A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder

OBJECTIVE: The goal of this study was to assess the effectiveness and tolerability of olanzapine in the treatment of acute mania in children and adolescents. METHODS: This was an 8-week, open-label, prospective study of olanzapine monotherapy (dose range 2.5-20 mg/day) involving 23 bipolar youths (manic, mixed, or hypomanic; 5-14 years old). Weekly assessments were made using the Young Mania Rating Scale (YMRS), Clinical Global Impressions Severity Scale (CGI-S), Brief Psychiatric Rating Scale, and Children's Depression Rating Scale. Adverse events were assessed through self-reports, vital sign and weight monitoring, laboratory analytes, and extrapyramidal symptom rating scales (Barnes Akathisia Scale, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale). RESULTS: Twenty-two of the 23 youths (96%) completed the study. Olanzapine treatment was associated with significant improvement in mean YMRS score (-19.0 +/- 9.2, p < 0.001). Using predefined criteria for improvement of > or = 30% decline in the YMRS and a CGI-S Mania score of < or = 3 at endpoint, the overall response rate was 61%. Overall, olanzapine was well tolerated, and extrapyramidal symptom measures were not significantly different from baseline. Body weight increased significantly over the study (5.0 +/- 2.3 kg, p < 0.001). CONCLUSIONS: Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted.     

Analyses of treatment-emergent mania with olanzapine/fluoxetine combination in the treatment of bipolar depression

BACKGROUND: Treatment-emergent mania is a potential risk when patients with bipolar disorder are treated with antidepressant agents. These subanalyses compare treatment-emergent mania rates in bipolar I depressed patients treated with olanzapine, placebo, or olanzapine/fluoxetine combination. METHOD: In this 8-week, double-blind investigation, patients with bipolar I depression (DSM-IV criteria) (N = 833, baseline Montgomery-Asberg Depression Rating Scale total score > or = 20) were randomly assigned to olanzapine (5-20 mg/day, N = 370), placebo (N = 377), or olanzapine/fluoxetine combination (6/25, 6/50, or 12/50 mg/day; N = 86). Treatment-emergent mania was evaluated with the Young Mania Rating Scale (YMRS), the Clinical Global Impressions-Bipolar Edition (CGI-BP) Severity of Mania scale, and adverse events records. RESULTS: Overall rates of study discontinuation due to mania were low and not significantly different among the therapy groups (p = .358). Incidence of treatment-emergent mania (defined as a YMRS score < 15 at baseline and > or = 15 at any subsequent visit) did not differ significantly among therapy groups (olanzapine 5.7%, placebo 6.7%, olanzapine/fluoxetine combination 6.4%; p = .861). Subjects receiving olanzapine or olanzapine/fluoxetine combination had greater mean decreases in YMRS scores than those receiving placebo (p < .001 for both). Subjects receiving olanzapine or olanzapine/fluoxetine combination also had greater mean decreases in CGI-BP scores than those receiving placebo (p = .040 and p = .003, respectively). CONCLUSION: These results suggest that olanzapine/fluoxetine combination does not present a greater risk of treatment-emergent mania compared to olanzapine or placebo over 8 weeks of acute treatment for bipolar I depression. Due to the cyclical nature of bipolar disorder, patients taking olanzapine/fluoxetine combination for bipolar depression should still be monitored for signs or symptoms of emerging mania.     

Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine

OBJECTIVE: In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder. METHOD: Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score < or =12 and 21-item Hamilton Depression Rating Scale [HAM-D] score or =15, HAM-D score > or =15, or hospitalization). RESULTS: Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic, depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2). CONCLUSIONS: Compared to placebo, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode.     

Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy.

BACKGROUND: A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes. METHODS: The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer). RESULTS: Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech. CONCLUSION: Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes.     

Olanzapine versus divalproex in the treatment of acute mania

OBJECTIVE: The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial. METHOD: A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures. RESULTS: The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (> or = 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment. CONCLUSIONS: The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex.     

