Variables as mediators or moderators in predicting relapse to any type of mood episode in a bipolar maintenance study.

OBJECTIVE: Post hoc mediator/moderator analyses were designed to identify risk factors and their relationships in predicting relapse in olanzapine- or lithium-treated bipolar patients with an index manic or mixed episode. The aim was to identify moderators that precede and influence other variables to affect relapse and mediators that explain how or why a second variable affects relapse. METHOD: We examined DSM-IV-diagnosed bipolar I disorder patients who met symptomatic remission criteria of an index manic or mixed (6.3%) episode after acute (6-12 weeks), open-label, combined therapy with olanzapine (5-20 mg/d; mean dose = 13.5 mg/d) plus lithium (300-1,800 mg/d; mean dose = 1,003.3 mg/d) followed by double-blind randomization to lithium (n = 214) or olanzapine (n = 217) for up to 52 weeks. The study started on August 5, 1999, and finished on June 14, 2002. Mediator/moderator analyses with α cut at .05 were used to understand how variables work together to impact rate of relapse. RESULTS: For lithium-treated patients, variables identified for relapse were country of residence, smoking status, previous episode history, and previous lithium use. For olanzapine-treated patients, risk factors included smoking status, previous episode history, amount of time patients had a 21-Item Hamilton Depression Rating Scale (HDRS-21) score ≤ 8 at pre-randomization, and HDRS-21 score at randomization. For lithium-treated patients, no mediators/moderators were identified among relapse variables. For olanzapine-treated patients, several baseline variables--such as previous number of mood episodes (manic or depressive)--operate through severity of depressive symptoms prior to remission (mediator) to affect relapse rate. On the other hand, the effect of the patient's pre-remission depressive symptoms on outcome is moderated by the polarity of the first episode, whether manic, depressive, or mixed. CONCLUSIONS: Mediators and moderators may provide valuable information in the treatment planning of patients with bipolar disorder and potentially influence treatment outcomes.

Clinical utility of early improvement to predict response or remission in acute mania: focus on olanzapine and risperidone.

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

Olanzapine plus carbamazepine v. carbamazepine alone in treating manic episodes.

BACKGROUND: Combinations of olanzapine and carbamazepine are often used in clinical practice in the management of mania. AIMS: To assess the efficacy and safety of olanzapine plus carbamazepine in mixed and manic bipolar episodes. METHOD: Randomised, double-blind, 6-week trial of olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day; n=58) v. placebo plus carbamazepine (n=60) followed by open-label, 20-week olanzapine (10-30 mg/day) plus carbamazepine (400-1200 mg/day, n=86), with change in manic symptoms as main outcome measure. Safety and pharmacokinetics were also evaluated. RESULTS: There were no significant differences (baseline to endpoint) in efficacy measures between treatment groups, but at 6 weeks triglyceride levels were significantly higher (P=0.008) and potentially clinically significant weight gain (>or=7%) occurred more frequently (24.6% v. 3.4%, P=0.002) in the combined olanzapine and carbamazepine group. Carbamazepine reduced olanzapine concentrations but olanzapine had no effect on carbamazepine concentrations. CONCLUSIONS: The combination of olanzapine and carbamazepine did not have superior efficacy to carbamazepine alone. The increases in weight and triglycerides observed during combination treatment are a matter of concern.

Going up in smoke: tobacco smoking is associated with worse treatment outcomes in mania.

BACKGROUND: This study aimed to compare the treatment responses between smokers and non-smokers in bipolar mania clinical trials. METHODS: Post-hoc analysis was conducted on data collected from three double-blind, randomised controlled trials in bipolar mania that had similar inclusion criteria. Patients were randomised to olanzapine (N=70) or placebo (N=69) for 3 weeks in Trial 1, olanzapine (N=234) or haloperidol (N=216) for 12 weeks in Trial 2, and olanzapine (N=125) or divalproex (N=126) for 47 weeks in Trial 3. This study analysed the Young Mania Rating Scale (YMRS) total scores and Clinical Global Impressions scale for bipolar disorder (CGI-BP) mania severity scores between smokers and non-smokers for each trial and for the pooled data from all three trials, using a mixed-effects model repeated measures approach. RESULTS: For the pooled data, non-smokers showed superior treatment outcomes on both the YMRS (P=0.002) and CGI-BP (P<0.001), as well as longer time to discontinuation for any cause utilising Kaplan-Meier survival curves. For the individual trials, non-smokers showed greater improvement than smokers on both CGI-BP and YMRS in both treatment arms of Trial 2 (CGI-BP: haloperidol P=0.011, olanzapine P=0.042; YMRS: haloperidol P=0.010, olanzapine P=0.019), and in the olanzapine arm of Trial 3 (CGI-BP: P=0.002; YMRS: P=0.006). No significant difference in outcomes was found between smokers and non-smokers in Trial 1. LIMITATIONS: Post-hoc design, categorical definition of smoking status, unavailable antipsychotic drug levels, confounding effects of trial medications and substance abuse. CONCLUSIONS: Smoking appears to be associated with worse treatment outcomes in mania.

The empirical redefinition of the psychometric criteria for remission in bipolar disorder.

BACKGROUND: Current definitions of remission for mania and bipolar depression are convention-rather than empirically-based, and their clinical salience is unclear, as few studies have attempted to calibrate them against objective clinical criteria. This study aimed to determine equivalence scores on two widely used clinical rating scales, the Young Mania Rating Scale (YMRS) and Montgomery-Asberg Depression Rating Scale (MADRS), that corresponded with an objective global clinical measure of remission in bipolar disorder patients. METHODS: Data from four pharmacological randomised controlled trials in bipolar I disorder were analysed. Two trials were conducted for bipolar depression (N=410 and 833), and two for manic or mixed episodes (N=136 and 110). In this study, a Clinical Global Impression-Bipolar Version (CGI-BP) severity score of 1 (normal, not at all ill) was used as the primary comparative measure of remission. The mean total YMRS and MADRS scores in the mania and depression studies, respectively, that corresponded with a CGI-BP severity score of 1 were determined. RESULTS: The mean YMRS score that corresponded with a CGI-BP severity score of 1 was <4 in both trials (2.6 and 3.0, respectively), and the mean corresponding MADRS score was <5 (4.1 and 4.6, respectively). LIMITATIONS: Utilising a psychometric definition of remission. CONCLUSIONS: This study suggests that a cut-off score of <5 on the MADRS and <4 on the YMRS approximates a CGI-BP definition of complete remission. Although lower than conventional cut-off scores, these perhaps better represent clinical reality and patient expectations. In the context of clinical trials, study end-points may be more difficult to reach with lower cut-offs, but the outcomes achieved are more likely to be clinically meaningful.