A comparison of initial duloxetine dosing strategies in patients with major depressive disorder.

OBJECTIVE: To compare the effects of starting doses of duloxetine taken with or without food on tolerability and efficacy in patients with major depressive disorder (MDD). METHOD: This double-blind, concurrent-dose-controlled, parallel-design trial contained a variable expected-duration placebo lead-in period and was conducted in adult outpatients with DSM-IV-TR-defined MDD at psychiatric outpatient sites between October 2004 and January 2006. In actuality, patients received placebo for 1 week and then were randomly assigned to duloxetine 30 mg once daily in the morning (q.a.m.) (N = 219), 30 mg twice daily (b.i.d.) (N = 213), or 60 mg q.a.m. (N = 215) for 1 week along with 1 of 2 instructions about food: take study drug with food or do not take within 1 hour of eating. For the remaining 5 weeks of acute treatment, all patients received 60 mg once daily. The primary objective was to compare incidence of treatment-emergent nausea at 30 mg q.a.m. versus 60 mg q.a.m. using item 112 (nausea) of the Association for Methodology and Documentation in Psychiatry adverse event scale (AMDP-5). Secondary outcome measures included mean change on AMDP-5 item 112, discontinuations due to adverse events, mean changes in AMDP-5 items and subscales, spontaneously reported treatment-emergent adverse events, and vital signs. Efficacy was evaluated by the 17-item Hamilton Rating Scale for Depression (HAM-D-17). RESULTS: The primary analysis, which combined data from both food groups, showed no significant difference in the incidence of nausea between starting doses of 30 mg q.a.m. and 60 mg q.a.m. (23% vs. 29%, respectively; p = .207). However, mean changes on the AMDP-5 nausea item revealed a significant main effect of food (p = .010) and a significant interaction between food and starting dose (p = .033). The food-by-dose interaction indicated that the benefit from taking drug with food was greatest in patients started at 60 mg q.a.m., and the benefit of starting at 30 mg q.a.m. was greatest in patients taking drug without food. In patients who took study drug without food, there was a significant difference across initial-dose groups for discontinuation due to adverse events (30 mg q.a.m. = 3.6%, 30 mg b.i.d. = 14.0%, 60 mg q.a.m. = 10.2%; 30 mg q.a.m. vs. 30 mg b.i.d., p = .008; 30 mg q.a.m. vs. 60 mg q.a.m., p = .066); however, in patients who took study drug with food, discontinuations due to adverse events did not significantly differ (30 mg q.a.m. = 5.4%, 30 mg b.i.d. = 7.5%, 60 mg q.a.m. = 7.4%; all p values > .50). Patients who started at 30 mg b.i.d. or 60 mg q.a.m. without food did not differ regarding mean changes (i.e., increases) in the common adverse events score after 1 week of treatment but had significantly greater mean changes than patients who started at 30 mg q.a.m. without food (0.87, 0.82, and 0, respectively; p < .05 vs. 30 mg b.i.d. and 60 mg q.a.m.). No significant differences were found between initial-dose groups in vital signs. CONCLUSIONS: These data imply that starting dulox-etine at 30 mg q.a.m. for 1 week with or without food or starting duloxetine at the therapeutic dose of 60 mg q.a.m. with food can improve the initial tolerability of the medication. Adding this information to existing knowledge of duloxetine will enable the clinician to tailor therapy most appropriately for the individual patient. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT 00191061.