Thank you so much for attending the Pediatric Bipolar Session, Advances in Diagnosis and Treatment. So one quick announcement is we will have the slides available on the app probably by the end of today, beginning of tomorrow. So feel free to take in the lecture, and you don't have to take any notes, they'll be available afterwards. Okay. So it is my distinguished pleasure to introduce Dr. Janet Wozniak. She has a very long bio. She is the Director of the Pediatric Bipolar Disorder Clinical and Research Program at the Massachusetts General Hospital. She was the recipient of the NIMH Career Development Award to study Pediatric Onset Bipolar Disorder. She has published the largest family study of Pediatric Onset Bipolar Disorder. She is also the Director of the MGH Child and Adolescent Psychiatry Outpatient Services and has an active clinical practice. She is also currently the PI on studying Addressing the Underpinnings of Pediatric Bipolar Disorder and PI on Clinical Trials of Complementary and Alternative Treatments. Please give a round of applause for Dr. Wozniak. »» Thank you Jacques, I appreciate that. One of our distinguished trainees, it's so wonderful to see the classes move through and they are all the same age and I'm just older every year, but it's great to see them in these new great roles. Disclosure slides. I've had a little coffee, which I don't know what it does in the mouse model, but in the Wozniak model it gives me a little of those manic symptoms, which may help me get through a million slides with you today. So as you just heard, studying Pediatric Onset Bipolar Disorder has made up my entire career as a psychiatrist. I started just shortly after my training, maybe still in my training, and at the time it was considered like an oxymoron, pediatric and bipolar, like they didn't go together. But we've come to find over the years through kind of converging areas of research that it's a highly morbid disorder, it's a valid condition, it affects a significant minority of children who use a lot of resources and have a lot of misery. It's often comorbid as well. So this is a little bit of a road map. I'll talk about the scope of the disorder, diagnostic description, talk about treatments, and also about its overlap with other disorders. I thought I would start out with a clinical example, two really, and then bring them back up towards the end. And then I'm looking forward to taking questions from everyone. And you can see there's a lot of words on here. This is just a fraction. When I get a referral for a child, I always say like the younger they are, the more paper there is. So this 12-year-old has a very detailed and long history, which I tried to summarize. In short, a mother wrote to me, really quite distraught, and I get a lot of these types of emails. My son is 12 years old and has had a complex story since age three. He started puberty and things are becoming more complex and dismal since he has not gotten any better. And we have seen every specialist and done every test we could think of. We are reaching a new level of crisis and cannot understand the complexities he exhibits. We do not know where else to turn. By age three, he had night terrors, hyperactivity, tantrums, general mood dysregulation, which was somewhat cyclical. He would say he was sad and mad, but he didn't know why. He saw his first psychiatrist and had his first medication treatment at the age of five. So for adult psychiatrists who think that the first episode starts when you're 18 or go into the hospital, then plenty has often gone on well before that. He's tried a dozen different medications. He's had two neuropsych evaluations and has had, at this point, several diagnoses, ADHD, oppositional defiant disorder, anxiety, most recently high-functioning autism. He's had horrendous medication reactions. One of them made him severely violent and he was hospitalized. Abilify was started just last summer because he could not sleep. And he was in his room pacing for hours at bedtime and in the middle of the night. Abilify helped. Sleep issues, but not everything. Side effects led to the discontinuation. Current symptoms are constant state of anger, depression, needing to be moving almost constantly, doing an activity on one hand, but at other times tired and moody. Obsessions over the years have waxed and waned that look like OCD. Currently artwork, and he rearranged part of the garage to accommodate a painting studio because he'll be a great painter. Other times he just sleeps. His meltdowns come out of nowhere, other times triggered by small events. The second neuropsych evaluation, now at age 12, has confirmed an autism diagnosis, which by the way is a clinical diagnosis. You don't need a neuropsychological test to do, but at any rate, we still don't know how to manage his mood swings. She says, I tried to tell his initial psychiatrist these things when he was 5 to 9, but he dismissed the possibility that this could be bipolar disorder. And hopefully the idea that children can have bipolar disorder is more and more at the forefront of people's minds when they see these children. Clinical example number two is a child who's half the age, currently age 6, but again probably twice as much records came to me. We've struggled with her since she was born. We're pretty much at the end of our rope, exhausted, devastated. She was born with a head that was somewhat misshapen after four hours of pushing during labor, but that turns out I think to be a red herring. Healthy baby, normal milestones, cried a lot, needed pacifiers, still uses pacifiers. At 12 months, in frustration, she would bang her head on the floor, the walls, the cabinets. Every time the diaper change would occur, it was a fight. Only her mother could get her out of bed or she'd scream for 30 minutes. Every transition was difficult. She liked the park, but getting her there, impossible. Mother stopped taking her on any simple errands. Unpredictably, she'd have an outburst, become demanding, have to leave the store abruptly. When she had a sibling, she poked her, provoked her, continues to do that and says, I just love to do it. Her daycare, the daycare director noted the sensory sensitivities that she had to music. She had a toe walking, funny walk, constantly putting things into her mouth, has had plenty of early intervention. By age three to four, she had a neuropsych assessment and had this nonverbal learning disability pattern, a high verbal IQ and a lower performance IQ. And the study said there's no specific diagnosis that