Rapid oral loading of extended release divalproex in patients with acute mania

General Hospital Psychiatry 27 (2005) 218 – 221

Rapid oral loading of extended release divalproex in patients with acute maniaB,BB Brian P. Miller, M.D., William Perry, Ph.D., Christine Y. Moutier, M.D., Shannon K. Robinson, M.D., David Feifel, M.D., Ph.D.T Neuropsychiatry and Behavioral Medicine Unit, University of California, San Diego Medical Center, San Diego, California 92103-8218, USA Received 7 November 2003; accepted 1 February 2005

Abstract Background: Oral loading with the delayed release formulation of divalproex sodium is widely used for the treatment of patients with acute mania and produces rapid attainment of therapeutic serum levels. Recently, an extended release formulation of divalproex sodium (divalproex ER) was approved for treatment of migraine headaches. This formulation may be a useful treatment option for patients with acute mania. Method: A retrospective review of medical records was conducted on 14 inpatients with acute mania whose treatment included initiation of divalproex ER at a dose of 30 mg kg 1 day 1 in a single dose. Doses, serum levels and side effects associated with this treatment were recorded from the medical records of these patients. Results: The average dose of divalproex ER was 2034 mg day 1 (range, 1500–3000 mg day 1). Two of the 14 patients (14%) had documented side effects, none of which were severe. The average level obtained on day 3 after initiation of divalproex ER treatment was 93.2 Ag ml 1 (range, 47–136 Ag ml 1), and in all but three patients valproate levels at this time point were within the therapeutic range of 50 –125 Ag ml 1. In no case was divalproex ER discontinued due to a perceived lack of efficacy. Conclusion: The results suggest that divalproex ER can be safely administered by oral loading in inpatients with acute mania and that using a standard loading protocol can result in therapeutic serum levels in most patients in 3 days or less. D 2005 Elsevier Inc. All rights reserved. Keywords: Divalproex extended release; Mania; Valproate; Rapid loading

1. Introduction Divalproex sodium in its original, delayed release formulation (divalproex DR) has been widely used as a treatment for mania. Divalproex is thought to be at least as effective as lithium in the treatment of acute mania, and possibly superior to lithium in the treatment of mixed manic states, and rapid-cycling bipolar disorder [1– 4]. Rapidloading strategies for divalproex DR have been shown to be safe and effective in treating acutely manic inpatients and provide the advantage of achieving therapeutic serum levels faster than conventional loading regiments [5–9]. An extended release formulation of divalproex sodium (divalproex ER) has recently been FDA approved for once-a-day B Disclosures: The following indicate authors association with Abbott Laboratories, the manufacturer of Depakote ER. Speakers bureau: BM, DF; consultant: SR; research grants: DF. BB This study was not funded by any external sources. T Corresponding author. Tel.: +1 619 543 2827; fax: +1 619 543 3738. E-mail address: [email protected] (D. Feifel).

0163-8343/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2005.02.001

dosing in the treatment of migraine headaches [10,11]. This new formulation results in more steady serum levels throughout the day compared to the DR formulation. This potentially produces fewer side effects associated with supratherapeutic peak levels and possible better symptom control due to the elimination of sub-therapeutic serum trough levels [12]. Furthermore, a once-a-day formulation is more convenient for patients than multi-dose regimens and, therefore, has the potential to increase compliance. It is reasonable to assume that the advantages of an extended release formulation of divalproex may also be useful in treating psychiatric patients with acute mania. In fact, preliminary studies support the safety and efficacy of divalproex ER in the treatment of psychiatric patients [13–17]. Rapid loading of divalproex DR has been widely employed by the authors for several years on the acute inpatient psychiatric unit (Neuropsychiatry and Behavioral Medicine Unit) at UCSD Medical Center. Recently, we have acquired experience adapting rapid oral loading strategies to initiate divalproex ER treatment for psychiatric inpatients

B.P. Miller et al. / General Hospital Psychiatry 27 (2005) 218 – 221

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changes, results of all valproate serum levels, any reported adverse effects, discontinuations due to adverse events, and concomitant medications prescribed.

