Effect of patient age on treatment response in a study of the acute exacerbation of psychosis in schizophrenia.

Younger patients with schizophrenia have most likely experienced fewer adverse consequences of the illness than older patients who may have experienced a lifetime of treatment as well as socio-economic problems as a consequence of the illness. There is limited information regarding differential efficacy of long-acting injectable (LAI) antipsychotic medications across the age span in patients with schizophrenia. We conducted a post hoc age and gender analysis of treatment response to aripiprazole lauroxil (AL; ARISTADA®; Alkermes, Inc.), in a 12-week, double-blind, placebo-controlled, multinational, Phase 3 study evaluating two doses of AL (441mg and 882mg) versus placebo in adult patients experiencing an acute exacerbation of schizophrenia within the previous 2months. We examined change in the total Positive and Negative Syndrome Scale (PANSS) scores from baseline using analysis of covariance and categorical treatment response (defined as ≥30% total PANSS score improvement from baseline) in the following age groups: <30, 30-39, 40-49, and 50-69years old. Age and gender did not moderate the treatment response in this study. Both AL 441mg and AL 882mg showed an early and significant improvement of the mean total PANSS scores and categorical treatment responses compared to placebo in all four age groups, including younger patients regardless of gender that was sustained over the 85-day treatment period.

Early weight gain as a predictor of substantial weight gain with olanzapine/fluoxetine combination: an analysis of 2 adult studies in treatment-resistant depression.

Weight gain during olanzapine/fluoxetine combination (OFC) therapy is very common. We examined early (at 2 weeks) weight gain as a predictor of later (at 26 weeks) substantial weight gain in patients with treatment-resistant depression during OFC pharmacotherapy. Data were analyzed from 2 studies (Study 1 and Study 2)-each with an acute, double-blind phase and an open-label phase-in patients who completed 26 weeks of open-label treatment (N = 306). Mean patient age was 46 years; the majority was female and white. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were examined using early weight gain of 2 kg or more as a predictor of 10 kg or more substantial weight gain. Sensitivity (true positive rate) and specificity for Study 1 (n = 73) were 33% and 71%, respectively; PPV and NPV were 23% and 80%, respectively. Sensitivity and specificity for Study 2 (n = 233) were 52% and 70%, respectively; PPV and NPV were 31% and 85%, respectively. Overall, in the 2 trials analyzed, for patients who did not gain 2 kg or more (2.54 lb) in the first 2 weeks of OFC treatment, the observed frequency was 16.3% for gaining 10 kg or more at 26 weeks. Compared to those with early weight gain, patients without early weight gain were less likely to have substantial weight gain after OFC treatment. Additional research is needed to further explore the predictive power of early weight gain for subsequent substantial weight gain in patients with treatment-resistant depression treated with OFC.

Early symptom change and prediction of subsequent remission with olanzapine augmentation in divalproex-resistant bipolar mixed episodes.

Potential predictors of remission in mixed bipolar I disorder were identified using early Clinical Global Impression-Severity (CGI-S) improvement criteria in divalproex-resistant patients randomized to olanzapine augmentation (olanzapine + divalproex; N = 101) in a 6-week, double-blind, placebo-controlled trial. In a post-hoc analysis, receiver operating characteristics of 1-point decreases in the CGI-S total score after 2, 4, 7, and 14 days were examined as predictors of endpoint (Week 6 or last observation) remission of depression and/or mania as defined by 21-item Hamilton Depression Rating Scale (HDRS-21) and Young Mania Rating Scale (YMRS) total score ≤8. Based on a 1-point improvement in CGI-S as a predictor of remission, all odds ratios (ORs) and 95% confidence intervals (CIs) were statistically significant for depression or mania remission criteria. ORs for mixed symptom remission with a decrease ≥1 in CGI-S scores at Day 2 for olanzapine augmentation were (6.727; CI: 2.382, 18.997; p < .001) with negative predictive value = 89.5% and positive predictive value = 44.2%. Changes in HDRS-21 and YMRS individual item scores after 2 days of augmentation as predictors of endpoint remission identified that decreases in HDRS-21 symptom item scores (early, middle, and/or late insomnia; paranoid; agitation; and somatic/gastrointestinal) predicted depressive symptom remission at endpoint, and decreases in YMRS item scores (language-thought disorder and irritability) were associated with manic symptom remission at endpoint. Because remission with augmentation therapy may occur in as few as one in ten individuals who lack very early symptom reduction, lack of early improvement may indicate a need to expediently reassess treatment strategy.

