Clozapine: We Can Handle It

I got a big charge out of a recent story about presidential candidate Hillary Clinton’s Area 51 connection. Why is there a Men In Black sort of aura about her?

Sure, we can handle the truth about Area 51, UFOs, Bigfoot, Santa Claus and whatnot. But can we handle the truth about the clozapine crisis?

What got me thinking about this was the Psychosomatic Medicine Interest Group (PMIG) meeting we had this past Monday. OK, so there’s really no crisis about clozapine, but for a long time now, psychiatrists, patients, families, and more recently the FDA, have been working very hard to address the tendency for clozapine to be underutilized in the U.S. for managing treatment-resistant schizophrenia.

There are probably more than a dozen reasons why it’s underutilized, only one of which is the blood-monitoring requirement for which the FDA has approved and mandated the creation of the Clozapine Risk Evaluation and Mitigation (REMS) Program. You know about that one because I had a lot of frustration trying to enroll as a prescriber in the registry (many of my colleagues and residents are still struggling with it) and even enjoyed poking fun at it.

By the way, Dr. E. Fuller Torrey’s take on the underutilization of clozapine links it to privatized state medicaid programs. Hmmm, Iowa’s Medicaid program just went private on April Fool’s Day.

“The fact that states using for-profit managed care companies have lower use of clozapine for individuals with schizophrenia on Medicaid raises additional questions. Since clozapine is administratively more expensive to use initially but has proved to save money in the long run by decreasing re-hospitalization rates, are the for-profit managed care companies only interested in short-term profits? And are for-profit managed care companies associated with other indicators of inferior psychiatric care? Since for-profit managed care is spreading rapidly, these questions need answers.” – See more at:

I tried to compare the problems associated with the opioid epidemic, including the sobering statistic of 28,647 overdose deaths from prescription painkillers in 2014, with deaths related to clozapine. So far, the more sobering fact is my inability to find what I would consider reliable statistics about it, except maybe here and the data seems…are you kidding me? However, some authors point out the favorable effect of clozapine on mortality:

Effects of clozapine treatment on patient mortality has been assessed and reviewed over the years in various populations. The evidence supports a clear advantage of clozapine therapy in terms of reduced mortality over other antipsychotic agents including FGAs, risperidone and quetiapine [1].

Why are there not REMS programs for opioids and opioids plus benzodiazepines? And how is the effectiveness of the Clozapine REMS Program to be measured against the frustrating logistical barriers against its use?

Can we handle the truth about clozapine? Sure we can. Fakra and Azorin call it “…the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe.” Yet they also call for educating all future physicians about how to use it because it’s the treatment of choice for those with refractory schizophrenia [2].

firehydrant2Sending mixed messages to doctors and other prescribers appears to be the norm over a broad array of health care system issues, clozapine prescribing being just one of them. On the one hand it’s the best drug for treatment resistant schizophrenia. On the other hand, the irony is that it’s difficult to for even the most experienced and tech savvy experts in psychiatry today to even get enrolled in the FDA approved Clozapine REMS Program, which reportedly was touted by “several researchers” to be one of the solutions to underprescribing by way of reducing the administrative burden (Ha Ha!). Severe neutropenia is only one of the many troubling side effects…but it’s the most easily monitored.

Talented resident: Dr. Usha Chhatlani, MD
Talented resident: Dr. Usha Chhatlani, MD

One of our talented residents presented a very nice summary of the challenges of clozapine along with suggested solutions, especially as it relates to its use in the general hospital, where it can be difficult navigating a complicated inpatient medical and surgical care system with many moving parts in order to make it accommodate the safe and efficient care of patients taking clozapine.

A dot phrase refers to the Epic electronic health record phrase for a short string of letters that expands to a longer chunk of text (one resident I know has over 200). It’s critically important for psychiatric consultants and their colleagues to work together like a well-oiled machine when a patient taking clozapine is admitted to the general hospital. One of the reference links in the slide set connects to a flow sheet that one Australian organization has developed in an effort to make the process more efficient.

Given the difficulties with the Clozapine REMS Program, including access, glitches in the website and the relatively low rate of severe neutropenia associated with it compared with the many other severe side effects, I think we can ask two questions:

  1. Do we really need the Clozapine REMS Program?
  2. Can we handle it?

We probably have to ask another question: Are we strong enough?


  1. Warnez, S. and S. Alessi-Severini (2014). “Clozapine: a review of clinical practice guidelines and prescribing trends.” BMC Psychiatry 14: 102.
    BACKGROUND: Clozapine effectiveness in the treatment of refractory schizophrenia has been sustained by published evidence in the last two decades, despite the introduction of safer options. DISCUSSION: Current clinical practice guidelines have strongly recommended the use of clozapine in treatment-resistant schizophrenia, but prescribing trends do not appear to have followed such recommendations. Clozapine is still underutilized especially in patients at risk of suicide. It seems that physicians are hesitant in prescribing clozapine due to concerns about serious adverse effects. Recent reports have highlighted the need to inform health professionals about the benefits of treating patients with clozapine and have voiced concerns about the underutilization of clozapine especially in patients at risk of suicide. SUMMARY: Guidelines and prescribing patterns reported in various countries worldwide are discussed. Suggestions on how to optimize clozapine utilization have been published but more efforts are needed to properly inform and support prescribers’ practices.
  2. Fakra, E. and J. M. Azorin (2012). “Clozapine for the treatment of schizophrenia.” Expert Opin Pharmacother 13(13): 1923-1935.
    INTRODUCTION: Despite considerable progress in the pharmacological treatment of schizophrenia, about 30% of patients are minimally responsive to antipsychotics and there is still an excessively high rate of mortality in schizophrenia patients. Clozapine , a D(2)-5HT(2) antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death. AREAS COVERED: The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of clozapine are covered in this article, based on a literature review (PubMed) from 1975 to 2012. Pivotal, as well as supporting, randomized controlled trials are reviewed, along with observational and/or naturalistic safety studies. This review of clozapine will allow the reader to determine the place for clozapine in the schizophrenia treatment landscape. EXPERT OPINION: Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.