Assessment of Efficacy and Safety of Zagotenemab: Results From PERISCOPE-ALZ, a Phase 2 Study in Early Symptomatic Alzheimer Disease.

BACKGROUND AND OBJECTIVES: Zagotenemab (LY3303560), a monoclonal antibody that preferentially targets misfolded, extracellular, aggregated tau, was assessed in the PERISCOPE-ALZ phase 2 study to determine its ability to slow cognitive and functional decline relative to placebo in early symptomatic Alzheimer disease (AD). METHODS: Participants were enrolled across 56 sites in North America and Japan. Key eligibility criteria included age of 60-85 years, Mini-Mental State Examination score of 20-28, and intermediate levels of brain tau on PET imaging. In this double-blind study, participants were equally randomized to 1,400 mg or 5,600 mg of zagotenemab, or placebo (IV infusion every 4 weeks for 100 weeks). The primary outcome was change on the Integrated AD Rating Scale (iADRS) assessed by a Bayesian Disease Progression model. Secondary measures include mixed model repeated measures analysis of additional cognitive and functional endpoints as well as biomarkers of AD pathology. RESULTS: A total of 360 participants (mean age = 75.4 years; female = 52.8%) were randomized, and 218 completed the treatment period. Demographics and baseline characteristics were reasonably balanced among arms. The mean disease progression ratio (proportional decline in the treated vs placebo group) with 95% credible intervals for the iADRS was 1.10 (0.959-1.265) for the zagotenemab low-dose group and 1.05 (0.907-1.209) for the high-dose, where a ratio less than 1 favors the treatment group. Secondary clinical endpoint measures failed to show a drug-placebo difference in favor of zagotenemab. No treatment effect was demonstrated by flortaucipir PET, volumetric MRI, or neurofilament light chain (NfL) analyses. A dose-related increase in plasma phosphorylated tau181 and total tau was demonstrated. Zagotenemab treatment groups reported a higher incidence of adverse events (AEs) (85.1%) compared with the placebo group (74.6%). This difference was not attributable to any specific AE or category of AEs. DISCUSSION: In participants with early symptomatic AD, zagotenemab failed to achieve significant slowing of clinical disease progression compared with placebo. Imaging biomarker and plasma NfL findings did not show evidence of pharmacodynamic activity or disease modification. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03518073. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with early symptomatic AD, zagotenemab does not slow clinical disease progression.

Safety, Tolerability, and Pharmacokinetics of Zagotenemab in Participants with Symptomatic Alzheimer's Disease: A Phase I Clinical Trial.

Background: Zagotenemab (LY3303560), a monoclonal antibody, preferentially binds to extracellular, misfolded, aggregated tau that has been implicated in Alzheimer's disease (AD). Objective: The goal of this study was to assess the safety and pharmacokinetics of multiple doses of zagotenemab in participants with AD. Methods: This was a Phase Ib, multi-site, participant- and investigator-blind, placebo-controlled, parallel-group study in participants with mild cognitive impairment due to AD or mild to moderate AD. After screening, participants were randomized to zagotenemab 70 mg, 210 mg, or placebo every 4 weeks for up to 49 weeks and were followed up for 16 weeks. Results: A total of 13 males and 9 females, aged 59 to 84 years, were dosed. No deaths occurred during this study. A total of 4 serious adverse events occurred in 2 participants who then discontinued the study. The most commonly reported (3 or more participants) treatment-emergent adverse events were sinus bradycardia, headache, fall, and bronchitis. The pharmacokinetics profile showed generally linear exposures across the dose range studied with a clearance of ~8 mL/h. The half-life of zagotenemab in serum was ~20 days. A dose-dependent increase in plasma tau was observed. No other significant pharmacodynamic differences were observed due to low dose levels and limited treatment duration. Conclusions: No dose-limiting adverse events were observed with zagotenemab treatment. Pharmacokinetics of zagotenemab were typical for a monoclonal antibody. Meaningful pharmacodynamic differences were not observed.Clinicaltrials.gov: NCT03019536.

Efficacy and safety of duloxetine 60 mg once daily in major depressive disorder: a review with expert commentary.

