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The Analysis of Antipsychotic Drugs in Human Biosamples by LC-MS

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LC-MS in Drug Bioanalysis

Abstract

Over the last 60 years extensive development has occurred in the ­pharmacological treatment of mental illnesses with currently over 40 different ­compounds being prescribed.

Antipsychotic drugs (APs) are today amongst the most commonly prescribed drug classes with “second generation” or “atypical” APs accounting for the ­majority of prescriptions worldwide. As noncompliance is a common problem amongst patients treated with APs, these drugs are frequently subject to therapeutic drug monitoring (TDM). LC-MS techniques have facilitated the detection of these drugs which are frequently associated with very low blood concentrations particularly after IM depot injections. Multiple methods for the detection and quantification of APs in human biological specimens have been published using LC-MS, particularly in the last decade, as this instrumentation has been available for routine laboratories. This chapter reviews published multianalyte methods and highlights the important ­criteria when developing an analytical method for the detection of APs, potential pitfalls, and the importance of appropriate method validation, in order to assure reproducibility of results.

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References

  1. Jones AW (2011) Perspectives in drug discovery 6. Antipsychotics. TIAFT Bull 41(2):16–19

    Google Scholar 

  2. Cade JF (1949) Lithium salts in the treatment of psychotic excitement. Med J Aust 2(10):349–352

    CAS  Google Scholar 

  3. Delay J, Deniker P, Harl JM (1952) Therapeutic method derived from hiberno-therapy in excitation and agitation states. Ann Med Psychol (Paris) 110(2(2)):267–273

    CAS  Google Scholar 

  4. Caroff SN, Mann SC (1993) Neuroleptic malignant syndrome. Med Clin North Am 77(1):185–202

    CAS  Google Scholar 

  5. Caroff SN (1980) The neuroleptic malignant syndrome. J Clin Psychiatry 41(3):79–83

    CAS  Google Scholar 

  6. Keck PE Jr, Caroff SN, McElroy SL (1995) Neuroleptic malignant syndrome and malignant hyperthermia: end of a controversy? J Neuropsychiatry Clin Neurosci 7(2):135–144

    Google Scholar 

  7. Stubner S, Rustenbeck E, Grohmann R, Wagner G, Engel R, Neundorfer G, Moller HJ, Hippius H, Ruther E (2004) Severe and uncommon involuntary movement disorders due to psychotropic drugs. Pharmacopsychiatry 37(Suppl 1):S54–S64. doi:10.1055/s-2004-815511

    Google Scholar 

  8. Carbone JR (2000) The neuroleptic malignant and serotonin syndromes. Emerg Med Clin North Am 18(2):317–325

    Article  CAS  Google Scholar 

  9. Welch R, Chue P (2000) Antipsychotic agents and qt changes. J Psychiatry Neurosci 25(2):154–160

    CAS  Google Scholar 

  10. Ray WA, Meredith S, Thapa PB, Meador KG, Hall K, Murray KT (2001) Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 58(12):1161–1167. doi: yoa20305 [pii]

    Article  CAS  Google Scholar 

  11. Straus SM, Bleumink GS, Dieleman JP, van der Lei J, ‘t Jong GW, Kingma JH, Sturkenboom MC, Stricker BH (2004) Antipsychotics and the risk of sudden cardiac death. Arch Intern Med 164(12):1293–1297. doi:10.1001/archinte.164.12.1293, 164/12/1293 [pii]

    Article  Google Scholar 

  12. Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99(Suppl):S18–S27

    Article  Google Scholar 

  13. Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, Houle S (1998) 5-ht2 and d2 receptor occupancy of olanzapine in schizophrenia: a pet investigation. Am J Psychiatry 155(7):921–928

    CAS  Google Scholar 

  14. Duinkerke SJ, Botter PA, Jansen AA, van Dongen PA, van Haaften AJ, Boom AJ, van Laarhoven JH, Busard HL (1993) Ritanserin, a selective 5-ht2/1c antagonist, and negative symptoms in schizophrenia. A placebo-controlled double-blind trial. Br J Psychiatry 163:451–455