captures the dysregulation of emotions and behaviors. Significant levels of anxiety seem to be a strong underlying factor. And so the diagnosis given was GAD. Nanny couldn't take care of her. Adults had to get her out of the car at daycare, biting, scratching, throwing shoes. Teachers adored her. She had a side of her that was funny, social, a leader in the class. She was a thrill seeker, engaging in risky play. The parents said, we walk on eggshells, we never know if she's going to explode. I've heard parents say that so many times, I sometimes say it before they do and they think I'm reading their mind. She's had extreme disruptive high energy, doesn't listen, extremely defiant. And after school, after a friend's house, after going out to a birthday party, she completely explodes with small precipitants. Her mother says it's as if she keeps it together for so long that she sees me and it's permission for her to release. Okay, well, the clinicians who saw and evaluated these children didn't see this slide, that bipolar disorder is now considered in the differential diagnosis for youngsters with mood symptoms. And I always say, if the chief complaint is that my child is wicked moody, then you have to think, well, maybe they've got a mood disorder. We discovered in our clinic early on, it was really the first paper I ever wrote, that about 16% of our outpatient referrals, the under age 12 children, were children who met criteria on a structured interview that was done by a separate rater for mania. And my job, my role at the time was to find out what's going on here. Are we making an error in our structured interviews that these parents are endorsing the mania symptoms or is this something that's been under recognized and misattributed? We went through this exercise twice in 1995 and then again in 2002 and found a very similar rate, 16 to 17% of our outpatient prepubertal referrals. So what are the symptoms of mania? You know them. They're the same in children as they are in adults, although we do think about what we'd say like a developmentally different presentation. So I like the Homeland performance of Claire Danes, you know, she has a mania and kind of displays a tremendous emotionality. That's very different from a small child who's kicking, hitting, biting, spitting, screaming, yelling, demanding, but yet the symptoms are similar. DSM-5 added this persistently increased goal-directed activity or energy. And the idea that bipolar disorder is really a disorder of energy more than moods per se or as much of energy is really intriguing. And the idea that you can have energy surges and then collapses of energy is a common story and not unusual in children who have tremendous hyperactivity and are quite disruptive and then can be couch potatoes. These are the DIGFAS, the additional symptoms, and as you all know them, and we use the same ones as we do in adults and children. You think of activities with painful consequences, hypersexuality, buying too many fur coats. Well, kids don't do that, but kids can have excessive interest in sex or sexual matters, seeking it out on the internet, engaging others in sexual play, touching people in appropriate and appropriate comments. We see all of those, and it's not always necessarily because they've been exposed to that material from other places or abuse. It sometimes can be generated just from their own mind that they're drawn to it. They also do spend a lot. They get online and steal their parents' credit cards, as it turns out. So in our investigations with these different clinical samples, we learned a couple of different major themes about these children who have mania. The first is that the major chief complaint of the parents who brought them in was not euphoria. There was euphoria there, but in a child, the euphoria is much less of a disruptive problem. The irritability, the anger, the rage, destructive, aggressive, that's a big problem. When we looked carefully at the mania and the depression and how they presented over time, we saw that the children had mostly mixed states. Mania and depression overlapped in time, making the clinical picture that much more difficult to disentangle. And then the children were just seldom well. They had mixed states. They had many cycles, and even when they weren't necessarily in a cycle, they have comorbid morbidity, high rates of other problems, mostly ADHD. So the underage 12 children, almost all of them met criteria for ADHD, and in fact, when I would see them in the clinic, parents, I'd say, tell me about your previous experiences, and parents would say, he's got terrible ADHD. And I would see that they checked off almost all of the ADHD symptoms. But in addition, they had other problems. It wasn't just ADHD. And if that's the lens, so in child psychiatry, ADHDs are bread and butter. If you're going to ask me, what's the next referral going to have, I'm going to say, but they have ADHD, because about 80% of our referrals to our psychopharmacology clinic are children who have ADHD. It's common, it's noticeable, it's disruptive, we have treatments for it. But it's not the same thing as mania, even though they share some symptoms and can overlap and be commonly co-occurring. ADHD is not a mood disorder. People who have ADHD may be grouchy or short-tempered when you make them do work that requires mental effort, but that's very different from the mood issues that are being presented with the children who meet criteria for mania. So here we go back to the mania symptoms. I put in blue the ADHD symptoms. So there's this energy thing. Well, these children with ADHD are very hyperactive and often seem to have these energy surges Distractibility, core symptom of ADHD. Increased activity, psychomotor agitation. Activities with painful consequences and impulsivity of ADHD can look a lot alike. And then there's pressured speech in mania, talkativeness in ADHD, blurting, interrupting. So there's substantial bidirectional overlap, and you can see this Venn diagram. So we have plenty of children in our clinic who have ADHD without bipolar disorder, but most of the children who meet criteria for bipolar disorder also have ADHD as a comorbid problem. And yet, this combined condition is different than just ADHD alone. So if you're a child psychiatrist and you hear my work and you're skeptical, you're going to say, I think, Janet, you're talking about moody ADHD kids who are having a hard time with ADHD. And if you're an adult psychiatrist, you may hear this and say, oh, so you're talking about