Professor Rasim Somer Diler Thank you. It’s a  pleasure being here and thank you for inviting me,   Dr Milavić, and I am glad that I’m speaking  after Boris, who set the ground for me to   focus on differentiation between unipolar  and bipolar depression. It’s a pleasure   to be with you all again. So, let me go  ahead and start with my presentation. So, my disclosure is funding from  NIH and learning objectives today is   identifying key features of depression, mixed  features, which is a new diagnostic feature,   and how to differentiate from other  conditions, mainly unipolar depression. So, why it’s important to diagnose bipolar  disorder, because if you give a diagnosis of   bipolar to someone who doesn’t have it, like  falsely diagnose bipolar, it’s costly. You   give medications, as Dr Birmahers was talking,  like, valproic acid or other mood stabilisers,   they will add to burden, side effects, and  they won’t get better. The contrast is also   as important, if not more, that you miss  the diagnosis of bipolar, you add stimulant,   irritability, you add antidepressant,  you induce mixed features and suicide,   and on average, it takes about ten years  from the onset of mania to correct diagnosis. Why do we then have this big gap  of ten years? It’s difficult,   we acknowledge, it’s time consuming. You need to  really sit in with the parent, with the child,   to get the timeline to identify the episodes  first and then look into those mania-like symptoms   within those episodes. And moody ADHD, DMBD,  which I’m going to talk with just one slide,   non-bipolar depression, high functioning autism  and differentiating subtle from developing child,   it’s a false statement. It happens  in Pittsburgh, everywhere, that “Oh,   he looks normal, so he may not have  bipolar.” Or he or she, or they,   may just say, “I look like exactly how I saw  on TikTok video.” It’s not the case either. They come in all shapes and  sizes, mainly with depression,   and why – and the background I have to  tell you about this differentiation is   that in addition to studies that Dr Milavić  nicely mentioned about, like the COBY, BIOS,   LAMS, I’m also running longitudinal assessment  of depressed mood in youth, like adolescents,   and we are trying to identify mixed manic  symptoms in them. They – none of them has bipolar,   and we monitor them over time. Plus, my clinical  daily workload is this, actually, that we have,   like, inpatient bipolar programme that’s still  na – the first in the nation and in the world,   that every day, we get a group of patients  admitted and it’s our job to figure out,   do they have bipolar? What type? If not, what are  their individual risks? Comorbidities are very   common. It’s actually – you will see ADHD when  they are younger. It will get less over time.   Substance use will, unfortunately, increase  over time that we need to keep an eye on it. So, no patient is the same, we know that, even  for similar symptoms. When they are not sleeping,   they tell you they are not sleeping. Until you  get more information and possibly collateral   information from parents, you don’t know if  they were in a manic state, not sleeping,   juggling things around, or depressed, trying  to count down the hours to find the morning,   or just intentionally, texting their friends. And  no single treatment option fits them all [pause]. Okay, and we know several symptoms are not mood  specific, including irritability, for example,   that it may come in other conditions, from ADHD,  oppositional defiant, PTSD, anxiety disorders,   autism and depression, that we are going  to be focusing on [pause]. Wait [pause]. Okay. So, when making the mood  diagnosis, we need to [pause]… Dr Gordana Milavić Rasim, just continue. Professor Rasim Somer Diler Okay. Dr Gordana Milavić And… Professor Rasim Somer Diler So, to make… Dr Gordana Milavić …to make  this all a different time. Professor Rasim Somer Diler …the mood diagnosis,  we need to identify the episode and then look into   those symptoms between that episode and  look at the duration and impairment. So,   here is, for example, a timeline in which  you can actually see and sit in with the   child and the parent to identify, like,  the huge chunk of symptoms happening,   up or down, and then go back in those  mood changes to find those symptoms. And the symptoms must be happening  together, present, sufficient time,   and happens in episodes. Even in patients  who have pre-existing ADHD, autism,   oppositional defiance, they have to be different  than pre-existing other conditions. What if,   for example, you have an ADHD patient who  has, already, inattentiveness, and they   come in with possible mania-like episode? Then,  you look into that inattentiveness/concentration   problem. Unless it gets considerably intensified  during the mood upswing or during the depression,   you don’t count that symptom. Then, it’s  a pre-existing conditions presentation. So, you may look into frequency in testing,  number of symptoms, duration of each episode   and focus on longitudinal course of the  mood and obtain collateral information.   Don’t expect that they will just tell you when  you ask, immediately. They may have different   reasons for not being too transparent with you.  And if you’re in doubt, provide psychoeducation.   