Professor Eesha Sharma Hello, everyone. My name   is Eesha Sharma. I’m a Psychiatrist and  I work with children and adolescents,   and in this presentation, I will be talking  about the basic principles of paediatric   psychopharmacology. I will begin with a brief  setting of the forum, move onto the kinetics,   dynamics and developmental aspects, give  a brief overview of the evidence base and   conclude with some thoughts on what the future  looks like for paediatric psychopharmacology. The beginnings of paediatric psychopharmacology  were quite interesting because they happened by   means of accidental discoveries of medication  being effective in calming down children who   were noisy, aggressive and domineering.  It then moved on to actually conducting   randomised controlled trials on children who  were in conflict with the law and perhaps,   also had high amounts of aggressive, noisy,  unmanageable behaviour. But from then on,   you know, the field did advance, but a  lot of these advances happened simply   as extrapolations of what psychopharmacological  practice in adults was evolving into. So, a lot   of molecules that were found useful for adults,  people started trying them out in children to see   if children with similar problems, as were being  diagnosed in adults, could benefit from them. What we also understood, you know, over the many  years of the evolution of child and adolescent   mental health, child and adolescent psychiatry,  is that for the large proportion, any aspect of   child mental health is largely determined by, and  is largely responsive to, psychosocial aspects.   So, if I could just bring your attention to  the orange text on the slide. “In this new   paradigm focus on the child’s psychosocial  environment is paramount and pharmacotherapy   becomes adjunctive to psychosocial interventions.”  So, in any child or adolescent presenting to us,   we first need to ensure that we understand what  the psychosocial origins of the presentation are,   whether we have covered enough in terms of  psychosocial interventions for those determinants,   and then, is it – you know, we choose that what  is going to be maximally benefitted, or what   pharmacological agent is going to maximally  help this child in this psychosocial context.  What we’ve also understood, and this is not just  true for child and adolescent psychiatry, but, you   know, true for all of mental health practice, is  that there is no longer an era of easy acceptance.   You know, you can’t just say that this molecule  works, and it seems to work in this condition,   so, you know, I could just use it. But there is  more and more scrutiny, which comes in not just   through regulatory authorities, but also through  the presence of empirical evidence. You know,   even patients will turn around and often ask  that “What evidence is there?” or, you know,   “What are my odds of benefitting from  this treatment?” Public attitudes towards   mental health, and when it comes to child and  adolescent mental health, public attitudes can   be very, very varied. Also, what the local  practitioner is comfortable with. You know,   “What has my experience been like in treating  children and adolescents in my practice?” So, child and adolescent psychopharmacology  practice exists in this very, very broad context,   where multiple considerations need  to be made before using any molecule   for any particular condition. However,  one major biologically informed shift   that has happened in child and  adolescent psychopharmacology is   that we’re no longer looking at the least  restrictive or the lowest effective dose,   but we’re actually increasingly talking  about the most effective treatment, you know. So, if a molecule is going to be used for a  child or adolescent with a psychiatric illness,   we want that enough receptor occupancy  exists, we want that as long as the drug   is safe and tolerable, we should use, you know,  higher amounts of the drug to make sure that   there is maximal benefit. So, it’s no longer  about using baby doses of a drug or using,   you know, low doses so that multiple  drugs can be used and benefitted from,   but it’s about using the most effective  treatments that exist, as for adults. I will now move onto talking a little bit about  the developmental, kinetic and dynamic aspects   of child and adolescent psychopharmacology. In  adults, very often, the goal of treatment is   to restore the premorbid self. But because of  the development happening over time and age in   children and adolescents, we can’t really be sure  about consistency of the premorbid self. Because   the premorbid itself, itself will change, you  know, from the time you start treating a child,   say at the age of seven, to, you know, when you  continue treating this child at the age of 12   or 13-years. So, because the premorbid self is a  moving target, one has to be very developmentally   informed in the symptoms that one picks up and the  symptom targets that one sets for pharmacology. So, it’s interesting that the mean age at  onset of different psychiatric disorders   across the