bipolar disorder where there's a lot of cognitive problems and adult ADHD, this co-occurring problem. This combined condition has been kind of an orphan condition, we used to say, because the adult psychiatrist didn't think of ADHD, the child psychiatrist weren't thinking of mania, so when the two came together, it was a blind spot. We spent a lot of time, because we're child psychiatrists, trying to parse these children out from the common ADHD group. So if you make criteria for mania versus only meeting criteria for ADHD, you can see there's much higher rates of all of these different comorbidities, all of which are listed here in the kind of severely impairing amount. Psychosis, not an ADHD correlate, but it is of mania. Defiance of oppositional defiant disorder, common problem in ADHD, much, much more common in mania. And conduct disorder, which is, it's not just a little bit of childhood misbehavior, it's pre-criminality, this is pre-sociopathy. This is, you know, if you were to say to me, I wish we could predict who's going to become criminals in our society, I'm like, we know, the conduct disorder children, this path often leads to incarceration problems in the juvenile justice system. 37%, I always say about 40% of the children I see with bipolar disorder have these symptoms of conduct disorder, lying, stealing, vandalizing, no remorse. And then there's anxiety. Anxiety is present, it's not the only thing there, but it's even more common in bipolar disorder. You can be disinhibited from mania and also be extremely inhibited and scared and nervous and worried from anxiety in the same person. And then when you look at their functioning, hospitalization, ADHD kids generally don't require hospitalization for their disruptive behaviors. Children with mania, bipolar disorder, depression and mania, they have self-inflicting problems, suicidality, and they have aggression and destruction. So I was telling you about this orphan condition, well, indeed, adults with ADHD have higher rates of bipolar disorder than adults without ADHD. And we've seen this in a number of different, very large samples. The National Epidemiologic Survey on Alcohol and Related Conditions, the National Comorbidity Survey replication. If you parse the adults who have ADHD, you're going to find higher rates of bipolar disorder in those subgroups. It's a combined condition that we see through the life cycle. And then there's some biologic data to support the idea that there's a subtype, perhaps, of bipolar disorder. But is bipolar disorder one thing? Is it just one diagnosis? I would say not, because we've really failed in finding a unifying biological underpinning for this disorder or disease. One way to parse may be by comorbidity, like with ADHD, or parse by age of onset, pediatric onset, to find distinct genetic and biological subtypes. So what is the rate of this disorder that we're talking about? Is it 50% of children? No, of course not. This is a disorder that probably affects between 1% and 3% of children. But in our clinic, it's 99% of our worries and our headaches and our difficulties. ADHD, anywhere between 5% and 10% of the population, a very large percentage of our psychopharmacology clinic. A tiny detour to talk about this diagnosis. When DSM-5 came out, there was two rooms, I think. The adult bipolar room, where they said, we have to make sure people aren't missing the diagnosis of bipolar disorder. We have to make sure that they're not treating depression when they should be treating bipolar disorder. How can we make that easier? In the pediatric room, they were saying, we have to stop these bipolar diagnoses. We have to find some other way to describe and treat these children. Indeed, to decrease the number of bipolar diagnoses, they came up with the magic wand of a new disorder, DMDD, Disruptive Mood Dysregulation Disorder. Sounds a little bit like it could be bipolar-ish, right? Diagnosing DMDD, it's not my quote, complex and futile, but I like the quote. It is a convoluted process, but the biggest problem is that in the end, even if you make the diagnosis, it doesn't tell you what to do. One way or another, you have to put down your dime and say, is this a mood disorder? Is it depressed? Is it depressive? Is it bipolar disorder? Is it irritability from some other source, ADHD? To treat it, you still have to use the diagnoses that we already have and which are fairly good. This slide illustrates the different symptoms of mania through these different two cohorts I described to you earlier. A couple of things are interesting. One is they're so similar. This is two distinct periods in time, different raters, different families, different parents reporting, but yet here's the set of symptoms that you see. The euphoria amount is rather low-ish. That's when you ask, have there been seven days or longer of impairing, elated, euphoric, overconfident, whatever words we use for it, moods. About 20% to 30% of parents endorsed that for these children, but 92% of the parents said, have there been seven days or longer of severely impairing, irritable mood of an extreme irritable type, yes. The age of presentation for these two cohorts, we parsed individuals under age 12, was about age 8. But let me tell you, that's not when their symptoms started. They started much younger. What happens is they have terrible time when they're very young and they're preschoolers and parents are told, discipline them that way, discipline them this way. Maybe they'll grow out of it. Maybe it's your fault. Maybe it's your fault. Then they get to kindergarten and they're not getting any better and they decide we better see a child psychiatrist and then it probably takes three years to get an appointment because there's just not enough accessibility. Then we see them average age of eight. These are children then who have already been suffering with mood dysregulation for more than half their lives. Back to the irritability and the euphoria part. Of parents who did endorse the euphoria, most of them also had irritability. Plain euphoria as a referral symptom was rare in our clinic, but severe irritability was very common. I was just saying to someone that in our vocabulary we have many words for, say, shades of green if you are looking at different types of plants or the Inuits have hundreds of words for how to describe different types of snow, but we don't have so many for irritability. I put some of the different ones that I ask. When the trainees come to me and say, this is a child who's very irritable, I'm always