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Caplyta (Lumateperone) approved for schizophrenia


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I've read into this one. It's pretty intriguing. It is a very potent 5HT2A antagonist such that the receptor is completely saturated and blocked on doses as low as 10mg. Then with increasing dose it begins to act as a serotonin reuptake inhibitor as well as a modulator of the D2 receptor, specifically it is an antagonist at D2L (post-synaptic) receptors and a partial agonist at D2S (pre-synaptic) receptors with a higher affinity for the latter type of D2 receptor, which may theoretically allow it to throttle dopamine outflow without blocking post-synaptic receptors, which can prevent prolactin elevations and the subsequent changes in metabolic parameters like blood glucose and lipids. It also has effects on the D1 receptor and may have effect on 5HT1A at higher doses (60mg+).

Edited by browri
wording
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8 minutes ago, browri said:

I've read into this one. It's pretty intriguing. It is a very potent 5HT2A antagonist such that the receptor is completely saturated and blocked on doses as low as 10mg. Then with increasing dose it begins to act as a serotonin reuptake inhibitor as well as a modulator of the D2 receptor, specifically it is an antagonist at D2L (post-synaptic) receptors and a partial agonist at D2S (pre-synaptic) receptors with a higher affinity for the latter type of D2 receptor, which may theoretically allow it to throttle dopamine outflow without blocking post-synaptic receptors, which can prevent prolactin elevations and the subsequent changes in metabolic parameters like blood glucose and lipids. It also has effects on the D1 receptor and may have effect on 5HT1A at higher doses (60mg+).

@browri  Thanks, that was more info than I was able to find 

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6 minutes ago, Iceberg said:

@browri  Thanks, that was more info than I was able to find 

Actually, looking at the prescribing information further, the 42mg dose is in fact the 60mg dose, or rather, it is 60mg of lumateperone tosylate containing 42mg of lumateperone, which matches up with what I read in trials. Everyone just generally did better at 60mg of lumateperone and it didn't require titration at all. I'd say it's not your average AAP.

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1 minute ago, browri said:

Actually, looking at the prescribing information further, the 42mg dose is in fact the 60mg dose, or rather, it is 60mg of lumateperone tosylate containing 42mg of lumateperone, which matches up with what I read in trials. Everyone just generally did better at 60mg of lumateperone and it didn't require titration at all. I'd say it's not your average AAP.

Yeah that whole one dosage thing seemed really interesting. Interesting to see if that will hold though, or if docs getting no response will try and jack up the dosages anyway 

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23 minutes ago, Iceberg said:

Yeah that whole one dosage thing seemed really interesting. Interesting to see if that will hold though, or if docs getting no response will try and jack up the dosages anyway 

Good luck.....it's a capsule lol

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OMG IT HAPPENED!!! :D  I didn't think it was going to happen but it did! Next pdoc appointment I'm going to ask about it. I know these meds take time to get to pharmacies though, so I might have to wait a few months, AND my insurance HATES covering brand-name new ANYTHING... So I'll probably have to get a PA and a letter of medical necessity, which my pdoc is not keen on doing (may have to go to GP for it...) I mean, I like Vraylar okay, I guess, but.... I guess this is new and shiny drug and I have to try it! XD lol 

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15 minutes ago, mikl_pls said:

OMG IT HAPPENED!!! :D  I didn't think it was going to happen but it did! Next pdoc appointment I'm going to ask about it. I know these meds take time to get to pharmacies though, so I might have to wait a few months, AND my insurance HATES covering brand-name new ANYTHING... So I'll probably have to get a PA and a letter of medical necessity, which my pdoc is not keen on doing (may have to go to GP for it...) I mean, I like Vraylar okay, I guess, but.... I guess this is new and shiny drug and I have to try it! XD lol 

I’d just be careful cuz they work somewhat differently so you might risk losing some of the Vraylar progress. Also, I think there are some plans for approval for BP depression, wonder how that’ll turn out 

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14 hours ago, Iceberg said:

I meant more like trying 2 caps instead of one

More than likely you would actually need less and not more in this case. Doses of lumateperone as low as 7mg were tested, with the 42mg dose being the approved dose because it was the most efficacious for schizophrenia.

However, the 7mg dose was found to have quite some benefit in the realm of sleep regulation in MDD as well as agitation related to Alzheimer's. That dose is advantageous because it completely saturates the 5HT2A receptor, making it a good adjunct for MDD to reduce agitation and anxiety as well as improve circadian rhythm. This dose also has far less effect on the D2 receptor which is advantageous for geriatric use where inhibition of dopamine signaling may not be desirable or safe.

Quote

Lumateperone has high binding affinity for serotonin 5-HT2A receptors (Ki = 0.54 nM) and moderate binding affinity for dopamine D2 (Ki = 32 nM) receptors. Lumateperone has moderate binding affinity for serotonin transporters (Ki = 33 nM). Lumateperone also has moderate binding affinity for dopamine D1 (41 nM) and D4 and adrenergic alpha1A and alpha1B receptors (Ki projected at < 100 nM) but has low binding affinity (less than 50% inhibition at 100 nM) for muscarinic and histaminergic receptors. 

The 42mg dose is a high enough dose to achieve non-inferior antipsychotic efficacy due to its 33 nM affinity for D2 and 41 nM affinity for D1. The advantage that lumateperone has is the additional antagonism of 5HT2A, the inhibition of the serotonin transporter, and even a little bit of brakes on the adrenergic system which should be beneficial for a wide variety of other disorders.

