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.”

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.

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.

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 ."

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.

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.

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."

“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."

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.

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.

“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."

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.

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.

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.

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.”

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.”

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.

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.

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.

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.

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.