like, what kind of irritability? Tell me some more about that. So hitting, kicking, biting, spitting. Say that a lot. Hitting, kicking, biting, spitting, swearing, wild, out of control, destroying, aggressive, destructive, threats, attacking, explosive, rageful. That's a kind of a capital letter, bold face, big font, irritability. It's not just a kind of little bit of a bad day, right? And the outbursts can be dangerous and then also long lasting. It's not just how bad is it, what's the quality, but what's the quantity? Is it happening every day? Do you ever go a day or more without it? If you go a day or more without it, do you go two or three days without it? Pretty soon you hear that it's a rather frequent problem and that the outbursts can go on for long periods of time, not just a tantrum, which is a normal phase of very early childhood, which is time limited and not so severe. Irritability is also a symptom of depression. It's not listed in the DSM, but it's certainly something that we as clinicians all know that grouchy, cranky, complainy, whiny, difficult to please, easily annoyed, this can be part of a depressive picture. And then when you think that mixed states are very common, you've got somebody who's irritable for one reason or another a lot of the time. Mixed states. So mixed states in our clinic are very common. They're pretty common in adult psychiatry as well. These kind of classic euphoria and depression, I sometimes call this like celebrity bipolar disorder because like Carrie Fisher kind of talks about it or you see it on TV and these depicted on hospital shows. So like a week or two of euphoria and elation, not sleeping, lots of makeup, going out, doing wild things, doing regrettable things, then crash, hopeless, depressed, suicidal, no energy, stays in bed, doesn't want to do anything. And then kind of comes out of it and has an intermorbid period of high functioning. That's not a very common form of bipolar disorder. It certainly exists. But most of what we're seeing in our clinic are individuals who have more of a chronic picture with very poor functioning. That intermorbid high functioning period, not so much. And those distinct phases that you can cleave apart, not so common. One of my colleagues did this graph of the kind of like different types of irritability. Irritability is in mania, it's in depression, it's a symptom in oppositional defiant disorder. And then we've got ADHD, which doesn't have irritability as a symptom, but can make people kind of grouchy. And if you kind of look at this irritability graph, there's some irritability there like all the time for these kids who are highly comorbid. It looks like a never well condition. So if your idea of bipolar disorder, first of all, is that you have to be functioning perfectly well and then all of a sudden have a terrible problem, you're not going to see that in these kids because it's an insidious onset for a lot of them from very early age. And if your idea of bipolar disorder is that you've got very distinct episodes that cleave apart and then people come out of them to a period of high functioning, that's also not what these kids are presenting like. So how about these top down studies? In 2004, I think it may have been for the first time, my colleagues in the adult psychiatry program thought, huh, this bipolar pediatric stuff, that's kind of wild. Does it really exist, Janet? And I'm like, well, yes. I've already been studying it for like a decade or two. And they said, well, why don't we ask the adults in our clinic about their ages of onset? And they devised a different questionnaire. Sixty-five percent of about a thousand patients in the STEP bipolar program reported a pediatric onset of bipolar disorder. Sixty-five percent. And these individuals with the very early onset had higher rates of comorbid anxiety and substance abuse, more recurrence, shorter periods of euthymia, more suicide attempts, more violence. Sounds a lot like the kids grown up, right? So if you say to me, are these kids you're seeing the same ones we see in the adult clinic? I'm like, well, yes, some of them. Some of them grow up and become those patients in the adult clinic. And then some of them have a later age of onset of their bipolar disorder. And then they parsed out by ADHD. All of a sudden, they realized adults can have ADHD. If you didn't know that, they indeed can. And they found about a 10 percent lifetime prevalence of comorbid ADHD in their adult bipolars. And then that group also looks a lot like the kids I'm treating. Early onset, chronicity, comorbidity, severity, suicide attempts, violence, legal problems. I mean, these are the big bad three really for bipolar disorder, right? Suicide attempts, completed suicide, violence towards others, aggression, getting arrested and involved in the criminal justice system. These are terrible. And substance abuse. Maybe add that number four. Pediatric bipolar disorder is persistent. So even if you did grow out of it, like if I found that these kids all kind of miraculously got well by the time they were 15 or 17 or whatever it was, we'd still want to identify it and treat it, right? Like childhood asthma or childhood allergies. Whatever it is. Childhood seizures. You're not going to say, ah, you're going to grow out of it. Come back in 10 years. Don't worry about it. No, you'd want to treat it. But this disorder does appear to be quite persistent, especially if you're looking for like a full remission that includes functional recovery. Seldom see that. Jacques had mentioned, you know, so many hours of work in our family study of pediatric bipolar disorder. The idea early on was to have this external validator of the disorder. So if you're going to take issue with my diagnosing these children or seeing the symptoms in the children, would you be convinced if I said they have way more bipolar disorder in their families than the kids who have ADHD without bipolar disorder? So that was the hypothesis. And we set out to do a family study. And it was based on some previous data that individuals with earlier onset seem to have higher rates of familiality than individuals in adult clinics. And familiality, by the way, is different from family history. Like if you ask me what's the family history of your cohort, that would be like how many of the programs, how many of the patients I see have a relative with bipolar disorder. That would, you know, probably about 40%. But familiality is different. It's the total number of relatives that they have with bipolar disorder