Abstract
Introduction:
Assessment of the relation between oral neuroleptic dose, serum drug levels and clinical response may provide important information for rational treatment decisions.
Methods:
Risperidone mono-therapy was administered to 82 schizophrenia patients in a 6-week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of Risperidone and 9-OH-Risperidone were carried out. Additionally, major CYP2D6 polymorphisms were genotyped.
Results:
Mean oral dose of risperidone was 4.4±1.0mg. Mean plasma level of both risperidone and 9-OH-Risperidone together („active moiety“) was 41.6±26.6 ng/ml. There was a positive linear correlation between risperidone plasma levels and dose (r=0.308, p≤.05). Therapy non-responder (PANSS improvement <30%) showed significantly higher plasma levels (p=.032) than responder (PANSS improvement ≥30%) without higher dosages (p=.258). Patients with a duration ≥ 5 years had significantly higher plasma levels than those with a duration <5 years (p=.028). EPS and plasma levels were not correlated (r=.028; p=.843). Patients initially receiving higher oral doses of risperidone were significantly more likely to develop extrapyramidal side effects later in the trial course. Eight of the patients (9.8%) were heterozygous for the CYP2D6 polymorphism. CYP2D6 polymorphisms did not predict clinical response, but tended to predict an increase in the Risperidone/9-OH-Risperidone-Ratio (p=0.095).
Discussion:
Several aspects of our study have an important implication for the clinical use:
The higher incidence of EPMS is related to a faster up-titration of Risperidone and higher plasma levels;
Non-responders to risperidone treatment showed higher plasma levels, indicating that a further increase in the daily dose is not recommended;
patients with a longer duration of illness showed higher plasma levels, although receiving the same oral dose.
The therapeutic monitoring of risperidone and 9-OH-risperidone blood levels is thus highly recommended.