WebMD concealed the identity and location of Mary M. and Andrew in order to protect the mental health and safety of Andrew and his family.
It’s May 13, 2022, and Mary M. is in a panic. Just a day earlier, she had hospitalized her adult son, Andrew, in a deep state of psychosis. Against her directions, the hospital gave her son haloperidol (Haldol), which exacerbated his symptoms, instead of the one drug she says keeps his paranoid delusions at bay: clozapine.
Now, hospital staff told her over the phone, he had cut himself. “what did he do?” she asks. But they won’t give more details until you get there. She rushes to the hospital to find out more.
Mary hasn’t seen her son sick since 2018, when the FDA’s iron-clad rules on clozapine stopped his medication after he missed one routine blood test.
Now, after a relatively stable 4 years, Andrew is back in the hospital. This time, he started missing blood tests and skipping medications in a self-continuing loop after being told by a misguided primary care physician that he “didn’t need clozapine” and was “just depressed.” The result was the same: loss of access to clozapine, followed by delusions, threatening voices, paranoia, hospitalization, physical limitations, and months of recovery.
But this time there is something more.
Somehow, even on the condition that he be watched closely by staff, Andrew managed to remove his right eyeball with his fingers and completely sever the optic nerve – not easy to achieve within 15 minutes between required room checks.
Months later, when he was back on clozapine and stable, he told his mother he was terrified of what he had done. He tells her in a voice that kept telling him to do so. He tried to ignore the voice, but the voice got meaner until he complied.
These weren’t the only times Mary couldn’t get doctors to give her son clozapine. Just finding a psychiatrist who would prescribe it for him in the first place took months of begging and pleading. On the face of it, it’s hard to see why.
Clozapine is the gold standard for treatment-resistant schizophrenia, Andrew’s Diagnosis Undisputed.
It’s the only drug approved by the Food and Drug Administration (FDA) for this condition, and it’s clearly mentioned in the American Psychiatric Association’s treatment guidelines as the only drug to use after poor response to two other medications — a threshold Andrew passed long ago.
And research shows that it works. Even compared to other antipsychotics, studies have shown that clozapine results in less suicidality and depression, less agitation, less psychosis, less substance abuse, and a better quality of life.
“Used correctly, it’s our most effective antipsychotic — by far — and it’s changed many people’s lives,” says Diana Kelly, MD, director of the Treatment Research Program at the Psychiatric Research Center in Maryland.
Treatment-resistant psychotic disorders such as Andrew’s disease account for 30% to 50% of psychotic disorders, but only about 4% are treated with clozapine in the US (in other countries, especially Western ones, clozapine use tracks closely with the rate of treatment resistance: 20% to 35 %.)
So why are doctors so reluctant to use it?
The root of the problem, Kelly says, is the FDA’s Risk Assessment and Mitigation Strategy, or REMS, for clozapine. (It is derived from the testing guidelines that came with clozapine when the FDA approved the drug in 1989, followed by the slogan “No blood, no medicine”.)
Of the thousands of drugs approved by the FDA, only about 70 require REMS—an additional regulatory layer. Clozapine REMS requires, among other things, weekly blood draws with a needle. This tapers to bi-monthly after 6 months and monthly after a year, but any interruption means you have to start the process all over again.
The only reason for this condition is to protect against a condition called severe neutropenia – a significant decrease in a type of white blood cell (neutrophils) that can lead to a life-threatening infection.
But the risk is very low. The mortality rate from severe neutropenia caused by clozapine is about 50 per 100,000, or 1/20th of 1%. It is likely to be much lower in the younger age groups most likely to benefit from the medication.
Many drugs that do not have FDA REMS or mandatory blood tests carry a much higher risk of developing neutropenia, including many cancer drugs at rates 10 to 100 times higher. One common antipsychotic, olanzapine, has shown neutropenia-related adverse events at a rate five times higher than clozapine in patients younger than 45 years of age, according to an FDA database.
Importantly, Kelly says, even after 30 years, there is no evidence that REMS blood draw requirements help reduce deaths from severe neutropenia. (During COVID, when the FDA relaxed blood test requirements, deaths and other adverse events from acute neutropenia remained unchanged.)
What is clear, Kelly says, is that interruption or delay in clozapine use can have serious consequences.
“People with schizophrenia are more likely to die from suicide from clozapine deficiency than from severe neutropenia if they take it,” says Robert Lightman, MD, a New York clinical clinician. Laitman, a nephrologist, has developed a model for treating psychosis with clozapine called the Purposeful Recovery Protocol.
The numbers seem to confirm this. The suicide rate among people with schizophrenia is tragically high—5,000 people per 100,000, mostly in the first year after diagnosis, compared to about 14 in the general population. Clozapine is the only drug approved by the US Food and Drug Administration (FDA) to reduce suicide attempts in people with psychosis, and studies show that this saves thousands of lives, even compared to other antipsychotic options.
Then there are the known risks of trying to stop clozapine too quickly. “It can cause a rebound effect,” says Lightman, who has treated hundreds of people with psychotic disorders over the past 10 years.
Within a day or so of missing a dose, a person with schizophrenia can begin to “uncompensate” in a psychotic state, he says.
