Pham is a combined internal medicine and psychiatry resident physician at the Medical College of Wisconsin.
When Christen White's brother had his first psychotic episode thinking Steven Spielberg was stalking him, it was a shocking and overwhelming experience for loved ones.
"My brother lived with schizophrenia for 10 years," White wrote to me in an email, "and our biggest battle was ensuring his safety and trying to keep him well. Unfortunately, the failures of the mental health care system compounded the challenges we faced." This led her to becoming involved with The Angry Moms, a grassroots effort advocating for the safe use of clozapine, an antipsychotic medication. (The Angry Moms has not received any donations from companies or corporations, but some members of the group are employed by or have financial ties to clozapine-related companies.)
They scored a victory recently. In November, an FDA advisory panel voted 14-1 against key regulatory aspects of the Clozapine Risk Evaluation and Mitigation Strategy, or REMS. The panel determined that REMS, the centralized patient registry designed to verify and document blood counts for patients taking the antipsychotic clozapine, was no longer necessary. The panel's recommendation represents a promising step toward eliminating a burden that has hindered access to this crucial medication for patients with treatment-resistant mental illness. Now, the FDA must decide whether it will follow the recommendations laid out by the advisory panel.
Clozapine has been FDA-approved since 1990 for use in individuals with treatment-resistant primary psychotic disorders, such as schizophrenia. However, its use is associated with a range of side effects, some of which can be serious, including the potential for fatal and severe infections due to severe neutropenia or an abnormally low count of a type of white blood cell that helps fend off infections. Following its approval, the FDA implemented a requirement for patients, providers, and pharmacies to be registered in the Clozapine REMS Registry.
This system imposes strict requirements for prescribing clozapine, creating a highly delicate and coordinated process. Patients must navigate a complex system involving prescribers, pharmacies, distributors, lab-testing facilities, and insurers.
Here is how it works:
First, the patient has their blood drawn. A registered psychiatrist or other prescriber reviews the results and reports them to the REMS administrator. If the blood count is acceptable, the psychiatrist submits the initial prescription to a certified pharmacy. The pharmacy then requests a REMS Dispense Authorization from the vendor before filling the prescription. Once approved, the patient can collect their initial prescription, which typically lasts about seven days.
By the fifth or sixth day, the patient must return to the lab for another blood test. This process repeats for subsequent prescriptions, requiring precise timing and coordination at every step. If they adhere to this process for six months, patients can relax their required blood drawn to either biweekly or monthly indefinitely.
Adding to this burden is the rigidity of the health care system. For instance, lab appointments frequently require patients to take time off work, and labs rarely offer walk-in services or availability outside standard business hours. This is especially concerning given that an estimated 10% to 20% of unhoused people have schizophrenia. They often lack the social support, financial resources, or reliable transportation needed to navigate this intricate system.
Even those who manage to attend appointments may have to face not-uncommon errors such as the wrong lab tests being drawn or results not being properly obtained, further complicating an already arduous process.
For many, though, dealing with this system is worth it. According to multiple guidelines including from the American Psychiatric Association, patients with persistent, treatment-resistant symptoms of schizophrenia, defined as those whose symptoms are not adequately controlled on at least two trials of antipsychotics, should be treated with clozapine. This recommendation is based on evidence that clozapine is the most effective antipsychotic for individuals who do not respond to other antipsychotics.
Several large-scale studies indicate that clozapine is associated with significantly higher levels of satisfaction for both patients and clinicians. Moreover, early initiation of clozapine is particularly important for young patients with treatment-refractory schizophrenia, providing an opportunity for symptom improvement and stabilization, laying the foundation for recovery.
For individuals with elevated and chronic risk factors, clozapine stands out as the only antipsychotic approved by the Food and Drug Administration for reducing suicidality. It has the lowest mortality rate among all antipsychotic treatments.
