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Clinicians recognize that monitoring psychotropic levels provides invaluable information to optimize therapy and track treatment adherence, but they lack formal training specifically focused on the use of plasma antipsychotic levels for these purposes. As new technologies emerge to rapidly provide these results, the opportunity to integrate this information into clinical care will grow. This practical handbook clarifies confusing concepts in the literature on use of antipsychotic levels, providing clear explanations for the logic underlying clinically relevant concepts such as the therapeutic threshold and the point of futility, and how these apply to individual antipsychotics.
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Library of Congress Cataloging-in-Publication Data
Names: Meyer, Jonathan M., 1962– author. | Stahl, Stephen M., 1951– author.
Title: The clinical use of antipsychotic plasma levels / Jonathan M Meyer, Stephen M Stahl; with illustrations by Nancy Munter.
Other titles: Stahl’s handbooks.
Description: Cambridge; New York, NY: Cambridge University Press, 2021. | Series: Stahl’s handbooks | Includes bibliographical references and index.
Identifiers: LCCN 2021012648 (print) | LCCN 2021012649 (ebook) | ISBN 9781009009898 (paperback) | ISBN 9781009002103 (ebook)
Subjects: MESH: Antipsychotic Agents–blood | Dose-Response Relationship, Drug | Antipsychotic Agents–therapeutic use | Dose-Response Relationship, Drug | Psychotic Disorders–drug therapy | Schizophrenia–drug therapy | BISAC: MEDICAL / Mental Health | MEDICAL / Mental Health
Classification: LCC RM333.5 (print) | LCC RM333.5 (ebook) | NLM QV 77.9 | DDC 615.7/882–dc23
LC record available at https://lccn.loc.gov/2021012648
LC ebook record available at https://lccn.loc.gov/2021012649
ISBN 978-1-009-00989-8 Paperback
Cambridge University Press has no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.
Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors, and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors, and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this book. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use.
In 1993, John Davis, Phil Janicak, and I co-edited a book titled Clinical Use of Neuroleptic Plasma Levels . The publication pre-dated the introduction of most of the antipsychotics that are currently in clinical use. Among the guiding principles was the conviction that the available antipsychotics had a relatively narrow therapeutic index and that plasma concentrations could be useful for making everyday clinical decisions. The most important concern at that time was focused on extrapyramidal side effects (EPS) and the challenge was to find a “therapeutic window” that was associated with clinical effectiveness and minimal discomfort. The introduction of another generation of antipsychotics – led by risperidone, olanzapine, and quetiapine – led many prescribers to believe that these medications were better tolerated and that the search for a therapeutic window was unnecessary. Unfortunately, this belief was naïve and research in the clinical use of antipsychotic plasma levels decreased substantially.
Experience with the newer drugs demonstrated that, although many patients appeared comfortable on higher doses of medications such as olanzapine, all of these medications had dose-related side effects, including metabolic effects for some and EPS for others. In other words, the use of plasma concentrations or therapeutic drug monitoring (TDM) for making clinical decisions has great promise and this volume by Jonathan Meyer in Stephen Stahl’s Handbook series is very welcome. An important strength of their approach is that it provides a thoughtful framework for interpreting plasma level information under different circumstances, and for differentiating nonadherence from kinetic issues when lower-than-expected levels are encountered. In most cases, patients will benefit when they are managed with drug doses within the recommended range, so there is not always a need to search for a plasma level window. On the other hand, TDM can be helpful for providing information when there are important clinical questions, as defined in a recent expert consensus . The most obvious use is when clinicians are monitoring medication adherence on an ongoing basis, or in order to determine why an individual fails to respond to what appears to be an adequate drug dose. TDM may also be helpful when patients are being treated with medications with a high side burden at doses that are clinically effective. This is commonly the case with clozapine where there is evidence for a threshold below which patients are unlikely to respond . For higher doses, this Handbook also introduces the concept of the point of futility, or a level above which there is a very low likelihood that patients will show additional improvement. Finally, TDM may also have a valuable role during long-term treatment when patients have minimal or few active symptoms and the goal is to prevent a psychotic relapse. Under these circumstances, symptoms cannot guide an assessment as to whether or not a patient is on an adequate amount of medication.