OBJECTIVE: Major depressive disorder (MDD) is a significant public health concern and challenges health care providers to intervene with appropriate treatment. This article provides an overview of efficacy and safety information for duloxetine 60 mg/day in the treatment of MDD, including its effect on painful physical symptoms (PPS). DESIGN: A literature search was conducted for articles and pooled analyses reporting information regarding the use of duloxetine 60 mg/day in placebo-controlled trials. SETTING: Placebo-controlled, active-comparator, short- and long-term studies were reviewed. PARTICIPANTS: Adult (≥18 years) patients with MDD. MEASUREMENTS: Effect sizes for continuous outcome (change from baseline to endpoint) and categorical outcome (response and remission rates) were calculated using the primary measures of 17-item Hamilton Rating Scale for Depression (HAMD-17) or Montgomery-Åsberg Depression Rating Scale (MADRS) total score. The Brief Pain Inventory and Visual Analogue Scales were used to assess improvements in PPS. Glass estimation method was used to calculate effect sizes, and numbers needed to treat (NNT) were calculated based on HAMD-17 and MADRS total scores for remission and response rates. Safety data were examined via the incidence of treatment-emergent adverse events and by mean changes in vital-sign measures. RESULTS: Treatment with duloxetine was associated with small-to-moderate effect sizes in the range of 0.12 to 0.72 for response rate and 0.07 to 0.65 for remission rate. NNTs were in the range of 3 to 16 for response and 3 to 29 for remission. Statistically significant improvements (p≤0.05) were observed in duloxetine-treated patients compared to placebo-treated patients in PPS and quality of life. The safety profile of the 60-mg dose was consistent with duloxetine labeling, with the most commonly observed significant adverse events being nausea, dry mouth, diarrhea, dizziness, constipation, fatigue, and decreased appetite. CONCLUSION: These results reinforce the efficacy and tolerability of duloxetine 60 mg/day as an effective short- and long-term treatment for adults with MDD. The evidence of the independent analgesic effect of duloxetine 60 mg/day supports its use as a treatment for patients with PPS associated with depression. This review is limited by the fact that it included randomized clinical trials with different study designs. Furthermore, data from randomized controlled trials may not generalize well to real clinical practice.

Sexual function during long-term duloxetine treatment in patients with recurrent major depressive disorder.

INTRODUCTION: Sexual dysfunction (SD) is frequently associated with major depressive disorder (MDD) in the untreated state and may be worsened by antidepressant treatment. AIM: We evaluated SD in duloxetine-treated patients during an MDD recurrence prevention study. METHOD: Patients (N = 514) received open-label duloxetine 60-120 mg/day for up to 34 weeks. Responders (N = 288) were randomly assigned to duloxetine or placebo during a further 52-week double-blind maintenance phase. MAIN OUTCOME MEASURES: The Arizona Sexual Experience Scale (ASEX) was used to assess sexual functioning. RESULTS: At study entry, 73.4% of patients met ASEX criteria for SD. After open-label duloxetine treatment, the probability of continued SD was 77.9% for nonresponders and 53.2% for responders. In patients without SD at study entry, the probability of emergent SD was 49.6% (nonresponders) and 33.2% (responders). In the double-blind maintenance phase, there was no significant difference (P = 0.105) in the probability of emergent SD between placebo-treated (49.2%) and duloxetine-treated (27.9%) patients without SD at baseline, with no significant treatment-by-gender interaction. In patients with a recurrence of MDD, the probability of emergent SD was similar between placebo- (71.3%) and duloxetine-treated (82.7%) patients. However, in patients with no recurrence of MDD, the probability of emergent SD in placebo patients (40.0%) was numerically higher than in duloxetine patients (12.9%). Spontaneous reports of adverse events related to sexual function were infrequent and no patients discontinued due to these events. CONCLUSIONS: In patients with MDD, the probability of continued or emergent SD after up to 34 weeks of open-label duloxetine treatment was associated with the response status of the patients. In patients who responded to duloxetine treatment, after up to a further 52 weeks of double-blind treatment either with duloxetine or placebo, the probability of continued or emergent SD appeared to be more related to MDD itself than the treatments that the patients received.

