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Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder

  • Review
  • Intervention

Authors


Keith Reid, Dept of Psychobiology, University of Newcastle, Newcastle, UK. K.S.Reid@ncl.ac.uk.

Abstract

Background

Although lithium has been the most commonly used maintenance treatment in bipolar disorder for several decades, valproate is being used increasingly - especially in the United States of America. There is a need to clarify whether the increasingly prominent prophylactic role of valproate in bipolar disorder is justified.

Objectives

To review the effectiveness of valproate, relative to placebo, other mood stabilisers and antipsychotics, in the prevention and/or attenuation of acute episodes of bipolar disorder. The effectiveness of valproate was considered in terms of mood symptoms, mortality, general health, social functioning, adverse effects and overall acceptability to patients.

Search methods

The CCDAN group search strategy was used. The following databases were searched: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), The Cochrane Controlled Clinical Trials Register (CCCTR), EMBASE , MEDLINE, LILACS , PsycLIT and Psyndex. Reference lists of relevant papers and major textbooks of mood disorder were examined. Authors, other experts in the field and pharmaceutical companies were contacted for knowledge of suitable published or unpublished trials.

Selection criteria

Randomised controlled trials which compared valproate with placebo, alternative mood stabilisers (including lithium and carbamazepine) or neuroleptics, where the stated intent of intervention was the maintenance treatment of bipolar disorder. Participants were males and females of all ages with a diagnosis of bipolar disorder however diagnosed, approximating to ICD 10 Code F31 and DSM IV 296, but including patients diagnosed as ICD-9 manic depressive psychosis and DSM-III and DSM-IIIR bipolar disorder.

Data collection and analysis

Data were extracted from the original reports individually by two reviewers. The main outcomes to be assessed were:
1.The effectiveness of valproate treatment in preventing or attenuating further episodes of bipolar disorder, including its effectiveness in rapid cycling disorder.
2.The acceptability of valproate treatment to patients.
3.The prevalence of side-effects.
4.Mortality on valproate treatment.

Outcomes concerning relapse/recurrence were analysed excluding data from discontinuation studies, which were to be analysed separately. Sub-group analyses were to be performed to examine the effects of valproate treatment in rapid cycling bipolar disorder and previous mood stabiliser non-responders. Data were analysed using Review Manager version 4.1.

Main results

One trial of 12 months duration with 372 participants was identified comparing lithium, divalproex and placebo. It had several methodological limitations. The primary analysis of time to occurrence of mood episode described in the main trial report found no reliable difference between the treatments, although there was a trend for divalproex to be more effective than lithium. In the analysis in this review, patients taking divalproex who left the study because of the occurrence of an mood episode were significantly less in number than those on placebo (RRR 37%; RR 0.63; 95% CI 0.44 to 0.90). There was no significant difference in the numbers of patients in receipt of divalproex compared with those in receipt of lithium who left the study because they suffered any mood episode. (RRR 22%; RR 0.78; 95% C.I. 0.52 to 1.17). There was insufficient information to allow sub-group analyses of rapid-cycling disorder. The divalproex group had significantly more patients suffering tremor (RRI 223%; RR 3.23; 95% C.I. 1.85 to 5.62), weight gain (RRI 187%; RR 2.87; 95% C.I. 1.34 to 6.17) and alopecia (RRI 143%; RR 2.43; 95% C.I. 1.05 to 5.65) than the placebo group. In comparison with the lithium, divalproex was associated with more frequent sedation (RRI 58%; RR 1.58; 95% C.I. 1.08 to 2.32) and infection (RRI 107%; RR 2.07; 95% C.I. 1.16 to 3.68), but less suffered thirst (RRR 62%; RR 0.38; 95% C.I. 0.18 to 0.81) and polyuria (RRR 57%; RR 0.43; 95% C.I. 0.22 to 0.82).

Authors' conclusions

In view of the equivocal findings of this review, conclusions about the efficacy and acceptability of valproate compared to placebo and lithium cannot be made with any degree of confidence. With current evidence, patients and clinicians would probably wish to use lithium before valproate for maintenance treatment. At present, the observed shift of prescribing practice to valproate is not based on reliable evidence of efficacy

摘要

背景

Valproic acid,valproate和divalproex在雙極性情感性疾病的維持治療

雖然鋰鹽數十年來是最常用來當作雙極性疾病的維持治療,不過 valproate的使用卻持續增加,特別是在美國。需要澄清的是,valproate在雙極性疾病逐漸提升的明顯預防角色是否合理。

目標

為了回顧valproate相對於安慰劑、其他情緒穩定劑或是抗精神病劑,在預防或是減緩雙極性疾病急性期的效用。評估Valproate效用的指標包括情緒症狀、死亡率、整體健康、社會功能、副作用以及病人的接受度。

