Two people in medical gowns try to access clozapine pills from a large, impenetrable bottle
Cathryn Virginia

The Psychiatric 'Wonder Drug' That Almost No One Is Using

Clozapine could save the lives of suicidal schizophrenic people who aren't responding to other treatments. So why are so few doctors using it?

When Nicholas* was a child, he heard a ringing in his ears. Over time, the ringing turned into voices. They were so loud, it was like an amp pressed against the right side of his head, blasting violent and vulgar phrases.

He had his first, full-blown psychotic break at 18, and was diagnosed with schizophrenia. “Have you ever seen the movie The Exorcist?” he said. “This is the type of thing I was dealing with. You know, before.”


Before. Before he was given a drug that allowed him to think clearly again, which turned down the volume on his hallucinations to just a whisper. Before the drug that made it possible to enroll at a university as a social work major, with a minor in psychology.

That drug was clozapine. Clozapine has been around since 1959 and is the most effective medication for patients with treatment-resistant schizophrenia. Multiple guidelines say that if a person hasn’t responded to any two antipsychotic drugs, or can’t tolerate their side effects, clozapine should be prescribed. These criteria apply to more than 30 percent of people with schizophrenia in the U.S. and yet, clozapine is actually prescribed to only about 4 percent of them.

Clozapine's dramatic under-use can be explained, in part, by a rare side effect that led to a cluster of deaths in 1975. Now, the FDA requires stringent monitoring of anyone who takes the drug, which is sold as a generic and under the brand name Clozaril. Patients must join an online registry, and submit to weekly mandatory blood testing. As a result, doctors don't feel comfortable using it, except as a drug of "last resort."

But clozapine advocates say that clinicians are too cautious of its rare potential harms, and that we've developed a “clozaphobia," missing out on the drug's benefits. Clozapine is twice as effective as other antipsychotics available for treatment-resistant schizophrenia and the only drug approved by the FDA to treat suicidal behaviors in people with the disorder. While these experts acknowledge that clozapine’s side effects exist, they think the risks are more than manageable, and that limiting access is a disservice to patients.


“I've had people who were in and out of hospitals 10 times—their parents said they had lost their children—and then after, they were not hospitalized again," said Fred Nucifora, a clinician scientist and director of the clozapine clinic at Johns Hopkins Bayview Medical Center. "I’ve seen miracles on clozapine."

“It was like somebody just wiped the slate clean. You're back to your normal self."

Robert Francis*, a 48-year-old licensed clinical social worker, who lives near Washington, D.C., has been on clozapine for 25 years. When he graduated from college, he started to have trouble sleeping, saying weird things out of context, and behaving strangely.

His family sent him to a hospital, where he received an injection of the antipsychotic drug haldol. Forty-five minutes later, his whole body tightened. He said it was like he had cerebral palsy from top to bottom, but it was caused by a severe allergic reaction. Then, the doctors tried an antipsychotic called Zyprexa, which made him feel like a zombie, foggy and tired. He stopped taking it and his symptoms flared up again.

“I was nearly catatonic at that time," he said. "I was so paranoid that I pretty much got up and sat down in a chair and watched people all day long because I was just so on edge."

At another hospital, Francis was given clozapine. Within three or four days, he said, he felt like himself again. “It was like somebody just wiped the slate clean. You're back to your normal self."


Nicholas wasn’t offered clozapine until he was hospitalized in 2009 at a Maryland institution, where researchers happened to be studying clozapine and its underutilization. “That was the first time I ever even heard the word clozapine,” he said. By that point, he’d seen somewhere between six and 12 doctors at multiple hospitals, tried three other antipsychotics, and been on “basically every other form of psychotropic drug.”

All antipsychotics modify levels of the neurotransmitter dopamine, a molecule associated with reward, mood, and behavior. But clozapine seems to do more than that. It affects many other receptors—though exactly which ones and how that helps schizophrenia symptoms is still a mystery.

Despite clozapine being recommended after two failed drug trials, patients in the U.S. sometimes try as many as five drugs—more than two-thirds tried at least three—before being offered clozapine. Instead, people are often given drugs at higher doses or, in an approach called polypharmacy, two or more antipsychotics are combined.

The mean wait time for clozapine is 48 months because doctors are putting patients on a number of different drugs and combinations of drugs before they opt for it. That’s much longer than it should be, said Deanna Kelly, a psychiatric pharmacist and chief of the Treatment Research Program at the Maryland Psychiatric Research Center. A trial of any antipsychotic is around six weeks, and 12 weeks is all that's needed to realize that one isn’t working. “There's no reason you should be waiting for years and years [to try clozapine],” she said.


