Professor Samuele Cortese Hello, my name is  Samuele Cortese. I am an NIHR Research Professor   and currently Professor of Child Adolescent  Psychiatry at the University of Southampton in the   UK and, also, a Professor of Child Neuropsychiatry  at the University of Bari in Italy and at the   University of New York in the United States. So,  in this presentation, I’m going to focus on some   key practical aspects on the “Pharmacological  Management of ADHD.” Right, so, before   starting my presentation, these are my possible  conflict of interest that I need to disclose. Right, so, what I will do is to present key  steps in the pharmacological treatment of ADHD,   and to discuss to what extent evidence can inform  these steps. So, the first step, of course,   after everybody agrees to start a medication, is  to choose – to select the right medication. And,   in this regard, I think we are aware that,  of course, the guidelines, such as the NICE   guidelines, recommend a specific hierarchy in the  selection of the medication. So, for instance,   the NICE guideline recommend methylphenidate as  the first choice, followed by lisdexamfetamine,   or amphetamines, and if these are not  efficacious or not well tolerated,   then non-stimulants, such as  atomoxetine or guanfacine. However, these recommendations are based on  average, so this is what on average we would   expect in times of response, but specific patients  respond specifically only to specific types of   medications. So, for instance, as represented in  this slide, if we consider 100 children with ADHD,   roughly 40% of them will respond equally well  to amphetamines or methylphenidate. However,   around 28% will respond better to amphetamines.  Around 16% will respond better to methylphenidate.   Around 12/13% will not respond to stimulants  and among these, in particular, among those   who do not respond to methylphenidate,  around 50% will respond to atomoxetine. Now, the issue, currently, is that unfortunately  we do not have any predictors that will allow us   to understand, based on specific  characteristics of the patient,   which is the best medication. So, after  decades we use these medication, we are   still implementing a trial and error process  in the selection of the medication. And so,   unfortunately, the progress of genetics and  pharmacogenomics are not there yet to support   the choice of the medication. So, unfortunately,  advert like these, that you can find commonly   on the internet, are not supported by  strong clinical and scientific evidence. So, the choice of the medication is still very  much based on the trial and error process. After   we find the right medication, an important  consideration is around the dose of the   medication, which, in my view, is really crucial  to make sure that we can treat in an effective   way our patients. So, what have we learnt in  terms of those? Well, basically, as shown in   this dose response meta-analysis, the message is  very simple, the higher you go in terms of dose,   the more likely it is that you get response.  However, once again, this is true at the group   level, but, at the individual level, we note  that some patients will respond to low dosages,   while for others, you will need to go higher, and  this is not necessarily related to age or weight. So, based on this evidence, what is from the  practical point of view, the recommendation? Well,   the recommendation is really to make sure that you  try all the possible range of doses in a specific   patient, and then you decide, with the patients  and their families, which is the best dose. This slide reports the recommendation from  Professor David Coghill and his group,   in terms of a weekly dose titration, which mirrors  what is usually done in randomised trials. So,   in his clinic actually, he uses a  four-week titration dose increments,   and at the end of this period then the prescriber  will discuss, with the patients and their family,   which among the four doses was  the best in terms of efficacy,   effectiveness and tolerability.  But it is important to try, also,   higher doses because if you stop at low or  moderate doses, you may miss the benefit of   the higher doses. Of course, you go as high as  you can, pending tolerability, which is crucial. Right, so, we have discussed so far the issue  of the choice of medication, the importance of   the dosing. I would like now to focus on an  important aspect in the clinical practice,   which is around the management of individuals  who have ADHD, but also comorbid conditions   or disorders. In particular, I will focus  on two of them, so individuals who have   ADHD and autism spectrum disorder, or autism, and  individuals with ADHD and emotional dysregulation. So, what are the recommendations in terms  of the pharmacological treatment of ADHD   symptoms in those individuals who also have  autism? There’s been an important systematic   review and meta-analysis on this topic, which was  published in JCPP a few years ago, and the authors   concluded that based on the systematic review, the  first-line of treatment for ADHD in children with   ADHD and autism should still be methylphenidate,  either immediate or extended-release. If this   is not effective, or not well tolerated, then  the second-line is represented by atomoxetine   or alpha-2 agonists, so, guanfacine or  clonidine, and eventually amphetamines. We need to bear in mind that, in general,  the efficacy and the effectiveness of   these medications in these individuals is  lower, in general, but this doesn’t mean   that it’s not worth trying them. And, also,  importantly, the tolerability is less