Comorbidity of pain and depression or anxiety is a challenging clinical phenomenon, often requiring the concurrent application of antidepressant and analgesic drugs. Growing evidence suggests that the analgesic metamizole exhibits cytochrome P450 inducing properties. In the present study, we assessed the impact of metamizole and ibuprofen on plasma concentrations of the selective serotonin reuptake inhibitor sertraline. Methods: Out of a therapeutic drug monitoring (TDM) database, three groups of patients were compared: patients receiving sertraline and metamizole (n = 15), patients receiving sertraline and ibuprofen (n = 19), and a matched control group without one of the analgesics (n = 19). Results: Metamizole was associated with 67% lower median sertraline plasma concentrations compared to the control group (14 vs 42 ng/mL, P < 0.001). In contrast, differences between the ibuprofen group and the control group did not reach statistical significance (31 vs 42 ng/mL, P = 0.128). Moreover, the metamizole group demonstrated lower dose-adjusted drug concentrations than the ibuprofen group (0.10 vs 0.26 (ng/mL)/(mg/day), P = 0.008). Finally, the metamizole group exhibited a higher proportion of patients whose sertraline concentrations were below the therapeutic reference range (40% in the metamizole group, 5% in the ibuprofen group, 0% in the control group, P = 0.005) indicating therapeutically insufficient drug concentrations. Conclusion: Our findings support preliminary evidence that metamizole acts as a potent inductor of cytochrome P450 isoenzymes CYP2B6 and CYP3A4. We observed a clinically meaningful pharmacokinetic interaction between metamizole and sertraline, leading to insufficiently low sertraline drug concentrations. Clinicians should therefore consider alternative drug combinations or apply TDM-guided dose adjustment of sertraline.

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Augmentation of antipsychotic treatment with antidepressants represents a common and beneficial treatment strategy in patients suffering from schizophrenia. Combining clozapine and the selective serotonin reuptake inhibitor (SSRI) sertraline represents a clinically important strategy in patients with therapy‐resistant schizophrenia, but there is limited knowledge about mutual pharmacokinetic interactions. In the present study, we assessed the impact of clozapine on sertraline plasma concentrations. Based on a therapeutic drug monitoring (TDM) database, sertraline plasma concentrations were compared between two groups: patients receiving a combined treatment with sertraline and clozapine (N = 15) and a matched control group receiving sertraline but no clozapine (N = 17). Group differences with respect to raw and dose‐adjusted concentrations were assessed using nonparametric tests. Comedication with clozapine was associated with 67% lower median sertraline plasma concentrations (16 vs. 48 ng/mL; p = .022) and 28% lower median dose‐adjusted plasma concentrations (C/D; 0.21 vs. 0.29 (ng/mL)/(mg/day); p = .049) as compared to the control group. Scatter plots revealed a complex relationship between the dosage of clozapine and dose‐adjusted sertraline concentrations composed of an initial decrease at clozapine doses below 300 mg, an increase between 300 and 600 mg and a final decrease at 800 mg which was best modeled by a third order polynomial term. Cotreatment with clozapine may lead to reduced sertraline plasma concentrations which may be explained by clozapine‐induced gastrointestinal hypo‐mobility already present at low doses and cytochrome P450 3A4 inducing properties at high clozapine doses. For this drug combination, clinicians should consider TDM to confirm therapeutically effective plasma concentrations of sertraline.

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