MINIMUM EFFECTIVE DOSE OF ARIPIPRAZOLE DURING MAINTENANCE FOR PATIENTS IN REMITTED STATE OF PSYCHOSIS GUIDED BY AN EXPONENTIAL TAPERING METHOD: VERIFICATION BY PLASMA DRUG CONCENTRATION

To enhance the quality of life by reducing antipsychotics, or to prevent relapse by maintaining dose, is a dilemma once patients with psychosis reached remission would face. Previously, a dose-reduction trial guided by an exponential tapering method revealed a possibility of reaching a lower dose that could improve patient’ s quality of life not at expense of increased risk of relapse

The study aims to verify the relationship between the minimum effective dose during tapering and the plasma drug levels of aripiprazole and its active metabolite dehydroaripiprazole.

A 2-year open-label randomized prospective cohort trial, including patients with schizophrenia-related psychotic disorders in remission under stable antipsychotic dosage, randomized 2:1 into guided dose reduction group versus maintenance treatment group, together with a group of naturalistic maintenance controls. The precise drug levels were determined using high-performance liquid chromatography experiments. We conducted Spearman correlation to examine the dose-response relationship. ANOVAs test was conducted to examine the difference of psychopathology and quality of life between high and low plasma drug level groups.

A total of 126 blood samples were collected from 31 patients undergoing treatment with aripiprazole at various doses and timepoints. The correlation coefficient between plasma aripiprazole and dehydroaripiprazole levels was 0.923 (p<.0001). After excluding 13 samples from patients who were confirmed non-adherent to prescribed medication doses, the correlation coefficients for the remaining 113 data points were 0.853 (p<.0001) and 0.864 (p<.0001) for the relationship between dosage and plasma aripiprazole level, and between dosage and plasma dehydroaripiprazole level, respectively.The plasma concentration-to-dose ratios were 17.79 ng/mL/mg and 6.27 ng/mL/mg for aripiprazole and dehydroaripiprazole, respectively. When comparing the group with higher plasma aripiprazole levels (>120ng/mL) to those with lower levels (<120 ng/mL), no significant differences were observed in terms of relapse rates, clinical severity, or occupational functioning. Notably, 3 out of 12 patients with drug levels <120 ng/mL and 4 of 19 patients with drug levels >120 ng/mL experienced relapse during 2-year follow-up (p = 0.798).

Previous review and meta-analysis suggest the reference range of target plasma aripiprazole level to be between 120-270 ng/mL. In our study, the lower doses reached by exponential tapering method were shown to improve quality of life with no worsened psychopathology. This study further verified the dose by showing good correlations between daily dose and plasma drug levels and confirmed that certain patients could maintain a stable clinical condition with a concentration below the previously recommended 120 ng/ml. Noteworthily, a higher concentration-to-dose ratio was observed compared to the Caucasian population, but it was consistent with the Asian population and may explain how our cohorts could maintain remitted under very low dose of aripiprazole. Furthermore, the strong correlation between plasma aripiprazole and dehydroaripiprazole levels suggests no need to measure both compounds and an exceptionally low plasma drug concentration may serve as an important signal of medication non- adherence.

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