with acute mania. The most common method used has been to initiate divalproex ER treatment at the available dose closest to 30 mg kg 1 day 1 given once per day. This dosing regimen was based upon work done by Hirschfeld et al [9] which showed that therapeutic valproate blood levels could be achieved safely by the third day of treatment when divalproex DR was initiated at 30 mg kg 1 day 1. Similarly, when divalproex ER is dosed using this strategy on our service, initial serum valproate levels are typically obtained on the third day after initiating treatment. Dosing adjustments are made according to clinical response and obtained valproate levels. Bowden et al [17] demonstrated that manic patients with valproate levels above 45 Ag ml 1 had a better clinical response than patients with lower valproate levels. Others have advocated a minimal therapeutic serum valproate level of 50 Ag ml 1 in manic patients [5–9]. In addition to serum valproate levels 3 days after initiation of divalproex treatment, steady-state levels are also often obtained 5 or more days after the final dose is initiated. Our experience has been that this method of initiating divalproex ER treatment is well tolerated and safe. In this paper, we provide a preliminary report, based upon a retrospective review of medical records, of the safety and tolerability of oral loading of divalproex ER in our inpatient service.

3. Results Table 1 summarizes the data collected from the first 14 charts identified in which oral loading with divalproex ER was used. The charts belonged to eight men and six women. Four patients had a diagnosis of bipolar disorder type I, and 10 had a diagnosis of schizoaffective disorder, bipolar type. Their ages ranged from 27 to 67 years old (mean =43). Initial doses of divalproex ER ranged from 1500 to 3000 mg day 1 (mean = 2034). Side effects were noted for only two of the 14 patients. One patient who received 1500 mg day 1 of divalproex ER and had a serum valproate level of 47 Ag ml 1 on the third day after the initiation of treatment complained of dry mouth. This side effect was not considered severe enough by the treating physician to result in a change in medications, and it resolved spontaneously during the course of inpatient treatment. Another patient who received a dose of 2500 mg day 1 divalproex ER and had a valproate level of 91 Ag ml 1 on the third day after divalproex ER initiation complained of dizziness, diplopia and GI distress. This patient was switched to the same dose of divalproex DR, administered in two divided doses, by the treating physician. The dizziness, diploplia and GI distress gradually resolved over the following week. All but one of the 14 patients had a valproate serum level drawn on the third day after initiation of divalproex ER treatment, and these valproate levels varied from 47 to 136 Ag ml 1 (mean= 93.2). Day-3 valproate levels of all patients were above Bowden’s cutoff of 45 Ag ml 1, but two patients had valproate levels that were slightly lower than the 50 Ag ml 1 cutoff advocated by others (47 and 48 Ag ml 1). One patient had a day-3 valproate level above the conventional

2. Methods Approval was obtained from the UCSD Human Research Protection Program for retrospective review of the medical records of inpatients with acute mania who had been treated with divalproex ER at the University of California at San Diego, Neuropsychiatry and Behavioral Medicine Unit. The first 14 patient medical records in which rapid oral loading of divalproex ER was used were reviewed to extract the following information: gender, age, diagnosis of record, initial dose of divlaproex ER and any subsequent dose

Table 1 Summary of inpatients treated with oral loading divalproex ER Patient No.

Age

Sex

Diagnosis

Initial dose (mg day 1)

Valproate level day 3 (Ag ml 1)

Valproate level day z 5 (Ag ml 1)

Concomitant medication

Reported side effects

1 2

37 47

F M

Bipolar Schizoaffective

1500 2500

100 101

106 72

Seroquel, neurontin Olanzapine

3 4 5 6 7 8 9 10 11 12 13 14 Mean

35 64 27 51 27 54 29 39 46 34 42 67 43

M F F F M M M M M M M F

Schizoaffective Schizoaffective Bipolar Bipolar Schizoaffective Schizoaffective Schizoaffective Schizoaffective Bipolar Schizoaffective Schizoaffective Schizoaffective

3000 2000 1500 2500 2500 1500 1500 2500 2500 1500 1500 2000 2034

59 112 136 95 120 111 47 64 117 48 ND 99 92.5

69 103 ND 101 119 ND ND ND ND ND 116 100 95.5

Risperidone Olanzapine Olanzapine, lithium Risperidone Olanzapine Risperidone Seroquel, neurontin, lorazepam Risperidone, lorazepam, trazadone

None Dizziness, diplopia, GI upset None None None None None None Dry mouth None None None None None