This volume addresses each of these clinical situations and others. It is also important to note that these situations are common and following the guidance provided by this volume has the potential for enhancing clinical care.
Stephen R. Marder, MD
Professor of Psychiatry and Director of the Section on Psychosis
UCLA Semel Institute for Neuroscience and Human Behavior
Director – VISN 22 Mental Illness Research, Education Clinical Center (MIRECC) for the Department of Veterans Affairs
1.Marder, S. R., Davis, J. M., and Janicak, P. G., eds. (1993). Clinical Use of Neuroleptic Plasma Levels. Washington, DC: American Psychiatric Press Inc.
2.Schoretsanitis, G., Kane, J. M., Correll, C. U., et al. (2020). Blood levels to optimize antipsychotic treatment in clinical practice: A joint consensus statement of the American Society of Clinical Psychopharmacology (ASCP) and the Therapeutic Drug Monitoring (TDM) Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). J Clin Psychiatry, 81, https://doi.org/10.4088/JCP.4019cs13169.
To best apply the information in this handbook, chapters 1-5 are worth reading initially, as they lay out some clinically important ideas such as coefficient of variation, time to steady state, the therapeutic threshold, and point of futility. One need not be an expert in antipsychotic kinetics to treat schizophrenia patients, but questions regarding oral medication adherence, when to obtain plasma levels, how to differentiate ultrarapid metabolizers from nonadherent patients, and the point at which further titration is unlikely to yield significant improvement are basic clinical decisions made every day. The sections covering specific antipsychotics builds on concepts explained in chapters 1–5 of the handbook. Reading the first five chapters will hopefully be enlightening, and provide the reader with the necessary tools to use plasma antipsychotic levels effectively. Those five chapters cover the following topics:
1. Sampling times for oral and long-acting injectable agents
2. The therapeutic threshold and the point of futility
3. Level interpretation including laboratory reporting issues, responding to high plasma levels, and special situations (hepatic dysfunction, renal dysfunction and hemodialysis, bariatric surgery)
4. Tracking oral antipsychotic adherence; differentiating treatment resistance from kinetic failure due to genetic variation or concurrent medications / environmental exposures, or adherence failure; use of pharmacogenomics
5. What is an adequate antipsychotic trial? Using plasma levels to optimize psychiatric response and tolerability (and when to use high-dose antipsychotics)
For easy reference, the following tables discussed elsewhere in this handbook are presented here:
Table P1 – Oral dose equivalency of commonly used first- and second-generation antipsychotics in acute schizophrenia
Table P2 – Antipsychotic nmol/l to ng/ml unit conversion
Table P3 – Mean half-life of commonly used oral antipsychotics and important metabolites
Table P4 – Mean half-life and kinetic properties of commonly used long-acting injectable antipsychotics
For easy access, the Appendix contains a single table that summarizes the therapeutic threshold, point of futility, and oral antipsychotic concentration–dose relationships.
|Medication||Oral equivalent (mg)|
a Clozapine dose equivalencies are not provided as the primary use is for treatment-resistant schizophrenia and there are no equivalent medications .
b Quetiapine dose equivalents are not provided as both naturalistic and clinical trials data raise concerns about efficacy as monotherapy for schizophrenia [4, 5]. When used at doses > 400 mg/d for schizophrenia treatment, quetiapine also has substantial metabolic adverse effects [6, 7].
Note: Other antipsychotic dose equivalencies for antipsychotics not listed here can be calculated using a spreadsheet developed by Professor Stefan Leucht and colleagues . The results are reported based on a variety of methods (e.g. minimum effective dose, 95% effective dose, etc.) and the spreadsheet can be downloaded from their website:
|Antipsychotic||To obtain plasma levels in ng/ml divide levels in nmol/l by the value below:|
|Asenapine transdermal patch||30c|
|Desmethylcariprazine (DCAR)||29.7–39.5 (DCAR)|
|Didesmethylcariprazine (DDCAR)||314–446 (DDCAR)|
|Paliperidone (9-OH risperidone)e||23|
Half-lives may be markedly prolonged in individuals receiving metabolic inhibitors or who have lower-functioning polymorphisms of cytochrome P450 enzymes, other relevant enzymes, or transporters involved in drug disposition. Conversely, half-lives may be significantly shorter than the mean in individuals exposed to inducers, or who have higher-functioning polymorphisms of cytochrome P450 enzymes, other relevant enzymes, or transporters involved in drug disposition.
