This session we are discussing ADHD in children and young people with autism, in relation to pharmacological treatment, with the focus on Dr. Stephanie Ameis’ in JCPP ‘Practitioner Review: Pharmacological treatment of attention‐deficit/hyperactivity disorder symptoms in children and youth with autism spectrum disorder: a systematic review and meta‐analysis’ first published 26 August 2020.
At the end of the recording Dr. Stephanie Ameis, Professor Samuele Cortese, have answered the four most popular questions that we didn’t have time to address in the session. Please look at our events section for the latest ‘CAMHS around the Campfire’ session.
To get the most from the session we suggest reading/watching the following resources;
- Our Research Digest of the paper, a 2 min read
- Mental Elf blog on the paper
- The full paper doi: 10.1111/jcpp.13305
Other resources recommend by Dr. Stephanie Ameis and Professor Samuele Cortese
- Pharmacologic Treatment of Attention Deficit-Hyperactivity Disorder – via The New England Journal of Medicine DOI: 10.1056/NEJMra1917069
- Systematic review and meta-analysis on prevalence of co-occurring mental health conditions including ADHD in ASD – https://doi.org/10.1016/S2215-0366(19)30289-5
Overlap between ASD and ADHD
- Decoding the overlap between autism and ADHD – via Spectrum
- The Association between Autism Symptoms and Child Functioning in a Sample with ADHD Recruited from the Community – via Journal of Attention Disorders doi.org/10.1177/1087054719886352
- ADHD and Autism Spectrum Disorder via Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD)
Assessment and management of ASD and ADHD
- Differentiating between ADHD and ASD in childhood: some directions for practitioners – via European Child & Adolescent Psychiatry https://doi.org/10.1007/s00787-018-1165-5
- Guidance for identification and treatment of individuals with attention deficit/hyperactivity disorder and autism spectrum disorder based upon expert consensus – via BMC Medicine https://doi.org/10.1186/s12916-020-01585-y
Non-distinct brain features found in ASD and ADHD
- Doctors’ Notes: New brain imaging data points to better treatments for autism and ADHD – via Toronto Star
- A Diffusion Tensor Imaging Study in Children With ADHD, Autism Spectrum Disorder, OCD, and Matched Controls: Distinct and Non-Distinct White Matter Disruption and Dimensional Brain-Behavior Relationships – The American Journal of Psychiatry https://doi.org/10.1176/appi.ajp.2016.15111435
- Association of White Matter Structure With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder – JAMA Psychiatry doi:10.1001/jamapsychiatry.2017.2573
Mental Health Resource for individuals with ASD
- Know Your Normal – via Ambitious About Autism
ACAMH’s vision is to be ‘Sharing best evidence, improving practice’, to this end in December 2020 we launched ‘CAMHS around the Campfire’, a free monthly virtual journal club, run in conjunction with André Tomlin. We use #CAMHScampfire on Twitter to amplify the discussion.
Each 1-hour meeting features a new piece of research, which we discuss in an informal journal club session. The focus is on critical appraisal of the research and implications for practice. Primarily targeted at CAMHS practitioners, and researchers, ‘CAMHS around the Campfire’ will be publicly accessible, free to attend, and relevant to a wider audience.
About the panel
Dr. Stephanie Ameis is the Associate Director of the Cundill Centre for Child and Youth Depression and a Clinician Scientist in the Brain Health Imaging Centre, The Margaret and Wallace McCain Centre for Child, Youth & Family Mental Health and the Campbell Family Mental Health Research Institute at CAMH. She collaborates closely with the Temerty Centre for Therapeutic Brain Intervention, the Kimel Family Translational Imaging-Genetics Laboratory and the Azrieli Adult Neurodevelopmental Centre at CAMH. Dr. Ameis is a child and youth psychiatrist at CAMH and is appointed to the Child and Youth Mental Health Collaborative at CAMH, the University of Toronto and SickKids. She is Associate Professor in the Department of Psychiatry in the Faculty of Medicine at the University of Toronto.
Bio and image via CAMH Canada website
Samuele Cortese, Child and Adolescent Psychiatrist, is Professor of Child and Adolescent Psychiatry at the University of Southampton and Honorary Consultant Child Psychiatrist at the Solent NHS Trust. He is also Adjunct Associate Professor at the University of New York, USA. His main clinical and research interests focus on the epidemiology, neurobiology and treatment of neurodevelopmental disorders (in particular on ADHD) and on evidence-based practice in child psychiatry. Dr. Cortese is author/co-author of more than 200 papers in international peer-reviewed journals. He is on the editorial board of the Journal of the American Academy of Child and Adolescent Psychiatry, (JAACAP), Child and Adolescent Mental Health (CAMH), Evidence Based Mental Health (EBMH), CNS Drugs and on the advisory board of the Journal of Child Psychology and Psychiatry. Dr. Cortese is a member of the European Network for Hyperkinetic Disorder (EUNETHYDIS), the European ADHD Guidelines Group (EAGG), and the Child & Adolescent Neuropsychopharmacology Network of the European College of Neuropsychopharmacology (ECNP).
