Our track record for treating mental illness is abysmal. I saw that up close and personal when I worked in the Neuropharmacology Laboratory at the New Jersey Neuropsychiatric Institute outside of Princeton, NJ. In those days, we had first generation antipsychotic drugs like chlorpromazine (Thorazine) and haloperidol (Haldol). They were a bit like chemical strait jackets for the brain. The FDA recently announced approval of a new medicine for schizophrenia. Is Cobenfy a breakthrough or a boondoggle?
A Short History of Treatment for Schizophrenia:
People with mental illness, especially schizophrenia, have been abused and neglected for centuries. Many past cultures interpreted the delusions of schizophrenics as signs of demonic possession.
In some cases, holes were drilled in their skulls so that evil spirits could escape. The Romans used electric eels to shock such people. They also used starvation and flogging to subdue unruly patients.
During the middle ages, people were jailed, chained or put in stocks. Women might be burned at the stake as witches.
More “Modern” Treatments of Mental Illness:
In the 20th century, physicians administered electroshock therapy or injected high doses of insulin to induce seizures. Then the lobotomy was developed in 1946. For this procedure, the frontal lobe of the brain was surgically destroyed with a tool like an ice pick. Lobotomies were widely used because they calmed agitated people and made them docile.
Dr. Jeffrey Lieberman has been a guest on The People’s Pharmacy nationally syndicated radio show (# 1373: Malady of the Mind). He was president of the American Psychiatric Association and chaired the Department of Psychiatry at the Columbia University Vagelos College of Physicians and Surgeons.
In his book, Shrinks: The Untold History of Psychiatry, Dr. Lieberman wrote:
“The purpose of the earliest mental institutions was neither treatment nor cure, but rather the enforced segregation of inmates from society. The mentally ill were considered social deviants or moral misfits suffering divine punishment for some inexcusable transgression.”
There was a time when physicians put patients who were suffering from delusions and hallucinations in padded cells and wrapped them in cold wet sheets. Mental hospitals used straitjackets to restrain unruly patients. This garment had long sleeves that stretched beyond the fingertips. The arms were crossed at the chest and tied at the person’s back. This “treatment” was supposed to protect a psychotic patient from harming himself. Too often, though, it was used to control someone who was hallucinating and unruly.
Medications for Schizophrenia:
Antipsychotic medications were supposed to help rehabilitate people suffering from schizophrenia. Chlorpromazine (Thorazine) was introduced in France in 1952 and received FDA approval in 1954.
Thorazine ushered in a new dawn in the treatment of mental illness because it was perceived as a dramatic improvement over past “therapies.” Patients who had been restrained and abandoned in state mental institutions could now interact with other people.
Similar drugs that were developed after chlorpromazine contributed to states’ shutting down their mental institutions (deinstitutionalization). There was a hope that patients could be cared for by their families or communities rather than the health professionals in the state mental hospitals.
But antipsychotic drugs like chlorpromazine, haloperidol (Haldol) and thioridazine (Mellaril) produce potentially serious side effects. Many patients found the drugs so sedating that they felt like zombies. They escaped “ice pick” surgery only to experience a kind of “chemical lobotomy.”
Others discovered that after months or years of treatment they developed uncontrollable muscle twitches or tics that were often irreversible, even after stopping the drugs. Symptoms of this condition, called tardive dyskinesia (TD), include uncontrollable movements of the face such as lip smacking, blinking and sticking the tongue out. Other parts of the body can also be affected.
Additional side effects included dizziness, urinary retention, dry mouth, constipation, blurred vision, nasal stuffiness, weight gain, diabetes, heart rhythm problems, fainting, sexual problems, insomnia and seizures.
Drugs like chlorpromazine can also cause akathesia, a profound restlessness that makes it hard for people to sit still. They feel as if they are about to jump out of their skin.
“Atypical” Antipsychotic Drugs:
Not surprisingly, patients often discontinued these “major tranquilizers.” Drugs that give you brain fog, make you dizzy, constipated and restless and take away your sex life are generally not very well received.
The pharmaceutical industry thought that it had come up with better solutions when it developed “atypical antipsychotics.” Drugs like aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel) and ziprasidone (Geodon) were supposed to provide relief from hallucinations and other symptoms of schizophrenia without so many unpleasant side effects.
