Questions and Answers About Clozapine: A Dialogue About the Use of Plasma Levels

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CATEGORY 1 CME

Premiere Date: June 20, 2024

Expiration Date: December 20, 2025

This activity offers CE credits for:

1. Physicians (CME)

2. Other

All other clinicians either will receive a CME Attendance Certificate or may choose any of the types of CE credit being offered.

ACTIVITY GOAL

To discuss methods for optimizing clozapine treatment with a focus on evidence-based use of plasma levels.

LEARNING OBJECTIVES

1. To outline best practices for utilizing clozapine plasma levels and the clozapine/norclozapine ratio to monitor clozapine therapy.

2. To educate clinicians about appropriate use of the clozapine response threshold and the expected time frame for response to guide future clozapine titration in nonresponders.

TARGET AUDIENCE

This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

ACCREDITATION/CREDIT DESIGNATION/FINANCIAL SUPPORT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Physicians’ Education Resource,® LLC, and Psychiatric Times.® Physicians’ Education Resource, LLC, is accredited by the ACCME to provide continuing medical education for physicians.

Physicians’ Education Resource, LLC, designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits.™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is funded entirely by Physicians’ Education Resource, LLC. No commercial support was received.

OFF-LABEL DISCLOSURE/DISCLAIMER

This accredited CE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this accredited CE activity is for continuing medical education purposes only and is not meant to substitute for the independent clinical judgment of a physician relative to diagnostic or treatment options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of Physicians’ Education Resource, LLC.

FACULTY, STAFF, AND PLANNERS’ DISCLOSURES AND CONFLICT OF INTEREST (COI) MITIGATION

Meyer reports that he receives grant/research support from Alkermes, Axsome, BioXcel, BMS/Karuna, Cerevel, ITCI, Neurocrine, Otsuka America, Inc, Relmada, Sumitomo Pharma, and Teva (as a consultant); AbbVie, Alkermes, Axsome, BMS/Karuna, ITCI, Neurocrine, Sumitomo Pharma, and Teva (Speaker’s Bureau); and 4M Therapeutics (as a stock/shareholder). None of the staff of Physicians’ Education Resource, LLC, or Psychiatric Times of this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing health care products used by or on patients.

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Clozapine remains the only effective medication for treatment-resistant schizophrenia (TRS), with response rates ≥ 40% in controlled trials, compared with < 5% for other antipsychotics, and 9% for high-dose olanzapine.^1-3 Despite the absence of compelling evidence for other treatment strategies, clozapine remains underutilized for patients with TRS, often related to clinician apprehensions regarding management due to inadequate formal training and limited experience with clozapine.^4,5

Although resources exist to guide clozapine prescribing,² prescribers often have questions that require further clarification. They also may be interested in opinions regarding approaches to certain issues or positions that can help each individual clinician devise a style most suited to their patient population and clinical situation.

As part of broader efforts in the psychiatric community to promote greater clozapine prescribing, the editors of Psychiatric Times elicited questions from readers on clozapine-related topics, with this article focusing on use of clozapine (and norclozapine) plasma levels. At the conclusion of this article, there will be a short list of useful resources for further education on clozapine.

The How and When of Plasma Level Monitoring

When drawing blood levels for clozapine, is this a fasting level or not?

The patient’s fasting status is not of importance when obtaining antipsychotic plasma levels.⁶ The biggest issue is that the morning dose of clozapine be held until the level is obtained. A common source of erroneously high plasma clozapine levels is a level drawn several hours after the morning dose.

When drawing blood clozapine levels, do we follow a trough level policy (eg, 12 hours after the last dose)?

In North America, clozapine is commonly administered as a single bedtime dose (QHS) to facilitate adherence and improve tolerability.⁷ Although there is no loss of efficacy with QHS dosing, some patients may receive multiple daily doses—however, the largest dose is typically administered at bedtime. Whether the patient is receiving a single QHS or multiple daily doses, by convention, plasma antipsychotic levels are obtained as 12-hour trough levels after the evening dose.⁶

Moreover, the bulk of modern therapeutic drug monitoring literature is based on psychotropic levels obtained 12 hours post dose, even though most agents are taken every 24 hours. In part, this is a pragmatic decision that relates to feasibility; drawing levels in the morning is easier for both inpatients and outpatients.