Kelly pointed to the fatal incident from 1975 to explain why. Clozapine was developed and being researched in Europe throughout the 1960s and 1970s until researchers from Finland reported in The Lancet that eight of their patients had died on clozapine. They had developed a blood disorder called agranulocytosis where there's a drop in white blood cell counts. These particular white blood cells, neutrophils, play a crucial role in the immune system, and losing them leaves patients vulnerable to infections. After the deaths, clozapine’s Swiss manufacturer stopped their active clinical trials on it.

But the FDA continued to let people use the drug through “compassionate-need programs,” which allow severe medical cases to try drugs that have not been approved, as some psychiatrists saw that their patients were getting better on clozapine.

In 1987 and 1988, two studies compared clozapine to other antipsychotics for treatment-resistant schizophrenia, finding it to be much more effective. They also noted that monitoring white blood cell counts could reduce the risk of agranulocytosis.

In 1989, more than a decade after the drug was pulled, the FDA approved clozapine for treatment-resistant schizophrenia, and it became widely available in 1990. But the FDA was still concerned about its side effects and mandated that patients be watched closely for agranulocytosis.

Today, if a patient takes clozapine, they have to register with a drug-safety program called the Clozapine Risk Evaluation and Mitigation Strategy, or REMS. So does their pharmacy and prescriber, who has to take a test before they are certified to prescribe the drug. Patients' white blood cell counts have to be entered into the REMS every week before a patient is allowed to pick up the next dose. The blood draws are weekly for the first six months, biweekly for the following six months, then once a month—but never stop. “Their motto is: 'No Blood, No Drug,'” Kelly said. “It's really strict.”


Nucifora said that all of the red tape can be time-consuming for the doctors, as well as for their patients. Clozapine's use has been declining in the United States, but not in other parts of the world: It comprises 36 to 39 percent of the antipsychotics used in Australia, 26 percent in China, and 20 to 30 percent in Taiwan. In those countries, the monitoring for agranulocytosis is not as rigorous, possibly a contributing factor to the drug's higher use.

We have to make sure they go to the labs, we have to check the labs, we have to enter it into the REMS—it adds a whole other level," Nucifora said. "If you're a busy psychiatrist, it may be difficult to manage that."

"There's no reason you should be waiting for years and years to try clozapine."

All antipsychotics can have side effects. Clozapine can also cause excess saliva, constipation, drowsiness, weight gain, and in rare cases, inflammation of the heart, or myocarditis. But others can increase the hormone prolactin, which can lead to bone loss, sexual dysfunction, and infertility. Some of the older schizophrenia drugs can cause tardive dyskinesia, an erratic movement disorder and other antipsychotics have a small risk of agranulocytosis, too, Nucifora said.

Yet no other psychiatric medication requires the registration and monitoring that clozapine does.

Kelly said these restrictions present a narrative that clozapine is impossibly difficult to use, but she doesn't find that to be the case in practice. With her patients, she starts the drug slowly and keeps an eye on their white blood cell counts. She said that many doctors aren't aware of the actual risk of agranulocytosis, which is less than 1 percent. About two thirds of prescribers also don’t know that the biggest risk for agranulocytosis happen within the first six months, and tapers off after that.


"If people haven’t seen someone respond to clozapine, they may not truly appreciate what the drug can do."

Gopal Vyas, an assistant professor at the University of Maryland School of Medicine and a psychiatrist who works with Kelly, said that in 13 years of using clozapine almost exclusively, he’s had only one patient with agranulocytosis. They hospitalized the patient as a precaution, gave him antibiotics and a medication to boost bone marrow—which helps produce white blood cells— and his counts returned to normal. “He didn't even get a runny nose,” Vyas said.

It's fair to assume that very sick patients can't handle the upkeep of a weekly blood draw, Nucifora said, but doctors may be overestimating that burden too. In surveys sent to patients and clinicians, most clinicians overestimated how often and how bad clozapine’s side effects were. And only 19 percent of the patents reported they were unhappy about the blood tests compared to 52 percent of the doctors who thought that their patients didn't like them.

Nicholas, meanwhile, said that clozapine can make him drowsy, but since he takes it before bed, it actually helps him sleep through the night. He takes a medication to help with related constipation, but has no other side effects. And compared to other drugs he's tried, like Zyprexa, which gave him racing thoughts, or Geodon, which gave him extreme pain in his legs—he said clozapine comes out on top.


"The physical side effects [of Geodon] were absolutely horrible for me," he said. "It was a very strange feeling. It could immobilize you."

Using clozapine could be more cost-effective too. In a study of veterans with treatment-resistant schizophrenia, researchers found that the Veterans Health Administration would save $22,444 per veteran in the first year if they gave their patients clozapine. If they doubled the overall amount of clozapine they used, the VHA could save around $80 million altogether. The savings come not from the cost of the drug, but from a decrease in inpatient days and hospitalizations. Multiple doctors interviewed didn't suspect that anyone is intentionally profiting from clozapine underuse, and that the barriers are better explained by the logistical struggles and lack of experience with the drug.

