Young Mania Rating Scale Response Research Articles

Cariprazine for the treatment of bipolar mania with mixed features: A post hoc pooled analysis of 3 trials

Background: When bipolar I disorder (BP-I) mania is accompanied by subsyndromal depressive symptoms, a more complicated illness presentation results. To qualify for the mixed features specifier during mania, the DSM-5 requires ≥3 “non-overlapping” depressive symptoms (DS); notwithstanding, concerns of this definition's ecological validity and implications for timely diagnosis remain.Methods: Herein, patients were pooled from three similarly-designed pivotal trials of cariprazine compared to placebo for BP-I mania (NCT00488618/NCT01058096/NCT01058668) in post hoc analyses of mixed features using three criteria: ≥3 DS (DSM-5), ≥2 DS, and Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥10. Efficacy of cariprazine compared to placebo was assessed (Week 3) by Young Mania Rating Scale (YMRS) and MADRS scores and rates of mania response and remission.Results: In pooled patients (N = 1037), cariprazine significantly improved mean YMRS scores compared to placebo for each criterion; LSMDs were ≥3 DS = -3.79 (P = .0248), ≥2 DS = -2.91 (P = .0207), and ≥10 MADRS = -5.49 (P < .0001). More cariprazine- than placebo-treated patients met YMRS response and remission criteria, reaching significance for response in ≥2 DS (34% versus 47%; number-needed-to-treat [NNT] = 8, P = .0483) and ≥10 MADRS(31% versus 57%, NNT = 4, P < .0001) and for remission in ≥2 DS (27% versus 39%, NNT = 9, P = .0462), ≥10 MADRS (23% versus 44%, NNT = 5, P < .0001). Depressive symptoms were improved compared to placebo, reaching statistical significance in the MADRS ≥10 subgroup (LSMD = -1.59, P = .0082).Limitations: Post hoc analysis, MADRS < 18 entry criterion may have prevented assessment of MADRS changes.Conclusions: Cariprazine significantly reduced manic and depressive symptoms in patients with mixed features with differential efficacy across the subgroups analyzed herein.

A randomized, double‐blind, placebo‐ and risperidone‐controlled study on valnoctamide for acute mania

Mood stabilizers administered for bipolar disorder during pregnancy, such as valproic acid, can increase the risk of congenital anomalies in offspring. Valnoctamide is a valproic acid derivative associated with a decreased risk for congenital abnormalities in animals. The present study evaluated the efficacy and safety of valnoctamide monotherapy, compared to placebo, in the treatment of patients in an acute manic episode. A 3-week, double-blind, randomized, placebo- and risperidone-controlled, parallel group trial was conducted on 173 patients in an acute manic episode. Patients were randomized to receive valnoctamide 1500mg/d (n=71), risperidone 6mg/d (n=32), or matching placebo (n=70). The primary outcome measure was the change in Young Mania Rating Scale (YMRS) scores. Valnoctamide did not differ significantly from placebo on any of the study endpoints (YMRS, Positive and Negative Syndrome Scale, and the Clinical Global Impression Scale for Bipolar Disorder [CGI-BP] scales; all P>.60). Mixed models for repeated measures showed that risperidone produced significantly more improvement than placebo in the overall bipolar disorder CGI-BP severity scale (P=.036), and the CGI-BP severity scale for mania (P=.021). The Kaplan-Meier survival curve revealed higher all-cause discontinuation rates (mainly due to lack of efficacy) in the valnoctamide group compared to the other study groups (P=.026). Patients with higher valnoctamide plasma levels had a numerically higher YMRS response, but this was not statistically significant. Valnoctamide was well tolerated at 1500mg/d but lacked efficacy in the treatment of symptoms in patients with acute mania. Possible differences between the biological mechanisms of action of valproic acid and valnoctamide are discussed.

