Baseline Young Mania Rating Scale Score Research Articles

0642 Effect of Iloperidone on Sleep Symptoms in Bipolar Patients with Manic and Mixed Episodes: A Randomized, Placebo Controlled Study

Abstract Introduction Iloperidone, a dopamine D2 receptor and serotonin 5HT2A receptor antagonist, was evaluated for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults in a phase 3 clinical trial. A core symptom of bipolar I disorder is disturbance in sleep. During manic episodes this commonly presents as reduced need for sleep with studies finding that 69%–99% of bipolar individuals report a lessened need for sleep or difficulties in falling and/or staying asleep. Here we present a post hoc analysis evaluating iloperidone effects on the sleep component of the Young Mania Rating Scale (YMRS) in patients with bipolar I disorder which addresses both sleep and the reduced need for sleep in that component. Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study of iloperidone in patients with acute manic or mixed episodes associated with bipolar I disorder. Patients received four weeks of double-blind treatment. The primary analysis demonstrating an overall improvement from baseline YMRS score in iloperidone assigned patients versus placebo assigned patients (p = 0.000008) at the end of the study (week 4). A YMRS item level analysis evaluated changes on YMRS single items including the sleep component in the intent-to-treat population (N = 392) using a mixed-effects model for repeated measures approach. Results The least squares mean difference (LSMD) in change from baseline to day 28 was statistically significant on the YMRS sleep component in favor of iloperidone versus placebo (iloperidone = -1.26, placebo = -0.95; p = 0.008). Conclusion In addition to improving overall mania symptoms as reported by the YMRS, improvements were also seen in iloperidone treated patients in the sleep component which at baseline included assessments of both decreased sleep and decreased need or denial of the need for sleep. Support (if any) This work was supported by Vanda Pharmaceuticals Inc.

A Randomized, Double-Blind Placebo-Controlled Trial on Effectiveness and Safety of Celecoxib Adjunctive Therapy in Adolescents with Acute Bipolar Mania.

Recent studies have focused on the role of inflammatory cascades as one of the possible etiologic factors of bipolar disorder. We hypothesize that celecoxib, through its anti-inflammatory properties, may have a therapeutic role in acute bipolar mania. Forty-two adolescent inpatients with the diagnosis of acute bipolar mania participated in a parallel, randomized, double-blind controlled trial, and 40 patients underwent an 8-week treatment with either celecoxib (100 mg twice daily) or placebo as an adjunctive treatment to lithium and risperidone. Patients were evaluated using Young Mania Rating Scale (YMRS) at baseline and weeks 2, 4, and 8. The primary outcome measure was to assess the efficacy of celecoxib compared with placebo in improving mania symptoms. General linear model repeated measures showed significant effect for time × treatment interaction on YMRS scores [F (2.54, 96.56) = 3.21, p = 0.03]. Significantly greater improvement was observed in YMRS scores in the celecoxib group compared with the placebo group from baseline YMRS score at week 8 (p = 0.04). Although a 35% greater response to treatment (considering a Clinical Global Impressions-Improvement score of ≤2, very much/much improved) was observed in the celecoxib group compared with the placebo group, the difference did not reach the statistical significance level (p = 0.09). No serious adverse event was reported. Celecoxib may be an effective adjuvant therapy in treatment of manic episodes (without psychotic features) of adolescents with bipolar mood disorder. The mood-stabilizing role of this drug might be mediated through its action on inflammatory cascades.

Efficacy of Sodium Valproate and Olanzapine in treating bipolar affective disorder 'mania' at a tertiary care hospital in Nepal: A comparative study