Long-term safety of duloxetine during open-label compassionate use treatment of patients who completed previous duloxetine clinical trials.

PURPOSE: To provide duloxetine for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), fibromyalgia (FM) and diabetic peripheral neuropathic pain (DPNP) to patients who had previously completed a duloxetine clinical study and for whom, in the opinion of the investigator, no effective alternative therapy was available. METHODS: Adult outpatients who had previously completed a duloxetine study for the treatment of MDD, GAD, DPNP, or FM received duloxetine 30 mg to 120 mg daily up until its local commercial availability. Safety analyses included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), AEs reported as reason for discontinuation, and vital signs. No efficacy measures were collected. RESULTS: Of 667 patients enrolled, 282 (42.3%) were still participating at the time the drug was made commercially available in their countries. Most patients had previously participated in a duloxetine MDD study (76.2%); were female (68.1%) and Caucasian (94.9%). The median duration of exposure was 328 days (range 3-1718 days). The most common reasons for discontinuation were patient decision (25.3%), adverse event (8.4%), and lack of efficacy (8.4%). Of the 86 SAEs experienced by 46 patients, most (including one death) were judged by the investigator to be unrelated to duloxetine treatment. The most common TEAEs were in the System Organ Class of gastrointestinal (28.3%), nervous system (28.0%), and psychiatric (25.8%) and were predominantly mild to moderate in severity. Increases of systolic blood pressure (1.9 mm Hg) and pulse rate (2.2 bpm) at endpoint were reported. CONCLUSION: The safety data from this long-term compassionate use study of duloxetine were consistent with previous experience and revealed no new safety signals. LIMITATIONS: The limitations include: lack of a control arm, no efficacy data were collected to assess the long-term efficacy, the results may not necessarily generalize to other ethnic groups as most patients were Caucasians, and lack of consistency in regard to duration of exposure at study entry as patients came from different trials with different study designs. CLINICAL TRIAL REGISTRY ID: www.clinicaltrials.gov--NCT00071708.

Duloxetine in the prevention of depressive recurrences: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy of duloxetine 60-120 mg once daily in the prevention of depressive recurrence in outpatients with recurrent major depressive disorder (MDD). METHOD: Eligible patients with at least 3 episodes of MDD (DSM-IV diagnosis) in the past 5 years received open-label duloxetine 60-120 mg/day for up to 34 weeks. Patients meeting response criteria were then randomly assigned to either duloxetine or placebo for up to 52 weeks of double-blind maintenance treatment. The primary outcome measure was time to recurrence of a major depressive episode. Safety and tolerability were assessed via analysis of treatment-emergent adverse events (TEAEs), vital signs, weight, and laboratory measures. Patients were recruited from 43 study centers in 5 European countries (France, Germany, Italy, Russia, and Sweden) and the United States. The study was conducted from March 2005 to January 2008. RESULTS: A total of 288 patients were randomly assigned to duloxetine or placebo. Time to a depressive recurrence was significantly longer in duloxetine-treated patients compared with placebo-treated patients (p < .001). During the double-blind maintenance phase, 33.1% of placebo-treated patients experienced a depressive recurrence compared with 14.4% of duloxetine-treated patients (p < .001). There were no significant differences between treatment groups in TEAEs, discontinuations due to adverse events, vital signs, or weight. CONCLUSIONS: Treatment with duloxetine was associated with a longer time to depressive recurrence and a significantly lower recurrence rate compared with placebo. TRIALS REGISTRATION: (ClinicalTrials.gov) Identifier: NCT00105989.

Switching to duloxetine in selective serotonin reuptake inhibitor non- and partial-responders: effects on painful physical symptoms of depression.