Cariprazine in the treatment of acute mania in bipolar I disorder: A double-blind, placebo-controlled, Phase III trial

BackgroundThis Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder. MethodsPatients were randomized to 3 weeks of double-blind treatment with cariprazine 3–12mg/day (n=158) or placebo (n=154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score. ResultsMean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3–12mg/day versus placebo (P=0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, P<0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (≥50% improvement: cariprazine, 58.9%; placebo, 44.1%; P=0.0097) and remission (YMRS total score≤12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025) and mean change in CGI-S (P=0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P=0.0035) total score. The most common cariprazine-related (≥10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups. LimitationsLack of active comparator arm; short duration of study. ConclusionIn this study, cariprazine 3–12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder.

The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial.

Cariprazine, an orally active and potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, is being developed for the treatment of schizophrenia and bipolar mania. This Phase II trial evaluated the efficacy, safety, and tolerability of cariprazine versus placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. This was a multinational, randomized, double-blind, placebo-controlled, flexible-dose study of cariprazine 3-12mg/day in patients with acute manic or mixed episodes associated with bipolar I disorder. Following washout, patients received three weeks of double-blind treatment. The primary and secondary efficacy parameters were change from baseline to Week 3 in Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S) scores, respectively. Post-hoc analysis evaluated changes on YMRS single items. In each group, 118 patients received double-blind treatment; 61.9% of placebo and 63.6% of cariprazine patients completed the study. The overall mean daily dose of cariprazine was 8.8mg/day. At Week 3, cariprazine significantly reduced YMRS and CGI-S scores versus placebo, with least square mean differences of -6.1 (p<0.001) and -0.6 (p<0.001), respectively. On each YMRS item, change from baseline to Week 3 was significantly greater for cariprazine versus placebo (all, p<0.05). A significantly greater percentage of cariprazine patients than placebo patients met YMRS response (48% versus 25%; p<0.001) and remission (42% versus 23%; p=0.002) criteria at Week 3. Adverse events (AEs) led to discontinuation of 12 (10%) placebo and 17 (14%) cariprazine patients. The most common AEs (> 10% for cariprazine) were extrapyramidal disorder, headache, akathisia, constipation, nausea, and dyspepsia. Changes in metabolic parameters were similar between groups, with the exception of fasting glucose; increases in glucose were significantly greater for cariprazine versus placebo (p<0.05). Based on Barnes Akathisia Rating Scale and Simpson-Angus Scale scores, more cariprazine than placebo patients experienced treatment-emergent akathisia (cariprazine: 22%; placebo: 6%) or extrapyramidal symptoms (parkinsonism) (cariprazine: 16%; placebo: 1%). Cariprazine demonstrated superior efficacy versus placebo and was generally well tolerated in patients experiencing acute manic or mixed episodes associated with bipolar I disorder.

EPA-0869 – Efficacy and safety of cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder

Cariprazine is a potent dopamine D 3 and D 2 receptor partial agonist with preferential binding to D 3 receptors. Summarize data from two Phase III, randomized, double-blind, placebo-controlled, flexible-dose, 3-week trials of cariprazine 3-12mg/d (NCT01058096) and cariprazine 3-6mg/d or 6-12mg/d (NCT01058668) in adults with bipolar I disorder and acute manic or mixed episodes. Evaluate the efficacy, safety, and tolerability of cariprazine in mania associated with bipolar I disorder. Primary and secondary efficacy parameters were change from baseline to Week 3 on the Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S), respectively, and were analyzed using a mixed-effects model for repeated measures. Randomized patient populations: 312 (NCT01058096; 154 placebo, 158 cariprazine 3–12mg/d) and 497 (NCT01058668; 161 placebo, 167 cariprazine 3–6mg/d, 169 cariprazine 6–12mg/d). Improvement from baseline to Week 3 on YMRS was significantly greater for each cariprazine group vs placebo ( P <0.001): least square mean difference (LSMD) was −4.3 (3–12mg/d), −6.1 (3–6mg/d) and −5.9 (6–12mg/d). For each cariprazine group, significantly more patients met YMRS response and remission criteria vs placebo. Cariprazine also was significantly superior to placebo on the CGI-S: LSMD was −0.4 (3–12mg/d, P =.0027), −0.6 (3–6mg/d, P <.001), −0.6 (6–12mg/d, P <.001). The only common cariprazine-related TEAEs (≥5% and twice rate of placebo) that occurred in both studies were akathisia and tremor. Changes in metabolic parameters were small and similar to placebo in both studies. Cariprazine was effective and generally well tolerated in the treatment of bipolar mania.

