Bipolar disorder is a highly prevalent lifelong neuropsychiatric syndrome characterized by recurrent mood episodes. Up to 40% of patients who respond to initial treatment suffer relapses within the first year, and most investigators agree that repeated episodes present a significant problem. Hence, prevention of mood episodes through the maintenance phase of treatment is critical for improving the long-term outcomes of bipolar patients.
The majority of treatment guidelines include lithium in their recommendations for first-line maintenance therapy.[4-7] However, alternatives to lithium are clearly needed for the maintenance treatment of bipolar disorder. Undesirable side-effects, adverse reactions, a narrow therapeutic index, and the increased risk of toxicity with overdose can make lithium therapy less than ideal for many patients. A search for adjunctive and alternative treatments revealed evidence that other medications have mood-stabilizing properties. Valproate has been used in the maintenance treatment of bipolar disorder for the past 5 decades. Based on the hypothesis that mania may result from the depletion of inhibitory neurotransmitters, such as GABA, it was postulated that the GABAergic effect of valproate may be therapeutic. Valproate is increasingly prescribed for both acute episodes and maintenance.[10, 11] Moreover, both valproate and lithium are recommended as first-line maintenance treatments following an episode of mania or hypomania.
However, clinicians often wonder whether to select valproate or lithium to treat patients with bipolar disorder. A few previous studies found lithium and valproate to be similarly effective in the maintenance treatment of bipolar disorder.[13-15] However, other studies reported results favoring lithium or valproate. In the context of these mixed results on the relative strengths and weaknesses of lithium and valproate, combination therapy has become the standard of care for the treatment of bipolar disorder. Yet, it is somewhat surprising that only a limited number of studies comparing the use of lithium and valproate in combination with atypical antipsychotics have been conducted. Hence, we performed this study to compare the 1-year rehospitalization rates associated with lithium and valproate when each was given along with an atypical antipsychotic to patients with bipolar I disorder who had been discharged after hospitalization due to an initial manic episode.
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To our knowledge, this is one of the first studies comparing the rehospitalization rates for lithium or valproate given in combination with an atypical antipsychotic to bipolar I patients with first-episode mania. We found that the time before rehospitalization for any mood episode was significantly longer in patients receiving valproate plus an atypical antipsychotic than in those receiving lithium plus an atypical antipsychotic. A trend toward a significant difference between the groups was also seen with respect to rates of rehospitalization due to manic or mixed episodes. Additionally, we found that patients with bipolar I disorder who were hospitalized due to a first manic episode and who received valproate plus an atypical antipsychotic had lower 1-year rehospitalization rates for any kind of mood episode than did those who received lithium plus an atypical antipsychotic, but the difference did not reach a statistically significant level.
The results of the present study are consistent with those of previous studies in which valproate was favored over lithium for relapse prevention in bipolar patients. Lambert and Venaud conducted a comparative study of valproate versus lithium for the prophylaxis of bipolar disorders. This 18-month open, randomized study reported 0.51 episodes per subject in the valproate group and 0.61 episodes per subject in the lithium group; although this difference was not statistically significant, these figures reflect a 20% lower rate of new episodes among valproate-treated than among lithium-treated patients. Bowden et al. conducted the first double-blind, randomized, controlled maintenance study in bipolar I disorder, which involved following patients from an index manic episode through a subsequent 52-week maintenance phase. The mean durations of survival in maintenance treatment were 198 days for the divalproex group and 152 days for the lithium group, reflecting a significant difference between the divalproex- and lithium-treated groups in favor of divalproex.
A few previous studies have compared the effectiveness of lithium and valproate monotherapy for preventing relapses of bipolar disorder. Findling et al. reported that lithium and divalproex treatment groups did not differ in the time to symptoms of relapse or to discontinuation for any reason. Another 20-month, double-blind study comparing lithium and divalproex monotherapy reported no significant differences in the time to relapse due to any kind of episode, the time to relapse due to a depressive episode, or the time to relapse due to a hypomanic/manic/mixed episode. However, these studies included pediatric bipolar patients or rapid-cycling bipolar patients, and methodological differences make it hard to compare the effectiveness of pharmacological treatments. Moreover, lithium monotherapy was more likely to prevent relapse than was valproate monotherapy according to a recent randomized, open-label trial. However, as the trial was primarily designed to compare lithium and valproate combination therapy with lithium or valproate monotherapy, conclusions about the comparative efficacy of the two agents should be made cautiously.
It is has been established that several clinical features are related to increased risk of relapse. Factors associated with shorter survival times include increased number of previous episodes, decreased interval between episodes, and persistence of affective symptoms. The results from the present study showing higher discharge CGI-BP-S scores associated with a higher risk of rehospitalization also confirm previous reports that residual affective symptoms are associated with outcomes.
Several possible weaknesses in our study design should be considered. The main limitations were the retrospective design and small sample. Moreover, we included only patients with at least 12 months of follow-up care who continued to receive the same combination regimen as was given at discharge. Hence, the results are most applicable to patients who can tolerate treatment with lithium or valproate in combination with an atypical antipsychotic and who are largely adherent to this regimen. Medication adherence is a well-known predictor of relapse in bipolar patients. The rehospitalization rates reported in this study may be underestimates, as we excluded patients who did not receive follow-up care for 12 months. Moreover, we did not use objective adherence monitoring and could not exclude the possibility that adherence issues substantially affected relapse or rehospitalization rates. Another concern was that clinical variables that can affect rehospitalization rates, such as number of previous depressive episodes, age at onset, and number of previous psychiatric hospitalizations, were not considered. Additionally, we did not examine plasma concentrations of lithium and valproate. Hence, the lithium and valproate plasma concentrations of some patients may have been suboptimal during the follow-up period. All researchers participating in this study were members of the Committee for a Korean Medication Algorithm for Bipolar Disorder. The Korean medication algorithm for bipolar disorder recommends lithium or valproate in combination with an atypical antipsychotic as the first-line strategy for acute mania. This may have affected clinical practice and contributed to the relatively even distribution of clinical variables and treatment preferences observed in the study data. Finally, we did not distinguish rehospitalizations due to the failure of acute treatment from those due to the failure of maintenance treatment. Some proportion of rehospitalized patients were experiencing a failure of acute treatment rather that a failure of maintenance treatment. However, the efficacy of lithium is comparable to that of valproate for the treatment of acute mania, but about 34% more patients relapse due to any kind of mood episode while receiving lithium than while receiving valproate. The results of the present study showing that valproate reduced the risk of rehospitalization are consistent with the results of a previous maintenance study.
Despite these limitations, our results indicate that treatment with valproate and an atypical antipsychotic may be more effective than treatment with lithium and an atypical antipsychotic to prolong the time to rehospitalization due to any kind of mood episode among patients with bipolar disorder I who have previously been hospitalized with their first episode of mania. Long-term, double-blind, randomized, controlled trials are needed to elucidate the effectiveness of combination therapy with lithium or valproate and atypical antipsychotics in terms of relapse prevention.