title: High throughput identification and quantification of 16 antipsychotics and 8 major metabolites in serum using ultra-high performance liquid chromatography-tandem mass spectrometry.
abstract: BACKGROUND
  Therapeutic drug monitoring of antipsychotics is important for optimizing therapy, explaining adverse effects, non-response or poor compliance. We developed a UHPLC-MS/MS method for quantification of 16 commonly used and recently marketed antipsychotics and 8 metabolites in serum.
  
  
  METHODS
  After liquid-liquid extraction using methyl tert-butyl ether, analysis was performed on an Agilent Technologies 1290 Infinity LC system coupled with an Agilent Technologies 6460 Triple Quadrupole MS. Separation with a C18 column and gradient elution at 0.5 mL/min resulted in a 6-min run-time. Detection was performed in dynamic MRM, monitoring 3 ion transitions per compound. Isotope labeled internal standards were used for every compound, except for bromperidol and levosulpiride.
  
  
  RESULTS
  Mean recovery was 86.8%. Matrix effects were -18.4 to +9.1%. Accuracy ranged between 91.3 and 107.0% at low, medium and high concentrations and between 76.2 and 113.9% at LLOQ. Within-run precision was <15% (CV), except for asenapine and hydroxy-iloperidone. Between-run precision was aberrant only for 7-hydroxy-N-desalkylquetiapine, asenapine and reduced haloperidol. No interferences were found. No problems of instability were observed, even for olanzapine. The method was successfully applied on patient samples.
  
  
  CONCLUSIONS
  The liquid-liquid extraction and UHPLC-MS/MS technique allows robust target screening and quantification of 23 antipsychotics and metabolites.
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium. Electronic address: lisbeth.patteet@uantwerpen.be.
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Patteet
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Kristof E
authors.initials: KE
authors.lastname: Maudens
authors.affiliation: Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Psychiatric Centre Sint-Norbertushuis, Stationstraat 22c, B-2570 Duffel, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Sabbe
authors.affiliation: Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium; Psychiatric Hospital Broeders Alexianen, Provinciesteenweg 408, B-2530 Boechout, Belgium.
authors.forename: Manuel
authors.initials: M
authors.lastname: Morrens
authors.affiliation: Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium.
authors.forename: Mireille
authors.initials: M
authors.lastname: De Doncker
authors.affiliation: Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Neels
mesh_terms: D014150:Antipsychotic Agents / Q000097:blood* / Q000302:isolation & purification / Q000378:metabolism*; D001774:Blood Chemical Analysis / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D059625:Liquid-Liquid Extraction; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents
keywords: 7-hydroxy-N-desalkyl-quetiapine; 7-hydroxy-quetiapine; 7OH-NDA-QUE; 7OH-QUE; AGNP; AMI; AP; ARI; ASE; Antipsychotics; Arbeidsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie; BRO; CI; CLO; DARI; EMA; ER; ESI; European Medicines Agency; FDA; Food and Drug Administration; HAL; HILO; ILO; LC; LC–MS/MS; LLE; LLOQ; LSUL; LUR; ME; MRM; MS; MTBE; Mass spectrometry; N-demethyl-clozapine; N-demethyl-olanzapine; NDM-CLO; NDM-OLA; Neuroleptics; OLA; PAL; PIP; QC; QUE; RHAL; RIS; RT; SER; SIL-IS; Therapeutic drug monitoring; UHPLC–MS/MS; ZUC; amisulpride; antipsychotics; aripiprazole; asenapine; bromperidol; clozapine; confidence interval; dehydro-aripiprazole; electrospray ionization; extraction recovery; haloperidol; hydroxy-iloperidone; iloperidone; levosulpiride; liquid chromatography; liquid chromatography–tandem mass spectrometry; liquid–liquid extraction; lower limit of quantification; lurasidone; mass spectrometry; matrix effects; methyl tert-butyl ether; multiple-reaction monitoring; olanzapine; paliperidone; pipamperone; quality control; quetiapine; reduced haloperidol; retention time; risperidone; sertindole; stable isotope labeled internal standard; ultra-high performance liquid chromatography–tandem mass spectrometry; zuclopenthixol