Duloxetine Compared with Pregabalin for Diabetic Peripheral Neuropathic Pain Management in Patients with Suboptimal Pain Response to Gabapentin and Treated with or without Antidepressants: A Post Hoc Analysis.

OBJECTIVE: To examine the efficacy of duloxetine vs. pregabalin in the treatment for diabetic peripheral neuropathic pain (DPNP), comparing patient subgroups with and without concomitant antidepressant use. METHODS: This post hoc analysis assessed data from a randomized 12-week study that confirmed the noninferiority of duloxetine to pregabalin. In the previously published study, patients with DPNP with inadequate response to gabapentin were switched to duloxetine monotherapy, combination therapy of duloxetine plus gabapentin, or pregabalin monotherapy. Current, stable antidepressant use was allowed; 79 patients were concomitantly treated with antidepressants and 328 without antidepressants. In this post hoc analysis, improvement in the weekly mean of diary-based average daily pain ratings (numerical rating scale: 0-10) in antidepressant users and nonusers was analyzed using a longitudinal mixed-models repeated-measures (MMRM) analysis, including a test of the 3-way interaction (antidepressant subgroup by treatment by week) to assess whether the differences among treatment groups over 12 weeks differ between the antidepressant-use subgroups. RESULTS: The 3-way interaction was significant (P = 0.035), demonstrating that treatment-group differences in pain reduction over time differ between the subgroups. Among patients without antidepressant use, patients treated with duloxetine had significantly greater pain reduction than pregabalin at Week 4 and at each successive week up to the 12-week endpoint (-2.8 for duloxetine and -2.1 for pregabalin; P = 0.031); patients treated with duloxetine plus gabapentin had greater pain reduction than pregabalin at Weeks 2, 3, 5, and 7 to 9 (P ≤ 0.05) but not at endpoint (-2.4; P = 0.222). Among concomitant antidepressant users, no treatment-group differences were found. CONCLUSIONS: In patients with DPNP inadequately treated with gabapentin without the concomitant use of antidepressants, switching to duloxetine instead of pregabalin may provide better pain reduction. Conversely, in nonresponders to gabapentin who are concomitantly using an antidepressant, switching to duloxetine or pregabalin may provide similar pain reductions.

A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) often report neuropathic pain (NP-MS). The purpose of this study was to assess the efficacy and tolerability of duloxetine as treatment for NP-MS. METHODS: In this study, 239 adults with NP-MS (duloxetine = 118, placebo = 121) were randomized to duloxetine 60 mg (30 mg for 1 week, then 60 mg for 5 weeks) or placebo once daily for a 6-week acute therapy phase, followed by a 12-week open-label extension phase (duloxetine 30 to 120 mg/day). Eligible patients had MS for ≥ 1 year and a score ≥ 4 on daily average pain intensity (API) ratings for ≥ 4 of 7 days immediately before randomization. Patients rated API daily on an 11-point numeric scale (0 [no pain] to 10 [worst possible pain]) in an electronic diary. The primary efficacy measure, change in weekly API ratings, was analyzed longitudinally with a mixed-model repeated-measures analysis. Completion, reasons for discontinuation, and treatment-emergent adverse event incidence were compared by Fisher's exact test. RESULTS: Duloxetine-treated patients had statistically greater mean improvement in API vs. placebo at Week 6 (-1.83 vs. -1.07, P = 0.001). Treatment completion did not significantly differ between groups. Discontinuation due to adverse events was statistically greater for duloxetine vs. placebo (13.6% vs. 4.1%, P = 0.012). Decreased appetite was reported significantly more often by duloxetine-treated patients (5.9% vs. 0%, P = 0.007). CONCLUSIONS: This study found analgesic efficacy of duloxetine for NP-MS. Duloxetine is not approved for treatment of this condition. The duloxetine safety profile of this study was consistent with the known profile in other patient populations.

Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison.