It is not just the unpredictability of psychosis that is the problem. Compensation damages the brain, says Lightman. “It’s neurodegeneration. Every time someone has a psychotic episode, they lose some of their gray matter.”
Lightman says these issues are harder for some minorities in the United States. People of African or Middle Eastern descent in particular can have healthy neutrophil ranges that are 30% lower than the white population. This makes these groups more likely to fail blood tests, though they are less likely to develop severe neutropenia, he says. The result is that they get less than average clozapine and stop a lot.
REMS is a huge burden for doctors, pharmacists, and patients, Kelly says.
“Imagine you start a new drug, and now every week you go to the lab to have your blood drawn. You can’t get a prescription next week. You have to go every week. You have to take a shot. It’s a lot.”
Kelly helped start a hotline in Maryland to help providers with all aspects of clozapine dosing and monitoring, which can be a little tricky if you don’t know the details. But this is not what patients or providers call it the most.
“The most common questions we receive by a large margin are about how the REMS program itself is managed. There are so many things that can go wrong,” says Kelly.
If you miss a blood draw, the clozapine is stopped. If you cannot find an approved pharmacy, discontinue clozapine. If you miss your medication, the clozapine is stopped. If the pharmacy does not get the report in a timely manner, the clozapine will be discontinued. If your doctor forgets to submit a monthly ‘patient case form’ (new requirement for 2021), the clozapine will stop. If the provider cannot stock the drug (a common problem due to REMS), the clozapine is discontinued. If the FDA REMS fails (as it did in 2021), clozapine is discontinued. And the list goes on.
In December 2021, the Food and Drug Administration (FDA) issued guidelines that temporarily allow a small leeway for certified physicians if they can find an approved pharmacy willing to dispense the drug without a blood test.
Lack of clarity and complex logistics have led most physicians, pharmacists and other players (such as pharmacy benefit managers) to either stick with strict patient testing requirements or simply opt out of dealing with clozapine altogether, Kelly says.
In addition, the FDA’s announcement of “additional enforcement discretion” is confusing to many and is sometimes interpreted as more restrictive, rather than less, according to some advocates.
In 1976, after 3 years of clinical testing, American research on clozapine was halted because of eight deaths of clozapine patients reported in Europe due to severe neutropenia, says psychologist and psychopharmacologist Gilbert Honigfeld, one of the architects of the original clozapine patient monitoring system. From the nineties.
This is what prompted the Food and Drug Administration to set stringent requirements for blood testing and monitoring. And after that, the disease never really went away, even after new research and new drugs showed it wasn’t necessary.
“It was understandable at the time,” says Honigfeld, who has worked on clozapine for 50 years. But now, he says, “I think the time to repeal this kind of mandate is long past.”
In the late 1990s, a comprehensive report by Honigfeld and colleagues showed that severe neutropenia induced by clozapine was much less common than previously thought, and that deaths from the condition were virtually unheard of. Plus, by then, there were much better medications to help treat severe neutropenia, Honigfeld says.
It’s true that clozapine can be a difficult drug, Honigfeld says. It has some potentially serious side effects that need to be managed efficiently.
But, as Honigfeld says in an open letter to the president of the American Psychiatric Association (APA) in March 2023, “psychiatrists are well equipped to handle prescribing clozapine and monitoring the patient without the corrupt apparatus of a federal program whose time has come and gone.”
On May 24, 2023, 30-year-old Annalisa Chase, who has schizophrenia, speaks at a briefing on Capitol Hill in Washington, D.C., put on by the Schizophrenia and Psychosis Action Alliance and the American Association of Psychiatric Pharmacists. She talked about the battle of getting clozapine in the first place, even after taking several other medications without success. She spoke of the nightmarish, months-long journey to get back on her feet after missing one weekly blood draw in 2018. She pleaded with the FDA to renew or remove REMS for clozapine.
The APA, along with a number of prominent psychiatrists such as E. Fuller Torrey, Robert Cotes, Brian Barnett and pharmacologist Raymond Love, have made similar public appeals. They’re joined by a bevy of advocacy groups like the treatment advocacy center, NAMI, and an appropriately named group of mothers of children with psychotic disorders, The Angry Moms.
The Food and Drug Administration recently issued a new request for comment on what to consider when changing REMS requirements, including testing the system, how to evaluate whether the change was successful, and how to plan for system failure.
We can only hope, says Honigfeld, that this is a sign of the FDA’s interest.
After Andrew lost his eye, he spent several months in and out of the hospital. He had to start over with a slow buildup of clozapine and weekly blood draws. He was very depressed about what had happened and the doctors kept him under heavy sedation. But over time, the clozapine has solidified and stabilized.
Mary says he has been home since October 2022 and has been recently stable. “In the hospital and without clozapine, he had two medical technicians watching him 24/7 and gloves on his hands to keep him from hurting himself. On clozapine, he lives in a townhouse.”
Participates in family activities and voluntarily participates in a local community mental health program. He takes his meds.
“If you met him on the street, you wouldn’t know he was seriously ill,” Mary says. “He has coherent conversations. He goes to the gym every day to exercise. He plays basketball every now and then and a lot of table tennis. Surprisingly, he beats everyone at ping-pong, even with one eye!”
The FDA did not respond to WebMD’s request for comment on the issue of clozapine’s REMS or the opinions of the experts in this article.