André Tomlin is an Information Scientist with 20 years experience working in evidence-based healthcare. He’s worked in the NHS, for Oxford University and since 2002 as Managing Director of Minervation Ltd, a consultancy company who do clever digital stuff for charities, universities and the public sector. Most recently André has been the driving force behind the Mental Elf and the National Elf Service. The Mental Elf is a blogging platform that presents expert summaries of the latest reliable research and disseminates this evidence across social media. They have published thousands of blogs over the last 10 years, written by experts and discussed by patients, practitioners and researchers. This innovative digital platform helps professionals keep up to date with simple, clear and engaging summaries of evidence-based research. André is a Trustee at the Centre for Mental Health and an Honorary Research Fellow at University College London Division of Psychiatry. He lives in Bristol, surrounded by dogs, elflings and lots of woodland! Bio via The Mental Elf
I am an information scientist with an interest in making knowledge from systematic research more accessible to people who need it. This means you. I’ve been attempting this in the area of Evidence-Based Health Care since 1995. So far the results have been mixed. For some reason we expected busy clinicians to search databases and appraise papers instead of seeing patients. We also expected publishers to make the research freely available to the people who paid for it. Ha! Hence The National Elf service.
Andre Tomlin – It’s nice to see such a wide variety of people on the webinar today. Welcome, everyone. Very warm welcome whether you’re a mental health professional or a researcher or a person with lived experience or a parent. We’ve got a really diverse group of you here today. That’s fantastic. So thank you for joining us. I’m going to give you a bit of an overview of what we’re going to cover. And then I’m going to introduce our panel and then I’m going to ask them some questions. So this webinar is about ADHD and autism in young people. And we’re delighted that we’re covering that topic and that we’ve got a really great piece of research that we’re going to summarise and discuss. In previous Campfires that we’ve had lots of people have asked for more events relating to these two topics, and so we’re really pleased that there’s a demand out there for this and that we can discuss how we can support young people.
So what we’re going to do, we’re going to start off by talking a bit about what life is like if you have autism and ADHD. We’re going to set the scene a little bit. We’re then going to critically appraise a piece of research. That sounds quite complicated if you’re not a researcher, but don’t worry. It basically just means we’re going to summarise a new piece of research and talk about the strengths and limitations of that research and talk about what we’re going to do now that we have that research; how can we use it in practise? And so, yes, it’s time to introduce people, so I’m going to ask our expert panellists to give a little wave as I introduce them, so you know who’s here in the room.
First of all, really happy to introduce Stephanie, Doctor Stephanie Ameis, who’s a psychiatrist… Hi Stephanie… from Canada, joining from Toronto, Canada. She’s Associate Director of the Cundill Centre for Child and Youth Depression, a Child and Youth psychiatrist at the Centre for Addiction and Mental Health in Toronto, and it’s her review that we’re going to look at today. We also have Sam here on the call, Samuele Cortese, Professor of Psychiatry, Child and Adolescent Psychiatry at the University of Southampton and also a practising consultant child and adolescent psychiatrist in Southampton at the hospital there. That’s a mouthful Sam. We also have Tom, who’s here said today. Tom is joining us just via audio. Tom is our lived experience representative. Very warm welcome Tom. Really pleased to have you on the call. Tom is a member of the McPin Young People’s Network and will be chiming in on his own experience of this issue. So, yes, great to have you on the call. Thanks for joining us. And then we have Douglas and Celine, my colleagues here at the CAMHS Campfire. Douglas Badenoch who is co-founder of the National Elf Service with me, an information scientist. He’s got a black belt in critical appraisal skills, so he’ll be drawing on those skills later on. And Celine, Doctor Celine Ryckaert, who’s a clinical lecturer… Hi Celine… at King’s College, London. Celine’s going to be moderating the Zoom chat today. So do say hello in the chat. Do use the Q&A function if you want to ask a question of our panel. This is very informal, very conversational, so yes, we’ll try and get the most out of it together and see what we can learn.
So I’m going to start off, Sam, by asking you to give us a little bit of context for this. Give us some background. Clearly, we’re all very different. But can you paint a picture of some of the challenges that face young people who are affected by autism and ADHD for us?
Prof. Samuele Cortese – So to set the scene, first of all, I think is probably important to start with a quick historical background where we started from to understand better what is the problem we discussed. So as many delegates to this event will know, until 2013, the year when one of the two major diagnostic systems we use in psychiatry, the DSM-5, was published, formerly it was not possible to diagnose ADHD and ASD in the same individual because it was thought that if a person with ASD has also symptoms, problems related to ADHD, typical of ADHD, so hyperactivity, impulsivity and inattention, this was in a way accounted for by ASD, by autism. So officially was not possible to give this double diagnosis. This veto was removed in the DSM-5. The concern was that actually not diagnosing ADHD in individuals with ASD, when on top of ASD they present also inattention, hyperactivity, impulsivity, was a problem because prevented them from receiving appropriate treatment for these symptoms, which can be very impairing alongside the symptoms of ASD. So the DSM-5 committed the decision to allow co-diagnosis, dual diagnosis. Since then, this is important from the research point of view because we have more studies that focus on individuals who officially are diagnosed with these two disorders. So more studies mean we are more able to understand the treatment that work and don’t work for this particular subpopulation of individuals with ASD. And it goes without saying that many clinicians used to diagnose ADHD in ASD well before the DSM-5, regardless of the official indication. But this is important in terms of research because since then the number of studies on this particular population has increased and we can assess better. We can compare them; we can pool them together as Stephanie did in this meta-analysis. So I think this is important as a first point to bear in mind.
