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06. Initiating and Optimizing Clozapine

Published on June 1, 2023 Certification expiration date: June 1, 2026

Brian Miller, M.D., Ph.D., M.P.H.

Professor - Augusta University

Key Points

The guiding principle of clozapine titration is to start low and go slow.
The average target dose of clozapine is 400 mg/day.
Blood levels can help guide clozapine titration.
Do not taper the pre-clozapine antipsychotic until clozapine is 100 mg–200 mg/day.

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Slides and Transcript

Slide 1 of 25

So now, we’ll talk about initiating and optimizing clozapine.

Initiating and Optimizing Clozapine Slide 1 of 25

Slide 2 of 25

So how do we titrate clozapine? Well, let’s review first the manufacturer’s guidelines which recommend an initial dose of 12.5 mg once or twice daily. The dose is increased by 25 to 50 mg per day if well tolerated to a target dose of between 300 to 450 mg daily by the end of week two.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 2 of 25

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Slide 3 of 25

Then subsequent dose increments should be made no more than once or twice a week, not exceeding a change of 100 mg. The guidelines recommend cautious titration and potentially divided dosing to minimize risks of adverse effects including orthostatic hypotension, seizures, and sedation.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 3 of 25

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The maximum daily dose of clozapine is 900 mg per day. In contrast to some of our other psychotropic medications where sometimes we have off-label dosing above the FDA maximum dose, I would strongly contend that 900 mg is a hard ceiling for clozapine dose and I never go above 900 mg a day.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 4 of 25

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Slide 5 of 25

Importantly, it’s mentioned an issue that if treatment with clozapine is interrupted for two to three days, for 48 or 72 hours that retitration is recommended.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 5 of 25

Slide 6 of 25

The issue of interrupted treatment for me most commonly occurs in the context of patients who can’t get their blood drawn and so the pharmacy won’t dispense the medicine. This often occurs when a blood draw happens to fall on a weekend or a holiday.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 6 of 25

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Slide 7 of 25

And there are several workarounds for that. Number one, the new clozapine REMS system allows for a clinician discretion option where as the patient status form can be completed even without the blood draw in hand if, for example, it’s a patient who’s been stable long-term on clozapine and they couldn’t get labs done because their usual blood draw day fell on a holiday during the week. And so that option to put in a clinician discretion can allow the patient to get the medicine and they can go get the blood work as soon as possible thereafter.

References:

Clozapine Product Manufacturers Group. (2021, August 15). What is the Clozapine REMS? https://www.newclozapinerems.com

Initiating and Optimizing Clozapine Slide 7 of 25

Slide 8 of 25

The other option if we run into an issue with getting the blood drawn is I have advised patients that on weekends or holidays it is possible to present to a local emergency department for a blood draw-only visit so that they don’t have to wait in triage for hours. At least, our emergency department is set up that, if patients need a therapeutic monitoring blood draw on a weekend or holiday, those patients could, in a pinch, present just for the blood draw.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 8 of 25

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Slide 9 of 25

So, what’s the speed of clozapine titration? I’ll share with you kind of the typical titration strategies that I use. I have different strategies whether the patient is inpatient versus outpatient. Because of the extensive monitoring on inpatient units, we tend to go much faster. So for inpatients, I will start 25 mg of clozapine on day one and increase that by 25 mg per day up to day four so that by day four the patient’s on 100 mg. Once we get to a 100 mg a day, we increase the clozapine dose by 50 mg per day thereafter.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 9 of 25

Slide 10 of 25

We can hold at a given dose for an extra day or even two days based on tolerability issues. We typically divide the doses initially but it’s important to note that if a patient has significant sedation we may opt to consolidate the medicine at bedtime even in the first couple of days.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 10 of 25

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Slide 11 of 25

And our endpoint for the clozapine titration is based on either symptomatic response or tolerability issues such as dose-limiting sedation, orthostasis, or tachycardia but otherwise we would continue to titrate clozapine based on symptomatic response until we see either near or hopefully full remission particularly of positive symptoms.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 11 of 25

Slide 12 of 25

By contrast, on an outpatient basis, rather than increasing initially by 25 mg a day, there are some cases where on an outpatient basis you could titrate more rapidly but on average, I find it’s easier for patients and families to increase the prescription just on a weekly basis.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 12 of 25

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Slide 13 of 25

So I do 25 on week one, 50 total on week two, 75 week three, and 100 week four. Same as inpatient, in outpatients after we get to a dose of 100, we increase by 50 mg a day thereafter.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 13 of 25

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So a couple of psychopharmacology pearls for you regarding clozapine. So clozapine gets metabolized to its active metabolite norclozapine primarily by cytochrome P450, CYP 1A2 but also 3A4. So as a result, people who are CYP1A2 ultra-rapid metabolizers or patients who are cigarette smokers which upregulate the activity of 1A2, those patients may experience lower clozapine blood levels even at higher doses.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.
Jann, M. W., Grimsley, S. R., Gray, E. C., & Chang, W. (1993). Pharmacokinetics and pharmacodynamics of clozapine. Clinical Pharmacokinetics, 24(2), 161-176.

Initiating and Optimizing Clozapine Slide 14 of 25

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Slide 15 of 25

By contrast, it’s important to note that the antidepressant agent fluvoxamine is a strong inhibitor of both CYP1A2 and 3A4 and therefore can increase blood levels of clozapine by 500%.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.
Jann, M. W., Grimsley, S. R., Gray, E. C., & Chang, W. (1993). Pharmacokinetics and pharmacodynamics of clozapine. Clinical Pharmacokinetics, 24(2), 161-176.

