Caplyta (lumateperone): New for Schizophrenia…and More?
Before we talk about Caplyta (lumateperone), I want to announce that I take no remuneration of any kind from any pharmaceutical or healthcare company. I am providing the following information solely for educational purposes.
Caplyta (lumateperone) has recently been approved by the FDA for the treatment of schizophrenia in adults, and it is expected to be available by prescription by late April 2020. This new drug seems to have a lot of promise, especially for patients who don’t do well on other drugs, or cannot tolerate the side effects of other drugs. This may sound strange, but scientists don’t actually know what the drug’s mechanism of action is, meaning that they don’t know exactly how it works. They have some educated guesses, and I’ll talk about those later. But believe it or not, it’s not that unusual for a drug’s mechanism of action to be partially or poorly understood…it happens frequently.
They’ll figure it all out in time, but what matters right now is that they do know the drug’s efficacy, which is it’s effectiveness, in treating schizophrenia in adults. I think that this will be a vitally important drug, especially for patients who don’t respond to other drugs and/ or cannot tolerate the side effects of other drugs. And I’ll go into that later as well. But first, I want to go over some general information about schizophrenia.
Schizophrenia is a very serious, disabling, and complex mental illness impacting approximately 2.4 million adults in the United States. It is most disabling because there is no for schizophrenia, but there are treatments, and it must be treated and monitored for a lifetime. Like many mental illnesses, it not only severely impacts patients, it also majorly impacts patients’ families. The clinical presentation of schizophrenia is very diverse. Acute episodes can be characterized by psychotic symptoms, such as hallucinations and delusions, and these can be so debilitating that these patients require hospitalization. The disease is chronic and lifelong, and is often accompanied by depression. There can also be a deterioration of social functioning and cognitive abilities. Patients with schizophrenia often discontinue treatment, stop taking their meds, because of major side effects, which can include weight gain, lactation, gynecomastia, and movement disorders. More on these side effects later. For now, suffice it to say that an effective and well tolerated treatment can be game-changing for people living with schizophrenia.
I thought it might be fun to have a little quiz, just to see what you do or don’t know about schizophrenia, all in an effort to educate and de-stigmatize. If you don’t know them now, you will when you finish. I’ll give you the answers and explanations later. No cheating, people!
1) Schizophrenia is the most disabling of all mental illnesses.
2) There are 50 million people with schizophrenia in America.
3) Schizophrenia is often called “split personality disorder.”
4) Psychosis means that a person…
A) Has suffered memory loss
B) Suffers from chronic insomnia
C) Can’t distinguish imagination from reality
D) Has a virus that affects the brain
5) The most common hallucination in schizophrenia is…
A) Visualizing shadows
B) Smelling smoke
C) Feeling cold
D) Hearing voices
6) The first symptoms of schizophrenia can include:
A) Irrational statements
B) Excessive crying
C) Outbursts of anger
D) All of the above
7) Who has more symptoms at the onset of schizophrenia?
8) Many schizophrenics believe that ____ actually eases their symptoms.
Let’s see how many you got right and I’ll explain the correct answers:
1) True/ False: Schizophrenia is the most disabling mental illness.
Correct answer: True
Explanation: Schizophrenia is an incurable, severe, and lifelong disease that is the most disabling of all mental illnesses. Treatments for schizophrenia focus on controlling the symptoms.
2) True/ False: There are 50 million people with schizophrenia in the US. Correct answer: False
Explanation: About 1% of people in the U.S. have schizophrenia, which is just over 2 million people.
3) True/ False: Schizophrenia is often called “split personality disorder”
Correct answer: True
Explanation: Schizophrenia is sometimes confused with other mental illnesses and may be mistakenly referred to as “split personality disorder.” While “schizo” does mean “split,” patients with schizophrenia do not have split personalities. What they do have is psychosis, which is a distorted perception of reality.
4) Psychosis means that a person…
Correct answer: C) Cannot distinguish imagination from reality
Explanation: Experts don’t know what causes schizophrenia. In some people, brain chemistry and brain structure are not normal. Family history may be a factor in some cases. Schizophrenia is never caused by anything a person did, or by any personal weakness, bad choices, or a person’s upbringing.