Relationship between African-American or Caucasian origin and outcomes in the olanzapine treatment of acute mania: a pooled analysis of three adult studies conducted in the United States of America.

The aim of this study was to explore the role of ethnic origin in the treatment of acute bipolar mania. Treatment outcomes were studied in a post-hoc analysis of African-American (AA, n=41) and Caucasian (CA, n=190) adults treated with olanzapine in three studies conducted in the United States of America. Baseline demographics were similar except that the AA cohort had fewer women compared with the CA cohort (37 vs. 58%; P=0.01). Daily mean modal olanzapine dose and study discontinuation rate for AA and CA were: 16.2 mg vs. 16.6 mg and 41.5 vs. 25.3% (P=0.03), respectively. There were four (23.5% of discontinuers) and 19 (39.6% of discontinuers, P=0.14) discontinuations because of a poor response in the AA and CA groups, respectively. Drug exposure for the AA cohort was 18.7 days and that of the CA cohort was 19.3 days. Both cohorts showed similar symptom improvements, and safety outcomes were not statistically significantly different except for the following treatment-emergent adverse event frequencies for AA and CA cohorts, respectively: agitation (24.4 vs. 10.5%, P=0.04); dysmenorrhoea (20.0 vs. 3.6%, P=0.04); and dizziness postural (7.3 vs. 1.1%, P=0.04). Although study findings [limited by a smaller (18% of total population) AA cohort] need replication, they suggest that while many outcomes were similar in both cohorts, clinicians could benefit from the awareness of factors in the AA population that possibly influence study discontinuation rates, treatment-emergent adverse event reporting, and participation by sex.

Symptoms predicting remission after divalproex augmentation with olanzapine in partially nonresponsive patients experiencing mixed bipolar I episode: a post-hoc analysis of a randomized controlled study.

BACKGROUND: Rating scale items in a 6-week clinical trial of olanzapine versus placebo augmentation in patients with mixed bipolar disorder partially nonresponsive to ≥14 days of divalproex monotherapy were analyzed to characterize symptom patterns that could predict remission. At baseline, the two treatment groups were similar. FINDINGS: Factor analysis with Varimax rotation was performed post hoc on baseline items of the 21-Item Hamilton Depression Rating Scale (HDRS-21) and Young Mania Rating Scale (YMRS). Backwards-elimination logistic regression ascertained factors predictive of protocol-defined endpoint remission (HDRS-21 score ≤ 8 and YMRS score ≤ 12) with subsequent determination of optimally predictive factor score cutoffs.Factors for Psychomotor activity (YMRS items for elevated mood, increased motor activity, and increased speech and HDRS-21 agitation item) and Guilt/Suicidality (HDRS-21 items for guilt and suicidality) significantly predicted endpoint remission in the divalproex+olanzapine group. No factor predicted remission in the divalproex+placebo group. Patients in the divalproex+olanzapine group with high pre-augmentation psychomotor activity (scores ≥10) were more likely to remit compared to those with lower psychomotor activity (odds ratio [OR] = 3.09, 95% confidence interval [CI] = 1.22-7.79), and patients with marginally high Guilt/Suicidality (scores ≥2) were less likely to remit than those with lower scores (OR = 0.37, 95% CI = 0.13-1.03). Remission rates for divalproex+placebo vs. divalproex+olanzapine patients with high psychomotor activity scores were 22% vs. 45% (p = 0.08) and 33% vs. 48% (p = 0.29) for patients with low Guilt/Suicidality scores. CONCLUSIONS: Patients who were partially nonresponsive to divalproex treatment with remaining high vs. low psychomotor activity levels or minimal vs. greater guilt/suicidality symptoms were more likely to remit with olanzapine augmentation. TRIAL REGISTRATION: ClinicalTrials.gov; http://clinicaltrials.gov/ct2/show/NCT00402324?term=NCT00402324&rank=1, Identifier: NCT00402324.

