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Background: Duloxetine is approved for the treatment of generalized anxiety disorder (GAD) in the United States and elsewhere. This study aimed to assess the efficacy, tolerability, and safety of duloxetine in Chinese patients with GAD., Methods: This 9-site study consisted of double-blind treatment for 15 weeks either with duloxetine 60 - 120 mg or with placebo. Patients with at least moderately severe GAD and a Sheehan Disability Scale (SDS) global functioning impairment total score ≥ 12 were included in this study. Patients who were randomly assigned to duloxetine received 60 mg for 7 weeks; at that point, for nonresponders the dose was increased to 120 mg for the remaining 8 weeks. The primary efficacy measure was mean change from baseline to endpoint on the Hospital Anxiety and Depression Scale-Anxiety subscale score (HADS-A). Secondary efficacy measures included the Hamilton Anxiety Rating Scale (HAMA), the SDS, and pain measures. Safety and tolerability were assessed., Results: Baseline characteristics did not differ significantly between treatment groups. Mean age of the subjects (n = 210) was 37.6 years, 50.5% were female, and 74.3% completed the 15 weeks treatment. Patients treated with duloxetine had significantly greater improvement compared to placebo on the HADS-A (mean change -6.6 vs. -4.9, respectively, P = 0.022). Improvement in anxiety was greater with duloxetine treatment at 7 weeks and continued through 15 weeks for both the HADS-A and the HAMA total score (0.01 ≤ P < 0.05). Compared with placebo, duloxetine was also associated with greater improvement on most secondary measures, but not on the SDS global functioning score. Nausea, dizziness, and somnolence occurred significantly more frequently as treatment-emergent adverse events with duloxetine treatment compared with placebo treatment., Conclusions: Duloxetine 60 - 120 mg once daily is effective and well-tolerated for the treatment of patients with GAD in China.

Objective: To assess whether hospitalized patients with severe depression and potential suicidal ideation/behavior have earlier and better response to duloxetine 120 mg daily than 60 mg daily., Method: Adults from 34 sites in 4 countries with severe major depressive disorder, defined by DSM-IV criteria, who were demonstrating Montgomery-Asberg Depression Rating Scale (MADRS) scores ≥ 30, 6-item Hamilton Depression Rating Scale (HDRS-6) scores ≥ 12, and Clinical Global Impressions-Severity of Illness scale (CGI-S) ≥ 4 and hospitalized ≥ 2 weeks underwent double-blind treatment with either duloxetine 60 mg (n = 167) or 120 mg (n = 171) daily for 8 weeks. Patients treated with 60 mg/d who did not respond had their doses titrated up to 120 mg/d. Primary outcome was the difference in baseline to week 4 change in MADRS scores between the groups. Secondary outcomes were baseline to week 8 changes in MADRS and HDRS-6 scores, response and remission, CGI-S scores, CGI-Improvement scores, Patient Global Impressions-Improvement, Hamilton Anxiety Rating Scale scores, and Reasons For Living inventory results. Safety was also assessed. The study was conducted between February 9, 2007, and August 26, 2008., Results: There was no significant difference in mean baseline to week 4 MADRS score change between the 60-mg (-20.1) and 120-mg (-19.9) groups (P = .88). At week 4, 96/166 (60 mg) and 106/170 (120 mg) patients responded and maintained responses at week 8 by further decreasing mean MADRS scores to 5.8 (60 mg) and 5.6 (120 mg). At week 8, 226/336 (67.3%) patients achieved remission, with no difference demonstrated between groups. Most secondary efficacy measures were significantly reduced from baseline to week 8 within each group and did not differ between groups. Treatment-emergent adverse events observed with > 10% frequency in both groups were headache and nausea., Conclusions: Duloxetine 60-mg and 120-mg doses were equally effective and demonstrated no significant differences in treating severe depressive symptoms in hospitalized patients. The safety and tolerability profile of duloxetine in both dosages did not differ and was similar to those reported in previous duloxetine studies., Trial Registration: clinicaltrials.gov Identifier: NCT00422162., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

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.

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.

Most antidepressants in clinical use are believed to function by enhancing neurotransmission of serotonin [5-hydroxytryptamine (5-HT)] and/or norepinephrine (NE) via inhibition of neurotransmitter reuptake. Agents that affect reuptake of both 5-HT and NE (serotonin-norepinephrine reuptake inhibitors) have been postulated to offer greater efficacy for the treatment of major depressive disorder (MDD). These dual-acting agents also display a broader spectrum of action, including efficacy for MDD and associated painful physical symptoms, diabetic peripheral neuropathic pain, generalized anxiety disorder, and fibromyalgia syndrome. Substantial preclinical evidence shows that duloxetine, an approved drug for the treatment of MDD, generalized anxiety disorder, and the management of diabetic peripheral neuropathic pain, inhibits reuptake of both 5-HT and NE. This paper reviews clinical and neurochemical evidence of duloxetine's effects on 5-HT and NE reuptake inhibition. The clinical evidence supporting duloxetine's effects on NE reuptake inhibition includes indirect measures such as altered excretion of NE metabolites, cardiovascular effects, and treatment-emergent adverse event profiles similar to those for other drugs believed to act through the inhibition of NE reuptake. In summary, the data presented in this report provide clinical evidence of a mechanism for duloxetine involving both 5-HT and NE reuptake inhibition in humans and are consistent with preclinical evidence for 5-HT/NE reuptake inhibition.

