Typology of patients with fibromyalgia: cluster analysis of duloxetine study patients.

BACKGROUND: To identify distinct groups of patients with fibromyalgia (FM) with respect to multiple outcome measures. METHODS: Data from 631 duloxetine-treated women in 4 randomized, placebo-controlled trials were included in a cluster analysis based on outcomes after up to 12 weeks of treatment. Corresponding classification rules were constructed using a classification tree method. Probabilities for transitioning from baseline to Week 12 category were estimated for placebo and duloxetine patients (Ntotal = 1188) using logistic regression. RESULTS: Five clusters were identified, from "worst" (high pain levels and severe mental/physical impairment) to "best" (low pain levels and nearly normal mental/physical function). For patients with moderate overall severity, mental and physical symptoms were less correlated, resulting in 2 distinct clusters based on these 2 symptom domains. Three key variables with threshold values were identified for classification of patients: Brief Pain Inventory (BPI) pain interference overall scores of <3.29 and <7.14, respectively, a Fibromyalgia Impact Questionnaire (FIQ) interference with work score of <2, and an FIQ depression score of ≥5. Patient characteristics and frequencies per baseline category were similar between treatments; >80% of patients were in the 3 worst categories. Duloxetine patients were significantly more likely to improve after 12 weeks than placebo patients. A sustained effect was seen with continued duloxetine treatment. CONCLUSIONS: FM patients are heterogeneous and can be classified into distinct subgroups by simple descriptive rules derived from only 3 variables, which may guide individual patient management. Duloxetine showed higher improvement rates than placebo and had a sustained effect beyond 12 weeks.

Antidepressants in the treatment for chronic low back pain: questioning the validity of meta-analyses.

OBJECTIVES: To contrast the analgesic effect of duloxetine with antidepressants reported in other published randomized clinical trials (RCTs) and review articles in patients with chronic low back pain (CLBP). METHODS: In this narrative review, the results of 13 RCTs and 5 systematic reviews examining the analgesic effect of various antidepressants in CLBP were contrasted with those of 3 placebo-controlled duloxetine RCTs. Treatment effects based on the Brief Pain Inventory (BPI) average score in the duloxetine RCTs were assessed in all completers (by study and overall) and in last-observation-carried-forward (LOCF) analyses (extracted from study reports). 30%- and 50%-reduction response rates were compared between duloxetine and placebo. RESULTS: Eleven different antidepressants were examined in 13 individual RCTs. Sample sizes, treatment durations, and analysis methods varied across studies. Reviews each included 5 to 9 of the RCTs and came to different conclusions regarding the analgesic effect of antidepressants: 2 found no evidence while 3 reported some evidence. The completer analysis showed greater improvements in BPI average scores with duloxetine vs. placebo (significant in 2 studies). Overall, the least square mean (standard error) difference between treatments was - 0.7 (0.15) (P < 0.0001). Overall response rates were significantly larger with duloxetine than with placebo. CONCLUSIONS: Due to the diversity of previous studies and the pooling methods used, the conclusions regarding the analgesic effect of antidepressants in CLBP drawn from systematic reviews must be interpreted with caution. Appropriately designed and powered studies similar to recently published duloxetine studies are recommended to demonstrate the analgesic effect of antidepressants.

Clinical and functional outcomes in patients with major depressive disorder and painful physical symptoms switched to treatment with duloxetine.

