Abstract
Based on the assumption that a relationship between blood levels and clinical effects (therapeutic effects, adverse events and toxicity) can be defined and considering that after equal doses plasma concentrations vary markedly between individual patients, therapeutic drug monitoring (TDM) can assist to personalize dose adjustment. Taken together, drug levels and a knowledge of the pharmacological profile of the administered drugs can enable the optimal dosage to be tailored according to the need of the individual patient. Therapeutic drug monitoring has been established for a limited number of drugs. In psychiatry, it has a 40-year-long history, which started with nortriptyline. Evidence has accumulated which shows that TDM is a valid tool for the optimization of psychopharmacotherapy. When used adequately, TDM is helpful for many patients and in many situations. Combined with pharmacogenetic tests, the metabolic status of a patient can be well characterized. Several new observations have been made during routine TDM that have stimulated clinical pharmacological research, such as investigations on inherited differences in drug metabolism that are closely linked to TDM in psychiatry. The contributions of individual forms of cytochrome P450 (CYP) to the metabolism of drugs was elicited by clinical observations on pharmacokinetic drug interactions. Therapeutic drug monitoring requires a close collaboration between the prescribing physician, the laboratory specialist, the clinical pharmacologist and the patient. This complexity may result in errors which can be detected by analysing the appropriate use of TDM in clinical practice. More education has to be provided to the prescribing clinicians on the pharmacology of the drugs and the algorithm of TDM. Moreover, clinical trials should include measurements of blood concentrations during drug development to generate valid data on the relationships between drug concentrations and clinical outcomes under well-controlled conditions. This would merely increase the amount of work and costs, as high-throughput methods are now available in many laboratories. Any progress in TDM has direct benefits for the treatment of many individual patients.
Similar content being viewed by others
References
Touw DJ, Neef C, Thomson AH, Vinks S (2005) Cost-effectiveness of therapeutic drug monitoring. Ther Drug Monit 27:10–17
Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Rao ML, Riederer P, Zernig G (2004) The AGNP-TDM expert group consensus guidelines: Therapeutic drug monitoring in psychiatry. Pharmacopsychiatria 37:243–265
Hammer WM, Brodie BB (1967) Application of isotope derivative technique to assay of secondary amines: estimation of desipramine by acetylation with H3-Acetic anhydride. J Pharmacol Exp Ther 157:503–508
Åsberg M, Cronholm B, Sjöqvist F, Tuck D (1970) Correlation of subjective side effects with plasma concentrations of nortriptyline. Br Med J 4:18–21
Åsberg M, Cronholm B, Sjöqvist F, Tuck D (1971) Relationship between plasma level and therapeutic effect of nortriptyline. Br Med J 3:331–334
Curry SH, Davis JM, Janowski DS, Marshall JHL (1970) Factors affecting chlorpromazine plasma levels in psychiatric patients. Arch Gen Psychiatry 22:209–215
Alexanderson BH, Evans DA, Sjöqvist S (1969) Steady_state plasma levels of nortriptyline in twins: influence of genetic factors and drug therapy. Br Med J 686:764–768
Bertilsson L, Mellström B, Sjöqvist F, Märtensson B, Åsberg M (1981) Slow hydroxylation of nortriptyline and concomitant poor debrisoquine hydroxylation: clinical implications. Lancet i:560–561
Gram LF, Overø KF (1972) Drug inhibition: Inhibitory effects of neuroleptics on metabolism of tricyclic antidepressants in man. Br Med J 1:463–465
Perry PJ (1987) The relationship between antidepressant response and tricyclic antidepressant plasma concentrations: a retrospective analysis of the literature using logistic regression analysis. Pharmacokinetics 13:381–392
Preskorn S, Jerkovich GS (1990) Central nervous system toxicity of tricyclic antidepressants: phenomenology, course, risk factors, and role of therapeutic drug monitoring. J Clin Psychopharmacol 10:88–95
Baldessarini RJ, Cohen BM, Teicher MH (1988) Significance of neuroleptic dose and plasma level in the pharmacological treatment of psychoses. Arch Gen Psychiatry 45:79–91
Perry PJ, Miller DD, Arndt SV, Cadoret RJ (1991) Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 148:231–235
