Background and Objectives: Antidepressants are often used to treat chronic daily headache disorders suchas transformed migraine, in part because of the high prevalence of associated mood disorder. We conducted thisstudy to evaluate the efficacy and tolerability of combined treatment with amitriptyline and fluoxetine comparedwith amitriptyline alone for chronic daily headache due to transformed migraine. Patients and Methods: Thirty-nine patients, 26 women and 13 men, aged 20 to 69 years (mean, 36.4; SD, 2.5)who fulfilled criteria for transformed migraine proposed by Silberstein et al were studied prospectively. Amitrip-tyline was dosed as follows: 8 mg/day for 6 days, 8 mg twice a day for 6 days, 20 mg/day for 6 days, and 20 mg twicea day for 45 days. In the group receiving combination therapy, fluoxetine was dosed and administered identically. The initial and end of the study (9 weeks) headache indices (frequency x intensity) were compared betweengroups. Results: Twenty-seven patients completed the study, 13 in the amitriptyline-alone group (group 1) and 14 inthe combination-therapy group (group 2). The most frequent adverse event in both groups was dry mouth, andthere was no significant difference in the occurrence of this or other adverse events between the two groups. Ini-tial headache indices were similar for groups 1 and 2. The mean difference between the initial and final headacheindex for group 1 was 513.5 (P<.0005) and 893 (P<.0017) for group 2. The difference between the final headacheindex for the two groups was not significant (P>.207).Conclusions: We were unable to demonstrate any significant benefit from amitriptyline plus fluoxetine overamitriptyline alone in the treatment of chronic daily headache/transformed migraine. Because of the small num-ber of subjects involved and the short duration of our study, a type II error cannot be excluded.