Ereshefsky L
College of Pharmacy, The University of Texas at Austin, USA.
J Clin Psychiatry. 1999;60 Suppl 10:20-30.
Recent advances in our understanding of schizophrenia along with neuroscience insights into antipsychotic medication mechanisms of action have led to a renaissance in new drug development, including an expanded therapeutic spectrum encompassing more of the symptoms encountered in schizophrenia. Atypical antipsychotics, or new generation therapies, also demonstrate greater selectivity for therapeutic actions than for extrapyramidal symptoms (EPS). Our modern armamentarium of drugs spans a wide range of pharmacologies, and it is more accurate to envision shades of gray rather than a black-and-white description for typical versus atypical properties of medications. As our paradigms for antipsychotic efficacy have shifted, a reexploration of the "older" neuroleptics is warranted to determine if they possess pharmacologic attributes that might have been overlooked during the era of high-dose neuroleptic therapy. Loxapine appears to be in the center of this spectrum, somewhere between haloperidol and risperidone. Dosing implications for drugs with a more even serotonin-2A (5-HT2A) receptor and dopamine-2 (D2) receptor blocking effect are discussed. Loxapine might have a window of partial atypicality at doses < or = 50 mg/day. These lower doses might have potential as both monotherapy in responsive patients with persistent psychotic disorders and as an adjunctive treatment in partially responding patients on concurrent atypical antipsychotic treatments. The pharmacologic properties of loxapine within its usable dosage range are quite complex and are the net sum of the parent's plus metabolites' contributions (demethylation and hydroxylation by cytochrome P450 enzymes). These pharmacologic effects include alpha-adrenergic blockade, inhibition of the noradrenergic transporter protein (reuptake inhibition), and antimuscarinic effects. Drug interactions and cigarette smoking might alter the parent-to-metabolite concentration ratios, affecting the relative atypicality of this antipsychotic therapy. Moreover, with the intramuscular formulation, which does not undergo first-pass metabolism, the parent compound of loxapine, i.e., not its metabolites, is predominantly detected in the plasma of patients, reducing the likelihood for EPS during emergency interventions in patients with positive symptoms. Further study is warranted to determine loxapine's place in our treatment of schizophrenia.
我们对精神分裂症认识的最新进展，以及神经科学对抗精神病药物作用机制的深入了解，引发了新药研发的复兴，包括扩大治疗范围以涵盖精神分裂症中出现的更多症状。非典型抗精神病药物，即新一代疗法，在治疗作用上也表现出比对锥体外系症状（EPS）更高的选择性。我们现代的药物库涵盖了广泛的药理学，对于药物的典型与非典型特性，用灰色阴影来描述比黑白分明的描述更为准确。随着我们对抗精神病药物疗效范式的转变，有必要重新审视“老一代”抗精神病药物，以确定它们是否具有在高剂量抗精神病药物治疗时代可能被忽视的药理学特性。洛沙平似乎处于这个范围的中间位置，介于氟哌啶醇和利培酮之间。本文讨论了具有更均衡的5-羟色胺2A（5-HT2A）受体和多巴胺2（D2）受体阻断作用的药物的给药意义。洛沙平在剂量≤50mg/天时可能处于部分非典型性的区间。这些较低剂量可能具有潜力，既可以作为持续性精神病性障碍有反应患者的单一疗法，也可以作为正在接受非典型抗精神病药物联合治疗但反应不完全患者的辅助治疗。洛沙平在其可用剂量范围内的药理学特性相当复杂，是母体药物及其代谢产物（细胞色素P450酶进行去甲基化和羟基化）贡献的总和。这些药理学作用包括α-肾上腺素能阻断、去甲肾上腺素能转运蛋白抑制（再摄取抑制）和抗毒蕈碱作用。药物相互作用和吸烟可能会改变母体药物与代谢产物的浓度比，影响这种抗精神病治疗的相对非典型性。此外，对于不经过首过代谢的肌肉注射制剂，在患者血浆中主要检测到的是洛沙平的母体化合物，而非其代谢产物，这降低了在阳性症状患者紧急干预期间出现EPS的可能性。有必要进行进一步研究以确定洛沙平在精神分裂症治疗中的地位。
