Clomipramine dose-effect study in patients with depression: Clinical end points and pharmacokinetics

Objective: To examine the problems of establishing dose-effect and concentr ation-effect relationships of antidepressant therapy with clomipramine. Methods: This randomized double-blind study compared five fixed doses of cl omipramine hydrochloride: 25, 50, 75, 125, and 200 mg/day in hospitalized o r day patients at nine clinical centers in Denmark. A 1-week washout period was followed by 6 weeks of active treatment and weekly depression ratings. In total, 151 patients (100 women and 51 men) with major depression scorin g greater than or equal to 18 on the Hamilton Depression Scale (HDS) or gre ater than or equal to 9 on the Hamilton Depression subscale (HDSS) before a nd after the washout period were randomized. The treatment groups (n = 29 t o 32) were well balanced with respect to sex, age, and depression rating. S erum concentrations of clomipramine plus metabolites were measured at weekl y intervals. A sparteine test was performed before and during drug treatmen t. Results: There was pronounced interpatient variability in response and kine tics at each dose. Drop-outs attributable to adverse events increased with rising doses, whereas drop-outs caused by worsening or lack of effect or no nresponse declined with increasing dose. Completer analyses showed a modera te and statistically significant relationship between depression rating and dose at all ratings after 1 to 6 weeks of treatment (trend analysis). HDS items representing core symptoms of depression showed a particularly consis tent dose-effect relationship. Early sustained response occurred more frequ ently with the two highest doses. Serum levels of clomipramine and desmethy lclomipramine showed weak correlation with depression ratings (R-s = -0.18 to -0.27; P <.05 to P <.01), A few blood pressure measurements and a fay ty pical side-effect ratings showed a statistically significant dose-effect an d concentration-effect relationship, Serum concentration of clomipramine an d desmethylclomipramine showed a pronounced disproportionate increase with increasing dose. Clomipramine inhibited in a dose-dependent fashion CYP2D6 (sparteine oxidation). Conclusion: The dose-effect curves, indicating the probability of a certain outcome at a given dose, were flat and overlapping suggesting a narrow the rapeutic range. This pattern is similar to that observed with newer antidep ressants.