Relationship of Acute Mania Symptomatology to Maintenance Treatment Response

Charles L. Bowden, MD


December 28, 2005

In This Article

Indications That Acute Treatment Predicts Maintenance Outcome

Treatment of bipolar disorders must address maintenance objectives. Since the year 2000, several large, blinded, randomized, placebo-controlled studies have been published analyzing background and symptomatic and acute treatment factors that contribute to maintenance effectiveness. These study results, summarized in this article, have involved over 3000 bipolar I patients and provide new evidence that can aid psychiatrists in maintenance treatment planning.

Acutely manic patients treated by psychiatrist's choice with either divalproex or lithium were randomized to 1 year of maintenance therapy with divalproex, placebo, or lithium.[1] Patients treated with divalproex for mania had significantly lower rates of premature discontinuation when randomized to maintenance divalproex (59%) compared with patients randomized to maintenance placebo (87%; P = .002). The same group of patients treated with open-phase divalproex who were then randomized to divalproex also had longer times to any mood episode than did patients randomized to either placebo or lithium, as well as longer duration in the maintenance phase (divalproex mean, 209 days), compared with those randomized to treatment with placebo (mean, 143 days; P =.03) or lithium (mean, 161 days; P = .01). The study also indicated that continuation with divalproex was associated with better long-term tolerability; in fact, the rate of premature discontinuation due to intolerance was 7.1% for those randomized to treatment with divalproex compared with 24.4% (P =.02) for those randomized to treatment with lithium.

Although a similar number of patients were treated with lithium and divalproex in the open acute phase, the proportion of patients randomized to lithium was only half of that randomized to divalproex. Thus, the study provided a weaker test of the relationship of lithium-to-lithium outcomes. However, there appeared to be neither advantage nor disadvantage for acute treatment with lithium in patients subsequently randomized to lithium.[2]

A few trials provide suggestive results indicating that for olanzapine and lamotrigine, acute-phase tolerability and improvement is associated with maintenance-phase effectiveness.[3,4,5,6] For both drugs, the published studies used designs requiring that the open phase of treatment include olanzapine or lamotrigine, respectively, although other medications could be used. In olanzapine studies comparing olanzapine with lithium[3] or valproate alone vs valproate combined with olanzapine[4] and in studies comparing lamotrigine with placebo and lithium,[5,6] the olanzapine- and lamotrigine-treated patients had significant superiority in 1 or more planned maintenance outcome analyses. In the results of the lamotrigine vs lithium or placebo study, dropout rates for intolerability were essentially the same for recently manic patients randomized to either lamotrigine or placebo (5% and 4%, respectively), but they were significantly higher among lithium-treated patients (25%).[5] Maintenance studies of quetiapine and aripiprazole also suggest similar benefits of efficacy for these 2 drugs when acute treatment is followed by continued blinded treatment with the same drugs and placebo.[7]

Only the divalproex-lithium-placebo study allowed psychiatrist's choice for acute-phase treatment of the 2 active treatments subsequently studied in the maintenance phase; therefore, less can be concluded from the olanzapine-lamotrigine-quetiapine-apripiprazole studies reviewed in this section regarding the acute relationship of drug treatment response to maintenance responsiveness.


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