Altamura A C
Department of Psychiatry, University of Milan, Italy.
Schizophr Res. 1993 Jan;8(3):187-98. doi: 10.1016/0920-9964(93)90017-d.
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.
尽管现有抗精神病药物（NDs）的有效性无可争议，但精神分裂症的短期和长期治疗效果往往不尽人意，耐药现象并不罕见。反应变异性的原因似乎主要是由于精神分裂症综合征在临床病史、症状和生物学模式方面的异质性。高不依从率是治疗失败的一个重要原因，尤其是在长期治疗期间。对NDs缺乏反应或反应不佳可能与特殊的药物处置模式有关，这通常会导致血浆浓度不足（过低或过高）。为了处理药代动力学方面的问题，本文讨论了两个主要主题：（A）生物利用度和代谢的个体差异，以及（B）血浆水平与临床反应的关系。了解这些方面可以显著有助于减少一些假性耐药现象。此外，强调需要将这些数据与这些疾病病理生理学的新发现相结合，以便在使用NDs治疗期间正确处理药物反应机制的复杂性。鉴于精神分裂症在临床病程、结局和生物学发现方面的异质性证据，应该考虑针对反应的新的启发式范例。因此，需要根据最近的临床、神经化学和神经形态学数据重新审视NDs（如抗抑郁药）的“治疗窗”概念（20世纪70年代提出）。最后，报告了NDs监测的指征（特别是对于氟哌啶醇和氟奋乃静等药物），表明多维操作策略可能特别适合处理耐药问题。
