title: Clomipramine dose-effect study in patients with depression: clinical end points and pharmacokinetics. Danish University Antidepressant Group (DUAG).
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 > 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.
  
  
  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 (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).
  
  
  CONCLUSIONS
  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.
mesh_terms: D000328:Adult; D000368:Aged; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D002997:Clomipramine / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D003718:Denmark; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011569:Psychiatric Status Rating Scales; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D013034:Sparteine / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000929:Antidepressive Agents, Tricyclic; D002997:Clomipramine; D017367:Selective Serotonin Reuptake Inhibitors; D013034:Sparteine; C012273:desmethylclomipramine