developmental lifespan corresponds  with the developmental course of maturation in   different brain areas, right? Now, if you  look at when the striatum matures, right,   so that’s about the mid to late teens  is when that matures, and that’s when,   you know, a whole lot of anxiety and  neurodevelopmental presentations have,   you know, come up and gone down, but certain  other diagnoses have become more prevalent. So, when one is looking at a teenager  who presents to us and we see a certain   set of symptoms, we should be  able to differentiate, you know,   which of these are more likely to be impacted  by development. So, can I wait? Can I use only   psychosocial interventions? And which  of these are, you know, unlikely to   respond just to developmental change and they  absolutely must be treated through medication? People have also tried to identify, you know,  is there an intelligent way of, you know,   picking up which drug is going to work for whom?  Can I really identify my dynamic target? You know,   which receptor is going to work the best, or,  you know, which neurotransmitter is most likely   implicated? But so far, any amount of biological  testing doesn’t really seem to give us any clear   winners, no matter what kind of a, you know,  genetic or dynamic study that you try to do. The same also goes into the place for  pharmacogenomics, such that the recommendations   around pharmacogenomics are, basically,  to say that, you know, it may have a role   in treatment non-responders. It may have a  role where you’re worried about drug-drug   interactions. But for the large proportion of  practice with young people, we, essentially,   need to start low and go slow and monitor as  we increase the dose of a particular molecule. There are some pharmacokinetic aspects, however,  that one must keep in mind when using medication   in young people. Now we know that there are  different developmental age groups and based upon   what the age of your patient is, you know, you  may want to remember that how a particular drug is   going to be handled in this young person’s body.  So, pharmacokinetic aspects can be studied under   absorption parameters, distribution parameters,  metabolism parameters, and excretion parameters. Now, for the large part, there’s actually not  too much to worry about, because absorption,   distribution and excretion, all these three  processes, essentially, reach, you know,   close to adult functioning by the end of the  preschool period. So, basically, by the time   a child is five or six years old, and which is  probably the most common time when, you know,   you may want to start using medication. Children  younger than five/six years generally don’t get   a lot of pharmacological prescriptions.  So, by the time a child is five or six,   you know, majority of the kinetic  parameters have actually matured. But it is the metabolic aspects that could still,  you know, have a role to play. For example,   you know, the hepatic functioning, protein  binding, etc., may still be different in   young people as compared to adults. So, medication  like carbamazepine, valproic acid, or any medicine   that has, you know, hepatic involvement in the  metabolism or formation of active metabolites,   any of those drugs must be cautiously used in  young children because you can’t really be sure   about what the maturity level in this child’s  liver, or this adolescent’s liver, is. So,   that’s the one parameter that we need to keep  in mind when using molecules in young children. So, having briefly touched upon the developmental,  kinetic and dynamic aspects, I would now like to   briefly cover, you know, the evidence base that  we have for child and adolescent practice in   young people. I’ve put this slide up just to,  you know, kind of, make the point that we are   no longer simply extrapolating from adult  evidence base, but we’re actually resting   upon strong empirical evidence, you know, from  studies conducted on children as young as seven   to ten-year-olds, presenting with common, you  know, psychiatric manifestations at this age. So, for example, the Multimodal Treatment of ADHD  Study was – you know, it focused on children with   ADHD, and it was beautifully designed, because it  had not just behavioural treatment, but it also   had medication management. It had a combination  treatment arm, as well as routine community care.   