OBJECTIVE: To determine whether duloxetine is noninferior to (as good as) pregabalin in the treatment of pain associated with diabetic peripheral neuropathy. PATIENTS AND METHODS: We performed a 12-week, open-label study of patients with diabetic peripheral neuropathic pain who had been treated with gabapentin (≥ 900 mg/d) and had an inadequate response (defined as a daily pain score of ≥ 4 on a numerical rating scale [0-10 points]). The first patient was enrolled on September 28, 2006, and the last patient visit occurred on August 26, 2009. Patients were randomized to duloxetine monotherapy (n=138), pregabalin monotherapy (n=134), or a combination of duloxetine and gabapentin (n=135). The primary objective was a noninferiority comparison between duloxetine and pregabalin on improvement in the weekly mean of the diary-based daily pain score (0- to 10-point scale) at end point. Noninferiority would be declared if the mean improvement for duloxetine was no worse than the mean improvement for pregabalin, within statistical variability, by a margin of -0.8 unit. RESULTS: The mean change in the pain rating at end point was -2.6 for duloxetine and -2.1 for pregabalin. The 97.5% lower confidence limit was a -0.05 difference in means, establishing noninferiority. As to adverse effects, nausea, insomnia, hyperhidrosis, and decreased appetite were more frequent with duloxetine than pregabalin; insomnia, more frequent with duloxetine than duloxetine plus gabapentin; peripheral edema, more frequent with pregabalin than with duloxetine; and nausea, hyperhidrosis, decreased appetite, and vomiting, more frequent with duloxetine plus gabapentin than with pregabalin. CONCLUSION: Duloxetine was noninferior to pregabalin for the treatment of pain in patients with diabetic peripheral neuropathy who had an inadequate pain response to gabapentin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00385671.

Does pain cause the perception of fatigue in patients with chronic pain? Findings from studies for management of diabetic peripheral neuropathic pain with duloxetine.

A major issue in pain literature is whether an etiological association between pain, sleep, and vitality exists. We utilized data from clinical trials of duloxetine for management of diabetic peripheral neuropathic pain (DPNP) to investigate these associations. Data were pooled from 3 double-blind, randomized, placebo-controlled, 12-week trials of patients without mood disorder (N = 1,139). After excluding 442 patients who reported maximum vitality at baseline, experienced treatment-emergent somnolence, asthenia or fatigue, or were taking sedating concomitant medications or duloxetine 20 mg/day, 697 were included in the analysis. Efficacy measures included weekly mean scores for average daily and night pain, pain interference with sleep, and vitality. Baseline to end point mean improvements in daily and night pain, Brief Pain Inventory sleep interference, and vitality were significantly superior for duloxetine compared with placebo (P < or = 0.001). Correlations between changes in daily and night pain, and sleep interference with vitality changes were -0.34, -0.32, and -0.28, respectively (P < 0.001). The direct effect of treatment on change in vitality was statistically significant (68%, P = 0.010) when assessed in an indirect manner through change in sleep interference alone but not in daily or night pain solely. Path analyses suggested vitality improvement in patients with chronic pain may be secondary to improvement in pain by duloxetine. Results do not prove pain causes fatigue, but indicate in DPNP patients with fatigue that treatment of pain can improve perception of improvement in fatigue. Thus, improvement of pain may be important in the context of trying to improve fatigue in DPNP patients.

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.

Differential efficacy of olanzapine and lithium in preventing manic or mixed recurrence in patients with bipolar I disorder based on number of previous manic or mixed episodes.

INTRODUCTION: Bipolar disorder outcome worsens as number of manic episodes increases, suggesting that prevention of recurrent episodes early during the disorder could improve patient prognosis. We investigated treatment efficacy in prevention of mood episodes in patients subgrouped by number of prior manic episodes. METHOD: This study was a post hoc analysis of data from a multicenter, double-blind, 12-month clinical trial of relapse/recurrence in 431 initially euthymic patients with at least 2 prior manic/ mixed episodes and a DSM-IV diagnosis of bipolar I disorder randomly assigned to olanzapine (5-20 mg/day) or lithium (serum concentration 0.6 to 1.2 mEq/L). Data were collected between August 1999 and June 2002. Patients were subcategorized by illness stage according to number of prior manic/mixed episodes-early stage: 2 prior episodes (N = 53, lithium; N = 48, olanzapine), intermediate stage: 3 to 5 prior episodes (N = 80, lithium; N = 98, olanzapine), and later stage: more than 5 prior episodes (N = 81, lithium; N = 71, olanzapine)-and were evaluated for rates of relapse/recurrence. RESULTS: There were significant effects for treatment (p < .001) and illness stage (p = .006) but no significant interaction (p = .107) on rate of manic/mixed relapse/recurrence. Rates of manic/ mixed relapse/recurrence for olanzapine versus lithium were 2.1% versus 26.4% (p = .008), 13.3% versus 23.8% (p = .073), and 23.9% versus 33.3% (p = .204) for early-, intermediate-, and later-stage groups, respectively. There was no significant effect for treatment (p = .096) or illness stage (p = .731) for depressive relapse/recurrence. CONCLUSIONS: Early-stage (but not intermediate-or later-stage) patients had a significantly lower rate of relapse/recurrence of manic/mixed episodes with olanzapine compared to lithium. Thus, olanzapine maintenance therapy may be particularly effective early in the course of bipolar illness.

