Clinical response in a risperidone-medicated naturalistic sample: patients’ characteristics and dose-dependent pharmacokinetic patterns

The purpose of this study was to disentangle an association between plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety, AM (RIS + 9-OH-RIS), and clinical response in a naturalistic sample. Plasma concentrations of RIS, 9-OH-RIS and AM in patients out of a therapeutic drug monitoring (TDM) database were compared between responders (n = 64) and non-responders (n = 526) using the Clinical Global Impressions (CGI) Scale. Daily dosage of risperidone did not differ between responders and non-responders. Differences for active moiety plasma levels between the two groups did not reach statistical significance. However, responders showed lower plasma concentrations of the parent compound RIS as well as lower metabolic ratios RIS/9-OH-RIS than non-responders (p = 0.017 and p = 0.034). These differences did not remain after controlling for age and baseline symptoms. Furthermore, the cohort was split into two subgroups based on the daily dosage: patients under high (ae6 mg/day) (R (H), n = 187) and patients under lower dosages (< 6 mg) (R (L), n = 403) of risperidone. Differences between responders and non-responders after controlling for demographic and clinical characteristics remained only for plasma concentrations of active moiety in the lower-dose medicated groups; non-responders showed higher active moiety plasma concentrations than responders. Understanding the mechanisms involved and factors associated with the clinical response in patients medicated with antipsychotics is of great interest. Our data imply that clinical response to an antipsychotic treatment cannot be attributed to a single pharmacokinetic pattern. It seems to be rather a complex patchwork of influencing factors such as demographic and clinical characteristics as well as the metabolizer status as surrogate of CYP activity. It seems that the ratio between RIS and 9-OH-RIS may play a crucial role in mediating the clinical effect