Still, the proponents for clozapine don't think monitoring should go away. Nucifora said the REMS should be more flexible, and that perhaps the blood draws shouldn't continue for life. Kelly just wants it to be thought of less as a drug of "last resort," and instead as the first-line option for treatment-resistant schizophrenia.

“The way it's going now is that people are putting patients on every other medicine before they get to clozapine,” Nucifora said. “People are suffering longer. And we know that the more episodes they have, the longer they’re ill, the worse they do in the long run."


Because the FDA’s standards were based on white patients, many Black patients weren’t eligible to even try clozapine.

Mr. C was a Black 29-year-old who first tried to kill himself at age 11. After being diagnosed with schizophrenia, he tried the antipsychotics risperidone, fluphenazine, and olanzapine, but they either caused severe side effects or didn’t help with his psychotic symptoms. When he went on clozapine, it eased his auditory hallucinations and thought disorders, but after he was discharged, clozapine was discontinued, “allegedly because of a low white blood cell count,” according to a case report from Kelly and her colleagues. He died by suicide 48 hours after stopping the drug.

Suicide risk is already extremely high for people with schizophrenia—about half of those diagnosed will attempt suicide and about 5 to 10 percent die by suicide. Clozapine is the only antipsychotic with FDA approval for treating suicidal behaviors. In a study of 88 patients, suicide attempts decreased 86 percent in the two years after they got clozapine, compared the two years prior. Data from more than 12,000 people in the U.K. and Ireland found a four-fold decrease in suicide in the patients who were prescribed clozapine.

But if people stop clozapine suddenly, it can cause “super sensitivity psychosis” which is a rapid worsening of delusions and hallucinations in the first couple of days. Nicholas had a friend who died by suicide because he was pulled off clozapine and wasn’t given an alternative fast enough. “He signed himself out of the hospital and shot himself,” Nicholas said. “You can become psychotic very quickly. That's all it takes for the psychosis to step back in.”


Mr. C’s case brings up another issue around lack of experience and access to clozapine, Kelly said. Many people of African and Middle Eastern backgrounds have benign ethnic neutropenia, which means that they naturally have lower white blood cell counts as a result of a genetic mutation that is protective against malaria. Because the FDA’s white blood cell counts are based on white patients, many Black patients weren’t eligible to even try clozapine, even though their low counts are normal for them and their bodies. Kelly and the other authors theorized that it was Mr. C’s naturally lower levels of white blood cells that contributed to him being pulled off the drug, and led to his subsequent death.

In 2015, new monitoring guidelines were created for people with benign ethnic neutropenia, but Vyas still worries that many practitioners would be nervous to try those patients on clozapine, or continue their prescriptions. Black people are twice as likely to stop getting clozapine because of their white blood cell counts, and studies have found that a fear of agranulocytosis was the most common reason given for stopping clozapine use when treating Black patients.

Kelly and Vyas give their Black patients clozapine anyway, with careful monitoring, and have found it to be safe. They’re wrapping up a clinical trial now which will be the largest prospective data set of Black clozapine patients in the world. “The rates of clozapine are embarrassingly low in the U.S., but are even worse for people in the African American community,” Vyas said. "We can't withhold this drug from them."

The underuse of clozapine has resulted in a vicious circle, Vyas said. It's a drug determined by the zeitgeist to be too unsafe, too complicated, too burdensome to use, which has caused fewer physicians to use and train the next generations with it, and inherit this hesitation.

There is a small, vocal cohort of clinicians trying to change this, but the impact so far has been incremental. This cycle also means fewer doctors get to see how profoundly the drug can help their patients. “If people haven’t seen someone respond to clozapine, they may not truly appreciate what the drug can do,” Vyas said. “It really is a tremendous feeling.”

Vyas had an intimate first-hand experience with clozapine when his mother, who had schizophrenia, finally took it. When he was growing up, his mom would write letters to senators and the governor about the cameras she thought were installed in her home. She went on hunger strikes to protest the imaginary surveillance. She was put on risperidone, which caused Parkinson’s-like side effects, and then she tried Seroquel, which just didn’t work, Vyas said. As a doctor in training, he lobbied her psychiatrist to try clozapine.

“It was a night-and-day difference with regard to how distressed she was and the conspiracies against her,” he said. “She also had moments where she was suicidal [in the past] and there was a big improvement there for her as well.” She died in 2011, from causes unrelated to schizophrenia, and had several years where she was mentally well, Vyas said.

Nicholas hopes that more people get the opportunity to try clozapine, not only to feel better, but to help decrease the stigma that can follow people with a schizophrenia diagnosis. “It’s tough to live in a society that doesn’t understand this disease and that looks down on it,” he said. “I know I wouldn’t be in the position I’m at without clozapine. In my opinion, It’s a wonder drug."

*Because of the sensitive information shared, a pseudonym has been used.

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