Navigating Schizophrenia: Role of Long-Acting Injectable Antipsychotics

0:02 hello everyone welcome to navigating schizophrenia part one which is a program of a four piece Series where we are looking at the role of long acting injectable antis psychotics today it's about treatment options my name is kristofh coral I'm professor of psychiatry in molecular medicine at the Donald and Barbara zaker school of medicine at hofra northwell Hamstead New York and I'm also professor and chair of the Department of Child and Psychiatry at the Char University in Berlin Germany and I'm joined by very esteemed colleagues first maybe you want to introduce yourself Les uh so happy to be here I I'm Dr Leslie citro clinical professor of Psychiatry and Behavioral Sciences at New York Medical College in

0:47 Valhalla New York and Rebecca I am Dr Rebecca Roma I'm a psychiatrist in Pittsburgh Pennsylvania I primarily work in clinical practice and I also teach medical students and residents at the University of Pittsburgh School of Medicine wonderful so we are grateful that you're here and we will discuss today long acting injectable antipsychotics this will be four different sections what are long- acting injectable antipsychotics or Lis and also which ones are currently available second we will talk about where do they fit within the treatment plan and you will hear some opinions from us about this because I think we're

1:34 here because we're strong Believers that lais should be considered early and thoroughly and can only be considered when you know about them that's what we'll be talking about today but also when they are offered in a certain way and when we know about the risks and the benefits and the Alternatives but when you think about an Lai we also need to think about how to get there and that's what we'll be talking about today how to switch from an oral to an Lai formulation and then once someone is on this medication in this formulation how do we actually monitor it because obviously we can't just give a so-called shot and then let the person go it's part of a treatment algorithm it should be a basket so let's

2:20 first talk about what are long acting injectables and where do they fit so long acting injectable antipsychotics utilize different designs to achieve drug Depot and extended release from the injection site that's basically desired because as you know when you take a medication 365 times a day or actually twice a day would be over 700 times then things can get lost along the shuffle and also we have a lot of peak and truff variation you basically put the medication into this mouth and then the GI tract that goes through the liver into the bloodstream and then it sinks again until you give another medication dose again wouldn't it be wonderful to

3:06 have the medication sitting and waiting there for it to slowly be released with relatively little Peak trough variations to have a steady delivery of the medication and obviously this is not an idea that's new we have that in many pieces and parts of medicine but somehow we're doing a little harder and have a more greater difficulty thinking about this in Psychiatry so Lai antis psychotics have higher bioavailability because they bypass the first pass effect and thereby they can also somehow reduce the variability within and across patients because you don't have the variability about absorption through the gastrointestinal tract after an IM or subq injection the

3:55 Lai drugs form a Depot at the side of injection and then slowly release the active drug into the system circulation over either weeks or months or many months and the rate of drug absorption depends on the drug properties the particle size how quickly they are broken down water solubility deliver vehicle injection volume as well as patient factors body weight fat and injection side the drug absorption rate is much slower than the elimination rate therefore the time to achieve steady state is determined not by the halflife of breakdown like in oral treatments but by the absorption rate that's called flipflop kinetics compared with oral

4:42 antic psychotics the slow absorption leads to a more predictable and stable plasma drug concentration which we believe is desirable now we have first generation Lis that are formulated on an oilbased vehicle they slowly release the decanoate or Esther into the system circulation but oil gets into water of the cell and that can be more painful second generation antic psychotics are all water-based and that makes sense because the solubility makes it less painful for them but they basically are low soluble and form Esters or salt forms and or also can have prodrug forms and we'll hear from Professor croome about that and there can be also polymers or microsphere Depot technology

5:29 and that achieves extended release so once the Esther salt or prodrug forms of the Lai are released into the systemic circulation they're converted to the active form via various mechanisms and patients may prefer water-based leis because again as I mentioned they may be less painful but Les what does that mean then for currently available formulations let put this into practice well I like to think of long acty injectables as a guaranteed Del delivery mechanism for antipsychotics that people need to take every day and rather indefinitely and the guaranteed delivery aspect of it is really critical here because people have fluctuating periods of insight and it's uh frankly difficult

