‘The use of Lurasidone in children and adolescents’ Dr. Jonathan Channing

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Dr. Jonathan Channing lecture on ‘The use of Lurasidone in children and adolescents’. This was recorded on 4 April 2019 at the ACAMH Southern Branch Research Day.

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Dr. Jonathan Channing
Dr. Jonathan Channing

Jonathan trained at Southampton University and spent several years working as a paediatrician before commencing psychiatry training. Dr. Channing published a case report and systematic review on the use of Lurasidone following successfully using this medication with a young person in an inpatient setting where other antipsychotics had either not been tolerated or not been effective. He now works as Consultant in the Paediatric Liaison team at Southampton General Hospital.

Transcript

So Lurasidone is a second generation atypical antipsychotic. It’s one of the newest ones brought out. I don’t know what people already know about receptors in other kind of psychotics but Lurasidone has quite a high affinity for D2, a high affinity for 5HT2A and 5HT7 and a medium affinity for 5HT1A, but almost no affinity for D4.

Apart from a few of us who are psychiatrists, the rest are not psychiatrists.

Not psychiatrists? Okay. So it probably doesn’t mean the same thing. Okay. So it’s a bit different in its structure basically to some of the other anti-depressants and some of the receptors which it has more are more similar to some of the antidepressant medications.

So it’s an antipsychotic but been found to be helpful for some depressive symptoms, as well as just psychosis sorts of things. So this is really sort of a summary of the information that I have presented in my paper. So there’s a pharmacokinetic study which is looking at how medications work in the body, how quickly they’re absorbed and this looked at 105 children. There would normally be an evidence in adults with more papers and things being done.

So the children’s study was really looking at whether or not it was similar to what was already found in adults because some medications affect children slightly differently to what they do for adult patients. So it’s quite a wide range of patients, six to 17 years, with quite a variety of disorders ranging from ADHD, autism, bipolar disorder, depression, schizophrenia. And quite a wide dose range between 20mg and 160mg. And the current recommended maximum is 148mg in the English BNF but that has been used at 160 American places. They found a linear dose effect.

So that essentially means that as the medication goes up in the dose then the amount that’s found in the body is proportional to that. So the medium T max is the time that it takes to reach its maximum state. And that generally takes about two hours. And the profile at the scene, comparing it to the previous adult studies that have been conducted was almost the same. The only slight difference was they broke it down into some age brackets. And in the six to nine year old age group there did seem to be a slightly higher drug level compared to the effect that might be expected. So moving on to thinking about its use in particular disorders in children and young people.

So this was following the results of a systematic review, which is where you take searches of most of the sort of major search engines to be able to look for all the evidence that has been published. So that included any randomised controlled trials, case studies, unpublished and published studies. And, essentially, there wasn’t really a huge amount on children. It was about…out of about 300 hits that came up there was about 12 relevant studies that were actually on children and adolescents with Lurasidone use.

So there was quite a big study conducted in 2017 on bipolar depression that included 347 children and adolescents. When it was in this randomised controlled trial stage it was a fairly short trial which is often the case with a randomised controlled trial, so six weeks. But after six weeks it showed significant improvement compared to a placebo on most of the measures. And of particular note which is something which Lurasidone seems to be beneficial compared to other antipsychotics is that the cognitive and functional symptoms were improved with no negative effect on cognition.

The effect size was 0.45. This is a statistical measure of kind of how much effect there is, which is a sort of moderate effect. It’s not a high level, but it’s not low. And then they looked at responders, which is almost to the scale of the sort of [inaudible 00:04:13] of the number of symptoms. And this showed that 59.5 compared to 36% responded to compared to [inaudible 00:04:24] two years, the number needed to treat. So that means that five patients would be needed to treat to have a definite benefit from the Lurasidone.

But unfortunately, despite the responders being quite significant, there wasn’t a statistical difference in the remission rate. So remission being where there’s a complete resolution of symptoms.

What was found in the study is that the higher the dose of medication used then the more likely it was to improve the MADRS score, which is a depression rating scale. And this was a similar finding to what has been found in adult patients. But it only used doses up to a maximum of 80mg. So we don’t know if it may have had a higher response if it had gone up to high levels, which is what has happened in adults, which has shown a better response.

But they decided, I think, not to use higher doses because of the fact that there was evidence that above 100 or 110mg there’s more side effects [inaudible 00:05:21]. So as well as the initial six week study, they also conducted an open label follow up study. So this was the same young people that were involved in the original study. But after the first six weeks, they were aware that they were no longer on the placebo. So the ones who were on placebo were changed to the active medication as well as those who were already on it staying on it.