Painful physical symptoms (PPS) are common in patients with depression. Our objective was to evaluate the presence of PPS in a sample of SSRI non- or partial-responders with MDD and examine the effect of a switch to duloxetine on those PPS. Outpatients who met criteria for MDD despite having taken an SSRI antidepressant for at least 6 weeks, and who had a Hamilton depression rating scale total score of at least 15 and a clinical global impression of severity score of at least 3, were randomized to switch to duloxetine by either a direct switch or a start-taper switch method. PPS were assessed at baseline and at the study endpoint using various measures including six visual analog scales (VAS) for pain (overall pain, headache, back pain, shoulder pain, interference with daily activities, and time in pain while awake), the pain subscale of the symptom questionnaire-somatic subscale, and the bodily pain subscale of the short form-36 item health survey. Clinically significant levels of pain (mean baseline VAS scores >30 mm) were seen across all VAS pain measures prior to switching. Switch to duloxetine was associated with significant improvements on all pain measures regardless of switch method, and there was evidence for an earlier reduction in pain in the start-taper switch group. In summary, MDD patients who were non- or partial-responders to SSRI treatment were found to have clinically significant pain which improved significantly following switch to duloxetine regardless of the switch method utilized.

Quality of life outcomes among patients with depression after 6 months of starting treatment: results from FINDER.

BACKGROUND: Health-related quality of life (HRQoL) data in depression are limited. We studied the impact of antidepressant (AD) treatment on HRQoL outcomes in depressed patients and investigated factors associated with these outcomes in routine practice settings. METHODS: The Factors Influencing Depression Endpoints Research (FINDER) study was a 6-month, European, prospective, observational study, designed to estimate HRQoL in 3468 adult patients with a clinically diagnosed episode of depression at baseline and at 3 and 6-months after commencing AD treatment. HRQoL was assessed by the Medical Outcome Short-Form (36) Health Survey (SF-36) and European Quality of Life-5 Dimensions (EQ-5D). Regression analysis identified baseline and treatment variables independently and significantly associated with HRQoL outcomes. RESULTS: Most HRQoL improvement occurred within 3 months of starting treatment. Better HRQoL outcomes were strongly associated with fewer somatic symptoms at baseline, AD treatment taken and not switching within AD groups. Education and occupational status were also important. Depression variables (number of previous depressions and current episode duration) were consistently associated with worse HRQoL outcomes. Self-rated depression severity was associated with poorer outcomes on the SF-36 mental component only. LIMITATIONS: As this was an observational study, the important finding that between and within AD group switching impacted HRQoL will need to be investigated in more controlled settings. CONCLUSIONS: Receiving an AD treatment was associated with large improvements in HRQoL, but switching within AD groups was consistently associated with poorer outcomes. Somatic symptoms, including painful symptoms, are often present in depressed patients and appear to negatively impact HRQoL outcomes.

"Caseness" for depression and anxiety in a depressed outpatient population: symptomatic outcome as a function of baseline diagnostic categories.

OBJECTIVE: To examine the diagnostic status of patients enrolled in the Factors Influencing Depression Endpoints Research (FINDER) study and symptomatic outcomes and baseline characteristics associated with remission 6 months after commencing antidepressant therapy. METHOD: Status of clinically diagnosed depressed patients was based on self-rated Hospital Anxiety and Depression Scale (HADS) scores. Five diagnostic categories were defined: noncaseness, mixed anxiety-depression (subthreshold depressive and anxious symptomatology), caseness for depression, caseness for anxiety, and caseness for comorbid anxiety-depression. Assessments included the Somatic Symptom Inventory and health-related quality of life (HRQoL) using the Medical Outcomes Study 36-item Short-Form Health Survey. Remission rates (based on HADS noncaseness for both depression and anxiety) and their associations with baseline characteristics were investigated. Patients were enrolled between May 2004 and September 2005. RESULTS: Of the 3,353 patients enrolled, 66.4% met the HADS criteria for probable depressive disorder and 74.1% met the HADS criteria for probable anxiety disorder. Somatic symptom severity (painful and nonpainful) was highest and HRQoL was lowest in the comorbid anxiety-depression group. After 6 months, remission rates were 50.2% for caseness for depression, 40.4% for caseness for anxiety, and 40.6% for caseness for comorbid anxiety-depression. A lower number of previous depressive episodes, shorter current episode duration, lower painful and nonpainful somatic symptom scores, being married, a higher educational level, and working for pay were most consistently associated with higher remission rates. CONCLUSIONS: Physicians do not always differentiate between anxiety and depressive symptoms when making a clinical diagnosis of depression. At baseline, most enrolled patients had significant emotional depressive and anxious symptoms, as well as significant nonpainful and painful somatic symptomatology, and these factors were associated with outcome.