However, the initiation of clozapine treatment is often delayed, with data showing that patients typically wait years and undergo far more than two failed antipsychotic trials before starting clozapine. Despite its proven efficacy, it remains under-prescribed in the U.S., with a prescription rate of approximately 4% -- far below the estimated 30% prevalence of treatment-resistant schizophrenia. Furthermore, the U.S. lags behind other developed countries such as Australia and China in clozapine utilization. Only six states report clozapine being prescribed in more than 10% of cases, while in some states, it accounts for less than 3% of all antipsychotic prescriptions.
"In the entire decade my brother battled this devastating illness, not a single doctor ever offered him clozapine or suggested it as a treatment option," White told me. Schizophrenia "was a constant fight for him and our family, but the lack of options and support from the system made it an even harder battle." But he was offered many other medications. "At the time of his death, my brother was on eight different antipsychotic and mood-stabilizing prescriptions -- eight pills a day, each with significant side effects," White wrote.
One contributing factor is the limited comfort and knowledge among prescribers. A study published in the Community Mental Health Journal highlights variability in U.S. psychiatrists' comfort with prescribing clozapine, likely influenced by how frequently it is prescribed in their practice settings.
But perhaps the most significant challenge is the intensive hematologic monitoring required for clozapine, which can lead to unintended consequences. Frequent blood work poses a considerable burden on patients, especially given the strict requirements of the REMS system. In one study, 60% of clozapine prescribers reported that these monitoring requirements often delayed patients from receiving their medication. Such delays can have serious repercussions, as missing even a single dose of clozapine may lead to discomfort, a worsening of psychotic symptoms, and, in some cases, psychiatric decompensation requiring hospitalization.
Clozapine is not the only medication associated with a risk of severe neutropenia, which occurs in less than 1% of cases according to a meta-analysis of over 250,000 clozapine-treated patients. Common medications like the antiseizure drug valproic acid and immunosuppressants have similar rates of neutropenia. A recent review identified 94 medications with a known potential to induce agranulocytosis, a severe form of neutropenia. However, among these, only one -- clozapine -- is subject to the FDA's stringent REMS mandate, despite similar risks associated with other drugs.
Beyond the logistical challenges of prescribing clozapine, there is also a critical issue of health equity. Individuals with benign ethnic neutropenia -- a condition more common among those of African or Middle Eastern ancestry -- have lower neutrophil counts than the standard laboratory reference range. However, this condition is not associated with an increased risk of infection. The failure to recognize this distinction has led to racial and ethnic disparities in historical access to clozapine. Many people who could have benefited from the medication were excluded due to assumptions about neutrophil levels, despite newer evidence showing that neutrophil functioning remains intact in these populations.
The decision to use clozapine must involve careful consideration of both its risks and benefits, a patient-centered approach, and evidence-based practices to ensure its safe and appropriate use. Putting the risk in perspective, 2 out of 5 patients with treatment-resistant schizophrenia experience benefit from prescribed clozapine. On average, 1 out of 7,700 patients prescribed clozapine die from severe neutropenia.
Eliminating the REMS program or even relaxing laboratory monitoring requirements won't be a simple fix to expand clozapine access. However, the REMS program can often act more as a barrier than a benefit. If a patient moves or a provider retires or leaves the field, finding another provider willing to take on the administrative burden of continuing clozapine treatment can be daunting.
There's a need to expand the pool of clinicians willing and able to prescribe clozapine, including calls to make it a competency requirement for future psychiatrists. As a clinician training to be certified in both internal medicine and psychiatry, I also see the need to establish stronger links between psychiatrists and primary care providers to help address issues and side effects that may arise during treatment.
By increasing the number of clozapine providers and enhancing their comfort with the medication, only then can one begin to think about broader systemic changes -- clozapine in health systems, correctional facilities, and public health authorities. And while drug discovery often takes decades, increasing interest in clozapine can encourage academic scientists and pharmaceutical researchers to better understand the half-century-old medicine, paving the way for newer medications that retain its efficacy while minimizing its most severe side effects.
If the FDA follows the committee's vote, it can potentially be a transformative step in the delivery of mental health care in this country, but that alone will be merely insufficient. "Clozapine REMS did not directly cause my brother's death, ignorance did," White said during her testimony at the FDA panel. "But the Clozapine REMS had contributed to fear, ignorance and systematic failure."