good,   which means that it is advisable to titrate  with caution the dose, so to go slow. Right, in terms of recommendation on the emotional  dysregulation management in those with ADHD,   I always like to cite this study, which to me is  very important. So, this was a trial conducted in   the United States, and the purpose of the trial  was to compare risperidone or divalproex sodium,   as adjunctive treatment to stimulants in  those children who had ADHD and emotional   dysregulations already treated with  stimulants. Now, before, however,   randomising these children to these arms of the  study, the authors implemented a optimisation of   the dose, as we just discussed, it’s  very important to optimise the dose. In doing so, they saw that, actually,  if you optimise correctly the dose,   so you achieve the best – the highest  possible dose in these children,   around 60% of them responded well in terms of  methylphenidate, not only for ADHD symptoms, but,   also, in terms of emotional dysregulation, which  means that in 60% of the cases, if you optimise   the treatment with methylphenidate, you will be  able to manage ADHD and emotional dysregulations. However, in the 40% this is not  enough, so, in that case, actually, the   addition of risperidone or divalproex were  effective, and there was no difference between   the two medications. So, I think a  very important message is to think   of optimising the dose before adding other  pharmacological treatments. Needless to say,   pharmacological treatment itself is oftentime  not enough to address the emotion dysregulation. So, the last aspect I wanted to mention in this  short presentation on key practical aspects of   the management, pharmacological management, of  ADHD, is around the management of side effects   because this is, of course, very important.  I will say that, on the one side, if we   overlook the importance of side effects, we may  expose, you know, the patient to a certain risk.   But if we are too concerned around  side effects, we may prevent many   patients from receiving a pharmacological  treatment which they may benefit from. So, it’s a very important topic and quite broad.  There are many possible side effect that will   deserve consideration, but in the interest  of time, I will focus on a few of them. And   if you are interested in knowing more about  this, I will invite you to read this paper   that we published quite a long time ago,  in JCPP, but I think it’s still valid in   terms of general recommendation. So, the way  this paper is structured is the following   we provided the evidence from empirical literature  on side effects, and then we provided our   recommendations on the management of side effect,  as members of the European ADHD Guidelines Group. So, let me give you an example, for instance, the  management of high blood pressure that may occur   before starting treatment or during the treatment,  so detected during the follow-up. As you can see   in this diagram, the recommendations from the  group, and this was a multidisciplinary group,   including also a Cardiologist, was, first of all,  to measure blood pressure at least three times,   and to average the values, because one  value in itself may not be informative.   And if the values – the average values  of blood pressure, diastolic or systolic,   are below the 95th percentile, it is okay  to continue or to start the treatment. However, if the values are above the  95th percentile, systolic or diastolic,   then the recommendation is either to decrease  the dose and to measure again, or to refer to   a specialist. The specialist will very likely  conduct a series of assessment to determine,   to establish, if there is a pathological  hypertension and, if this is the case, they will   treat the hypertension pharmacologically. Once  the blood pressure goes back to normal, below the   95th percentile, then it is recommended to start,  or to start again, the treatment with stimulants. As I said, in that paper, there are  many side effects that are discussed,   and I have summarised in this table for  you, in the last slide of my presentation,   I will quickly just mention a few of them. So,  for instance, what is the approach to manage   the occurrence of tics during treatment?  So, we need to bear in mind that tics my   co-occur with ADHD and may be independent, so  the fact that we see an increase in tics does   not necessarily mean that this is due – this is  caused by medication. Tics are waxing and waning,   so the recommendation is, rather than stopping  the treatment for ADHD, if it is working well,   is just to monitor the evolution of tics over  a period of three months. And if, however,   it is clear that the tics are induced by  medication, then options are to reduce the   dose or consider a change to alternative  types of medications, such as guanfacine. Seizure, if seizure are new or worsening, review  ADHD medication and stop any medication that may   contribute to seizure and reintroduce ADHD  medication if it is unlikely that this is the   cause of seizure. Psychotic symptoms, there has  been a lot of concern, but there is no evidence   that stimulants cause psychotic symptom. And  actually, if there is an occurrence of psychotic   event during treatment with stimulants, the  recommendation is to stop the stimulant and in 95%   of the cases, psychotic symptom will decrease,  even without the use of an antipsychotic. As I said, there is much more in that  article, but, in the interests of time,   I will stop here, and I hope you enjoyed  this presentation on the “Practical   Aspects of the Pharmacological  Management of ADHD.” Thank you.