Application of the AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry to patients under therapy with the antipsychotics clozapine, olanzapine, and risperidone in a community hospital in Germany

To improve psychopharmacotherapy, the expert group of the AGNP issued guidelines for TDM, in which therapeutic reference ranges (TR), dose related reference ranges (C/D) and expected drug metabolite to parent drug ratios (M/P) for many psychoactive drugs are provided to optimize drug therapy. Our study attempted to assess the prevalence of patients within the anticipated TR for clozapine, olanzapine, or risperidone and to assess whether the C/D and M/P can be useful to give reasons for drug concentrations outside the TR.

Clozapine/norclozapine, olanzapine/desmethyl-olanzapine and risperidone/9-OH-risperidone were gauged in 852 plasma samples of 204 patients (82 female, 122 male; 19 – 76 years) between 2010 and 2013 under steady state conditions by a validated LC-MS/MS method. C/D and M/P were calculated in accordance to AGNP-Guidelines. Patients were divided in groups with and without co-medication and categorized corresponding to median concentrations from at least 3 up to 5 measurements.

Patients outside TR were preponderantly below the TR. With clozapine (n = 66) only 50% of patients were within, 45% below and 5% above TR, respectively. With olanzapine (n = 76) most patients (78%) were within, 18% below, and 4% above TR. With risperidone (n = 62) the majority of patients (66%) was also within TR, 27% below, and 6% above. Co-medication had no essential effect. An aberrant C/D was noted in 41% of all patients below the TR. An increased M/P was noted in 23% of patients below TR and a decreased M/P in 40% of patients above TR.

Our results show that 22% to 50% of medicated patients are not within the TR of their drugs despite regular TDM. In patients below TR more than half of the cases could be avowed by dosing errors or non-compliance (C/D) and/or increased drug metabolism (M/P). Patients above TR had in 40% an inhibited drug metabolism. Our study suggests that the calculation of C/D and M/P according to the AGNP guidelines can be a useful tool to better individualize pharmacotherapy in an antipsychotic treatment.