Reduction In Young Mania Rating Scale Score Research Articles

Levetiracetam adjunct to quetiapine for the acute manic phase of bipolar disorder: a randomized, double-blind and placebo-controlled clinical trial of efficacy, safety and tolerability.

Unsatisfactory responses to bipolar disorder treatments have necessitated novel therapeutic approaches. Evidence of levetiracetam's effectiveness in mania was reported in previous studies. This study evaluated its efficacy, safety and tolerability as an adjunct to quetiapine in mania. Forty-four patients with Young Mania Rating Scale (YMRS) score ≥20 entered and were randomized to receive levetiracetam plus quetiapine or placebo plus quetiapine for 6 weeks. Patients were assessed using the YMRS and Beck Scale for Suicidal Ideations (BSSI) at baseline and weeks 2, 4 and 6. Changes in the scores, remission rates and response to treatment were compared between the groups. Forty patients completed the trial. The general linear model (GLM) repeated measures demonstrated a significant effect for time × treatment interaction on the YMRS score during the trial (P = 0.04). A greater reduction in YMRS scores was seen in the levetiracetam group compared with the placebo group from baseline to week 4 (P = 0.045). Response to treatment was significantly better in the levetiracetam group (P = 0.046). No significant effect for time × treatment interaction on BSSI score was seen in GLM repeated measures. Finally, there was no significant difference in the frequency of adverse events. Adjunctive levetiracetam is effective, safe and well-tolerated in patients with mania. Further high-quality, large-scale trials are recommended.

A Randomized, Double-Blind, Controlled Trial of Lithium Versus Quetiapine for the Treatment of Acute Mania in Youth with Early Course Bipolar Disorder.

Objective: To compare the efficacy and tolerability of lithium versus quetiapine for the treatment of manic or mixed episodes in youths with early course bipolar I disorder. Methods: Six-week, randomized, double-blind clinical trial of lithium versus quetiapine for the treatment of adolescents with acute manic/mixed episode. Target dose of quetiapine dose was adjusted to a target dose of 400-600 mg and target serum level for lithium was 1.0-1.2 mEq/L. Primary outcome measure was baseline-to-endpoint change in the Young Mania Rating Scale (YMRS). Secondary outcomes were treatment response (50% or more decrease from baseline in YMRS score) and remission (YMRS score ≤12, Children's Depression Rating Scale-Revised [CDRS-R] total score ≤28 and Clinical Global Impression Bipolar Severity Scale [CGI-BP-S] overall score of ≤3, respectively). Results: A total of 109 patients were randomized (quetiapine = 58 and lithium = 51). Participants in the quetiapine treatment group showed a significantly greater reduction in YMRS score than those in the lithium group (-11.0 vs. -13.2; p < 0.001; effect size 0.39). Response rate was 72% in the quetiapine group and 49% in the lithium group (p = 0.012); no differences in remission rates between groups were observed. Most frequent side effects for lithium were headaches (60.8%), nausea (39.2%), somnolence (27.5%), and tremor (27.5%); for quetiapine somnolence (63.8%), headaches (55.2%), tremor (36.2%), and dizziness (36.2%) were evidenced. Participants receiving quetiapine experienced more somnolence (p < 0.001), dizziness (p < 0.05), and weight gain (p < 0.05). Conclusions: Treatment with both lithium and quetiapine led to clinical improvement. Most study participants in this study experienced a clinical response; however, less than half of the participants in this study achieved symptomatic remission. The head-to-head comparison of both treatment groups showed quetiapine was associated with a statistically significant greater rate of response and overall symptom reduction compared with lithium. Trial registration: clinicaltrials.gov NCT00893581.

Comparison of the effect of lithium plus quetiapine with lithium plus risperidone in children and adolescents with bipolar I disorder: a randomized clinical trial.