Implications of pain in generalized anxiety disorder: efficacy of duloxetine.

OBJECTIVE: To conduct a post hoc evaluation of the prevalence of clinically significant pain and the efficacy of duloxetine in patients with generalized anxiety disorder (GAD) and concurrent pain. METHOD: Data from two 9- to 10-week double-blind, placebo-controlled, randomized clinical trials of duloxetine (60 to 120 mg) in DSM-IV-defined GAD were analyzed (study 1 was conducted from July 2004 to September 2005; study 2 was conducted from August 2004 to June 2005). Efficacy was assessed with the Hamilton Rating Scale for Anxiety (HAM-A), visual analog scales (VAS) for pain, the Hospital Anxiety Depression Scale (HADS), the Clinical Global Impressions-Improvement of Illness (CGI-I) scale, the Patient Global Impressions-Improvement (PGI-I) scale, and the Sheehan Disability Scale (SDS) global functional impairment scale. RESULTS: Of 840 patients randomly assigned to treatment, 61.3% (302 duloxetine, 213 placebo) had VAS scores ≥ 30 mm on at least 1 of the pain scales, indicating clinically significant pain. Among those patients with concurrent pain at baseline, change from baseline to endpoint in the HAM-A total score (42.9% change in mean scores for duloxetine, 31.4% for placebo), HADS anxiety scale (40.3% vs. 22.8%), HADS depression scale (36.1% vs. 20.5%), HAM-A psychic factor (45.9% vs. 29.9%), and SDS global functional improvement score (45.5% vs. 22.1%) was significantly (all p's < .001) greater for duloxetine compared with placebo. Improvement on the CGI-I (p = .003) and PGI-I (p < .001) was also significantly greater for duloxetine. Response (HAM-A total score decrease ≥ 50%) (49% vs. 29%) and remission (HAM-A total score ≤ 7 at endpoint) (29% vs. 18%) rates were significantly greater for duloxetine compared with placebo (p < .001 and p = .041, respectively). Duloxetine demonstrated statistically significantly greater reduction in pain on all 6 VAS pain scales (all p's < .001 except headaches with p < .002) (for duloxetine, percent change in means from baseline to endpoint ranged from 40.1% to 45.2% across the 6 VAS scales; for placebo, 22.0% to 26.3%). CONCLUSION: Duloxetine, relative to placebo, improves anxiety symptoms, pain, and functional impairment among patients with GAD with concurrent clinically significant pain. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00122824 (study 1) and NCT00475969 (study 2).

Switching to duloxetine from selective serotonin reuptake inhibitor antidepressants: a multicenter trial comparing 2 switching techniques.

OBJECTIVE: To compare 2 methods of switching selective serotonin reuptake inhibitor (SSRI) non-responders or partial responders to duloxetine. METHOD: Adult outpatients with DSM-IV major depressive disorder, a Hamilton Rating Scale for Depression (HAM-D(17)) total score of >or= 15, and a Clinical Global Impressions-Severity of Illness score of >or= 3 despite at least 6 weeks of SSRI treatment were randomly assigned to either abrupt discontinuation of SSRI immediately followed by initiation of duloxetine (direct switch [DS]; N = 183) or tapered discontinuation of SSRI over 2 weeks and simultaneous administration of duloxetine (start-taper switch [STS]; N = 185). Efficacy, safety, and tolerability outcomes associated with these 2 switch methods were compared following switch and after 10 weeks of duloxetine treatment. The study was conducted from August 2004 to March 2006. RESULTS: There was a significant improvement in depressive symptom severity in both switch groups as measured by mean change in HAM-D(17) total score (p

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.

A randomized, controlled trial of duloxetine alone vs. duloxetine plus a telephone intervention in the treatment of depression.