    Article  CAS  Google Scholar 

  15. Seeman P (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47(1):27–38

    Google Scholar 

  16. Seeman P, Tallerico T (1999) Rapid release of antipsychotic drugs from dopamine d2 receptors: An explanation for low receptor occupancy and early clinical relapse upon withdrawal of clozapine or quetiapine. Am J Psychiatry 156(6):876–884

    CAS  Google Scholar 

  17. Ray WA, Chung CP, Murray KT, Hall K, Stein CM (2009) Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 360(3):225–235. doi: 360/3/225 [pii] 10.1056/NEJMoa0806994

    Article  CAS  Google Scholar 

  18. Muench J, Hamer AM (2010) Adverse effects of antipsychotic medications. Am Fam Physician 81(5):617–622

    Google Scholar 

  19. Ananth J, Parameswaran S, Gunatilake S (2004) Antipsychotic polypharmacy. Curr Pharm Des 10(18):2231–2238

    Article  CAS  Google Scholar 

  20. Barbui C, Ciuna A, Nose M, Patten SB, Stegagno M, Burti L, Amaddeo F, Tansella M (2004) Off-label and non-classical prescriptions of antipsychotic agents in ordinary in-patient practice. Acta Psychiatr Scand 109(4):275–278. doi: 283 [pii]

    Article  CAS  Google Scholar 

  21. Fleischhacker WW (2003) Second-generation antipsychotics: Discrepancies between licensed indications, evidence base and actual use. Psychopharmacology (Berl) 169(2):207–210. doi:10.1007/s00213-003-1496-9

    Article  CAS  Google Scholar 

  22. Barnes TR, Curson DA (1994) Long-term depot antipsychotics. A risk-benefit assessment. Drug Saf 10(6):464–479

    Article  CAS  Google Scholar 

  23. Milton GV, Jann MW (1995) Emergency treatment of psychotic symptoms. Pharmacokinetic considerations for antipsychotic drugs. Clin Pharmacokinet 28(6):494–504

    Article  CAS  Google Scholar 

  24. Jones B, Taylor CC, Meehan K (2001) The efficacy of a rapid-acting intramuscular formulation of olanzapine for positive symptoms. J Clin Psychiatry 62(Suppl 2):22–24

    CAS  Google Scholar 

  25. Jorgensen A, Andersen J, Bjorndal N, Dencker SJ, Lundin L, Malm U (1982) Serum concentrations of cis(z)-flupentixol and prolactin in chronic schizophrenic patients treated with flupentixol and cis(z)-flupentixol decanoate. Psychopharmacology (Berl) 77(1):58–65

    Article  CAS  Google Scholar 

  26. Maurer HH (1992) Systematic toxicological analysis of drugs and their metabolites by gas chromatography-mass spectrometry. J Chromatogr 580(1–2):3–41

    CAS  Google Scholar 

  27. Arinobu T, Hattori H, Iwai M, Ishii A, Kumazawa T, Suzuki O, Seno H (2002) Liquid chromatographic-mass spectrometric determination of haloperidol and its metabolites in human plasma and urine. J Chromatogr B Analyt Technol Biomed Life Sci 776(1):107–113. doi: S1570023202001757 [pii]

    Article  CAS  Google Scholar 

  28. De Meulder M, Remmerie BM, de Vries R, Sips LL, Boom S, Hooijschuur EW, van de Merbel NC, Timmerman PM (2008) Validated lc-ms/ms methods for the determination of risperidone and the enantiomers of 9-hydroxyrisperidone in human plasma and urine. J Chromatogr B Analyt Technol Biomed Life Sci 870(1):8–16. doi: S1570-0232(08)00281-X [pii] 10.1016/j.jchromb.2008.04.041

    Article  Google Scholar 

  29. Josefsson M, Kronstrand R, Andersson J, Roman M (2003) Evaluation of electrospray ionisation liquid chromatography-tandem mass spectrometry for rational determination of a number of neuroleptics and their major metabolites in human body fluids and tissues. J Chromatogr B Analyt Technol Biomed Life Sci 789(1):151–167. doi: S1570023203002071 [pii]