An open-label trial of risperidone in children and adolescents with bipolar disorder

OBJECTIVE: The aim of this study was to evaluate the potential of risperidone as a treatment of pediatric bipolar disorder. METHODS: This was an 8-week, open-label, prospective study of risperidone monotherapy (1.25 +/- 1.5 mg/d) for 30 bipolar youths (manic, mixed, or hypomanic; 6-17 years of age). RESULTS: Twenty-two of the 30 youths (73%) completed the study. Using predefined criteria for improvement (a Clinical Global Impressions Improvement in Mania score of < or =2 at endpoint), the response rate for manic symptoms was 70%. The significant reduction in symptoms of mania resulted in a mean Young Mania Rating Scale (YMRS) score 13.5 at endpoint, indicating mild residual symptoms. Weight increased significantly from baseline (2.1 +/- 2.0 kg; p < 0.001) and there was a four-fold increase in prolactin levels from baseline (p < 0.001). CONCLUSIONS: Open-label risperidone treatment was associated with a significant shortterm improvement of symptoms of pediatric bipolar disorder. Future placebo-controlled, double-blind studies are needed to confirm these preliminary results.     

Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials

OBJECTIVE: To evaluate the efficacy and tolerability of topiramate monotherapy in adults with acute manic or mixed episodes of bipolar I disorder. METHODS: In four trials, adults hospitalized with acute mania, a diagnosis of bipolar I disorder, history of > or =1 previous manic or mixed episodes, and > or =20 Young Mania Rating Scale (YMRS) score were randomized to double-blind treatment with topiramate (target doses: 200, 400, or 600 mg/day) or placebo; two trials included an active comparator (lithium, 1500 mg/day). The core study duration in all trials was 3 weeks; three trials also had 9-week double-blind extensions. The primary efficacy variable was mean change from baseline in YMRS in the core 3-week study. RESULTS: Changes in YMRS score during 3 weeks were not significantly different for topiramate versus placebo (mean YMRS reductions, -5.1 to -8.4). Mean YMRS reductions in lithium-treated groups were significantly greater (p < or = 0.001 versus placebo and topiramate). A similar pattern was observed after 12 weeks of double-blind treatment in studies with double-blind extensions. Paresthesia, appetite decrease, dry mouth, and weight loss were more frequently associated with topiramate than with placebo. CONCLUSIONS: These studies do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder. Topiramate was not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression. Lithium was confirmed as an effective therapy in this population.     

Risperidone in combination with mood stabilizers: a 10-week continuation phase study in bipolar I disorder

BACKGROUND: Combination therapy (risperidone and a mood stabilizer) for patients with a history of bipolar disorder (DSM-IV) and hospitalized for treatment of a manic episode was assessed in a 13-week study. METHOD: Subjects received flexible doses of a mood stabilizer (lithium or divalproex) plus placebo, risperidone, or haloperidol in a 3-week double-blind study. They could then enter a 10-week open-label study during which they received risperidone combined with a mood stabilizer. RESULTS: Of the 156 patients enrolled in the 3-week study, 85 entered the 10-week open-label extension, of whom 48 completed 10 weeks of treatment. The mean +/- SE doses of risperidone were 3.8 +/- 0.3 mg/day during the 3-week study and 3.1 +/- 0.2 mg/day during the 10-week study. At double-blind endpoint, mean reductions in Young Mania Rating Scale (YMRS) scores were significantly greater in patients receiving risperidone plus mood stabilizer than in those receiving placebo plus mood stabilizer (-14.3 vs. -8.2, p <.001). Further significant (p <.001) reductions were seen during the 10 weeks of treatment with risperidone plus mood stabilizer. Symptom remission (YMRS score 相似文献   

Risperidone monotherapy in manic inpatients: an open label, multicentre trial.

OBJECTIVE: The efficacy of risperidone in acute mania has been established in several controlled clinical studies. However, this may not necessarily resemble the clinical effectiveness of this treatment, as patient populations in controlled studies are considered as being not representative. This study examined risperidone monotherapy in a sample of severe manic patients in admission ward settings. METHODS: Open label monotherapy with risperidone was examined for 3 weeks in 30 inpatients. Subjects were evaluated with structured clinical rating scales: Young Mania Rating Scale (YMRS), Clinical Global Impression, bipolar version (CGI-BP), and the Extrapyramidal Symptom Rating Scale (ESRS). In addition, the amount of concomitant use of benzodiazepines was documented. Data were analysed using a last observation carried forward method on all subjects given medication at baseline. RESULTS: Significant improvement from baseline to exit was observed both for the YMRS and CGI-BP. Responder analysis revealed that two-thirds of the patients showed a reduction of 50% in the YMRS score, and 69% of the patients were rated as very much improved or much improved on the CGI-BP mania scale at study exit. Only three patients dropped out due to adverse events, in one case due to extrapyramidal symptoms. CONCLUSIONS: The efficacy of risperidone in the acute treatment of mania as observed in controlled studies could be replicated in this open monotherapy study in a severely manic inpatient population. Considering the mean maximal dosage of 5.5+/-0.9 mg risperidone, the tolerability and safety profile appeared satisfactory.     

Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial

OBJECTIVE: The authors compared the efficacy of olanzapine and lithium in the prevention of mood episode relapse/recurrence. METHOD: Patients with a diagnosis of bipolar disorder (manic/mixed), a history of two or more manic or mixed episodes within 6 years, and a Young Mania Rating Scale total score > or =20 entered the study and received open-label co-treatment with olanzapine and lithium for 6-12 weeks. Those meeting symptomatic remission criteria (Young Mania Rating Scale score < or =12; 21-item Hamilton depression scale score < or =8) were randomly assigned to 52 weeks of double-blind monotherapy with olanzapine, 5-20 mg/day (N=217), or lithium (target blood level: 0.6-1.2 meq/liter) (N=214). RESULTS: Symptomatic relapse/recurrence (score > or =15 on either the Young Mania Rating Scale or Hamilton depression scale) occurred in 30.0% of olanzapine-treated and 38.8% of lithium-treated patients. The noninferiority of olanzapine relative to lithium (primary objective) in preventing relapse/recurrence was met, since the lower limit of the 95% confidence interval on the 8.8% risk difference (-0.1% to 17.8%) exceeded the predefined noninferiority margin (-7.3%). Secondary results showed that compared with lithium, olanzapine had significantly lower risks of manic episode and mixed episode relapse/recurrence. Depression relapse/recurrence occurred in 15.7% of olanzapine-treated and 10.7% of lithium-treated patients. Mean weight gain during open-label co-treatment was 2.7 kg; during double-blind monotherapy, weight gain was significantly greater with olanzapine (1.8 kg) than with lithium (-1.4 kg). CONCLUSIONS: These results suggest that olanzapine was significantly more effective than lithium in preventing manic and mixed episode relapse/recurrence in patients acutely stabilized with olanzapine and lithium co-treatment. Both agents were comparable in preventing depression relapse/recurrence.     

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

INTRODUCTION: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.     

A prospective open-label treatment trial of ziprasidone monotherapy in children and adolescents with bipolar disorder

OBJECTIVE: To assess the effectiveness and tolerability of ziprasidone for treating pediatric mania. METHODS: This was an eight-week, open-label, prospective study of ziprasidone monotherapy (57.3 +/- 33.9 mg/day) in 21 bipolar youth [manic, mixed, or bipolar not otherwise specified (NOS); 6-17 years old]. Assessments included the Young Mania Rating Scale (YMRS), Clinical Global Impressions-Improvement scale (CGI-I), and Brief Psychiatric Rating Scale (BPRS). Adverse events were assessed through spontaneous self-reports, vital signs, weight monitoring, and laboratory analysis. RESULTS: Fourteen of the 21 youth (67%) completed the study. Ziprasidone treatment was associated with clinically and statistically significant improvement in mean YMRS scores (-10.8 +/- 8.4, p < 0.0001) and 57% had a CGI-I 相似文献   

氟西汀合并奥氮平治疗难治性抑郁症的双盲对照研究

目的本研究探讨氟西汀合并奥氮平治疗难治性抑郁症的安全性和疗效。方法采用双盲对照研究,将52例诊断为难治性抑郁症的患者随机分为两组,一组采用氟西汀治疗,一组采用氟西汀合并奥氮平治疗,分别在治疗后第2、4、6、8周末,评定汉密顿抑郁量表(HAMD)和临床总体印象量表(CGI),同时采用Asberg抗抑郁剂副反应量表评定两组的药物副反应。结果氟西汀联合奥氮平治疗难治性抑郁症的疗效要明显优于单一应用氟西汀治疗(P<0.05),药物副反应两组间无明显差异(P>0.05)。结论氟西汀联合奥氮平治疗难治性抑郁症的疗效要明显优于单一应用氟西汀治疗(P<0.05),药物副反应两组间无明显差异(P>0.05)。     