Unfortunately, these medications also produced adverse reactions. Some people gained a lot of weight and still developed TD, type 2 diabetes, dry mouth, irregular heart rhythms, headaches, blurred vision , cognitive impairment, elevated cholesterol or blood disorders.
The FDA has approved a number of these atypical antipsychotic medications to treat depression. You will read about this development in this article:
“Abilify Side Effects Can Be Scary!
There are hundreds of reader comments at the end of the article
A Brand New and Very Different Antipsychotic Drug:
Is Cobenfy a Breakthrough Against Mental Illness?
The FDA recently approved a completely different type of treatment for schizophrenia. Most antipsychotics modify a neurotransmitter called dopamine. The new medicine, Cobenfy (xanomeline plus trospium) works primarily by interacting with receptors for the neurotransmitter acetylcholine.
A Little Background On Cobenfy:
This drug got its start in the early 1990s. Researchers were looking at a novel chemical entity labeled LY246708 (xanomeline) to treat Alzheimer’s disease. The pharmacology gets very complicated very quickly. Here is the quick and dirty version.
The are a number of neurotransmitters in the brain. These are chemical messengers like serotonin, norepinephrine, dopamine and acetylcholine. My mentor at the University of Michigan was Dr. Edward Domino. He was one of the country’s leading experts in cholinergic neuropharmacology. Acetylcholine is a neurotransmitter that is critical for learning, memory, mood and muscle movement.
Acetylcholine and Muscarinic Receptors:
Dr. Domino instilled in me a great interest in drugs that interact with muscarinic and nicotinic cholinergic receptors. People with Alzheimer’s disease tend to have lower levels of acetylcholine in their central nervous system. It’s hardly surprising, then, that researchers would be interested in boosting cholinergic activity in the brain.
Enter xanomeline. This compound had a high affinity for muscarinic receptors (Journal of Pharmacology and Experimental Therapeutics, April, 1994). Researchers at Eli Lilly reported in the journal Alzheimer Disease and Associated Disorders (Suppl 4: S16-22, 1997) that this drug reduced:
“…vocal outbursts, suspiciousness, delusions, agitation, and hallucinations.”
There was also evidence of improvement in a cognitive assessment test.
Cholinergic Side Effects:
But there was also a problem. The drug produced adverse gastrointestinal side effects that the researchers thought would “limit its use.” In fact, Eli Lilly abandoned the drug because of side effects such as nausea and vomiting.
Fast Forward to Karuna Therapeutics. This company thought it could harness the benefits of xanomeline and mitigate its complications. The goal was to stimulate muscarinic receptors in the brain but block that effect in the rest of the body by adding a second drug.
The second drug was trospium. It was approved by the FDA in 2004 to treat overactive bladder and incontinence under the name Sanctura. The brand name product has been discontinued, but generic trospium remains available.
Trospium is an anticholinergic drug. That means it blocks the effects of acetylcholine in the body. Side effects are classic for such medications: dry mouth, constipation, flatulence, abdominal distension, nausea, dry eyes, urinary retention, blurred vision, rapid heart rate and nasal dryness.
The theory was that with the combination of xanomeline (that stimulates muscarinic receptors in the brain) and trospium (that blocks muscarinic receptors in the body) you could get best of both worlds. Think of this a bit as if you were driving with your foot on the gas pedal and the brake simultaneously.
Bristol-Myers Squibb Buys Karuna:
Bristol-Myers Squibb must have thought Karuna Therapeutics had struck gold. The combo drug of xanomeline and trospium would get the name Cobenfy (also called KarXT). Bristol-Myers Squibb paid $14 billion to acquire Karuna. Even in the pharmaceutical industry that is a lot of money. But is Cobenfy a breakthrough?
I suspect that Bristol-Myers Squibb believes Cobenfy is a breakthrough for schizophrenia. That’s because it works via a completely different mechanism than traditional antipsychotic medications. It may even be helpful against some of the manifestations of Alzheimer’s disease.
According to a pundit consulted by the Wall Street Journal (Oct. 7, 2024):
“…Cobenfy will eventually garner $3.9 billion in annual Alzheimer’s sales in addition to $2.4 billion in sales for schizophrenia.”