    Article  CAS  Google Scholar 

  30. Kumazawa T, Seno H, Watanabe-Suzuki K, Hattori H, Ishii A, Sato K, Suzuki O (2000) Determination of phenothiazines in human body fluids by solid-phase microextraction and liquid chromatography/tandem mass spectrometry. J Mass Spectrom 35(9):1091–1099. doi:10.1002/1096-9888(200009)35:9<1091::AID-JMS31>3.0.CO;2-M [pii] 10.1002/1096-9888(200009)35:9<1091::AID-JMS31>3.0.CO;2-M

    Article  CAS  Google Scholar 

  31. Flarakos J, Luo W, Aman M, Svinarov D, Gerber N, Vouros P (2004) Quantification of risperidone and 9-hydroxyrisperidone in plasma and saliva from adult and pediatric patients by liquid chromatography-mass spectrometry. J Chromatogr A 1026(1–2):175–183

    CAS  Google Scholar 

  32. Josefsson M, Roman M, Skogh E, Dahl ML (2010) Liquid chromatography/tandem mass spectrometry method for determination of olanzapine and n-desmethylolanzapine in human serum and cerebrospinal fluid. J Pharm Biomed Anal 53(3):576–582. doi: S0731-7085(10)00221-9 [pii] 10.1016/j.jpba.2010.03.040

    Article  CAS  Google Scholar 

  33. McClean S, O’Kane EJ, Smyth WF (2000) Electrospray ionisation-mass spectrometric characterisation of selected anti-psychotic drugs and their detection and determination in human hair samples by liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl 740(2):141–157

    Article  CAS  Google Scholar 

  34. Muller C, Vogt S, Goerke R, Kordon A, Weinmann W (2000) Identification of selected psychopharmaceuticals and their metabolites in hair by lc/esi-cid/ms and lc/ms/ms. Forensic Sci Int 113(1–3):415–421. doi: S0379073800002024 [pii]

    Article  CAS  Google Scholar 

  35. Nielsen MK, Johansen SS, Dalsgaard PW, Linnet K (2010) Simultaneous screening and quantification of 52 common pharmaceuticals and drugs of abuse in hair using uplc-tof-ms. Forensic Sci Int 196(1–3):85–92. doi: S0379-0738(09)00528-3 [pii] 10.1016/j.forsciint.2009.12.027

    Article  CAS  Google Scholar 

  36. Thieme D, Sachs H (2007) Examination of a long-term clozapine administration by high resolution segmental hair analysis. Forensic Sci Int 166(2–3):110–114. doi: S0379-0738(06)00267-2 [pii] 10.1016/j.forsciint.2006.04.015

    Article  CAS  Google Scholar 

  37. Weinmann W, Muller C, Vogt S, Frei A (2002) Lc-ms-ms analysis of the neuroleptics clozapine, flupentixol, haloperidol, penfluridol, thioridazine, and zuclopenthixol in hair obtained from psychiatric patients. J Anal Toxicol 26(5):303–307

    CAS  Google Scholar 

  38. Skopp G (2009) Postmortem toxicology: artifacts. In: Wiley encyclopedia of forensic science. doi:10.1002/9780470061589.fsa417

    Google Scholar 

  39. Kirchherr H, Kuhn-Velten WN (2006) Quantitative determination of forty-eight antidepressants and antipsychotics in human serum by hplc tandem mass spectrometry: a multi-level, single-sample approach. J Chromatogr B Analyt Technol Biomed Life Sci 843(1):100–113. doi: S1570-0232(06)00445-4 [pii] 10.1016/j.jchromb.2006.05.031

    Article  CAS  Google Scholar 

  40. Kratzsch C, Peters FT, Kraemer T, Weber AA, Maurer HH (2003) Screening, library-assisted identification and validated quantification of fifteen neuroleptics and three of their metabolites in plasma by liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization. J Mass Spectrom 38(3):283–295. doi:10.1002/jms.440

    Article  CAS  Google Scholar 

  41. Saar E, Gerostamoulos D, Drummer OH, Beyer J (2010) Identification and quantification of 30 antipsychotics in blood using lc-ms/ms. J Mass Spectrom 45(8):915–925. doi:10.1002/jms.1783