OBJECTIVE: This post hoc analysis of a multicenter, single-arm, open-label trial (the Attributes of Response in Depressed Patients Switched to Treatment with Duloxetine [ARDENT] study) assessed the relationship between functional improvement in the Sheehan Disability Scale (SDS) and clinical outcomes of mood, pain, and anxiety over 8 weeks after switching treatment to duloxetine in patients with major depressive disorder. METHODS: Analyses included all 195 patients who completed the study. Pearson's correlation and multivariate regression analyses were used to evaluate the relationship between change from baseline in SDS total score and 17-item Hamilton Rating Scale for Depression (HAMD(17)) Maier score (mood), Brief Pain Inventory-Short Form average pain score (pain), and Hamilton Anxiety Rating Scale total score (anxiety) at week 8. RESULTS: At week 8, change in SDS total score was positively correlated with change in mood (r = 0.49), anxiety (r = 0.44), and pain (r = 0.40). Multivariate linear regression coefficients for mood and pain were estimated at 1.21 (standard error [SE] = 0.184) and 1.16 (SE = 0.180), respectively (both p < 0.0001) compared with 0.02 (SE = 0.097; p = 0.82) for anxiety. Overall, 43% of patients achieved both HAMD(17) and SDS total remission. CONCLUSIONS: Functional improvement at 8 weeks was positively correlated with mood, pain, and anxiety in patients with major depressive disorder switched to duloxetine. Change in mood and pain exerted a relatively stronger joint effect on functioning than did anxiety in this patient population. Copyright © 2011 John Wiley & Sons, Ltd.

A Canadian naturalistic study of a community-based cohort treated for bipolar disorder.

BACKGROUND: Bipolar illness is associated with significant psychosocial morbidity and health resource utilization. Second generation antipsychotics, used alone or in combination with mood stabilizers are effective in treating acute mania in community settings. This study was designed to compare the change in clinical parameters and resource utilization at one month in a group of patients who required treatment intervention for exacerbation of mania. The clinical response at one year was also evaluated. METHODS: 496 patients were enrolled at 75 psychiatric practices across Canada. The Olanzapine cohort (n = 287) included patients who had olanzapine added to their medication regimen or the dose of olanzapine increased. The Other cohort (n = 209) had a medication other than olanzapine added or the dose adjusted. Changes from baseline in the Young Mania Rating Scale (YMRS), Montgomery Asberg Depression Rating Scale, Beck Anxiety Inventory and SF-12 Health Survey were compared at one month using ANCOVA. Categorical variables at one month for health resource utilization, employment status, abuse/dependency, and the number of suicide attempts were compared using Fisher's Exact test. Patients were followed for one year and a subgroup was evaluated. RESULTS: At one month, patients in the Olanzapine cohort recorded a mean reduction in the YMRS of 11.5, significantly greater than the mean reduction in the Other cohort of 9.7 (ANCOVA P = 0.002). The Olanzapine cohort was significantly improved compared to the Other cohort on the scales for depression and anxiety and did not experience the deterioration in physical functioning seen in the Other cohort. No significant differences were detected in health-related quality-of-life measures, employment status, drug abuse/dependency, number of suicide attempts, mental functioning, emergency room visits or inpatient psychiatric hospitalizations. In a subgroup treated for 12 months with a single second generation antipsychotic, improvements in illness severity measures were maintained with no evidence of significant differences among the antipsychotics. CONCLUSIONS: Patients with bipolar disorder requiring treatment intervention for exacerbation of mania in the community setting responded to olanzapine at one month. In a subset analysis, second generation antipsychotic treatment continued to be beneficial in reducing bipolar symptoms at one year.

Number needed to treat or harm analyses of olanzapine for maintenance treatment of bipolar disorder.

The number-needed-to-treat (NNT) or the number-needed-to-harm (NNH) analysis was performed on olanzapine and comparators for all known controlled clinical studies of olanzapine for bipolar maintenance treatment or relapse prevention to assess safety and efficacy. Studies compared olanzapine (n = 225) and placebo (n = 136) for 12 months, olanzapine (n = 217) and lithium (n = 214) for 12 months, and olanzapine plus lithium or valproate (n = 72) and placebo plus lithium or valproate (n = 64) for 18 months. For prevention of all-cause treatment discontinuation, the NNT was 7 to 8. For 9 of 11 efficacy and disposition measures examined, beneficial outcomes were more common with olanzapine than placebo. Beneficial outcomes were more common with olanzapine than lithium for 7 measures and more common for olanzapine plus lithium or valproate than placebo plus lithium or valproate for 1 measure. The NNHs of 5 to 8 for a weight gain of 7% or higher and 10 to 11 for the increase in body mass index category to overweight or obese during maintenance treatment indicated that these outcomes were more common for olanzapine or olanzapine plus mood stabilizers than for the comparators. All efficacy and disposition measures showing significant differences between groups for 12 to 18 months have NNTs favoring olanzapine or olanzapine plus lithium or valproate over placebo, lithium, or placebo plus lithium or valproate. However, the NNHs favor these comparators for avoidance of weight gain and of increase in body mass index category to overweight or obese. Clinicians should consider these and other potential benefits and risks in using maintenance treatments for patients with a bipolar disorder.

