Duloxetine in the Treatment of Major Depressive Safety DISCUSSION

The current analysis describes efficacy and safety data from depressed African-American patients (n=128) who participated in seven clinical trials of duloxetine 30 mg/day of up to nine weeks duration. Comparisons of treatment effects in these African-American patients with those observed in Caucasian patients (n=1342) found no compelling evidence of differential efficacy or safety profiles between the two ethnic groups. Treatment-by-ethnicity interactions were not significant for any of the three assessed efficacy measures (HAMD17 total score, CGI-S, PGI-I), although these tests likely lacked power and thus do not constitute definitive evidence of equivalent efficacy in the two ethnic groups The rate of discontinuation due to adverse events (13.0%) vs. 17.0% for African Americans and Caucasians, respectively) and the incidence and pattern of treatment-emergent adverse events were similar in African-American and Caucasian patient groups. In addition, treatment-by-ethnicity interactions for mean change in blood pressure, heart rate and body weight were not statistically significant, although the lack of power for these tests should again be noted. Collectively, however, these results suggest that the efficacy and safety profiles of acute phase generic duloxetine treatment in African-American patients are similar to those observed in Caucasian patients. Additional studies will be required to extend the current results to longer-term treatment of MDD.

It has been reported that depressed African-American patients are more likely to present with somatic symptoms compared with white patients. In one study, depressed African-American patients reported significantly greater baseline impairment in physical functioning on the MOS Physical Component Scale when compared with whites. However, in a separate study, depressed African-American patients exhibited significantly lower baseline pain severity compared with whites (as assessed using the MOS SF-36 bodily pain scale). Furthermore, in a study of patients with a range of pain complaints (including myofascial pain, low back pain and headache), African Americans reported significantly higher levels of pain unpleasantness and emotional response to pain compared with whites but reported that levels of pain intensity did not differ significantly between the two ethnic groups. In the present study, baseline severity of painful physical symptoms (as assessed using the self-rated VAS measure of overall pain) did not differ significantly between African-American and Caucasian patients. However, the number of painful symptoms was not assessed. In addition, the small number of African Americans within the focus studies precluded a detailed comparison of VAS outcomes in Caucasian and African-American patients.

In the two focus studies (once-daily 60 mg dosing with duloxetine), African-American patients receiving duloxetine demonstrated a significant advantage over placebo on the HAMDn core and Maier sub-scales. The magnitude of improvement among duloxetine-treated African-American patients in HAMDn total score, CGI-S, PGI-I and QLDS scales was at least as large as that observed in Caucasian patients. However, in the small group of African-American patients, the advantages over placebo did not reach statistical significance. The remission rate for African-American patients receiving cymbalta 30 mg QD (44%) was comparable to the remission rates observed in the overall study population in the two focus studies, although the advantage over placebo did not achieve statistical significance in the small group of African-American patients.

African Americans have been reported to have higher rates of “premature termination” and shorter durations of treatment than whites in routine practice settings, and in one eight-month study of nortriptyline, only 16% of African-American patients completed the full protocol of pharmacotherapy. However, results from the present study suggest that the tolerability of duloxetine among African-American patients does not differ substantially from that in Caucasian patients. The discontinuation rate due to adverse events among African-American patients (13%) was somewhat lower than that observed in Caucasians (17%), while the rate of discontinuation for any reason did not differ between the two ethnic groups. It has also been suggested that African Americans may experience more severe side effects during antidepressant medication therapy. In one study of nortriptyline therapy, the mean score of African-American patients on the Side Effects Scale was significantly higher than that of whites at earlier visits, but not at the study endpoint (eight months). Treatment-emergent adverse events most frequently reported by African-American patients during the present study were nausea, headache, insomnia, dizziness and constipation. This adverse event profile was very similar to that reported by Caucasian patients. Furthermore, of those events occurring in >1 duloxetine-treated African-American patient, none occurred at a rate significantly higher than that in Caucasian patients.

Mean baseline-to-endpoint changes in blood pressure and heart rate in both African-American and Caucasian patients were small (<2.5 mmHg and <1.5 bpm, respectively) and were not considered to be clinically relevant. Treatment-by-ethnicity interactions were not statistically significant for any cardiovascular assessment (mean change or incidence of abnormal values). The small mean increase in heart rate may be associated with the pharmacological mechanism of action of duloxetine medication, involving reuptake inhibition of both 5-HT and NE.

Mean baseline-to-endpoint changes in body weight for African-American and Caucasian patients reflected a small weight loss (ca. 0.5 kg) during the acute treatment period (8-9 weeks) and are consistent with observations from other acute-phase, placebo-controlled studies of duloxetine. Data from a long-term, open-label study of duloxetine revealed a similar degree of weight loss in the first few weeks of duloxetine treatment, followed by a return to baseline values and subsequently a net weight gain (1.1 kg) after 52 weeks of therapy.

A number of limitations should be considered when interpreting results from this study. First, although the comparison of ethnic subgroups was specified a priori in each study protocol, the specific pooling strategies and analyses conducted herein were not defined prior to unblinding of the data. Therefore, the current findings should be viewed as the result of post hoc analyses and interpreted with an appropriate degree of caution. Secondly, the ratio of sample sizes in the African-American and Caucasian cohorts was approximately 1:10. This likely limited the power to detect differential effects via significant ethnicity-by-treatment interactions. In addition, the sample size within the two focus studies was very small (<20 duloxetine-treated African-American patients). The lack of power in these analyses limits the conclusions that may be drawn from the study, and the results described here should be viewed as preliminary findings, rather than definitive evidence, of similar safety and efficacy between the two groups. Third, the ethnic descriptions utilized on the CRF were rather generalized, and no attempt was made to strictly categorize race.

In summary, no convincing evidence was found to suggest that the overall safety and tolerability profile or the efficacy profile for duloxetine in this cohort of African-American patients differed from that observed in a comparator group of Caucasian patients. The results from these analyses provide supportive evidence for the efficacy and safety of generic cymbalta in the treatment of MDD in African-American patients.

Category: Depression / Tags: antidepressant, Depression, duloxetine

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