title: Antipsychotic dosing and drug delivery.
abstract: This chapter addresses the current state of affairs regarding proposed mechanism of action for antipsychotic medications and how this mechanism relates to dosing and delivery strategies. The initial portion describes the history of antipsychotic medication, including key discoveries that contribute to the dopamine hypothesis of schizophrenia and provide evidence that dopamine D2 receptor antagonism remains the most copasetic explanation for both determination of dose and degree of efficacy for current antipsychotic medications. Early observations regarding the unique properties of clozapine and how those observations led to the misconception and misnomer of atypicality are also discussed. Subsequent sections relate the dosing of available medications using chlorpromazine equivalents, with a discussion of non-D2-related mechanisms to antipsychotic effects. The balance of the chapter explores the temporal pattern of receptor occupancy as a key determinant of antipsychotic effectiveness, noting that continuous infusion would present the optimal method of treatment. In addition to the pharmacodynamic benefits of continuous long-term delivery systems, the incidence, causes, and clinical consequences of poor adherence are addressed. These observations are then discussed in the context of clinical studies and meta-analyses, demonstrating superiority of long-term depot preparations over oral administration. However, despite overwhelming evidence in favor of long-term delivery systems, few options are available to provide such ideal medication delivery profiles. Barriers to creating traditional depot preparations for a large number of antipsychotic agents, as well as efforts to address these limitations with polymer-based microspheres are described. The potential extension of current formulations to very long-term delivery implants using biodegradable and nonbiodegradable platforms is then described. Benefits as well as limitations of such systems are discussed with respect to clinical and ethical issues as well as a brief description of potential regulatory and logistic barriers to developing better delivery options. In summary, this chapter describes the basis for relating the dose of all existing antipsychotic medications to dopamine D2 receptor affinity and the potential contribution of continuous occupancy to enhanced efficacy through superior biological effects and improved adherence.
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA. cara.rabin@gmail.com
authors.forename: Cara R
authors.initials: CR
authors.lastname: Rabin
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Siegel
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D001672:Biocompatible Materials; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006801:Humans; D055118:Medication Adherence; D008954:Models, Biological; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D001672:Biocompatible Materials; D011954:Receptors, Dopamine