Duloxetine in the treatment of major depressive disorder: an open-label study

<p>Abstract</p> <p>Background</p> <p>Major depressive disorder (MDD) is a chronic and highly disabling condition. Existing pharmacotherapies produce full remission in only 30% to 40% of treated patients. Antidepressants exhibiting dual reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE) may achieve higher rates of remission compared with those acting upon a single neurotransmitter. In this study, the safety and efficacy of duloxetine, a potent dual reuptake inhibitor of 5-HT and NE, were examined.</p> <p>Methods</p> <p>Patients (N = 533) meeting DSM-IV criteria for MDD received open-label duloxetine (60 mg once a day [QD]) for 12 weeks during the initial phase of a relapse prevention trial. Patients were required to have a 17-item Hamilton Rating Scale for Depression (HAMD₁₇) total score ≥18 and a Clinical Global Impression of Severity (CGI-S) score ≥4 at baseline. Efficacy measures included the HAMD₁₇total score, HAMD₁₇subscales, the CGI-S, the Patient Global Impression of Improvement (PGI-I) scale, Visual Analog Scales (VAS) for pain, and the Symptom Questionnaire, Somatic Subscale (SQ-SS). Quality of life was assessed using the Sheehan Disability Scale (SDS) and the Quality of Life in Depression Scale (QLDS). Safety was evaluated by recording spontaneously-reported treatment-emergent adverse events, changes in vital signs and laboratory analytes, and the Patient Global Impression of Sexual Function (PGI-SF) scale.</p> <p>Results</p> <p>The rate of discontinuation due to adverse events was 11.3%. Treatment-emergent adverse events reported by ≥10% duloxetine-treated patients were nausea, headache, dry mouth, somnolence, insomnia, and dizziness. Following 12 weeks of open-label duloxetine therapy, significant improvements were observed in all assessed efficacy and quality of life measures. In assessments of depression severity (HAMD₁₇, CGI-S) the magnitude of symptom improvement continued to increase at each study visit, while for painful physical symptoms the onset of improvement was rapid and reached a maximum after 2 to 3 weeks of treatment.</p> <p>Conclusion</p> <p>In this open-label phase of a relapse prevention study, duloxetine (60 mg QD) was shown to be safe and effective in the treatment of MDD.</p> <p>Trial registration</p> <p>NCT00036309.</p

Practical application of cure mixture model for long-term censored survivor data from a withdrawal clinical trial of patients with major depressive disorder

<p>Abstract</p> <p>Background</p> <p>Survival analysis methods such as the Kaplan-Meier method, log-rank test, and Cox proportional hazards regression (Cox regression) are commonly used to analyze data from randomized withdrawal studies in patients with major depressive disorder. However, unfortunately, such common methods may be inappropriate when a long-term censored relapse-free time appears in data as the methods assume that if complete follow-up were possible for all individuals, each would eventually experience the event of interest.</p> <p>Methods</p> <p>In this paper, to analyse data including such a long-term censored relapse-free time, we discuss a semi-parametric cure regression (Cox cure regression), which combines a logistic formulation for the probability of occurrence of an event with a Cox proportional hazards specification for the time of occurrence of the event. In specifying the treatment's effect on disease-free survival, we consider the fraction of long-term survivors and the risks associated with a relapse of the disease. In addition, we develop a tree-based method for the time to event data to identify groups of patients with differing prognoses (cure survival CART). Although analysis methods typically adapt the log-rank statistic for recursive partitioning procedures, the method applied here used a likelihood ratio (LR) test statistic from a fitting of cure survival regression assuming exponential and Weibull distributions for the latency time of relapse.</p> <p>Results</p> <p>The method is illustrated using data from a sertraline randomized withdrawal study in patients with major depressive disorder.</p> <p>Conclusions</p> <p>We concluded that Cox cure regression reveals facts on who may be cured, and how the treatment and other factors effect on the cured incidence and on the relapse time of uncured patients, and that cure survival CART output provides easily understandable and interpretable information, useful both in identifying groups of patients with differing prognoses and in utilizing Cox cure regression models leading to meaningful interpretations.</p

