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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    • "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
    Frontiers in Pharmacology 01/2013; 4:4. DOI:10.3389/fphar.2013.00004 · 3.80 Impact Factor
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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.
    International clinical psychopharmacology 07/2012; 27(5):256-66. DOI:10.1097/YIC.0b013e328356ac92 · 2.46 Impact Factor
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    • "may produce rapid onset of antimanic and antipsychotic response comparable to that of haloperidol and with minimal side-effects in the initial treatment of acute psychotic mania in a subset of bipolar patients (McElroy et al., 1996). Valproate loading is reported to be safe and well tolerated (Hirschfeld et al., 1999). Valproate was reported to be more effective and faster acting than carbamazepine (Vasudev et al., 2000). "
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    ABSTRACT: This paper is a systematic review of the available data concerning the treatment of bipolar disorder: a systematic Medline search concerning treatment guidelines and clinical trials. The search for treatment guidelines returned 583 articles and 913 papers for RCTs. The search was last performed on 1 March 2008. An additional search included repositories of clinical trials and previous systematic reviews in order to trace especially older trials. The literature suggests that lithium is useful during the acute manic and the maintenance phase. Both first- and second-generation antipsychotics are efficacious in the treatment of acute mania. Quetiapine and the olanzapine-fluoxetine combination are also effective for treating bipolar depression, while olanzapine, quetiapine and aripiprazole are effective during the maintenance phase. Anticonvulsants, particularly valproate and carbamazepine have antimanic properties, whereas lamotrigine may be preferably effective in the treatment of depression but not mania. Antidepressants should always be used in combination with an antimanic agent because they were reported to induce switching to mania or hypomania, mixed episodes, and rapid cycling when given as monotherapy. The best evidence-based psychosocial interventions for bipolar disorder are group- and family-focused psychoeducation. Electroconvulsive therapy is an option for refractory patients. Although a variety of treatment options for bipolar disorder is currently available, their effectiveness is far from satisfactory, especially against bipolar depression and maintenance. Combination therapy may improve treatment outcome but it also carries the burden of more side-effects. Further research as well as the development of better guidelines and algorithms for step-by-step rational treatment are necessary.
    The International Journal of Neuropsychopharmacology 09/2008; 11(7):999-1029. DOI:10.1017/S1461145708009231 · 4.01 Impact Factor
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