divided by the total number of relatives. So we, it depends really on the, and it's better for determining a genetic risk. That's how we use familiality. And so this is my familiality study. It all boiled down to this one slide, but countless, countless hours over countless years of many, many children and their first degree relatives. And we found what we suspected, which was that there was a great, much higher risk of familiality in the children who had bipolar disorder versus the ADHD children who did not have mania or depression. Let's move on to talk a little bit about treatment. So we have a lot of FDA approved treatments for use with emotional dysregulation. All of them have either serious or annoying or both types of side effects. The ones in red are the ones we have that are FDA approved for mania or mixed states in children. The youngest we have approval for is down to age 10 because that's how, what the studies did. And then there's two that are approved for pediatric bipolar depression. And when you think about using these medications, all of which have serious and annoying side effects, you have to do a risk benefit analysis. The treatment has to include the risk, the decision has to include the risk of not treating. Not treating. What if we do nothing? I'm so scared to give my child a medicine because what if they have a side effect? I'd feel so terrible and guilty forever. Well, what if you don't treat your child and they become suicidal and they develop a substance use problem? Are they getting put in jail for some reckless, stupid, impulsive act that they do in one of their manic states? Well, that's a big risk and it's a risk we know exists in bipolar disorder. Addiction, suicide, poor judgment. So each decision is a shared decision and it has to do with the degree of morbidity associated with the symptoms for that particular child. And the general algorithm for treatment, I wish I could tell you it was something fancier than this. Start with a mood stabilizer. Add augmentation. Switch to monotherapy, a different monotherapy if that doesn't work. Try combining second generation antipsychotic with classic old time mood stabilizers. Try combining two or more of them. Try combining three more of them. At the very end, we've got ECT and clozapine, both of which are severely underutilized throughout the life cycle. And it's unfortunate because clozapine can be really a uniquely useful medication, certainly in schizophrenia and in bipolar disorder as well. In schizophrenia, we know that it's really important to begin the treatment of schizophrenia as soon as possible. That you're more likely to have improved functioning and fewer symptoms and higher GAF scores in individuals who receive their intervention very proximal to the onset of their symptoms. Minimize duration of untreated psychosis. I don't have a similar slide to show you for pediatric bipolar disorder, but we do have plenty of data that shows that individuals who had their treatment much later in their life, who had longer periods of illness that was unattended to, tend to be more treatment resistant and do worse. And what do we treat these children with? A lot of children have participated in trials of antiemetic treatments over the years. I showed you the FDA approved treatments, which if you didn't notice were mostly SGA, first generation antipsychotics. These are robust treatments for adults with bipolar disorder. And when we did this large meta-analysis of the traditional mood stabilizers, which were in that category, carbamazepine, valproic acid, and lithium versus other anticonvulsants versus atypicals and then the natural treatments, the atypical antipsychotics had a much greater reduction in mania symptoms, which is depicted here on this slide. So I use SGA's for these children. Why? Because I love them, because I think they're safe and healthy and good for you. Well no, they've got all kinds of problems. We use them because they work. They're more likely to get rid of the symptoms more rapidly than the other treatments. It's not that these other treatments don't work, but their response rates are just kind of so-so compared to what we see. Also there's high dropout rates, there's need for rescue medications. Plenty of data to show how SGA's perform better. Here's one, chart reviews and double-blind RCTs, SGA's do better than valproic. This is a very large retrospective Medicaid study of pediatric bipolar disorder. And the patients who started on an SGA were less likely to discontinue their treatment. So as awful as they are, they may have less side effects than some of the other things that we use. And the patients who initiated on the SGA were less likely to receive treatment augmentation. So if you're going to start somebody on valproic acid, and they're going to end up needing an SGA anyway, well why do you need two treatments? Lithium's long been FDA approved for pediatric bipolar disorder, but it was grandfathered in because the first double-blind randomized clinical trial was in 2015 that Dr. Findling did. And he showed that lithium was helpful in this group. But again, the amount that was much or very much improved is still a fraction of what we would see in the SGA trials. A few words about side effects because we have to attend to them. Tardive dyskinesia is a dreaded side effect. Our data is limited by small sample sizes, low doses, limited durations. We have to watch for it. You don't want to give most side effects go away when you take the medicine away. This is one that might not. So you need to watch carefully and educate parents to watch for abnormal involuntary movements. But this is a problem that doesn't happen right away. It happens after long-term treatment, and you have to weigh out the risk of using this versus the risk of not given the symptoms that you're dealing with. Weight gain, though, is definitely a problem. It's a problem of living in the United States, and it's also a bigger problem of using any of these psychiatric medications. You can see these astounding amount of weight that's gained in little children over a 12-week period. Olanzapine, far worse than all the rest. I say if you just even say the word olanzapine, you gain a few pounds. Intervene for abnormalities. So here's just an algorithm for how to monitor BMI four to eight to 12 weeks, monitor labs. And why do you do that? Just to watch somebody get bigger and bigger and bigger? No. You would like to be able to intervene, maybe switch them to a different agent that has less liability for weight