Safety and Tolerability of Oral Loading Divalproex Sodium in Acutely Manic Bipolar Patients

University of Texas Medical Branch at Galveston, 77555-0188, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 12/1999; 60(12):815-8. DOI: 10.4088/JCP.v60n1202
Source: PubMed


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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    • "In acute mania, valproate oral loading (doses of 20– 30 mg/Kg body weight) produces a rapid antimanic and antipsychotic response with minimal side-effects [11] [12] [13]. "
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    ABSTRACT: Valproate is an effective antimanic agent and is recommended as a first-line medication in the treatment of acute mania. Current evidence based guidelines recommend that valproate should be given as a loading dose as it produces a rapid antimanic and antipsychotic response with minimal side-effects. However, no clear guidelines are available on the appropriate dosing or serum levels of valproate in the continuation or maintenance phase of bipolar disorder. We present 4 clinical cases to hypothesize that the higher doses of valproate, such as those used in the treatment of acute mania, may cause a depressive switch. So consideration should be given to reducing the dose of valproate if a patient develops depressive symptoms following recovery from the manic episode, as a therapeutic strategy. The cases also indicate that relatively lower doses and serum levels of valproate are effective in the maintenance phase compared to those needed in the acute manic phase of bipolar disorder. This is the first set of case series that questions the depressogenic potential of valproate in patients remitting from an acute manic episode. It highlights that different doses and serum levels of valproate may be therapeutic in different phases of bipolar disorder.
    Full-text · Article · Dec 2015
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    • "A 3-week-randomized study was conducted by Hirschfeld et al. (1999) in 134 manic patients receiving risperidone (mean dose of 4.1 mg/day) as compared to placebo (15 patients). The YMRS scores were significantly decreased in the risperidone group as early as the third day: 43% of those randomized to risperidone met the response criteria at endpoint versus only 24% in the placebo group. "
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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 pharmamaceutical companies and investigators as a prerequisite for the clinical evaluation of potential antimanic properties of medications. The main difficulty remains the comparison between 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 asthat 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 ziprazidone. It is paradoxical to note that, 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 lines of manic symptoms can be identified. Antipsy
    Full-text · Article · Jan 2013 · Frontiers in Pharmacology
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    • "There is consistent evidence that valproate is an efficacious treatment for acute mania. A rapid VPA titration scheme named 'VPA loading' has been reported to be safe and well tolerated (Hirschfeld et al., 1999). However, VPA also harbours a potential risk of embryonic malformation and polycystic ovaries (Joffe et al., 2006). "
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    ABSTRACT: The increasing number of pharmacological treatment options for bipolar disorder seems to be paralleled by the number of evidence-based guidelines published previously. The aim of this study was to systematically examine the adherence to published guidelines and any change in prescription habits over time in a psychiatric hospital setting. This is a retrospective study of 531 bipolar in patients who were consecutively admitted to the Department for Psychiatry and Psychotherapy in Innsbruck. Their complete medical histories were evaluated for psychotropic medications, with a special focus on mood stabilizers (MSs). To compare the use of individual MSs or combinations with other psychotropic medications in two preselected observation periods (1999-2003 and 2004-2007), we used Fisher's exact test. Overall, the proportion of patients receiving at least one MS increased significantly from 1999-2003 to 2004-2007 (74.1 vs. 83.1%, P=0.011). Among the individual MSs, valproate was used most frequently in both time periods, showing a significant increase (P<0.001). Prescriptions of quetiapine (P<0.001) and lamotrigine (P=0.033) increased significantly, carbamazepine showed a significant decrease (P<0.001). Prescriptions of lithium and olanzapine decreased without reaching significance. The significant increase in the prescription of MS reflects the increasing awareness and implementation of recent evidence-based medicine guidelines into clinical practice. Clinical decision making, usually made on the basis of individual clinical experience, should always be reevaluated using periodically updated evidence-based medicine guidelines.
    Full-text · Article · Jul 2012 · International clinical psychopharmacology
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