Effect of Abrupt Change From Standard to Low Serum Levels of Lithium: A Reanalysis of Double-Blind Lithium Maintenance Data

Department of Psychiatry, Massachusetts General Hospital, 50 Staniford Street, Boston, MA 02114, USA.
American Journal of Psychiatry (Impact Factor: 12.3). 07/2002; 159(7):1155-9. DOI: 10.1176/appi.ajp.159.7.1155
Source: PubMed


Growing evidence suggests that abrupt lithium discontinuation increases the risk of recurrence for patients with bipolar disorder. To assess the effect of abrupt change in lithium dose, the authors reanalyzed data from a previously reported, randomized, double-blind trial of standard- versus low-dose lithium for maintenance therapy in bipolar disorder.
In the original study, serum lithium levels were obtained during a 2-month open stabilization period for 94 patients with bipolar disorder who were then randomly assigned to be maintained on a low (serum level=0.4-0.6 meq/liter) or a standard (0.8-1.0 meq/liter) level of lithium therapy. Patients were then followed for up to 182 weeks. This reanalysis examined the potential confounding influence of prerandomization lithium level and change in lithium level on the outcome of subjects assigned to a standard or low maintenance dose of lithium.
In a Cox proportional hazards model incorporating pre- and postrandomization lithium levels and the interaction of these factors, only the interaction term remained significantly associated with time to recurrence.
The findings indicate that change in serum lithium level may be a more powerful predictor of recurrence of bipolar disorder than the absolute assignment to a low or a standard dose of lithium and suggest that an abrupt decrease in lithium level should be avoided. This reanalysis did not directly address optimal maintenance lithium levels but raises questions about the original study's finding of superiority for lithium levels > or =0.8 meq/liter. The results underscore the importance of accounting for the possible confounding effects of changes in the intensity of pharmacotherapy in studies of maintenance therapies for bipolar disorder.

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    • "However, a recent large study, involving a 24-week follow-up, revealed no association between an improvement in depression or mania ratings in patients with BD and their blood lithium levels [low (<0.4 mEq/l) vs. high (0.4–0.9 mEq/l)] (9). Furthermore, a reanalysis of the study by Gelenberg et al (7) demonstrated that patients treated with low levels of lithium during the pre- and post-randomization phases remained stable during the study period (10). These results may encourage a more limited use of higher lithium doses, even in acute mood episodes in BD. "
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    ABSTRACT: Lithium has a narrow therapeutic index with a subtle balance between effectiveness and adverse effects. Current guidelines recommend the use of lithium as a treatment for acute bipolar depression; however, the therapeutic range for the treatment has not been fully defined. Recently, the adjunctive lower lithium dose in bipolar depression has revealed potential efficacy; however, no study has investigated it predominantly in monotherapy. In this open-label, proof-of-concept study, 31 individuals with bipolar disorder during a depressive episode were randomized and 29 were followed up for six weeks with flexible lithium dosing. All subjects had a 21-item Hamilton Rating Scale for Depression (HAM-D) score of ≥18 at baseline. Subjects were divided into two groups, with higher (Li ≥0.5 mEq/l) or lower (Li <0.5 mEq/l) blood lithium levels. Response and remission rates were evaluated using the HAM-D scores. Following 6 weeks of lithium treatment, the remission rate for all patients was 62.0%. The plasma lithium levels did not impact the clinical response. However, subjects with higher blood lithium levels had an increased prevalence of nausea, restlessness, headaches and cognitive complaints. The results indicate that the lithium dose for the treatment of bipolar depression in an individual should be based on the clinical efficacy and side-effects. In the context of personalized psychiatric treatments, it is necessary to evaluate the therapeutic action of lithium with individual regimens in order to develop more tolerable and effective treatment approaches.
    Full-text · Article · Oct 2014 · Experimental and therapeutic medicine
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    • "Patients may reject the option of taking lithium in combination with other medications because of prior adverse experiences with higher doses of lithium. Lower and more tolerable doses of lithium (o0.6 meq/L) could be effective when combined with other medications, particularly for long-term treatment (Kessing et al., 2007; Perlis et al., 2002; Severus et al., 2008). Given the extensive clinical and research track record of lithium, there is a great public health need to assess the effectiveness of tolerable doses of lithium added to flexible medication regimens of other established drugs for acute and continuation treatment of bipolar disorder. "
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    ABSTRACT: Efficacy-based double-blind placebo controlled trials were conducted to establish efficacy and safety for FDA approval. Such designs allowed and encouraged the use of exclusion criteria to improve assay sensitivity and internal validity. The LiTMUS trial increased the representation of real-world individuals with bipolar disorder despite the acknowledgment that this compromises assay sensitivity. To maximize generalizability, LiTMUS used broad inclusion and narrow exclusion criteria: participants experiencing mood symptoms of sufficient intensity (at least with a CGI-BP ≥3) that would warrant a change in treatment, and that lithium treatment would be a reasonable therapeutic option if they were randomized to it. At baseline demographic, illness, clinical, and treatment characteristics were collected. The LiTMUS study design and baseline sociodemographic data were compared to previous efficacy studies. As compared to the previous bipolar disorder efficacy studies, LiTMUS participants were of similar age, gender, weight and illness severity; however LiTMUS participants were more racially and ethnically representative of the general population, had a greater number of mood episodes in the past 12 months, more Axis I/II comorbidity, a greater number of prior suicide attempts, and higher functional capacity. LiTMUS was a comparative effectiveness trial that had broad inclusion and minimal exclusion criteria that produced a more representative sample comprised of real-world participants. This design enables the results of the LiTMUS study to be a more representative of real world pharmacotherapuetic outcomes. Limitations include possible selection bias, paucity of sociodemographic data in efficacy trials, and lack of a placebo.
    Full-text · Article · Jul 2013 · Journal of Affective Disorders
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    • "Despite some earlier doubts, there is now a consensus that discontinuing lithium increases the risk of relapse of manic depression over and above the levels associated with the natural course of the disorder [16]. The evidence consists of the fact that the increased risk of relapse is concentrated in the first few months after discontinuation and tails off thereafter [17], that higher rates of relapse are observed after rapid compared with gradual withdrawal [18] [19], and that the rate of recurrence after lithium withdrawal exceeds the rate of episodes prior to lithium's initiation [17] [20]. It is still uncertain whether only manic relapses are increased or all relapses. "
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    ABSTRACT: In this paper, I argue that the problems that occur after discontinuation or reduction of long-term psychiatric drug treatment may be caused by the process of drug withdrawal itself, rather than representing the course of the underlying illness. Adverse effects induced by discontinuation of psychiatric medication include: (1) a somatic discontinuation syndrome that includes psychological symptoms which may be mistaken for relapse, (2) a rapid onset psychotic reaction after withdrawal of both conventional neuroleptic drugs and some atypicals, notably clozapine (sometimes referred to as supersensitivity psychosis), (3) a psychological reaction to withdrawal, which may be mistaken for relapse or may itself precipitate relapse, (4) a genuine relapse of the underlying condition precipitated by the process of withdrawal. The implications of these effects include the possibility that much of the research on maintenance treatment is flawed and that the recurrent nature of psychiatric conditions may sometimes be iatrogenic. If withdrawal induced adverse effects could be effectively managed, the success of drug discontinuation might be much greater than usually assumed and might outweigh the disadvantages of continued treatment.
    Preview · Article · Feb 2006 · Medical Hypotheses
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