As many as 3.7 million people in the United States have schizophrenia, an incurable chronic brain disease that has a profound, negative impact on the lives of those who suffer from it.

Schizophrenia disrupts the normal production of dopamine, an important hormone and neurotransmitter that controls movement, among other functions. The resulting symptoms include delusions, hallucinations, paranoia, problems organizing thoughts, caring for oneself, social isolation, and more.

Individuals with schizophrenia bear the greatest burden of the disease. But it also imposes a significant and growing cost on society – an estimated $343 billion in direct and indirect costs in 2019, up from $156 billion in 2013.

For decades, providers have relied on two generations of antipsychotic drugs to treat schizophrenia. The drugs are often effective in controlling symptoms, but they also cause serious side effects and, as a result, it’s common for patients to stop taking them.

In late September, health experts at the U.S. Food and Drug Administration (FDA) announced approval of a new drug, Cobenfy, that offers a new mechanism for treating schizophrenia – one that does not target dopamine directly and shows promise in not only relieving symptoms but also reducing the punishing side effects.

The initial trials of Cobenfy were relatively short, and there is still much data to be gathered about the drug’s effectiveness, said Christine Hagerman, a psychiatric pharmacist at UCHealth University of Colorado Hospital. Questions about insurance coverage and costs are still being ironed out as well. We spoke with Hagerman to understand more about schizophrenia generally, and Cobenfy specifically.

What causes schizophrenia?

Biologically, it is caused by disruptions to levels of the hormone dopamine in the brain.

“Schizophrenia has a strong genetic link,” Hagerman said.

Researchers also are studying links to environmental factors along with prenatal risks, drug use and socioeconomic status which can be tied to increased risk of schizophrenia.

“We don’t have years of data to figure out what are true risk factors in an abundance of patients,” Hagerman said.

How does schizophrenia affect patients?

It varies. In practicing with the Veterans Administration as a psychiatric pharmacist, Hagerman said she initially focused on treating delusions and hallucinations that plagued mostly older patients diagnosed with schizophrenia. These are “positive symptoms” caused by too much activity of dopamine in the brain.

However, people with schizophrenia may also have too little dopamine in other parts of the brain, Hagerman said. That can create cognitive issues and “negative symptoms,” which  include “having poor insight into their schizophrenia, an inability to experience pleasure, and problems taking care of themselves,” she explained. Patients who have these symptoms “aren’t necessarily motivated to take care of other aspects of their health.”

One devastating result of these challenges: people with schizophrenia tend to have a much shorter life expectancy, Hagerman said. One large review of studies conducted across all continents except South America placed the shorter life span at about 16 years for adult males and 14 years for adult females.

What antipsychotic medications currently are used to treat schizophrenia?

Broadly speaking, there are two generations of antipsychotic medications, Hagerman said. First- generation antipsychotics began with chlorpromazine (brand name Thorazine) in the 1950s. Chlorpromazine and drugs that followed focused on blocking dopamine receptors in the brain and thus easing the positive symptoms of schizophrenia.

Second-generation antipsychotics also work primarily on dopamine, Hagerman said, but they also target serotonin, a different hormone and neurotransmitter that is also a culprit in schizophrenia. The major benefit of these drugs is that they decrease the painful, involuntary muscle movements and other problems, known as extrapyramidal side effects (EPS), that patients experience with first-generation antipsychotics, Hagerman said.

How effective are the older antipsychotic drugs?

“First-generation anti-psychotics, which directly work on dopamine, work very well” to decrease hallucinations and delusions, Hagerman said. Second-generation antipsychotic medications also accomplish that while easing the burden of EPS, she said.

Are there challenges with the existing second-generation antipsychotics?

Yes. Second-generation drugs cause metabolic side effects, including weight gain and longer-term risks for heart attacks, strokes, and diabetes, Hagerman said. In fact, cardiovascular disease is the leading cause of death in people with schizophrenia. However, the outcomes of these long-term risks may take years to develop, which creates a dilemma for providers, she added.

“It’s hard to think about these long-term risks to patients and their health when we are trying to treat them right in the moment,” Hagerman said.

Are there restrictions on any second-generation antipsychotics?

Yes, in one case. Clozapine requires a Risk Evaluation and Mitigation Strategy (REMS) because it is associated with neutropenia, a condition that reduces the number of neutrophils, a type of infection-fighting white blood cell, in the body, Hagerman said.