5) The most common hallucination in schizophrenia is…
Correct answer: D) Hearing voices Explanation: Auditory hallucinations, or “hearing voices” is the most common hallucination in schizophrenia. Voices can seem to be coming from within one’s own mind or externally, as if a person is talking to them. These voices may tell the person with schizophrenia to do things, or they may comment on their behavior. The voices may even talk with one another. It is common for people with schizophrenia to hear voices for a long time before anyone else notices the problem. Other kinds of hallucinations experienced by people with schizophrenia include seeing people or objects that are not there, feeling as if they are being touched by invisible fingers, or smelling odors that no one else can smell.
6) The first symptoms of schizophrenia can include…
Correct answer: All of the above
Explanation: There are numerous early symptoms of schizophrenia. In some cases, family and friends may notice a shift in behavior or sense something is “off” about the person who is schizophrenic. Early signs and symptoms of schizophrenia may include irrational statements, excessive crying or inability to cry, outbursts of anger, social withdrawal, and extreme reactions.
7) Who has more symptoms at the onset of schizophrenia?
Correct answer: Men
Explanation: Schizophrenia affects men and women at equal rates, and symptoms may start suddenly or occur gradually. Men tend to develop schizophrenia slightly earlier, between 16 and 25 years old, while women develop symptoms several years later, in the late 20s to 30s. Schizophrenia symptoms tend to be more severe in men, while women with schizophrenia may have more depressive symptoms and paranoia.
8) Many schizophrenics believe that _______ eases their symptoms.
Correct answer: Smoking
Explanation: Many schizophrenics believe smoking cigarettes eases their symptoms, and up to three times more schizophrenics smoke than in the general population. It is thought that smoking may be a kind of self-medication. The nicotine seems to help with some of the cognitive and sensory symptoms experienced by schizophrenics, and it can ease some of the side effects of medications commonly prescribed. However, it’s important to note that smoking still causes cancer, lung disease, and heart disease.
Now that you probably know a little more about schizophrenia than you did 15 minutes ago, let’s talk about this new drug treatment, Caplyta, generic name lumateperone. Obviously, since it hasn’t been released yet, I haven’t had the opportunity to prescribe it to my patients, but I have been following its development and have read about it extensively. Based on that, I think this drug will be well tolerated, and a valuable drug in the armamentarium for the treatment of schizophrenia. In addition, I think it will be valuable in treating bipolar disorder and could also benefit patients with Alzheimer’s and/ or dementia with agitation.
Let’s talk turkey. Why is it good to have a new option for treating schizophrenia? Here’s where those side effects I mentioned before come in. The current drugs used to treat schizophrenia are chock full of side effects, some of which are stigmatizing and intolerable to patients. So a new drug, a better tolerated one, is a big deal. Older drugs like Olanzapine cause weight gain, metabolic syndromes, insulin resistant diabetes, increased cholesterol, and increased triglycerides. Other drugs like Risperdal are known to cause elevations in prolactin, which causes lactation, milk production in women, and breast enlargement in men, all of which are very unsetteling to patients, to say the least. Another major factor in older antipsychotic drugs like Aripiprazole, Brexpiprazole, and Haloperidol involve what are termed extrapyramidal symptoms, dystonia and tardive dyskinesia. All those fancy words just mean involuntary muscle contractions that can cause repetitive movements like tics, ie grimacing and eye blinking, muscle spasms, and all sorts of uncontrollable muscular movements that people obviously find very uncomfortable and cosmetically disfiguring. These extrapyramidal symptoms are problematic in terms of compliance, meaning that patients don’t take the drugs, they are not not compliant, because while they are already stigmatized by their illness, they are further stigmatized by these side effects of breast enlargement and lactation, and the disfiguring extrapyramidal muscular movements and motor tics the drugs cause.