Is Cobenfy a Breakthrough? Data from the FDA:
According to the Food and Drug Administration:
“Cobenfy’s effectiveness for the treatment of schizophrenia in adults was evaluated in two studies with identical designs. Study 1 and Study 2 were 5-week, randomized, double-blind, placebo-controlled, multi-center studies in adults with a diagnosis of schizophrenia according to DSM-5 criteria.”
Yikes! Five weeks is a very short period of time to assess the effectiveness of a drug for severe mental illness. I would like to see the results of a much longer clinical trial.
The FDA has not revealed much information other than:
“The primary efficacy measure was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at week 5. The PANSS is a 30-item scale that measures symptoms of schizophrenia. Each item is rated by a clinician on a seven-point scale. In both studies, the participants who received Cobenfy experienced a meaningful reduction in symptoms from baseline to Week 5 as measured by the PANSS Total Score compared to the placebo group.”
Numbers Please! I want to know how much improvement there was over the 5-week clinical trial. To find out I went digging through the research on PubMed and found one of the studies (the EMERGENT-2 trial). It was published in the Lancet (Jan. 13, 2024).
This was not a huge study. There were 126 participants who received KarXT (Cobenfy) and 126 patients who got placebo. The baseline score on the PANSS (Positive and Negative Syndrome Scale) was 98.3 for those who got the drug and 97.9 for those who got placebo. The score decreased by 21.2 points for those on Cobenfy and 11.6 points for those on placebo. That’s a difference of 9.6 points.
The EMERGENT-3 trial data were published in JAMA Psychiatry (Aug. 1, 2024). This too was not a huge trial. There were 125 in the Cobenfy group and 131 in the placebo group. After 5 weeks the PANSS score was reduced by 20.6 points in the Cobenfy group and 12.2 points in the placebo group for a difference of 8.4 points.
These clinical ratings do not easily translate into clinical benefits that both patients and family members can identify. The “Secondary Efficacy Outcomes Measures” were less impressive.
I won’t bore you with the details except to report that:
“The prespecified PANSS negative subscale score did not meet statistical significance at week 5…”
How Many Dropped Out of the Clinical Trial?
I always like to see how many participants dropped out of the trial. That is a key metric that reveals a lot about both effectiveness and adverse reactions.
In the EMERGENT-3 trial:
“A total of 46 participants (36.8%) in the xanomeline-trospium group and 38 participants (29.0%) in the placebo group discontinued the trial early, with the most common reasons being withdrawal of consent followed by AEs [adverse events].”
Put another way, 79 subjects who took Cobenfy completed the 5-week trial and 93 subjects who took placebo completed the 5-week trial.
I will let you draw your own conclusions.
Cobenfy a Breakthrough with Significant Side Effects?
Because it works so differently, clinicians are excited about Cobenfy. It appears less likely to cause weight gain, drowsiness and movement disorders. But the drug can lead to digestive disorders such as heartburn, stomach pain, nausea, vomiting, diarrhea and constipation. Other adverse reactions can include dizziness, high blood pressure and reflux.
Cobenfy may also make it hard to urinate (urinary retention). The drug should not be prescribed to people with liver or kidney disease. An allergic reaction called angioedema that involves swelling of the face and lips can be serious.
The cost of the new drug will be steep, at over $20,000 a year.
The authors of the EMERGENT-3 trial point out that:
“…schizophrenia is a lifelong illness and longer trials are needed to assess the durability of the effect and long-term safety and tolerability of xanomeline-trospium [Cobenfy].”
Long-term effectiveness has yet to be established. Nevertheless, the authors state:
“Xanomeline-trospium was associated with rapid improvement in psychotic symptoms starting at week 2 and it continued to separate from placebo at week 5, suggesting additional improvement may occur at later time points.”
I certainly hope that the answer to the question is Cobenfy a breakthrough will be yes! We desperately need much better medications to treat schizophrenia. Only time will tell if patients are happy with the results. The wholesale cost is expected to be around $1,850 a month. Bristol-Myers Squibb suggests that most patients will be covered by Medicare or Medicaid.
Final Words:
I welcome your thoughts about this new drug for mental illness in the comment section below. Is Cobenfy a breakthrough? For some, perhaps. I look forward to longer clinical trials and will report them as soon as they become available.