Clozapine, lorazepam Topiramate, risperidone Risperidone, lorazepam

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B.P. Miller et al. / General Hospital Psychiatry 27 (2005) 218 – 221 1

ceiling threshold of 125 Ag ml (136 Ag ml 1), but no adverse effects were noted in this patient’s chart. Seven of the 14 charts reviewed had at least one steady-state serum valproate level drawn 5 or more days after initiation of the divalproex ER. These ranged from 68 to 119 Ag ml 1 (mean= 95.5). All patients were treated concomitantly with other psychotropic mediations while they received divalproex ER, including antipsychotics (12/12), benzodiazepines (11/12), antidepressant (1/12) and anticonvulsants (2/12). In no case was divalproex ER discontinued due to a perceived lack of efficacy. 4. Conclusions To the best of our knowledge this is the first published report of the use of rapid oral loading strategy with divalproex ER. Based upon this limited sample, oral loading of divalproex ER was well tolerated by a majority of the patients. Only two of the 14 (14 %) patients receiving this regimen had noteworthy side effects, and in only one case was treatment discontinued. In two retrospective studies of rapid loading with divalproex sodium, 31% [6] and 33% [7] of patients reported some adverse effects, respectively. In two prospective studies, the reported rate of adverse effects was 26% [5] and 60% [9] of patients. In none of these studies was there a report of the adverse events requiring the patient to discontinue treatment with divalproex. In the current study, only one patient was discontinued from treatment with divalproex ER due to diplopia, dizziness and GI distress, and that patient was switched to the same dose of divalproex DR. As the adverse effect did not improve immediately with this switch but rather improved gradually, it is not possible to conclude whether the ER formulation contributed to the adverse effects in this patient, and if a similar rate of improvement would have occurred if the patient was maintained on divalproex ER. With respect to tolerability, this review of these medical records indicates that rapid loading of divalproex ER is well tolerated and produces adverse effect rates that appear to be lower than those reported for rapid loading regimens of divalproex DR, a finding which supports the idea that the extended release formulation may be more tolerable due to lower peak serum levels. All of the patients receiving the rapid loading regimen of divalproex ER had serum valproate levels above the minimum therapeutic cutoff of 45 Ag ml 1 established by Bowden et al [17]. Many investigators [5–9] use a minimum threshold of 50 Ag ml 1 rather than 45 Ag ml 1, and in this regard, two patients had day-3 serum vaproate that were slightly lower than this therapeutic cutoff (47 and 48 Ag ml 1). The mean serum level on day 3 was 92.5 Ag ml 1. This is similar to the results of previous studies using rapid loading regimens of divalproex DR where the rates of achieving therapeutic serum levels by days 2–3 ranged from 84% to 100%, and the average serum level in those studies ranged from 83.8 to 93.5 Ag ml 1

[5–9]. In contrast, only approximately 30% of patients given divalproex DR in a non-rapid-loading fashion achieve serum levels greater than 50 Ag ml 1 [9] by the third day. One of the patients treated had a serum level on day 3 that was beyond the upper therapeutic range (136 Ag ml 1), but this patient did not experience any adverse effects. This is the first case series which employed a loading dose when concomitant medication therapy was used and therefore supports the safety of this mode of dosing in acutely manic hospitalized patients. The purpose of this study was to determine the safety and tolerability of a rapid loading strategy and to determine its efficacy in terms of achieving therapeutic plasma ranges. We did not attempt to formerly address clinical efficacy. Furthermore, because concomitant medications were typically administered, it is difficult to draw conclusions regarding the efficacy of divalproex. However, the molecular structure of divalproex ER and divalproex DR are identical, and, therefore, it is reasonable to assume that the ER formulation retains the efficacy of the DR formulation. Furthermore, four published preliminary studies examining the efficacy of divalproex ER as mood stabilizer in bipolar, schizophrenia and schizoaffective disorder have concluded that it appears to have comparable efficacy to the DR formulation [13 –17]. As this is a retrospective medical record review on a small number of patients, these findings should be considered preliminary and preclude a definitive assessment of relative efficacy or relative tolerability of divalproex ER compared to divalproex DR or other treatments. However, although we report here only on a small, initial sample of inpatients treated on our inpatient unit with orally loaded divalproex ER, a collective positive experience by the authors and other clinicians on our service using this procedure beyond these first 14 patients has led to its continued routine use on our inpatient service where it has replaced rapid loading of divalproex DR as a standard intervention for patients with acute mania. Definitive determination of whether divalproex ER represents an advantage in the tolerance or efficacy compared to the regular release formulation will require double-blind, controlled, prospective studies. References [1] Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 1994; 271:918 – 24. [2] Calabrese JR, Delucchi GA. Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder. Am J Psychiatry 1990; 147:431 – 4. [3] Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000;57(5):481 – 9. [4] Dalkilic A, Diaz E, Baker CB, et al. Effects of divalproex versus lithium on length of hospital stay among patients with bipolar disorder. Psychiatr Serv 2000;51:1184 – 6.

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