Are changes in the pharmacokinetic (PK) and pharmacodynamic (PD) properties of antipsychotics able to improve efficacy and safety?

Although atypical antipsychotics have provided clinical advantages over conventional medications, data from trials such as CATIE [1] have highlighted that there is still a need for improved medications to support continued adherence and optimal clinical outcomes. In particular, it would be of benefit to minimize side effects such as extrapyramidal symptoms (EPS) and weight gain. One approach to optimize antipsychotic activity is to modulate the pharmacokinetic profile and thus deliver improved pharmacodynamic effects. Oral formulations of antipsychotics are generally characterized by a relatively rapid rise and fall in plasma concentrations with levels above and below threshold levels being associated with an increased risk of side effects and reduced antipsychotic efficacy, respectively [2]. Achieving steady plasma levels at which the drug achieves maximum symptom control but below levels at which adverse events occur therefore remains the ideal profile. For atypical antipsychotics, efficacy begins at approximately 60% occupancy of the D2 receptor, and occupancy above 80% can lead to EPS [2–4]. Approaches to reduce the peak-to-trough fluctuations compared with immediate-release oral agents include the use of long-acting injectable agents which have smoother plasma concentration-time profiles [2, 5]. For those patients who prefer oral agents, alongside the choice of agents such as olanzapine, quetiapine, ziprasidone and risperidone, there is the option of using paliperidone ER which uses oral osmotic pump (OROS) extended-release technology [6]. This provides a continual release of medication leading to minimal peaks and troughs in plasma concentrations over a 24-hour period. A sustained release formulation of quetiapine is also currently being assessed in clinical trials [7].