And then they were looked at at 28 weeks. And there is a plan for it to follow up after two years. But when I did a recent search there wasn’t anymore recent data on that. So this was just 155 participants who continued. And at six months there was continued improvement in depressive symptoms that were seen. And also no deterioration in cognition compared to the results from the placebo at the end of the six week study. So it wasn’t a kind of continued improvement in cognition but there wasn’t any negative effect from it.

The main side effects which were noted from this study was headache, nausea and anxiety, which is fairly similar to the other studies and adult studies. It didn’t mention so much about [inaudible 00:06:29] which is feeling sleepy, which is a side effect which was noted in some of the other ones. And the other important thing with Lurasidone compared to other medications is that nearly all of the other antipsychotic medications have a significant impact on weight as well as on diabetes with increased lipids and increased sugar profiles. In Lurasidone, as in the adult studies, there’s almost no effect noted on metabolic parameters or on weight and no effect on prolactin levels compared to a placebo.

So moving on to think about schizophrenia. So there was a randomised controlled trial in 2016 with 237 adolescents. And this was reported in two or three different places by two or three different people, but it was the same study. And, again, they chose to use doses of 40mg and 80mg which was the same as the bipolar depression study and didn’t go up any higher than that. And they found significant improvement in the PANAS scale, which is a positive and negative symptom scale.

So it’s a measure of severity of both the frank kind of psychotic symptoms in terms of voices, hallucinations, delusions and those sorts of things. Then the negative symptoms would be more things like the initial affect being reduced, being slower [inaudible 00:07:54] and being more apathetic and those sorts of negative symptoms. So there was more effects noted on the positive sub scale with an effect size around 0.5 which is slightly higher than the bipolar study. And similarly to the bipolar study, again, found around 60 to 65% responded on the 40mg and the 80mg doses versus 42% with the placebo.

It is interesting in these studies that even in schizophrenia it’s still saying there’s a 42% response rate in the placebo which I think is a bit higher than some of the adult studies. So it would maybe lead you to question a little bit what a definite schizophrenia in the adolescent patients.

Female speaker – What are you using [inaudible 00:08:34] value of the diagnosis or was it just purely the assessments?

Dr. Channing – I think it was mainly clinical assessment, but it certainly stated that they did fulfil criteria for the schizophrenia criteria, the ICP10 I think it was. Or it might have been 5 but it was one of them.

Female speaker – when we come to discussions and discuss about how many of them we do actually diagnose with schizophrenia that often.

Dr. Channing – Yeah, there is quite a lot of adolescents you find.

Female speaker – [Inaudible 00:09:12] presentation rather than a [crosstalk 00:09:13].

Dr. Channing – Yes. So, again, similar to the biploar study, although there was a significant difference in responders, there wasn’t statistical significant difference in remission rates. And the side effects in this study was nausea and [s.l. somnolence 00:09:32] being the most common, which is similar to the adult studies. So moving on to autism spectrum disorder.

Female speaker – Just sort of on the last question, I was just looking at side-effects between the two studies. Would that be peer patient characteristics?

Dr. Channing – That’s certainly possible, yes. I mean, I think on the multi disorder studies as well   it also mentions somnolence as well. I think it was mentioned as a side effect, but it wasn’t one of the most prominent ones I think in the study.

Female speaker – And that was in comparison to a placebo you said? I suspect there has been no [crosstalk 00:10:18]?

Dr. Channing – There hasn’t been any head to head trials in children. There has in adults but there hasn’t been [crosstalk 00:10:20].

Female speaker – Sorry Jonathon.

Dr. Channing – That’s OK. So the head to head ones in adults it was found that it’s as effective as Quetiapine or slightly more effective than Quetiapine but not quite as effective as Risperidone or Olanzapine.

Dr. Channing – So for ASD there was one randomised controlled trial with 150 children with autism spectrum disorder and irritability or agitation and/or self [inaudible 00:10:47] behaviours. And in this study Lurasidone wasn’t superior to placebo on the programme outcome or most secondary outcomes. Having said that, there was significant difference seen on the low dose of 20mg on the CGI scale, which is the Cognition Global Improvement scale. So I think it’s a reasonably subjective measure. I had it on my notes but it’s not coming up on the screen alongside. but it’s a fairly subjective scale but it would have been randomised. They would have been blind to know who was on placebo and who wasn’t.

The discontinuation rate, interestingly, was lower on Lurasidone than it was on placebo. It might point to something to do with the global impression of getting some benefit from it. Apart from that study there’s also one case report which showed benefits when Lusparidone and [inaudible 00:11:44] had failed in a young person with autism who had had aggressive behaviour and agitation and  having responded, as well as having more side effects with the [inaudible 00:11:56] Risperidone.