6:15 to remember to take something every day for anyone with a chronic illness so let's get to what's available in the United States we have first generation lais such as flu fenine dean8 and haloperidol dean8 and professor Corella as you mentioned these are based in sesame seed oil and uh rather technically more difficult to administer than a waterbased injectable both fluen isine decano and helipal Deano are generally injected into the muscle although fluen isine decanoate can be injected subcutaneously that that is rarely done fluen isine decanoate is generally administered every two weeks and halip peral decanoate every four weeks but these are first generation an psychotics and come with some baggage in

7:02 particular movement disorders such as drug induced parkinsonism and distonia and so on and really we've gravitated towards second generation long acting injectable anticho of which we have three essential molecules here we have the resperidone or paliperidone family of choices we have the AR prol family and we have currently one candidate for the at enene family let me go through these in sequence with rared on microspheres every two weeks we had the first second generation lii in our hands and it was uh very popular very quickly but it's every two weeks and paliperidone palmitate emerged as a in

7:48 my mind a replacement for this remember that paliperidone is the main active metabolite of resperidone it's also called Nine hydroxy resperidone and paliperidone palmitate was initially available as a once monthly injectable another key differentiating factor was that respone microspheres required a 3-w week period of oral supplementation upon initiation whereas piperon palmitate could be initiated without any oral supplementation at all however you do need two injections at the start separated by about a week difference and then piperon palmitate became available every 3 months or every six months for those who are successfully treated with the once monthly formulation now newly available is a

8:36 subcutaneous formulation of resperidone a polymer that's injected subcutaneously and right from the start it can be ejected every month or every two months without a loading dose and without oral supplementation so that's the raridon and paladone family of injectables and we have now the ariol family of two choices AR piersol monohydrate which was the first to come on the scene with a monthly injection uh with a together with a two week oral supplementation period at initiation and AR pierola roxil that first emerged every month or every six months as a potential interval uh for injection and that required a

9:22 3-week oral supplementation period but over time uh the arerol Lor roxil option also emerged as an every twomon option as well as an option to initiate it in one day with a second injection and a single oral dose arerol monohydrate emerg rather recently as an every TW month option and outside of the United States there is a way to initiate it in one day with two injections and a single oral dose in terms of a lopine right now we have is a lanine pamoate that can be given every two or four weeks it's given I am without an oral supplementation

10:08 although a higher dose is given uh and then ultimately a maintenance dose is uh is given at a it's somewhat reduced but a major disadvantage there with the lpen pamoate is the requirement by a Rems for observation for uh 3 hours after each injection because of the RIS risk of post injection Del delirium sedation syndrome which happens in 0.007% of injections not very often but often enough to require this three-hour observation period where patients need to be in the clinic or office and they need to be accompanied home in the works is a polymer version of a lanzapine long AC injectable to be injected

10:55 subcutaneously now I wish there were other molecules available to uh to administer in a long acting formulation maybe there will be in the future but right now this is what we have well that was uh really a very nice summary thank you so much uh Professor satr well let let's hear from Dr Roma how do we actually start Lis and when should we be doing this in the treatment plan is it something as a last option as we've heard for decades so thank you for that um actually actually historically long acting injectable antipsychotics were used in patients who already had chronic non-adherence already had failed

11:42 multiple oral formulations but I think that given the fact that there have been multiple studies now comparing outcomes of long acting injectables versus oral and long acting injectables delaying time to relapse keeping patients out of the hospital as well as helping with morbidity and mortality of schizophrenia the American Psychiatric association now is recommending earlier use of long acting injectables in fact you know this group here and the reason why we're doing this presentation is because we all believe in the benefit of long

12:29 acting injectables early on in the course of schizophrenia so let's dive a little deeper into what the American Psychiatric association practice guidelines of 2020 actually say first of all they say that you should be using long acting injectables in patients who prefer long acting injectables well if you're not offering a long acting injectable for ulation to your patients how do you know whether or not your patient prefers a long acting injectable secondly they're saying that long acting injectable should be used not only in

13:15 patients who have chronic nonadherence but in any patient who has a risk of non-adherence and those risk factors are enumerated as one if a patient is changing treatment settings so going from inpatient to outpatient going from incarceration to the community any of these transitions are possible stumbling blocks to create medication gaps for our patients so transitioning settings comorbid substance abuse because our patients who have comorbid substance abuse have higher risk of forgetting doses as well as poor insight