Second, I think that the focus here is to understand really what is the value, if any, of pharmacological treatment to decrease the severity of the symptoms of ADHD. And as I mentioned earlier, of course, I guess the majority of delegates are aware, but for those who are not very familiar, when we talk about ADHD symptoms, we refer to three core symptoms. We call them core symptoms because they define the disorder: inattention, hyperactivity, impulsivity. Every child has some trait of these, but we call them a disorder when they are excessive in comparison to the developmental stage of the child or the individual and when they are impairing.
So the question is really what is the value finally of pharmacological treatment in individuals with ASD plus ADHD for ADHD symptoms. Now, when we look at individuals with just ADHD, we do have quite a large body of evidence. Actually it is quite clear that the body of evidence on pharmacologic treatment for ADHD, just ADHD, is the largest body of evidence we have in child adolescent psychopharmacology. These are the most studied medication. They have been there for decades from the 40s, 50s, so these are quite well known medication, quite controversial. They have always been controversial, but we do have a large body of evidence which point to the fact that in general for individuals with just ADHD that tend to be quite efficacious and effective. Actually, we have a large body of evidence from randomised trial that shows that they are better than placebo; they are much better in general. In research, we use a term, which is the effect size, which means to which extent the medication are better than placebo and the effect size of this medication are the highest one we have in psychiatry, so better than antipsychotic, antidepressants, [inaudible 00:08:51] and so on and so forth.
Interesting, we also have a large body of evidence from real life studies because one of the critique is that, of course, randomised trials are quite artificial, but in real world it has been shown that this medication in individuals with just ADHD they decreased significantly important negative outcomes that’s been shown that they needed to decrease criminal act, anti-social act, physical injuries, car accident and so on and so forth. They do have side effects as all medication, but I would say the good news, so to speak, is that in general the side effects are temporary; they can be managed, and they lead to discontinuation of this treatment just in a minority of patients. So overall, we can say that even if they are concerned around the quality of the evidence… We can talk about this later on… in general available evidence points to the positive effect of this medication with an important impact in daily life.
Now, the question we are discussing today with the paper Stephanie led as senior author, is what is the efficacy? So how well do they work in trials and what is the tolerability? So do they have side effects? Are they well tolerated in individuals who in addition to ADHD have also ASD? Because we may expect, maybe the effect is the same, but it may be different. So we really need a systematic appraisal of the evidence and analysis to answer this question because this is important. When we discuss with our patients, we need to provide solid information to have a decision, a shared decision in terms of the choice of the medication and understanding the beneficial effects and their limitations. So I think this is really the question that we address today.
Andre Tomlin – Yes, thank you. Great. That’s a great introduction. I want to broaden it out a little bit, and before we get into talking specifically about how well medication works to treat ADHD in people who have autism as well, I’d like to open it up to the rest of the panel really just to reflect on, as I said earlier, what life is like if you have autism and ADHD, how you interact with the world, what the challenges are specifically that face you. I don’t know if anybody else on the panel wants to come in on that? Ah, Tom, you’ve got your hand up, would you like to speak now?
Tom – I think being autistic and having symptoms of ADHD can be really, really tough and hard, especially when there’s little or no awareness from other people that you have it. At the same time, it can be quite easy for… It can be quite easy except [inaudible 00:12:23] if you have the right people who will support you. But there’s not really a definitive answer from my opinion in terms of what life is like for someone who has ADHD and autism. It’s important to say that people feel differently on this, but what I do think we’d all agree on is it’s easier for us when life is better and more pleasant. We have people who are there for us, who can recognise some of our difficulties and needs and make adjustments.
Andre Tomlin – Thank you. It’s so good to have your voice as part of the conversation Tom. Thank you so much for joining us. I think it’s really important that we ground what we’re thinking about here today in the lived experience of people like yourself, so it’s really fantastic that you’ve been able to join us. I’m sure we can come back to you later. Do chime in with your thoughts as we go along please. Stephanie, do you want to add to that at all?
Dr. Stephanie Ameis – Well, no, I think Tom said it really perfectly that there’s such a variety of experiences and individuals who are on the autism spectrum. They have a variety of mental health, physical health, co-occurring disorders that that can increase impairment and make it even more difficult over and above some of the challenges that are associated with being on the autism spectrum to function in certain settings, especially when the person environment fit is not quite aligned very nicely. So, yes, I think that being on this panel is a wonderful privilege and it’s a really great opportunity for our paper to be highlighted and featured in this edition of The Campfire.
Maybe I’ll take a moment now to talk a little bit about what the impetus was for our paper.
Andre Tomlin – Thank you.
Dr. Stephanie Ameis – Okay, all right. Okay, so this paper was really a team effort. So I’m here representing our big team. And it was a collaboration between a bunch of clinicians and clinician scientists who tend to have more expertise on the ASD and the ADHD management clinical trial side. And then those were folks at the University of Toronto and we collaborated with the methodologies at the University of Western Ontario. So my co-senior author on this paper is Doctor Kelly Anderson, and then the first author was Rebecca Rodrigues, who really undertook a lot of the method based thinking about the systematic review and meta-analysis. And then the clinicians really took that and tried to really translate it into a synthesis and a guidance to help clinicians in the field who are trying to make decisions and help families and young people that they are working with to figure out what the best way forward is in terms of management of ADHD symptoms and ASD.
