A patient’s dose could be decreased to 30 mg/day of duloxetine if they were unable to tolerate the starting dose. All patients who remained in the study were gradually increased to their randomly assigned dose over a two week period. The patients in the duloxetine groups were randomly assigned to either abrupt discontinuation or gradual (2 week) taper at the end of the study.3 The results of the first study yielded a statistically signiﬁcant (p 0.001) improvement in HAM-A scores with duloxetine when compared to placebo (see Table 1). At 60 mg/day of duloxetine the mean decrease in HAM-A score was 12.8 compared with only 8.4 for placebo. At 120 mg/day the mean decrease in HAM-A score was 12.5.3 Response was deﬁned as 50% reduction in HAM-A at treatment endpoint. Sustained improvement was deﬁned as a 30% reduction in HAM-A that was sustained at all subsequent visits. Remission was deﬁned as a HAMA total score 7 at completion of the study.3 Duloxetine demonstrated response rates of 58% at 60 mg/day and 56% at 120 mg/day compared to 31%, for placebo (p 0.001). Remission rates were 31% at 60 mg/day and 38% at 120 mg/day compared with 19% for placebo (p 0.01 and p 0.001 respectively). Sustained improvement rates were 63.6% at 60 mg/day and 66.9% at 120 mg/day compared with 42.8% for placebo (p 0.001). Further, both duloxetine groups had greater improvements in Sheehan Disability Scale global scores (p 0.001), HAM-A psychic factor (p 0.001), and HAM-A somatic factor scores (p 0.01).3 Effect on overall disability will be discussed in more detail later. The second and third studies were ﬂexible-dose trials, also using mean change in HAM-A score to assess efﬁcacy.13,14 The third study also provided a comparison to venlafaxine XR.13,14 The second study was a 10 week multi-center, double-blind, placebo-controlled trial. The study randomized 327 patients meeting DSM-IV-TR criteria for GAD to a duloxetine treatment group or to placebo (Table 1). The duloxetine arm received 60–120 mg of duloxetine with progressive titration and ﬂexible Table 1 Efﬁcacy studies of duloxetine in the treatment of GAD Study Number Average Gender Study length of subjects age Koponen et al3 513 43.8 67% ♀ 9 week Rynn et al13 327 41.6 61.7% ♀ 10 week Hartford et al14 487a 40.4b 64.2%b ♀ 10 week Duloxetine for GAD dosing.13 The study involved 27 outpatient treatment centers. Patients were screened using the same CGI-Severity of Illness and HAD criteria as the ﬁrst study. Patients were also required to score at least a 4 on the Covi Anxiety Scale.13 Exclusion criteria were essentially the same as the ﬁrst study with 188 patients failing to meet the entry criteria.13 The study was single-blinded for the ﬁrst week with all patients receiving placebo. Starting in week 2, the study was double-blind and patients were randomly assigned to receive 60 mg per day of duloxetine or placebo. Study visits were held at 1,2,4,7 and 10 weeks. A dosage decrease from 60 mg to 30 mg per day was allowed in the ﬁrst 2 weeks, with all patients in the duloxetine arm required to take the 60 mg dose by the end of the second week. The dose of duloxetine was increased if a patient’s CGI score was 3. The maximum dose was 120 mg/day. 62% of the original sample completed the ten week therapy.13 The third study utilized the same inclusion and exclusion criteria as the second study. Besides that, third study also excluded patients meeting criteria for any Axis II disorder or having history of antisocial behavior. In the third study patients were randomized to duloxetine (n = 162), venlafaxine (n = 164), or placebo groups (n = 161) (Table 1). Duloxetine was started at a dose of 30 mg per day for 1 week and was then increased to a range of 60 to 120 mg per day thereafter. The dosage increases for duloxetine followed the same algorithm as the second study following the second week of treatment, with a maximum dosage of 120 mg per day.14 Venlafaxine was utilized in the XR formulation and was started at 37.5 mg per day and increased to a dosage range of 75 to 225 mg per day. According to Eli Lilly the study was not “powered to compare efﬁcacy between Cymbalta and Effexor XR.”8 Eli Lilly states that data from another study will be pooled with data from this study to provide a more statistically powerful head-to-head comparison of duloxetine and venlafaxine XR.8 Results of both study 2 and study 3 showed a statistically signiﬁcant decrease in HAM-A scores for the duloxetine Design Dosing Change in HAM-A Placebo-controlled Placebo-controlled Placebo-controlled Fixed Flexible Flexible ↓12.8 (60 mg/day) ↓8.12 ↓11.8 Statistical signiﬁcance p 0.001 p = 0.023 p 0.001 aduloxetine efﬁcacy study with venlafaxine XR comparator arm [duloxetine (n = 162), venlafaxine (n = 164), and placebo groups (n = 161)] bduloxetine group. Neuropsychiatric Disease and Treatment 2009:5 27