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The optimal pharmacological maintenance treatment of bipolar disorder requires titration of any single mood-stabilizing medication to eradicate subsyndromal symptoms and prevent relapse. However, outcome assessments from randomized, controlled trials and naturalistic studies indicate that only a minority of patients with bipolar disorder experience optimal benefit (no relapse or recurrences, minimal to no subsyndromal symptoms) from monotherapy with any single mood stabilizer. Combination therapy is therefore frequently necessary and is commonplace in clinical practice. Unfortunately, very few studies have addressed specific mood stabilizer combinations, their relative therapeutic advantages, and their tolerability. As described earlier (see "Maintenance Treatment" section earlier in chapter), the combination of olanzapine with lithium or divalproex was significantly more likely to prevent relapse compared with lithium or divalproex (with placebo) in patients initially responsive to the combination (Tohen et al. 2004). In the only other study reported, Solomon et al. (1997) compared the efficacy of lithium alone versus the combination of lithium and divalproex for 1 year in 12 patients. The combination significantly reduced the risk of recurrence of mania or depression but was associated with more side effects. Thus, the clinical practice of combining mood stabilizers has greatly outstripped the limited data available from formal studies. Combinations of lithium and divalproex, lithium and carbamazepine, and divalproex and carbamazepine; triple therapy with all three agents; and lithium and/or divalproex with atypical antipsychotics, antidepressants, and lamotrigine have all been reported in case series to be useful maintenance treatment strategies (M. P. Freeman and Stoll 1998).

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