Caplyta, lumateperone is apparently different. And this is where I’ll explain a little about the mechanism of action, how I believe it works. We know from previous accepted research that the undesirable extrapyramidal motor symptoms like tics and spasms associated with antipsychotic medications are the result of a high affinity for a receptor called the D2 receptor. Having a high affinity for a receptor basically means that a drug likes to bind there, and in doing so, it blocks that receptor. That would be a mechanism: the binding of a drug to a receptor and its subsequent blocking of that receptor. So, the older antipsychotic drugs have a high affinity to, they like to bind to, D2 receptors, blocking them. But this new drug, lumateperone, has low affinity for these receptors, the D2 receptors, so they are left unbound and unblocked. As a result, those stigmatizing involuntary muscle movements and tics are absent. Before I go further, here’s a quick and simplified synopsis on the basics of clinical trials: when drugs are tested in clinical trials, they begin with randomly giving the drug being tested to a certain number of subjects, while giving a placebo (an inactive substance, sometimes called a “sugar” pill) to the other people in the trial. The study is randomized, meaning the people in the study don’t know if they’re being given the drug being tested or the placebo. In most studies, even the people running it and those dispensing the study “medications” don’t know which is which or who’s getting what. That way there is no bias, people just honestly report their symptoms. At the end of the study, when the results are tabulated, the drug company hopes to be able to clearly see the difference between the study drug and the placebo in symptoms and efficacy and whatever other traits they want to look at. Then they use those numbers to report the findings of the testing drug versus the placebo. So for this new schizophrenia drug Caplyta (lumateperone), the reported trial numbers shake out to subjects taking the study drug lumateperone reported having extrapyramidal symptoms/ side effects only 0.4% more than reported by subjects taking the placebo, and that is evidently due to its very low affinity for the D2 receptor, so those D2 receptors are mostly open. D2 receptors blocked= extrapyramidal symptoms, involuntary motor tics. D2 receptors open= no extrapyramidal symptoms. Make sense? This is all very simplified, and there are more receptors and pathways in the body than you would ever want to know…and they all do different things depending on if they are open or blocked, presynaptic or postsynaptic, agonistic or antagonistic, upstream or downstream, activated or inactivated, partially or completely and everything in between. It’s complex stuff…I just want you to have an idea of why drugs cause or don’t cause different side effects, because that’s the name of the game when it comes to efficacy and tolerance of drugs, and that’s what determines patient compliance in taking drugs, and that’s what determines how much their mental illness affects them, and that’s what determines their place in this world. Phew! Get it? It’s a big deal.
So that’s an example of how lumateperone avoids those extrapyramidal side effects. Now you may ask how it works in controlling the hallmark syptoms of schizophrenia: delusions, hallucinations, disorganized speech, and disorganized behavior. That mainly has to do with its effect on another receptor, the Serotonin 5-HT2A receptor. Lumataperone has a high affinity for this receptor; it binds and blocks it. We know that a drug called Pimavanserin does the same thing, and Pimavanserin is used to treat Parkinson’s disease psychosis, so we can correctly infer that blocking and binding the Serotonin 5-HT2A receptor in lumataperone makes it effective as an antipsychotic drug, controlling delusions, hallucinations, disorganized speech, and disorganized behavior associated with schizophrenia. Along those same lines, lumataperone also affects dopamine receptors in a specific pathway called the mesolimbic pathway. That happens to be the pathway that blocks hallucinations, delusions, disorganized speech, and disorganized behavior. This is all good stuff.
What else? Lumataperone has decreased muscarinic receptor activity. When activated, muscarinic receptors cause dry mouth, pupil dilation, blurred vision, constipation, and flushing. Because that activity is decreased, those effects are reduced or absent, so no dry mouth, dilated pupils, blurry vision, constipation, or flushing. It also does not cause or lead to any metabolic syndromes, elevation in cholesterol, significant weight gain, and insulin resistance, another big plus.
Lumataperone has decreased effects on the alpha adrenergic receptor, which causes orthostatic hypotension, meaning a drop in blood pressure upon standing that often leads to a fainting episode. Because of lumataperone’s decreased effects on this receptor, this removes this risk.
Lumataperone also has minimal effects on the endocrine system, and therefore it does not affect prolactin like the older drug Risperdal does, so female patients do not experience lactation and milk production, and men do not get breast enlargement. This is majorly important in drug compliance. Patients are more likely to take the medication if they don’t have to leak milk from existing breasts or grow breasts where they don’t belong.
Lumataperone metabolics and dosing is convenient becuase it does not require titration, meaning patients don’t have to build up to the full dose by taking smaller doses first. Patients start at 42 milligrams, peak plasma level is in 3-4 hours, and it has a half-life of about 13 hours. This is nice, because that means it can be taken just once a day, because the half-life is long enough.
While lumateperone seems to be far superior to the older schizophrenia drugs in nearly every way, there is no such thing as a perfect drug…yet. It does have some possible side effects, including nausea, dizziness, fatigue, and vomiting. But these appear to be fairly insignificant, not affecting quality of life. It has also been shown to cause drowsiness; I think it must have something called a histaminic effect. This is really its most major side effect, with anywhere between 10% and 24% of people to experience drowsiness. But we can turn that frown upside down…we can use this drowsiness to our advantage by dosing it when it’s time to go nite-nite. And since it’s dosed once a day, it works out great.
