fluvoxamine and desmethylclomipramine

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.. 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.. 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.. 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.

Topics: Adult; Aged; Antidepressive Agents, Tricyclic; Clomipramine; Depressive Disorder; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Electroencephalography; Female; Fluvoxamine; Humans; Male; Middle Aged; Obsessive-Compulsive Disorder; Selective Serotonin Reuptake Inhibitors

A simple reversed-phase liquid chromatographic method enabling the simultaneous analysis in plasma of the tricyclic antidepressant clomipramine, its demethylated metabolite, and the selective serotonin reuptake inhibitor fluvoxamine, was developed. The drugs and dibenzepine, the internal standard, were extracted from 1 mL plasma through an automated solid-phase procedure, eluted in a total chromatographic time of approximately 14 min and detected by means of an ultraviolet spectrophotometer preset at 254 nm. An assay sensitivity of 10 microg/L was observed for all analytes. Recoveries for these drugs and their metabolites ranged between 65% and 98% and their coefficient of variation (within-day and day-to-day) between 1.9% and 2.9%. In spiked plasma, within-day and day-to-day imprecision data were less than 5%. The simultaneous determination of clomipramine, N-desmethylclomipramine, and fluvoxamine with adequate sensitivity and accuracy may be useful for the monitoring of drug treatment in depression and obsessive-compulsive disorder, where combinations of such drugs are employed.

Topics: Adult; Antidepressive Agents; Chromatography, High Pressure Liquid; Clomipramine; Female; Fluvoxamine; Humans; Male