The negative impact of vitamin D on antipsychotic drug exposure may counteract its potential benefits in schizophrenia

Abstract

Aims Patients with schizophrenia frequently show insufficient vitamin D levels, which are associated with somatic comorbidity and may contribute to psychopathology. For many reasons, vitamin D supplementation may be indicated for this patient cohort. However, there is growing evidence for a vitamin D‐mediated increase of drug metabolism by induction of cytochrome P450 (CYP) 3A4. Hence, this study aimed to assess vitamin D's impact on both antipsychotic drug concentrations and psychopathology in a non‐interventional manner. Methods Totals of 107 serum concentrations of different antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone), 80 serum concentrations of vitamin D and psychopathological assessments were obtained from 80 patients with schizophrenia. The impact of Vitamin D on antipsychotic drug concentrations and symptomatology was assessed using a generalized linear model, path and correlation analyses. Results We observed a negative relationship between vitamin D and dose‐adjusted antipsychotic drug concentrations, which was particularly pronounced for drugs which are predominantly metabolized via CYP3A4 (i.e., aripiprazole and quetiapine). A path analysis suggested a relieving effect of vitamin D on symptomatology which was, however, counteracted by its negative impact on antipsychotic drug levels. Finally, patients with vitamin D levels above the median exhibited a significantly higher proportion of therapeutically insufficient dose‐normalized drug concentrations of aripiprazole and quetiapine. Conclusion Despite vitamin D's potential benefits on physical and mental health, clinicians should be aware of its negative impact on blood concentrations of antipsychotics metabolized by CYP3A4 in patients with schizophrenia. Therefore, when considering its supplementation, therapeutic drug monitoring should be applied to guide dose adjustment.

Discovering interactions in augmentation strategies: Impact of duloxetine on the metabolism of aripiprazole

“…Indeed, a previous study even revealed increased serum levels of both, aripiprazole and dehydroaripiprazole, following the application of the CYP3A4‐inhibitor itraconazole corresponding to an increased active moiety 19 . Accordingly, our own previous research suggested that serum concentrations of 25‐OH vitamin D, an inducer of CYP3A4, were negatively correlated with the active moiety of aripiprazole 42 . Therefore, we expect that a co‐treatment with duloxetine might also increase the active moiety of aripiprazole and dehydroaripiprazole.…”

“…19 Accordingly, our own previous research suggested that serum concentrations of 25-OH vitamin D, an inducer of CYP3A4, were negatively correlated with the active moiety of aripiprazole. 42 Therefore, we expect that a co-treatment with duloxetine might also increase the active moiety of aripiprazole and dehydroaripiprazole. Future studies should seek to confirm this hypothesis by investigating both, the parent compound and its active metabolite, in patients with or without co-treatment with duloxetine.…”

Lower sertraline plasma concentration in patients co‐medicated with clozapine—Implications for pharmacological augmentation strategies in schizophrenia

“…Therefore, the quantitative estimates of clozapine's impact on sertraline plasma concentrations have to be considered as rather uncertain. Another limitation is the non-normal (right-skewed) distribution of plasma levels requiring nonparametric statistical tests, which is however, a common finding related to TDM studies ( 46,47 ). As a further limitation, plasma concentrations of desmethylsertraline, the main metabolite of sertraline, were not available.…”