Background and Objectives: Bipolar affective disorder, mania is the mood of an abnormally elevated arousal energy level or a state of heightened overall activation with enhanced affective expression together with lability of affect. The objective of the study was to compare the efficacy of sodium valproate and olanzapine in bipolar affective disorder, mania patients at a tertiary care hospital in NepalMaterial and Methods: A randomized observational prospective open label study was conducted for one and half year at College of Medical Sciences-Teaching Hospital (CMS-TH), Bharatpur, Nepal in the Psychiatry Department. Sixty patients diagnosed with bipolar affective disorder, mania were enrolled. 30 patients received sodium valproate and 30 patients received olanzapine. Patients were monitored and evaluated on baseline (day 0), day 7 and day 30 and compared to the baseline for the severity of illness using the 11-item Young Mania Rating Scale (YMRS).Results: The mean baseline YMRS score for all cases on sodium valproate (n=30) on day 0 was 38.87 ± 3.73, while it was reduced to 13.90 ± 1.95 (p < 0.001) on day 30. Similarly, the mean baseline YMRS score for all cases on olanzapine (n=30) on day 0was 40.83 ± 6.50, while it was reduced to 14.47 ± 2.83 (p < 0.001) on day 30.The mean decrease in YMRS score by sodium valproate was 64.24% and by olanzapine was 64.56%.Conclusion: Treatment with sodium valproate and olanzapine significantly improves the mean mania ratings score and there is no statistically significant difference in efficacy of both the drugs in patients diagnosed with bipolar affective disorder, mania.Janaki Medical College Journal of Medical Sciences (2016) Vol. 4(1): 27-35

Lithium in the Acute Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled Study.

Lithium is a benchmark treatment for bipolar disorder in adults. Definitive studies of lithium in pediatric bipolar I disorder (BP-I) are lacking. This multicenter, randomized, double-blind, placebo-controlled study of pediatric participants (ages 7-17 years) with BP-I/manic or mixed episodes compared lithium (n = 53) versus placebo (n = 28) for up to 8 weeks. The a priori primary efficacy measure was change from baseline to the end of study (week 8/ET) in the Young Mania Rating Scale (YMRS) score, based on last-observation-carried-forward analysis. The change in YMRS score was significantly larger in lithium-treated participants (5.51 [95% confidence interval: 0.51 to 10.50]) after adjustment for baseline YMRS score, age group, weight group, gender, and study site (P = .03). Overall Clinical Global Impression-Improvement scores favored lithium (n = 25; 47% very much/much improved) compared with placebo (n = 6; 21% very much/much improved) at week 8/ET (P = .03). A statistically significant increase in thyrotropin concentration was seen with lithium (3.0 ± 3.1 mIU/L) compared with placebo (-0.1 ± 0.9 mIU/L; P < .001). There was no statistically significant between-group difference with respect to weight gain. Lithium was superior to placebo in reducing manic symptoms in pediatric patients treated for BP-I in this clinical trial. Lithium was generally well tolerated in this patient population and was not associated with weight gain, distinguishing it from other agents commonly used to treat youth with bipolar disorder.

Asenapine in Clinical Practice: Responders Vs Non-responders

Introduction Asenapine is a second-generation antipsychotic approved in Europe for the treatment of manic or mixed episodes. Objective To describe the clinical features of Asenapine responders and non-responders. Methods A naturalistic, observational study is ongoing in patients treated with Asenapine. We have already recruited 37 manic patients with a lifetime diagnosis of Bipolar I (BDI) or Schizoaffective Disorder referring to our Psychiatric Ward. Patients are assessed with the Young Mania Rating Scale (YMRS) at baseline (T0), and after 1 (T1) and 4 weeks (T2) of treatment. According to YMRS scores, patients are classified as responders and non-responders. Results The preliminary results highlight a significant improvement of the YMRS score from T0 to T2 in most patients. Asenapine seems particularly effective in patients with less severe manic symptoms, and responders are more likely to have lower baseline YMRS score. No correlation has currently emerged between responder status and diagnosis. Non-responders in our sample are females sharing some clinical features: early onset BDI diagnosis, several previous treatments (antipsychotics, mood stabilizers), initial cognitive impairment confirmed with the Mini Mental State Examination, Alzheimer Disease Assessment Scale and neuroimaging. Conclusions Elderly manic patients with neurological impairment and/or dementia may have poorer therapeutic outcomes and poorer response to pharmacological treatment, which may prove effective in reducing agitation but not mania ratings. Diagnosis (BDI or schizoaffective disorder) does not seem to have a significant impact on Asenapine efficacy. The further recruitment and assessment of patients is expected to support the results described above.

