THE EFFECTS OF PERPHENAZINE ON THE CONCENTRATION OF NORTRIPTYLINE ANDITS HYDROXYMETABOLITES IN OLDER PATIENTS

Twenty-five older patients who presented with psychotic depression wer e treated with a combination of nortriptyline and perphenazine, Plasma levels of nortriptyline, E-, and Z-10-OH nortriptyline (E- and Z-10-O H-NT) were measured before and after addition of perphenazine. The mea n (+/-SD) initial nortriptyline dose was 59 +/- 24 mg/day, whereas the mean final nortriptyline and perphenazine doses were 56 +/- 24 and 19 +/- 13 mg/day, respectively. The mean plasma level to dose quotient f or perphenazine (0.45 +/- 0.34 nM divided by mg/day) was comparable to the mean quotient reported previously in older psychotic patients tre ated with perphenazine alone, After addition of perphenazine, the medi an quotient of nortriptyline plasma level to nortriptyline dose (L/D) increased significantly (from 6.1 to 8.6). This change was inversely c orrelated with baseline nortriptyline L/D. The median Patio of E-10-OH -NT to nortriptyline plasma level decreased significantly (from 1.6 to 1.3), whereas the median ratio of Z-10-OH-NT to nortriptyline plasma level did not change significantly. These results are consistent with the known inhibition by perphenazine of the cytochrome P450 2D6 (spart eine/debrisoquine hydroxylase), tile major enzyme involved in the oxid ative metabolism of nortriptyline, mostly through the formation of E-1 0-OH-NT. This complex alteration in the metabolism of nortriptyline in duced by perphenazine emphasizes the relevance of measuring plasma lev els not only of nortriptyline but also of its hydroxymetabolites in ol der patients who are more likely to be sensitive to their differing ca rdiovascular, anticholinergic, and cognitive effects.