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.

Quality of life assessment in patients with bipolar disorder treated with olanzapine added to lithium or valproic acid.

BACKGROUND: The objective of this study was to determine the clinical and quality of life outcomes associated with adjunctive treatment of olanzapine added to either lithium or valproic acid/divalproex sodium in patients with bipolar disorder. METHODS: Patients with bipolar I disorder, were randomized to receive either olanzapine (5-20 mg) added to mood stabilizer therapy (n=224), or placebo added to mood stabilizer therapy (n=112) for 6 weeks. Changes in clinical outcomes over 6 weeks were measured by the Young Mania Rating Scale (Y-MRS) and the Hamilton Rating Scale for Depression (HAM-D). Quality of life was measured by the Lehman Brief Quality of Life Interview (QLI). RESULTS: Patients treated with olanzapine added to mood stabilizers, experienced significantly greater mean clinical improvements from baseline on both the Y-MRS and the HAM-D compared to those treated with placebo added to mood stabilizers. Over 6 weeks, patients treated with olanzapine added to mood stabilizers had significantly greater mean improvements from baseline on five of the nine subjective scales on the QLI, compared to patients treated with placebo added to mood stabilizers. Changes in scores on the subjective scales of the QLI were more strongly correlated to changes in depressive symptomatology measured by the HAM-D, than to changes in symptoms of mania measured by the Y-MRS. CONCLUSION: The results of this study demonstrate that patients receiving adjunctive treatment have significantly greater improvements in both clinical and quality of life outcomes compared to monotherapy with mood stabilizers.

Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone.

BACKGROUND: Few controlled studies have examined the use of atypical antipsychotic drugs for prevention of relapse in patients with bipolar I disorder. Aims To evaluate whether olanzapine plus either lithium or valproate reduces the rate of relapse, compared with lithium or valproate alone. METHOD: Patients achieving syndromic remission after 6 weeks'treatment with olanzapine plus either lithium (0.6-1.2 mmol/l) or valproate (50-125 microg/ml) received lithium or valproate plus either olanzapine 5-20 mg/day (combination therapy) or placebo (monotherapy), and were followed in a double-masked trial for 18 months. RESULTS: The treatment difference in time to relapse into either mania or depression was not significant for syndromic relapse (median time to relapse: combination therapy 94 days, monotherapy 40.5 days; P=0.742), but was significant for symptomatic relapse (combination therapy 163 days, monotherapy 42 days; P=0.023). CONCLUSIONS: Patients taking olanzapine added to lithium or valproate experienced sustained symptomatic remission, but not syndromic remission, for longer than those receiving lithium or valproate monotherapy.

Effects of olanzapine alone and olanzapine/fluoxetine combination on health-related quality of life in patients with bipolar depression: secondary analyses of a double-blind, placebo-controlled, randomized clinical trial.

