One double-blind, randomized, controlled trial to date has analyzed the combination of an antipsychotic and a mood stabilizer in bipolar maintenance treatment. The study by Tohen and colleagues55 looked at relapse prevention using a combination of olanzapine and valproate/lithium versus placebo plus valproate/lithium. The trial consisted of 99 patients who achieved syndromic remission from an index manic or mixed episode after receiving olanzapine plus valproate/lithium for 6 weeks. Patients randomized to combination therapy were given an average olanzapine dose of 8.6 mg, while lithium and valproate were within therapeutic ranges in both groups. A significantly larger percentage of patients who received combination therapy completed the trial (31% vs 10%). Time until discontinuation was also longer for the combination therapy group (111 days vs 82 days). However, time to syndromic relapse of any mood episode, time to a manic episode, and time to a depressive episode did not differ between treatment groups.
In a subgroup analysis of 68 patients with both syndromic and symptomatic remission upon study entry, combination therapy was associated with a significantly longer time until symptomatic relapse of a mood episode (163 days vs 42 days). However, recurrence rates did not differ. Additional subgroup analyses found that both women and white subjects had a prolonged time to symptomatic relapse of any mood episode with combination therapy. Subjects treated with combination therapy had significantly greater weight gain (3.1 kg vs –1.8 kg).
The majority of mood stabilizers and antipsychotics used in the treatment of bipolar disorder are associated with significant adverse effects. Commonly reported adverse events include weight gain, somnolence, tremor, rash, and EPS. Studies have analyzed the relationship between medication dosing and side effects to see if a correlation exists. Bowden and colleagues noted that divalproex was associated with greater weight gain when the serum concentration rose above 125 µg/mL.8 In the same study, lithium levels exceeding 1.5 mEq/L correlated with diarrhea and tremor. Kinon and Gilmore56 did not find a correlation between higher olanzapine doses and greater weight gain in the dose range of 5 to 20 mg. In contrast, Beasley and colleagues57 noted greater weight gain associated with increasing olanzapine doses.
Many common adverse effects can be mitigated through medication selection and dosing strategies. For example, atypical antipsychotics are recommended over typical antipsychotics because of their reduced risk of EPS.31 Within the atypical antipsychotic class, risperidone is associated with the highest risk of EPS.58 This risk can be minimized by limiting the daily dose to 6 mg or less. The titration schedule of medications can also be important. Lamotrigine is associated with a benign rash in 10% of patients.59 However, a slow titration schedule and dermatologic precautions (avoiding new foods or allergens) can reduce that risk to less than 5%.60
Weight gain is one of the most problematic side effects of treatment given its association with heart disease, diabetes, hypertension, and cancer. Notable in the bipolar maintenance trials was a tendency for patients to gain weight early in treatment. The preponderance of weight gain occurred during short-duration open-label phases, with markedly less weight gain seen in the longer maintenance phases.52,54,55 In order to minimize early weight gain, it is important that behavioral modifications be encouraged at the start of treatment.
The inpatient setting can be an ideal location for behavior modification education. A retrospective analysis of 143 hospitalized patients taking olanzapine found that 4 simple diet changes significantly reduced inpatient weight gain over a 3-week period.61 Eliminating desserts, offering healthier snacks, encouraging water intake, and eliminating double portions resulted in a 5.7 lb reduction in weight gain compared with patients admitted before diet modification. When the same 4-step approach was encouraged among 22 outpatients taking olanzapine, weight gain over 7 months averaged 5.3 lb, which was 40% to 60% less than weight gain seen without a structured intervention.62 Additional behavior modifications have also been effective in mitigating weight gain (Table 2). These trials demonstrate that behavioral modifications can significantly decrease weight gain associated with mood stabilizer and antipsychotic medications.
Studies have shown that many pharmacologic agents are effective in the treatment of acute mania and bipolar relapse education. The duration of manic episodes is reduced by valproate/divalproex, lithium, chlorpromazine, carbamazepine, olanzapine, aripiprazole, risperidone, quetiapine, and ziprasidone relative to placebo. The majority of trials directly comparing these agents have not found significant differences. However, the combination of mood stabilizers and atypical antipsychotics has demonstrated significant improvements compared with monotherapy. In addition, the dosing and titration of medications can have a significant impact on both the speed and degree of clinical response.
Effective bipolar relapse reduction has been demonstrated with lithium, lamotrigine, aripiprazole, and olanzapine. Patients who predominantly experience depressive episodes would probably benefit from treatment with lamotrigine or olanzapine, while all 4 maintenance agents have shown efficacy in delaying the time to a manic episode. In head-to-head trials, olanzapine was superior to lithium, and lithium was superior to lamotrigine in delaying the onset of a manic episode. Patients with suicidal ideation or a history of suicide attempts may preferentially benefit from lithium maintenance therapy.
Given the often significant side effects associated with psychopharmacologic treatment, it is important that clinicians encourage behavioral modifications that can mitigate adverse effects such as weight gain. Ultimately, the risks versus benefits of different treatment plans must be considered for each patient, and the treatment plans tailored to each patient’s needs.
Drugs Mentioned in This Article
Carbamazepine (Carbatrol, Tegretol, others)
Chloral hydrate (Aquachloral)
Chlorpromazine (Largactil, Thorazine)
Divalproex (Epival, Depakote)
Lithium (Eskalith, Lithane, Lithobid)
Valproate/Valproic acid (Depakote, others)
Zolpidem tartrate (Ambien)
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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