Duloxetine generic Versus Placebo in Preventing Relapse of Major Depressive Disorder

Author: Michael J. Detke, MD, PhD, Indiana University School of Medicine, Indianapolis, and Medical Director for Cymbalta, Lilly Research Laboratories

It has been well established for more than a decade that major depressive disorder (MDD) is characterized by several distinct stages:

• an acute phase for 12 weeks, followed by remission after treatment
• a continuation phase of four to nine months, during which time relapses sometimes occur
• a maintenance phase of a year or more, with a potential for recurrence

Studies have revealed relapse rates between 7% and 26% (usually about 20%) with antidepressants, compared with rates of 19% to 56% (usually, 40%^50%) with placebo. Although most experts agree that the treatment of depression should continue for four to six months or up to a year after acute recovery, there have been few controlled data to define the treatment period.

In one open-label study of fluoxetine canadian (Prozac generic, Eli Lilly) treatment for 14, 38, or 50 weeks, the rate of relapse at 14 weeks was significantly reduced (26%), compared with a rate of 49% for placebo. The rate of relapse after 38 weeks of treatment was 9%, compared with a rate of 23% for placebo. At 50 weeks, the reduction rates (11% for treated patients vs. 16% for placebo patients) were not significant, suggesting the need for at least six weeks of continuation therapy after a period of acute (short-term) treatment of roughly 12 weeks.

On the basis of these findings, the present study was designed to determine whether canadian duloxetine HCl (DLX, Cymbalta drug, Eli Lilly), at a starting dose of 60 mg once a day, would be effective in preventing relapse of depressive symptoms in patients who had previously responded to the drug. DLX is an inhibitor of both serotonin and norepinephrine uptake and has demonstrated efficacy in MDD in six short-term studies (of eight to nine weeks’ duration).

The present trial enrolled 553 patients. Patients received open-label DLX 60 mg once daily for 12 weeks. Thereafter, the responders (n = 278) were randomly selected to continue therapy for 26 weeks with either DLX or placebo in a double-blind study. The mean age of the responders was 45 years; two-thirds of the patients in the DLX group were women, and three-quarters of the patients in the placebo group were women. Patients experiencing relapse were entered into a “rescue” phase (12 weeks), with some (n = 29) assigned to receive a doubled dose of DLX at 60 mg twice a day.

Participants met the DSM-IV criteria for MDD, as assessed by the modified Mini International Neuropsychiatric Interview (MINI) and the 17-item Hamilton Psychiatric Rating Scale for Depression (HAM-D17), for a total score of 18 or greater and a Clinical Global Impressions-Severity (CGI-S) score of 4 or more at visits 1 and 2.

Responders were defined by a HAM-D17 score of 9 or below, by a CGI-S score of 2 or less, and by no longer meeting the criteria for MDD at weeks 10 and 12.
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Relapse was defined by an increase in the CGI-S score of 2 points or more, as compared with the scores at week 12, for two consecutive visits in addition to meeting MINI depression module MDD criteria. Because the effects of DLX on both serotonin and norepinephrine have been known to be beneficial for pain, investigators assessed pain through a 100-point Visual Analogue Scale (VAS).

In the continuation phase, the HAM-D17 total scores increased significantly (P< .05) within a week of randomization for the placebo group and remained elevated through 38 weeks. A slight increase in HAM-D17 scores in the DLX group immediately after randomization might be attributed to the patients’ awareness of the possibility that they were not receiving active treatment. Relapse rates significantly favored DLX (17.4% of treated patients vs. 28.5% of placebo patients; P < .05) by protocol-defined criteria. When relapse was evaluated by investigators, the differences were more pronounced (21.9% vs. 43.1°%; P < .001).

Among 56 patients in “rescue” treatment at 60 mg once daily, 77% responded (a 50% reduction or more in HAM-D17 scores) and 57% experienced remission (defined as a HAM-D17 score of 7 or below). Among 29 patients receiving 60 mg twice daily, 62% responded and 38% experienced remission.

Overall, DLX decreases were consistent for all HAM-D17 components and for seven of eight VAS components. Adverse drug events (ADEs) were similar to those found with other selective serotonin reuptake inhibitors (SSRIs), with the addition of some dry mouth, constipation, and sweating, consistent with the norepinephrine component of DLX. Similarly, an increase in the heart rate of approximately 1.5 beats per minute is attributable to norepinephrine reuptake inhibition. canadian antibiotics

The investigators concluded that DLX 60 mg once daily was effective in preventing relapse of MDD in patients who responded to short-term therapy. The safety and tolerability profile of DLX is similar to that of the most widely prescribed “modern” antidepressants. A “dose-doubling” strategy is effective, safe, and tolerable for most patients experiencing MDD relapse.