Objective: To compare the safety and tolerability profile of duloxetine versus placebo in elderly (> or = 65 years) patients with major depressive disorder (MDD)., Methods: Patients were randomized (2:1) to duloxetine 60 mg/d (once daily) (n = 207) or placebo (n = 104) for 8 weeks. Safety and tolerability measures were analyzed in the total cohort of patients, as well as in subgroups defined by age and preexisting hypertension., Results: Patients had a median age of 72 years (65-90 years). No deaths occurred in the study. Discontinuation rates due to adverse events were similar for duloxetine and placebo (9.7% vs 8.7%). Treatment-emergent dry mouth, nausea, and diarrhea occurred significantly (P < or = 0.05) more frequently with duloxetine compared with placebo. Changes in supine and standing blood pressure (BP) and pulse and in corrected QT (QTc) interval were not significantly different between duloxetine and placebo, except for change in orthostatic systolic BP (-2.45 vs 0.93 mm Hg; P = .017). Incidences of sustained elevation in BP and treatment-emergent orthostatic hypotension were similar for duloxetine compared with placebo (0.5% vs 1.0% and 15.6% vs 20.5%, respectively). The duloxetine group showed significant weight loss compared with the placebo group (-0.73 kg vs -0.13 kg; P = 0.009). Of 5 hepatic analytes, the only significant difference was an increase in alkaline phosphatase in duloxetine compared with placebo (P = 0.017); this difference was not considered clinically relevant. The incidence of 1 or more discontinuation-emergent adverse events was not significantly different between the duloxetine and placebo groups (17.3% vs 11.3%)., Conclusions: This study suggests that duloxetine is safe and well tolerated in elderly patients with major depressive disorder.

Objective: Experience of pain in major depressive disorder (MDD) can complicate diagnosis and impair treatment outcomes. This study evaluated the efficacy and safety of duloxetine in the treatment of patients with moderate pain associated with depression., Method: In this double-blind, placebo-controlled, 8-week study, conducted from May 2005 to May 2006, outpatients 18 years of age or older, presenting with major depressive disorder (DSM-IV criteria; Montgomery-Asberg Depression Rating Scale [MADRS] score >or= 20), moderate pain (Brief Pain Inventory-Short Form [BPI-SF] average pain score >or= 3), and Clinical Global Impressions-Severity of Illness scale (CGI-S) score >or= 4 were randomly assigned to either placebo (N = 165) or duloxetine 60 mg (N = 162) once daily. Primary outcome was change in item 5 score (average pain in the last 24 hours) of the BPI-SF from baseline. Secondary measures were MADRS total score, other BPI-SF items, CGI-S, CGI-Improvement scale, Patient Global Impressions-Improvement scale, Symptom Checklist-90-Revised, response and remission rates, safety, and tolerability., Results: Duloxetine, compared with placebo, significantly reduced pain and improved depression with significant mean changes at endpoint in both BPI-SF average pain scores (-2.57 vs. -1.64, p < .001) and in MADRS total scores (-16.69 vs. -11.31, p < .001). Remission of MDD and response rates in pain and MDD were significantly (p or= 10%) in duloxetine-treated patients were nausea, hyperhidrosis, and dry mouth., Conclusion: These results support duloxetine's efficacy and tolerability in the treatment of pain and depression in patients with at least moderate pain associated with depression., Trial Registration: ClinicalTrials.gov identifier NCT00191919 (http://www.clinicaltrials.gov).

