate return to baseline activity levels which neither dose of LiCl significantly affected. 4. The absence of interactive effects suggests that the influence of lithium and amphetamine on activity are mediated by different neurotransmitter systems.

Topics: Animals; Bipolar Disorder; Chlorides; Dextroamphetamine; Disease Models, Animal; Lithium; Lithium Chloride; Male; Motor Activity; Rats; Rats, Inbred Strains; Reference Values; Substance Withdrawal Syndrome

Cultured fibroblasts were prepared from six normal controls, five DSM-III manic patients, and six DSM-III schizophrenic patients. Lithium (Li+) uptake, 24-hour Li+ ratios, and steady-state membrane potential were measured in these cell lines. The uptake of 10 mM Li+ reached maximum at 2 hours, with an intracellular concentration of approximately 15 mM. No significant difference in uptake was found among subject groups. Twenty-four hour Li+ (ratio of intracellular/extracellular Li+) ratios were determined by incubating the cell lines for 24 hours in the presence of 2 mM Li+. No significant difference was observed among groups; nor was there any significant correlation between the fibroblast 24-hour ratios and 24-hour in vitro ratios determined in donor red cells. The relationship between membrane potential and the 24 hour Li+ ratio in fibroblasts was determined. The average potential in these cell lines was -56 mV and was not affected by Li+ treatment. No correlation between the Li+ ratio and membrane potential was found.

Topics: Adult; Bipolar Disorder; Chlorides; Circadian Rhythm; Erythrocytes; Fibroblasts; Humans; Lithium; Lithium Chloride; Membrane Potentials; Schizophrenia

Because lithium is extruded from cells by means of coupled exchange for external sodium (Na+-Li+ countertransport), we hypothesized that clinical treatment with this agent could lead to significant augmentation of net cellular sodium influx. We therefore directly measured sodium influx in vitro using erythrocytes (RBCs) from 27 depressed bipolar patients. When cells were loaded with sufficient lithium to maximally stimulate Na+-Li+ countertransport activity (5.1 mmoles/1 RBCs), there was a significant 44% increase in mean sodium influx. To approximate clinical conditions more closely, we also studied sodium influx in a subset of eight subjects after loading cells with 0, 0.40, 0.66, and 1.55 mmoles lithium/1 RBCs. Over this range of lithium concentrations, sodium influx increased progressively. In separate experiments, we found that RBC sodium content measured in eight subjects did not change significantly during a 4-week course of lithium treatment. Thus, excess cellular sodium during such treatment may be extruded by increased activity of the membrane Na+-K+ pump, which has electrogenic properties and thereby could augment the membrane potential. In the nervous system, such an effect could stabilize cell membranes electrophysiologically, and possibly affect processes, such as behavioral sensitization or kindling, proposed to have a role in the development of recurrent affective disorders.

Topics: Bipolar Disorder; Chlorides; Erythrocyte Membrane; Humans; Ion Channels; Lithium; Lithium Chloride; Membrane Potentials; Sodium

LiCl in vitro markedly inhibits forskolin-stimulated human platelet adenylate cyclase activity by competing competitively with Mg2+ for a site on the catalytic subunit. The sensitivity of platelet membrane adenylate cyclase to lithium inhibition for individual manic patients was determined by the Dixon plot procedure: marked individual differences in sensitivity to lithium were observed pretreatment (0.66 mM-3.15 mM LiCl). After 3 weeks of continuous treatment with lithium in vivo a significant decrease in adenylate cyclase affinity for lithium was observed (pretreatment average Ki = 1.38 +/- 0.92 mM vs. treatment average Ki = 2.98 +/- 1.35 mM LiCl, n = 10). The clinical implications of these findings relating to chronic lithium exposure are discussed.