The last important footprint of Lumateperone has to do with it’s metabolism by the Cytochrome P450 3A4 system (I told you this stuff can get a little complicated). Abbreviated CYP3A4, this is a very important enzyme in the body, mainly found in the liver and the intestine. It oxidizes small foreign organic molecules, such as toxins or drugs, so that they can be removed from the body. Patients taking lumateperone should not take any drug which blocks CYP3A4 enzyme concomitantly. This is really the only contraindication at this time.
So, when we put all of this stuff together, what do we have?
– Caplyta (lumateperone) for schizophrenia
– Dosing: 42 milligrams, once per day, with food, at night if causing drowsiness.
– Works mainly by affecting dopamine, serotonin, and glutamine.
– Binds and blocks Serotonin 5-HT2A receptors, eliminating negative symptoms of schizophrenia: delusions, hallucinations, disorganized thoughts, and disorganized behaviors.
– Low affinity for D2 receptors leaves them unbound and unblocked, eliminating the stigmatizing extrapyramidal symptoms of involuntary muscle movements and tics, dystonia and tardive dyskinesia.
– Minimal endocrine effects, preventing female patients from experiencing lactation, and male patients from breast enlargement, and relieving patients of these stigmatizing side effects.
– Decreased muscarinic receptor activity, eliminating dry mouth, dilated pupils, blurry vision, constipation, and flushing.
– Elimination of metabolic syndromes: no elevated cholesterol, no significant weight gain, no insulin resistance, no diabetes.
– Decreased effects on the alpha adrenergic receptor, eliminating fainting episodes due to orthostatic hypotension.
– Possible side effects: nausea, dizziness, fatigue, and vomiting. But these appear to be fairly insignificant, not affecting quality of life.
– The only significant side effect is drowsiness, 10% to 24%. This can be turned around and used to help insomnia when dosed at night.
– Utilizes CYP3A4: lumateperone is contraindicated in patients taking
drug(s) which block CYP3A4 enzyme.
Essentially, that adds up to getting all the good stuff for treating schizophrenia without getting any of the bad stuff, and all it’s going to cost you is maybe some minor nausea, vomiting, and/ or fatigue, all of which will likely go away after two weeks. You might have some drowsiness, but I see that as a plus, as lots of patients complain of insomnia, and it can be taken only at night due to its once a day dosing.
Schizophrenia for now…what about later? Lumateperone is a weak serotonin transporter pump inhibitor just like SSRI (Selective Serotonin Reuptake Inhibitor) antidepressants are. To simplify the mechanism: serotonin is a happy neurotransmitter regulated by a pump. It’s pumped out, but can be removed by being “uptaken,” if you will, which leads to low serotonin levels commonly found in people with depression. So an SSRI drug, an antidepressant, is given. The SSRI is employed, and the RI, which stands for reuptake inhibitor, stops (inhibits) the reuptake of the serotonin, leaving higher levels of free happy serotonin circulating and thereby increasing mood. It has other antidepressant effects which I think will make it very effective for treating depression and bipolar disorder. And because it has a low affinity for D2 receptors, leaving them open, I think it could control agitation in people with Alzheimer’s and/ or dementia without causing any of those horrible side effects of current antipsychotic medications. When physicians prescribe Caplyta for anything other than schizophrenia, or prescribe any drug for any diagnosis it was not labelled for (ie originally developed for), it is called off-label prescribing, and it is a common practice in psychiatry, as the regulation of receptors and pathways overlap in many different mental illnesses.
In summary, Caplyta (lumateperone) shows a great deal of promise, and I’m looking forward to being able to offer it to my schizophrenia patients that are having compliance issues due to the stigmatizing side effects of current antipsychotic therapeutics. This could be a game changer and a life changer for them. And then once I really see how it’s tolerated, I’ll give great consideration to using it off-label for bipolar depression and to combat agitation in my Alzheimer’s and dementia patients. It could be a much needed breakthrough for them as well.
If you liked this blog, please comment and pass it along. Even posting simple comments and sharing information help reduce the stigma of mental illness…and it’s certainly high time for that. If you’re interested in reading more about the subjects discussed here, and a lot more, check out my book, Tales from the Couch, available in my office or on Amazon.com.Learn More