Asenapine versus olanzapine in acute mania: a double‐blind extension study

Objective: To assess the efficacy and tolerability of asenapine versus olanzapine in the extended treatment of bipolar mania. Methods: Patients with bipolar I disorder experiencing acute manic or mixed episodes who completed either of two 3‐week, double‐blind trials with asenapine 5 or 10 mg twice daily, olanzapine 5 to 20 mg once daily, or placebo were eligible for this 9‐week, double‐blind extension study. Patients receiving active medication in the 3‐week trials continued the same regimen; those who had received placebo were blindly switched to asenapine but were assessed for safety outcomes only. The primary efficacy measure was the change from baseline to day 84 on the Young Mania Rating Scale (YMRS) total score in the per‐protocol population. Results on the primary efficacy outcome were used to determine the noninferiority of asenapine versus olanzapine. Results: A total of 504 patients (placebo/asenapine, n = 94; asenapine, n = 181; olanzapine, n = 229) were enrolled in the extension study. At day 84, the mean (SD) change from baseline in YMRS total score was ?24.4 (8.7) for asenapine and ?23.9 (7.9) for olanzapine. Prespecified statistical analysis for noninferiority indicated no significant difference between asenapine and olanzapine. The overall incidence of treatment‐emergent adverse events was similar across treatment groups (77% placebo/asenapine, 77% asenapine, 78% olanzapine). Clinically significant weight gain occurred in 10%, 19%, and 31% of the placebo/asenapine, asenapine, and olanzapine groups, respectively. Conclusions: Asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder.     

Risperidone in the treatment of mixed state bipolar patients: Results from a 24-week, multicenter, open-label study in Korea

Aims:  The goal of the present study was to evaluate the efficacy of risperidone combined with mood stabilizers for treating bipolar mixed state.
Methods:  The present study was a 24-week, open-label, combination, prospective investigation of the efficacy of risperidone in combination with mood stabilizers. Risperidone (1–6 mg/day) was given in combination with mood stabilizers in flexible doses according to clinical response and tolerability for 114 patients in mixed or manic episode.
Results:  Forty-four patients met our criteria for mixed state bipolar disorder and 70 met the criteria for pure mania. Mean age for the subjects was 39.0 ± 11.0 years and 55.3% were female. The combination of risperidone with mood stabilizers significantly improved the scores on the Young Mania Rating Scale (YMRS), 17-item Hamilton Rating Scale for Depression (HAMD), 18-item Brief Psychiatric Rating Scale (BPRS), Global Assessment Scale (GAS), and Clinical Global Impression Scale for use in bipolar illness Severity (CGI-BP) at 24 weeks ( P  < 0.0001). Analysis of the YMRS, BPRS, GAS, and CGI-BP scores showed significant improvement in both the manic and mixed groups. The rate of response in YMRS scores was 84.2% ( n  = 96) and the rate of YMRS remission was 77.2% ( n  = 88) at week 24 in the total population. Seventy-four patients met both YMRS ≤ 12 and HAMD ≤ 7 at week 24 (64.9%). Risperidone was well tolerated, and adverse events were mostly mild.
Conclusion:  The combination of risperidone with mood stabilizers was an effective and safe treatment for manic symptoms and coexisting depressive symptoms of bipolar disorder.     

A 24-week open-label extension study of olanzapine-fluoxetine combination and olanzapine monotherapy in the treatment of bipolar depression

OBJECTIVE: Olanzapine-fluoxetine combination has shown efficacy in the acute treatment of depressive episodes in patients with bipolar I disorder. The present analyses examined the efficacy and safety of longer term treatment with olanzapine-fluoxetine combination or olanzapine monotherapy in a 6-month open-label extension study. METHOD: 376 patients with DSM-IV bipolar I disorder, depressed, who completed an acute trial entered the open-label study and received 1 week of olanzapine monotherapy (5-20 mg/day). At all subsequent visits, patients could choose between olanzapine monotherapy or olanzapine-fluoxetine combination (6/25, 6/50, or 12/50 mg/day). Three treatment groups were defined retrospectively according to the medication course taken from week 1: olanzapine, olanzapine-fluoxetine combination, or switched. The efficacy measures were the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions-Bipolar Version, and Young Mania Rating Scale. The study was conducted from July 2000 to May 2002. RESULTS: Among patients who started in remission, MADRS total scores did not change significantly from baseline to endpoint in the olanzapine-fluoxetine combination (0.8) or olanzapine (0.3) groups, but increased slightly in the switched (2.3, p = .02) group. For patients who started in nonremission, MADRS total scores decreased significantly in all groups (olanzapine-fluoxetine combination: -5.7, p = .001; olanzapine: -11.6, p = .004; switched: -6.4, p = .015). The majority of patients who entered the study in nonremission achieved remission (MADRS total score < or = 12) during the trial (olanzapine-fluoxetine combination: 66.7%, olanzapine: 64.7%, switched: 62.5%). The overall rate of depressive relapse was 27.4%, and the overall incidence of mania emergence was 5.9%. CONCLUSIONS: The present findings suggest that long-term treatment with olanzapine-fluoxetine combination may be a useful option for the management of depressive symptoms and carries a low risk of mania emergence.     