c After patch removal.
e When administered as oral paliperidone.
f When derived from orally administered risperidone.
|Drug||Vehicle||Dosage||Tmax||T1/2 multiple dosing||Able to be loaded|
|Fluphenazine decanoate||Sesame oil||
||0.3–1.5 days||14 days||Yes|
|Haloperidol decanoate||Sesame oil||
||3–9 days||21 days||Yes|
|Perphenazine decanoate||Sesame oil||27–216 mg/3–4 weeks||7 days||27 days||Yes|
|Flupenthixol decanoate||Coconut oil||
||4–7 days||17 days||Yes|
|Zuclopenthixol decanoate||Coconut oil||
||3–7 days||19 days||Yes|
||Water||90–120 mg/4 weeks||7–8 days||9–11 days||Not needed|
||Water||12.5–50 mg/2 weeks||21 days||See note a||
||Water||39–234 mg/4 weeks||13 days||25–49 days||Yes|
||Water||273–819 mg/12 weeks||
||7 days||30 days||Yes|
||Water||300–400 mg/4 weeks||6.5–7.1 days||29.9–46.5 days||
|Aripiprazole lauroxil nanocrystal (Aristada Initio®)d||Water||675 mg once||27 days(range: 16 to 35 days)||15–18 days(single dose)||–|
b Only for those on paliperidone palmitate monthly for 4 months. Cannot be converted from oral medication.
c Requires 21 days oral overlap unless starting with aripiprazole lauroxil nanocrystal (ALNC) + a single 30 mg oral dose.
d Aripiprazole lauroxil nanocrystal (ALNC) is only used for initiation of treatment with aripiprazole lauroxil, or for resumption of treatment. It is always administered together with the clinician-determined dose of aripiprazole lauroxil, although the latter can be given up to 10 days after the aripiprazole lauroxil nanocrystal (ALNC) injection.
For further reading about use of LAI antipsychotics, please see the comprehensive edited book Antipsychotic Long-Acting Injections, now in its 2nd edition .
1.Leucht, S., Samara, M., Heres, S., et al. (2016). Dose equivalents for antipsychotic drugs: The DDD method. Schizophr Bull, 42 Suppl 1, S90–94.
2.Leucht, S., Crippa, A., Siafis, S., et al. (2020). Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry, 177, 342–353.
3.Meyer, J. M. and Stahl, S. M. (2019). The Clozapine Handbook. Cambridge: Cambridge University Press.
4.Asmal, L., Flegar, S. J., Wang, J., et al. (2013). Quetiapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev, CD006625.
5.Vanasse, A., Blais, L., Courteau, J., et al. (2016). Comparative effectiveness and safety of antipsychotic drugs in schizophrenia treatment: A real-world observational study. Acta Psychiatr Scand, 134, 374–384.
6.Meyer, J. M., Davis, V. G., Goff, D. C., et al. (2008). Change in metabolic syndrome parameters with antipsychotic treatment in the CATIE Schizophrenia Trial: Prospective data from phase 1. Schizophr Res, 101, 273–286.
7.Meyer, J. M. (2010). Antipsychotics and metabolics in the post-CATIE era. Curr Top Behav Neurosci, 4, 23–42.
8.Simpson, G. M., Cooper, T. B., Lee, J. H., et al. (1978). Clinical and plasma level characteristics of intramuscular and oral loxapine. Psychopharmacology (Berl), 56, 225–232.
9.Zetin, M., Cramer, M., Garber, D., et al. (1985). Bioavailability of oral and intramuscular molindone hydrochloride in schizophrenic patients. Clin Ther, 7, 169–175.