14:05 into the need for medication so all of these risk factors have now been enumerated and it has stated that it may be appropriate to start long acting injectables earlier in the course of disease so how do we have these conversations when should we have these conversations uh suggested that even as early as first episode psychosis or early stage schizophrenia that is when patients May benefit the most we should be bringing up the option of long acting injectables with every conversation until the patient is ready and able to accept that

14:53 treatment we should use things such as motivational interviewing to to help explore some of the resistance that we might get back from patients and family members you know if we think about it first episode and early stage schizophrenia that's before there has been a lot of brain damage treatment resistance that has developed so if we offer long acting injectables and we're able to delay time to relapse or reduce relapses perhaps we can reduce some of this co-occurring damage to the brain we can reduce some of this treatment

15:39 resistance we can reduce some of the poly Pharmacy that we see happening throughout the US so early use of long acting antischool.us and as I've suggested reduce some of the structural neurologic changes that we see early on in disease we see these changes as early as the first and second relapse so given that and given that our message the American Psychiatric association's message the National Council behavioral healths message is to

16:26 start long acting anti-yo earlier let's look at some of the advantages and the disadvantages of long acting injectable antipsychotics well first of all as Professor citrome had said it's easier to measure and confirm adherence because your patient either shows up for their injection or they don't show up for their injection and so they're either getting 0% or 100% of the dose it eliminates the need for daily oral medication it reduces the risk of Overdose and I think other than adherence what we often see with our

17:13 patients is partial adherence and that's when the question comes up what dose of your med of medication is your patient actually on you know that with certainty if a patient is on a long- acting injection so we're reducing the risk of rebound symptoms and abrupt relapse we are again decreasing these Peaks and these troughs that can occur with oral medication in serum concentrations of the medication and we will still have regular contact with our patients to monitor them and see how they're doing and to observe whether or not they're having breakthrough symptoms so so what

17:59 are some of the disadvantages well we talked about first generation antis psychotics and second generation anticho and oftentimes I hear people complain about the cost of second generation anticho well think about the cost of just a single day of hospitalization or the cost of work lost in our patients who are having relapses limited flexibility for dose adjustments delayed time to reach steady state in some formulations if a patient should have an adverse effect or a side effect sometimes we're worried because we can't

18:45 undo the fact that we gave them a long acting injection so they have prolonged exposure to the culprit pain and burden of injections sometimes people don't have facil ities where they think it's convenient to give an injection and then we have travel and other logistics for injection appointments well that was a very nice summary grounding Us in the pros and cons but also what to bring up during a discussion in order to introduce patients and caregivers who may actually help us discuss with the patient that this might be an option to use an Lai in in order to find out that maybe the

19:31 illness and the Brain can function in a different way and there's more degree of Freedom when having lais because sometimes there's this lure like oh my God I'm giving up control I'm being controlled by medication well we want to give patients back degrees of freedom and functionality but when trying to do that we have to transition from an oral to an Lai formulation and so we need to bear in mind three things that transition first is how to start the lii second how to discontinue the oral treatment and Third how to maintain the lii so first of all before you give something that lasts two weeks four weeks eight weeks three months or even

20:17 six months you want to know that this medication in an oral formulation at least doesn't cause an allergic reaction and some of us may even feel that you need to give it for a certain time that V ability is established and some of us might even want some efficacy signal you can either glean that from the past or have a leadin phase with an oral medication then the oral to dosing lii dosing conversion is provided in the labeling of the medications and basically it has to do with some of the pharmacokinetic characteristics of the drugs that Professor cro was talking about so there are treatments that have have to be given with an overlap of oral treatments so for example three weeks

21:03 with bi-weekly respirator microspheres three weeks with our ariol aroxol two weeks with ariol monohydrate but then we have now two injection starts with approved in the United States microspheres of arol roal plus the um Regular injection or hopefully coming to vs soon and being approved in Europe having a two injection start of 400 milligrams of arzol once monthly we can have drugs that need a loading dose you start at a higher dose and in the deltoid compartment like for example poly paradon and then you need a booster injection uh one week later there are other treatments that don't need that

21:49 like already mentioned the subcutaneous form of resperidone and the one that's in development for orpine where within a day get therapeutic blood levels without having a booster injection without having a loading strategy or also the need for oral cold treatment so this can be considered when starting the medication generally when you come same to same you can then down tirate after steady state is reached or during the reaching of the study State the oral medication goes down but when you come from for example a more sedating drug or a more anti dopaminergic drug going from a pen to a d or a pip so alanine for

