Delivery systems and dosing for antipsychotics.

Schizophrenia is a devastating illness, affecting approximately 1-2 % of the world population. Age of onset is generally between 20 and 30 years of age with a chronic, unremitting course for the duration of the patient's life. Although schizophrenia is among the most severe and debilitating illnesses known to medicine, its treatment has remained virtually unchanged for over 50 years. This chapter covers several major concepts in experimental drug development and delivery: (1) the concept of "typical" vs. "atypical" classifications for antipsychotic drugs as it relates to dosing; (2) the development of depot formulations for improved medication adherence; and (3) several promising areas for future therapeutic advances related to the methods and duration of drug administration. These areas include sublingual, injectable, and implantable drug delivery strategies that have the potential to effect rapid and dramatic improvements in schizophrenia outcomes.

Antipsychotic dosing and drug delivery.

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.

Ketamine exposure in adult mice leads to increased cell death in C3H, DBA2 and FVB inbred mouse strains.

BACKGROUND: Drug abuse is common among adolescents and young adults. Although the consequences of intoxication are known, sequelae of drugs emerging on campuses and in clubs nationwide are not. We previously demonstrated that ketamine exposure results in lasting physiological abnormalities in mice. However, the extent to which these deficits reflect neuropathologic changes is not known. METHODS: The current study examines neuropathologic changes following sub-anesthetic ketamine administration (5mg/kg i.p. x 5) to three inbred mouse strains. Stereologic quantification of silver stained nuclear and linear profiles as well as activated caspase-3 labeling was used to address: (1) whether or not ketamine increases excitotoxic and apoptotic cell death in hippocampal CA3 and (2) whether or not ketamine-induced cell death varies by genetic background. RESULTS: Ketamine increased cell death in hippocampal CA3 of adult C3H, DBA2 and FVB mice. Neither silver staining nor activated caspase-3 labeling varied by strain, nor was there an interaction between ketamine-induced cell death and strain. CONCLUSIONS: Ketamine exposure among young adults, even in limited amounts, may lead to irreversible changes in both brain function and structure. Loss of CA3 hippocampal cells may underlie persistent ERP changes previously shown in mice and possibly contribute to lasting cognitive deficits among ketamine abusers.