Onset of response with duloxetine treatment in patients with osteoarthritis knee pain and chronic low back pain: a post hoc analysis of placebo-controlled trials.

BACKGROUND: Knowing when to change pain-medication strategy is not well researched and remains a gap in treating chronic pain. OBJECTIVE: Our aim was to determine how long to treat osteoarthritis (OA) knee pain and chronic low back pain (CLBP) with duloxetine before considering a change in medication strategy. METHODS: We employed a post hoc analysis of changes in pain-severity data from placebo-controlled studies of duloxetine treatment in nondepressed patients with OA knee pain and CLBP. The studies were selected for inclusion in the analyses based on similarity of study design. Pain severity was recorded daily in patient diaries using an ordinal 11-point numerical rating scale (0 = no pain to 10 = most severe pain). The weekly means of the daily 24-hour average pain severity ratings from these diaries were pooled within disease states. Moderate response was defined as at least a 30% reduction from baseline in pain severity, and minimal improvement was defined as <10% reduction from baseline. The probability of achieving at least moderate pain reduction during 3 months treatment with duloxetine was estimated by Kaplan-Meier methods in patients with no or minimal improvement after 2, 4, and 6 weeks of treatment, as well as in all patients who had not yet achieved a moderate response (<30% reduction in pain severity). RESULTS: There were 239 OA patients and 541 CLBP patients who were randomly assigned to treatment with duloxetine 60/120 mg/d. OA and CLBP patients with minimal improvement at 2 weeks of treatment had <40% probability of achieving a moderate response, and at 4 weeks of treatment their chances were reduced to <30% in OA patients and <25% in CLBP patients. In patients showing <30% improvement at week 2 of treatment, OA patients had a 62% probability of achieving a moderate response, and CLBP patients had a 52% probability for a moderate response, and at 4 weeks of treatment, their chances were reduced to <50% in OA patients and <40% in CLBP patients. CONCLUSIONS: Patients taking duloxetine for OA or CLBP who have <10% reduction in pain after 4 weeks of treatment have limited possibility for eventually achieving even moderate pain reduction by the end of 12 weeks. ClinicalTrials.gov identifier: NCT00433290, NCT00408421, NCT00424593, NCT00408876, NCT00767806.

Evaluation of the effect of duloxetine treatment on functioning as measured by the Sheehan disability scale: pooled analysis of data from six randomized, double-blind, placebo-controlled clinical studies.

The purpose of this work is to describe the effect of duloxetine on functioning as measured by the Sheehan disability scale (SDS) compared with placebo in patients with major depressive disorder (MDD). Pooled data from six randomized, parallel, double-blind, placebo-controlled duloxetine studies in adult MDD patients were analyzed at the short-term (7-13 weeks) and the long-term (>24 weeks) endpoint. The primary variable was the SDS total score. Secondary variables included functional remission (SDS total ≤ 6) rates, Hamilton rating scale for depression total score, and pain visual analog scale. Analysis of covariance and logistic regression methods were used to assess differences in treatment and identify prognostic baseline factors. In total, 2496 patients (1424 duloxetine; 1072 placebo) were included. The between-treatment difference of -2.52 between duloxetine and placebo in the SDS total score at the short-term endpoint was statistically significant in favor of duloxetine vs. placebo (95% confidence interval: -3.17, -1.87; P < 0.001). The endpoint functional remission rates were 39.5% with duloxetine and 28.7% with placebo. Time since first depression episode, antidepressant pretreatment (yes/no), baseline visual analog scale pain (≤30 / >30 mm), and sex were significant prognostic factors. The effect of duloxetine was maintained at the long-term endpoint. Duloxetine is effective in improving MDD patients' functioning. Further antidepressant studies focusing on functioning would be helpful.