22:35 example copine to resperidone or piperidone or ariol you may want to overlap a little longer so that there is no rebound from the sedation same when you come from a full dopamine blocker like resperidone or halop paradol and you go to a partial Agonist again take a little bit longer for the weaning of the prior oral medication that has more blockade on receptors that the new drug wouldn't have and then we have to maintain the medication and choose the right injection interval there are often choices now which is wonderful you have respirador options that can be given every two weeks once a month or even two monthly there are are pipol options that can be given once a month every six

23:23 weeks or two months and then you know the poip paradon option you go either once a month every three months or six months but to get to three or six months you have to have at least five injections and four months of the one monthly injection or basically also two doses that are the same and maintained before you go to the three-monthly and then the injection goes either into the deltoid which is a smaller compartment it's necessary for the first injection for po paradon but otherwise you get higher Peak values when you go into the deltoid and you get longer Half Lives when you go to the dorsal glal side and that all has to be discussed with the patient what they prefer and also looking at the

24:09 duration and durability of the medication effect there is pdss with the current intramuscular orpine as already mentioned that's the post injection theum sedation syndrome and we hope that the subcutaneous form will not have that and then injection volume length of the needle and need for reconstitute tion or Refrigeration are also all considerations when to consider going from an oral to an Lai formulation but let's enter now the last chapter before we close our first SE session of the sequence of four programs Professor cro what are potential adverse reactions and effects of Lai treatments and what's the monitoring need well the good news is that the systemic adverse event profile

24:56 for any of the lais reflect what the patient would have experienced with the oral formulation so when we go from oral to Lai of the same molecule I wouldn't expect anything different if anything you'll be likely to use a lower overall dose because you're going to have guaranteed delivery of the injectable dose rather than the varying degree of oral adherence that's a big question mark before uh the injection strategy was was adopted by that patient so I I I think there's no surprises here however injection sight pain is a concern about that patients have and uh they heard about needles they don't like needles and there are a few things that I like to say about that one is to the patient

25:43 this is not like the needle you got in the emergency department when you were held down by four people because you were agitated this is a voluntary administration of an injection into the muscle uh sort of like that flu shot that you got month or two ago or something like that and then I would tell them you know research has been done with regard to injection site pain and they ask patients regarding how painful is something on a scale of zero to 100 with zero being no pain and 100 being excruciating pain and the research tells us that patients rated this in the single digits certainly less than 10 and in many instances less than five out of a 100 so this puts it into perspective

26:29 if they actually have a tattoo I point out that tattoo hurt a lot more than what we're talking about I also mentioned this is not uh if someone has a history of intravenous drug abuse this is not injected into a vein it's injected into a muscle which is technically much easier than what you did on your very own when you were abusing heroin or whatever so I I do take into account a patient's experiences with needles try to incorporate that into the conversation when when talking about injection sight pain sometimes there's some hesitancy from the prescriber uh that they're not worried about you know the side effects they're worried about is it going to work and I asked them well how long are you going to wait until you decide whether something is working or not and

27:14 I'm usually told about a month and I said well you know if you give a once monthly injectable you'll know your answer and you don't have to worry if they took the medicine or not so there there are many advantages to lais I really like the guaranteed delivery aspect of it and if you know the molecule you will know about the Lai well thank you very much that was really a very well-rounded group discussion and presentation maybe Dr Ruma do you want to give a little clinical Pearl last 30 seconds each of you before I thank the audience for their participation I just want to say that often times it's not the patients who are refusing the acting injectables

27:59 when I think about what's holding us back I tell people to hold up a mirror because if we excited about it then our patients will be excited about it that's a wonderful closing quote from you and Professor sron well I spent most of my career in the state hospital system in New York I wish I can go back in time and treat those patients earlier on and uh encourage them to take an Lai they would not have ended up in the state hospital again introducing this medication option earlier to change the trajectory of the illness well I want to thank the audience and obviously thank you too for joining me this was part one of a four-part program navigating schizophrenia and please join tomorrow

28:46 same time a path to stability using long acting injectables in order to select the right treatment and this will be given again with Professor croome but also Professor de Perkins we want to thank you for participating please scan the QR code to claim your CME credit and we hope to see you tomorrow again