So, it was a very stringently conducted  RCT, where, you know, it was multi-sites,   the parent, school, child components, all  three arms were involved, and there was,   you know, very intensive assessments done, both at  baseline, as well as in follow-up. Outcomes were   also studied across multiple different, you know,  aspects of the child’s behaviour and functioning. And what did we find? We found that in children,  you know, of this particular age group,   which is probably the commonest age group  where we end up using ADHD medication,   medications were efficacious. Were side  effects present? Yes, they were present,   but they were severe enough to discontinue  the medicine only in 4% of the children. And   they also found that there were strong moderators  and mediators of treatment, so again, emphasising   the role of the psychosocial aspect and a more  holistic coverage of treatment in young people. Then people have even moved, you know, to  younger ages, because everybody started   talking about that, you know, “What if the child  is not yet seven or ten, but what if the child   is four or five-years-old and their behaviour  or activity levels are problematic? You know,   can we use medication there? Does  it make any sense? Can we, you know,   use it safely? Will the child tolerate it, and  more than that, will there be benefit?” So,   the Preschool ADHD Treatment Study was designed  to answer just that. Again, it was an NIMH study,   multicentric, used, you know, different  forms of ADHD and, you know, it had – again,   had, you know, a complicated design, where  different treatment modalities were tested. And, you know, again, we found that even in  children as young as, you know, preschoolers,   methylphenidate could be used. The majority  of children did tolerate it. Of course,   side effects were more. You know, almost 30%  had moderate to severe side effects, so much,   much more, almost seven times more than what we  saw in older children. But what was interesting   was that in follow-up, and follow-up has  also been done for multiple years now,   80% children retained the diagnosis. So, what  that means is that if ADHD features seem to   be present in young children, it’s probably  true that ADHD is there. And you can treat it,   and if you do decide to treat it, you are  more likely to be correct than wrong that,   you know, you are – the child would  have benefitted with medication. So, we have enough evidence to say that  ADHD benefits with treatment. That there   are efficacious molecules that can be reliably  used, and side effects can be identified,   you know, in young children, as well  as in older children, which, you know,   could bring into the talk about whether you want  to continue medication of not. So, as of today,   the most efficacious molecules that we have  for the treatment of ADHD are usually one of   three types. So, one is the stimulant group,  represented by methylphenidate here, then the   atomoxetine group, which is the non-stimulant  treatment for ADHD, and the clonidine group. All of these, you know, in one or the other  way, act on related neurotransmitter systems.   Methylphenidate, of course, has its  major impact on the dopaminergic system,   whereas both atomoxetine and clonidine work more  on the adrenergic systems. There are, you know,   dose ranges that are prescribed, but these dose  ranges are guidelines. In an individual person,   the dose that you use, the dose that they  tolerate is more clinically determined than,   you know, based on any particular guideline.  You know, they are divided across the day,   based on what the half-life is and how the  drug is metabolised and handled in the body. It’s interesting that even though, you know,  this is the stimulant group and atomoxetine   is the non-stimulant group, you may get very  similar side effects with both these medications,   because essentially, you know, the common thing  across both of them is that they increase or   stimulate the frontal lobe’s ability, the  prefrontal cortex’s ability, to regulate the   subcortical areas. So, that stimulation aspect  is common to both these medication groups,   and which is why you could have, you  know, side effects that look very similar. But methylphenidate and clonidine are, you know,  are also similar in one of the side effects and   which is the rebound withdrawal effects, because  both of these drugs have very short half-lives.   So, if, you know, a child takes it in the morning  and takes it in the afternoon and, you know,   there is not enough coverage or enough serum  level in the – in-between, then there can be quite   severe rebound effects. So – which means that both  of these drugs require a more even presence in the   body throughout the waking hours, right, and  that goes into the dose considerations and the   dosing regimen that you use with any child  or adolescent. And with methylphenidate,   now we know that sustained release preparations  have become quite common for this very reason. Atomoxetine does come with some black box warnings  for hepatitis, aggression and suicidality,   that the practitioner must remember. Is there any  way to choose across these molecules? You know,   can I say that in this patient, I am going to  choose atomoxetine and not methylphenidate for X,   Y or Z reason? Well, overall, there may not  really be, you know, that kind of a choice,   because if one asks which is the most efficacious  molecule, it probably is the stimulant group   of medicines for ADHD. So, methylphenidate  is undoubtedly, and, you know, and similar   molecules like methylphenidate, are undoubtedly  the most effective treatment options for ADHD. However, if, you know, an adolescent comes to  you, where there is a mix of depressive/anxiety   symptoms, along with ADHD, one may want to  use those properties of atomoxetine first,   before moving to MPH. Similarly, if a young  child comes to you with tics combined with ADHD,   clonidine may have a better efficacy. So,  there may be some clinical presentations   where we may want to choose one over  the other, but in terms of the overall   efficacy on ADHD symptom reduction, MPH  or methylphenidate is the clear winner. The other bigger considerations in choice  of treatment involve follow-up feasibility,   your ability to monitor side effects.  