gain, maybe give them access to nutritionists and other supports. But also you could co-treat. Metformin is commonly used to offset the weight gain associated with antipsychotics. This is a slide of a schizophrenia sample, and you can see that when metformin is used, weight loss occurred. Then there's these new agents, the GLP-1 agonists, which I think in California everyone's on or something, right? Maybe it's just in LA. But they are quite miraculous at helping weight to come off and can be a very useful augmentation for our patients. I used to say that as psychiatrists, we had to become cardiologists when we were using tricyclic antidepressants. Now we have to become endocrinologists because there's not enough endocrinologists to prescribe all of this stuff. So we need to become more skilled in how to use them. Let me talk a little bit about comorbidity. And these are the kind of major comorbidities, right? And some words about autism. Emotional dysregulation is not one of the diagnostic features of autism. It's a lifelong disorder. It's characterized by social communication deficits, restricted repertoire of behaviors. The rate affects about 2% of children and adolescents, but the rate keeps rising. The rate may still, may indeed be rising in the population, but we must all be aware that our definition of this is also expanded. But it often presents with emotional instability. It's a co-occurring problem. And so understanding the poor emotional control of the autistic child in front of you is part of their intervention. We don't have like a pill for the autism, but we can treat the co-occurring conditions that are compromising their life, further compromising their life. These are two papers by a colleague of mine depicting the heavy burden of comorbidity in both childhood and children, adolescents, and adults who have autism spectrum disorder. And the mood disorders in the youth and the adults were pretty common. In youth, depression was present in about 56%, bipolar, about 30%. And in adults, similar numbers, maybe even more for depression. It raised this question of, is this bipolar disorder in autism a bona fide bipolar disorder? Because one of the first papers I ever wrote about it came back with a review or a response maybe in the journal that said, Dr. Wozniak is making a grave error. This is just a symptom of autism. But it's not. Not all individuals with autism have tremendous emotional dysregulation that meets the criteria for mania and depression. We looked at the familiality of bipolar disorder in the youth with and without, bipolar youth with and without autism, and it was similar, suggesting that it's a bona fide comorbidity. Autism is often excluded from clinical trials, unfortunately, but we had a number of open label clinical trials for SGAs for bipolar disorder. We included individuals who had autism spectrum disorder. We were able to parse out that subgroup to see if they responded any differently. First of all, we found that whether you had autism or not, your scores for the mania rating scale, the depression rating scale, ADHD and the BPRS were quite similar. They looked quite similar. And we found no difference in the antiemetic response of the SGAs in the youth with or without autism. So, I mean, you may have seen on my slide of treatments that we have an FDA approval for irritability and autism for aripiprazole and risperidone, which I would say is, should be, and it's an FDA approval for treating bipolar disorder in that population. But for whatever reason, it's an approval to treat a symptom, not to treat a disorder. How about ADHD? Can you give stimulants to an individual with bipolar disorder? Well, there's some data to suggest that you can. So this is a study, again, by Dr. Findling. These studies about stimulants, they are also shorter term, short duration, individuals who are fully mood-stabilized to start and using rather gentle doses of stimulants. But they found therapeutic benefit without exacerbation of mania. Same was true in this study of amphetamine salts. Started out with individuals who were really pretty fully stabilized and added a small amount of amphetamine, and then over six or eight weeks, they did fine. In my clinical practice, I kind of say it's 50-50, that 50% of the time, I end up having to take the stimulant away because it seems to be causing a roughening of mood. And it's rare for me to find somebody who's fully stabilized because bipolar disorder is so difficult to treat. This is a much larger study, Swedish National Registry of Adults with Bipolar Disorder, and it showed within this large sample that if the individual was taking a mood-stabilizing medication, then stimulant medications did not compromise their course. If they weren't taking a mood-stabilizing medication, well, then there was much higher rates of hospitalization and need for additional treatments. Okay, comorbidity, depression, well, it's part of the disorder, right? And yet, it is kind of its own thing, because depressive symptoms are really often our biggest clinical problem throughout the life cycle. It's very hard to treat the depressive part of bipolar disorder. We have a lot of antidepressants, right? But most of them will make somebody with bipolar disorder much more destabilized, increase their mood cycling. So this slide just illustrates the problem, that in these longitudinal studies, children with bipolar disorder spent a lot of time depressed. Now remember the DSM-5 rooms, the adult room and the pediatric room? Well, over in the adult room, they made it much easier to call a major depressive episode mixed. So a major depressive episode is mixed if you have three out of the seven additional manic symptoms, three of them. So the idea being, depression sometimes is easy to see. Somebody is hopeless and suicidal. People often present in their depressed states because they're so unpleasant. But if they have these additional manic symptoms, all of a sudden you're dealing with somebody not with unipolar depression, but mixed depression. And mixed depression, you need to be cautious. It's common in depressed patients, 20 to 70% have mixed states. They tend to be occurring more in the younger ones, longer episode duration, worse outcomes. They have more suicidality. They do worse than the individuals with depression that aren't mixed. And antidepressants should be avoided in all types of bipolar disorder, whether it's with subthreshold mania, mixed symptoms, or full syndrome mania. Children with depression, just who present with unipolar