10.Midha, K. K., Hawes, E. M., Hubbard, J. W., et al. (1988). Variation in the single dose pharmacokinetics of fluphenazine in psychiatric patients. Psychopharmacology (Berl), 96, 206–211.
11.Dahl, M. L., Ekqvist, B., Widén, J., et al. (1991). Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans. Acta Psychiatr Scand, 84, 99–102.
12.Midha, K. K., Hubbard, J. W., McKay, G., et al. (1993). The role of metabolites in a bioequivalence study I: Loxapine, 7-hydroxyloxapine and 8-hydroxyloxapine. Int J Clin Pharmacol Ther Toxicol, 31, 177–183.
13.Yeung, P. K., Hubbard, J. W., Korchinski, E. D., et al. (1993). Pharmacokinetics of chlorpromazine and key metabolites. Eur J Clin Pharmacol, 45, 563–569.
14.Wong, S. L. and Granneman, G. R. (1998). Modeling of sertindole pharmacokinetic disposition in healthy volunteers in short term dose-escalation studies. J Pharm Sci, 87, 1629–1631.
15.Kudo, S. and Ishizaki, T. (1999). Pharmacokinetics of haloperidol: An update. Clin Pharmacokinet, 37, 435–456.
16.Mauri, M. C., Volonteri, L. S., Colasanti, A., et al. (2007). Clinical pharmacokinetics of atypical antipsychotics: A critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet, 46, 359–388.
17.Meyer, J. M. (2018). Pharmacotherapy of psychosis and mania. In L. L. Brunton, R. Hilal-Dandan, and B. C. Knollmann, eds., Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th edn. Chicago, IL: McGraw-Hill, pp. 279–302.
18.Yu, C. and Gopalakrishnan, G. (2018). In vitro pharmacological characterization of SPN-810 M (molindone). J Exp Pharmacol, 10, 65–73.
19.Meyer, J. M. (2020). Lumateperone for schizophrenia. Curr Psychiatr, 19, 33–39.
20.Schoretsanitis, G., Kane, J. M., Correll, C. U., et al. (2020). Blood levels to optimize antipsychotic treatment in clinical practice: A joint consensus statement of the American Society of Clinical Psychopharmacology (ASCP) and the Therapeutic Drug Monitoring (TDM) Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). J Clin Psychiatry, 81, https://doi.org/10.4088/JCP.4019cs13169.
21.Spyker, D. A., Voloshko, P., Heyman, E. R., et al. (2014). Loxapine delivered as a thermally generated aerosol does not prolong QTc in a thorough QT/QTc study in healthy subjects. J Clin Pharmacol, 54, 665–674.
22.Meyer, J. M., Loebel, A. D., and Schweizer, E. (2009). Lurasidone: A new drug in development for schizophrenia. Expert Opin Investig Drugs, 18, 1715–1726.
23.Larsen, N. E. and Hansen, L. B. (1989). Prediction of the optimal perphenazine decanoate dose based on blood samples drawn within the first three weeks. Ther Drug Monit, 11, 642–646.
24.Altamura, A. C., Sassella, F., Santini, A., et al. (2003). Intramuscular preparations of antipsychotics: Uses and relevance in clinical practice. Drugs, 63, 493–512.
25.Spanarello, S. and La Ferla, T. (2014). The pharmacokinetics of long-acting antipsychotic medications. Curr Clin Pharamacol, 9, 310–317.
26.Meyer, J. M. (2020). Monitoring and improving antipsychotic adherence in outpatient forensic diversion programs. CNS Spectr, 25, 136–144.
27.Hard, M. L., Mills, R. J., Sadler, B. M., et al. (2017). Aripiprazole lauroxil: Pharmacokinetic profile of this long-acting injectable antipsychotic in persons with schizophrenia. J Clin Psychopharmacol, 37, 289–295.
28.Hard, M. L., Mills, R. J., Sadler, B. M., et al. (2017). Pharmacokinetic profile of a 2-month dose regimen of aripiprazole lauroxil: A phase I study and a population pharmacokinetic model. CNS Drugs, 31, 617–624.