Comorbidity patterns, you know, for example,   if somebody has a seizure disorder or they  have bipolar disorder, then methylphenidate   and atomoxetine may be difficult choices to  make. Abuse potential, as well as whether you   can actually maintain objective feedback from the  Teachers, from the parents, using rating scales   which actually help you titrate and decide the  efficacy or non-efficacy of a particular drug. A common worry that has, you know, come  up, especially in the recent years,   is – has been about stimulant-induced growth  suppression. Because longitudinal studies   showed that there were significant reductions  in weight and height within 11 months of the   treatment starting, and what did they measure  in these studies? They measured growth velocity,   because it is obviously quite hard to  predict what a person’s ultimate height   is going to be like. So, what Researchers  have done is that they have studied growth   velocity to see whether there was a  significant change between the time   that a child was not on the medication, to  the time when they started the medication. Since this is a real concern and parents are  probably going to ask the practitioner about this,   it is important to be aware and to know  what we are going to do if we do notice,   you know, any changes in the growth velocity.  So, beginning with monitoring their appetite,   weight, height and body mass index, to  differentiating between pre-treatment eating   problems and medication-induced eating  problems. Using medication after meals,   rather than before, the benefit with high  calorific snacks, late evening meals,   dose reduction, or switching to an alternative  class or formulation. Drug holidays for catch-up   growth, weekends or some vacations, winter  vacations, can be usefully used as drug   off periods. And this becomes more easy  to do with a drug like methylphenidate,   which has a quick onset of action and a quick  offset of action, than say with clonidine   and atomoxetine. But if we do notice that, you  know, the values are below critical thresholds,   a referral to the Paediatric Endocrinologist  or a growth specialist must be made. A little bit about selective serotonin reuptake  inhibitors in children. They are the most   extensively used antidepressants in children. The  reason being that a) there is maximum empirical   support. So, a large number of studies that have  been conducted have used one or the other SSRI.   But the other more important reason is that the  developing brain in children and adolescents   has a serotonergic system that matures much  earlier than the noradrenergic system. So,   TCAs it’s not that they have not been tested.  They have been tested in children and adolescents,   but repeated studies have found that they  actually don’t seem to make much of a difference.   And probably, that is because of, you know, the  immature noradrenergic system in young children. There is FDA approval for certain medication  in particular conditions. However, overall,   you know, any and all SSRIs have been used  in children. Like I was mentioning earlier,   the starting doses are probably much  lower than we would say, use for adults,   and the reason being, again, because all of  these molecules are handled by the liver,   some of them have active metabolites and in young  children, you know, we can’t really be sure about   which child is going to respond poorly to the  choi – to a particular drug, or what side effects   they may have. So, it is always the safe thing  to do to start at much lower than adult doses,   do weekly increments, to actually finally reach  the same dose range as you do in adults. So,   it’s the start low, go slow, reach the same target  approach that, you know, we use for children. Paroxetine is not widely recommended in  children and adolescents because paroxetine   has a very short half-life compared to all  the other SSRIs and this short half-life   makes children vulnerable to all kinds of side  effects that SSRIs could possibly pose. So,   most guidelines recommend that you  must avoid paroxetine in young people. How long are you going to treat is really  a matter of clinical judgment. You know,   we know that relapse rates are high  upon medication discontinuation. Plus,   certain disorders, like OCD, may actually  persist into adulthood. So, it’s really   a clinical call that the Clinician makes in  conversation with the child and the family. Adverse effects are largely similar to what we  see in adults, except for behavioural activation,   which may be much more prevalent in young  children, and