depression, often switch over time and develop mania, and then have the diagnosis of bipolar disorder. And the adult literature has consistently reported that early onset in the adult world, not under age 25, not under age 5 like in my world, but that early onset mood symptoms pose an increased risk of switching. So I'm always teaching individuals that when you treat a child with an antidepressant, you have to do a couple of things. You have to find out if they have any current symptoms of mania that would make the picture mixed or bipolar disorder. You have to find out if they had any past symptoms of mania, which means that they've cycled out of mania and they're now in depression. And then once you give them that antidepressant, you better be watching to see if they're developing any future symptoms of mania, because a very common clinical error is to give an antidepressant to a depressed child, see a worsening course, and give them more antidepressant, and more antidepressant, and more antidepressant, not realizing that perhaps the antidepressant is contributing to the worsening course. A number of studies have outlined features of pediatric depression that can predict switch, family history of mood disorders, aggressive conduct, disruptive behavior. Well, I might argue whether those are already subthreshold symptoms of mania, emotional dysregulation. There's this dose response of these different features, conduct disorder plus school behavior problems, plus a parental mood disorder, way more likely to lead to switching or end up with a bipolar ultimate state. Here are some other predictors of switching from a number of different studies. And just let me draw your attention to this one, antidepressant-induced mania. You give an antidepressant and you have to watch carefully. This is especially important in a public health way, because given the absence of trained psychiatric prescribers, pediatricians, thank goodness, are taking over a lot of mental health care. But they're not as well trained as we are to watch carefully for these worsening courses. So creating safety nets for that, I think, is an important public health problem. And I say that antidepressants is like this double-edged sword. In one of our studies, antidepressants led to the most improvement in individuals with bipolar depression, pediatric individuals. But it also, if you followed them over time, ended up leading to the most mood cycling and destabilization. So as my colleague, Dr. Nuremberg, told me once, antidepressants win that battle the short term, but you lose the war over the long term. So sometimes you know there is terrible depression, and you layer on an antidepressant to a mood stabilizer because you feel like you have to do something to divert someone from a terrible depressive course. But you need to use them with extreme caution. And maybe consider not to use them at all if there's any mania. Rates of switching is much higher in individuals who've received antidepressants in childhood. Pharmacologically induced hypomania is a predictor of bipolar course. Antidepressant-induced mood change is more often seen in bipolar depression. So here's our FDA-approved treatments. We have very few for bipolar depression. Very few. Those are the FDA-approved ones. And the management of bipolar depression is very difficult. And so I mentioned the L's, lamotrigine, and lithium, and lorazodone. Lorazodone is one of the FDA-approved ones. But there's the other two, which are used in adults for bipolar depression. Cretiapine has been used in adult bipolar depression, but was not effective in adolescent bipolar depression in this study by Dr. Delbello. But the placebo response was very high. So sometimes it's one of the strategies people think about. Lorazodone did significantly reduce depressive symptoms in children. Had minimal effects on weight and metabolic parameters. You'd think, yay, it's like a miracle. But it behaves sometimes like an antidepressant, like sertraline or fluoxetine. And some people will roughen and have increased cycling with lorazodone. Should be used with caution. There's a number of open-label trials suggesting lamotrigine and lithium can also be used effectively. But keep in mind that SGAs themselves have antidepressant qualities. And that there's a number of reports that show that if you use an SGA for bipolar disorder to reduce the mania, depression may also reduce as well. Maybe not obliterate it, but can reduce it. There's also the newer antipsychotics, which are promising in child pediatric populations where the afterthought. So we don't have as big an evidence base for using those, not yet. I'm not gonna get into the treatment of anxiety. There are lots of different types of anxieties. But we go right back to what do we usually give for really severe panic and anxiety? We usually think about our good old SSRIs in this population if there's anxiety plus bipolar disorder, caution, caution. Subthreshold states. So like the mixed states. What if you have a few symptoms of mania? Do you just kind of ignore it and think it's not full syndrome, I'm not gonna treat it, I'm not gonna think about it? Well, there's enough evidence to suggest we should pay attention to these subthreshold states. Prevalence of subthreshold bipolar disorder ranges in adolescents between one and 13%, so it's pretty common. High-risk offspring of bipolar parents often have these subsyndromal presentations, which we probably assume is heralding a further compromised course later on. Subthreshold mania was one of the risk factors for switching. So we need to pay attention to subthreshold cases. In the course and outcome of bipolar youth study from Pittsburgh, bipolar II and bipolar not otherwise specified, bipolar not otherwise specified was very liberally defined. One or two manic symptoms for a few hours every year or two, or something to that effect. It was really a very small amount of manic symptoms. 