Sub-effective doses of a bendroflumethiazide-imipramine combination offer greater synergistic antidepressant effect compared to a bendroflumethiazide-fluoxetine combination: an isobolographic analysis

Background: Bendroflumethiazide is often prescribed with fluoxetine or imipramine for patients with both depression and hypertension. However, there is little data on the potential interactions between these drugs. Objective: The objective of this study was to investigate the potential antidepressant effects of bendroflumethiazide, as well as sub-effective dose combinations of bendroflumethiazide with fluoxetine or imipramine. Methods: Forced swimming and tail suspension tests were used to investigate the behavioural effects of bendroflumethiazide [5-20 mg/kg; per os (p.o],imipramine (3-30 mg/kg; p.o) and fluoxetine (3-30 mg/kg; p.o). Mean immobility, swimming, climbing, curling,and swinging scores were measured. Median effective dose (ED50) values were calculated from the immobility scores. The antidepressant effect of the combination of bendroflumethiazide with imipramine or fluoxetine at sub-effective doses was then investigated. Isobolographic analyses were performed on these combinations to investigate possible synergism, additivity or antagonism. Results: Bendroflumethiazide produced a significant diminution in mean immobility scores, suggestive of an antidepressant-like effect, while increasing swimming, climbing and swinging scores. Imipramine and fluoxetine also exhibited antidepressant-like effects. A combination of bendroflumethiazide and imipramine at sub-effective doses showed a synergistic antidepressant-like effect with an interaction index of 0.31 as did the bendroflumethiazide-fluoxetine combination (interaction index:0.41). Conclusion: This study demonstrated the acute antidepressant-like effect of bendroflumethiazide. Moreover, bendroflumethiazide-imipramine combinations offer greater synergy when compared to bendroflumethiazide-fluoxetine combinations.