Latest maintenance data on lithium in bipolar disorder

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Abstract

Although lithium is generally considered to be the gold standard for maintenance therapy in bipolar disorder, evidence of its efficacy has rested on only a small number of adequately designed studies. Results from the lamotrigine bipolar trials, which included lithium as an active comparator, will substantially increase confidence in long-term lithium treatment. In a meta-analysis of these data, lithium was significantly more effective than placebo in preventing relapse in patients with bipolar disorder (relative risk [RR] 0.65; 95% confidence interval [CI] 0.50, 0.84). Furthermore, lithium had significant efficacy against manic relapse (RR 0.61; 95% CI 0.39, 0.95), with a less substantial, not statistically significant, effect against depressive relapse (RR 0.72; 95% CI 0.49, 1.07). Factors such as disease subtype, likelihood of adherence to treatment regimen, tolerability, and dose uncertainty should be considered in the selection of lithium maintenance therapy.

Introduction

Lithium is widely regarded as the gold standard for long-term treatment of bipolar disorder. However, the early trials that established lithium as a maintenance treatment have been criticised because a number of them employed discontinuation designs, whereby patients who were stable on lithium were randomised either to continued lithium treatment or placebo substitution. It is now recognised that abrupt withdrawal of lithium can provoke a new episode of mania (Goodwin, 1994, Suppes et al., 1991) and this may have driven increases in the number of early placebo relapses, producing inflated estimates of the apparent therapeutic efficacy of lithium. This weakness has probably been over-stated in the most sceptical current analysis (Moncrieff, 1997) because when the more extreme discontinuation designs were excluded there is still a treatment benefit (Burgess et al., 2001). Nevertheless, other factors such as the emphasis on acute treatment as a model for long-term treatment, the introduction of new medicines with apparent potential for bipolar disorder, the side-effect burden, neurotoxicity in overdose, and the difficulties associated with long-term lithium use may also have contributed to lithium’s diminishing reputation for effectiveness in recent years (Goodwin, 2002).

This paper describes how recent positive results from long-term studies of lamotrigine in bipolar I disorder, which included lithium as an active comparator, should increase confidence in the use of lithium for maintenance therapy. Additional issues surrounding the long-term use of lithium are also considered.

Section snippets

Previous maintenance data

A meta-analysis of randomised, placebo-controlled trials of lithium as maintenance treatment for mood disorders has been performed (Burgess et al., 2001). After elimination of studies with a discontinuation design, nine studies were included in the review (n=825). Overall, lithium was more effective than placebo in preventing all relapses (irrespective of the definition used) in patients with mixed diagnoses of mood disorder (unipolar, bipolar, and unspecified) over periods of up to 4 years

Latest evidence from lamotrigine studies

New data on the efficacy of lithium come from two large randomised, double-blind, placebo-controlled, 18-month trials of lamotrigine and lithium in the prevention of relapse and recurrence of mood episodes in patients with bipolar I disorder (Calabrese et al., in press; Bowden et al., 2003). The two studies were prospectively designed for combined analysis, and pooled results have recently been reported (Goodwin et al., submitted). Individual and combined results from the two studies are

Methods

Patients aged 18 years or over were included in these studies if they had a current or recent (within 60 days) episode of DSM-IV depression (study GW605/2003) or mania, hypomania, or mixed mood states (study GW606/2006). Both studies consisted of a 2-week screening phase, followed by an 8- to 16-week open-label period during which lamotrigine (100–200 mg/day) was initiated and other psychotropic drugs were discontinued (Fig. 1). Patients were enrolled in the double-blind phase of the study if

Use in different subtypes of bipolar disorder

As demonstrated above, lithium is clearly effective in preventing relapse or recurrence of unselected bipolar I disorder. Current evidence supports the use of lithium in patients with a classic presentation of the illness. The Multicenter Study of Long-Term Treatment of Affective and Schizoaffective Psychoses (MAP study) compared the differential efficacy of lithium versus carbamazepine in 171 patients with bipolar disorder over a period of 2.5 years (Kleindienst and Greil, 2000). A

Conclusions

Results from the lamotrigine bipolar trials have demonstrated that lithium is effective as maintenance therapy in bipolar I disorder independent of an enriched or discontinuation study design. These new findings, therefore, substantially increase the confidence in long-term lithium treatment. In particular, the relative efficacy of lithium against different poles of the illness is now more clearly defined; lithium has significant efficacy against manic relapse, while its effect against

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