OBJECTIVE: We hypothesized that combining antidepressant medication with a standardized telephone adherence support intervention would lead to superior outcomes in the treatment of depression compared with antidepressant medication alone. METHOD: Patients with depression were randomized to receive the antidepressant duloxetine alone (DLX), or duloxetine plus a standardized telephone intervention (DLX+TI), for 12 weeks of open-label treatment. The primary outcome measure was remission (HAMD 17 total score 90% at every visit) in both groups. CONCLUSIONS: A telephone intervention in combination with antidepressant medication (duloxetine) did not improve depression outcomes compared with antidepressant alone in this clinical trial, perhaps due to high drug adherence in both treatment groups. Addition of a telephone intervention was, however, associated with increased reporting of AEs.

A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of patients with major depressive disorder.

BACKGROUND: Clinical trials assessing antidepressant therapies typically include separate assessments of efficacy (benefit) and adverse events (risk). Global benefit-risk (GBR) assessment allows the simultaneous evaluation of both efficacy and adverse events. The objective was to compare the serotonin and norepinephrine reuptake inhibitors (SNRIs) duloxetine and venlafaxine using GBR assessment. METHODS: Data were combined from two similarly designed, multicenter, randomized, double-blind, parallel group studies in which patients with major depressive disorder were randomized to either duloxetine 60 mg/day or venlafaxine extended release (XR) 150 mg/day (75 mg/day for the first 2 weeks) for a 6-week fixed dosing period followed by an additional 6 weeks of treatment in which the dose could be increased up to 120 mg/day for duloxetine and 225 mg/day for venlafaxine. Patients completing the study (or receiving study drug for 2 weeks or more) were eligible to enter a taper period where the dose of study drug was gradually reduced over 1-2 weeks prior to drug discontinuation. The primary outcome measure (defined a priori) was the GBR comparison of duloxetine 60 mg/day and venlafaxine XR 150 mg/day after 6 weeks of treatment. In the GBR analysis, benefit was defined as remission at endpoint [17-item Hamilton Depression Rating Scale (HAMD17) 7]. Risk was defined by four categories: patients having either no adverse events (AEs), AEs with no severity rating greater than moderate, AEs with at least one severity rating of severe, or having discontinued with a reason of self-reported adverse event (regardless of any AE severity). Additional efficacy measures included HAMD17 total score and subscales, HAMA, CGI-S, and PGI-I. Safety and tolerability were assessed via analysis of reasons for discontinuation, treatment-emergent adverse events (TEAEs), discontinuation-emergent adverse events, and changes in vital signs, weight, and laboratory analytes. RESULTS: There were no significant differences between duloxetine 60 mg/day and venlafaxine 150 mg/day as measured by GBR assessment at the end of 6 weeks (-1.418 vs. -1.079, P = 0.217) or 12 weeks (-0.349 vs. -0.121, P = 0.440), nor were there significant differences between treatment groups on the majority of efficacy measures. Significantly more venlafaxine-treated patients (74.5%) completed 12 weeks of treatment compared with duloxetine-treated patients (64.8%, P =.006). Nausea was the most common treatment-emergent adverse event (TEAE) for both drugs, and was significantly higher with duloxetine 60 mg/day compared to venlafaxine 150 mg/day during the first 6 weeks of treatment (43.6% vs. 35.0%, P0.05). During the taper period, significantly more venlafaxine-treated patients reported discontinuation-emergent adverse events (DEAEs) than duloxetine-treated patients. From a safety perspective, significantly more venlafaxine-treated patients (n = 4) than duloxetine-treated patients (n=0, P =.047) experienced sustained elevations of systolic blood pressure during the fixed dosing period. Otherwise, there were few significant differences in safety measures found between treatment groups during 6 and 12 weeks of therapy. CONCLUSIONS: Duloxetine 60 mg/day and venlafaxine XR 150 mg/day have similar benefit-risk profiles on the basis of a comparison utilizing GBR assessment. The implications of the more subtle differences between these drugs, as well as for interpreting the GBR assessment, are discussed.

Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect?