this is more likely to happen if   early on in the treatment, any time that there is  a dose increase, or if we’re giving two molecules,   you know, which interact and, you know,  together increase the serotonergic flow in   the body. And this will present as restlessness,  insomnia, impulsivity and disinhibited behaviour. We’re also worried about hypomania or mania  being triggered in young people, and again,   young people may be more prone to this side  effect for two reasons. One is that, you know,   the behavioural activation can sometimes  actually look like hypomania or mania. So,   the first thing is we should appreciate that. And  the second is that childhood-onset depression is   associated with future bipolarity at a much  higher odds than adult-onset depression. There has been a lot of talk around suicidality  being triggered with the use of SSRIs in young   people, and, you know, a lot of systematically  conducted reviews now tell us that it’s not that   you can leave depression or anxiety untreated in  young people, because the risk of harm and the   risk of suicide from untreated mental illness  is still higher, as compared to the possible   emergence of suicidal ideas when you use these  molecules. So, the, you know, the better thing to   do would actually be that if we pick up depression  or anxiety, we must treat it, but again,   do it with a lot of monitoring, with a lot of  supervision and make sure that the young person   is under close observation, at least during the  initial several months of starting the molecule. What about other antidepressants?  Is – do they have a role? Well,   tricyclic antidepressants don’t, for the  much part, have a role to play in depression   or anxiety. However, they have sometimes  been used in other conditions, but again,   with a lot of side effects that may cause a lot  of worry, you know, much more than any possible   benefit from their use. However, medication  like bupropion and venlafaxine have been,   you know, usefully employed, especially when  we treat adolescents. So, with adolescents,   where SSRIs don’t work, one may look at  the choice of bupropion or venlafaxine. Other drugs, like trazadone and mirtazapine,  don’t really have a lot of randomised controlled   trial-based evidence. So, you know, that they  can be off-label use of these medication,   but again, young people are much more susceptible  to the side effects with any of these molecules,   especially the metabolic side effects  that can be seen with mirtazapine. Antipsychotics, again, the entire spectrum of  antipsychotics has been tried for young people   in a variety of conditions, ranging from psychosis  to augmentation for, you know, other disorders,   to fix, to adjust the management of aggressive  behaviour. Of course, the most widely used   antipsychotics are risperidone, olanzapine and  all the second-generation molecules. Sometimes,   when they don’t work, people have also  usefully employed first-generation molecules,   like haloperidol and chlorpromazine. But we know  that the metabolic side effects that we’re all   worried about with the use of antipsychotics can  be much more prevalent in young people, so that is   something the Clinician has to keep in mind when  using these molecules in them. The other thing is,   again, you know, that the starting doses of any  and all of these molecules are much lower in young   people as compared to what we would do in adults,  for similar reasons as I discussed earlier. We are worried about the weight gain  and metabolic disturbances, but some   young people, it may also come with cognitive  blunting. They may report dysphoria. You know,   some people have come and said that, you know,  “Now I no longer feel anything. I feel that,   you know, everything is just blank, I don’t  have emotions. I don’t know how to interact   with my friends. I feel anhedonic all the  time.” So, these things can be much more   apparent in young people because young  people’s brains may be more sensitive to   these kind of effects of these medication. So,  it’s something that the Clinician must elicit   and then maybe work around the doses to see if,  you know, those side effects can be cut down. Anticholinergic agents, you know, that  we very often use in adults when we’re   prescribing antipsychotics, can be used in  young children, but to the extent possible,   the dose must be kept low and, you know,  if possible, they should be used in a time   limited manner, because long-term use has been  associated with conditions like Sjögren syndrome. When we treat paediatric bipolar disorder, it  is important to note that just like adults,   lithium is the clear winner. And when  we’re treating an acute manic episode,   for example, you know, serum ranges of as high  as 1.4mEq/L can be used. Other than lithium,   you know, we rely, again, on antipsychotics and   sometimes we rely on combination of olanzapine  and fluoxetine for depressive episodes. They have largely been tested in,  you know, early teens or late teens,   not so much in children younger than  that. So, children younger than ten years,   we’re still using them off-label. There’s not a  lot of empirical evidence to support their use.   