A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes

BACKGROUND: Carbamazepine has been used to treat mania for over 2 decades. Most evaluations of carbamazepine have had important limitations, such as absence of a parallel placebo group, small sample size, or the confounding influence of concomitant treatment. All studies have used conventional, immediate-release carbamazepine formulations. We assessed the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ; SPD417) in bipolar disorder patients with manic or mixed episodes. METHOD: Following a single-blind placebo lead-in, DSM-IV-defined bipolar disorder patients with manic or mixed episodes were randomly assigned to receive ERC-CBZ (N = 101) or placebo (N = 103) for 3 weeks. Patients were hospitalized through the first 7 days of the double-blind period. ERC-CBZ was initiated at 400 mg/day and increased, as necessary and tolerated, up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression (HAM-D). Data were gathered from December 1999 to June 2001. RESULTS: Ninety-six (47.1%) of 204 patients completed the study. The mean +/- SD final ERC-CBZ dose was 756.44 +/- 413.38 mg/day with a mean plasma drug level of 8.9 microg/mL. Starting at week 2, ERC-CBZ was associated with significantly greater improvements in YMRS (p =.032) using last-observation-carried-forward analyses. At end point, the responder rate (patients with at least a 50% decrease in YMRS score) also favored ERC-CBZ (41.5% vs. 22.4%; p =.0074). In a post hoc analysis of mixed patients, HAM-D score was significantly improved in patients remaining on ERC-CBZ treatment on day 21 (p =.01). Adverse events occurring more frequently in the ERC-CBZ group than in the placebo group included dizziness, nausea, and somnolence. CONCLUSION: We found ERC-CBZ to be effective in the first large, randomized, double-blind, placebo-controlled parallel trial of carbamazepine monotherapy in acute mania. This trial provides important additional evidence supporting the use of carbamazepine in acute mania.     

Efficacy and safety of risperidone in the treatment of schizoaffective disorder: initial results from a large, multicenter surveillance study. Group for the Study of Risperidone in Affective Disorders (GSRAD)

BACKGROUND: An adequate therapy for psychotic disorders needs to be effective against mood as well as psychotic symptoms. Analyses of data from clinical trials of risperidone in schizophrenia and small open-label studies in mania suggest that risperidone may have this broad efficacy profile. We present data on a 6-week trial of risperidone for the treatment of schizoaffective disorder that was part of a larger, 6-month surveillance study of patients with affective disorders. METHOD: One hundred two patients suffering from schizoaffective disorder (DSM-IV or ICD-10) entered the trial. Inclusion criteria consisted of a current DSM-IV diagnosis of schizoaffective disorder, bipolar type; DSM-IV manic or mixed psychotic episode; and a Young Mania Rating Scale (YMRS) score > 7 for a mixed episode (> 20 for a manic episode). Assessments included the YMRS, the Positive and Negative Syndrome Scale (PANSS), the Hamilton Rating Scale for Depression (HAM-D), the 4-item Clinical Global Impressions (CGI) scale, and the UKU Side Effect Rating Scale subscale for neurologic side effects. For patients entering the study, open-label risperidone therapy was added to their existing regimens of mood-stabilizing treatments. Other antipsychotic drugs were not allowed. RESULTS: Ninety-five patients completed the 6-week trial. At week 6, the mean +/- SD dose of risperidone was 4.7+/-2.5 mg/day. The mean scores on the assessment scales at baseline and week 6 (unless otherwise stated) were as follows: YMRS, 22.7 and 4.7, an improvement of 18.0 points (p < .0001); PANSS (at baseline and week 4), 74.1 and 54.2, an improvement of 19.9 points (p < .0001); HAM-D, 14.0 and 7.4, an improvement of 6.6 points (p < .0001); CGI (at baseline and week 4), 2.6 and 1.7, an improvement of 0.9 points (p < .0001). At week 4, most patients had shown improvement in symptom severity, and 9.3% were completely symptom-free. There were no statistically significant differences between baseline and week 4 in the severity of extrapyramidal symptoms as measured by the UKU. Risperidone was well tolerated; side effects were few and generally mild. CONCLUSION: The results to date with risperidone indicate that it may have both antipsychotic and mood-stabilizing properties. Despite the limitations of the open-label design, the results indicate that risperidone is a safe and effective therapy in combination with mood-stabilizers for the treatment of patients with manic, hypomanic, and depressive symptoms of mixed episodes in schizoaffective disorder, bipolar type.     