Let them know what you are trying to monitor  and keep monitoring. We have mood monitoring   tools. The best tool is whichever the patient  and the family are comfortable in completing. So, if you talk about the mood episodes, manic  episode is, like, seven days long, or they get   admitted during that mood upswing and they have  to have functional impairments. So, the energy   drives them, to a degree. They get in trouble.  Functional impairment or psychosis symptoms   is a must to make the mania diagnosis, and one  manic episode in DSM will be equal to bipolar   diagnosis. They may or may not have previous  depression, but as for bipolar II, they have to   have at least one major depressive episode, based  on DSM. But for ICD, for hypomanic episode, it is   described as ‘several days’. In DSM it’s ‘four  days’ straight, it’s, like, clear-cut. And for   the same diagnostic classification systems, they  have to have a ‘distinct change’ from baseline. So, that brings up to the same question, what  were their baselines? So, you need to know the   child’s functioning first, before you assign that  symptom possibly towards hypomania or not. So,   baseline changes in a patient who are – who is  persistently depressed is even more difficult,   now that our talk is about depression, and I  see lots of teenagers who come in with one year,   two years, three years, longer,  persistent depressive episode,   and then they say they had mood upswings.  We have to make sure it’s beyond relief   from depression. In other words, it’s not  just depression is from – moving from more   severe to less severe or more severe to no  depression. You really need to have, like,   comparisons with the childs himself,  herself, or with the other peers, too. Like, for example, a teenager who was telling  me that she was kissing everyone at the mall,   whoever comes to her way, because she felt so  beautiful, and she thought everyone was in love   with her. I had to ask if other kids in her group  was doing same, or how they were treating her,   to make sure it wasn’t like one of those  TikTok games. And you also want to make sure,   like in a case that I had with hypomanic episode,  who was in depressed mood state when she came in,   saying that she was climbing up a tree when she  was in, like, mood upswing. So, what’s wrong in   climbing up a tree? It’s just normal, right?  For most people, but for that girl, who has   never came close to a tree, afraid of the heights  and would never, ever do it unless she was having   other symptoms, clustering, feeling on the top of  the world, really talking faster, racing talks,   and wants to do things, buy things. And  then, she climbs up a tree and she feels   she’s invincible and she rules the world. So,  it’s not just one symptom, how they cluster. And how about shorter episodes that look  like mania? So, pearls to help the diagnosis,   more mania specific symptoms, like elation,  it’s more specific to mania. Grandiosity,   again, you need to look at what the  baseline is. It’s not like in ADHD,   for example, patient bragging about what they  can accomplish. Decreased need for sleep,   it’s not sleeping less, it’s sleeping to a  degree that it’s different than the previous   sleep pattern without the mood upswing. Like  sleeping maybe two hours less, or four hours less,   or no sleep, but don’t feel the need for sleep  the next day. Flight of ideas, racing thoughts,   but it’s not, like, in a PTSD that you circles  around the traumatic event, or in a generalised   anxiety that’s circling around what’s going  to happen tomorrow. And hypersexuality not   due to sexual abuse, again, symptom must add to  cluster and be abnormal for developmental phase. So, in DSM-5, increased energy and activity  now is a must. Why did they do it? In the past,   it was just elated mood plus three more symptoms,  irritable mood plus four more symptoms. Now,   we have increased energy as a part of this  diagnostic criteria. They wanted to make sure   the objectivity is stronger, reliability will be  better. This is in addition to elated irritable   mood during an hypomanic episode. So, to give you  a better visualisation of how symptoms cluster,   you look at elated mood and irri – or  irritability, either/or, and then one   of the manic symptoms have to be increased goal  directed activity or motor hyperactivity. That   all are clustering with at least three or more  of the below symptoms, as I described before. Other manic symptoms. We talk about, already,  sleep is very important, more talkative, pressure   to keep talking. That’s different than flight of  ideas. The first one is how the speech come out of   their mouth. The second one is how the thoughts  are being processed [inaudible – 1157] wise   or connectivity wise with one of them.  