Olanzapine-divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study.

OBJECTIVE: This 6-week, randomized, double-blind, placebo-controlled trial used simultaneous depression and mania criteria to compare a single mood stabilizer, divalproex, with and without adjunctive olanzapine in patients with bipolar I disorder experiencing acute mixed episodes. METHOD: Two hundred two adults, aged 18 to 60 years, who met DSM-IV-TR criteria for bipolar disorder with a current mixed episode and had been taking divalproex for >or=14 days at levels of 75 to 125 microg/mL with inadequate efficacy (21-item Hamilton Depression Rating Scale [HDRS-21] and Young Mania Rating Scale [YMRS] scores >or=16) were randomly assigned to olanzapine 5 to 20 mg/d versus placebo augmentation. HDRS-21, YMRS, Clinical Global Impressions for Bipolar Disorder (CGI-BP), hospitalizations, concomitant medications, and adverse events were assessed. Comparisons included changes in both HDRS-21 and YMRS (primary outcome measure), time to partial response and time to response, CGI-BP improvement, hospitalizations, and safety (secondary outcome measures). The study was conducted from December 2006 to February 2008. RESULTS: Mean (SD) baseline HDRS-21 and YMRS scores were 22.2 (4.5) and 20.9 (4.4), respectively, with 59% female and 51% white subjects. Mean +/- SE score changes from baseline across the 6-week treatment period for adjunctive olanzapine (n = 100) versus adjunctive placebo (n = 101) arms, respectively, were -9.37 +/- 0.55 versus -7.69 +/- 0.54, P = .022, on the HDRS-21 and -10.15 +/- 0.44 versus -7.68 +/- 0.44 P < .001, on the YMRS. Mean +/- SE score changes from baseline to last observation carried forward for CGI-BP measures were -1.34 +/- 0.11 for adjunctive olanzapine versus -1.06 +/- 0.11 for adjunctive placebo, P = .056. Time to partial response (>or=25% HDRS-21 and YMRS decreases, median 7 versus 14 days) and time to response (>or=50% HDRS-21 and YMRS decreases, median 25 versus 49 days) were significantly shorter with adjunctive olanzapine. Increases in weight (total and >or=7%) and fasting blood glucose were significantly greater with adjunctive olanzapine. CONCLUSION: Adjunctive olanzapine yielded greater and earlier reduction of manic and depressive symptoms in mixed-episode patients with inadequate response to at least 2 weeks of divalproex. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00402324.

Effectiveness and safety of the combination of fluoxetine and olanzapine in outpatients with bipolar depression: an open-label, randomized, flexible-dose study in Puerto Rico.

We studied the effectiveness of olanzapine/fluoxetine combination (OFC) treatment of bipolar depressive episode (7 weeks, study period 1 [SP1]). Study period 1 responders (mean modal daily OFC dosage, 10.8/27.8 mg) were randomized to OFC continuation treatment or olanzapine (OLZ) monotherapy starting at 10 mg (12 weeks, SP2). Seventy-three percent of the 114 patients who entered into SP2 completed the trial. The Montgomery-Asberg Depression Rating Scale total score changes from baseline in SP1 (primary outcome) were significant (-20 +/- 10, P < 0.001) and, during SP2, worsened for patients in the OLZ group (OFC vs OLZ, -0.4 +/- 7.55 vs +8.2 +/- 14.1, respectively; P < 0.001). During SP1, 69% responded and 59% remitted. During SP2, significantly more patients in the OFC group maintained response (31.3% vs 12.5%) and remission (71.4% vs 39.6%) than patients in the OLZ group. Treatment-emergent adverse events with OFC (SP1 and SP2) included increased appetite, increased weight, somnolence, anxiety, insomnia, and depressed mood. Since visit 1, the mean weight increases (in pounds) were 4.8 +/- 6.8 for SP1 (P < 0.001) and 6.3 +/- 10.3 (OFC) or 10.7 +/- 11.3 (OLZ) for SP2; 50% (OLZ) and 33% (OFC) of the patients had a 7% or higher weight increase. For cholesterol, triglycerides, and low-density lipoprotein levels and some hepatic enzymes, there were statistically and clinically significant changes in both study periods but no differences between the SP2 groups. Study limitations included the open-label design and exclusion of the SP1 nonresponders from SP2. These study results suggest that improvements resulting from 7 weeks of acute OFC treatment of a bipolar depressive episode are maintained in responders for an additional 12 weeks with OFC, but switching to OLZ alone may result in symptom worsening.