Background: In the treatment of bipolar disorder in youths, often more than one medication should be prescribed. In the current study, we compared the efficacy and tolerability of the combination of lithium and quetiapine with lithium and risperidone in the treatment of manic or mixed episodes in children and adolescents. Methods: Thirty patients (aged 10-18 years) who were hospitalized for a manic or mixed episode were recruited from consecutive inpatient admissions to the Child and Adolescent Psychiatric Unit at Razi Psychiatric Hospital (University of Social Welfare and Rehabilitation Sciences, Tehran, Iran) from June 2012 to September. They were randomly treated with lithium (with the usual dose to achieve blood levels 0.8-1) and quetiapine (400-600 mg per day) or risperidone (0.5-6 mg per day). The primary outcome measure with respect to efficacy was the mean decrease in Young Mania Rating Scale (YMRS) score. Side effects were also assessed. The independent t test and two-factor repeated measure analysis of variance (ANOVA) was used for data analysis. P-value of less than 0.05 was considered statistically significant. Results: The reduction in YMRS scores was similar in both groups. The remission rate (YMRS <12) in the group treated with quetiapine was 80% and with risperidone was 66.6%; the difference was not significant. The most common side effect was sedation in both groups. Extrapyramidal side effects were observed only with risperidone. Both drugs caused increased levels of prolactin. Conclusion: Both protocols were effective. Quetiapine in combination with lithium in manic or mixed episodes of bipolar I disorder in children and adolescents was not superior to lithium and risperidone, but was associated with fewer complications.

Does the efficacy of asenapine in bipolar disorder increase in the presence of comorbidity with a substance use disorder? A naturalistic study.

Asenapine is a second-generation antipsychotic approved in Europe for treating moderate-to-severe manic episodes in adults affected by type I bipolar disorder (BD-I). We aimed to compare its efficacy in psychiatric inpatients with BD-I, with or without substance use disorder (SUD). We administered flexible asenapine doses ranging from 5-20 mg/day to 119 voluntarily hospitalized patients with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) BD-I diagnosis, with or without SUD. Patients were assessed with clinician-rated questionnaires [i.e. Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Global Assessment of Functioning (GAF)]. Assessments were carried out at baseline (T0, prior to treatment), and 3 (T1), 7 (T2), 15 (T3), and 30 days (T4) after starting treatment for all clinical scales and at T0 and T4 for the GAF. Patients improved on all scales (p < 0.001) across all timepoints, as shown both by paired-sample comparisons and by applying a repeated-measures, generalized linear model (GLM). Patients without comorbid SUD showed greater reductions in BPRS scores at T2 and T3, greater reduction in YMRS scores at T3, and lower HARS scores at all timepoints. HDRS scores did not differ between the two groups at any timepoint. However, the reduction in HARS scores in the comorbid group was stronger than in the BD-I only group, albeit not significantly. Side effects were few and mild-to-moderate. The open-label design and the relatively short observation period may expose to both type I and type II statistical errors (false positive and false negatives). Asenapine showed effectiveness and safety in hospitalized BD-I patients. Its effect was stronger in patients without comorbid SUD.

Assessment of the efficacy and safety of eslicarbazepine acetate in acute mania and prevention of recurrence: Experience from multicentre, double-blind, randomised phase II clinical studies in patients with bipolar disorder I

BackgroundEslicarbazepine acetate (ESL) is an anticonvulsant approved as an adjunctive therapy in adults with partial-onset seizures. ObjectiveTo evaluate the efficacy, safety and tolerability of ESL in the treatment of acute mania and prevention of recurrence in bipolar disorder I. MethodsTwo 3-week multicentre, double-blind, randomised, placebo-controlled studies in acute mania (study BIA-2093-203: dose titrated by response, ESL 600–1800mg or 800–2400mg, once-daily; study BIA-2093-204: fixed doses of 600, 1200 and 1800mg, once-daily) were followed by a recurrence prevention study consisting of a 2-week open-label period (900mg, once-daily) continued by a double-blind, parallel-group, fixed dose (300, 900 and 1800mg, once-daily) period for a minimum of 6 months. The primary endpoint was changed from baseline until the end of the 3-week treatment period in Young Mania Rating Scale (YMRS) in studies BIA-2093-203 and BIA-2093-204, and the proportion of patients showing no worsening according to the Clinical Global Impressions – Bipolar Version (CGI-BP) over Part II in study BIA-2093-205. ResultsIn study BIA-2093-203 (n=160, ITT), neither dose group was statistically different from placebo in the primary endpoint, though the ESL 800–2400mg showed a greater reduction in YMRS score (p=0.0523). CGI-BP score changes for mania and overall bipolar illness indicate a significant improvement in patient symptomatology for the ESL 800–2400mg group (from preceding and worst phase) and for ESL 600–1800mg group (from worst phase only) when compared to placebo. Study BIA-2093-204 (n=38) results were inconclusive due to premature termination caused by recruitment difficulties. In study BIA-2093-205 (n=85, ITT), at least 50% of patients showed no worsening in all treatment groups (p=0.250). ESL adverse events were mostly of mild and moderate intensities and consistent with previously reported observations for ESL. ConclusionESL treatment was not significantly different from placebo in manic patients in the primary outcome, but secondary outcomes may be suggestive of efficacy. The recurrence prevention study provides preliminary support for efficacy of ESL in patients recovered from an acute manic episode.