Early improvement with lithium in classic mania and its association with later response

Despite lithium's clinical efficacy in treating mania in bipolar disorder (BD), studies evaluating early improvement and subsequent treatment response are sparse. This study investigated whether early improvement (within one week) to lithium monotherapy predicted later response and remission in individuals with BD mania. BD-I patients (n=46) experiencing a manic episode received lithium monotherapy for four weeks (initial dose: 600mg/d, adjusted to therapeutic levels); individuals experiencing a mixed episode, rapid cyclers, previous non-responders to lithium, and those with current drug abuse/dependence were excluded. Symptoms were rated using the Young Mania Rating Scale (YMRS) at baseline and at Days 7, 14, 21, and 28. Thirty-three percent of the total sample responded to lithium within the first week of treatment, defined as a ≥50% decrease from baseline YMRS scores; 63% responded by study endpoint. In addition, 39% of the total sample showed early improvement (at least 20% decrease in YMRS scores) after one week of treatment. In this group, 79% responded to lithium by study endpoint. Among those showing less than 20% improvement at Week 1, only 23% responded to lithium by study endpoint. History of episodes sequence was not assessed. Early improvement in response to lithium monotherapy in subjects with BD mania predicted later response and remission. Most patients who did not show early improvement in response to lithium during the first week of treatment showed no response after one month. The findings provide a valuable clinical tool for early identification of those patients most likely to benefit from lithium in clinical practice.

Correlates of Treatment Response in Depressed Older Adults With Bipolar Disorder

To identify baseline clinical factors associated with acute treatment response in depressed older adults with bipolar disorder (BD) receiving lamotrigine. Secondary analysis of a multisite, 12-week, open-label, uncontrolled study of add-on lamotrigine in 57 adults 60 years and older with BD I or II depression. Measures included the Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Cardiometabolic risk was measured with total serum cholesterol and the Cumulative Illness Rating Scale-Geriatric (CIRS-G) item #13 (endocrine/metabolic burden). Neurocognitive (executive) function was evaluated using the Trail Making Test. Greater reduction in MADRS from baseline was associated with higher baseline cardiometabolic burden at 6 and 9 weeks and lower YMRS scores at 9 weeks. At 12 weeks, improvement in the MADRS from baseline was no longer significantly related to baseline cardiometabolic burden or YMRS scores. A longitudinal mixed model of MADRS scores corroborated these findings with a significant finding of time-by-baseline cholesterol level interaction. In a subset of participants, better baseline executive function was related to greater improvement in the MADRS at 9 weeks but not at 6 or 12 weeks. Among all participants, higher baseline YMRS scores were related to greater likelihood of dropout. Lamotrigine appears to work best in depressed elderly patients with BD who have high cardiometabolic risk and low level of mania. Agents like lamotrigine that act primarily on neuroprogressive pathways involving oxidative stress, neurotrophins, and inflammation may be particularly effective in individuals with BD who have significant cardiometabolic burden because of their effects on shared vulnerability factors in BD and medical illness.

Episode length and mixed features as predictors of ECT nonresponse in patients with medication-resistant major depression

This study aimed to ascertain predictors of nonresponse to electroconvulsive therapy (ECT) in a large sample of major depressive patients resistant to pharmacologic treatment. A total of 208 depressive patients (31 with major depression [UP], 101 with bipolar disorder II [BP II], and 76 with bipolar disorder I [BP I] according to DSM-IV criteria) were included in the study and treated with bilateral ECT on a twice-a-week schedule. The patients were assessed before (baseline) and a week after the ECT course (final score) using the Hamilton Rating Scale for Depression-17 items (HAM-D-17), the Young Mania Rating Scale (YMRS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Improvement (CGI). Responders were defined as those patients with a reduction of at least 50% in HAM-D-17 score and a rating of 2 ("much improved") or 1 ("very much improved") in the CGI-Improvement subscale. At the end of the ECT course, 152 patients (64%) were classified as responders and 56 patients (36%) were classified as nonresponders. On backward stepwise logistic regression, bipolar subtype (odds ratio [OR]=17.85; 95% confidence level [CL]=1.786-178.407), higher mean baseline YMRS scores (OR=1.094; 95% CL=1.025-1.166), lower mean baseline HAM-D-17 scores (OR=0.928; 95% CL=0.860-1.002), and length of current episode (OR=1.047; 95% CL=1.009-1.086) were identified as statistically significant predictors of nonresponse. ECT was an effective treatment for approximately two-thirds of the patients with medication-resistant depression who were included in this study. ECT nonresponse was associated with bipolar subtype, presence of manic symptoms during depression, slightly less severe depressive symptomatology, and protracted duration of the episode.