Ulrich S, Wurthmann C, Brosz M, Meyer FP (1989) The relationship between serum concentration and therapeutic effect of haloperidol in patients with acute schizophrenia. Clin Pharmacokinet 34:227–263
van Putten T, Marder SR, Wirshing WC, Aravagiri M, Chabert N (1991) Neuroleptic plasma levels. Schizophr Bull 17:197–216
Hippius H (1989) The history of clozapine. Psychopharmacology 99:S3–S5
Kane JM, Honigfeld G, Singer J, Meltzer H (1988) Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 24:62–67
Perry PJ, Miller DD, Arndt SV, Cadoret RJ (1991) Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry 148:231–235
Hiemke C, Weigmann H, Härtter S, Dahmen N, Wetzel H, Müller H (1994) Elevated levels of clozapine in serum after addition of fluvoxamine. J Clin Psychopharmacol 14:279–281
Jerling M, Lindström L, Bondesson U, Bertilsson L (1994) Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 16:368–374
Bengtsson F (2004) Therapeutic drug monitoring of psychotropic drugs TDM "nouveau". Ther Drug Monit 26:145–151
Jaquenoud Sirot E, van der Velden JW, Rentsch K, Eap CB, Baumann P (2006) Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance. Drug Safety 29:735–68
Gutteck U, Rentsch KM (2003)Therapeutic drug monitoring of 13 antidepressant and five neuroleptic drugs in serum with liquid chromatography-electrospray ionization mass spectrometry. Clin Chem Lab Med 41:1571–1579
Kirchherr H, Kühn-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 843:100–113
Härtter S, Hiemke C (1992) Column switching and high-performance liquid chromatography in the analysis of amitriptyline, nortriptyline and hydroxylated metabolites in human plasma or serum. J Chromatogr 578:273–282
Härtter S, Weigmann H, Hiemke C (2000) Automated determination of reboxetine by high-performance liquid chromatography with column-switching and ultraviolet detection. J Chromatogr B 740:135–140
Saint-Marcoux F, Sauvage FL, Marquet P (2007) Current role of LC-MS in therapeutic drug monitoring. Anal Bioanal Chem 388:1327–1349
Farde L, Nordström AL, Wiesel F-A, Pauli S, Halldin C, Sedvall G (1992). Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch Gen Psychiatry 49:538–544
Farde L, Wiesel FA, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76
Gründer G, Siessmeier T, Piel T, Vernaleken I, Buchholz H-G, Zhou Y, Hiemke C, Wong DF, Rösch F, Bartenstein P (2003) Quantification of D2-like dopamine receptors in human brain with [18F]desmethoxyfallypride. J Nucl Med 44:109–116
Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000) A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57:553-559
Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA et al (1998) 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 155:921–928
Medori R, Mannaert E, Gründer G (2006) Plasma antipsychotic concentration and receptor occupancy, with special focus on risperidone long-acting injectable. Eur Neuropsychopharmacol 16:233–240
Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry 161:826–835
Nordström A-L, Farde L, Wiesel F-A, Forslund K, Pauli S, Halldin C, Uppfeldt G (1993) Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biol Psychiatry 33:227–235
Talbot PS, Laruelle M (2002) The role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development. Eur Neuropsychopharmacol 12:503–511
Talvik M, Nordstrom AL, Larsen NE, Jucaite A, Cervenka S, Halldin C, Farde L (2004) A cross-validation study on the relationship between central D2 receptor occupancy and serum perphenazine concentration. Psychopharmacology (Berl) 175:148–153
Vernaleken I, Siessmeier T, Buchholz HG, Härtter S, Hiemke C, Stoeter P, Rösch F, Bartenstein P, Gründer G (2004) High striatal occupancy of D2-like dopamine receptors by amisulpride in the brain of patients with schizophrenia. Int J Neuropsychopharmacol 7:421–430
Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF (2002) Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 27:248–259
Hiemke C, Dragicevic A, Gründer G, Härtter S, Sachse J, Vernaleken I, Müller MJ Therapeutic monitoring of new antipsychotic drugs. Ther Drug Monit 26:156–160
Lundmark J, Bengtsson F, Nordin C, Reis M, Walinder J (2000) Therapeutic drug monitoring of selective serotonin reuptake inhibitors influences clinical dosing strategies and reduces drug costs in depressed elderly patients. Acta Psychiat Scand 101:354–359
Müller MJ, Regenbogen B, Härtter S, Eich FX, Hiemke C (2007) Therapeutic drug monitoring for optimizing amisulpride therapy in patients with schizophrenia J Psychiatr Res 41:673–679