And so some of the factors that led into us undertaking this systematic review and meta-analysis and then the knowledge synthesis piece in the practitioner review was when there had been a bit of time since the previous pathways had been published. It was about 2012, 2013 that the Autism Treatment Network, which is a North American network of clinicians and families, had undertaken a clinical pathway undertaking, as well as a narrative review of the literature. And at that time there was really just clinical trials, and most of them were not RCTs, that they reviewed that focussed on methylphenidate treatment. And then the next year there was another systematic review… there was a systematic review and meta analysis led by [inaudible 00:17:03] and that tried to look at medications broadly, but at the time, really, there was still only methylphenidate that you could really pool what Samuele was talking about in terms of pooling effect sizes to really synthesise what the evidence was across trials that were available.
Since then, there have been a few studies that have looked at one medication class, but no update that looked across classes. And we’ve had a small number of additional studies that are what we call the highest rigour in terms of design RCTs, randomised controlled trials, that had been published that we wanted to put together. And so we really wanted to provide for the clinicians out there a comprehensive guide that looked across different medication classes that we could compare what the evidence looked like to the extent that we could. And so that was part of the impetus. And then in the background, we see that the rates of medication prescriptions in young people on the autism spectrum are going up. ADHD is one of the most common reasons why medications are prescribed in autism, and they’re also probably the primary reason for a long-term use of medications.
And so we wanted to go back and be able to pool all the evidence that we have and look across different medication classes to see, one, what’s the evidence of efficacy? What are adverse effects looking like? But then we wanted to go beyond what had been published previously and really to look at what Samuele was someone was talking about before, which is more of the everyday impact, the importance of outcomes that maybe have more meaning to individuals. Some of those that we were wanting to look at were everyday functioning, school functioning, and oppositional defiant disorder symptoms. So really, we wanted to go back, give a comprehensive guide, look across different domains, and then really synthesise the literature so that we can give an updated pathway for the clinicians who are undertaking decision-making with their patients and families in this arena.
Andre Tomlin – Wonderful. Thank you. So I’m interested, first of all, before we talk about the evidence and the pathway that you’re recommending, what happens currently to treat and manage ADHD in young people who have autism? Do you want to start, Stephanie, by telling us what happens in Canada? Do you know?
Dr. Stephanie Ameis – I don’t think we know in a systematic way. I can definitely tell you anecdotally amongst my colleagues what our experiences are, but typically, unfortunately, we still in child psychiatry and in a lot of areas of medicine, we don’t necessarily use standardised pathways. So treatment approaches may differ quite a bit depending on what clinician you happen to be able to get access to. So that’s definitely our experience. So the approach, what medication might be tried first, whether behavioural interventions get tried before medications, and even the rigour in terms of the assessment of ADHD and ASD varies quite a lot from clinician to clinician. And so we’re moving towards standardised pathways and what we call measurement based care where we’re trying to really standardise our approaches, use similar outcomes, but we’re really not there yet. So that’s a little bit about what the experience is like.
Andre Tomlin – Okay, thank you. And how about here in the UK Sam? We know that, I think it’s something like one in three young people with autism have symptoms of ADHD, how is that managed currently within the health service?
Prof Samuele Cortese – Sure. So interestingly, I think when we look at the treatment, we should always look also at what is the outcome. So what are the things that we want to change because it’s possible the different interventions do different things. So when we look at ADHD, of course, as I mentioned earlier, it is defined by three core symptoms. So if we look at the effect of treatment just on these three core symptoms, inattention, hyperactivity, impulsivity, evidence in general suggests that the pharmacologic treatment is the best approach to decrease the severity of these problems. And arguably many a clinician in CAMHS, normal CAMHS, tend to use this medication in children with ADHD, with or without ASD tackle ADHD symptoms.
However, we do know that ADHD is much more than these three symptoms. Beyond these trials there is a person with strengths, difficulties, so looking broadly at other outcomes, like… I don’t know… sleep and more broadly quality of life and so on and so forth, we clearly understand that an individual pharmacologic treatment is probably not enough. So we really need to consider that the way these individuals are treated is quite different, according to the clinical picture, the needs, the strengths. And so hopefully when we move beyond the diagnosis to look at the formulation, this will suggest additional treatments, additional interventions. So clearly, if we look just at the ADHD core symptoms it’s quite common to see these children or adults treated with ADHD medication, but in addition to this there may be a whole panel of other interventions. And it goes without saying that, of course, this depends on to which extent these are available in the service because we can read guidelines and recommendations that provide some hierarchy of treatments, but when it comes to the reality, if there are no therapists trained on particular therapies, then practitioners are left with the option of the medication. So the availability of treatment also influences the way these individuals are treated. But definitely I would say that [crosstalk 00:23:59]…
Andre Tomlin – Oh, sounds like you need to mute. Thank you, Sam, and I think that’s really pertinent for all the people that are joining the webinar from low and middle income countries. I noticed when people were introducing themselves, there were from all sorts of places. I think the availability of treatment is clearly an issue, not just in the UK, but all over the world. Yes, Stephanie?
Dr. Stephanie Ameis – I just want to add to that because I think that’s a really important point, especially in the current climate. Globally, we’re all still dealing with this pandemic and the availability of psychosocial interventions have shifted virtually in a lot of settings, and people have lost services and lost critical access to school support. And so we are seeing in Canada that across mental health prescribers tend to be drawing on what they can in terms of their toolboxes and relying more on medications because just the access to psychosocial intervention has diminished in this climate.