Study design and patient characteristics and outcome in acute mania clinical trials

The objective of this systematic review was to identify trial design and patient characteristics associated with symptom improvement in acute mania clinical trials. Drug trials in acute mania that used the Young Mania Rating Scale (YMRS) score as the primary endpoint were identified using a systematic search strategy. Details of the trial, patient population, and treatment assignment were recorded. Covariates associated with change in YMRS were analyzed using a multiple regression model. A total of 41 studies, comprising 89 treatment arms and 10,471 patients, were selected for this analysis. Three variables were statistically significantly associated with change in YMRS score: treatment assignment, baseline mania score, and study location. Compared with placebo, greater mean (95% confidence interval) reductions in YMRS score were noted for all three active treatment arms [-4.7 (-6.4 to -3.0) for mood stabilizers; -5.9 (-7.6 to -4.2) for antipsychotics; and -8.3 (-10.2 to -6.4) for combined mood stabilizer/antipsychotics; all comparisons p < 0.0001]. Greater changes in YMRS score were associated with higher baseline YMRS scores (p = 0.002) and with studies performed outside of the USA (p= 0.02). Year of study publication was not associated with YMRS score change. Study size, number of study sites, YMRS score required for study entry, inclusion of patients with mixed mania or treatment resistance, and enrollment of inpatients versus outpatients had no significant influence on change in YMRS score. These findings may assist in the design of future drug trials for acute mania.

Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression

Objective: Treatment-emergent mania can have substantial negative impact on overall mood and psychosocial stability in patients receiving treatment for bipolar depression. This study examined the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression. Method: A total of 176 adult outpatients with bipolar disorder in a 10-week trial of adjunctive antidepressant treatment for depression were categorized into three groups based on the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N=85), those who did not respond to antidepressant treatment (N=45), and those who had treatment-emergent mania or hypomania (N=46). Symptom severity was measured with the Inventory of Depressive Symptomatology and the Young Mania Rating Scale (YMRS) at baseline and bimonthly intervals. Factor analysis was used to examine correlates of treatment-emergent mania. Results: Baseline YMRS scores were significantly different between groups. Otherwise, there were no significant between-group differences in demographic or clinical characteristics. Factor analysis showed that a subset of the YMRS items predicted treatment-emergent mania in this sample: increased motor activity, speech, and language-thought disorder. Conclusions: These data suggest that minimal manic symptoms at baseline co-existing with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania. A careful examination of motor activation, pressured speech, and racing thoughts is warranted before starting antidepressant treatment in bipolar depression. (Reprinted with permission from American Journal of Psychiatry 2009; 166:164–172)

Correlates of Treatment-Emergent Mania Associated With Antidepressant Treatment in Bipolar Depression

Treatment-emergent mania can have substantial negative impact on overall mood and psychosocial stability in patients receiving treatment for bipolar depression. This study examined the correlates associated with treatment-emergent mania in patients receiving adjunctive antidepressant treatment for bipolar depression. A total of 176 adult outpatients with bipolar disorder in a 10-week trial of adjunctive antidepressant treatment for depression were categorized into three groups based on the Clinical Global Impression Scale for Bipolar Disorder: those who responded to antidepressant treatment (N=85), those who did not respond to antidepressant treatment (N=45), and those who had treatment-emergent mania or hypomania (N=46). Symptom severity was measured with the Inventory of Depressive Symptomatology and the Young Mania Rating Scale (YMRS) at baseline and bimonthly intervals. Factor analysis was used to examine correlates of treatment-emergent mania. Baseline YMRS scores were significantly different between groups. Otherwise, there were no significant between-group differences in demographic or clinical characteristics. Factor analysis showed that a subset of the YMRS items predicted treatment-emergent mania in this sample: increased motor activity, speech, and language-thought disorder. These data suggest that minimal manic symptoms at baseline coexisting with otherwise full syndromal bipolar depression are associated with antidepressant treatment-emergent mania or hypomania. A careful examination of motor activation, pressured speech, and racing thoughts is warranted before starting antidepressant treatment in bipolar depression.

