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

Abstract

Objective To examine the problems of establishing dose‐effect and concentration‐effect relationships of antidepressant therapy with clomipramine. Methods This randomized double‐blind study compared five fixed doses of clomipramine hydrochloride: 25, 50, 75, 125, and 200 mg/day in hospitalized or 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 scoring ≥18 on the Hamilton Depression Scale (HDS) or ≥9 on the Hamilton Depression subscale (HDSS) before and after the washout period were randomized. The treatment groups (n = 29 to 32) were well balanced with respect to sex, age, and depression rating. Serum concentrations of clomipramine plus metabolites were measured at weekly intervals. A sparteine test was performed before and during drug treatment. Results There was pronounced interpatient variability in response and kinetics at each dose. Drop‐outs attributable to adverse events increased with rising doses, whereas drop‐outs caused by worsening or lack of effect or nonresponse declined with increasing dose. Completer analyses showed a moderate 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 consistent dose‐effect relationship. Early sustained response occurred more frequently with the two highest doses. Serum levels of clomipramine and desmethylclomipramine 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 few typical side‐effect ratings showed a statistically significant dose‐effect and concentration‐effect relationship. Serum concentration of clomipramine and 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 therapeutic range. This pattern is similar to that observed with newer antidepressants. Clinical Pharmacology & Therapeutics (1999) 66, 152–165; doi:

Antidepressant Drugs Effects on Blood Pressure

“…It elicits a more potent action than amitriptyline as a SERT than as a NET inhibitor. Orthostatic hypotension is an important complication of imipramine (−26 mmHg of systolic BP) (198)(199)(200), amitriptyline, clomipramine (with a decrease of systolic BP of 5-10 mmHg), and its metabolite, desmethylclomipramine (201,202), especially in older patients (203) and when doses are rapidly up-titrated (Table 2) (202,(204)(205)(206). However, other reports found no changes, or only minor effects (149,207,208), and even an increase in supine BP mainly after longterm treatment (209).…”