Objective: At effective doses, patients with major depressive disorder (MDD) treated with duloxetine have been found to experience significant symptom improvement as measured by HAMD(17) total score. In addition, duloxetine-treated patients have significantly higher remission and response rates compared with placebo. The objective of this analysis is to determine the optimal dose of duloxetine in MDD., Materials and Methods: Effect size for duloxetine 40mg, 60mg, 80mg, and 120mg per day were estimated using all 6 acute phase III clinical trials in patients with MDD. The tolerability of duloxetine 40mg, 60mg, 80mg, and 120mg were evaluated using pooled data from the 6 studies. The primary efficacy measure in all trials was the HAMD(17) total score, from which were determined the effect size for HAMD(17) change scores, response rates (50% reduction from baseline to endpoint), and remission rates (HAMD(17) total score < or =7)., Results: A total of 1619 randomized patients were included in these studies, of which 632 were treated with placebo; 177 with duloxetine 40mg/day; 251 with 60mg/day; 363 with 80mg/day; and 196 with 120mg/day. An evaluation of increments in effect size between doses consistently showed that the most notable gain in effect size for efficacy was the 40-60mg/day dosage range. All dosages from 60 to 120mg were effective. The tolerability assessment indicated duloxetine at 40-120mg/day is well tolerated. Furthermore, the initial doses of 40-80mg/day were found to have comparable tolerability., Conclusions: The effect size analyses demonstrate that duloxetine 40mg has minimum efficacy, and that duloxetine 60-120mg/day is effective in the treatment of patients with MDD. An initial dose less than 60mg/day might provide better tolerability for some patients diagnosed with MDD.

Background: The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential., Methods: Electrocardiograms were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy female subjects aged 19 to 74 years. Duloxetine dosages escalated from 60 mg twice daily to 200 mg twice daily; a single moxifloxacin 400 mg dose was used as a positive control. Data were analyzed using 3 QT interval correction methods: mixed-effect analysis of covariance model with RR interval change from baseline as the covariate, the QT Fridericia's correction method, and the individual QT correction method. Concentrations of duloxetine and its 2 major metabolites were measured., Results: Compared with placebo, the mean change from baseline in QTc decreased with duloxetine 200 mg twice daily. The upper limits of the 2-sided 90% confidence intervals for duloxetine vs. placebo were <0 msec at each time point by any correction method. No subject had absolute QT Fridericia's correction values >445 msec with duloxetine, and the change in QT Fridericia's correction from baseline with duloxetine did not exceed 36 msec. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites even though average duloxetine concentrations ranged to more than 5 times those achieved at therapeutic doses. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method., Conclusions: Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.

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.

The efficacy of an antidepressant typically is assessed by comparing it with placebo using a validated rating scale. This type of analysis, however, does not translate well to the clinical settings. For clinicians, a more meaningful measure is the number needed to treat (NNT). The objective of this analysis is to assess the efficacy of duloxetine in terms of NNT. Data were obtained from nine clinical trials designed to assess the efficacy and safety of duloxetine as a treatment for major depressive disorder. These studies examined 8-9 weeks of acute treatment with duloxetine. NNT estimates were determined for duloxetine, selective serotonin reuptake inhibitor comparators from six multi-dose studies, and for duloxetine in patients > or =65 years of age. The NNT was based on the Hamilton Depression Rating Scale (HAMD17) for response and remission, and improvements defined by the Clinical Global Impression (CGI) were estimated and compared. The NNT was favorable for both duloxetine and selective serotonin reuptake inhibitor compared with placebo. The patients receiving duloxetine had NNT for HAMD17 response of 6.0, remission 7-9, and CGI-defined improvement 6-7 by 8 weeks. The NNTs for selective serotonin reuptake inhibitors (fluoxetine or paroxetine, 20 mg/day) were around 7 for response, 11 for remission, and 8 for CGI-defined improvement. The NNTs in the elderly were similar. The NNT for several measures of efficacy including remission consistently demonstrated the treatment benefits of duloxetine as well as of fluoxetine and paroxetine compared with placebo.

Background: Discontinuation symptoms are common following antidepressant treatment. This report characterizes symptoms following duloxetine discontinuation., Methods: Data were obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder (MDD)., Results: In a pooled analysis of 6 short-term treatment trials, in which treatment was stopped abruptly, discontinuation-emergent adverse events (DEAEs) were reported by 44.3% and 22.9% of duloxetine- and placebo-treated patients, respectively (p<0.05). Among duloxetine-treated patients reporting at least 1 DEAE, the mean number of symptoms was 2.4. DEAEs reported significantly more frequently on abrupt discontinuation of duloxetine compared with placebo were dizziness (12.4%), nausea (5.9%), headache (5.3%), paresthesia (2.9%), vomiting (2.4%), irritability (2.4%), and nightmares (2.0%). Dizziness was also the most frequently reported DEAE in the analyses of 3 long-term duloxetine studies. Across the short- and long-term data sets, 45.1% of DEAEs had resolved in the duloxetine-treated populations by the end of the respective studies, and the majority of these (65.0%) resolved within 7 days. Most patients rated the severity of their symptoms as mild or moderate. A higher proportion of patients reporting DEAEs were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one DEAE differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of DEAEs., Conclusions: Abrupt discontinuation of duloxetine is associated with a DEAE profile similar to that seen with other selective serotonin reuptake inhibitor (SSRI) and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressants. It is recommended that, whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment., Limitations: The main limitation is the use of spontaneously reported DEAEs.