For patients already on a high dose of clozapine (600 mg/d to 900 mg/d), is there any benefit to checking blood levels other than to document adherence?

If the dose is still being titrated, the clinician should perform plasma level monitoring to make sure each dose increase is reflected in the clozapine level and to avoid generating very high levels that are beyond the point of futility (1000 ng/mL), even if tolerability is not limiting.⁶ Among patients on stable doses, the primary reason to obtain periodic blood levels is indeed to assure adherence, and the same applies to other orally administered psychotropics such as lithium and valproate. Although studies indicate that adherence to clozapine is at least equal to that of other antipsychotic medications,⁸ oral medication adherence is dynamic,⁹ so regular plasma level monitoring helps detect a pattern of nonadherence before the patient relapses.¹⁰

Secondly, factors other than nonadherence can influence clozapine levels, with cigarette smoking being a major culprit. Aryl hydrocarbons generated from burning the tobacco leaf induce cytochrome P450 (CYP) 1A2 expression.¹¹ The net result is that when a patient who was previously not smoking begins to smoke, they may decrease their clozapine levels by 30% or more. In addition, they may also decrease the clozapine/norclozapine ratio, as clozapine is converted more rapidly to its metabolite.^12,13 (Notably, vaping does not induce CYP 1A2. No organic material is burned, and no aryl hydrocarbons are produced by heating a nicotine solution.)

Conversely, a patient who switches from smoking via cigarettes to smoking via vaping may experience significant increases in the plasma clozapine level due to the loss of CYP 1A2 induction, with a concomitant increase in the cloza- pine/norclozapine ratio.^14,15

It is important to remember that patients may fail to disclose changes in their smoking behavior. However, routine monitoring will identify significant alterations in the clozapine level and clozapine/norclozapine ratio that will alert clinicians to further explore the reasons for this change despite stable prescribed dosages.

Most labs provide the clozapine level, the norclozapine level, and the total. Which of these do we use, and what is the recommended therapeutic or reference ranges for each?

There is no question that norclozapine contributes to cloza- pine’s efficacy, as norclozapine possesses multiple antipsychotic mechanisms including muscarinic M1 agonism,^16,17 muscarinic M4 agonism,^18-20 and dopamine D2/D3 partial agonism.²¹ Nonetheless, analyses of clinical trial data fail to substantiate a significant correlation between norclozapine levels and symptom improvement for patients.

The most recent meta-analysis published in 2023 comprised 15 trials. In this meta-analysis, the investigators once again concluded that norclozapine plasma concentrations were not associated with clinical response, while clozapine levels were significantly associated with clinical response, especially when they exceeded a threshold value of 407 ng/mL (sensitivity 71%, specificity 89%).²²

Clinical decisions are therefore based on the clozapine level rather than the sum of clozapine plus norclozapine concentrations. As previously discussed, the clozapine/norclozapine ratio may be useful in certain situations, especially when it deviates from the patient’s baseline.

Table 1. Reasons That Achieving Response Threshold Is No Guarantee of Response²⁶

The recommendation to achieve a clozapine blood level of 450 ng/mL for more than 4 weeks is too low for therapeutic benefit in my experience. Do we have any recent expert recommendations for this?

Table 2. Important Articles^29-33

The plasma-level schizophrenia response thresholds for any antipsychotic are usually calculated from trials involving acutely symptomatic patients,²³ although values based on relapse risk are sometimes reported.¹⁰ When using acute trial data, patients are classified as responders or nonresponders, their end point plasma clozapine level is noted, and receiver operating characteristic curves are generated that provide an optimal plasma level cutoff for separating responders from nonresponders.⁶ A range of response thresholds have been published for clozapine, with 350 ng/mL being the most commonly cited number, although values as high as 550 ng/mL have also been reported.^24,25

Table 3. Web-Based Resources

The important concept is that achieving the response threshold is no guarantee of response for 2 reasons, which are noted in Table 1.²⁶ The response or therapeutic threshold is best employed as an initial target for nonresponders, as levels below this value are associated with a lower likelihood of response. However, failure to respond to a plasma level that just exceeds this threshold does not necessarily imply that the patient is a clozapine nonresponder.

