A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolar mania

Division of Mood Disorders, University of British Columbia, UBC Hospital, Vancouver, British Columbia, Canada.
International Clinical Psychopharmacology (Impact Factor: 2.46). 08/2007; 22(4):212-20. DOI: 10.1097/YIC.0b013e328080ca57
Source: PubMed


The aim of this study was to evaluate the efficacy and tolerability of quetiapine combined with lithium or divalproex in the treatment of bipolar mania. Patients were randomized to 6 weeks of quetiapine (up to 800 mg/day) and lithium/divalproex (Li/DVP) (target trough serum concentrations of 0.7-1.0 mEq/L and 50-100 microg/mL, respectively) or placebo and lithium/divalproex. Quetiapine+lithium/divalproex treatment (n=104) showed a 2.0-point greater improvement on the primary outcome (change from baseline in Young Mania Rating Scale total score at day 21) compared with placebo+lithium/divalproex (n=96), and a 2.8-point greater difference by day 42, but the differences between groups were not statistically significant. Other efficacy measures, however, did show a statistically significant advantage in favor of quetiapine+lithium/divalproex over lithium/divalproex monotherapy at day 42. Improvement of mean Young Mania Rating Scale scores with quetiapine+lithium/divalproex was numerically but not statistically significantly greater than lithium/divalproex monotherapy in the treatment of bipolar mania. Potential reasons for the failure of quetiapine+lithium/divalproex to differentiate from placebo+lithium/divalproex treatment on the primary outcome measure and the implications of this for the treatment of mania and future studies are discussed. Overall, the combination of quetiapine with lithium or divalproex was well tolerated.

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    • "RSP + SH > PBO + SH Sachs et al., 2004 [41] QTP + SH (91) PBO + SH (100) QTP + SH > PBO + SH Akhondzadeh et al., 2006 [47] ALP + HAL + Li (38) PBO + HAL + Li (37) ALP + HAL + Li > PBO + HAL + Li McIntyre et al., 2007 [42] QTP + SH (197) PBO + SH (205) QTP + SH > PBO + SH Yatham et al., 2007 [43] QTP + SH (104) PBO + SH (96) QTP + SH > PBO + SH Sussmam et al., 2007 [48] QTP + SH (197) PBO + SH (205) QTP + SH > PBO + SH Vieta et al., 2008 [44] ARI + SH (253) PBO + SH (131) ARI + SH > PBO + SH Tohen et al., 2008 [49] "
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    ABSTRACT: Bipolar disorder (BD) is the seventh leading cause of disability per year of life among all diseases in the population aged 15 to 44. It is a group of heterogeneous diseases, with frequent comorbid psychiatric or somatic disorders, variable treatment response and frequent residual symptoms between episodes. The major impairment associated with this disorder is related to the high relapse and recurrence rates, the functional impact of comorbidities and cognitive impairment between episodes. The prognosis of the disease relies on the efficacy of relapse and recurrence prevention interventions. Given the heterogeneity of the disorder, relapse and recurrence prevention needs to develop a personalized care plan from the start of the acute phase. In such a complex situation, guideline-driven algorithms of decision are known to improve overall care of patients with bipolar disorder, compared to standard treatment decisions. Although guidelines do not account for all the situations encountered with patients, this systematic approach contributes to the development of personalized medicine. We present a critical review of recent international recommendations for the management of manic phases. We summarize treatment options that reach consensus (monotherapy and combination therapy) and comment on options that differ across guidelines. The synthesis of recent international guidelines shows a consensus for the initial treatment for manic phases. For acute and long-term management, the anti-manic drugs proposed are traditional mood stabilizers (lithium or valproate) and atypical antipsychotics (APA - olanzapine, risperidone, aripiprazole and quetiapine). All guidelines indicate stopping antidepressant drugs during manic phases. International guidelines also present with some differences. First, as monotherapy is often non sufficient in clinical practice, combination therapy with a traditional mood stabilizer and an APA are disputed either in first line treatment for severe cases or in second line. Second, mixed episodes treatment is not consensual either and some guidelines propose in first line valproate, carbamazepine and some APA, and advice not to use lithium. On the other hand, some guidelines do not propose specific treatment for mixed episodes and group them with manic episodes management. Duration of treatment is unclear. Guidelines utilization has shown that the systemic use by clinicians of decision algorithms in comparison to "treatment as usual" modality improves the overall care of patients with BD. Future data from cohorts of patients seem necessary to complement the existing data from clinical trials. These cohort studies will help to take into account the different individual profiles of BD and thus may help to propose a more personalized medicine.
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    • "Quetiapine was also tested in two placebo con - trolled combination studies as add on to lithium or valproate . Whereas one study showed superiority of the combination quetiapine / lithium or valproate ( Sachs et al . 2004 ) , the other failed to do so ( Yatham et al . 2007 ) . Further evidence for the antimanic action of quetiapine stems from two controlled studies in adolescents , one placebo - controlled add on study to valproate ( DelBello et al . 2002 ) , and one head - to head comparison against valproate ( DelBello et al . 2006 ) . It has been suggested that quetiapine doses in the registration tria"
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    • "Adding quetiapine to valproate increases efficacy against acute mania in adolescents (Delbello et al., 2002) and adding it to lithium or valproate in adult manic patients again improves outcome (54.3 % vs. 32.6 % and 55.7 % vs. 41.6 %) (Sachs et al., 2004; Suppes et al., 2008b; Yatham et al., 2004). However, a more recent study does not support the above (Yatham et al., 2007). Two recent placebo-controlled add-on trials of quetiapine+mood stabilizer during maintenance Treatment of bipolar disorder : a systematic review 1005 treatment, suggest that quetiapine is superior to placebo in the prevention of manic and depressive recurrences in either manic, depressive, or mixed index episode over a period of 2 yr (Vieta et al., 2007b). "
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