Clinical Utility of Early Improvement to Predict Response or Remission in Acute Mania

To evaluate early improvement associated with atypical antipsychotic treatment as a predictor of later response or remission among patients experiencing an acute manic or mixed episode without psychotic features. A post hoc analysis was performed on data from a 3-week, randomized, double-blind clinical trial of olanzapine (N = 147) or risperidone (N = 127) to treat inpatients aged 18-70 years meeting DSM-IV criteria for bipolar I disorder. Early improvement, measured as percent change (≥ 25% and ≥ 50% cut points) in the Young Mania Rating Scale (YMRS) total score, was assessed after 2 days and 1 week of treatment. Receiver operating characteristic curves, sensitivity and specificity, and positive and negative predictive values were calculated to determine whether early improvement predicted endpoint (week 3) response or remission. The study was conducted from July 2001 through June 2002. Among 234 patients with ≥ 25% reduction in YMRS total score at week one, 167 (71.4%) responded and 121 (51.7%) remitted at endpoint. Of the 40 patients with < 25% improvement, 25% (n = 10) responded and 5% (n = 2) remitted at endpoint. A total of 157 patients had a ≥ 50% reduction in week 1 YMRS total score, of whom 132 (84.1%) responded and 101 (64.3%) remitted at endpoint. Of the 117 patients with < 50% improvement, 45 (38.5%) responded and 22 (18.8%) remitted at endpoint. Improvement in manic or mixed symptoms at week 1 appears to be a good predictor of treatment outcome. Patients not having sufficient improvement (< 25% reduction in YMRS score) were less likely to reach response or remission by week 3. Patients who achieved response by week 1 (≥ 50% reduction in YMRS score) were likely to remain responders at endpoint. These data suggest the potential to assess benefit in the treatment of manic or mixed symptoms within 1 week of initiating olanzapine or risperidone.

P.3.c.055 Asenapine: short-term tolerability, safety, and pharmacokinetic profile in older patients with psychosis

Eslicarbazepine acetate (ESL) is an anticonvulsant approved as an adjunctive therapy in adults with partial-onset seizures.To evaluate the efficacy, safety and tolerability of ESL in the treatment of acute mania and prevention of recurrence in bipolar disorder I.Two 3-week multicentre, double-blind, randomised, placebo-controlled studies in acute mania (study BIA-2093-203: dose titrated by response, ESL 600–1800 mg or 800–2400 mg, once-daily; study BIA-2093-204: fixed doses of 600, 1200 and 1800 mg, once-daily) were followed by a recurrence prevention study consisting of a 2-week open-label period (900 mg, once-daily) continued by a double-blind, parallel-group, fixed dose (300, 900 and 1800 mg, once-daily) period for a minimum of 6 months. The primary endpoint was changed from baseline until the end of the 3-week treatment period in Young Mania Rating Scale (YMRS) in studies BIA-2093-203 and BIA-2093-204, and the proportion of patients showing no worsening according to the Clinical Global Impressions – Bipolar Version (CGI-BP) over Part II in study BIA-2093-205.In study BIA-2093-203 (n=160, ITT), neither dose group was statistically different from placebo in the primary endpoint, though the ESL 800–2400 mg showed a greater reduction in YMRS score (p=0.0523). CGI-BP score changes for mania and overall bipolar illness indicate a significant improvement in patient symptomatology for the ESL 800–2400 mg group (from preceding and worst phase) and for ESL 600–1800 mg group (from worst phase only) when compared to placebo. Study BIA-2093-204 (n=38) results were inconclusive due to premature termination caused by recruitment difficulties. In study BIA-2093-205 (n=85, ITT), at least 50% of patients showed no worsening in all treatment groups (p=0.250). ESL adverse events were mostly of mild and moderate intensities and consistent with previously reported observations for ESL.ESL treatment was not significantly different from placebo in manic patients in the primary outcome, but secondary outcomes may be suggestive of efficacy. The recurrence prevention study provides preliminary support for efficacy of ESL in patients recovered from an acute manic episode.