Table 4. Useful Books^2,34

It is incumbent on the clinician to manage limiting tolerability issues and continue the titration to explore whether the patient might respond at a higher plasma level, with certain sources advocating that levels as high as 1000 ng/mL can be considered, although adverse effects become more problematic at levels > 750 ng/mL.^27,28

Another important concept is that when a patient does respond to clozapine, this response is noted, on average, 17 (± 14) days after the dose increase that achieved response.²⁹ Late response (ie, > 60 days after a dose increase) does not occur, so the failure to achieve a clinically noticeable benefit from any dose increase after 2 to 3 weeks should impel the clinician to promptly continue the clozapine titration.

Additional Resources

Interested readers can learn more via the resources in Table 2,^29-33 Table 3, and Table 4.^2,34

Dr Meyer is a voluntary clinical professor of psychiatry at the University of California, San Diego.

References

1. Lindenmayer JP, Czobor P, Volavka J, et al. Olanzapine in refractory schizophrenia after failure of typical or atypical antipsychotic treatment: an open-label switch study. J Clin Psychiatry. 2002;63(10):931-935.

2. Meyer JM, Stahl SM. The Clozapine Handbook: Stahl’s Handbooks. Cambridge University Press; 2019.

3. Seppälä A, Pylvänäinen J, Lehtiniemi H, et al. Predictors of response to pharmacological treatments in treatment-resistant schizophrenia—a systematic review and meta-analysis. Schizophr Res. 2021;236:123-134.

4. Cohen D. Prescribers fear as a major side-effect of clozapine. Acta Psychiatr Scand. 2014;130(2):154-155.

5. Gee S, Vergunst F, Howes O, Taylor D. Practitioner attitudes to clozapine initiation. Acta Psychiatr Scand. 2014;130(1):16-24.

6. Meyer JM, Stahl SM. The Clinical Use of Antipsychotic Plasma Levels—Stahl’s Handbooks. Cambridge University Press; 2021:382.

7. Takeuchi H, Powell V, Geisler S, et al. Clozapine administration in clinical practice: once-daily versus divided dosing. Acta Psychiatr Scand. 2016;134(3):234-240.

8. Takeuchi H, Borlido C, Sanches M, et al. Adherence to clozapine vs. other antipsychotics in schizophrenia. Acta Psychiatr Scand. 2020;142(2):87-95.

9. MacEwan JP, Forma FM, Shafrin J, et al. Patterns of adherence to oral atypical antipsychotics among patients diagnosed with schizophrenia. J Manag Care Spec Pharm. 2016;22(11):1349-1361.

10. Ulrich S, Baumann B, Wolf R, et al. Therapeutic drug monitoring of clozapine and relapse—a retrospective study of routine clinical data. Int J Clin Pharmacol Ther. 2003;41(1):3-13.

11. Meyer JM. Individual changes in clozapine levels after smoking cessation: results and a predictive model. J Clin Psychopharmacol. 2001;21(6):569-574.

12. Rostami-Hodjegan A, Amin AM, Spencer EP, et al. Influence of dose, cigarette smoking, age, sex, and metabolic activity on plasma clozapine concentrations: a predictive model and nomograms to aid clozapine dose adjustment and to assess compliance in individual patients. J Clin Psychopharmacol. 2004;24(1):70-78.

13. Wagner E, McMahon L, Falkai P, et al. Impact of smoking behavior on clozapine blood levels—a systematic review and meta-analysis. Acta Psychiatr Scand. 2020;142(6):456-466.

14. Berm EJ, Ruijsbroek R, Loonen AJ, et al. Switching to e-cigarettes affects drug concentration. Ned Tijdschr Geneeskd. 2015;159:A9090.

