Article

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: 13.56). 07/2002; 159(7):1155-9. DOI: 10.1176/appi.ajp.159.7.1155
Source: PubMed

ABSTRACT 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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    • "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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    • "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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