Efficacy of Sodium Valproate and Haloperidol in the Management of Acute Mania: A Randomized Open‐Label Comparative Study

This study was carried out to compare the efficacy of intravenous sodium valproate with intramuscular haloperidol in patients with acute mania. A total of 30 patients meeting DSM-IV criteria for acute manic episodes were enrolled. They were randomly assigned to 2 groups of 15 patients each. Both groups were treated twice daily with haloperidol (10 mg, intramuscular) and sodium valproate (500 mg, intravenous). The patients were assessed on days 1, 5, 9, and 13. Improvement in symptoms was assessed by reduction in the Young Mania Rating Scale (YMRS). Outcome criterions for analysis were latency of response and remission; additional drugs were required for sedation. At the end of the 2-week study period, overall response rate in both the groups was similar (P > .1). In comparison to haloperidol group, patients treated with sodium valproate showed faster response, and on day 5, significant reduction in YMRS score was observed in the group treated with sodium valproate (P < .05). Total amount of lorazepam was less in patients treated with sodium valproate. Extrapyramidal symptom episodes were observed in 60% of patients treated with haloperidol. Sodium valproate in the treatment of acute mania is as efficacious as haloperidol but provides a faster response. It is safer compared to haloperidol.

Comparison of Open-Label, 8-Week Trials of Olanzapine Monotherapy and Topiramate Augmentation of Olanzapine for the Treatment of Pediatric Bipolar Disorder

The aim of this study was to test the efficacy and safety of olanzapine + topiramate versus olanzapine monotherapy in the treatment of bipolar disorder (BPD) and treatment-attendant weight gain in children and adolescents. Subjects (N = 40) were outpatients of both sexes, 6-17 years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) diagnosis of BPD (manic, hypomanic, or mixed) and Young Mania Rating Scale (YMRS) total score of >15 treated over 8-week periods in two partially concurrent open-label trials with olanzapine (n = 17) or olanzapine + topiramate (n = 23). Subjects in both groups experienced a statistically significant reduction in YMRS scores after 8-week, open-label treatment with olanzapine (baseline YMRS = 26.7 +/- 9.5; end-point YMRS = 18.2 +/- 12.5, p = 0.04) and olanzapine +topiramate (baseline YMRS = 31.3 +/- 7.9; end-point YMRS = 20.4 +/- 11.4, p = 0.04). There was no difference in response between the two groups based on YMRS or Clinical Global Impressions-Improvement (CGI-I) scores. Adverse events were few and mild and similar between the two groups, with the exception of weight gain. The weight gain in the olanzapine group was 5.3 +/- 2.1 kg and the weight gain in the olanzapine + topiramate group was statistically significantly lower, 2.6 +/- 3.6 kg. Augmentation of olanzapine with topiramate resulted in a reduced weight gain over the course of an 8-week, open-label trial when compared with olanzapine treatment alone, but did not lead to greater reduction in symptoms of mania.

Quetiapine for the treatment of bipolar mania in older adults

A post hoc analysis of pooled data from two quetiapine monotherapy clinical trials was conducted to evaluate the efficacy and tolerability of quetiapine therapy (twice daily, 400-800 mg/day) among bipolar manic adults aged 55 years and older. The primary efficacy endpoint was the change from baseline in Young Mania Rating Scale (YMRS) total score at Day 21. A secondary endpoint was change from baseline in YMRS score at Day 84. A total of 407 patients made up the safety population, consisting of 59 older adults (aged >or=55 years) and 348 younger adults. A total of 403 patients made up the efficacy population, consisting of 59 older adults and 344 younger adults. Efficacy outcomes were analyzed using covariance models (ANCOVA); descriptive statistics are presented for safety outcomes. Both older and younger individuals treated with quetiapine had significant improvement from baseline on YMRS scores compared with placebo-treated patients. The older adult group demonstrated a sustained reduction in YMRS score compared with placebo that was apparent by Day 4 of treatment. For the quetiapine treatment groups, the most common adverse effects (at a frequency >or=10%) were dry mouth, somnolence, postural hypotension, insomnia, weight gain, and dizziness in older adults, and dry mouth, somnolence, and insomnia in younger adults. For the placebo treatment groups, insomnia was the most common adverse event in both older and younger adults. This secondary analysis suggests that quetiapine represents a potentially useful treatment option among older adults with bipolar I mania. Studies with a primary focus of geriatric bipolar mania, and including larger patient numbers, are needed to confirm these findings.