But clinical evidence does suggest that they, you  know, can be employed and, you know, one must,   again, watch for side effects, do a very, very  slow up-titration and so on. Starting dose range,   again, to be paid attention to, much, much  lower than what one will use for adults. For conditions like autism spectrum disorder,  you know, do we have pharmacological options?   The main thing to do is to allow children and  adolescents to maximise their benefits from   behavioural and psychoeducational interventions.  What does that mean? That means that, for example,   if a child with autism has a lot of hyperactivity,  and because of the hyperactivity, is unable to   meaningfully engage in speech interventions or  any other naturalistic behavioural interventions,   then it might make sense to use a molecule with  the capacity to bring down this hyperactivity.   So that the sitting tolerance becomes better, the  child stays with the Therapist for a longer time   and participates in an activity more gainfully.  So, the medication use here is, first of all,   it is always adjunctive, because we know  that there are no medicines that are   clinically prescribed, as of today, which will  actually change the core features of autism. So,   medication use is not for the core features,  but medication use is more to increase the young   person’s benefit from the other psychological  behavioural interventions being done. There is a lot of inter-individual  variability in how a person with autism   may tolerate the medicine. So it’s important to  be watchful of the side effects and, you know,   other problems much more than in other children  and adolescents. So, other than hyperactivity,   one could use medication for temper tantrums,  aggressive behaviours, repetitive behaviours   and sleep problems. So, controlling these  target symptoms, with useful addition of   pharmacological agents, may benefit the child  in terms of their developmental improvement. What about the use of molecules for aggression?  Aggression is a very common clinical concern,   we all know that, and almost any and every  medication available to a Psychiatrist has   undergone an RCT for aggression, right? From  stimulants to antidepressants, to even medications   like clonidine and propranolol. And the effect  sizes are quite variable. Almost everything seems   to work, but everything seems to work at just  about moderate dose ranges. But the important   thing to understand is which molecule you’re  going to use really depends upon what your ABC   analysis shows, because it is the antecedent that  the pharmacotherapy should be targeted towards. If the antecedent is a negative mood state,  you want to use an SSRI. If the antecedent is   distractibility and hyperactivity, you want to  use stimulants. If the antecedent is, you know,   pre-mediated aggressive behaviour, where there is  a lot of wilful, you know, violation of other’s   rights, basically, you know, the disruptive  spectrum, then you may actually want to use   an antipsychotic agent. Whereas if there is mood  dysregulation, you know, which is the antecedent,   then, you know, mood stabilisers or other  medications that help with bipolar disorders,   or other mood disorders, can be useful. So,  using medication in aggression is really about   understanding what is bringing this aggressive  behaviour to the fore in this particular child. Finally, I’m going to leave you with a few  thoughts for what the future’s going to look like.   A lot of parents and caregivers will come and ask,  “Is this drug really going to benefit my child?”   And, you know, “How long are you going  to keep my child on this drug? Will   there not be any long-term side effects of  using?” Until, you know, quite recently,   we didn’t really have a lot of answers to any  of these questions. What we could say was that,   you know, if the child has  a more regulated behaviour,   they are more likely to benefit in their  overall development by interacting with   the environment than if this dysregulated  behaviour persists. But then, one didn’t   really know what would happen ten years down the  line, or five years down the line, and so on. More importantly, is there a critical window  period for beneficial effects? What actually   mediates the brain changes and clinical  benefits? How do trajectories differ in   children on long-term treatments? We, you know,  didn’t really have a lot of clear answers. Then   came this very interesting concept of  neuronal or neurochemical imprinting,   wherein the long-term effects of drug exposure  are delayed and come to expression once   the vulnerable system reaches maturation, you  know. So, the very, very valid questions that   parents will bring to you, that – you know, “How  do you know it’s going to be okay ten years down   the line?” right. So, we didn’t really  know how to respond to that question now.  