The evidence that the effects of the antidepressant duloxetine on painful physical symptoms in depression and chronic pain disorders are a direct analgesic effect rather than an indirect antidepressant effect is reviewed. Data from placebo-controlled acute studies of duloxetine in major depressive disorder, diabetic peripheral neuropathic pain and fibromyalgia syndrome are included in this review. In placebo-controlled studies of duloxetine in patients with major depressive disorder, non-depressed diabetic peripheral neuropathic pain, and fibromyalgia syndrome, duloxetine has a statistically significantly greater effect on pain than placebo. Path analysis suggests that in these patient populations, approximately 50, 90, and 80%, respectively, of the observed effect on pain is a direct analgesic effect rather than an indirect antidepressant effect. In fibromyalgia syndrome studies, duloxetine had similar and substantial effects on pain regardless of whether patients had comorbid major depressive disorder. Pain is a complex experience, involving both the physiological responses of the nociceptive system and the processing of that information in brain regions associated with emotion. While some effects of duloxetine on painful symptoms can be accounted for by its antidepressant action, the data strongly suggest that duloxetine also exerts a substantial direct analgesic effect over and above its antidepressant effects, in patients with major depressive disorder, diabetic peripheral neuropathic pain, and fibromyalgia syndrome.

Duloxetine in the treatment of major depressive disorder: an assessment of the relationship between outcomes and episode characteristics.

Duloxetine, an inhibitor of serotonin and norepinephrine reuptake, has been approved for the treatment of major depressive disorder. In this analysis, data from eight, double-blind, placebo-controlled duloxetine trials were pooled, and the response to duloxetine treatment (40-120 mg/day) was compared between patients experiencing their first episode of depression (n=581) or a subsequent episode (n=1321), and between patients experiencing a depressive episode of short (n=596), medium (n=669), or long (n=649) duration based on tertile divisions. Treatment response was determined on the basis of changes from baseline in the 17-item Hamilton Rating Scale for Depression total score, the Clinical Global Impressions of Severity Scale, and painful physical symptoms (Somatic Symptom Inventory and Visual Analog Scales). Overall, changes on all outcome measures and response and remission rates were significantly greater in duloxetine-treated patients than in placebo-treated patients. Furthermore, the effect of duloxetine was similar across all episode characteristic groups (first/subsequent episode, short/medium/long episode duration). Only for the Somatic Symptom Inventory was the effect of duloxetine significantly different between groups (greater in the subsequent episode group than in the first episode group). Duloxetine was effective in the treatment of first and subsequent episodes of major depressive disorder, and regardless of duration of the current depressive episode.

Effects of the antidepressant duloxetine on body weight: analyses of 10 clinical studies.

OBJECTIVE: To assess the effect of duloxetine, an inhibitor of serotonin and norepinephrine reup-take, on body weight of patients with major depressive disorder (MDD). METHOD: Body weight data were obtained from all 10 phase II and III registration studies of duloxetine in the treatment of MDD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), performed by Eli Lilly and Company between February 1999 and July 2003. Both acute (8-9 weeks) and long-term (26, 34, and 52 weeks) studies were analyzed. RESULTS: In the acute placebo-controlled studies, duloxetine-treated patients had a mean change of -0.5 kg compared with a change of 0.2 kg for placebo-treated patients (p < .001); no consistent relationship between duloxetine dose and weight change was observed. In placebo-controlled studies including an active comparator arm, similar acute mean weight changes were seen in duloxetine-treated and fluoxetine-treated patients (-0.7 kg vs. -0.6 kg) and in duloxetine-treated and paroxetine-treated patients (-0.3 kg vs. -0.2 kg). During longer-term treatment (34 weeks), mean weight change in patients treated with duloxetine 40 mg b.i.d. was not significantly different from that seen in placebo-treated patients (0.7 kg vs. 0.1 kg), while patients treated with the higher duloxetine dose of 60 mg b.i.d. or with paroxetine gained significantly (p ≤?.05) more weight than placebo-treated patients (0.9 kg, 1.0 kg, and 0.1 kg, respectively). In a 52-week open-label study, duloxetine-treated patients had a mean weight gain of 1.1 kg at endpoint (p < .001). CONCLUSION: Duloxetine-treated patients experienced weight loss after short-term treatment, followed by modest weight gain on longer-term treatment. The size of the weight changes observed suggests that the antidepressant duloxetine has minimal effects on weight for the majority of patients.