Double‐blind randomized controlled study comparing short‐term efficacy of bifrontal and bitemporal electroconvulsive therapy in acute mania

Bifrontal electrode placement is as efficacious as bitemporal placement during electroconvulsive therapy (ECT) in depression but is associated with fewer cognitive adverse effects. There are no studies comparing these techniques in acute mania. This study compared the short-term efficacy and adverse effects of bifrontal and bitemporal ECT in the treatment of acute mania. Thirty-six DSM-IV mania inpatients referred for ECT were recruited for study. They were randomized to receive bifrontal (BFECT; n = 17) or bitemporal (BTECT; n = 19) ECT. None of the subjects were on mood stabilizers during the course of ECT. Severity of mania was measured on the Young Mania Rating Scale (YMRS) before beginning ECT and then on Days 3, 7, 11, 14, and 21 of treatment. Cognitive functions were assessed eight hours after the fifth ECT session using the Mini-Mental Status Examination (MMSE), Paired Associate Learning Test, Complex Figure Test, Verbal Fluency Test (animals and fruits categories), and Trail Making Test, Part A. The subjects in the two groups were comparable on sociodemographic and clinical variables, including severity of mania at baseline. They were also similar in ECT parameters, including seizure threshold and seizure duration. Mean YMRS scores showed faster decline in the BFECT than in the BTECT group. Kaplan-Meier survival analysis showed that a greater proportion of subjects in the BFECT group responded (50% reduction in YMRS score) significantly earlier than in the BTECT group. There were no significant differences between the groups in performance on cognitive function tests. In this pilot study, mania patients treated with BFECT responded faster than those treated with BTECT, with comparable cognitive adverse effects. Since ECT is usually prescribed for rapid control of symptoms, BFECT may be preferred over BTECT in the treatment of acute mania.

Response and Remission in Adolescent Mania: Signal Detection Analyses of the Young Mania Rating Scale

The purpose of this study was to determine optimal criteria for defining response and remission in adolescents with acute mania. Data were analyzed from three treatment studies of adolescents with acute mania (N = 99). Trained raters completed the Young Mania Rating Scale (YMRS), and clinicians completed the Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP) independent of YMRS ratings. For response, the percentages of reduction in YMRS scores from baseline to endpoint were compared with CGI-BP Mania Improvement scores. For remission, endpoint YMRS scores were compared with CGI-BP Mania Severity scores. Signal detection analyses were conducted to evaluate the efficiency of selected cutoffs associated with response and remission. A > or =55% reduction in YMRS scores from baseline to endpoint was the optimal cutoff defining response. An absolute endpoint YMRS score < or =12 was the optimal cutoff defining remission. The results of this signal detection analysis in adolescent mania suggest that current commonly used cutoffs to define response (> or =50% reduction) and remission (< or =12) may be appropriate with regard to efficiency. Studies with methods specifically tailored to evaluate and compare these rating scales and larger patient samples from multiple sites are needed to confirm these preliminary findings.

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.

A double‐blind, placebo‐controlled trial of adjunctive donepezil in treatment‐resistant mania

Because there is a high rate of partial response to standard thymoleptic medication, novel augmentation strategies for treatment-resistant bipolar disorder are needed. In an open trial, donepezil augmentation was associated with improvement in manic symptoms in 9 of 11 subjects. We conducted a 6-week, double-blind, placebo-controlled trial of donepezil for treatment-resistant bipolar mania. Eligible subjects had a Young Mania Rating Scale (YMRS) score of at least 15 despite two or more weeks of proven therapeutic levels of lithium or valproate. Subjects who completed the trial were eligible for an 8-week open trial of donepezil. Subjects were started on donepezil 5 mg/day and were eligible for dose increase to 10 mg/day after 4 weeks. Twelve subjects were enrolled. Eleven subjects received at least 1 week of study medication and were included in the analysis. No subjects in the donepezil group (0/6) and 60% (3/5) in the placebo group met response criteria of >30% reduction in YMRS score (Fisher's Exact p = 0.061). YMRS scores were higher at trial endpoint in the donepezil group 20.17 (3.66) compared with the placebo group [11.20 (4.60), Z = -2.476, p = 0.01]. There were no differences at trial endpoint in Hamilton Rating Scale for Depression (HAM-D) or Brief Psychiatric Rating Scale (BPRS) scores in either the intent-to-treat or the completer analyses. Donepezil does not appear to be an effective adjunctive treatment for refractory manic symptoms. The strength of the conclusion of this trial is limited by the possibility of a false-negative result due to the small sample.