Bifrontal Versus Bitemporal Electroconvulsive Therapy in Severe Manic Patients

To compare the efficacy and safety of moderate-dose bifrontal (BF) with low-dose bitemporal (BT) electroconvulsive therapy (ECT) in the treatment of patients with severe mania. In a parallel, double-blind, randomized clinical trial, 28 patients with severe mania admitted to a university hospital were assigned randomly to moderate-dose BF (n = 14) and low-dose BT (n= 14) ECT. The primary outcome measures included the Mini-Mental State Examination (MMSE) and the Young Mania Rating Scale (YMRS). All patients received at least 6 sessions of ECT. The 2 groups did not show any difference in their baseline MMSE or YMRS scores (P > 0.05). There was a significant difference between the MMSE scores of the BF compared with the BT group after both the sixth ECT (P < 0.05) and final ECT treatments (P < 0.05). Young Mania Rating Scale scores did not differ between the 2 groups after either the sixth or the last ECT sessions (P > 0.05). Moderate-dose BF ECT was as effective as BT ECT but was associated with fewer cognitive side effects in the treatment of patients with severe mania.

C.17.03 Increasing compliance with anti-depressant treatment

To analyze the available evidence from randomized clinical trials regarding the effective dose range and optimal dose of quetiapine when treating bipolar I disorder patients with acute mania.Patients with acute mania were treated with quetiapine as monotherapy (for 12 weeks) or in combination with lithium (mean serum concentration 0.76 mEq/L) or divalproex (mean serum concentration 69.5 μg/mL) (Li/DVP) (for 3–6 weeks) in four double-blind, placebo-controlled studies according to a predetermined dosing schedule. Guidance for the dosing of quetiapine involved increasing the first day's dose (100 mg/day) by 100 mg on a daily basis until Day 4 (400 mg/day), then adjusting the dose up to 600 mg/day at Day 5, and up to 800 mg/day thereafter. Pooled data from the two monotherapy studies and the two combination therapy studies have been used to evaluate the effective quetiapine dose range. As the dose was flexible, effective dose was estimated by the mean last-week dose among responders. The mean last-week dose was defined as the median dose during the 7 days before the last available Young Mania Rating Scale (YMRS) assessment. Patients who achieved a ≥ 50% decrease in the YMRS total score from baseline to end of treatment with quetiapine were considered responders. Tolerability was assessed from direct patient reports.According to randomized clinical trials, administration of quetiapine compared with placebo achieved a statistically significant improvement in change from baseline YMRS score within the first week and onward, as monotherapy or in combination with Li/DVP. The average quetiapine dose (± SD) in responders during the last week of treatment was 575 (± 175) at Day 21 and 598 (± 198) mg/day at Day 84 for monotherapy, and 584 ± 208 mg/day at Day 21 for combination therapy, with most responders receiving doses within the range of 400–800 mg/day. Dose escalation was rapid, with 92% of patients treated with monotherapy and 80% of patients treated with combination therapy reaching doses of 400 mg/day by Day 4, in accordance with protocol-defined dosing guidance. This dose administration schedule was generally well tolerated.The mean last-week median dose among responders suggests that 600 mg/day of quetiapine is an effective target dose in acute mania.