Bauer M, Whybrow PC, Angst J, Versiani M, Möller HJ (2002) World federation of societies of biological psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, Part 1: acute and continuation treatment of major depressive disorder World J Biol Psychiatry 3:5–43
Stassen HH, Angst J, Daniel H, Scharfetter C, Szegedi A (2007) Is there a common resilience mechanism underlying antidepressant drug response. Evidence from 2848 patients. J Clin Psychiatry 68:1105–1205
Beasley CM Jr, Stauffer VL, Liu-Seifert H, Taylor CC, Dunayevich E, Davis JM (2007) All-cause treatment discontinuation in schizophrenia during treatment with olanzapine relative to other antipsychotics: an integrated analysis. J Clin Psychopharmacol 27:252–258
Dolder CR, Lacro JP, Dunn LB, Jeste DV (2002) Antipsychotic medication adherence: is there a difference between typical and atypical agents? Am J Psychiatry 59:103–108
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–23
Chang Y-C, Lane HY, Yang KH, Huang CL (2006) Optimizing early prediction for antipsychotic response in schizophrenia. J Clin Psychopharmacol 26:554–559
Leucht S, Busch R, Kissling W, Kane JM (2007) Early prediction of antipsychotic nonresponse among patients with schizophrenia. J Clin Psychiatry 68:352–360
Leucht S, Davis JM, Engel RR, Kane JM, Wagenpfeil S (2007) Defining “response” in antipsychotic drug trials: recommendation for the use of scale-derived cutoffs. Neuropsychopharmacology (in press)
Szegedi A, Müller MJ, Anghelescu I, Klawe C, Kohnen R, Benkert O (2003) Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression. J Clin Psychiatry 64:413–420
Frank D, Jaehde U, Fuhr U (2007) Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur J Clin Pharmacol 63:321–333
Faber MS, Jetter A, Fuhr U (2005) Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol 97:125–1234
Streetman DS, Bertino JS Jr, Nafziger AN (2000) Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes. Pharmacogenetics 10:187–216
Tanaka E, Kurata N, Yasuhara H (2003) How useful is the “cocktail approach” for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotyping probes in vivo? J Clin Pharm Ther 28:157–65
Nelson DR (2006) Cytochrome P450 nomenclature, 2004. Methods Mol Biol 320:1–10
Aranow AB, Hudson JI, Pope HG Jr, Grady TA, Laage TA, Bell IR, Cole JO (1989) Elevated antidepressant plasma levels after addition of fluoxetine. Am J Psychiatry 146:911–913
Bertschy G, Vandel S, Vandel B, Allers G, Volmat R (1991) Fluvoxamine-tricyclic antidepressant interaction. An accidental finding. Eur J Clin Pharmacol 40:119–120
Jerling M, Lindström L, Bondesson U, Bertilsson L (1994) Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 16:368–374
Müller MJ, Dragicevic A, Fric M, Gaertner I, Grasmäder K, Härtter S, Hermann E, Kuss HJ, Laux G, Oehl W, Rao ML, Rollmann N, Weigmann H, Weber-Labonte M, Hiemke C (2003) Therapeutic drug monitoring of tricyclic antidepressants: How does it work under clinical conditions Pharmacopsychiatry 36:98–104
Zernig G, Lechner T, Kramer-Reinstadler K, Hinterhuber H, Hiemke C, Saria A (2004) What the clinician still has to be reminded of. Ther Drug Monit 26:582
Vuille F, Amey M, Baumann P (1991) Use of plasma level monitoring of antidepressants in clinical practive – Towards an analysis of clinical utility. Pharmacopsychiatry 24:190–195
Mann K, Hiemke C, Schmidt LG, Bates DW (2006) Appropriateness of therapeutic drug monitoring for antidepressants in routine psychiatric inpatient care. Ther Drug Monit 28:83–88
Mann K, Hiemke C, Lotz J, Schmidt LG, Lackner KJ, Bates DW (2006) Appropriateness of plasma level determinations for lithium and valproate in routine care of psychiatric inpatients with affective disorders. J Clin Psychopharmacol 26:671–673
Acknowledgements
The author (C. Hiemke) has received research grants and lecture fees from the pharmaceutical companies Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Lundbeck, Pfizer, Servier, Sanofi-Aventis and Wyeth. The author indicates that no potential conflict of interest exists with products described in this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hiemke, C. Clinical utility of drug measurement and pharmacokinetics – therapeutic drug monitoring in psychiatry. Eur J Clin Pharmacol 64, 159–166 (2008). https://doi.org/10.1007/s00228-007-0430-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-007-0430-1