    Article  CAS  Google Scholar 

  42. Bhatt J, Subbaiah G, Singh S (2006) Liquid chromatography/tandem mass spectrometry method for simultaneous determination of risperidone and its active metabolite 9-hydroxyrisperidone in human plasma. Rapid Commun Mass Spectrom 20(14):2109–2114. doi:10.1002/rcm.2537

    Article  CAS  Google Scholar 

  43. Nielsen MK, Johansen SS (2009) Determination of olanzapine in whole blood using simple protein precipitation and liquid chromatography-tandem mass spectrometry. J Anal Toxicol 33(4):212–217

    CAS  Google Scholar 

  44. Kollroser M, Schober C (2002) Direct-injection high performance liquid chromatography ion trap mass spectrometry for the quantitative determination of olanzapine, clozapine and n-desmethylclozapine in human plasma. Rapid Commun Mass Spectrom 16(13):1266–1272. doi:10.1002/rcm.718

    Article  CAS  Google Scholar 

  45. Berna M, Shugert R, Mullen J (1998) Determination of olanzapine in human plasma and serum by liquid chromatography/tandem mass spectrometry. J Mass Spectrom 33(10):1003–1008. doi:10.1002/(SICI)1096-9888(1998100)33:10<1003::AID-JMS716>3.0.CO;2-P [pii] 10.1002/(SICI)1096-9888(1998100)33:10<1003::AID-JMS716>3.0.CO;2-P

    Article  CAS  Google Scholar 

  46. Hasselstrom J (2011) Quantification of antidepressants and antipsychotics in human serum by precipitation and ultra high pressure liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 879(1):123–128. doi: S1570-0232(10)00727-0 [pii] 10.1016/j.jchromb.2010.11.024

    Article  CAS  Google Scholar 

  47. Moody DE, Laycock JD, Huang W, Foltz RL (2004) A high-performance liquid chromatographic-atmospheric pressure chemical ionization-tandem mass spectrometric method for determination of risperidone and 9-hydroxyrisperidone in human plasma. J Anal Toxicol 28(6):494–497

    CAS  Google Scholar 

  48. Berna M, Ackermann B, Ruterbories K, Glass S (2002) Determination of olanzapine in human blood by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 767(1):163–168

    Article  CAS  Google Scholar 

  49. Dams R, Huestis MA, Lambert WE, Murphy CM (2003) Matrix effect in bio-analysis of illicit drugs with lc-ms/ms: Influence of ionization type, sample preparation, and biofluid. J Am Soc Mass Spectrom 14(11):1290–1294. doi: S1044030503005749 [pii]

    Article  CAS  Google Scholar 

  50. Bonfiglio R, King RC, Olah TV, Merkle K (1999) The effects of sample preparation methods on the variability of the electrospray ionization response for model drug compounds. Rapid Commun Mass Spectrom 13(12):1175–1185. doi:10.1002/(SICI)1097-0231(19990630)13:12<1175::AID-RCM639>3.0.CO;2-0 [pii] 10.1002/(SICI)1097-0231(19990630)13:12<1175::AID-RCM639>3.0.CO;2-0

    Article  CAS  Google Scholar 

  51. Matuszewski BK, Constanzer ML, Chavez-Eng CM (2003) Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on hplc-ms/ms. Anal Chem 75(13):3019–3030

    Article  CAS  Google Scholar 

  52. Maurer HH (2005) Advances in analytical toxicology: the current role of liquid chromatography-mass spectrometry in drug quantification in blood and oral fluid. Anal Bioanal Chem 381(1):110–118. doi:10.1007/s00216-004-2774-z

    Article  CAS  Google Scholar 

  53. Cabovska B, Cox SL, Vinks AA (2007) Determination of risperidone and enantiomers of 9-hydroxyrisperidone in plasma by lc-ms/ms. J Chromatogr B Analyt Technol Biomed Life Sci 852(1–2):497–504. doi: S1570-0232(07)00105-5 [pii] 10.1016/j.jchromb.2007.02.007