“When patients are started on the medication they require weekly blood monitoring for six months. After that first six months, they go to every-other-week blood monitoring. After 12 months of uninterrupted treatment, the patients will remain on monthly blood monitoring as long as they are taking clozapine,” Hagerman said.

She stressed that clozapine treatment is typically reserved for patients who have not gotten relief from two other antipsychotic drugs. The strict REMS requirements can be a barrier to treatment for patients, and the FDA recently took temporary steps “to address the problem and to ensure continuity of care for patients taking clozapine.”

Can side effects of the antipsychotic drugs interfere with patients taking their medications for schizophrenia?

They can. “It is very commonly reported that patients stop taking their medications,” Hagerman said. “At least one big part of people not taking their medications is the side effects that they experience. On average, we can assume, if we’re lucky, that patients adhere to their medications at least half the time.” She cited weight gain as a “particularly distressing” side effect for patients.

How does Cobenfy work?

“It’s a completely new mechanism,” Hagerman said. Cobenfy, which received FDA approval in late September, does not directly block dopamine or serotonin. Instead, it combines two drugs. One, xanomeline – originally developed to treat Alzheimer’s disease – targets and binds to two central nervous system receptors called muscarinic receptors, which are involved in cognition and control of behavior. In binding to these receptors, the drug decreases the production of dopamine, the primary schizophrenia culprit, Hagerman explained.

“The big takeaway is that it is not working directly on dopamine,” she said. “It’s working on a completely different receptor, and that inadvertently decreases the hyperactivity of dopamine.”

The second drug in Cobenfy, trospium chloride, counters peripheral side effects – those that cause movement problems, for example – that are  created when xanomeline binds with the two muscarinic receptors.

What are the future improvements for patients in the development of Cobenfy?

In developing Cobenfy, researchers wanted to maintain the effectiveness of the first- and second-generation medications but decrease the side effects, Hagerman said. “It’s not necessarily saying that [the new medication] is better for symptom control. It’s that they also have less risk of EPS and less risk of metabolic symptoms, like weight gain. In theory, that would help patients with schizophrenia stay on their medications if the side effects are a big barrier, and why they don’t take their meds,” she said.

Hagerman added that Cobenfy will not be subject to the REMS program restrictions applied to Clozapine, as described above.

What are the side effects of Cobenfy?

The most common side effects of Cobenfy are constipation, heartburn, headache and drowsiness, Hagerman said. Importantly, the clinical trials of Cobenfy did not show changes in blood sugar, weight gain or EPS, she added.

How do patients take Cobenfy (orally, with food, how often, etc.)?

It is a twice-daily oral medication that can be taken with or without food, Hagerman said.

Are there patients who should not take Cobenfy?

At this point, not specifically. However, Hagerman said patients who are 65 years and older should be cautious in taking it. That is because trospium chloride, which helps to counter some side effects in Cobenfy, is among a class of drugs called anticholinergics, that can cause confusion and delirium and increase their risk of falls, Hagerman noted.

“We have to be mindful of that in our patients who are 65 and older,” Hagerman said.

Can Cobenfy be taken in combination with other schizophrenia drugs?

“It is common in patients with schizophrenia that sometimes one medication is not enough,” Hagerman said. She noted that if, for example, patients receive two first-generation medications, the risk of EPS greatly increases.

“Where I do think Cobenfy will be a really good option is as an add-on therapy if we’re not getting as much benefit from our first medication as we want,” Hagerman said. She looks forward to additional trials that investigate that approach and the outcomes it achieves.

Is Cobenfy available to UCHealth patients now?

Not as yet. Hagerman noted that a majority of UCHealth psychiatric inpatients are covered by Medicaid, which does not yet cover the Cobenfy. Insurance generally will cover first- and second-generation antipsychotics, which have plenty of data to support their effectiveness and for now are much less expensive, she said.

“It doesn’t mean that patients will never get it, especially if a lot of medications they have taken have failed,” Hagerman added. If more data on Cobenfy shows that it produces good outcomes, providers would be able to argue to insurers that it should be covered. Positive outcomes could also convince mental health professionals to add the drug to their treatment guidelines, she said. “It’s not a ‘never’ [as to availability], just not right now.”

What future developments do you see for Cobenfy?

Aside from building a data track record, Hagerman said new trials of the drug are investigating how it works beyond six weeks. It may also be studied to see how well it works with other diseases, such as bipolar depression.

“They will start adding it on different indications or different patient populations,” she said. “That’s pretty typical of what drug manufacturers do.”