Distractibility, in contrast to depression,   which we are going to be talking about, where they  don’t have energy to even put their concentration   in whatever is going on. In here, they just  move from one topic to the next, to the next,   and they just can’t stick, like a Teflon, that  they can actually get their concentration on. And increased goal-directed activities,  psychomotor retardation, risky/dangerous   behaviours, which again, could be for someone,  like, in a hypomanic state, cleaning the room,   which they have never done before, or starting  cleaning the kitchen and the whole room,   and parents usually don’t stop them. Whereas,  like, in a manic state, they may just get out   of the house and then, go to a crack house  to do something that’s – that they didn’t do   before. Sometimes in a younger kid, if they  watch cartoons, sometimes my Clinician ask,   “Are you, like, Disney-like happy or  SpongeBob happy?” You need to get their   own description of what they mean by hypomania  or mania, to keep track of what’s going on. So, other changes in DSM is that there is no  ‘mixed episode’ anymore. So, before, in DSM-IV,   there were, like, in mixed episode, a week-long  timeframe when the patient was meeting the full   criteria for major depressive episode and manic  episode. They thought it’s not happening as much   as they thought they would, so they created a new  feature, though, new mixed feature for those who   are in a manic episode, meaning some people are  flat, like continuously manic, but some people   are manic, but still, like, cheerful, suicidal and  low self-esteem, despite having all other manic   symptoms. And mixed features for major depressive  episode, some people are flat depressed, I’m going   to show quicker slide, but some having three or  more of manic symptoms while they are depressed.   And there’s also new medication induced bipolar  and related to disorder within bipolar section. When it comes to other specified bipolar, it’s,  kind of, vague in DSM-IV and 5. It’s formerly   “Bipolar not otherwise specified (NOS)” in DSM-IV.  The new DSM-5 changed the name as ‘unspecified’   when you have no other collateral information  or ‘other specified’ when you know why you don’t   give bipolar I and II. And usually, it’s, like,  duration criteria not met. Like the – they have   their mood upswings, but less than four days  in hypomania, or less than seven days in mania. This is the first study Dr Birmaher ran. It’s the  COBY Study, in which people are allowed to come in   with one symptom short of manias presentation,  or the symptoms might last in an episode less   than half of the day. So, the decision was four  days, in a day it could be one hour time four,   two hours’ time two, and they don’t have to  be consecutive, but four times, lifetime, day,   period of these mood upswings. From this  angle, only 3% had not enough symptoms,   and about 11% hypomania without major  depressive episode. Most of them around 86%,   they had similar presentation, like  a manic episode, but lasting short. When again, they come in depression, as I  mentioned, some on the top of the right part   of the slide, that they come in with depressed,  some it, kind of, fluctuates within depression.   And this is the study that we are running in  Pittsburgh, and this is also a not clear group   of people. Some come in with, like, a milkshake  presentation. They’re continuously depressed,   but they have some manic symptoms throughout the  day. Some go – it’s very small blips of going   into mania and coming down very shortly, but  remain depressed for the most part of the day. And I’m going to talk about disruptive mood  dysregulation briefly, because it’s listed in   DSM as a part of depressive disorder, although  depression is not a criterion in this, just to   highlight. And they intentionally clarified  that this can – this starts before age ten.   To differentiate the longitudinal course of the  illness, early onset of the illness, and we know   most mood disorders start by adolescence, although  we know that although the incidence is lower,   people may still have mood disorders before age  12, or age ten, or even before elementary school,   the incidence goes lower, but they may happen. But  for this diagnosis, the mental age at least six,   it has to start before age ten, “Chronically  irritable for one year, without any good mood more   than three months.” This is, like, persistent,  kind of, oppositional defiance behaviour that   is coming with some “verbal/physical  anger outbursts three times a week.” You need to keep in mind if you  are giving bipolar diagnosis,   it trumps this DMDD diagnosis. And it’s not  something we use a lot, because our patient   population is mostly coming with bipolar  diagnosis. If the mania is more than a day,   then you can’t give this diagnosis. If you  give this diagnosis, then you cannot give   ODD/impulse control disorder. Still, most  scholars argue whether it exist or not. Okay, so, why depression is important. So,  it’s usually the first episode. When you see   a child with depression, you really need to  think whether they had past mania/hypomania,   or they may be on the path to develop bipolar.  Not all of them, but we need to keep in mind the   depression increases the risk for morbidity and  mortality. Even they have bipolar, it’s still   most common presentation. Then you look at major  depressive episode, and I would like you all to   keep a perspective and differentiation  between symptom, episode, disorder. And symptom, depressive symptom, doesn’t mean  major depressive episode. Major depression   doesn’t mean major depressive disorder. It’s  an episode in which it’s just most of the day,   nearly every day. It doesn’t have to be lasting  all day long. And if you look at major depressive   episode, it’s mood/anhedonia, depressed  cognitions, physical/vegetative symptoms,   domains actually come in. And most of  the day, nearly every day for two weeks,   five symptoms out of nine, and then, comes  with impairment. Again, depressive episode can   be a part of bipolar disorder, substance in use,  major depressive disorder, persistent depression. So, bipolar versus unipolar depression,  more severe depression, more hopelessness,   more suicidality, lower functioning, more  comorbidity and more inpatient psychiatric   treatment, but they are not specific enough  to differentiate bipolar disorder. So,   we have to keep asking questions about past mania  presentations. So, what suggests bipolar during a   depressive episode? Psychotic features, these are  red flags, but not diagnostic. Atypical symptoms,   such as psychomotor retardation, extreme fatigue,  eating more, sleeping more, and mixed features.   