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02. Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders

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

Clozapine is recommended for patients with schizophrenia who have failed 2 adequate trials of other antipsychotics.
The APA practice guidelines also recommend clozapine for patients with schizophrenia and risk of suicide or aggression.
There is modest evidence for off-label clozapine use in bipolar disorder and psychotic depression.

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Slides and Transcript

Slide 1 of 13

Now, we're going to talk about using clozapine for treatment-resistant psychosis as well as mood disorders. And here, I'd like to highlight several expert consensus guidelines and algorithms regarding the use of clozapine.

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 1 of 13

Slide 2 of 13

So beginning with treatment-resistant psychosis, there are three such guidelines that I'd like to share with you. The first is the so-called TMAP or Texas Medication Algorithm Project for antipsychotics. Step one in that algorithm is a trial of a single second-generation antipsychotic for an adequate dose and duration. If the patient has only a partial or nonresponse, step two is a trial of a different single second-generation antipsychotic or alternatively a first-generation antipsychotic. And again, if after an adequate trial in terms of dose and duration there's a partial or nonresponse, stage three would be a trial of clozapine.

References:

Moore, T. A., & Buchanan, R. W. (2007). The Texas medication algorithm project antipsychotic algorithm for schizophrenia. The Journal of Clinical Psychiatry, 68(11), 1751-1762.

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 2 of 13

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Slide 3 of 13

I think this is very interesting because those of us who treat patients with schizophrenia and other psychotic disorders when we take a psychiatric history and we ask about what antipsychotic medications the patient has taken in the past, it's not uncommon to get a laundry list of five, six or even more different antipsychotics that they've been tried on. And when we ask about have you ever heard of clozapine or were you ever on clozapine, there's kind of a deer-in-headlights look that we receive. Yet, this particular algorithm suggests clozapine is third line after just two failed trials.

References:

Moore, T. A., & Buchanan, R. W. (2007). The Texas medication algorithm project antipsychotic algorithm for schizophrenia. The Journal of Clinical Psychiatry, 68(11), 1751-1762.

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 3 of 13

Slide 4 of 13

And even more importantly, clozapine could be considered earlier in this algorithm in patients who have a history of recurrent suicidality, violence, or substance use comorbidity, so exactly what we were discussing previously about clozapine's indication.

References:

Moore, T. A., & Buchanan, R. W. (2007). The Texas medication algorithm project antipsychotic algorithm for schizophrenia. The Journal of Clinical Psychiatry, 68(11), 1751-1762.

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 4 of 13

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Slide 5 of 13

Nevertheless, if patients have persistent positive symptoms of psychosis (hallucinations and delusions) for more than two years warrants and more than five years really requires a clozapine trial. I try to instill in our psychiatry residents that it would be almost tantamount to malpractice to not at least offer a clozapine trial for a patient who has had such a degree of persistent positive symptoms.

References:

Moore, T. A., & Buchanan, R. W. (2007). The Texas medication algorithm project antipsychotic algorithm for schizophrenia. The Journal of Clinical Psychiatry, 68(11), 1751-1762.

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 5 of 13

Slide 6 of 13

I also rely heavily on the schizophrenia PORT expert consensus guidelines. Those are the Patient Outcomes Research Team expert consensus guidelines which, very similar to the TMAP, argue that clozapine should be offered to people with schizophrenia who experience persistent and clinically significant positive symptoms after two adequate trials of other antipsychotic agents.

References:

Buchanan, R. W., Kreyenbuhl, J., Kelly, D. L., Noel, J. M., Boggs, D. L., Fischer, B. A., Himelhoch, S., Fang, B., Peterson, E., Aquino, P. R., & Keller, W. (2009). The 2009 schizophrenia PORT Psychopharmacological treatment recommendations and summary statements. Schizophrenia Bulletin, 36(1), 71-93.

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Slide 7 of 13

And here, I think this gets to kind of an important definition. We've been saying an adequate trial and that's often defined as at least six weeks at a dose of 1000 mg per day chlorpromazine equivalents.

References:

Buchanan, R. W., Kreyenbuhl, J., Kelly, D. L., Noel, J. M., Boggs, D. L., Fischer, B. A., Himelhoch, S., Fang, B., Peterson, E., Aquino, P. R., & Keller, W. (2009). The 2009 schizophrenia PORT Psychopharmacological treatment recommendations and summary statements. Schizophrenia Bulletin, 36(1), 71-93.

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 7 of 13

Slide 8 of 13

And then most recently, we have the new American Psychiatric Association practice guidelines for schizophrenia, third edition and those guidelines recommend clozapine for patients with treatment-resistant schizophrenia but also patients with schizophrenia and substantial suicide risk despite other treatments. These guidelines also suggest clozapine for patients with schizophrenia and substantial aggression risk despite other treatments.

References:

American Psychiatric Association. (2021). The American psychiatric association practice guideline for the treatment of patients with schizophrenia (3rd ed.). American Psychiatric Pub.

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Slide 9 of 13

So as you can see, all of these guidelines are really hammering this point home that for schizophrenia, the gold standard for resistant illness is clozapine and that clozapine should potentially play a role in the treatment of our patients with schizophrenia who have significant risks of suicide and aggression.

References:

Moore, T. A., & Buchanan, R. W. (2007). The Texas medication algorithm project antipsychotic algorithm for schizophrenia. The Journal of Clinical Psychiatry, 68(11), 1751-1762.
Buchanan, R. W., Kreyenbuhl, J., Kelly, D. L., Noel, J. M., Boggs, D. L., Fischer, B. A., Himelhoch, S., Fang, B., Peterson, E., Aquino, P. R., & Keller, W. (2009). The 2009 schizophrenia PORT Psychopharmacological treatment recommendations and summary statements. Schizophrenia Bulletin, 36(1), 71-93.

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 9 of 13

Slide 10 of 13

In terms of mood disorders, clozapine is not just for patients with psychosis. There's evidence for mood disorders and there are randomized controlled trials as well as open-label studies that have shown modest evidence for mood stabilization in bipolar disorder and there are a number of case reports for improvements in psychotic major depressive disorder with clozapine.

References:

Green, A. I., Tohen, M., Patel, J. K., Banov, M., DuRand, C., Berman, I., Chang, H., Zarate, C., Jr, Posener, J., Lee, H., Dawson, R., Richards, C., Cole, J. O., & Schatzberg, A. F. (2000). Clozapine in the treatment of refractory psychotic mania. The American Journal of Psychiatry, 157(6), 982–986.
Jeyapaul, P., & Vieweg, R. (2006). A case study evaluating the use of clozapine in depression with psychotic features. Annals of General Psychiatry, 5(1).

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Slide 11 of 13

So in review, clozapine is recommended for patients with schizophrenia who have failed two adequate trials of other antipsychotics. The APA practice guidelines also recommend clozapine for patients with schizophrenia who are at significant risk of suicide and suggest it for patients who have substantial risk of aggression.

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 11 of 13

Slide 12 of 13

There's also modest evidence for off-label clozapine use in both bipolar disorder and psychotic depression.

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Slide 13 of 13

Using Clozapine for Treatment-Resistant Psychosis and Mood Disorders Slide 13 of 13

Next Section

03. Using Clozapine for Suicide Risk and Aggression

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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