15. Khorassani F, Kaufman M, Lopez LV. Supratherapeutic serum clozapine concentration after transition from traditional to electronic cigarettes. J Clin Psychopharmacol. 2018;38(4):391-392.

16. Weiner DM, Meltzer HY, Veinbergs I, et al. The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology. 2004;177(1-2):207-216.

17. Lameh J, Burstein ES, Taylor E, et al. Pharmacology of N-desmethylclozapine. Pharmacol Ther. 2007;115(2):223-231.

18. Thomas DR, Dada A, Jones GA, et al. N-desmethylclozapine (NDMC) is an antagonist at the human native muscarinic M(1) receptor. Neuropharmacology. 2010;58(8):1206-1214.

19. Gigout S, Wierschke S, Dehnicke C, Deisz RA. Different pharmacology of N-desmethylclozapine at human and rat M2 and M4 mAChRs in neocortex. Naunyn Schmiedebergs Arch Pharmacol. 2015;388(5):487-496.

20. Costa-Dookhan KA, Agarwal SM, Chintoh A, et al. The clozapine to norclozapine ratio: a narrative review of the clinical utility to minimize metabolic risk and enhance clozapine efficacy. Expert Opin Drug Saf. 2020;19(1):43-57.

21. Burstein ES, Ma J, Wong S, et al. Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J Pharmacol Exp Ther. 2005;315(3):1278-1287.

22. Tralongo F, Konecki C, Feliu C, et al. Association between clozapine plasma concentrations and treatment response: a systematic review, meta-analysis and individual participant data meta-analysis. Clin Pharmacokinet. 2023;62(6):807-818.

23. Perry PJ, Miller DD, Arndt SV, Cadoret RJ. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry. 1991;148(2):231-235.

24. Llorca PM, Lancon C, Disdier B, et al. Effectiveness of clozapine in neuroleptic-resistant schizophrenia: clinical response and plasma concentrations. J Psychiatry Neurosci. 2002;27(1):30-37.

25. Schoretsanitis G, Kane JM, Correll CU, et al. 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 f ür Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). J Clin Psychiatry. 2020;81(3):19cs13169.

26. Remington G, Agid O, Foussias G, et al. Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold? Psychopharmacology (Berl). 2013;225(3):505-518.

27. Yada Y, Kitagawa K, Sakamoto S, et al. The relationship between plasma clozapine concentration and clinical outcome: a cross-sectional study. Acta Psych Scandinavica. 2021;143(3):227-237.

28. Bogers J, Schulte PFJ, Broekman TG, de Haan L. Feasibility and effect of increasing clozapine plasma levels in long-stay patients with treatment-resistant schizophrenia. J Clin Psychopharmacol. 2023;43(2):97-105.

29. Conley RR, Carpenter WT Jr, Tamminga CA. Time to clozapine response in a standardized trial. Am J Psychiatry. 1997154(9):1243-1247.

30. Howes OD, McCutcheon R, Agid O, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174(3):216-229.

31. Siskind D, Orr S, Sinha S, et al. Rates of treatment-resistant schizophrenia from first-episode cohorts: systematic review and meta-analysis. Br J Psychiatry. 2022;220(3):115-120.

32. Wagner E, Kane JM, Correll CU, et al. Clozapine combination and augmentation strategies in patients with schizophrenia—recommendations from an international expert survey among the Treatment Response and Resistance in Psychosis (TRRIP) working group. Schizophr Bull. 2020;46(6):1459-1470.

33. Wagner E, Siskind D, Falkai P, et al. Clozapine optimization: a Delphi Consensus Guideline from the Treatment Response and Resistance in Psychosis working group. Schizophr Bull. 2023;49(4):962-972.

34. Laitman RS, Opler LA, Mandel Laitman A, Laitman D. Meaningful Recovery From Schizophrenia and Serious Mental Illness With Clozapine: Hope & Help. CreateSpace Independent Publishing Platform; 2017.