3 Barriers to Improving Clozapine Use in Treatment-Resistant Schizophrenia


Robert O. Cotes, MD, discusses why the proven agent clozapine may still be underutilized in schizophrenia.

As previously covered at the American Psychiatric Association (APA) 2024 Annual Meeting in New York, NY, this week, psychiatrists are encountering difficulties to facilitate proven, viable treatment to ideal patients with schizophrenia.1

A frequent example of this frustration is clozapine, an antipsychotic indicated for the treatment of adults with treatment-resistant schizophrenia. As John Kane, MD, co-director and professor at the Institute of Behavioral Science at Feinstein Institutes for Medical Research, told HCPLive, few if any drugs have shown greater efficacy for this patient population than clozapine—yet its perception among his peers may believe it’s not worth the hurdles of prescribing and monitoring it.

Another expert would agree with Kane, noting that the real struggles to improve clozapine buy-in is three-fold. Robert O. Cote, MD, associate professor in the department of psychiatry and behavioral sciences at Emory University School of Medicine, spoke with HCPLive at APA 2024 regarding clozapine, a “highly underutilized” agent for treatment-resistant schizophrenia.

“Right now, about 4.8% of people with schizophrenia are taking clozapine, despite 25 - 30% of people with schizophrenia might benefit from it,” Cotes said. “And that doesn't even take into account its indications for helping people with suicidality.”

Cotes described what he sees as 3 key barriers to improving the utilization of clozapine in schizophrenia.


The Clozapine Risk Evaluation and Mitigation Strategy (REMS) safety program is required by the US Food and Drug Administration (FDA) to assess patients receiving the agent for any adverse hematologic outcomes such as severe neutropenia, as observed in clinical trials.2

Prescriber difficulties

This may be due to either prescriber hesitancies to initiate clozapine in an eligible patient, or due to a failure to even identify an eligible patient in the first place, Cotes said.

“One thing that we know is clozapine even more effective for people who are identified early in their illness,” Cotes explained. “So, if you can start someone on clozapine say, 2 years after you have identified that they have treatment-resistant schizophrenia, they're much more likely to have a better response. Now, that doesn't mean that somebody still can't have a nice response after being on clozapine after not having clozapine for a longer period of time. They can still respond well, but early introduction is very important.”

Patient buy-in

This issue may manifest due to a number of factors surrounding the intravenous drug: does the patient have adequate transportation? Are they okay with blood draws? Can they fit the regimen into their personal and professional schedules? Are there other logistical issues?

Cotes noted it could even be common for these 3 factors to overlap: how do you adequately monitor hematologic risks in a patient with a full-time job?

“There's a number of approaches, but I think that really working with people around their schedule, figuring out if there's ways where you can do phlebotomy on the weekend at different types of labs to make it more flexible,” Cotes said. “And then I think another really great thing is this idea of point-of-care monitoring that allows you to get the absolute neutrophil count only in a matter of minutes.”

In order to properly address these barriers to care, clinicians need to be ready and willing to have a thorough, balanced and empathetic conversation with patients, Cotes explained.

“And sometimes, actually, we may have some biases about clozapine that might come up in the conversation that maybe a patient could maybe sense some of that, and they might be less likely to take it,” Cotes said. “I think when you talk about clozapine, it's really important to balance the potential benefits with the potential risks in a relatively equal way.”


  1. Kunzmann K. Clozapine and Second-Generation Antipsychotics for Schizophrenia, with John Kane, MD. HCPLive. Published May 6, 2024. https://www.hcplive.com/view/clozapine-second-generation-antipsychotics-schizophrenia-john-kane
  2. US Food & Drug Administration. Information on Clozapine. Web page. Last updated April 25, 2024. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-clozapine
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