And medication induced hypomania  is also an important one. Number   one single predictor is actually  family history of bipolar disorder. When me looked at bipolar depressed youth versus  unipolar depressed youth and they both are in a   depressed state, we wanted to quantify if they  had any mixed symptoms, if so, which ones?   Irritability, anger comes, motor hyperactivity  comes. When we looked at area under curve,   we actually see anhedonia, social withdrawal,  hopelessness as depressive symptoms,   irritability and motor hyperactivity,  distractibility for mania symptoms,   that distinguishes bipolar  depression from unipolar depression. It’s not that these mixed symptoms are happening  only when they have bipolar. If they’re at risk   to develop bipolar, in which we did the analysis  with the biostudy sample for Bipolar Offspring   Study, and none of these groups had bipolar  disorder, but the offspring of bipolar parents   are at risk to develop, and we see they  had even higher elation, racing thoughts,   mood lability, than unipolar depressed kids  who didn’t have parents with bipolar disorder. So, always remember developmental changes, they  start with early, non-specific symptoms, later   prodromal symptoms, full syndromal comes next, but  comorbid conditions may change, too. Like ADHD and   disruptive behaviour disorders may improve over  time. In COBY Study, Dr Birmaher published a very   important study, in which he showed four different  classes of kids, that one of them continued to   do well, one of them at the bottom continued to  do worse, and we have a group that – in orange,   that start at the bottom, but they showed  improvement over time. So, there is a hope. So, how can we identify mood episodes sooner?  Here in Pittsburgh, in – on our Inpatient Unit,   we use Mood and Energy Thermometer to get them  rate their mood from minus ten to plus ten, in   which they are able to tell us if it’s really  from depression or if they get pushed into   mood upswing. We also get them rate their energy  side-by-side. So, we not only monitor their mood,   but also, self-energy reporting, and  we actually monitor them over time,   creates – because they scan themselves on the unit  and then it goes into our electronic database,   which creates some graphs for us to monitor their  progress over time, as you see in these slides. So, we see how elated mood increase, energy, low  mood, tiredness improved, and we are actually   putting them in one big presentation slide that  we can actually gui – monitor their progress over   time. In addi – and as I said, they complete  this and we send them real-time to parents,   so we can monitor their progress. Recently,  we added actigraphy. They are not diagnostic,   they are not diagnostic device, there is no  real-time monitoring option, but it gives us   their activity score throughout the day, which we  map on their self-report mood and energy changes. So, neuroimaging is the area that I’m focusing  on to help identify some neural signatures that   can differentiate bipolar from unipolar, but  it’s – so far, it’s research based. We don’t   yet get to a point to tell parents, “Your kid  is bipolar” or “not,” based on their imaging   findings. And we know, like, subcortical regions  improve and maturate by age 12 in everyone,   but it’s overflowing, overactive in  bipolar patients, whereas the prefrontal   cortex is actually moving – developing slower. The other area that people are looking at is,   is there a dimensional measure that we  can use? CBCL is one of them. Some people   thought it can help make the diagnosis.  It actually helps to tell which patients   are actually dysfunctioning more or impaired  more. In this study, the suggested triple A   aggression, attention, anxious/depressed,  are more prevalent in bipolar patients,   but they are not diagnostic. It’s not like you’re  going to give the scale and say, “Okay, you are   bipolar.” It will just tell you higher scores  in bipolar because they are functioning worsely. And we are using Child Mania Rating Scales as  a screening measure and our take home messages   will be – for you, is that it’s difficult to  diagnose and differentiate from other conditions,   has significant implications for treatment. Pay  more attention to identify episodes and changes   from baseline. Increased activity and energy level  are now required for a mania episode diagnosis,   and differential diagnosis is a continuous  process with developmental progression and   changes in clinical presentation. Also  pay attention to medical conditions. This is our team from our holiday  party a few months ago. So,   I appreciate your attention and it’s a  pleasure being with you, Dr Milavić, here. Dr Gordana Milavić Well, such good  practical advice for all of us,   and it’s nice to be reminded about  some of the DSM-5 criteria, as well,   which have changed. So, we have time  for a couple of questions. I will read   out the first one. “If you are not 100% sure of  diagnosis and would ideally prefer to monitor,   do you ever give early trial of medication  because of a degree of distress or impairment?” Professor Rasim Somer Diler It’s a wonderful  question. It depends on to what degree they are   impaired and suffering from. For example, if  they are, like, coming with extreme suicidal   behaviours, to a degree that they have hard time  to keep safe at home, or if they’re coming in,   like, level of aggression, then I  will still try to figure out the area   that medication can be helpful for. I’m not  going to jump into giving the bipolar diagnosis.   