Treatment patterns associated with Duloxetine and Venlafaxine use for Major Depressive Disorder

<p>Abstract</p> <p>Background</p> <p>Duloxetine and venlafaxine extended release (venlafaxine XR) are SNRIs indicated for the treatment of MDD. This study addresses whether duloxetine and venlafaxine XR are interchangeable in their patterns of use with patients who are depressed or are used more selectively based on treatment history, background characteristics, and presenting symptoms.</p> <p>Methods</p> <p>This was a retrospective analysis of an administrative insurance claims database. We studied patients in managed care with major depressive disorder (MDD) treated with duloxetine or venlafaxine XR. Predictors of treatment and cost were assessed using Chi-square and logistic regression analyses of demographics and past-year medication use and comorbidities.</p> <p>Results</p> <p>Patients with MDD treated with duloxetine (n = 9,641) versus venlafaxine XR (n = 8,514) tended to be older, slightly more likely to be female, and treated by a psychiatrist (<it>P </it>< 0.0001). In the prior year, more duloxetine patients (vs. venlafaxine XR) received ≥3 unique antidepressants (20.8% vs. 16.6%), ≥3 unique pain medications (25.5% vs. 15.6%), and had ≥8 unique diagnosed comorbid medical and psychiatric conditions (38.6% vs. 29.1%). The prior 6-month total health care costs were $1,731 higher for duloxetine than for venlafaxine XR and declined for both medications in the 6 months after treatment began. Logistic regression analysis revealed that 61% of duloxetine patients and 61% of venlafaxine XR patients were predictable from prior patient and treatment factors.</p> <p>Conclusions</p> <p>Patients with MDD treated with duloxetine tended to have a more complex and costly antecedent clinical presentation compared with venlafaxine XR patients, suggesting that physicians do not use the medications interchangeably.</p

The risk of bleeding with duloxetine treatment in patients who use nonsteroidal anti-inflammatory drugs (NSAIDs): analysis of placebo-controlled trials and post-marketing adverse event reports

David G Perahia,1 Mark E Bangs,2 Qi Zhang,2 Yingkai Cheng,2 Jonna Ahl,2 Elijah P Frakes,2 Michael J Adams,2 James M Martinez2 1Neurosciences, Lilly Research Centre, Windlesham, Surrey, UK; 2Neurosciences, Eli Lilly and Company, Indianapolis, IN, USA Purpose: To assess the safety of duloxetine with regards to bleeding-related events in patients who concomitantly did, versus did not, use nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. Methods: Safety data from all placebo-controlled trials of duloxetine conducted between December 1993 and December 2010, and post-marketing reports from duloxetine-treated patients in the US Food and Drug Administration Adverse Event Reporting System (FAERS), were searched for bleeding-related treatment-emergent adverse events (TEAEs). The percentage of patients with bleeding-related TEAEs was summarized and compared between treatment groups in all the placebo-controlled studies. Differences between NSAID user and non-user subgroups from clinical trial data were analyzed by a logistic regression model that included therapy, NSAID use, and therapy-by-NSAID subgroup interaction. In addition, to determine if higher duloxetine doses are associated with an increased incidence of bleeding-related TEAEs, and whether the use of concomitant NSAIDs might influence the dose effect if one exists, placebo-controlled clinical trials with duloxetine fixed doses of 60 mg, 120 mg, and placebo were analyzed. Also, the incidence of bleeding-related TEAEs reported for duloxetine alone was compared with the incidence in patients treated with duloxetine and concomitant NSAIDs. Finally, the number of bleeding-related cases reported for duloxetine in the FAERS database was compared with the numbers reported for all other drugs. Results: Across duloxetine clinical trials, there was a significantly greater incidence of bleeding-related TEAEs in duloxetine- versus placebo-treated patients overall and also in those patients who did not take concomitant NSAIDS, but no significant difference was seen among those patients who did take concomitant NSAIDS. There was no significant difference in the incidence of bleeding-related TEAEs in the subset of patients treated with duloxetine 120 mg once daily versus those treated with 60 mg once daily regardless of concomitant NSAID use. The combination of duloxetine and NSAIDs was associated with a statistically significantly higher incidence of bleeding-related TEAEs compared with duloxetine alone. A similarly higher incidence of bleeding-related TEAEs was seen in patients treated with placebo and concomitant NSAIDs compared with placebo alone. Bleeding-related TEAEs reported in the FAERS database were disproportionally more frequent for duloxetine taken with NSAIDs compared with the full FAERS background, but there was no difference in the reporting of bleeding-related TEAEs when the cases reported for duloxetine taken with NSAIDs were compared against the cases reported for NSAIDs alone. Conclusion: Concomitant use of NSAIDs was associated with a higher incidence of bleeding-related TEAEs in clinical trials regardless of whether patients were taking duloxetine or placebo; bleeding-related TEAEs did not appear to increase along with duloxetine dose regardless of NSAID use. In spontaneously reported post-marketing data, the combination of duloxetine and NSAID use was not associated with an increased reporting of bleeding-related events when compared to NSAID use alone. Keywords: antidepressant, gastrointestinal bleeding, NSAID, aspiri

