title: Combination treatment with clomipramine and fluvoxamine: drug monitoring, safety, and tolerability data.
abstract: BACKGROUND
  Combination treatment with tricyclic antidepressants (TCAs) and serotonin selective reuptake inhibitors (SSRIs) is an increasingly employed strategy especially in depressed patients unresponsive to monotherapy. Comedications with SSRIs, however, may be hazardous owing to pharmacokinetic interactions that can result in elevated serum TCA levels. For the combinations, safety and tolerability data are lacking.
  
  
  METHODS
  We report tolerability and safety of combined treatment with fluvoxamine and clomipramine (CMI) in 22 patients. Most patients suffered from depression and obsessive-compulsive symptoms. Diagnoses were made according to DSM-III-R criteria. Serum levels of CMI, N-desmethylclomipramine (DCMI), and 8-hydroxylated metabolites were determined. EEG, ECG, and laboratory parameters and adverse effects reported by the patients, as well as global clinical improvement, were assessed.
  
  
  RESULTS
  Generally, fluvoxamine/clomipramine comedication was well tolerated. Serum CMI levels reached 500 to 1200 ng/mL in half of the patients, while corresponding levels for DCMI and 8-hydroxylated metabolites were low. Moreover, the ratios of N-demethylation DCMI:CMI calculated from the ratios of drug concentrations in serum were markedly lower under comedication than under CMI monotherapy. Alterations in EEG, ECG, and laboratory parameters that had clinical relevance were rarely observed and were reversible after dose reduction of CMI. However, 2 patients developed myoclonic jerks. A majority of patients improved clinically during combination treatment. Clinically relevant side effects were absent in patients with serum CMI and DCMI levels below 450 ng/mL and ratios of N-demethylation below 0.3.
  
  
  CONCLUSIONS
  Our results suggest that comedication of fluvoxamine and clomipramine will result in markedly elevated serum clomipramine levels. Therefore, combination treatment with fluvoxamine and clomipramine should be carefully monitored by determination of serum levels of the TCA. Clinically, the pharmacokinetic interactions between fluvoxamine and clomipramine may be well tolerated in a majority of patients. However, in a few patients, higher serum levels may be associated with an increased risk of EEG changes and changes of intracardiac conductance. EEG and ECG should be used regularly to monitor comedicated patients.
authors.affiliation: Department of Psychiatry, University of Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Szegedi
authors.forename: H
authors.initials: H
authors.lastname: Wetzel
authors.forename: M
authors.initials: M
authors.lastname: Leal
authors.forename: S
authors.initials: S
authors.lastname: Härtter
authors.forename: C
authors.initials: C
authors.lastname: Hiemke
mesh_terms: D000328:Adult; D000368:Aged; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000627:therapeutic use*; D002997:Clomipramine / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use*; D003866:Depressive Disorder / Q000097:blood / Q000188:drug therapy* / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D016666:Fluvoxamine / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009771:Obsessive-Compulsive Disorder / Q000097:blood / Q000188:drug therapy* / Q000523:psychology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D002997:Clomipramine; D016666:Fluvoxamine; D017367:Selective Serotonin Reuptake Inhibitors; C012273:desmethylclomipramine