Definitely, I will prefer to monitor, and I may  not jump into giving a mood stabiliser first,   before confirming the diagnosis. I will initiate  behavioural intervention on the Inpatient Unit,   behavioural modification on the  Outpatient Unit. I will just get,   for example, more definable factors in place,  for example, sleep hygiene. Giving patients   and parents some ways to monitor those  behaviours, sleep, mood cycles, better. So – but I know, in most practices, not only  the distress impairments level, they don’t have   enough time to make the diagnosis. In patients  with, like, bad ADHD, they add mood stabiliser,   hoping it will help, and some of those medications  non-specifically improve irritability level,   but it doesn’t make the diagnosis because it  helps irritability. We still need to monitor. Dr Gordana Milavić Thank you, Rasim.  “Where does cyclothymia fit in?” Professor Rasim Somer Diler That’s  another wonderful question. I want to add,   also, hyperthymia, too, which is, like,  cyclothymia, you go in and out of mood,   up and down, and hyperthymia, you are just  continuously up and dysthymia, as we know,   it’s continuously down. But for cyclothymia, they  should not ever meet the criteria for either,   like, an episode of the major depression  or the manic or hypomanic episode. So,   they fluctuate in-between. We see very  few cyclothymia patients, but they exist,   even in children. We just need to monitor that  carefully and if it’s cyclothymia, I will not   jump to medication. I will try to help parents  and the child monitor these symptoms and help   improve their functioning. Functioning focused  therapy approaches will be my best approach. Dr Gordana Milavić And Rasim, finally, “How  would you treat depressive episodes within   the context of bipolar disorder?” What is your  current favourite pharmacotherapeutic approach? Professor Rasim Somer Diler That’s a wonderful  question that I wish I can tell you, like,   one approach fits all. But usually, if  we are confirming the bipolar diagnosis   and the patient comes in with depression, I  will try using mood stabiliser that I know   help improve the depressive features,  as well. Like, in adults, for example,   quetiapine or Seroquel is approved for  bipolar I and II depression. In children,   the studies were not conclusive, but lurasidone  is one of them that’s approved for both bipolar   depression in youth and in adults. And Lamictal  is also an option in regards to preventing future   depressive episodes, although its help for acute  depressive symptoms are still not conclusive. The main question comes to mind  is that when and if we can add   antidepressant. I do add antidepressant  only I’m – after I’m sure that the mood   stabiliser is strong enough that prevented  the mania, or stopped mania and hypomania,   and the child remained either severely anxious  that provokes or invites more depressive episodes,   or the depressive symptoms still  linger that affects the child. The studies in adults were saying that  antidepressant do not make things worse,   do not make things better, so why to add it?  But they didn’t look into if it helps anxiety   and secondarily helps the depression,  and we have a really large study with   olanzapine and fluoxetine, so we know that  maybe combining antidepressant with a typical   antipsychotic would do better than combining  with just an antiepileptic mood stabiliser. And the other thing we may need to  consider and keep in mind, lithium.   You need to really pick your patient carefully  for which patient may respond to lithium. Like   family store lithium, great choice, and high  suicide risk, lithium is known to help reduce   suicide risk. And if the episodes are clear-cut  depression, mania and good inter-episode recovery,   lithium can be a good option, too.  And if the first episode is mania,   lithium can be a good option, too. But we don’t  prescribe lithium if parents cannot safeguard   the medication. We don’t want to add another risk  of overdosing on lithium, which could be lethal. Dr Gordana Milavić Rasim, I’ll have to interrupt  you there. Thank you very much, as always, and   I should mention that Rasim has done some ACAMH  masterclasses and I hope you will join us again,   Rasim, in the future. But thank you so much, and  I hope people can write to you at your address,   here on the screen, if there are any  other remaining burning questions. Professor Rasim Somer Diler There’s one question   here and I will just reply on  the message. Thanks very much. Dr Gordana Milavić Okay, thank you very much. Professor Rasim Somer Diler Okay. Dr Gordana Milavić That’s amazing. Professor Rasim Somer Diler It’s my pleasure.