A MULTIDIMENSIONAL (PHARMACOKINETIC AND CLINICAL-BIOLOGICAL) APPROACH TO NEUROLEPTIC RESPONSE IN SCHIZOPHRENIA - WITH PARTICULAR REFERENCE TO DRUG-RESISTANCE

Despite the undisputable effectiveness of the available neuroleptic medications (NDs), short and long term outcome of schizophrenic disorders is often unsatisfactory and drug resistance phenomena are not uncommon. The causes of variability in the response seem to be primarily due to the heterogeneity of schizophrenic syndromes in terms of clinical history, symptoms, and biological patterns. The high non-compliance rate is an important source of therapeutic failure particularly during long-term treatment. The lacking or poor response to NDs can be linked to peculiar drug disposition patterns, which lead generally to inadequate plasma concentrations (too low or too high). To deal with pharmacokinetic aspects two main topics are discussed in this paper: (A) the interindividual differences in bioavailability and metabolism and (B) the plasma level-clinical response relationship. The knowledge of these aspects can significantly contribute to reducing some pseudo-drug resistance phenomena. Moreover, the need to combine these data with the new acquisitions on the pathophysiology of these disorders is emphasized, to deal properly with the complexity of drug response mechanisms during therapy with NDs. New heuristic paradigms for schizophrenic disorders, stemming from the evidences of their heterogeneity, in terms of clinical course, outcome and biological findings, should be considered in relation to response. Accordingly, the concept of 'therapeutic window' (as conceived in the '70s) for NDs (as for antidepressants) needs to be reexamined in relation to recent clinical, neurochemical and neuromorphological data. Finally, the indications for NDs monitoring (particularly for drugs like haloperidol and fluphenazine) are reported, suggesting that a multidimensional operational strategy could be particularly suitable to deal with drug resistance problems.