29.Gefvert, O., Eriksson, B., Persson, P., et al. (2005). Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia. Int J Neuropsychopharmacol, 8, 27–36.
30.Haddad, P., Lambert, T., and Lauriello, J., eds. (2016). Antipsychotic Long-Acting Injections, 2nd edn. New York: Oxford University Press.
|Antipsychotic||Therapeutic threshold (ng/ml)||Point of futility (ng/ml)||AGNP/ASCP laboratory alert level (ng/ml)||Oral concentration–dose relationshipa|
|Asenapine (sublingual)||1.0||(Based on maximal licensed dose of 10 mg sublingual BID)||10||
|Asenapine (transdermal)b||1.0||(Based on maximal licensed dose of 7.8 mg/24 hours)||10||0.53|
|Brexpiprazole||36||(Based on maximal licensed dose of 4 mg QHS)||280||
|Cariprazinec||5.6||(Based on maximal licensed dose of 6 mg QHS)||40c||1.91|
|Flupenthixol (cis isomer)||0.43||3.0||15||0.20|
|Lurasidoned||7.2||(Based on maximal licensed dose of 160 mg with an evening meal)||120||0.18|
|Risperidone (active moiety)e||15||112||120||7.0|
CYP: cytochrome P450; EM: extensive metabolizer; IM: intermediate metabolizer; PM: poor metabolizer
a Multiply by the conversion factor to obtain 12h trough levels in ng/ml for patients receiving all or most of their dose at bedtime. These mean values apply to patients not exposed to metabolic inhibitors or inducers, and who are extensive metabolizers for the relevant enzymes. Due to extensive population variation for most 12h trough levels, low levels may not reflect poor adherence. A second data point on the same dose will be of significant help in differentiating kinetic and adherence issues (see Chapter 4).
b Although the lowest transdermal formulation dose of 3.8 mg/24 hours provides equivalent asenapine exposure to the sublingual dose of 5 mg BID (as calculated by the AUC), the trough levels for the sublingual dose are lower due to higher peak–trough variation. This conversion factor of 0.53 is for the transdermal dose (per 24 hours). Example: 3.8 mg/24 hours x 0.53 = 2.0 ng/ml.
c The values provided for cariprazine do not include the metabolites. At steady state on 6 mg/d, the active moiety is: cariprazine 28%, DCAR 9%, and DDCAR 63% . However, very few laboratories have cariprazine assays, and none reports the metabolites at present. Should this change, the active moiety values represented will be four-fold higher. For example, the steady state cariprazine level on 6 mg/d is 11.2 ng/ml, but the active moiety level will be approximately 40 ng/ml . The rationale behind the AGNP/ASCP laboratory alert level of 40 ng/ml is not clearly delineated in the paper .
d The concentration–dose relationships for lurasidone are based on 12h trough values obtained at steady state (day 9 or later) and with lurasidone administered within 30 minutes of an evening meal of at least 350 kcal. This does not include the active metabolite ID-14283 (exohydroxylurasidone), which comprises 25% of the active moiety, but whose levels are not reported by commercial laboratories presently .
e The risperidone active moiety is the sum of risperidone + 9-OH risperidone levels.
1.FDA Center for Drug Evaluation and Research (2015). Cariprazine pharmacology/toxicology NDA review and evaluation.
2.Periclou, A., Willavize, S., Jaworowicz, D., et al. (2020). Relationship between plasma concentrations and clinical effects of cariprazine in patients with schizophrenia or bipolar mania. Clin Transl Sci, 13, 362–371.
3.Schoretsanitis, G., Kane, J. M., Correll, C. U., et al. (2020). Blood levels to optimize antipsychotic treatment in clinical practice: a joint consensus statement of the American Society of Clinical Psychopharmacology (ASCP) and the Therapeutic Drug Monitoring (TDM) Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). J Clin Psychiatry, 81, https://doi.org/10.4088/JCP.4019cs13169.
4.Findling, R. L., Goldman, R., Chiu, Y. Y., et al. (2015). Pharmacokinetics and tolerability of lurasidone in children and adolescents with psychiatric disorders. Clin Ther, 37, 2788–2797.