Andre Tomlin – I noticed, Tom, you put your hand up there. I wondered if you had anything to add about your own experience of what support people get currently in the UK? No pressure to say anything if you don’t want to, but yes.
Tom – The support you will get in the UK, the main support I’m aware of, is adaptations.
Andre Tomlin – Sorry, Tom, could you say that again? The main support people get is…
Tom – So the main support I’m aware of is adaptations to the environment.
Andre Tomlin – Yes.
Tom – So like in a work setting, for example, people with autism and ADHD may be offered specialist equipment or somewhere where they’re less sensitive to noise and light. I know there’s other specialist support, which can be put in place or considered, like an organisation with expertise can provide some sort of diagnosis or treatment or care plan with occupational health. I think with support I hope that is provided. It’s fair to say we can’t ever be complacent about what people need or might need going forward, I think. As the research, which has been carried out will show there’s not going to be a point where we can put things to rest. There’s always going to be something new that comes about or needs to change and may affect what we know. So while we’ve been thinking about support and how we help with medical conditions in general or more specifically with something like ADHD and ASD it’s important to recognise that as well because I think, personally, there are some people who are more aware of that and took into account it would have helped me and other people who have had some experiences of not getting the right interventions in at the right time.
Andre Tomlin – Thank you. That’s a loud and clear message, I think it feels to me like we’re at the very start of a journey to support diverse individuals and to change society in a way which is much more better organised for everyone who lives in it. But yes, that’s a really clear message. Thank you, Tom. Okay, I’m just looking at the clock and we need to move on now to the next part of the webinar. So I’m going to hand over to my colleague Douglas, who is going to talk specifically now about the review that Stephanie and her colleagues recently published and he’s going to give you some pointers as to how we can look at this kind of research. So, yes, over to you Douglas.
Douglas Badenoch – Thanks very much. I think that’s been a really, really fascinating introduction, set the scene for this research really well. So my thanks to my colleagues, especially Tom, for contributing. Matt, I was wondering if you could pop up the next poll question. We’re now going to look at a piece of research, which is a systematic review, but I just wanted to get a quick feel from the audience what your knowledge of systematic reviews is. So are you someone who can do systematic reviews? Are you somebody who can read them or are you someone who can learn about them? So it would be very helpful and would affect which slides I show, depending on your response to that question. What we’re trying to do with a systematic review is very much what we’ve got in this clinical situation where we have lots of different research, lots of different interventions, we’ve got different drugs that are used, we’ve got slightly different ways of measuring outcomes. And so the idea of something that brings together all of the existing evidence and presents it in a single place is obviously something that is going to be very useful for us. Thanks very much Matt. We’ve got the results now. So I think we could probably do with a quick introduction, which just maybe tells folk what systematic reviews are. So I’ll try to be quite quick about this. Hopefully you can all see the slides now. Thank you, Stephanie.
So, as I said, we can have a number of different studies on a topic. Here we’ve got four studies. Let’s imagine we’ve got red pills and green pills, and we’re comparing their performance and we want to try and find out an answer. Is red pill better than the green one? You look at that data you can see there is a bit of inconsistency, and that’s something that we’ll quite often see when there’s conflicting evidence or evidence that seems to conflict. So the idea of a systematic review is that we combine it all and not just put it all in a big mess, we extract the data from each study and try to find a definitive answer. And in this case, you can see each study is represented by a line on the graph. If that horizontal line crosses the line in the middle, that means there’s no difference between the two treatments or that’s not statistically significant, but once we combine the data at the bottom, the lozenge shape at the bottom shows you that the results overall favour the red pill as opposed to the green one in this instance. So that effectively is what we’re doing with a systematic review and, in this case, a meta-analysis where we combine all the data to try and get a definitive result. Now what happens if our review is not systematic is that we can run into problems. So this is why they’re called systematic reviews and not reviews of stuff that I happened to have lying around on my desk. In this case, study C, let’s say our search for evidence missed that study, we would get a different result. So with study C, it shows in favour of red, but then if we lose that, then we’ve lost the clarity of that evidence. So it’s very important that systematic reviews find everything that’s been done on the question.
The other crucial thing about systematic reviews is that they manage the situation where there might be slight differences between treatments or between the patients who are involved in the study or between the outcomes that they measured. So in this case, we’ve got a purple pill. Now is that different enough from a red pill? So what the researchers in the systematic review need to do is to come up with a way of managing all the different studies, so we’re not combining apples and oranges, we’re actually combining things that it’s okay to combine. And those are the two crucial things you’re looking for when you’re reading a systematic review. Just the high level message is this is why we do them. They give you an unbiased overview of what’s already known. We’ve got a better chance of providing reliable answers to people’s questions, more precise estimates of the effects of treatments. We reduce waste in research by stopping doing studies when we don’t need to. And there’s also pretty good evidence that by not doing them in the past people have suffered harm as a result.
I’ve got a very quick example. Feel free to follow up the reference; there’s a really good paper here. But take the example of cot death. Some of us will remember the campaigns in the 80s and 90s to put children on their backs to sleep, little babies, rather than on the front. Now, for years, people had been advised to put babies down to sleep on their front. Doctor Spock, for example, his book, Baby and Child Care, recommended putting babies to sleep on their front because they thought they might asphyxiate; if they vomit in their sleep, they might asphyxiate. So there was a kind of rationale behind that advice. But when we look at the studies that people had done, we find if you look at the top half of this graph, the studies are all over the place. And they’re small studies; they’re over a long period of time. And as time went on and people started to do more research into it, then we started to get more data. So what the second half of this graph shows is what if we’d been doing systematic reviews as we went along, if we’d been combining this pool of data into one and doing an analysis on it? Well, it’s quite stark. We would have known in about 1970 that we should put babies on their back to go to sleep. And you can see quite clearly how the estimate gets more precise as we add more data to it.
