Two double-blind, randomized controlled trials investigated the efficacy and safety of duloxetine at 60 mg and 120 mg daily doses in patients with major depressive disorder (MDD). The first study focused on nonremitters and remitters after initial 6-week treatment, while the second study examined severely depressed hospitalized patients. In both trials, researchers found no significant clinical advantages of the 120 mg dose over the 60 mg dose. The first study revealed that nonremitters randomly reassigned to either 60 mg or 120 mg achieved similar remission rates (approximately 30%), with 85.5% of initial remitters maintaining their improvement. The second study, involving hospitalized patients with severe depression, demonstrated comparable outcomes across both dosage groups, with 67.3% of patients achieving remission by week 8. Adverse events were similar between groups, with minor variations such as increased hyperhidrosis and chest pain in the 120 mg group. Headache and nausea were the most frequently reported treatment-emergent adverse events. Both studies concluded that duloxetine was well-tolerated and showed comparable efficacy at 60 mg and 120 mg daily doses, suggesting that dose escalation may not necessarily provide substantial additional clinical benefits for most patients with major depressive disorder. [1], [2]
A 2014 study conducted across 47 sites in nine countries undertook a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of duloxetine in treating generalized anxiety disorder (GAD) among older adults aged 65 and above. The study employed a flexible-dose design, administering duloxetine at 30-120 mg once daily. The primary efficacy measure was the Hamilton Anxiety Rating Scale (HAM-A) total score, with a primary endpoint at the 10-week mark. Secondary outcomes included evaluations of global functioning with the Sheehan Disability Scale (SDS), along with analysis of treatment-emergent adverse events, serious adverse events, laboratory analyses, and vital sign monitoring to assess safety and tolerability. Over the course of the trial, 48 (31.8%) patients in the duloxetine arm did not receive a dose escalation, remaining on the 30 mg dose. A total of 52 (34.4%) patients had one escalation to 60 mg, while 36 (23.8%) had two escalations to 90 mg, and 15 (9.9%) had three escalations to 120 mg. According to the findings detailed in the 2014 publication, duloxetine showed superior efficacy compared to placebo, as evidenced by significant improvement in HAM-A scores (mean change of -15.9 vs. -11.7, p<0.001) and SDS global scores (-8.6 vs. -5.4, p<0.001). These improvements were apparent from as early as four weeks and persisted throughout the 10-week study period. The incidence of treatment-emergent adverse events, such as dry mouth, constipation, and somnolence, was significantly higher among duloxetine-treated patients, though the safety profile remained consistent with previous studies. The results underscore duloxetine's potential as an effective treatment for alleviating anxiety symptoms in older adults with GAD, with manageable safety concerns. [3]
A 2015 randomized, placebo-controlled trial evaluated duloxetine in children and adolescents aged 7 to 17 years with GAD. Participants were randomized to receive flexibly dosed duloxetine (30-120 mg daily, n= 135) or placebo (n= 137) for 10 weeks, followed by an 18-week open-label extension with duloxetine. The mean duloxetine dose during the acute phase was 53.6 mg. At the end of the 10-week period, the last prescribed dose for duloxetine patients was 30 mg in 27.4%, 60 mg in 30.4%, 90 mg in 29.6%, and 120 mg in 12.6% of the patients. The most frequently used (modal) dose was 30 mg in 35.6%, 60 mg in 34.8%, 90 mg in 20.7%, and 120 mg in 8.9% of patients. Adherence was higher in the placebo group at the 2-week time point (98% vs. 91%, p<0.05), but no differences in adherence were observed after that. Mean Pediatric Anxiety Rating Scale (PARS) severity scores improved by -9.7 points with duloxetine compared to -7.1 points with placebo (p≤.001; Cohen's d = 0.5). Response rates (defined as ≥50% improvement on PARS) were 59% for duloxetine and 42% for placebo. Remission rates (PARS ≤8) were 50% for duloxetine and 34% for placebo, and functional remission rates (CGAS >70) were 37% and 24%, respectively (all p≤.05). No significant differences were observed between groups in blood pressure changes or discontinuation due to adverse events. However, duloxetine was associated with a higher incidence of gastrointestinal-related adverse events, oropharyngeal pain, dizziness, cough, and palpitations. Mean increases in pulse (+6.5 vs. +2.0 beats/min) and changes in weight (-0.1 kg vs. +1.1 kg) were significantly different between groups (p≤.01). The findings suggested that duloxetine demonstrated greater improvement in anxiety symptoms, response, and remission rates compared to placebo, with a safety profile consistent with previous findings in pediatric and adult populations. [4]
