Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients.
ABSTRACT Achieving therapeutic blood levels of a mood stabilizer as quickly as possible is desirable in patients with acute mania. We examined the feasibility and safety of an accelerated oral loading strategy (divalproex, 30 mg/kg/day, on days 1 and 2, followed by 20 mg/kg/day on days 3-10) designed to bring serum valproate concentrations to therapeutic levels (i.e., above 50 microg/mL).
Fifty-nine patients who met DSM-IV diagnostic criteria for current manic episode and who had a Mania Rating Scale score > or = 14 were randomly assigned on a double-blind basis to receive divalproex oral loading (N = 20); divalproex nonloading (N = 20) at a starting dose of 250 mg t.i.d. on days 1 and 2, followed by standard dose titration for days 3 to 10; or lithium carbonate (N = 19) at a starting dose of 300 mg t.i.d., followed by standard dose titration for days 3 to 10.
Eighty-four percent of the divalproex-loading patients, but only 30% of the divalproex-nonloading patients, had valproate serum levels above 50 microg/mL at day 3 of the study. None of the lithium-treated patients had serum lithium levels above 0.8 mEq/L at study day 3. No patient was removed from the study because of an adverse event. There were no significant differences between the groups in the frequencies or types of adverse events.
Accelerated oral loading with divalproex sodium is a feasible and safe method to bring serum valproate concentrations to effective levels rapidly.
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ABSTRACT: Bipolar affective disorder is a serious mental disease associated with significant morbidity and mortality. Good-quality research available to guide treatment strategies remains insufficient, particularly with regard to manic or hypomanic episodes. A critical review of the various stages of mania might be helpful for pharmaceutical companies and investigators as a prerequisite for the clinical evaluation of potential antimanic properties of medications. The main difficulty is with a comparison between anticonvulsants, antipsychotics, and mood stabilizers such as lithium (with equal efficacy in the acute phase and the prevention of recurrent manic episodes). No consensus has been reached with regard to the treatment of bouts of acute mania in various parts of the world. Controlled clinical trials have, at last, provided irrefutable evidence of the activity of lithium, which has long been used alone, as well as that of divalproate or its derivatives and, to a lesser extent, carbamazepine. The new antipsychotic agents have more recently established their efficacy, especially aripiprazole, asenapine, quetiapine; olanzapine, risperidone, and ziprasidone (not sure where the paradox is). In Europe, haloperidol is still the reference substance used in clinical trials despite the fact that it is not officially indicated in the treatment of mania. In the USA, lithium, divalproate, or antipsychotics can be prescribed as first-line treatment. In Europe, lithium remains the first-line medication, whereas divalproate and atypical antipsychotic agents are used only as second-line therapy. Although both types of medication (antipsychotics, normothymic agents, and/or anticonvulsants) have proved to be clinically effective in the management of mania by reducing the mania scores overall, the same does not apply, however, to all symptoms of mania. Factorial approaches to mania have all shown that since there are several clinical forms of mania, several clusters of manic symptoms can be identified. Antipsychotic and normothymic agents and/or anticonvulsants do not appear to have the same effects on each of these identifiable clusters of symptoms, mainly psychotic features. We believe that it is vitally important for future clinical trials of mania treatment to focus on the treatment effect by adopting a factorial approach to characterization of the episode using an appropriate methodological structure. These questions highlight the uncertainty shrouding the very structure of manic episodes, namely that these are predominantly of a thymic or psychotic nature. The Europeans undoubtedly consider mania to be more of a thymic episode and prefer lithium as the first-line treatment, whereas the Americans believe that psychotic symptoms dominate and widely prescribe antipsychotic agents. However, from the standpoint of clinical trials currently available, even though antipsychotic agents are certainly effective in reducing the scores on the mania scales, it is not clear whether they can be considered purely as antimania treatments.Frontiers in Pharmacology 01/2013; 4:4. DOI:10.3389/fphar.2013.00004
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ABSTRACT: To review the efficacy of pharmacological agents in bipolar mixed states. We conducted a PubMed search of all English-language articles involving Food and Drug Administration (FDA)-approved agents for manic/mixed states in adults with bipolar I disorder. We also included names of agents established as efficacious in acute mania/mixed states that have not received FDA approval for bipolar disorder. Bibliographies from relevant articles were also searched. The efficacy of each agent in the mixed state subpopulation was reviewed, as evidenced by change from baseline on total scores of mania [e.g., Young Mania Rating Scale (YMRS)] and depression [e.g., Montgomery-Åsberg Depression Rating Scale (MADRS)] measures. No available study is dedicated exclusively to the evaluation of mixed state populations. Although key inclusion and exclusion criteria are similar across treatment studies, mixed states have been variably defined and measured. The use of conventional manic and depressive metrics in bipolar mixed states perpetuates the unproven notion that mixed states are the consequence of coexisting depression and mania. Notwithstanding the methodological limitations, there are numerically more studies that exist for atypical antipsychotic agents than for any other class. On the basis of symptomatic improvement, recommendations for and/or strong admonishments against any established antimanic agents (e.g., lithium) cannot be made. An emergent signal supports combination treatment strategies (e.g., atypical antipsychotic plus divalproex) over mood stabilizer monotherapy (e.g., divalproex). Available evidence does not empirically support the hypothesis that conventional antipsychotics engender and/or amplify depressive symptoms in bipolar mixed states. All proven antimanic agents (including lithium), can be recommended in the treatment of mixed/dysphoric states. The totality of evidence with attention paid to the therapeutic index of each agent would suggest that atypical antipsychotics and divalproex be considered as first-line treatment, with lithium and carbamazepine as second-line. Most individuals will require combination therapy for the treatment of mixed states; variable combinations of atypical antipsychotics and conventional mood stabilizers have the most replicated evidence.Bipolar Disorders 05/2012; 14 Suppl 2:22-36. DOI:10.1111/j.1399-5618.2012.00990.x · 4.89 Impact Factor