Latest Hope for Omega-3 Fatty Acids Shot Down for Child Bipolar Illness

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessLatest Hope for Omega-3 Fatty Acids Shot Down for Child Bipolar IllnessAron LevinAron LevinSearch for more papers by this authorPublished Online:6 Apr 2007https://doi.org/10.1176/pn.42.7.0022aIt would be too much to hope that an over-the-counter dietary supplement might help treat bipolar and other psychiatric disorders, and that appears to be the case.Omega-3 fatty acid supplementation has been suggested to alleviate symptoms of several psychiatric disorders, but results have generally proved inclusive, according to a number of studies. However, a small, open-label study claims to have found some improvement in manic symptoms in children with bipolar illness.Conventional mood stabilizers such as lithium, divalproex, or carbamazepine may cause unacceptable side effects and subsequent poor compliance when prescribed for young patients.The trial tested a commercial formulation of omega-3 fatty acids for eight weeks in 20 outpatients aged 6 to 17 years. To be eligible, the patients had to record a score over 15 on the Young Mania Rating Scale (YMRS) and not be taking any mood stabilizer, anticonvulsant, antidepressant, or neuroleptic pharmacotherapy. Psychostimulants were permitted, if clinicians deemed it appropriate. Nondrug therapies could be continued but not initiated during the trial. Study clinicians diagnosed each patient in the trial according to DSM-IV criteria.Each gel cap of the study drug contained 375 mg of eicosapentaenoic acid (EPA) and 55 mg of docosahexaenoic acid (DHA). Dosing began at three capsules a day and could escalate to 10 a day. Mean dosage at the study's end was 2,600 mg/day.Ten subjects (50 percent) had baseline YMRS scores reduced by 30 percent, and there was an average 8.9 point drop at the end of eight weeks. However, the subjects remained symptomatic. Scores on the Brief Psychotic Rating Scale and the Children's Depression Rating Scale declined, too.“Given the modest level of improvement in this open-label study, the likelihood exists that nonspecific study effects were responsible for the improvement,” wrote Janet Wozniak, M.D., an assistant professor of psychiatry at Harvard Medical School and director of the Pediatric Bipolar Clinical and Research Program in Pediatric Psychopharmacology at Massachusetts General Hospital, and colleagues. Their study was published online ahead of print in the January 25 European Neuropsychopharmacology.The authors cited previous research suggesting that the fatty-acid composition of the phospholipids of cell membranes may affect neurotransmitter receptors. They also ask if dietary deficiencies of omega-3 fatty acids in bipolar youth may offer an opening for treatment.Several systematic reviews of omega-3 fatty acid supplementation have been published in the last year and concluded that its effectiveness for the treatment of depression or bipolar disorder remains mixed or inconclusive. A review by Australian researchers in the June 2006 American Journal of Psychiatry said that much work needed to be done on selecting outcome measures, appropriate placebos, concurrent psychot ropic medicat ions, dosage levels, and fatty-acid composition of the supplement to develop useful clinical trials.An abstract of “Omega-3 Fatty Acid Monotherapy for Pediatric Bipolar Disorder: A Prospective Open-Label Trial” is posted at<www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17258897&query_hl=7&itool=pubmed_docsum>.“ Omega-3 Fatty Acids and Mood Disorders” is posted at<http://ajp.psychiatryonline.org/cgi/content/abstract/163/6/96>.▪ ISSUES NewArchived

Quetiapine in the treatment of acute mania: Target dose for efficacious treatment

Objective To analyze the available evidence from randomized clinical trials regarding the effective dose range and optimal dose of quetiapine when treating bipolar I disorder patients with acute mania. Methods Patients with acute mania were treated with quetiapine as monotherapy (for 12 weeks) or in combination with lithium (mean serum concentration 0.76 mEq/L) or divalproex (mean serum concentration 69.5 μg/mL) (Li/DVP) (for 3–6 weeks) in four double-blind, placebo-controlled studies according to a predetermined dosing schedule. Guidance for the dosing of quetiapine involved increasing the first day's dose (100 mg/day) by 100 mg on a daily basis until Day 4 (400 mg/day), then adjusting the dose up to 600 mg/day at Day 5, and up to 800 mg/day thereafter. Pooled data from the two monotherapy studies and the two combination therapy studies have been used to evaluate the effective quetiapine dose range. As the dose was flexible, effective dose was estimated by the mean last-week dose among responders. The mean last-week dose was defined as the median dose during the 7 days before the last available Young Mania Rating Scale (YMRS) assessment. Patients who achieved a ≥ 50% decrease in the YMRS total score from baseline to end of treatment with quetiapine were considered responders. Tolerability was assessed from direct patient reports. Results According to randomized clinical trials, administration of quetiapine compared with placebo achieved a statistically significant improvement in change from baseline YMRS score within the first week and onward, as monotherapy or in combination with Li/DVP. The average quetiapine dose (± SD) in responders during the last week of treatment was 575 (± 175) at Day 21 and 598 (± 198) mg/day at Day 84 for monotherapy, and 584 ± 208 mg/day at Day 21 for combination therapy, with most responders receiving doses within the range of 400–800 mg/day. Dose escalation was rapid, with 92% of patients treated with monotherapy and 80% of patients treated with combination therapy reaching doses of 400 mg/day by Day 4, in accordance with protocol-defined dosing guidance. This dose administration schedule was generally well tolerated. Conclusions The mean last-week median dose among responders suggests that 600 mg/day of quetiapine is an effective target dose in acute mania.

Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study

This study compares the efficacy, safety, and tolerability of a partial dopamine agonist, aripiprazole, with placebo in the treatment of patients with bipolar I disorder experiencing an acute manic or mixed episode. In total, 272 hospitalized patients were randomized to aripiprazole 30 mg/day or placebo in this 3-week, double-blind, placebo-controlled trial. Dosing could be reduced to 15 mg/day for tolerability and, subsequently, increased to 30 mg/day based on clinical response. Primary efficacy measure was mean change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score; response was defined as > or = 50% decrease from baseline YMRS score. Aripiprazole-treated patients demonstrated significantly greater improvement from baseline to endpoint in mean YMRS total scores compared with placebo-treated patients as early as Day 4 and sustained through Week 3. A significantly higher response rate was observed in aripiprazole-treated patients (53% vs. 32% at endpoint). Aripiprazole produced significantly greater improvements from baseline on other efficacy assessments compared with placebo, including Clinical Global Impression - Bipolar Version Severity and Improvement scores. The 30 mg/day dose was maintained by 85% of aripiprazole-treated patients. Incidence of discontinuations due to adverse events was similar for aripiprazole (8.8%) and placebo (7.5%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight and was not associated with elevated serum prolactin or QTc prolongation. In conclusion, aripiprazole demonstrated superior efficacy to placebo in the treatment of patients with bipolar I disorder presenting with acute manic or mixed episodes, and exhibited a favourable safety and tolerability profile.

Symptomatic Remission in Patients With Bipolar Mania

The purpose of this analysis was to assess rates of symptomatic remission in patients with bipolar mania receiving risperidone in a double-blind, parallel-group, multicenter, placebo-controlled trial conducted in India. Two hundred ninety-one adult patients who met DSM-IV criteria for bipolar I disorder manic or mixed episode were randomly assigned to flexible doses of risperidone (1-6 mg/day, N = 146) or placebo (N = 145) for up to 3 weeks. An entry Young Mania Rating Scale (YMRS) score of >or= 20 was required at trial screening and baseline. Remission was defined as achieving and maintaining a YMRS score <or= 8 for the remainder of the trial or until censor. Time to first onset of remission was assessed using Cox proportional hazards model. Presence or absence of remission was analyzed using logistic regression. Data were collected from March 2001 to December 2001. Of the 291 patients randomly assigned to treatment, 290 received at least 1 postbaseline assessment and were included in the analysis. The patients' mean YMRS score at baseline was 37.2 +/- 7.9. Remission was achieved by 42% of patients in the risperidone group and 13% of patients in the placebo group. After adjusting for psychosis, baseline YMRS score, sex, number of mood cycles in the previous year, and treatment, the odds of remission for patients receiving risperidone was 5.6 (95% CI = 3.0 to 10.4; chi(2) = 29.9, p < .0001). Similarly, the adjusted hazard of remission for the risperidone patients was 4.0 (95% CI = 2.3 to 6.8; chi(2) = 25.9, p < .0001). A significant proportion of acutely manic patients receiving risperidone monotherapy achieved symptomatic remission within 3 weeks.