BACKGROUND: Improving patients' health-related quality of life (HRQOL) could be a treatment goal for bipolar depression. OBJECTIVES: The objectives of these secondary analyses of a previous report were to determine the benefits of olanzapine alone and olanzapine-fluoxetine combination (OFC) for improving HRQOL in patients with bipolar depression using both a generic and a depression-specific HRQOL instrument, and to examine the association between the 2 HRQOL instruments and the construct validity of the depression-specific HRQOL instrument. METHODS: This was a double-blind, placebo-controlled, 83-site, international, randomized trial. Adults with bipolar I disorder, most recent episode depressed (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), were randomly assigned to receive olanzapine (6-20 mg/d), OFC (6/25, 12/25, or 12/50 mg/d), or placebo for 8 weeks. HRQOL improvement was calculated as last-observation-carried-forward changes in dimension and component summary scores on Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and total score on the Quality of Life in Depression Scale (QLDS). RESULTS: Patients were assigned to receive olanzapine (n = 370), [corrected] OFC (n = 86), or placebo (n = 377) [corrected] for 8 weeks. Of 833 enrolled patients, 454 discontinued (olanzapine, 191/370 [51.6%] [corrected]OFC, 31/86 [36.0%]; and placebo, 232/377 [61.6%]) [corrected] Compared with placebo, olanzapine-treated patients exhibited greater improvements on SF-36 mental component summary (MCS) score ( P=0.002) and 3 of 8 SF-36 dimension scores (mental health [P=0.015], role-emotional [P=0.046], and social functioning [P=0.006). OFC-treated patients exhibited greater improvements on MCS score ( P<0.001) vs both placebo and olanzapine), 5 SF-36 dimension scores (general health perception (P<0.001) vs placebo; (P<0.001) vs olanzapinel, mental health [ P=0.001] vs both placebo and olanzapine], role-emotional [ P<0.001] vs placebo; [P=0.007] vs olanzapine], social functioning [ P=0.001] vs placebo; [P=0.032] vs olanzapine], and vitality [P=0.002] vs placebo; [P=0.011] vs olanzapine]), and QLDS total score ( P<0.001] vs both placebo and olanzapine). Changes in SF-36 scores of mental health, social functioning, role-emotional, and vitality were highly correlated to changes in the QLDS total score (all p < -0.5). CONCLUSIONS: Based on these analyses, patients with bipolar depression receiving olanzapine or OFC for 8 weeks had greater improvement in HRQOL than those receiving placebo. OFC treatment was associated with greater improvement in HRQOL than olanzapine alone. The correlation results support the construct validity of the QLDS.

A 12-week, double-blind comparison of olanzapine vs haloperidol in the treatment of acute mania.

BACKGROUND: This randomized controlled trial compares the efficacy and safety of olanzapine vs haloperidol, as well as the quality of life of patients taking these drugs, in patients with bipolar mania. METHODS: The design consisted of 2 successive, 6-week, double-blind periods and compared flexible dosing of olanzapine (5-20 mg/d, n = 234) with haloperidol (3-15 mg/d, n = 219). RESULTS: Rates of remission (Young-Mania Rating Scale score of < or =12 and 21-item Hamilton Rating Scale for Depression score of < or =8 at week 6) were similar for olanzapine- and haloperidol-treated patients (52.1% vs 46.1%, respectively; P =.15). For the subgroup of patients whose index episode did not include psychotic features, rates of remission were significantly greater for the olanzapine group compared with the haloperidol group (56.7% vs 41.6%, P =.04). Relapse into an affective episode (mania and/or depression) occurred in 13.1% and 14.8% of olanzapine- and haloperidol-treated patients, respectively (P =.56). Switch to depression occurred significantly more rapidly with haloperidol than with olanzapine when using survival analysis techniques (P =.04), and significantly more haloperidol-treated patients experienced worsening of extrapyramidal symptoms, as indicated by several measures. Weight gain was significantly greater in the olanzapine group compared with the haloperidol group (2.82 vs 0.02 kg, P<.001). The olanzapine group had significant improvement in quality of life on several dimensions compared with the haloperidol group. CONCLUSIONS: These data suggest that olanzapine does not differ from haloperidol in achieving overall remission of bipolar mania. However, haloperidol carries a higher rate of extrapyramidal symptoms, whereas olanzapine is associated with weight gain.

Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression.

