Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients

Pharmacol Res. 1995 Jun;31(6):347-53. doi: 10.1016/1043-6618(95)80088-3.


The in vivo pharmacokinetic interaction between two selective serotonin reuptake inhibitors (SSRI) (fluvoxamine, fluoxetine) and tricyclic antidepressants (TCAs) (amitriptyline, clomipramine) or neuroleptics (haloperidol, cyamemazine, levomepromazine, propericiazine) was assessed in 29 in-patients. They were phenotyped twice with dextromethorphan and mephenytoin: first in steady state conditions while under treatment with TCAs or neuroleptics; and also 10 days after an associated treatment with fluvoxamine (150 mg day(-1)) or fluoxetine (20 mg day(-1)). A clear and statistically significant increase in the mean urinary metabolic ratio (MR) of dextromethorphan/dextrorphan and in the mean mephenytoin S/R ratio (S/R) was seen with the fluvoxamine and fluoxetine treatment. The mean MR increased from 0.13 to 0.27 (P<0.01) with fluoxetine and from 0.34 to 0.84 with fluvoxamine (P<0.05). The (dextromethorphan) 'extensive metabolizer' phenotype switched to the 'poor metabolizer' phenotype in six patients by the 10-day fluoxetine treatment, and in two patients by the fluvoxamine treatment. The mean S/R increased from 0.24 to 0.34 (P<0.05) with fluoxetine, and from 0.33 to 0.58 (P<0.002) with fluvoxamine. These results are in agreement with the observed modification of TCA plasma levels after the SSRI association. During fluvoxamine treatment, amitriptyline and clomipramine plasma levels (P<0.06 both) tendentially increased, and those of demethylclomiprarnine decreased (P<0.06). Fluoxetine addition lead to a significant increase (P<0.02) of the desmethylclomipramine plasma levels. Fluvoxamine induced a moderate augmentation of the plasma levels of haloperidol and its reduced metabolite and no change in the plasma levels of cyamemazine and levomepromazine. But patients treated with neuroleptics are to few to draw any firm conclusion. This study suggests, that fluoxetine and fluvoxamine differ in their interaction with the metabolism of some other basic psychotropic drugs, by a mechanism which implies CYP2D6 and CYPmeph and possibly other isoformes of cytochrome P-450. Moreover, the interactions produced varied with the TCA prescribed.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial

MeSH terms

  • Adult
  • Amitriptyline / pharmacokinetics
  • Amitriptyline / pharmacology
  • Antipsychotic Agents / pharmacokinetics
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use
  • Clomipramine / pharmacokinetics
  • Clomipramine / pharmacology
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / genetics
  • Drug Interactions
  • Female
  • Fluoxetine / pharmacokinetics
  • Fluoxetine / pharmacology*
  • Fluoxetine / therapeutic use
  • Fluvoxamine / pharmacokinetics
  • Fluvoxamine / pharmacology*
  • Fluvoxamine / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenetics
  • Phenotype


  • Antipsychotic Agents
  • Fluoxetine
  • Amitriptyline
  • Clomipramine
  • Fluvoxamine