Therapeutic Monitoring of New Antipsychotic Drugs

Abstract

Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate. Positron emission tomography (PET), which enables measurement of the occupancy of dopamine D2 receptors, revealed that receptor occupancy correlated better with plasma concentrations than with doses of the antipsychotics. Regarding plasma levels related to therapeutic effects, optimal concentrations have been established for clozapine (350-600 ng/mL), risperidone (20-60 ng/mL), and olanzapine (20-80 ng/mL) but not for the other new antipsychotics. Studies that included analyses of drug levels in blood reported mean concentrations of 68 ng/mL for quetiapine and 317 ng/mL for amisulpride under therapeutic doses of the antipsychotic drugs. For ziprasidone or aripriprazole, data on therapeutic drug concentrations are so far lacking. In conclusion, evidence is growing that TDM may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop side effects under therapeutic doses. The few reported investigations, however, need to be confirmed and extended.

A PET Study Evaluating Dopamine D2 Receptor Occupancy for Long-Acting Injectable Risperidone

“…There are well-recognized concerns regarding the impact of inter-and intraindividual variability in plasma antipsychotic levels and efforts to establish "therapeutic windows" (30)(31)(32). Bearing in mind this caveat, the current estimate actually dovetails nicely with a more recent review of this topic suggesting an optimal therapeutic range for risperidone plus 9-hydroxyrisperidone of 20-60 ng/ml (33). As seen in Figure 2, 20 ng/ml is associated with 65% D 2 occupancy, while 60 ng/ml represents 84% D 2 occupancy.…”

Therapeutic drug monitoring of atypical antipsychotic drugs

“…Wanted and unwanted drug effects depend on concentrations of the drug at its target site (11). After a given dose, the resulting blood concentrations of antipsychotic drugs are higly variable among individuals.…”

“…Optimal response was seen at 70-80 % receptor occupancy, and 80 % receptor occupancy was defined as the threshold for the occurrence of extrapyramidal side effects (12,13). Therefore, the antipsychotic drug plasma concentration is a valid measure of the drug at its primary target structure in the brain (11). Therapeutic drug monitoring of atypical antipsychotics affords the opportunity to reduce toxicity and increase adherence (14).…”

Controlled Release Matrix Tablets of Olanzapine: Influence of Polymers on the In Vitro Release and Bioavailability

“…Peak blood concentration (C max ) of olanzapine was detected as 5-50 ng/mL in the case of 2.5-to 17.5-mg daily doses (5) and 8-31 ng/mL in the case of 10-to 20-mg daily doses (3). The optimal therapeutic range of olanzapine was suggested as 20-50 ng/mL by Mauri et al (6) and 20-60 ng/mL by Hiemke et al (7).…”