P.6.081 Topiramate in bipolar and schizoaffective disorders

Eslicarbazepine acetate (ESL) is an anticonvulsant approved as an adjunctive therapy in adults with partial-onset seizures.To evaluate the efficacy, safety and tolerability of ESL in the treatment of acute mania and prevention of recurrence in bipolar disorder I.Two 3-week multicentre, double-blind, randomised, placebo-controlled studies in acute mania (study BIA-2093-203: dose titrated by response, ESL 600–1800 mg or 800–2400 mg, once-daily; study BIA-2093-204: fixed doses of 600, 1200 and 1800 mg, once-daily) were followed by a recurrence prevention study consisting of a 2-week open-label period (900 mg, once-daily) continued by a double-blind, parallel-group, fixed dose (300, 900 and 1800 mg, once-daily) period for a minimum of 6 months. The primary endpoint was changed from baseline until the end of the 3-week treatment period in Young Mania Rating Scale (YMRS) in studies BIA-2093-203 and BIA-2093-204, and the proportion of patients showing no worsening according to the Clinical Global Impressions – Bipolar Version (CGI-BP) over Part II in study BIA-2093-205.In study BIA-2093-203 (n=160, ITT), neither dose group was statistically different from placebo in the primary endpoint, though the ESL 800–2400 mg showed a greater reduction in YMRS score (p=0.0523). CGI-BP score changes for mania and overall bipolar illness indicate a significant improvement in patient symptomatology for the ESL 800–2400 mg group (from preceding and worst phase) and for ESL 600–1800 mg group (from worst phase only) when compared to placebo. Study BIA-2093-204 (n=38) results were inconclusive due to premature termination caused by recruitment difficulties. In study BIA-2093-205 (n=85, ITT), at least 50% of patients showed no worsening in all treatment groups (p=0.250). ESL adverse events were mostly of mild and moderate intensities and consistent with previously reported observations for ESL.ESL treatment was not significantly different from placebo in manic patients in the primary outcome, but secondary outcomes may be suggestive of efficacy. The recurrence prevention study provides preliminary support for efficacy of ESL in patients recovered from an acute manic episode.

Risperidone in acute and continuation treatment of mania

In a prospective study, we examined the efficacy of risperidone added-on to mood stabilizers in the acute and continuation treatment of mania over a 12-week period. Patients (n=108) with a DSM-IV diagnosis of bipolar disorder, manic or mixed episode requiring treatment with an antipsychotic were recruited. All subjects were on one or two mood stabilizers at the time of initiation of risperidone (range 0.5–4 mg). No other antipsychotic medication or ongoing benzodiazepine therapy was allowed. There was a significant decrease in mean Young Mania Rating Scale (YMRS) scores from baseline (27.5±7.5) to week 1 (-10.8,P< 0.0001), week 3 (-17.7,P<0.0001) and to week 12(-22.6,P< 0.0001). When response was defined as >= 50% reduction in YMRS scores from baseline, 32%, 68% and 90% of patients met criteria at week 1, week 3 and week 12, respectively. Significant decreases in mean 21-item Hamilton Depression Rating Scale scores from baseline (12.2±7.7) to week 3 (-5.7,P< 0.0001) and week 12 (-5.7,P<0.0001) were also observed. No significant changes in extrapyramidal symptoms were noted between baseline and endpoint. The mean daily dose of risperidone was 2 mg with a median of 1.8 mg. These findings support the results of the two previous double-blind, randomized trials and indicate that the addition of risperidone to mood stabilizers is a safe and effective treatment for acute and continuation treatment of mania. Risperidone add-on does not induce depressive symptoms and, furthermore, risperi-done may have efficacy in treating comorbid depressive symptoms in bipolar patients.

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.

A pilot study of topiramate as monotherapy in the treatment of acute mania.

This small-scale pilot study was performed to grossly document safety and any evidence of efficacy of topiramate in bipolar disorder. Ten patients hospitalized for acute mania were given open-label topiramate monotherapy for up to 28 days. The mean Young Mania Rating Scale (YMRS) score decreased from 32 (range, 26-40) at baseline to 22 (range, 2-40) at the end of the study. Five patients exhibited evidence of moderate to marked improvement, three subjects had at least a 50% reduction in YMRS scores, and the other two patients experienced an improvement of 25% to 49% on the YMRS. The preliminary findings of this small series suggest that topiramate may be effective in acute mania. Double-blind controlled trials are now needed to further investigate the efficacy and safety of topiramate in bipolar disorder.