Prescribing patterns of antidepressants in Europe: Results from the Factors Influencing Depression Endpoints Research (FINDER) study.

Antidepressant prescribing patterns and factors influencing the choice of antidepressant for the treatment of depression were examined in the Factors Influencing Depression Endpoints Research (FINDER) study, a prospective, observational study in 12 European countries of 3468 adults about to start antidepressant medication for their first episode of depression or a new episode of recurrent depression. Selective serotonin reuptake inhibitors (SSRIs) were the most commonly prescribed antidepressant (63.3% patients), followed by serotonin-norepinephrine reuptake inhibitors (SNRIs, 13.6%), but there was considerable variation across countries. Notably, tricyclic and tetracyclic antidepressants (TCAs) were prescribed for 26.5% patients in Germany. The choice of the antidepressant prescribed was strongly influenced by the previous use of antidepressants, which was significantly associated with the prescription of a SSRI (OR 0.64; 95% CI 0.54, 0.76), a SNRI (OR 1.49; 95% CI 1.18, 1.88) or a combination of antidepressants (OR 2.78; 95% CI 1.96, 3.96). Physician factors (age, gender, speciality) and patient factors (severity of depression, age, education, smoking, number of current physical conditions and functional syndromes) were associated with initial antidepressant choice in some models. In conclusion, the prescribing of antidepressants varies by country, and the type of antidepressant chosen is influenced by physician- as well as patient-related factors

Factors influencing depression endpoints research (FINDER): Study design and population characteristics.

Factors influencing outcomes of depression in clinical practice, especially health-related quality of life (HRQoL), are poorly understood. The Factors Influencing Depression Endpoints Research (FINDER) study is a European prospective, observational study designed to estimate the HRQoL of adults with a clinically diagnosed depressive episode at baseline, and 3 and 6 months after commencing antidepressant medication. We report here the study design and baseline patient characteristics. HRQoL was assessed by the 36-item Short-Form Health Survey (SF-36) and European Quality of Life-5 Dimensions (EQ-5D). Patient ratings on Hospital Anxiety and Depression Scale (HADS) and pain Visual Analogue Scale (VAS) were also obtained. Results (n=3468) showed that SF-36 mental component summary (mean 22.2) was more than two SDs below general population norms (mean 50.0) and one SD below clinical depression norms (mean 34.8); the physical component summary (mean 46.1) was similar to general population (mean 50.0) and clinical depression norms (mean 45.0). Mean EQ-5D scores were also lower than general population norms. Mean HADS-Depression and -Anxiety subscores were 12.3 and 13.0, respectively. Fifty-six percent of patients reported an overall pain VAS score of at least 30mm and 70% of these patients had no physical explanation for their pain. Further investigation into factors associated with HRQoL in depression after treatment initiation is warranted