IMPACT OF CLINICAL PHARMACOKINETICS ON NEUROLEPTIC THERAPY IN PATIENTS WITH SCHIZOPHRENIA

This review covers some recent work on: 1. the effects of route of adm inistration on the pharmacokinetics of fluphenazine and some of its me tabolites; 2. the clinical pharmacokinetics of fluphenazine in acute p atients medicated with oral fluphenazine; 3. the clinical pharmacokine tics of haloperidol in acute patients medicated with oral haloperidol; 4. the clinical pharmacokinetics of fluphenazine in the maintenance o f individuals with chronic schizophrenia with fluphenazine decanoate; 5. a systematic dose reduction study in maintenance treatment refracto ry patients with oral haloperidol. A study in which plasma levels of f luphenazine and fluphenazine sulfoxide were measured in a group of DSM -III-R patients with schizophrenia before and after switching from ora l fluphenazine to depot fluphenazine, decanoate revealed much higher l evels of fluphenzaine sulfoxide with oral medication compared with tho se found with depot fluphenazine. These data illustrate the effect of ''first pass'' metabolism after oral fluphenzaine. Thus in a group of 33 patients randomly assigned to receive 5 mg, 10 mg or 25 mg oral flu phenazine daily, steady state plasma fluphenzaine levels at each dose were significantly lower that those of fluphenazine sulfoxide or 7-hyd roxy-fluphenazine, although there were no significant differences betw een the levels of fluphenazine and fluphenazine N4-oxide. On the other hand, plasma levels of the parent drug were significantly higher than those of any metabolite in a corresponding group of patients at stead y state on depot medication. These observations underscore the importa nce of route dependent differences in the pharmacokinetics of fluphena zine which can lead to problems when switching patients from oral to d epot neuroleptics. The concept of ''disabling side-effects'' is an imp ortant development in understanding relationships between plasma level s of neuroleptic drugs and clinical response in patients with schizoph renia. Risk-benefit analysis shows clearly that evaluation of relation ships between plasma levels and clinical response must take into accou nt the consequences of side-effects which the patient feels have a neg ating effect on therapy. Emerging data on putative therapeutic plasma level ranges in maintenance therapy are potentially important and may be particularly useful in the maintenance of patients on low dose ther apy. It is noteworthy that in a carefully executed dose reduction stud y in treatment resistant patients under medication with haloperidol, t he mean lowest effective dose (8.7 ng/mL) lay within the optimal thera peutic range (5 ng/mL to 12 ng/mL) found in acutely psychotic patients . The study showed that gradual dose reduction of neuroleptic was poss ible in chronic treatment resistant patients with schizophrenia who we re originally thought by ward staff to require high doses of neurolept ic. After dosage reduction, the patients experienced fewer side-effect s; they were less depressed and hence demonstrated a degree of improve ment.