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2 hours ago, confused said:

I know it must decrease dopamine and increase seratonin,. what does it do with glutamate?   I asked pdoc about caplyta and he has not heard of this med, yet.  I am doing fine on abilify.

The manufacturer claims that lumateperone modulates glutamate via it's action on D1.

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On 1/20/2020 at 11:33 AM, confused said:

@browri can you explain that a little further.?  I read that, but have trouble understanding.

like a ssri inhibits the reuptake of seratonin, so it is around longer. Does it make the glutamate work more or less? 

Sorry for the delay @confused. I'll try to explain best I can, but I will say up front that I'm not a medical professional. Anyone else out there who can check me on these explanations would be appreciated.

I also want to apologize in advance if this is a bit of a brain dump but I just recently started the ketogenic diet and my Depakote levels are low so I'm kind of hypomanic at the moment.

The brain is a constant seesaw and it adheres to a sort of broken law of physics. Every action in the brain will elicit some sort of reaction from other neurotransmitters in the brain, but the reaction is not always equal in magnitude to the initial action and it isn't always necessary the opposite action either. You can have a chain reaction through several neurotransmitter systems that amplifies or degrades as it goes. And an increase in signaling in one system can cause an increase OR a decrease in another system. No one signaling pathway in the brain is identical to the next.

In the case of selective serotonin reuptake inhibitors, they reduce the action of a protein called the serotonin transporter (otherwise abbreviated as 5HTT or SERT). Neurons will eject neurotransmitters across the synapse to each other, and it's the responsibility of the transporter proteins to return those neurotransmitters to the sending (pre-synaptic) neuron after their "mission" is complete. The old Prozac hypothesis was that people with depression either A) had lower serotonin levels, which paired with normal levels of SERT would lead to reduced serotonin signaling, or B) had normal serotonin levels but higher levels of serotonin transporter proteins leading to premature reuptake and therefore diminished signaling. A serotonin reuptake inhibitor like Prozac could therefore solve either issue. In the case of A, if the person had lower basal serotonin levels then inhibiting the transporter would encourage more of it to be in the synapse where it could (indirectly) promote healthy serotonin signaling, and in the case of B you would be actually calming an overactive protein by directly inhibiting that overactive protein.

This is a tunnel vision hypothesis because it focuses on a single instrument (serotonin) in an orchestra (that also includes dopamine, norepinephrine/epinephrine/adrenaline, acetylcholine, histamine, GABA, glutamate, etc.). What researchers never took into account was that when you cause a systemic increase in synaptic serotonin levels and increase activation of central 5HT1 receptors, it causes a massive downstream release of dopamine. And due to more recent research, we know that increasing dopamine signaling will also cause a downstream increase in glutamate signaling as well. The increase of all three of these neurotransmitters at once is a highly suspect explanation for why SSRIs can initially be activating/agitating and can cause insomnia as well as other initial side effects in other bodily systems that correspond to stimulation such as increased gut motility.

Now that we better understand this chain reaction, researchers are looking hard at glutamate to understand what role it has in bipolar disorder, schizophrenia, major depressive disorder, anxiety disorders, etc. More recent research shows many of these disorders do indeed have critical glutamatergic dysfunction. As a note, glutamate is an excitatory neurotransmitter. It is also the chemical opposite of GABA, which is the neurotransmitter key to central nervous system depression (don't think mood, think sedation/calm). This is where alcohol works. Benzos. Date rape drugs like GHB and Rohypnol (which most people don't realize is otherwise known as flunitrazepam). So we believe now that in the case of bipolar disorder, the mood swings could be due to a seesaw effect that occurs between serotonin<-->dopamine and between glutamate<-->GABA. In schizophrenia, there would generally be increased glutamate and dopamine signaling leading to psychosis. In general major depressive disorder, glutamate may be underactive, but there may just be a version of major depressive disorder with anxious distress that involves OVER-active glutamate signaling.

The confusion never ends.......or rather the spectrum never does. But that's what we need to realize. This is why one medication works for a handful of people and not for one other person. Major depressive disorder and bipolar disorder and schizoaffective disorder are truly just categories that  we put many people in, even though many of them are nothing alike. Because of how many genes we have, we now know there could be tens or hundreds of variations of each disorder that is better addressed one way than for the next person.

FINALLY, to get to the meat of your original question, D1 receptors are pretty central (pre-frontal cortex). They are the site of the therapeutic effects of stimulants, which cause neurons to expel dopamine into the synapse. For people with ADHD, increased binding/activity at D1 receptors has a stimulating effect, and we can hypothesize that downstream increase in glutamate signaling must have something to do with it. The idea with Caplyta (lumateperone) is that blocking D1 with moderate affinity will reduce downstream glutamate signaling without harming executive function, concentration/focus, etc. (working like the "opposite" of a stimulant) However, this reduction in glutamate activity can have positive effects on bipolar disorder and schizophrenia by generally reducing excitability of neurotransmitter systems. Additionally, because glutamate <--> GABA work on a "seesaw" when you reduce glutamate signaling, glutamate is more readily metabolized inside neurons into GABA, which can be used to further calm the brain (bit of a snowball effect).

What I won't go into in this post is receptor sensitivity and the process of desensitization and resensitization. Easily doubles the length of this post.

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