Olanzapine versus risperidone in the treatment of manic or mixed States in bipolar I disorder: a randomized, double-blind trial.

OBJECTIVE: To compare olanzapine and risperidone in the treatment of nonpsychotic acute manic or mixed episodes. METHOD: This 3-week, randomized, controlled, double-blind, parallel multicenter study compared olanzapine (5-20 mg/day; N = 165) and risperidone (1-6 mg/day; N = 164) among hospital inpatients who met DSM-IV criteria for bipolar I disorder, manic or mixed episode, without psychotic features. The study was conducted at 30 sites in the United States between July 2001 and June 2002. The primary outcome measure was the mean change in the Young Mania Rating Scale (YMRS) total score. Secondary measures included the 21-item Hamilton Rating Scale for Depression (HAM-D-21), the Montgomery-Asberg Depression Rating Scale (MADRS), the Clinical Global Impressions-Bipolar Version (CGI-BP) severity of illness scale, and the Cognitive Test for Delirium (CTD). Quality of life (Short Form Health Survey [SF-12]), psychological well-being (Psychological General Well-Being [PGWB] inventory), and sexual functioning were also compared. RESULTS: Mean modal doses for olanzapine and risperidone were 14.7 mg/day and 3.9 mg/day, respectively. Between treatments, there was no difference in mean change in the YMRS, MADRS, CTD, PGWB, or SF-12 measures or in remission or response rates. Significantly more olanzapine-treated patients completed the study compared with risperidone patients (78.7% vs. 67.0%; p = .019). Olanzapine-treated patients had greater HAM-D-21 (p = .040) and CGI-BP (p = .026) score improvement across the study. Olanzapine-treated patients experienced greater elevations in liver function enzymes (p < .05) and increase in weight (2.5 kg vs. 1.6 kg; p = .004), while risperidone-treated patients were more likely to experience prolactin elevation (51.73 ng/mL vs. 8.23 ng/mL; p < .001) and sexual dysfunction (total score increase of 1.75 vs. 0.64; p = .049). CONCLUSION: Both olanzapine and risperidone treatment yielded similar improvements in mania. The olanzapine group had significantly greater improvements in secondary measures of severity and depressive symptoms and better study completion rates but experienced more weight gain.

Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial.

OBJECTIVE: To assess morbidity in patients with severe sepsis managed with and without drotrecogin alfa (activated). DESIGN: Analysis of secondary end points in a prospective, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (PROWESS). SETTING: A total of 164 medical institutions in 11 countries. PATIENTS: A total of 1,690 consecutive adult patients with severe sepsis. INTERVENTIONS: A 96-hr infusion of drotrecogin alfa (activated) (human recombinant activated protein C) or placebo. MEASUREMENTS AND MAIN RESULTS: Sequential Organ Failure Assessment (SOFA) scores for cardiovascular, respiratory, renal, hematologic, and hepatic organ systems were measured for 28 days. Mean cardiovascular SOFA scores were significantly lower for patients treated with drotrecogin alfa (activated) compared with placebo patients over this time period (p = .022). Drotrecogin alfa (activated)-treated patients also showed significantly faster resolution of cardiovascular (p = .009) and respiratory (p = .009) dysfunction and significantly slower onset of hematologic organ dysfunction (p = .041) compared with placebo patients for days 1 to 7. No significant differences in morbidity were observed between treatment groups among 28-day survivors. CONCLUSION: Drotrecogin alfa (activated) demonstrated significant improvements in organ function compared with placebo in a large phase 3 clinical trial that has shown a mortality benefit in patients with severe sepsis.