Tauscher J, Kapur S
Schizophrenia-PET Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada.
CNS Drugs. 2001;15(9):671-8. doi: 10.2165/00023210-200115090-00001.
Despite vast clinical experience with antipsychotics, there is no broad consensus on the doses of these substances that should be administered. Currently, most antipsychotics are administered empirically according to clinical dose-finding studies, in which arbitrarily selected doses were tested to find the "most efficient" dose range in a patient population, with no regard for the molecular effects of the tested drug. Brain imaging studies using nuclear medical techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), can now provide a rationale for doses, directly derived from the central effects of the drugs on neurotransmitter receptors measured in vivo. PET results indicate that occupancy of at least 65% of dopamine D(2) receptors is needed for clinical response to antipsychotics, and that occupancy rates exceeding 72 and 78% are associated with a high risk for elevation of prolactin levels and motor adverse effects, respectively. For example, clinical studies with haloperidol do not point to an advantage of dosages exceeding 5 mg/day. The relevance of D(2) receptor occupancy for drug administration is also borne out by studies relating the effects of antipsychotics to their D(2) receptor occupancy in relevant animal models. Taken together, neuroimaging and clinical studies, as well as animal models, provide a rationale for the use of relatively low doses of typical antipsychotics and equivalent doses of novel antipsychotics. The lower risk of adverse effects with appropriate doses of antipsychotics may further enhance compliance and outcome. This seems to be particularly important in individuals experiencing a first episode of schizophrenia, as they appear to be especially responsive to pharmacotherapy and quite sensitive to adverse effects.
尽管在抗精神病药物方面有丰富的临床经验，但对于这些药物的给药剂量并没有广泛的共识。目前，大多数抗精神病药物是根据临床剂量探索研究经验性给药的，在这些研究中，任意选择剂量进行测试，以在患者群体中找到“最有效”的剂量范围，而不考虑受试药物的分子效应。使用正电子发射断层扫描（PET）或单光子发射计算机断层扫描（SPECT）等核医学技术的脑成像研究，现在可以为剂量提供理论依据，该依据直接源于药物对体内测量的神经递质受体的中枢效应。PET结果表明，抗精神病药物产生临床反应需要至少占据65%的多巴胺D₂受体，而占据率超过72%和78%分别与催乳素水平升高和运动不良反应的高风险相关。例如，氟哌啶醇的临床研究并未表明剂量超过5毫克/天有优势。抗精神病药物的作用与其在相关动物模型中的D₂受体占据率之间的关系研究，也证实了D₂受体占据率与药物给药的相关性。综合来看，神经影像学和临床研究以及动物模型，为使用相对低剂量的传统抗精神病药物和等效剂量的新型抗精神病药物提供了理论依据。使用适当剂量的抗精神病药物时不良反应风险较低，这可能会进一步提高依从性和治疗效果。这在首次发作精神分裂症的个体中似乎尤为重要，因为他们似乎对药物治疗特别敏感，且对不良反应相当敏感。