So, there have been initiatives like the Effects  of Psychotropic Drugs on the Developing Brain   Study, or the ePOD Study. This particular study,  for instance, is looking at the short-term age   dependency and the long-term effects of  methylphenidate in young boys and men who   are on treatment with methylphenidate, with  stimulants. And they’re using a variety of   outcome measures to actually understand and, you  know, gain insights into various odd questions. They have already started finding some  interesting things, for example, the right   medial cortex shows a time-by-medication-by-age  interaction. Those on methylphenidate treatment   had less cortical thinning in the child group,  but not in the adult or the placebo group. So,   this is probably more to do with the  short-term age dependency effects. After four months of methylphenidate, they  were able to demonstrate that there are   significant increases in cerebral blood  flow. There are increases in dopaminergic   neurotransmission. Alterations in the brain,  however, so the local brain changes, however,   didn’t seem to primarily mediate either the  clinical benefits or any side effects that   they observed. Long-term consequences,  of course, remained to be established. So, you know, there are some interesting insights  we are getting about what these molecules actually   go and do in the brain, but it will still probably  take some time for us to really know, you know,   whether the brain changes in any substantial way  by the use of these molecules. They could also   have effects on sleep efficiency, sleep onset  latency, total sleep time and how much of this   is rebound effect, how much of this is long-term  effect. All of this still needs to be established. So, 20 years of progress in  paediatric psychopharmacology,   what have we accomplished? We know that, you  know, there is comparative effectiveness,   not just that drugs are more helpful  than placebo, but even within drugs,   there are certain groups that are more  effective than other groups. For example,   SSRIs are more effective than TCAs, lithium  more effective than antipsychotics, and so on. We also have enough data now on safety  assessments. So, we know that cardiac   events with stimulants, risk of abuse  with stimulants, cardiometabolic side   effects with antipsychotics and suicidality  with antidepressants are areas of concern   and something that the Clinician needs to keep in  mind when practising pharmacology in young people. However, there still remain a lot of unmet  needs. Real world outcomes, you know, are,   of course, very different from what we see  in clinical trials. So, we don’t always see,   you know, an equivocal translation of what we  find in RCTs’ individual clinical practice. Also,   there have not been a lot of empirical  evidence where you compare a drug with   a psychosocial intervention. So, that’s  something that still needs to be established. How much of the use of these molecule really  modifies the disease, versus just control   symptoms, you know, that’s, of course, the  big debate in all of psychiatry and one that   persists for children and adolescents, too. Are  we just targeting dimensions of psychopathology,   or are we altering disease? You know, again  something that needs more insight. And we   haven’t really come around to doing neuroscience  informed psychopharmacology. To some extent,   we are, but to a large extent, we still don’t  know the absolute, clear neurobiological   basis for every psychiatric disorder for our  pharmacological practice to be informed thereof. So, I would like to conclude by saying that there  is a primacy of, and a greater advocacy for,   non-pharmacological methods. Combination treatment  is the gold standard. It is important to set clear   therapeutic targets, because everything that you  do with children and adolescents is adjunctive to   psychosocial interventions. We must always begin  at a low dose, go slow, monitor efficacy and   adverse reactions. Multiple medication may often  be required, especially if a child is severely   ill, because we don’t know which neurotransmitter  system is maturing in which way and contributing   how much, so one must not be too hesitant to, you  know, really use combination treatments, even in   young people, as long as you’re certain about the  symptom target and the molecule rationing thereof. We must allow time for an adequate trial of  treatment. Young people’s brains can vary quite   a lot in, you know, how they respond and the time  to response. So, one must allow enough trial or   time for to – you know, to actually decide whether  the treatment is working or not. Where possible,   we make one drug change at a time, a good practice  across age, I would say. And with children,   especially, it is important to monitor outcome  in more than one setting, right? In fact,   some of the child psychiatric diagnoses even ask  for that. You know, does – do these symptoms cause   impairment in more than one setting? And if  they are impairing in more than one setting,   then the treatments must also create  differences in more than one setting. With that, I would like to  conclude this presentation.   Thank you very much for listening to it.