One study analyzing combination therapy failed to separate from monotherapy at the primary end point of YMRS score reduction.41 In this trial, risperidone was combined with valproate/divalproex, lithium, or carbamazepine and compared to monotherapy with valproate/divalproex, lithium, or carbamazepine. Although YMRS score changes did not differ from those seen with monotherapy, response rates were significantly higher with combination therapy. In a post hoc analysis, the authors excluded patients in the carbamazepine polytherapy group after discovering that carbamazepine reduced risperidone concentrations by 40%. Excluding carbamazepine, combination therapy separated from monotherapy in YMRS score reduction.
SGA dosing: combination therapy versus monotherapy. No clinical trials to date have directly compared SGA combination therapy versus SGA monotherapy. Nevertheless, it is helpful to analyze the efficacy and dosing of SGA polytherapy and SGA monotherapy trials when deciding upon treatment medications. On average, combination trials used lower doses of SGAs compared to monotherapy trials. Doses were 5.3 mg lower with olanzapine, 0.7 mg lower with risperidone, and 115 mg lower with quetiapine.39-41,43 Despite the reduced doses, clinical response favored polytherapy versus antipsychotic monotherapy. Response rates were 11% higher with olanzapine polytherapy, 1.3% higher with risperidone polytherapy, and 8% higher with quetiapine polytherapy. The risperidone polytherapy response rate included a CGI-I rating of much or very much improved,40 while response rates in all other studies represent a 50% reduction in YMRS score. This probably accounts for the lower risperidone polytherapy response rate. Although comparisons between SGA combination therapy and SGA monotherapy trials are often unreliable given different study designs, patient populations, and in the case of olanzapine, different study lengths, the response rates suggest that lower antipsychotic doses can be used in polytherapy treatment with good results.
Adverse events with combination therapy. Side effects in combination therapy were generally greater than those with mood stabilizer monotherapy. Study discontinuations because of adverse events occurred more frequently with olanzapine polytherapy, while no statistical difference was seen in other studies. Combination therapy with olanzapine resulted in a higher frequency of somnolence, dry mouth, tremor, speech disorder, increased appetite, and weight gain (3.1 kg vs 0.23 kg). Risperidone polytherapy was associated with increased EPS in 1 of 2 studies and greater weight gain in both studies (averaging 2.05 kg). Quetiapine polytherapy was associated with more somnolence, dry mouth, asthenia, postural hypotension, and a weight gain of 1.97 kg compared with 0.27 kg in monotherapy.
Overall, polytherapy with an SGA and mood stabilizer produced greater improvements in YMRS scores and clinical response than mood stabilizer monotherapy. Combination therapy also resulted in more weight gain, somnolence and, in the case of risperidone, EPS.
Maintenance therapy is an important component of treatment in bipolar disorder and can effectively reduce the rate of relapse. Practice guidelines for bipolar disorder recommend initiation of maintenance treatment following an initial manic episode to prevent relapse, facilitate functional improvement, reduce the frequency of cycling, and decrease the risk of suicide.31 Four agents have been FDA-approved for maintenance therapy in bipolar disorder: lithium, lamotrigine, olanzapine, and aripiprazole. In addition, valproate/divalproex is commonly used in clinical practice. As with acute mania, studies have analyzed individual medications versus placebo, active comparisons between medications, and combination therapy regimens.
Individual medications versus placebo
Lithium. Much of the early research in bipolar maintenance therapy focused on lithium monotherapy and often showed impressive results. However, early studies were associated with numerous statistical problems, including poor diagnostic criteria, inclusion of unipolar patients, failure to use last observation carried forward methodology, and abrupt discontinuation of lithium at randomization to placebo. It was not until the last decade that comparisons between lithium and placebo occurred using modern methodology, often in studies analyzing newer medications needing an active comparator arm.
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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