Review of Efficacy and Safety of Duloxetine 40 to 60 mg Once Daily in Patients with Diabetic Peripheral Neuropathic Pain.

We summarize efficacy and safety findings from 4 double-blind, placebo-controlled, 12-week studies and 1 open-label, uncontrolled, 34-week maintenance-of-effect (MOE) study that examine duloxetine 40 and 60 mg once daily (QD) in patients with diabetic peripheral neuropathic pain (DPNP). In all placebo-controlled studies, duloxetine showed significantly (P ≤ .01) greater reduction in pain severity (weekly mean of 24-hour average pain severity ratings, primary outcome measure) compared with placebo. In all placebo-controlled studies, duloxetine showed significantly (P ≤ .05) greater improvement on brief pain inventory-Interference ratings. Patient global impression of improvement ratings were superior to placebo (P ≤ .01) for duloxetine patients in all placebo-controlled studies. Response rates (based on 30% pain reduction) ranged from 57% to 68% for duloxetine and from 35% to 47% for placebo and were statistically significantly different (P ≤ .01) between treatment groups in 3 out of 4 studies. The open-label study showed maintenance of analgesic effect of duloxetine in DPNP. In the duloxetine groups, 4.3% to 14.9% of patients discontinued because of adverse events (placebo groups: 2.6% to 7.4%). Most commonly reported treatment-emergent adverse events were nausea, somnolence, and headache. Duloxetine 40 and 60 mg QD was efficacious and well tolerated in the management of DPNP.

Topiramate versus bupropion SR when added to mood stabilizer therapy for the depressive phase of bipolar disorder: a preliminary single-blind study.

OBJECTIVE: Antiepileptic drugs (AEDs) are commonly employed in the treatment of bipolar disorder. The efficacy and tolerability of topiramate, a novel anticonvulsant, and bupropion SR when added to mood stabilizer therapy were compared under single-blind conditions (rater-blinded) in patients meeting DSM-IV criteria for bipolar I/II depression. METHODS: A total of 36 out-patients with Hamilton Depression Rating Scale (HDRS-17) scores > or = 16 were randomized to receive escalating doses of either topiramate (50-300 mg/day) or bupropion SR (100-400 mg/day) for 8 weeks. Data were analyzed on an intent-to-treat basis using the last observation carried forward method. RESULTS: The percentage of patients meeting a priori response criteria (> or = 50% decrease from baseline in mean HDRS-17 total score) was significant for both topiramate (56%) and bupropion SR (59%) [t(17) = 2.542, p = 0.04 and t(17) = 2.661, p = 0.03, respectively]. Baseline demographic and clinical parameters were comparable between the two treatment groups. The mean doses of study medication were 176 mg/day (SD = 102 mg/day) for the topiramate-treated group and 250 mg/day (SD = 133 mg/day) for the bupropion SR-treated group. A significant and comparable reduction in depressive symptoms was observed from baseline to endpoint following topiramate and bupropion SR treatment, according to a > or = 50% reduction in the HDRS-17. Total mean HDRS-17 scores significantly decreased from baseline to endpoint in both groups (p = 0.001), however, differences between the topiramate-treated group and the bupropion SR-treated group were not significant [t(36) = 1.754, p = 0.097]. Both topiramate and bupropion SR were generally well tolerated. Thirteen patients discontinued the study: 2 because of lack of efficacy, 1 due to withdrawal of consent and 10 following side-effects (six in the topiramate and four in the bupropion SR-treated group). There were no cases of affective switch in either arm. Weight loss was experienced by patients in both groups (mean weight loss at endpoint was 1.2 kg in bupropion SR and 5.8 kg in topiramate) [t(17) = 2.325, p = 0.061 and t(17) = 2.481, p = 0.043, respectively]. CONCLUSIONS: These preliminary data suggest that adjunctive topiramate may reduce depressive symptom severity in acute bipolar depression. The antidepressant efficacy of this compound requires confirmation via double-blind placebo controlled investigation.