Which clinical factors predict response to prophylactic lithium? A systematic review for bipolar disorders

OBJECTIVES: The aim of this study was to systematically integrate the available evidence on response prediction to prophylactic lithium based on clinical factors. METHODS: Each clinical variable that was related to lithium response in at least one prior study was examined with respect to response prediction. If several studies were located for the same variable, results were integrated using the meta-analytic approach as suggested by DerSimonian and Laird which was developed for substantial heterogeneity in primary studies. RESULTS: Of 42 potential clinical predictors investigated, five variables were identified as possible response predictors of prophylactic lithium: [1] An episodic pattern of mania-depression-interval, and [2] a high age of illness onset were identified as potentially protective against a recurrence under lithium. [3] A high number of previous hospitalizations, [4] an episodic pattern of depression-mania-interval, and [5] continuous cycling were identified as potential risk factors. Six further variables were found to be significantly related to lithium response, though calculation of fail-safe numbers indicates that current evidence is not sufficient to hold these variables as reliable predictors of lithium response. All effect-sizes relating clinical predictors to response were small to moderate. CONCLUSIONS: Although a few variables are quite robustly supported as response-predictors in this review, a more in-depth analysis of each potential predictor is needed. As none of the potential predictors had a very strong impact on response, prediction of lithium response should be based on a multitude of variables.     

Guidelines for maintenance treatment of bipolar disorder: are there discrepancies between European and North American recommendations?

Practice policies and guidelines for the long-term management of bipolar patients have appeared in many parts of Europe and North America. Although recommendations in most areas do concur remarkable differences are apparent both regarding diagnostic practice and pharmacological management. Differences among recommendations point towards professional and cultural differences between Europe and North America but also towards areas with unresolved research questions and lack of scientific evidence.     

Review of Lithium in the Aquatic Environment: Distribution in the United States,Toxicity and Case Example of Groundwater Contamination

Lithium is found at low concentrations in the major rivers of the United States (about 0.002mgl^–1) and as a mineral or salt in pegmatites and brines. The United States produces many lithium materials and consumes the greatest amount of Li in the world for use in ceramics, glass, aluminum, pharmaceuticals, batteries, etc. From 1950 to 1970, Li was central to many nuclear-related US Department of Energy (DOE) activities. The historical and current use of Li has not prompted many studies of the toxicity of this element to aquatic organisms. Here, we review the distribution and use of Li in the US with emphasis on usage by DOE. We also summarize information on the toxicity of lithium to aquatic biota. A case-example is provided which demonstrates the potential for contamination of groundwater with Li, evaluates the toxicity of the Li-contaminated groundwater, and identifies a treatment alternative.     

Effect of chronic Li+ treatment on free intracellular Mg2+ in human neuroblastoma SH-SY5Y cells

Objectives:  Previous findings have demonstrated Li⁺/Mg²⁺ competition at therapeutic intracellular Li⁺ levels after acute Li⁺ treatment in human neuroblastoma SH-SY5Y cells. In the current study, we examined whether Li⁺/Mg²⁺ competition exists at therapeutically relevant extra- and intracellular [Li⁺] after chronic Li⁺ loading times.
Methods:  In human neuroblastoma cells, intracellular free Mg²⁺ was determined by fluorescence spectroscopy with the fluorophore furaptra. Intracellular Li⁺ and Mg²⁺ were measured by atomic absorption spectrophotometry.
Results:  After loading of the neuroblastoma cells with 1–2 mM extracellular Li⁺ for 24–72 h, the observed, increased intracellular free [Mg²⁺] levels were significantly higher (p < 0.03) than those in matched Li⁺ free cells, and intracellular [Li⁺] was found to be at therapeutic intracellular levels (0.7–1.5 mM).
Conclusions:  The results demonstrate that Li⁺/Mg²⁺ competition exists after chronic treatment with Li⁺ at therapeutically relevant intracellular Li⁺ levels in neuroblastoma cells. We found differences between acute and chronic Li⁺ treatment effects on the extent of Li⁺/Mg²⁺ competition. Possible reasons for these differences are discussed.     

Bipolar depression: criteria for treatment selection,definition of refractoriness,and treatment options

Objective:  This paper reviews controlled studies of bipolar depression, outlines criteria for choosing treatment, defines refractoriness in bipolar depression, and provides options for treatment of refractory bipolar depression.
Methods:  Controlled studies that examined the efficacy of treatments for acute and long-term treatment of bipolar depression were located through electronic searches of several databases and by manual crosssearch of references and proceedings of international meetings.
Results:  Lithium comes close to fulfilling the proposed criteria for first-line treatment for bipolar depression, and those not responding to lithium should be considered to have refractory bipolar depression. Options for such patients include addition of lamotrigine or a second mood stabilizer, or a newer-generation antidepressant such as a serotonin re-uptake inhibitor or bupropion, or the atypical antipsychotic olanzapine.
Conclusions:  Although there is a paucity of research in the treatment of refractory bipolar depression, available data could be used for providing rational treatment options for such patients. However, further studies are urgently needed to determine which options are most appropriate for which type of patients .     