Topics: Adenylyl Cyclase Inhibitors; Adult; Bipolar Disorder; Blood Platelets; Chlorides; Cyclic AMP; Female; Humans; Lithium; Lithium Chloride; Long-Term Care; Male; Middle Aged; Phosphatidylinositols; Receptors, Cyclic AMP

Lithium chloride and rubidium chloride were tested under conditions in which the effects of their chronic administration on aversively-controlled behavior could be assessed. Lithium attenuated shock-induced suppression of open-field activity when that suppression was under the control of mild or moderate stimulus parameters, but had no effect on the suppression produced by the presence of shock itself. Rubidium, on the other hand, increased shock-induced suppression under all conditions. When shock was removed and extinction of the activity suppression was investigated, lithium subjects failed to return to their original baseline activity levels, while subjects receiving rubidium recovered baselines in a manner indistinguishable from that observed in control animals.

Topics: Animals; Avoidance Learning; Bipolar Disorder; Chlorides; Electroshock; Extinction, Psychological; Lithium; Lithium Chloride; Male; Models, Biological; Motor Activity; Rats; Rubidium

Topics: Bipolar Disorder; Chlorides; Diet, Sodium-Restricted; Dose-Response Relationship, Drug; Humans; Lithium; Lithium Carbonate; Lithium Chloride; Renal Dialysis

Lithium incorporation in cultured human skin fibroblasts was measured in a group of 10 manic-depressives and 10 controls. This system was believed to eliminate many of the sources of variability to which measurement of the lithium ratio in erythrocytes (RBCs) is subject. A fibroblast lithium ratio calculated from 1-hr lithium incorporation studies correlated highly with an in vitro RBC lithium ratio in medication-free controls. Manic-depressives and controls did not differ in lithium incorporation or fibroblast lithium ratio, leading to the conclusion that the lithium ratio is probably not a good measure for differentiating the two populations.

Topics: Adult; Aged; Bipolar Disorder; Chlorides; Erythrocytes; Female; Fibroblasts; Humans; Kinetics; Lithium; Lithium Chloride; Male; Middle Aged

Topics: Beer; Bipolar Disorder; Chlorides; History, 19th Century; History, 20th Century; Humans; Information Centers; Lithium; Lithium Carbonate; Lithium Chloride; Wisconsin

Topics: Bipolar Disorder; Chlorides; Humans; Lithium; Lithium Chloride; Solubility

The 24-hr urinary excretion of calcium, magnesium and phosphate was measured in 76 normal control persons, 95 manic-melancholic patients not on lithium treatment and 74 lithium-treated manic-melancholic patients. The mean value of the urinary excretion for each of the four seasons during a 5-year period was calculated. The normal control persons had a higher excretion of calcium during the summer months than during the rest of the year; this seasonal variation was not present in the two groups of manic-melancholic patients. Previously reported changes in electrolyte metabolism during lithium treatment were confirmed, but some of the results varied with the season.

Topics: Bipolar Disorder; Calcium; Chlorides; Circadian Rhythm; Female; Humans; Lithium; Lithium Chloride; Magnesium; Male; Phosphates; Seasons

Topics: Adult; Aged; Albuterol; Antibody-Producing Cells; Bipolar Disorder; Cell Survival; Chlorides; Female; Hemolytic Plaque Technique; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Lithium; Lithium Chloride; Lymphocytes; Male; Middle Aged; Pokeweed Mitogens; Theophylline

Lithium hydroxybutyrate (10 mg/kg) prevents the amphetamine-induced EEG arousal and amplitude frequency alterations in the motor and visual cortex, posterior hypothalamus, midbrain reticular formation, and caudate nucleus but potentiates the action of the psychostimulant on the EEG of the hippocamp and amygdala. The response to the light flickering rhythm in the visual cortex remains within initial upon concurrent administration of both the drugs.

Topics: Amphetamine; Animals; Bipolar Disorder; Cerebral Cortex; Chlorides; Disease Models, Animal; Drug Interactions; Electroencephalography; Humans; Hydroxybutyrates; Lithium; Lithium Chloride; Organometallic Compounds; Rabbits; Schizophrenia