Jul 10, 2019
By Jacqueline Posada, MD, 4th-year resident in the department of
psychiatry & behavioral sciences at George Washington
In this episode, Lorenzo
Norris, MD, host of the MDedge Psychcast, interviews Jonathan M.
Meyer, MD, about prescribing clozapine and understanding
barriers of use.
Dr. Meyer is clinical professor of psychiatry, University of
California, San Diego, and a psychopharmacology consultant with the
California Department of State Hospitals.
Overview of clozapine
- Clozapine is an effective medication for treatment-resistant
schizophrenia and lethality/suicide.
- Clozapine is underused by clinicians for many reasons.
- Clinicians have less comfort with prescribing clozapine.
- Too few trainees are exposed during residency to prescribing
- Using clozapine during training provides the knowledge and
comfort necessary to prescribe it once out in practice.
- Fear of prescribing clozapine outweighs the benefits to
patients who need it.
- Other barriers include monitoring burdens in confluence with
Indications for use
- Treatment-resistant schizophrenia is defined as an inadequate
response to two antipsychotic trials, and treatment-resistant
schizophrenia occurs in about 30% of patients with schizophrenia.
- People with treatment-resistant schizophrenia have a 5% chance
of responding to other antipsychotic medications, while the
response rate to clozapine is about 40%.
- In light of those statistics, getting patients with
schizophrenia on clozapine should be a priority.
- Everyone benefits when a patient with treatment-resistant
schizophrenia is started on clozapine.
- Clozapine treatment leads to decreased symptoms and suffering,
improved quality of life, decreased suicidality and aggression, and
lower hospitalization rates, which in turn, lead to decreased
health care costs.
Barriers to using clozapine
- Education is key to empowering physicians to start prescribing
clozapine and overcoming the initial resistance to
- SMI Adviser is a website
sponsored by the American Psychiatric Association (APA) and the
Substance Abuse and Mental Health Services Administration (SAMHSA)
that provides access to education, data, and consultations for
clinicians who treat serious mental illness.
- SAMHSA also has sponsored “centers of excellence” in New York
state and the Netherlands that provide consultation and on-demand
answers to questions about prescribing.
The Clozapine Handbook, written by Dr. Meyer and Stephen
M. Stahl, MD, PhD, is another centralized resource for
- Dr. Meyer and Dr. Stahl wrote the handbook to educate and
encourage clinicians to prescribe clozapine and improve patient
Adverse events and monitoring
- Myocarditis: Rate of myocarditis ranges from 0.5% to 3% (most
rates from Australia), an adverse event that happens primarily
within the first 6 weeks of clozapine therapy.
- Symptoms suggesting myocarditis include fever and elevated
troponin level more than twice the upper limit of normal.
Clinicians can order a C-reactive protein test, which can help rule
in myocarditis if troponins are elevated but not at twice the upper
- In the first 6 weeks of therapy, clinicians are encouraged to
order a troponin test during the patients' weekly labs.
- Isolated fever does not mean myocarditis, because fever is a
common side effect during titration, and clinicians can complete
the fever work-up.
- Cigarette smoke can induce cytochrome P450 (CYP) enzyme,
- It is not necessary to have patients stop smoking when they
- Clinicians can adjust the clozapine dose based on response and
- Induction of CYP1A2 enzyme happens only when people smoke or
burn the actual leaf of tobacco or marijuana.
- Vaping or e-cigarettes will not induce CYP1A2 and change
- Threshold of response is 350 ng/mL, however levels that lead to
response differ with each individual and will be influenced by
- Other common side effects include orthostasis, sedation, and
New technologies are available to reduce barriers of prescribing
clozapine and to improve patient adherence to hematologic
- Athelas is a company
that manufactures a Food and Drug Administration–cleared
point-of-care device to measure neutrophil count by way of a finger
- Results are dispensed real time.
- Athelas also will take care of medication dispensing.
- A point-of-care device is in development for plasma clozapine
levels with fingerstick, which will allow clinicians to make
titration decisions in real time instead of 1 week after levels.
- The device already is available in Europe.
Creating a system that allows for adherence
- Using case managers to improve clozapine adherence is cost
effective when the amount saved from avoiding hospitalization is
taken into account.
- Clozapine can lead to a functional recovery in terms of how a
patient interacts with family, friends, and society at large.
- Clozapine has the ability to improve productivity leading to
employment, which is another way the benefits of creating a system
to improve clozapine adherence outweigh financial costs.
Kane JM et al. Clinical guidance on the identification and
management of treatment-resistant schizophrenia. J Clin Psychiatry.
2019 Mar 5;80(2):
Suskind D et al. Clozapine response rates among people with
treatment-resistant schizophrenia: Data from a systematic review
and meta-analysis. Can J Psychiatry. 2017 Nov;62(11):772-7.
Kelly DL et al. Addressing barriers to clozapine
underutilization: A national effort. Psychiatr Serv. 2018
Bui HN et al. Evaluation of the performance of a point-of-care
method for total and differential white blood cell count in
clozapine users. Int J Lab Hematol.
Clozapine Center of Excellence, sponsored by the APA and
The Clozapine Handbook (Cambridge University Press, 2019).
Clozapine and smoking cessation (NSW Health, Australia).
Point of care neutrophil
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