Initiating and Optimizing Clozapine Slide 15 of 25

Slide 16 of 25

So, what’s the target dose of clozapine? Well, no specific therapeutic levels have been established but blood levels of clozapine are available and the typical reference range for clozapine is a level of greater than 350. We also with that get levels of the active metabolite norclozapine and then the reference range for the total of clozapine plus norclozapine is greater than 450.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 16 of 25

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Slide 17 of 25

So what we see is that on patients who are on a dose of at least 400 mg per day of clozapine for four weeks, those patients were most likely to have a significant therapeutic response to clozapine when the total clozapine level plus norclozapine was greater than 450. So, but with that, what I would say is that patients show a tremendous variation in both their symptomatic response to clozapine as well as side effects.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 17 of 25

Slide 18 of 25

So what we see is that in patients with treatment-resistant psychosis, I would say the average final dose is about 400 mg per day, but the typical range for response is 300 to 900 mg per day. I would say 300 to 600 is a middle of the road clozapine dose, low-dose clozapine which some patients respond to which would be doses less than 300 mg a day and then we have other patients who need higher doses of clozapine in the range of 600 to 900 mg a day for an adequate response.

References:

Freudenreich, O., McEvoy, J., Marder, S., & Hermann, R. (2015). Guidelines for prescribing clozapine in schizophrenia. UpToDate: Topic, 14772.

Initiating and Optimizing Clozapine Slide 18 of 25

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Slide 19 of 25

So an important pearl here is what do we do with the pre-switch antipsychotic when we start our patients on clozapine. So there’s really minimal evidence in the literature to guide how we stop the pre-clozapine antipsychotic. I would contend that unless there’s some urgent need due to a serious adverse effect that it’s common to start tapering off the pre-switch antipsychotic when we get to a clozapine dose between 100 to 200 mg per day and that’s the strategy I use in my clinical practice.

References:

Takeuchi, H., Lee, J., Fervaha, G., Foussias, G., Agid, O., & Remington, G. (2017). Switching to clozapine using immediate versus gradual antipsychotic discontinuation: A pilot, double-blind, randomized controlled trial. The Journal of Clinical Psychiatry, 78(2), 223–228.

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And so that said, the dose of the pre-switch antipsychotic can be reduced based on clinical response to clozapine. And so if the patient’s getting rapidly significantly better, we could potentially reduce the pre-switch antipsychotic earlier or more quickly.

References:

Takeuchi, H., Lee, J., Fervaha, G., Foussias, G., Agid, O., & Remington, G. (2017). Switching to clozapine using immediate versus gradual antipsychotic discontinuation: A pilot, double-blind, randomized controlled trial. The Journal of Clinical Psychiatry, 78(2), 223–228.

Initiating and Optimizing Clozapine Slide 20 of 25

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Slide 21 of 25

I would say one approach is to reduce the dose of the pre-clozapine antipsychotic by about one-quarter once or twice weekly, typically once a week in the outpatient setting or it could be done twice weekly as an inpatient. So again, the speed of tapering may be influenced by clinical setting.

References:

Takeuchi, H., Lee, J., Fervaha, G., Foussias, G., Agid, O., & Remington, G. (2017). Switching to clozapine using immediate versus gradual antipsychotic discontinuation: A pilot, double-blind, randomized controlled trial. The Journal of Clinical Psychiatry, 78(2), 223–228.

Initiating and Optimizing Clozapine Slide 21 of 25

Slide 22 of 25

But again, my rule of thumb is that I want to reduce the dose of the pre-switch antipsychotic by about 25% per week. So if the patient’s on 20 mg of a particular antipsychotic, over four weeks I’m going to taper them down from 15 to 10 to 5 and then to finally stopping the medication.

References:

Takeuchi, H., Lee, J., Fervaha, G., Foussias, G., Agid, O., & Remington, G. (2017). Switching to clozapine using immediate versus gradual antipsychotic discontinuation: A pilot, double-blind, randomized controlled trial. The Journal of Clinical Psychiatry, 78(2), 223–228.

Initiating and Optimizing Clozapine Slide 22 of 25

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Slide 23 of 25

So in summary, the guiding principle of clozapine titration is truly start low and go slow, although it can be titrated more rapidly in inpatients. The average target dose of clozapine is 400 mg per day. Blood levels can help guide our titration.

Initiating and Optimizing Clozapine Slide 23 of 25

Slide 24 of 25

And I would advise you not to taper the pre-clozapine antipsychotic until you get to a dose of 100 to 200 mg per day of clozapine.

Initiating and Optimizing Clozapine Slide 24 of 25

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Initiating and Optimizing Clozapine Slide 25 of 25

Next Section

07. Clozapine Monitoring: REMS System

Learning Objectives:

After completing this activity, the learner will be able to:

Recognize the different approved and off-label indications of clozapine.
Assess and successfully manage any potential side effects of clozapine.
Identify the clinical scenarios in which clozapine should be prescribed and confidently do so.

Original Release Date: June 1, 2023

Review and Re-release Date: March 1, 2024

Expiration Date: June 1, 2026

Expert: Brian Miller, M.D.

Medical Editor: Paz Badía, M.D.

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None of the faculty, planners, and reviewers for this educational activity have relevant financial relationships to disclose during the last 24 months with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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