BACKGROUND: Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression. OBJECTIVE: To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. DESIGN: Double-blind, 8-week, randomized controlled trial. SETTING: Eighty-four sites (inpatient and outpatient) in 13 countries. Patients A total of 833 randomized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20. Intervention Patients were randomly assigned to receive placebo (n = 377); olanzapine, 5 to 20 mg/d (n = 370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86). MAIN OUTCOME MEASURE: Changes in MADRS total scores using mixed-effects model repeated-measures analyses. RESULTS: During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group (P<.001 for all). The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8. At week 8, MADRS total scores were lower than at baseline by 11.9, 15.0, and 18.5 points in the placebo, olanzapine, and olanzapine-fluoxetine groups, respectively. Remission criteria were met by 24.5% (87/355) of the placebo group, 32.8% (115/351) of the olanzapine group, and 48.8% (40/82) of the olanzapine-fluoxetine group. Treatment-emergent mania (Young Mania Rating Scale score <15 at baseline and > or =15 subsequently) did not differ among groups (placebo, 6.7% [23/345]; olanzapine, 5.7% [19/335]; and olanzapine-fluoxetine, 6.4% [5/78]). Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea. CONCLUSIONS: Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.

Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study.

OBJECTIVE: Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex. METHOD: This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest. RESULTS: Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness. CONCLUSIONS: In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.

Acute dysphoric mania: treatment response to olanzapine versus placebo.

A substantial number of patients with mania have significant concomitant depressive features, and they may respond differently to mood stabilizers than patients with pure mania. This post-hoc analysis explored the response characteristics of olanzapine versus placebo in bipolar I manic patients with dysphoric and nondysphoric mania (differentiated by baseline Hamilton Depression Rating Scale [HAM-D] score of >20). Two similar, double-blind, randomized trials comparing olanzapine, 5-20 mg, to placebo were pooled for these analyses (N = 246). Mean changes in Young-Mania Rating Scale (Y-MRS) and HAM-D scores during 3 weeks of treatment were examined. Twenty-eight percent of patients had dysphoric mania (olanzapine, n = 33; placebo, n = 35). Among these patients, olanzapine-treated patients had greater improvement within 1 week than did placebo-treated patients on both mania ratings (Y-MRS: -9.7 vs. -3.0 points; = 0.011) and depressive symptom ratings (HAM-D: -9.9 vs. -5.4 points; = 0.025). Among those manic subjects without prominent depressive symptoms (olanzapine, n = 91; placebo, n = 87), mean Y-MRS improvement from baseline to endpoint with olanzapine (-11.5 points) versus placebo (-6.13 points) was comparable to the improvement seen with olanzapine versus placebo in the dysphoric mania subgroup ( = 0.476, test of interaction). In acutely ill manic patients with significant depressive symptoms, olanzapine demonstrated a broad spectrum of efficacy, effectively treating both manic and depressive symptoms. The magnitude of the antimanic response appears similar, regardless of baseline depressive features. Additional experience with putative mood stabilizers and atypical agents in mixed mania should include an exploration of their efficacy in treating both manic and depressive mood symptoms.

Economic, clinical, and quality-of-life outcomes associated with olanzapine treatment in mania. Results from a randomized controlled trial.

INTRODUCTION: The objectives of this study were to determine the economic, clinical, and quality-of-life outcomes associated with olanzapine treatment in patients diagnosed with mania. METHODS: Patients with a diagnosis of bipolar I disorder with manic or mixed episodes were enrolled in a randomized controlled trial. The study design comprised a 3-week acute phase followed by a 49-week open label extension. In the open label extension, the use of lithium and fluoxetine was permitted for patients who experienced breakthrough symptoms. Clinical, economic, and quality-of-life outcomes of treatment were assessed. RESULTS: During the acute phase, olanzapine patients experienced a statistically significant greater mean improvement from baseline on the Y-MRS total score compared to the placebo patients. In the open label extension, patients experienced a statistically significant mean change of 11.8 units on the Y-MRS from the end of the acute phase. When compared to costs incurred in the previous 12 months of therapy, patients experienced savings of almost $900 per month during the 49 weeks of olanzapine therapy. These cost savings were largely driven by reductions in in-patient costs during the open label extension. Health-related quality of life improvements measured by the SF-36 were seen on several dimensions both in the 3-week acute phase as well as in the 49-week open label extension. CONCLUSION: From a clinical, economic, and quality-of-life outcomes standpoint, olanzapine had a significant impact in the treatment of mania, and could be considered a cost-effective treatment option for use in this population if these findings are extrapolated to non-clinical trial populations.

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.

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.