Active comparator trials
Active comparator trials for bipolar maintenance have evaluated lithium versus olanzapine, lithium versus divalproex, lithium versus lamotrigine, and olanzapine versus divalproex. Although many primary and secondary end points failed to separate between active comparators, differences that exist highlight the benefits and drawbacks of each medication.
Lithium versus lamotrigine. Bowden and colleagues44and Calabrese and colleagues45 compared lithium with lamotrigine in patients recovering from manic and depressive episodes. In a combined analysis of both studies, there was no difference in time to intervention of a mood episode.50 However, lithium was found to be superior to lamotrigine in delaying the time to intervention for a manic episode. Lamotrigine was numerically, but not statistically, more effective than lithium in delaying the time to intervention for a depressive episode. A significantly larger percentage of patients who received lithium withdrew from the studies because of adverse events. In addition, lithium was associated with a higher frequency of tremor and diarrhea.
Lithium versus olanzapine. Lithium was compared with olanzapine in a randomized, double-blind, controlled trial made up of 431 subjects in symptomatic remission from a manic or mixed episode after receiving open-label cotreatment with olanzapine and lithium.54 Subjects in the olanzapine group were more likely to complete the trial (47% vs 33%) than those in the lithium treatment group, with a longer time until discontinuation (303 vs 207 days). However, the recurrence rate and time to any mood episode did not differ between groups. On analysis of secondary end points, olanzapine significantly prolonged the time to a manic episode compared with lithium. The medications did not differ in time to a depressive episode. Lithium and olanzapine were both associated with notable side effects. Lithium caused significantly more insomnia and nausea, while olanzapine resulted in more weight gain (1.8 kg vs –1.4 kg) and hypersomnia.
Lithium versus divalproex. Lithium and divalproex were compared in a study by Bowden and colleagues.8 In this 52-week trial, the time to discontinuation was significantly longer in the divalproex group compared with the lithium group. There was no statistical difference in the time to any mood episode, although the data trended toward divalproex (P = .06). Lithium and divalproex did not significantly differ in the time to a manic episode or time to a depressive episode. Both medications were associated with unfavorable side effects. Lithium resulted in greater polyuria and thirst, while divalproex was associated with more sedation, infection, and tinnitus. Patients treated with lithium had significantly higher termination rates for drug intolerance and noncompliance.
Olanzapine versus divalproex. Olanzapine and divalproex were compared in a 47-week study involving 251 patients with an acute manic or mixed episode.37 The mean dosage for subjects in the olanzapine group was 16.2 mg/d, while subjects in the divalproex group received 1585 µg/mL. Divalproex serum levels at weeks 3 through 47 ranged from 58.2 to 83.9 µg/mL. No differences were seen in the overall rate of discontinuation or time to symptomatic or syndromic recurrence of an affective episode. Adverse events leading to study discontinuation did not differ between groups. Olanzapine was associated with more somnolence, dry mouth, increased appetite, weight gain, akathisia, elevated cholesterol level, and elevated liver function tests. Subjects in the divalproex group had significantly higher rates of nausea and nervousness.
Drugs Mentioned in This Article
Aripiprazole (Abilify)
Carbamazepine (Carbatrol, Tegretol, others)
Chloral hydrate (Aquachloral)
Chlorpromazine (Largactil, Thorazine)
Diazepam (Valium)
Divalproex (Epival, Depakote)
Lamotrigine (Lamictal)
Lithium (Eskalith, Lithane, Lithobid)
Lorazepam (Ativan)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Temazepam (Restoril)
Valproate/Valproic acid (Depakote, others)
Zaleplon (Sonata)
Ziprasidone (Geodon)
Zoliclone
Zolpidem tartrate (Ambien)
Evidence-Based References
Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;2:S57-S66.
Tohen M, Greil W, Calabrese JR, et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month randomized, double blind, controlled clinical trial. Am J Psychiatry. 2005;162:1282-1290.
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