Divalproex sodium for pediatric mixed mania: a 6‐month prospective trial

This prospective 6-month open trial examined the effectiveness and safety of divalproex sodium (DVPX) in pediatric mixed mania. Thirty-four subjects with a mean age of 12.3 (SD = 3.7) years, DSM-IV diagnosis of a current mixed episode and a baseline Young Mania Rating Scale (YMRS) score >20 were treated with DVPX monotherapy. The primary outcome measures were the YMRS and the Child Depression Rating Scale-Revised. Secondary measures were the Clinical Global Impression Scale for Bipolar Disorder (CGI-BP) and the Children's Global Assessment of Functioning Scale (C-GAS). Measures of safety and tolerability were also administered. Effect size (Cohen's d) based on change scores from baseline was 2.9 for the YMRS and 1.23 for the CDRS-R. Response rate (> or =50% change from baseline YMRS score and < or =40 score on CDRS-R at the end of study) was 73.5%. The remission rate (> or =50% change from baseline on YMRS, < or =40 on CDRS-R, CGI-BP-Improvement subscale of < or =2, and > or =51 CGAS score) was 52.9%. Significant improvements (p < 0.001) from baseline were seen for mean scores on all outcome measures (i.e., YMRS, CGI-BP, CDRS-R, and C-GAS). DVPX was safe and well tolerated with no serious adverse events during the 6-month trial. This study provides evidence for the effectiveness and safety of DVPX in the treatment of pediatric mixed mania over a 6-month period. Placebo-controlled, randomized trials involving larger samples will ultimately shed light on the efficacy of this agent.

P.3.127 A randomised, double-blind clinical trial comparing treatment with amisulpride or risperidone for six weeks in elderly patients with schizophrenia

Background: Published case reports describe apparent induction or exacerbation of manic-like symptoms during treatment with the atypical antipsychotics olanzapine and risperidone. To date, such reports are from uncontrolled clinical experience and therefore cannot clarify whether the atypical antipsychotics caused such manic-like states or simply failed to prevent them. Presumably, bipolar patients would be at increased risk for this putative adverse event. Therefore, we evaluated the potential of olanzapine to exacerbate symptoms of mania compared to placebo during treatment of bipolar mania. Methods: Two inpatient, double-blind, randomized trials investigating the efficacy of olanzapine 5–20 mg daily versus placebo for the treatment of acute mania were combined. Two hundred and fifty-four subjects participated (placebo n=129; olanzapine n=125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to 3 weeks, categorical comparison of olanzapine and placebo groups was made for any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). Results: The percentage of subjects with exacerbation at endpoint were: any worsening, placebo 37.7%, olanzapine 21.8% (P=0.005); ≥10% worsening, placebo 24.6%, olanzapine 14.5% (P=0.039); ≥20% worsening, placebo 15.6%, olanzapine 8.1% (P=0.064). Conclusion: Mania rating scores worsened for some patients during olanzapine therapy. However, this was significantly less common with olanzapine than with placebo. These controlled data suggest that clinical case reports of occurrence of ‘mania’ during treatment with olanzapine, and possibly those with other atypical antipsychotics, reflect exacerbation in the natural history of bipolar illness, rather than an adverse pharmacological effect. Limitations: Post-hoc analysis of pooled data from two different studies.

P.3.129 Aripiprazole for relapse prevention in bipolar disorder: a 26-week placebo-controlled study

Background: Published case reports describe apparent induction or exacerbation of manic-like symptoms during treatment with the atypical antipsychotics olanzapine and risperidone. To date, such reports are from uncontrolled clinical experience and therefore cannot clarify whether the atypical antipsychotics caused such manic-like states or simply failed to prevent them. Presumably, bipolar patients would be at increased risk for this putative adverse event. Therefore, we evaluated the potential of olanzapine to exacerbate symptoms of mania compared to placebo during treatment of bipolar mania. Methods: Two inpatient, double-blind, randomized trials investigating the efficacy of olanzapine 5–20 mg daily versus placebo for the treatment of acute mania were combined. Two hundred and fifty-four subjects participated (placebo n=129; olanzapine n=125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to 3 weeks, categorical comparison of olanzapine and placebo groups was made for any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). Results: The percentage of subjects with exacerbation at endpoint were: any worsening, placebo 37.7%, olanzapine 21.8% (P=0.005); ≥10% worsening, placebo 24.6%, olanzapine 14.5% (P=0.039); ≥20% worsening, placebo 15.6%, olanzapine 8.1% (P=0.064). Conclusion: Mania rating scores worsened for some patients during olanzapine therapy. However, this was significantly less common with olanzapine than with placebo. These controlled data suggest that clinical case reports of occurrence of ‘mania’ during treatment with olanzapine, and possibly those with other atypical antipsychotics, reflect exacerbation in the natural history of bipolar illness, rather than an adverse pharmacological effect. Limitations: Post-hoc analysis of pooled data from two different studies.