P.2.e.016 Cariprazine in the treatment of acute mania in bipolar disorder: a double-blind, placebo-controlled, phase III trial

Background: This Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder. Methods: Patients were randomized to 3 weeks of double-blind treatment with cariprazine 3–12 mg/day (n¼158) or placebo (n¼154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score. Results: Mean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3–12 mg/day versus placebo (P¼0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, Po0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (Z50% improvement: cariprazine, 58.9%; placebo, 44.1%; P¼0.0097) and remission (YMRS total scorer12: cariprazine, 51.9%; placebo, 34.9%; P¼0.0025) and mean change in CGI-S (P¼0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P¼0.0035) total score. The most common cariprazine-related (Z10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups. Limitations: Lack of active comparator arm; short duration of study. Conclusion: In this study, cariprazine 3–12 mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder. & 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Asenapine as Adjunctive Treatment for Acute Mania Associated With Bipolar Disorder

In a 12-week randomized, placebo-controlled study evaluating the efficacy and safety of adjunctive asenapine, bipolar I disorder patients experiencing manic or mixed episodes despite pretreatment with lithium or valproate monotherapy were treated with flexible-dose, twice-daily asenapine 5 or 10 mg (n = 158) or placebo (n = 166). The primary efficacy end point was change from baseline Young Mania Rating Scale (YMRS) total score at week 3. Secondary outcomes included YMRS response and remission and Clinical Global Impression for Bipolar Disorder and Montgomery-Asberg Depression Rating Scale score changes. Patients completing the core study were eligible for a 40-week double-blind extension assessing safety and tolerability. Adjunctive asenapine significantly improved mania versus placebo at week 3 (primary end point) and weeks 2 to 12. The YMRS response rates were similar at week 3 but significantly better with asenapine at week 12. The YMRS remission rates and changes from baseline on Clinical Global Impression for Bipolar Disorder for mania and overall illness were significantly better with asenapine at weeks 3 and 12. No other statistically significant differences on secondary outcomes were observed. Only a small number of patients entered the extension, making firm statistical conclusions on efficacy difficult. Treatment-emergent adverse events reported by 5% or more of asenapine patients and at twice the incidence of placebo were sedation, somnolence, depression/depressive symptoms, oral hypoesthesia, and increased weight in the 12-week core study. Adjunctive asenapine to lithium or valproate was more effective than mood stabilizer monotherapy in the core study and was well tolerated for up to 52 weeks.

Extended-Release Quetiapine as Monotherapy for the Treatment of Adults With Acute Mania: A Randomized, Double-Blind, 3-Week Trial