So as well as the original pharmacokinetic study which we’ll say was conducted across multiple disorders there was also a [inaudible 00:12:07] study across multiple disorders which was a smaller study with 56 patients, and it was a retrospective review. So this wasn’t a randomised controlled trial. And 18% discontinued. But for those who didn’t discontinue, for 45 out of the 56 patients, it was found to be effective with improvement seen an average on day four. It didn’t quite quantify the results so much in terms of their scales. But 75% reported experiencing no side effects at all.

And the disorders in this study was quite a variety, quite a lot of mood stabilisation, some for depression, some for bipolar disorder, as well as psychotic symptoms. So moving on to the reason why I sort of started looking at Lurasidone and doing the report was following an involvement with a case of a 14 year old girl who was seen when I was working at Lee House Hospital which is our local adolescent hospital. And she presented with what appeared to be frank psychotic, frank psychosis presentation, having initially presented the year before with anorexia.

And she met the full criteria for anexoria. And at that time [inaudible 00:13:23] quite prominent anorexic voice which is not uncommon in young people with anorexia. And in view of the intensity of her symptoms and the agitation from the voice, she was started on some Olanzapine at that time which she was still taking a discharge dose of 5mg which was decreased to 2.5mg. Two months after discharge she then started to experience low mood. She was started on Fluoxetine antidepressant 20mg and initially experienced some benefit. But two months later she then had very prominent auditory, visual and olfactory hallucinations.

So she was reporting seeing terrorists dropping bombs from planes and feeling the heat of the fire and being very fearful to go out, seeing people hiding behind bushes. She sort of consistently appeared to be terrified by staff and family. And she had been very high functioning. She had been involved in high level sporting activities, competing at a national level as well as having good friendships but became fearful to leave the house and withdraw from the friendships. So the Olanzapine was increased but was noticeable sedation and no real improvement in symptoms.

And in view of her risk [inaudible 00:14:40] she ended up being admitted to one of the private CAMHS inpatient units, still as an NHS patient but to a different unit before coming to Lee House. And at that time the Olanzapine was increased right up to 20mg which is the highest dose that’s usually used in young people. But severe sedation made it really difficult for her to function. And she was just very sleepy most of the time. So she was then changed to Risperidone, which is another antipsychotic, and a dose up to 3mg.

And around that point she then transferred to Lee House as moving closer to home. At that point she met criteria for early onset psychosis or schizophrenia criteria. But she was experiencing side effects from Risperidone with an extra parameter of side effects. So she was reporting feeling very stiff in her shoulders and her back as well as having quite frequent, severe, nose bleeds, which is another one that’s mentioned on the possible side effects with Risperidone. Her prolactin levels raised which is again [inaudible 00:15:43] Risperidone. And one known treatment for that is to start [inaudible 00:15:45] antipsychotic which as well as being an antipsychotic but in its own right has the effect of reducing prolactin, so, that was added in.

But in view of limited improvement seen on the Risperidone, she was then transitioned over to [inaudible 00:15:52] as the sole antipsychotic and she was increased up to 25mg a day, which is quite a high level but quite often young people don’t get above about 15 or so. And she seemed to tolerate that reasonably well with improvements noticed with each increment when it was increased. She started to function better and she managed some home leave but continued to report the voices as well as the auditory…as well as the visual hallucinations being present, being very fearful to go outside the house. The residential building where the bedrooms are is in one building and the school is in another building. And she was very fearful to walk between the two buildings, still reporting seeing terrorists and people waiting behind bushes.

She deteriorated significantly during her GCSE exams. She was a very bright girl and functioned very well academically. But the stress of the exams seemed to make her deteriorate significantly. So she was taken out of the exams at that point. And she was saying the voices were much stronger and were telling her that the medication, as well as [inaudible 00:17:06] food and fluid was poisoned. So, because of that, when she was already on the maximum dose of Aripiprazole, we considered, at that point, what antipsychotic to consider next.

And one factor which she was not keen on by this point was the weight gain in view of her previous anorexia.

She had gained some weight. She wasn’t yet overweight, but she was approaching the 75th grade high centile, which is the sort of upper end of the healthy range. So one antipsychotic that was considered was Quetiapine which is another…it is probably the fourth most common antipsychotic used. And the reason that we were considering that, in terms of guidance, for psychosis treatment, if you failed on two antipsychotics, the recommendation is often to consider Clozapine. But particularly with her being very against weight gain as well as the fact that although she had been on the different antipsychotics, she largely hadn’t tolerated them apart from the Aripiprazole and the sort of treatment dose for a significant period of time.

