desmethylclomipramine and Depressive-Disorder--Major

To examine the problems of establishing dose-effect and concentration-effect relationships of antidepressant therapy with clomipramine.. 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 > or =18 on the Hamilton Depression Scale (HDS) or > 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.. 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 (Rs = -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).. 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.

Topics: Adult; Aged; Antidepressive Agents, Tricyclic; Clomipramine; Denmark; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Phenotype; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Sparteine; Treatment Outcome

The use of antidepressants during pregnancy continues to garner considerable attention, though there are limited investigations that have sought to quantify fetal exposure.. Maternal and umbilical cord sera were collected at delivery from ten women taking nortriptyline and seven taking clomipramine. Placental passage was calculated as the ratio of umbilical cord to maternal serum concentration. Obstetrical outcome data were gathered from subjects at delivery.. The placental passage ratio of nortriptyline and its active metabolite, cis-10-hydroxynortriptyline, were .68 +/- .40, 1.40 +/- 2.40, respectively. Clomipramine and desmethylclomipramine ratios were .60 +/- .50, .80 +/- .60. Obstetrical complications, such as pre-term delivery and pregnancy induced hypertension, were increased compared to the national average.. The in vivo ratios of umbilical cord to maternal serum drug concentrations demonstrate considerable fetal exposure and differ greatly from previous results utilizing ex vivo perfusion.

Topics: Antidepressive Agents, Tricyclic; Birth Weight; Clomipramine; Depressive Disorder, Major; Dose-Response Relationship, Drug; Female; Humans; Infant, Newborn; Male; Maternal-Fetal Exchange; Nortriptyline; Pregnancy; Pregnancy Complications