搜尋策略

使用The CCDAN group的搜尋策略並搜尋,以下的資料庫:The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), The Cochrane Controlled Clinical Trials Register (CCCTR), EMBASE, MEDLINE, LILACS, PsycLIT and Psyndex。檢視相關論文以及情感性疾病主要的教科書的參考文獻,同時也聯繫作者,此領域的專家以及藥廠來進一步探求有無相關的已發表或未發表的試驗可供參考。

選擇標準

隨機對照試驗,以雙極性疾病的維持治療為目的,去比較valproate和安慰劑,替代性情緒穩定劑(包含鋰鹽和carbamazepine)或抗精神病藥物的差異。受試者包含所有年紀的男性、女性,並且有雙極性疾病的診斷。(近似CD 10 Code F31 以及 DSM IV 296診斷碼),但也包括ICD9 manic depressive psychosis 以及 DSMIII 和 DSMIIIR bipolar disorder 診斷的病人。

資料收集與分析

資料由兩位評論者從原始文獻個別地擷取出來。主要被評估的預後指標是:1. valproate在預防或減少之後,雙極性疾病發作的治療效果,包括快速循環型疾患。2.病人對valproate治療的接受度。3.副作用的盛行率。4.使用 valproate治療的死亡率。關於再發/復發的預後分析,會排除來自終止藥物治療研究的資料(這些資料將被分開分析)。次組別分析則是去檢視valproate對於快速循環型雙極性患者以及對之前情緒穩定劑無反應患者的治療效果。所有資料是使用Review Manager version 4.1軟體來分析。

主要結論

有一個人數372人,為期12個月,比較鋰鹽、divalproex和安慰劑的試驗,它存在幾個方法學上的限制。在主要分析中分析情感症狀期復發的時間,發現不同的治療並沒有確實的差異,雖然divalproex傾向比鋰鹽有效,在這篇回顧的分析中,服用divalproex的病人,因情感症狀復發而離開研究的人數顯著地少於安慰劑組(RRR 37%; RR 0.63; 95% CI 0.44 to 0.90),至於服用divalproex和服用鋰鹽的則沒有統計上的差異(RRR 22%; RR 0.78; 95% C.I. 0.52 to 1.17)。沒有足夠的資料來對快速循環型疾病做次組別分析。使用divalproex與安慰劑相比,有顯著較多的病人出現顫抖(RRI 223%; RR 3.23; 95% C.I. 1.85 to 5.62),體重增加(RRI 187%; RR 2.87; 95% C.I. 1.34 to 6.17)以及掉髮(RRI 143%; RR 2.43; 95% C.I. 1.05 to 5.65)。和鋰鹽相比,divalproex較會出現鎮定(RRI 58%; RR 1.58; 95% C.I. 1.08 to 2.32)以及感染(RRI 107%; RR 2.07; 95% C.I. 1.16 to 3.68),但是比較沒有口渴(RRR 62%; RR 0.38; 95% C.I. 0.18 to 0.81)和多尿(RRR 57%; RR 0.43; 95% C.I. 0.22 to 0.82)的問題。

作者結論

在這篇回顧中,關於valproatec的效力與接受度和安慰劑與鋰鹽的比較,我們還無法下定論。以目前的證據而言,病人和臨床醫師或許仍會傾向使用鋰鹽來作為維持治療。目前所觀察到使用藥物轉移到valproate的現象,並不是根據可信的效力證據。

翻譯人

本摘要由彰化基督教醫院謝明翰翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

這篇回顧檢視了valproate的效力與接受度和安慰劑與其他情緒穩定劑在雙極性疾病維持治療上的比較。只有一個隨機對照試驗符合這篇回顧的納入條件。這個試驗比較了divalproex和安慰劑以及和鋰鹽長達12個月的時間。這個試驗有幾個方法學上的限制,因而降低了結果的可信度。然而,受試者中,和安慰劑相比,服用divalproex,比較不會復發,但是鋰鹽和divalproex就沒有差異。和服用安慰劑相比,較多服用divalproex的病人因為副作用離開研究,但此服用鋰鹽相比則要來得少。

Plain language summary

Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder

This review investigated the efficacy and acceptability of valproate compared to placebo and other mood stabilisers in the maintenance treatment of bipolar disorder. Only one randomised controlled trial met the inclusion criteria for the review. This trial was a comparison of divalproex with placebo and with lithium over a twelve month period. The trial had several methodological limitations that limit the reliability of the results. However, trial participants who took divalproex were less likely to relapse than those on placebo and there was no difference between lithium and divalproex. More patients on divalproex left the study due to side-effects than those on placebo, but fewer than on lithium.

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