So Quetiapine was decided not to go with partly because of the effects of sedation that she’s already experienced with the Olanzapine as well as the concerns about weight gain. So, at that point, we looked at the literature and this was before these two big studies had been brought out on its use in adolescents in schizophrenia and bipolar disorder.

But it was clear from the adult literature that there was the least expectation of gaining weight. And the studies indicated that it was at least as effective as Quetiapine as well as an improvement of effects. So in view of it not being used very much in young people with that much trial evidence, we started very cautiously at half the recommended BNF starting dose. And started it alongside [inaudible 00:18:59] because it does indicate that an extra parameter of side effects can be a similar rate to Risperidone and she’d already experienced some extra parameter of side effects with that.

[Inaudible 00:19:04]  up every three to four days and got up to a dose of 74mg which is the sort of medium level. But it’s a round dose which has been used in the studies, while at the same time reducing the Aripiprazole. Unfortunately, around this time, and that showed significant deterioration as the [inaudible 00:19:27] was coming down and the other one was going up with voices telling her that medications as well as food and fluid were poisoned. So she was refusing to have medications and she did miss several doses. So at that point we were considering intramuscular medication and Lurasidone isn’t one that can be used intramuscularly.

Also considering giving medication by an NG tube. When it was discussed with her and thinking about [inaudible 00:19:50] she actually was consenting for an NG tube to be used. Although she was finding it difficult with support, she was able to accept food as well as medication via an NG tube. And, interestingly, from a practical point of view, Lurasidone dissolves almost completely when it’s put into a liquid formula, which it doesn’t mention on the [inaudible 00:20:10] characteristics. But it was very convenient to use by NG.

So the dose of Lurasidone continued to be increased every one to two weeks, going up to the BNF maximum dose of 148mg. And during this time she improved significantly in her interaction with peers and with parents and went on some leave. And after a week of being on the 148mg, had a significant improvement in her mental state with the voices significantly reduced. She was discharged around four weeks after being on the 148mg of Lurasidone. And at that point it was reporting that she was at her best mental state that she had ever been in the past two years. The only side effect that was really noted at that point was causing her some sedation.

But less so than it has been on the Olanzapine or Risperidone and she was still managing to do her usual activities.

So, in terms of her weight gain, she gained 0.5kg compared to when she started on the Lurasidone although she was still within the healthy range, but that compared to gaining 2kg when she was on the Aripiprazole for the two month period. I think it’s also worth bearing in mind that a lot of young people in Lee House tend to gain weight, whether, or not, they’re on medication. I think part of the amount of kind of food and regularity that’s available as well as probably more limited activity than they would usually have in a community setting.

So [inaudible 00:21:39]. So the evidence from the adult literature shows that Lurasidone has a similar efficacy to Risperidone and superior to Quetiapine with improved cognitive effects as well as bipolar depression and schizophrenia. It’s also found to be effective for depression and schizophrenia in adults. [Inaudible 00:21:58] studies that I mentioned for schizophrenia and bipolar depression indicate that it’s effective in adolescents with a dose related response. But it is a shame that neither study went above 80mg.

I guess what the case report kind of indicates as well as clinical experience is that although adolescents tend to be more sensitive to side effects, it’s quite common, if they have a frank psychosis, to need to go up to maximum doses in order to get a full treatment response.

So Lurasidone appears to be a good choice for the treatment of psychosis in young people. The other thing that has been done in adults but not done in children and adolescents is a costs benefit analysis. And it showed that although it is slightly more expensive than some of the other antipsychotic medications, in view of the reduced hospitalisations, reduced weight gain with then reduced incidents of diabetes, the health saving is quite significant when they did the analysis. And, in theory, if we are talking about young people who aren’t presenting with a transient psychosis but if it is the start of a true schizophrenia picture, then it could represent a significant cost as well as health benefit.

So similar pharmacokinetics to adults, increasing evidence for benefit of bipolar depression and schizophrenia. And some evidence for use in other disorders, possibly a second or third line including bipolar disorder, mood stabilisation and autistic spectrum disorders. So, certainly if autistic spectrum is a lot less evidence than it is then you wouldn’t be wanting to use it as first line. But there is some evidence certainly from the Clinical [inaudible 00:23:39] Depression scale that there is potential benefit if other antipsychotic medications have failed.

But, ultimately, we don’t really know for sure whether or not higher doses of medication may lead to more remission, which would be following the adult results. So that would be a direction, hopefully, that someone will take for further research.

 

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