Rates of response,euthymia and remission in two placebo-controlled olanzapine trials for bipolar mania

Objective:  Clinically meaningful recovery from acute mania may not be captured by conventionally reported response categorizations. We defined new and stringent criteria for remission in bipolar mania. Using a cohort of patients with acute mania randomized to treatment with either olanzapine or placebo, we contrasted remission rates to findings using previously reported but more lenient categorical outcome measures of response and euthymia.
Methods:  We pooled and reanalyzed results through 3 weeks from two published randomized double-blind trials of olanzapine versus placebo for treating acute bipolar mania ( 1, 2 ). Response was previously defined as ≥ 50% decrease from baseline to endpoint total Young Mania Rating Scale ( 3 ) (Y-MRS) scores, and euthymia as an endpoint total Y-MRS score of ≤ 12. In this report, remission required an endpoint total Y-MRS score of ≤ 7, and an endpoint total Hamilton Depression Rating Scale, (HAM-D21) ( 4 ) score of ≤ 7 and an endpoint Clinical Global Impression Scale – Bipolar version, CGI-BP ( 5 ), overall severity score of ≤ 2.
Results:  Olanzapine treated subjects achieved statistically significantly greater rates of clinical response, euthymia and remission than those assigned to placebo, 55% versus 29.5%, 50% versus 27%, and 18% versus 7%, respectively.
Conclusions:  Olanzapine monotherapy resulted in discernable clinical improvements in mania in over 50% of subjects and just under 20% of subjects achieved a near complete resolution of manic and accompanying depressive symptoms after 3 weeks of treatment. Full remission is an important but potentially elusive goal during short-term management of acute mania.     

Short-term fluoxetine monotherapy for bipolar type II or bipolar NOS major depression - low manic switch rate

Objectives:  Current guidelines for the initial treatment of bipolar type II (BP II) major depressive episode (MDE) recommend using either a mood stabilizer alone or a combination of a mood stabilizer plus a selective serotonin re-uptake inhibitor (SSRI). This recommendation is the result of concern over antidepressant-induced manic switch episodes. However, recent evidence suggests that the manic switch rate may be low in BP II MDE during SSRI therapy.
Methods:  As part of a randomized, double-blind, placebo-controlled relapse-prevention study of fluoxetine monotherapy in BP II MDE, 37 patients received open-label fluoxetine 20 mg every day for up to 8 weeks. Outcome measures included the Hamilton Depression Rating (HAM-D 17) rating and the Young Mania Rating (YMR) scale.
Results:  Eleven of 23 patients (48%) who completed 8 weeks of fluoxetine treatment showed a HAM-D 17 reduction of ≥50%, while 14 (38%) of all treated patients had ≥50% reduction in baseline HAM-D 17 score. Using a conservative YMR score of ≥8 to identify hypomanic symptoms, the frequency of patients with YMR score ≥8 during fluoxetine did not differ from that seen during the screen and baseline period. Only three patients (7.3%) had symptoms suggestive of hypomania, and only one patient stopped treatment because of a rapid mood swing into depression.
Limitations:  Fluoxetine was given at a fixed dose of 20 mg everyday. Fluoxetine was prescribed in an open-label manner, and the sample size was limited.
Conclusions:  These observations support the findings of a low manic switch rate during SSRI monotherapy of BP II MDE, and suggest that fluoxetine monotherapy may be a safe and effective initial treatment of BP II MDE.