So this is what we’re trying to do with this question. We’re trying to get as much data as we can that’s valid to combine and get as precise a measure of the benefits. And this hopefully shows you why people think systematic reviews are so important. The other thing to say is that reviews do need to take account of the risk of bias in health research. Now I’m not going to do a big lecture on this. There are some great links in those if you want to follow it up. Quite often we talk about bias, and if you’re new to research, you might be thinking, hang on, what? How come these researchers are biased? What’s going on? But it’s not just simple as that. There are things we know about the way we do studies that we know can lead to systematic error in the results in one direction or another. And usually where bias exists, it tends to favour treatments. So there’s a good list of studies there, if you want to follow that up, but this underlines what Stephanie said earlier on, that randomised trials are considered to be the best design for this type of research because they are least likely to be biased, to be affected by bias.
So how do we apply this process to systematic reviews? So what I’ve got here on the screen is just an effective copy lifted a checklist of questions from CASP, which is a Critical Appraisal Skills Programme. And there’s another link there that you can follow if you want to follow that up. Basically, we break this down into does the review address a clearly focussed question? And within that we look for that systematic review plan to be published in advance, so that we know how they’re going to go about doing the review and we can check their progress. We need to make sure that they looked for the right type of study We need to make sure that they evaluated it correctly, that they did enough to find everything, so we haven’t missed important data, and to assess whether it makes sense to combine it all. So these are the questions that we run through when we’re doing a critical appraisal of a review.
So we’re going to move on. Sorry, that’s the very speed read guide to critical appraisal of systematic reviews for someone who’s never heard of them. But please feel free to follow up those links for more detail. We’ve already heard quite, I think, in quite good detail about the background of this research. But an important thing I think it’s helpful to look at when you’re reading a review are the inclusion criteria because that will list all the different… all the types of participants, all the interventions that they evaluated, and the outcomes that they measured at the end. So running through the checklist we can see we’ve already discussed the question… It’s quite a complicated question because we were interested in side effects and we’re interested in different kinds of treatments as well.
We looked for randomised trials, and I think this is a case where you’ve done a lot of work, Stephanie, you and your team, to make sure that you found everything. So you did… as well as searching databases… you contacted the authors, you looked at the lists of tables of contents because sometimes databases contain errors and don’t contain everything. Sometimes an author will know about a study where there’s data that hasn’t been published. So they pretty much did as much as is humanly possible to find all the important studies. They also went through a process of evaluating the quality of those studies and of extracting the data, and they did that by checking their work as they went along. The gold standard here is that you have more than one reviewer looking at the data and they compare notes independently from one another to make sure that they’ve got a consistent conclusion.
So we can see all these steps described in the paper and as well as conducting a meta- analysis where they put all the data they tested whether the findings varied to test their assumptions. So you can have techniques called sensitivity analysis and heterogeneity tests that you can apply, fancy statistics that will tell you whether is there a risk this data has been affected by bias or are there important differences between the studies, so we should be cautious about combining them. So quite a lot there. This is a study where everything is quite clearly reported and it passes the muster with flying colours, I think, on the CASP checklist.
We now then move on to think about the results. Are they important? And this figure in the paper is one which distils all the main outcomes into one graphic. And you can just glance at that graph and you can see that the results tend to favour drug treatment, that within each drug they’re quite consistent. What’s quite interesting about the way the results are being presented here is that we can see whether the outcomes are assessed by parents, teachers, whether they’re assessed by investigators or specialists, the patterns are similar. So that gives us a bit of comfort on the apples and oranges front. It looks like, within these set groups, the studies are looking at similar things and showing a similar effect.
The results themselves, I think it’s worth just mentioning how they’re presented. When we measure hyperactivity or ADHD symptoms, generally we use a scale, a score that’s derived from scoring different symptoms. And so there’s a question then of how you combine those from different studies. Sorry, how you compare the different groups. Basically, what the researchers do is they look at the mean improvement in the drug treatment group and compare it to the mean improvement in the control group. So they’re looking at the average difference, average improvement, if you like, in the two groups and comparing them. So that’s a very important distinction to make because averages are very useful when you’re talking about populations. There can be variations, of course; averages can conceal a bit of… You can have outliers. So sometimes it’s not the full story, but it does mean that we can get a fairly reliable measure of the overall effects in the population in general that we’re dealing with.
So in the blog that goes along with this session, we’ve put together a table based on the data from the paper, some of it from the supplementary information, which people will find useful if they want to explore the results in more detail. And so here you can see both, I suppose, you see the good and the bad of this evidence in this one table. We show that there are effects on hyperactivity, beneficial effects on hyperactivity and inattention for some of the treatments. But there are question marks about the individual studies, some of them very small or there were very short term. And I guess that’s something that we could talk about in a bit more detail, Stephanie, when we come to explore the implications in a minute. There’s also people are concerned about side effects, and there’s a really valuable table of information which lists all of the side effects that were reported across all the different interventions, which will be very helpful to people. I guess that might be something that is worth picking up in the discussion afterwards. We mentioned it at the start, but there are things that we know about and we may be able to deal with.