Background Bipolar disorder, a highly recurrent and chronic condition, often necessitates periods of hospitalization and requires lifelong treatment with medication. It is characterized by alternating episodes of mania and depression. Given the severity of mania, physicians must be able to control symptoms rapidly. Objective The purpose of this pivotal, Phase III trial was to evaluate the efficacy and tolerability of once-daily extended-release quetiapine fumarate (quetiapine XR) monotherapy in improving manic symptoms in patients with bipolar I disorder. Methods This was a 3-week, randomized, parallel-group, double-blind, placebo-controlled study. Patients aged 18 to 65 years with bipolar I disorder (most recent episode manic or mixed; with or without rapid cycling) were randomized to receive placebo or quetiapine XR monotherapy once daily (300 mg on day 1; 600 mg on day 2; flexible dosing, 400–800 mg, from day 3 through day 22 [study end point, week 3]). The primary outcome measure was the change from baseline to study end in the Young Mania Rating Scale (YMRS) total score. Secondary outcome measures included the Montgomery–Åsberg Depression Rating Scale (MADRS) total score, YMRS response (≥50% reduction in YMRS) and remission (YMRS score ≤12 at final visit) rates, and change from baseline to week 3 in Clinical Global Impression-Bipolar-Severity of Illness (CGI-BP-S) and CGI-BP-Change (CGI-BP-C) scores. Safety profile and tolerability evaluations included monitoring of adverse events, clinical laboratory values, vital signs, extrapyramidal symptoms (including akathisia), and electrocardiogram results. Results Compared with placebo (n = 159), quetiapine XR monotherapy (n = 149; mean daily dose, 604 mg) significantly improved manic symptoms starting at day 4 (first assessment; P < 0.001), with sustained improvement to study end (week 3; P < 0.001). MADRS scores showed greater improvement from baseline to study end with quetiapine XR than with placebo ( P = 0.004). Response and remission rates were significantly greater ( P < 0.01) with quetiapine XR than with placebo at study end. Quetiapine XR also resulted in significant improvements over placebo in CGI-BP-S and CGI-BP-C scores ( P < 0.001 and P < 0.001, respectively). Adverse events were mild to moderate in intensity; the most common ones associated with quetiapine XR were sedation, dry mouth, and somnolence. Conclusion This 3-week trial suggests that quetiapine XR (400–800 mg) once-daily monotherapy is efficacious (from day 4) and generally well tolerated in patients with manic or mixed episodes of bipolar I disorder. ClinicalTrials.gov identifier: NCT00422123.

PMH7 Aasenapine Versus Other Antipsychotics in Bipolar I Disorder: Indirect Comparisons at Twelve Weeks

Asenapine is a novel antipsychotic indicated for the treatment of moderate to severe manic episodes associated with bipolar I disorder. The clinical programme included one 12-week trial versus olanzapine in monotherapy and one 12-week adjunct therapy trial versus placebo. While no head-to-head data were available to compare asenapine with all atypical antipsychotics, the objective of this project was to provide comparative efficacy data of asenapine versus olanzapine, quetiapine and aripiprazole in both monotherapy and adjunct therapy using indirect comparison techniques. All twelve-week randomised controlled trials of olanzapine, quetiapine and aripiprazole conducted in monotherapy or in adjunct therapy were identified through a literature review. Five monotherapy studies were found, allowing the comparison of asenapine versus quetiapine and aripiprazole, with olanzapine and haloperidol as common references, using Bucher's method (Bucher et al., J Clin Epidemiol 1997). One twelve-week and four six-week placebo-controlled adjunctive therapy trials were identified, enabling the comparison of asenapine to olanzapine, quetiapine and aripiprazole through pairwise comparisons using placebo as a common reference. The outcomes used for comparison were the Young Mania Rating Scale (YMRS) change from baseline, YMRS response and remission rates. In monotherapy, the differences of mean YMRS change from baseline to week 12 between asenapine versus quetiapine and aripiprazole were 0.10 (p=0.959) and 1.76 (p=0.342), respectively. Relative risks for response and remission were close to one. In adjunct therapy, the differences of mean YMRS change from baseline to week 6 between asenapine versus olanzapine, quetiapine and aripiprazole were 0.63 (p=0.656), 0.10 (p=0.967) and -0.10 (p=0.946), respectively. Relative risks for response and remission were numerically in favour of asenapine but not statistically significant. The results of these indirect comparisons consistently showed comparable efficacy of asenapine versus the investigated atypical antipsychotics.

P01-185 Effectiveness of extended-release formulation of quetiapine as monotherapy for the treatment of acute bipolar mania (trial D144CC00004)