Lithium use in octogenarians

OBJECTIVES: To assess the tolerability and side-effect profile of lithium use in a group of octogenarians attending a specialized lithium clinic. METHODS: This is a cross-sectional study looking at all patients of eighty years and over attending a lithium clinic. Charts were examined to assess renal function, thyroid function and level of side-effects during their course of lithium treatment in order to assess the tolerability of this medication in octogenarians. RESULTS: Twelve patients of 80 years and over (with an average age of 83.6 years) were taking lithium for an average period of 53.7 months. They had a mean serum level of 0.42 mmol/l. No patient had to discontinue lithium therapy because of side-effects, even though some patients did develop transient abnormalities of renal function. One patient developed diabetes insipidus. One female patient developed hypothyroidism. CONCLUSIONS: Lithium was well tolerated and was administered safely to this cohort of octogenarians. Monitoring of serum lithium levels and kidney and thyroid function should preferably be done in the setting of a specialized lithium clinic.     

A pilot study of rapid lithium administration in the treatment of acute mania

Objectives: The use of rapid lithium dosage administration, a strategy that could lead to rapid improvement in mania, has been largely unexamined. In this open-label, pilot, acute-treatment study, we sought to determine the safety and tolerability of lithium administered at 20 mg/kg/day. A secondary aim was to provide preliminary data regarding the efficacy of this strategy in ameliorating manic, depressive, and psychotic symptoms. Methods: Fifteen patients hospitalized with DSM-IV bipolar disorder, manic or mixed, and who provided written informed consent, received lithium 20 mg/kg/day for up to 10 days. Patients were evaluated for adverse effects daily. Lithium levels were obtained on days 2, 3, 4, 5, 7, and 10 or at study termination. Electrocardiograms (EKGs) were performed at baseline and on days 1–5, 7, and 10 or at study termination. Symptomatic improvement was assessed daily using the Young Mania Rating Scale, 24-item Hamilton Depression Rating Scale, and the Scale for Assessment of Positive Symptoms (SAPS). Results: Five of the 15 patients completed the 10-day study period. Two patients dropped out due to adverse events. Seven patients did not complete the inpatient trial because of improvement sufficient to allow hospital discharge. All patients achieved serum lithium concentrations ≥0.6 mEq/L after 1 day of treatment; the mean±SD concentration on day 5 was 1.1 (±0.1) mEq/L on day 5. There were significant reductions from baseline to endpoint on all rating scales, except the SAPS bizarre behavior subscale. Conclusions: These pilot data suggest that lithium 20 mg/kg/day was well tolerated and that this strategy may produce rapid improvement in affective and psychotic symptoms. These impressions require confirmation in double-blind, randomized trials.     

Lithium monitoring before and after the distribution of clinical practice guidelines

OBJECTIVE: To determine whether distribution of clinical practice guidelines improves lithium monitoring and whether standards of monitoring differed between patients in psychiatric contact and those seen only in primary care. METHOD: Standards of monitoring were assessed for patients on lithium in northeast Scotland throughout 1995 and/or throughout 1996. Guidelines were circulated in January 1996 to all local general practitioners and psychiatrists. Monitoring was compared between 1995 and 1996 and for patients with and without psychiatric contact. RESULTS: Both primary care and psychiatric records were scrutinized for 422 and 403 patients prescribed lithium throughout 1995 and 1996, respectively. While monitoring was poor on several parameters during both years, frequency of measurement of both thyroid and renal function improved in 1996. Standards of monitoring were better for patients in psychiatric care. CONCLUSION: Standards of lithium monitoring require further improvement. Locally agreed practice guidelines are helpful but patients on lithium should be in continuing contact with an experienced psychiatrist.     

Mania: differential effects of previous depressive and manic episodes on response to treatment

OBJECTIVE: We compared effects of previous depressive or manic episodes on antimanic response. METHOD: In-patients in a parallel-groups, double-blind comparison of lithium, divalproex or placebo for manic episodes had comprehensive evaluations of illness history. We used non-linear curve fitting of change in Manic Syndrome Score (MSS) of the Schedule for Affective Disorders and Schizophrenia (SADS) versus previous depressive or manic episodes to investigate their relationships to MSS improvement. RESULTS: Response to lithium, but not to divalproex or placebo, worsened with increased depressive or manic episodes. More than 11 manic, or four depressive, episodes was associated with response to lithium that did not differ from placebo. Effects of previous depressive and manic episodes appeared independent, and could not be accounted for by increased rapid cycling or mixed states. CONCLUSION: At least four previous depressive or 12 previous manic episodes are associated with reduced antimanic response to lithium.