So my conclusion of this appraisal was we could see some consistent evidence of benefit, particularly in hyperactivity symptoms. We’ve got some limitations in the evidence as it’s presented, specifically in this population, around long-term studies. Perhaps we need some bigger studies. And there’s also outcomes that we were interested in looking at that the evidence is slightly patchy; it’s not fully reported perhaps. Not all the studies recorded the outcomes about quality of life, about some of the other things that might matter more to patients and families. So these are perhaps some of the recommendations we can make for future evidence. But I think we’re in a situation here where we need to think about the decision making can benefit from this evidence about studies that have been done since the last review, so in the last eight to ten years. I think it clarifies the picture on the things that we need to balance when we’re making decisions about offering this kind of treatment. So thanks, Matt. You’ve put up the next question and it’ll be interesting to see what people’s responses are. While we’re filling it in, I’ll pass back to the team to… I think it’ll be interesting, particularly, as we said, pick up some of the issues around the evidence that you found, Stephanie, and is there other evidence that can plug some of these gaps that we already know about? That would be particularly interesting to know about. Thanks very much for listening. Hope you enjoyed that.
Andre Tomlin – Thanks Douglas. Yes, over to Stephanie. What do you think of what Douglas has said about your review first of all?
Dr. Stephanie Ameis – Well, thank you very much. I guess I can wipe the beads of sweat off my forehead to make sure that we did a good job. I mean, we really did try and pull together a good team that we could really present a rigorous review and meta-analysis and then also really synthesise it. And Rebecca Rodrigues really deserves a lot of kudos. It was her idea to bring in that table that lists all of the different medication classes together, which I really think helps the clinician, who’s maybe pressed for time and really trying to get an overview of what the treatment literature looks like and really can see a comparison between these different studies. Some of the things that I think is really worthwhile to highlight, which you already highlighted in terms of the conclusions, is that we’re really still in the early days in terms of addressing the evidence gaps that remain in terms of ADHD treatment and ASD, and in terms of treatment of the majority of co-occurring mental health conditions in autism. So I saw from the chat, which I’ve been monitoring a little bit, that there’s lots of questions about the heterogeneity that we see, that Tom has described, among autistic individuals that really when you describe somebody who has autism, it’s really one person. And there are elevated rates of co-occurring mental health conditions across common mental health conditions that we see: elevated rates of anxiety, of depression, of psychosis, of suicidal thinking. And so those are all things that we have to think about. Sorry, I don’t know if my audio just cut out a little bit. Is it okay?
Andre Tomlin – Yes, you’re fine.
Dr. Stephanie Ameis – You’re okay? Okay, good. In terms of the literature that we reviewed, definitely some of the things that continue to be issues that need to be addressed are small sample sizes, short durations of studies, so we really can’t say anything about long term efficacy. In our search for clinically meaningful secondary outcomes in terms of looking at oppositional defiant disorder symptoms, everyday functioning, school functioning, there’s really very little that has been written about and evaluated systematically in the literature in this co-occurring presentation of ASD and ADHD. And there’s lots of heterogeneity, so there are a lot of differences between studies in terms of what we found with respect to effects. And some of that heterogeneity reduced a little bit when we looked at medication dosages, so this is particularly for methylphenidate. We did some sensitivity analyses, as Douglas mentioned, where we looked at different dose effects, and we saw that there was a hint that the effect sizes might be larger with medium and high doses as opposed to low doses, and that improved some of the heterogeneity between studies. But there was still significant heterogeneity that remained amongst a lot of the outcome measures. So there’s still a lot of this fine-tuning, nuanced approach that we can’t really answer with the literature. And that’s where we hope that this paper really provides an opportunity for the clinician to get a broad, comprehensive look at what’s available and have a frank discussion with their patients and the families that they’re working with to clarify what would be an appropriate choice for that specific individual, based on their circumstances, their classroom environment, how engaged their teacher is, what are the available behavioural interventions that you can draw on first before thinking about medications, which is part of our pathway, which maybe we’ll have some time to discuss.
Andre Tomlin – Yes, let’s look at that now shall we? Because there’s a lot of people asking… [background noise] excuse me… in the chat, what’s this pathway all about? And unfortunately, the pathway is part of the paper, which is not an open access paper, so we can’t share it with you guys. Publishers, I don’t know. But we have got some slides that Douglas can share, so maybe, Stephanie, you could just talk us through the pathway and just tell us what your review is recommending in terms of treatments and particularly focussing on the first line of treatment. So you’re not recommending medication as the first place that clinicians go. You’re recommending behavioural support. So what does that mean, behavioural support?
Dr. Stephanie Ameis – Yes, so there’s good evidence from the non-ASD literature that behavioural interventions really help. So these are strategies, learning strategies that can be taught to parents, and a lot of teachers will have formal education around these strategies. And it’s really to enhance one on one strategies to help people redirect their attention towards the topic matter. So if you have that one on one support to make sure people don’t get so distracted, that can help quite a lot. You chunk information, so you break down information. Rather than giving somebody ten questions, they do two questions; they take a break; they come back. That tends to enhance their ability to attend and get work done. Being close to the teacher, reducing background noises, all of those things are in the realm of behavioural interventions. And they can be broader than that in terms of ASD. Really in terms of the treatment evidence that we have for supporting individuals who have autism, who are on the autism spectrum, behavioural interventions are number one, not medications. Medications are facilitators that sometimes are needed to target specific symptoms, but it’s really those behavioural interventions, support for parents to learn some strategies of how to engage their children in subject matter and for teachers as well. So that’s the first line. And from the non-ASD literature, we know that if you start with that that actually seems to improve efficacy outcomes. We don’t know that from ASD, but that seems to be the case in non ASD ADHD. And so once you’ve… yes…
Andre Tomlin – Sorry, I’m just conscious of time. We’ve only got a few minutes left and I want to get through the pathway for people because there’s three more slides after this one. So maybe we could move on to the next one and talk about once it comes to a choice about medication, what the process is.