Objectives:To evaluate the effectiveness of extended release quetiapine fumarate (quetiapine XR) as once-daily monotherapy for manic symptoms in bipolar I disorder.Methods:In this 3-week, randomized, parallel-group, double-blind study, adults with bipolar I disorder (most recent episode manic or mixed; with or without rapid cycling) were randomized to once-daily treatment with either quetiapine XR (n=149; Day 1, 300 mg; Day 2, 600 mg; Day 3 through Week 3, 400-800 mg flexibly dosed) or placebo (n=159). Primary outcome measure was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. Secondary outcome measures included YMRS response and remission and change in Clinical Global Impression-Bipolar (CGI-BP)-Severity of Illness and -Change scales. Change from baseline was compared between groups with analysis of covariance, using the last observation carried forward approach for missing data.Results:Once-daily quetiapine XR was associated with significant, sustained improvement in manic symptoms compared with placebo, beginning on Day 4 (P&lt; 0.001) and continuing through Week 3 (mean change: -14.34 versus -10.52; P&lt; 0.001). At Week 3, quetiapine XR-treated patients showed significantly greater response (P&lt; 0.01) and remission (P&lt; 0.01) rates and improvement in CGI-BP-associated scores than placebo-treated patients. Adverse events were mild to moderate in intensity, the most common being sedation, dry mouth, and somnolence for quetiapine XR.Conclusions:Once-daily quetiapine XR monotherapy (400-800 mg) was efficacious (from Day 4 through Week 3) and generally well tolerated in the treatment of manic episodes associated with bipolar I disorder.Supported by funding from AstraZeneca Pharmaceuticals LP.

Valproate Use in Children and Adolescents with Bipolar Disorder

This review aims to provide an update on valproate use in children and adolescents with bipolar disorder by summarising currently available clinical trials results. Guidelines for the treatment of type I bipolar disorder in children and adolescents, with or without psychotic features, recommend valproate, alone or in combination with an atypical antipsychotic, as a first-line treatment option; however, most randomised and open-label studies investigating valproate in paediatric populations have only evaluated a small number of participants. Therefore, the data from these studies need to be interpreted cautiously. A further complicating issue is the controversy surrounding the definition and diagnosis of bipolar disorders in this age group. Data suggest that valproate may be particularly useful for patients whose symptoms have not been responsive to lithium, or as part of combination therapy. Evidence from randomised controlled trials show that valproate monotherapy is associated with a Young Mania Rating Scale (YMRS) response rate (percentage of patients with a reduction in YMRS score from baseline to endpoint of >/=50%) of 53%, while combination therapy with valproate plus quetiapine is associated with a YMRS response rate of 87%; however, placebo response rates were high, emphasising the need for caution when interpreting data from open-label trials. At present, data supporting the efficacy and safety of mood stabilisers for the treatment of bipolar disorders in children and adolescents are limited; therefore, well designed, randomised controlled clinical studies are needed to identify and confirm the potential roles of valproate in children and adolescents with bipolar disorders, particularly in those with psychiatric co-morbidities. Furthermore, clinical studies are required to clarify the efficacy and tolerability profile of valproate in comparison with other agents used in paediatric and adolescent bipolar disorder.

Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies

ABSTRACTObjective: To evaluate the efficacy and safety of quetiapine monotherapy for mania in bipolar disorder by an a priori defined combined analysis of data from two placebo-controlled studies.Method: The intent-to-treat (ITT) populations from two studies of patients with DSM-IV bipolar I disorder, manic episode, randomised to 12 weeks of double-blind treatment with quetiapine (up to 800 mg/day) or placebo were combined. The primary efficacy endpoint was change in Young Mania Rating Scale (YMRS) score from baseline to Day 21. Secondary endpoints included change from baseline in YMRS to Day 84, YMRS response and remission rates and change from baseline to Days 21 and 84 in the Montgomery–Asberg Depression Rating Scale (MADRS), Clinical Global Impressions (CGI), Clinical Global Impressions – Bipolar (CGI-BP) and the Positive and Negative Syndrome Scale (PANSS). These endpoints were analysed as continuous variables, using an analysis of covariance (ANCOVA), with the baseline as covariate. In order to account for any difference in response between studies, the analyses were stratified by study as a fixed effect, and centre as a random effect. The Cochran–Mantel–Haenszel test was used to analyse binary variables. A chi square test was used to compare the frequency of adverse events between the treatment groups.Results: The combined analysis included a total of 403 patients from two quetiapine monotherapy studies in patients with bipolar I disorder. A significant improvement in YMRS score was observed from Day 4 ( p = 0.021) onward in the quetiapine group compared with placebo. The treatment advantage of quetiapine over placebo continued to increase to Day 21 ( p < 0.001) and Day 84 ( p < 0.001). Significantly more quetiapine-treated than placebo-treated patients achieved a response ( p < 0.001). The average quetiapine dose in responders was approximately 600 mg daily. Of adverse events occurring in ≥ 5% of patients, quetiapine-treated patients had a significantly greater incidence versus placebo of somnolence (16.3% vs. 4.0%), dry mouth (15.8% vs. 3%), weight gain (9.1% vs. 1.5%) and dizziness (6.7% vs. 2.5%).Conclusions: The data from this combined analysis support the results from the individual studies and indicate that quetiapine monotherapy is effective across a broad range of mood symptoms, fast-acting and well tolerated in the treatment of mania.

A Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Quetiapine or Lithium as Monotherapy for Mania in Bipolar Disorder

To evaluate the efficacy and tolerability of quetiapine monotherapy versus placebo for the treatment of mania associated with bipolar disorder. In an international, multicenter, double-blind, parallel-group, 12-week study, patients with a DSM-IV diagnosis of bipolar I disorder (manic episode) were randomly assigned to treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or lithium. The primary efficacy measure was change from baseline in Young Mania Rating Scale (YMRS) score at day 21. Data were gathered from April 2001 to May 2002. More patients in the quetiapine (72/107) and lithium (67/98) groups completed the study compared with the placebo group (35/97). Improvement (reduction) in YMRS score was significantly greater for quetiapine than placebo at day 7 (-8.03 vs. -4.89; p < .01), and the difference between groups continued to increase over time to day 21 (-14.6 vs. -6.7; p < .001) and to endpoint at day 84 (-20.3 vs. -9.0; p < .001). Significantly more quetiapine patients compared with placebo patients fulfilled YMRS response criteria at day 21 (53.3% vs. 27.4%; p < .001) and at day 84 (72.0% vs. 41.1%; p < .001). Quetiapine was also superior to placebo in efficacy at day 21 and day 84 by all secondary measures. Lithium-treated patients improved significantly compared with placebo patients and similarly to quetiapine-treated patients on the primary efficacy measure. The most common adverse events for quetiapine were dry mouth, somnolence, and weight gain, while lithium was associated with tremor and insomnia. The quetiapine and placebo groups had similar, low levels of extrapyramidal symptom-related adverse events. Quetiapine demonstrated superior efficacy to placebo in patients with bipolar mania and was well tolerated.

A Double-Blind, Randomized, Placebo-Controlled Study of Quetiapine as Adjunctive Treatment for Adolescent Mania

This randomized, double-blind, placebo-controlled study examined the efficacy and tolerability of quetiapine in combination with divalproex (DVP) for acute mania in adolescents with bipolar disorder. It was hypothesized that DVP in combination with quetiapine would be more effective than DVP alone for treating mania associated with adolescent bipolar disorder. Furthermore, it was hypothesized that quetiapine would be well tolerated. Thirty manic or mixed bipolar I adolescents (12-18 years) received an initial DVP dose of 20 mg/kg and were randomly assigned to 6 weeks of combination therapy with quetiapine, which was titrated to 450 mg/day (n = 15) or placebo (n = 15). Primary efficacy measures were change from baseline to endpoint in Young Mania Rating Scale (YMRS) score and YMRS response rate. Safety and tolerability were assessed weekly. The DVP + quetiapine group demonstrated a statistically significantly greater reduction in YMRS scores from baseline to endpoint than the DVP + placebo group (F(1,27) = 5.04, p =.03). Moreover, YMRS response rate was significantly greater in the DVP + quetiapine group than in the DVP + placebo group (87% versus 53%; Fisher exact test, p =.05). No significant group differences from baseline to endpoint in safety measures were noted. Sedation, rated as mild or moderate, was significantly more common in the DVP + quetiapine group than in the DVP + placebo group. The findings of this study indicate that quetiapine in combination with DVP is more effective for the treatment of adolescent bipolar mania than DVP alone. In addition, the results suggest that quetiapine is well tolerated when used in combination with DVP for the treatment of mania.