Augmentation of fluoxetine's antidepressant action by pindolol: Analysis of clinical, pharmacokinetic, and methodologic factors

In a controlled trial, the beta -adrenoceptor/5-hydroxytryptamine-1A (5-HT1 A) receptor antagonist pindolol accelerated and enhanced the antidepressant effect of fluoxetine. The median times to sustained response (greater than or equal to 50% reduction of baseline severity maintained until endpoint) were 19 days for fluoxetine plus pindolol (N = 55) and 29 days for fluoxeti ne plus placebo (N = 56) (p = 0.01). The response rate at endpoint was 16% greater in patients treated with the combination. The plasma concentration of pindolol remained stable between 3 days (first blood sampling) and 6 wee ks. Mean values were similar to 26 nM, a concentration higher than the K-i of (-)pindolol for human 5-HT1A autoreceptors (11 nM). Plasma. fluoxetine a nd norfluoxetine concentrations increased steadily until the fourth week of treatment. Fluoxetine concentrations were lower in patients receiving the combination (p = 0.043), but there was no significant relationship to the c linical response in either group. A reanalysis of the data using a survival analysis revealed that significant differences in the time to sustained re sponse between both groups would have also been detected (1) in a 2-week tr ial, (2) without a placebo lead-in phase, and (3) with less frequent visits . However, the use of "response" instead of "sustained response" as measure of clinically relevant change would have greatly diminished the difference between treatment arms (p = 0.08 instead of p = 0.01). This emphasizes the need of using stringent outcome criteria in antidepressant drug trials. A comparison of the data. of all sustained responders (N = 27) in the fluoxet ine-plus-placebo group with the first 27 responders in the fluoxetine-plus- pindolol group (of a total of 38) revealed a highly significant difference in the time to sustained response (18 and 10 days, respectively; p = 0.0002 ). This indicates that the faster response in the fluoxetine-plus-pindolol group is not a result of the greater proportion of responders.