A 2004 open-label, single-arm study evaluated the long-term efficacy and safety of duloxetine in patients aged 65 and older with MDD based on DSM-IV criteria. A total of 101 patients received duloxetine at doses of 80 mg/day (40 mg twice daily) to 120 mg/day (60 mg twice daily). All patients began treatment with duloxetine 40 mg twice daily during the first week. If a patient could not tolerate this dose, it could be temporarily reduced to 20 mg twice daily, but they were required to return to 40 mg twice daily by Week 2. Patients who still could not tolerate 40 mg twice daily were withdrawn from the study. After the initial two weeks, dosing could be adjusted between 40 mg and 60 mg twice daily based on the physician’s assessment of the patient’s response and tolerability. Results showed significant reductions in mean the 17-item Hamilton Rating Scale for Depression (HAMD17) total scores from baseline to Weeks 6, 28, and 52 (-13.0, -17.4, and -17.5, respectively; all p<0.001). The the Clinical Global Impression of Severity (CGI-S) and patient-rated (PGI-I) assessments demonstrated significant improvement by Week 1, which was sustained through the end of the study. Observed case response rates were 62.9% at Week 6, 84.9% at Week 28, and 89.4% at Week 52. Remission rates at the same time points were 41.4%, 69.8%, and 72.3%, respectively. Adverse events led to treatment discontinuation in 26.7% (27 patients). Treatment-emergent adverse events reported by more than 10% of patients included dizziness, nausea, constipation, somnolence, insomnia, dry mouth, and diarrhea, most of which occurred early in treatment. Mean changes in blood pressure and body weight at study endpoint were minimal (less than 2.0 mm Hg and -0.1 kg, respectively). Overall, the study found duloxetine to be effective, safe, and well tolerated for long-term treatment of MDD in elderly patients. [5]
A 2012 open-label investigation explored the safety, tolerability, and pharmacokinetics of duloxetine in pediatric patients suffering from MDD. This study involved 72 children and adolescents aged 7 to 17 years, who were treated with a flexible dosing regimen of duloxetine ranging from 20 to 120 mg once daily. The dosage adjustments were made based on clinical improvements and individual patient tolerability. Pharmacokinetic samples were obtained intermittently across the dosing range, and the data were analyzed using population modeling techniques. Results showed that the majority of patients required doses of 60 mg or higher to achieve optimal efficacy, and the typical clearance of duloxetine in this younger cohort was notably higher than that observed in adults. An insightful discovery from this research highlights that pediatric patients generally tolerated duloxetine well within the studied dose range, although many experienced transient, potentially clinically significant elevations in blood pressure. Notably, adjustments in the daily dosage of duloxetine based on body weight or age were deemed unnecessary, suggesting that pediatric patients may not require different dosages relative to adults. The pharmacokinetic analysis revealed that factors such as age and body weight did not significantly affect duloxetine’s pharmacokinetic parameters, indicating that duloxetine’s pharmacokinetic profile is consistent across these subgroups. This foundational study provides crucial insights into the pediatric use of duloxetine for MDD, setting the stage for further extensive, controlled trials to confirm these findings and refine dosing regimens. [6]
Lastly, a 2014 double-blind study evaluated the efficacy and safety of flexible-dose duloxetine in children and adolescents with major depressive disorder over a 36-week period, including a 10-week acute phase and 26-week extension. A total of 337 patients were randomized to receive duloxetine (60-120 mg once daily, n= 117), fluoxetine (20-40 mg once daily, n= 117), or placebo (n= 103). Patients initiated duloxetine at 30 mg or fluoxetine at 10 mg daily, with automatic escalation to duloxetine 60 mg or fluoxetine 20 mg at Week 2. Duloxetine could be increased to 90 mg at Week 4 and 120 mg at Week 7 or later; fluoxetine could be increased to 40 mg at Week 4 or later. Placebo patients were transitioned to duloxetine at the start of the extension period, beginning at 30 mg daily with automatic escalation and flexible dosing thereafter. Neither duloxetine nor fluoxetine separated significantly from placebo on the primary efficacy endpoint: change in Children’s Depression Rating Scale-Revised (CDRS-R) total score from baseline to Week 10 (p<0.05). There were no statistically significant differences between treatment groups in serious adverse events, total treatment-emergent adverse events, or discontinuations due to AEs during the acute phase. No completed suicides, deaths, or clinically significant ECG abnormalities were observed. The trial results were deemed inconclusive, as neither active treatment demonstrated a statistically significant advantage over placebo at 10 weeks; however, the safety profile of duloxetine was consistent with that seen in adults, with no new safety concerns identified. [7]