Double-Blind 18-Month Trial of Lithium Versus Divalproex Maintenance Treatment in Pediatric Bipolar Disorder

Department of Psychiatry, Case Western Reserve University, USA.
Journal of the American Academy of Child & Adolescent Psychiatry (Impact Factor: 7.26). 06/2005; 44(5):409-17. DOI: 10.1097/01.chi.0000155981.83865.ea
Source: PubMed


To determine whether divalproex sodium (DVPX) was superior to lithium carbonate (Li+) in the maintenance monotherapy treatment of youths diagnosed with bipolar disorder who had been previously stabilized on combination Li+ and DVPX (Li+/DVPX) pharmacotherapy.
Youths ages 5-17 years with bipolar I or II disorder were initially treated with Li /DVPX. Patients meeting remission criteria for four consecutive weeks were then randomized in a double-blind fashion to treatment with either Li+ or DVPX for up to 76 weeks. Study participation ended if the subject required additional clinical intervention or if the subject did not adhere to study procedures.
Patients were recruited between July 1998 and May 2002. One hundred thirty-nine youths with a mean (SD) age of 10.8 (3.5) years were initially treated with Li+/DVPX for a mean (SD) duration of 10.7 (5.4) weeks. Sixty youths were then randomized to receive monotherapy with Li+ (n = 30) or DVPX (n = 30). The Li+ and DVPX treatment groups did not differ in survival time until emerging symptoms of relapse (p = .55) or survival time until discontinuation for any reason (p = .72).
DVPX was not found to be superior to Li+ as maintenance treatment in youths who stabilized on combination Li+/DVPX pharmacotherapy.

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    • "In the long-term RCTs, recurrence risk during treatment with a mood-stabilizing or antipsychotic drug averaged 39.3% (21.9%/year). This risk ranged more widely (4.8-fold) than the naturalistic trials (1.5-fold), from 9.25%/ year (with a combination of lithium or valproate with quetiapine; Vieta et al., 2008), to 44.5%/year (with valproate alone; Findling et al., 2005). Recurrences averaged 30.3%/year with placebo, ranging from 21.7 (Keck et al., 2007) to 40.9%/year (Bowden et al., 2003), with strong separation of active treatments from placebo in the six trials that included a placebo condition (Table 4; Figure 1 "
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    ABSTRACT: Bipolar disorder (BD) is a recurrent, lifelong illness with high risks of disability and excess mortality. Despite many treatment options with demonstrated short-term efficacy, evidence concerning long-term treatment effectiveness in BD remains limited and the relative value of naturalistic studies versus randomized, controlled trials (RCTs) in its assessment, uncertain. Systematic computer-searching yielded 10 naturalistic studies and 15 RCTs suitable for analysis of recurrence rates and their association with treatments and selected clinical factors. In naturalistic studies (3904 BD subjects, 53.3% women, 85.8% BD-I, mean onset age 29.1, followed up to 2.1 years), the pooled recurrence rate was 55.2% (26.3%/year). In RCTs (4828 subjects, 50.9% women, 96.0% BD-I, mean onset age 23.1, followed up to 1.9 years), the pooled recurrence rate was 39.3% (21.9%/year) with mood-stabilizing drug-treatment versus 60.6% (31.3%/year) with placebo; drug-versus-placebo outcomes favored antipsychotics over lithium, and disfavor an approved anticonvulsant. Depressive episode-polarity increased from 27.7% at intake to 52.0% at first-recurrence (p<0.0001). Recurrence rate (%/year) did not differ by study-type, was greater with younger onset and rapid-cycling, and paradoxically declined with longer observation. In short, recurrences of major affective episodes up to two years during putative mood-stabilizing treatment of BD patients in prospective, naturalistic studies and RCTs were substantial and similar (26.3 vs. 21.9%/year). Episode-polarity shifted strongly toward depressive first-recurrences. These findings support the value of naturalistic studies to complement long-term RCTs, and add to indications that control of depression in BD remains particularly unsatisfactory. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2015; 25(10). DOI:10.1016/j.euroneuro.2015.07.013 · 4.37 Impact Factor
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    • "For example, Findling and colleagues [131] indicated that children and adolescents who ranged in age from 5 to 17 years and who met criteria for bipolar I disorder or bipolar II disorder were treated safely and effectively using a combination of lithium and divalproex sodium. Once stabilized on this combination of medications, some children and adolescents could continue to be maintained and do well on either lithium or divalproex sodium; however, many children and adolescents experienced relapse or adverse events [132]. In order to effectively combine these medications, however, multiple algorithms were proposed that systematically introduced both mood stabilizers and antipsychotics according to the individual needs of the children and adolescents and their respective treatment responses [112, 133]. "
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    ABSTRACT: Although bipolar disorder historically was thought to only occur rarely in children and adolescents, there has been a significant increase in children and adolescents who are receiving this diagnosis more recently (Carlson, 2005). Nonetheless, the applicability of the current bipolar disorder diagnostic criteria for children, particularly preschool children, remains unclear, even though much work has been focused on this area. As a result, more work needs to be done to further the understanding of bipolar symptoms in children. It is hoped that this paper can assist psychologists and other health service providers in gleaning a snapshot of the literature in this area so that they can gain an understanding of the diagnostic criteria and other behaviors that may be relevant and be informed about potential approaches for assessment and treatment with children who meet bipolar disorder criteria. First, the history of bipolar symptoms and current diagnostic criteria will be discussed. Next, assessment strategies that may prove helpful for identifying bipolar disorder will be discussed. Then, treatments that may have relevance to children and their families will be discussed. Finally, conclusions regarding work with children who may have a bipolar disorder diagnosis will be offered.
    02/2014; 2014(4):928685. DOI:10.1155/2014/928685
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    • "Some studies have commented on the efficacy of lithium in preventing relapse [26, 51]. Findling et al. noted that both lithium and valproate were good maintenance agents but noted that, in both trials, symptoms returned subsequently in about 16 weeks [52]. Another study noted that aripiprazole was superior to placebo at 30 weeks [53]. "
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    ABSTRACT: . Despite controversy, bipolar disorder (BD) is being increasingly diagnosed in under 18s. There is scant information regarding its treatment and uncertainty regarding the status of “severe mood dysregulation (SMD)” and how it overlaps with BD. This article collates available research on treatment of BD in under 18s and explores the status of SMD. Methods . Literature on treatment of BD in under 18s and on SMD were identified using major search engines; these were then collated and reviewed. Results . Some markers have been proposed to differentiate BD from disruptive behaviour disorders (DBD) in children. Pharmacotherapy restricted to short-term trials of mood-stabilizers and atypical-antipsychotics show mixed results. Data on maintenance treatment and non-pharmacological interventions are scant. It is unclear whether SMD is an independent disorder or an early manifestation of another disorder. Conclusions . Valproate, lithium, risperidone, olanzapine, aripiprazole and quetiapine remain first line treatments for acute episodes in the under 18s with BD. Their efficacy in maintenance treatment remains unclear. There is no validated treatment for SMD. It is likely that some children who are currently diagnosed with BD and DBD and possibly most children currently diagnosed with SMD will be subsumed under the proposed category in the DSM V of disruptive mood dysregulation disorder with dysphoria.
    Depression research and treatment 01/2012; 2012(1):967302. DOI:10.1155/2012/967302
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