Dr. Stephanie Ameis – So I’m going to distil it down because I think we only have one minute left, so really from the 2012 pathway, the key differences are the first line medication treatment is methylphenidate. That was the same in the 2012 pathway. But the second line has changed. So now we’ve bumped down the evidence the level of amphetamines. We don’t have any studies of amphetamines in ASD and we’re concerned that maybe tolerability will be an issue because we see tolerability problems and lower effect sizes for methylphenidate and we think that tolerability might be an issue for amphetamines. So if young people don’t have significant problems with tolerability with methylphenidate, you can use amphetamines as a second choice. But if there are significant tolerability issues, we suggest that you just go down the second line choices to atomoxetine and guanfacine, which are medications that we do now have RCT level evidence in autism and ADHD. So atomoxetine and guanfacine and amphetamines are all second line choices. And that’s the overview, and there’s lots of details in the paper that people can go through.
Andre Tomlin – Yes, thank you. I wanted to bring Sam in now. Just a very general question, Sam, because I think the people who’ve been watching the presentation and looking at the evidence that this review brings together might be surprised that actually, we don’t have very good evidence for using medication for ADHD symptoms in people with autism. Yes, is that a concern to you that we’re actually doing this in practise, but we have quite poor evidence for it?
Prof. Samuele Cortese – Yes, well I would say that it’s important, it’s crucial to bear in mind that evidence [inaudible 00:56:06], even a very good one as this one, is just one of the elements that guide clinical decision making. There are also a specific characteristic of the patient, preferences of the patient, and also the expertise, the experience of the practitioner. So there’s sometimes if you… if the clinical guidelines, based on the evidence, suggest that you should use A, but for some reasons you use B, that’s could be okay. So I would say that definitely medications are one of the elements in our armamentarium and not the only one, but they can help. They don’t always help, but they help. And I’m sure that, let’s say, if tonight I call my patients who have ASD and ADHD and I told them, starting from tomorrow, you will need to stop your medication because the evidence is low I bet that I will have a lot of phone calls tomorrow, very anxious. So I guess that we always need to take this with a grain of salt and as something that can guide, but we know that even the best evidence can change over time and should be taken into a global perspective.
Also, in terms of the quality of evidence it’s very important to bear in mind that the way we rate it depends a lot on the type of information that is available from the paper on that particular study. When it is not clear how certain aspects of this study were conducted we usually rate it as uncertain, which downgrades the level of the evidence. But this doesn’t mean that necessarily the study was bad. It just meant that we don’t have information. Actually in another meta-analysis we conducted on ADHD, a network meta-analysis, we took almost 18 months to contact all the authors to clarify with drug companies. And after gathering this unpublished information, the quality of the evidence increased because we had more elements to state better. So I’m not saying that the evidence is necessarily good, but I’m saying that we need to consider that this is not the absolute truth.
I think that’s another element important that was highlighted there was around the fact that we have information in the short term, and of course, in the clinical practise, we don’t treat for 12 weeks; we treat for more. So we need more evidence on that. And there are some studies that allow us to understand the long-term effects. For instance, the so-called withdrawal trials, where people who have been treated, they continue the treatment or are randomised to placebo, so they discontinue them. We can see if there is maintenance of the effect. There are studies in ADHD without ASD showing that medication seems to maintain a certain effectiveness, but probably less than the one we have in the short term. So we need more study on this.
And once again, I think, finally, the key message, I think, the key aspect, is we really need to consider that not all medication are made equal, so some medication are better than others. One of the key messages from this review is that probably antipsychotics don’t have… should not have a major role in this. And this is concerning because the rate of antipsychotics are increasing, but probably even if it’s not large evidence, body of evidence, we do have more data on stimulants in terms of effectiveness [inaudible 00:59:52]. And second, of course, once again, as I mentioned at the beginning, it’s really important the target, what we want to improve, so that medication may improve some aspects, but not others. So they may be complementary to behavioural therapy, non-pharmacologic treatment, vice versa. Non- pharmacologic treatment may not necessarily tackle some aspects that are improved by medication.
Andre Tomlin – Thank you. Brilliant. Well, we’re running over time, so apologies for that. Thank you very much for joining us to our expert panel. We’ve got great feedback there. So thanks, everyone for that. Thank you to Stephanie, to Sam and to Tom, who’ve all shared their thoughts brilliantly. Thanks also to Douglas and to Celine for their fantastic involvement and for everyone who’s joined us today much appreciated. Do tweet about CAMHS Campfire and tell people all about it. We’re going to be running these sessions every month throughout the rest of the year and we’ll be announcing the topics that we’re going to be covering over the next few months in the next few days. So, yes, thanks very much for joining us, everyone, and we’ll see you next time around the campfire.