    CAS  Google Scholar 

  54. Roman M, Kronstrand R, Lindstedt D, Josefsson M (2008) Quantitation of seven low-dosage antipsychotic drugs in human postmortem blood using lc-ms-ms. J Anal Toxicol 32(2):147–155

    CAS  Google Scholar 

  55. Remane D, Meyer MR, Wissenbach DK, Maurer HH (2010) Ion suppression and enhancement effects of co-eluting analytes in multi-analyte approaches: systematic investigation using ultra-high-performance liquid chromatography/mass spectrometry with atmospheric-pressure chemical ionization or electrospray ionization. Rapid Commun Mass Spectrom 24(21):3103–3108. doi:10.1002/rcm.4736

    Article  CAS  Google Scholar 

  56. U.S. Department of Health and Human Services. Guidance for industry: mass spectrometry for confirmation of the identity of animal drug residues, final guidance. Available at: http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm. Accessed 15 Jan 2012.

  57. (WADA) TWA-DA (2010) Identification criteria for qualitative assays document td2003idcr

    Google Scholar 

  58. Union CotE (2002) Validation concepts for pesticide residues in food of animal origin 2002/657/ec

    Google Scholar 

  59. Peters FT, Maurer HH (2002) Bioanalytical method validation and its implications for forensic and clinical toxicology - a review. Accred Qual Assur 7(11):441–449

    Article  CAS  Google Scholar 

  60. Peters FT, Drummer OH, Musshoff F (2007) Validation of new methods. Forensic Sci Int 165(2–3):216–224. doi: S0379-0738(06)00323-9 [pii] 10.1016/j.forsciint.2006.05.021

    Article  CAS  Google Scholar 

  61. Shah VP, Midha KK, Findlay JW, Hill HM, Hulse JD, McGilveray IJ, McKay G, Miller KJ, Patnaik RN, Powell ML, Tonelli A, Viswanathan CT, Yacobi A (2000) Bioanalytical method validation–a revisit with a decade of progress. Pharm Res 17(12):1551–1557

    Article  CAS  Google Scholar 

  62. Chew WM, Xu MJ, Cordova CA, Chow HH (2006) Quantification of a cytochrome p450 3a4 substrate, buspirone, in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 844(2):235–239. doi: S1570-0232(06)00542-3 [pii] 10.1016/j.jchromb.2006.07.005

    Article  CAS  Google Scholar 

  63. Gschwend MH, Arnold P, Ring J, Martin W (2006) Selective and sensitive determination of amisulpride in human plasma by liquid chromatography-tandem mass spectrometry with positive electrospray ionisation and multiple reaction monitoring. J Chromatogr B Analyt Technol Biomed Life Sci 831(1–2):132–139. doi: S1570-0232(05)00890-1 [pii] 10.1016/j.jchromb.2005.11.042

    CAS  Google Scholar 

  64. Saar E, Gerostamoulos D, Drummer OH, Beyer J (2011) Assessment of the stability of 30 antipsychotic drugs in stored blood specimens. Forensic Sci Int. doi: S0379-0738(11)00104-6 [pii] 10.1016/j.forsciint.2011.02.022

    Google Scholar 

  65. Olesen OV, Linnet K (1998) Determination of olanzapine in serum by high-performance liquid chromatography using ultraviolet detection considering the easy oxidability of the compound and the presence of other psychotropic drugs. J Chromatogr B Biomed Sci Appl 714(2):309–315

    Article  CAS  Google Scholar 

  66. Zhou Z, Li X, Li K, Xie Z, Cheng Z, Peng W, Wang F, Zhu R, Li H (2004) Simultaneous determination of clozapine, olanzapine, risperidone and quetiapine in plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 802(2):257–262. doi: 10.1016/j.jchromb.2003.11.037 S1570023203010109 [pii]

    Article  CAS  Google Scholar 

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Saar, E., Gerostamoulos, D., Drummer, O.H., Beyer, J. (2012). The Analysis of Antipsychotic Drugs in Human Biosamples by LC-MS. In: Xu, Q., Madden, T. (eds) LC-MS in Drug Bioanalysis. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-3828-1_8

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