38% of them over a four-year follow-up switched to bipolar I or bipolar II. And the same for people with bipolar II, they went on to have bipolar type I. So they gathered more symptoms as time went on. Here's what I just said, COBE bipolar NOS definition was super liberal. High rate of persistence. So the other thing, over time, when we do our longitudinal studies, if you're looking for who no longer has bipolar type I, bipolar type I's who no longer meet the full threshold criteria, well, then you might have a study that says a lot of people got better. But that's not really better, is it? If you continue to have subthreshold symptoms of mania, if you continue to have depression but not mania, or subthreshold symptoms of depression, or maybe you don't have any symptoms but you're on three mood stabilizers and you're not functioning well, those are all not reasons to celebrate a remission. So when you, these longitudinal studies, it's important to use these different definitions of persistence because that's what's meaningful to our patients. Subthreshold is also not like better. Like I'll have patients who say, can you tell me if I have bipolar I or bipolar II or bipolar NOS, and it's usually because they're thinking, I hope I have bipolar II because it's like milder and doesn't sound so bad. But in fact, people with bipolar II often have more impairment, comorbidity, suicide attempts, they often spend more time depressed. Bipolar II doesn't necessarily mean you have an easier or easier to treat course. So we've generally, unless I'm doing a study in which I have to recruit people who have DSM I or II, I talk about bipolar spectrum disorder because symptoms evolve and change over time. And people who have subthreshold states, as you see, often go on to have full threshold states. And whether it's one or two or one, it doesn't predict treatment and it doesn't predict outcome. So not particularly helpful, huh? Subthreshold diagnoses have been hailed as useful and subject of criticism. There's, you know, some critics call them rubbish. What's the other one? Wastebasket, lack reliability, catch-all terms. But in our clinic, these are our patients and we can't send them out the door if they've got symptoms that we're concerned about. There are some family history studies that suggest that subthreshold bipolar disorder, it may be as bona fide genetic subtype as bipolar type I. These are some different studies here that I've quoted about high-risk offspring who have high rates of subthreshold mania, community samples of adolescents. You know, the full and subthreshold programs similarly elevated by numbers of bipolar disorder in relatives. Well, we did our own family study. Remember, I did that family study. We also had, on the side, some individuals who met subthreshold who we didn't include in the bipolar type I findings. And when we looked at the familiarity for that group, it was similarly familiar, familial. So pediatric subthreshold and full syndrome bipolar have similar rates of familiarity of bipolar type I and both are different from the ADHD and controls. Subsyndromal conditions are important to diagnose. So let's go back to these clinical examples and then we'll take time for questions. And now that I've kind of told you all of this stuff, I'm, let's go back and look at these two individuals. Here's the 12-year-old boy who is problemed since the age of three, sad and mad and doesn't know why. Two neuropsych evaluations. Doesn't include mania in any of those, but it's certainly sounding like the level of emotional dysregulation he had already did meet that criteria. And then the high-functioning autism, not diagnosed until age 12. It's very difficult to assess a child's social skills and capacity when they're tremendously emotionally dysregulated. So I always teach that you need to be watchful about the, and suspicious that autism may be part of the clinical picture. Whether it's a true comorbidity or whether it's because social skills learning has been interrupted by all of that emotionality, we don't know. But we do know that once you start to ask the questions and watch these children grow up, you see them separating, lagging behind their age-matched peers, not because they're getting, dropping any skills, but because their age-matched peers are developing more social skills and capacities and nuances, and then these poor children are not. Horrendous medication reactions. Good. Doesn't give you the diagnosis of mania, but it certainly makes you suspicious. Finally, at age 12, Abilify was given, which seemed to help. It was given to help him sleep, but why was he not sleeping and in his room pacing for hours in the middle of the night? It sounds like he may have been manic. And what the observation was from the notes that I received was it didn't seem to help. He was still swearing, he was still obsessive. Well, there's a lot of comorbidity. Maybe it treated some of the mania, but didn't treat all of his depression, or didn't treat all of the anxiety that was comorbid. In this particular patient, the Abilify was discontinued due to the terrible adverse events, weight gain, and what I'm told is that he's still in a constant state of anger, has depression. He's either moving constantly or tired and moody. This is an interesting one, obsessions over the years, which may look like OCD. Well, OCD is an anxiety disorder, one of the number of anxiety disorders that does co-occur in mania and bipolar disorder. But this type of kind of high focus can also be seen in individuals who are in manic episodes, increased goal-directed activities. I'm gonna plant a garden that's gonna save the world. I'm gonna make origamis all night for every kid in my class. I'm gonna paint and paint because I'm gonna be the greatest painter in the world. So sometimes these obsessions or passions are kind of manic-driven or manic-fueled. Maybe they're also fueled by obsessive-compulsive disorder. I have to make so many numbers of origamis. It's not always easy to tell. And then the third thing that can fuel this particular symptoms is the perseveration in autism. Individuals with autism have a tendency to have a restricted repertoire of interests and tend to get stuck, like a broken record, over and over and over and over on one thing. Bugs, bugs, I'm only gonna learn. I only wanna talk about bugs to you because I'm interested in bugs and I've read everything about bugs. So it can also look like they have an obsession, but is it obsession or perseveration or manic-driven? Or in my patients, maybe all three are contributing to this difficult hyper-focus and rigidity that these children can have, which can be very frustrating to parents and families. Meltdowns come out of nowhere, other times triggered. Sometimes I'll say, does your child have any outbursts? And a parent will say, well, oh, he's in reaction to something. And I'll hear that the reaction was they're having spaghetti and not chicken for dinner and that he upended his room and trashed and put three holes in the wall. Well, that's a big reaction to a small precipitant. I can see that it was triggered in that moment, but it looked like he was ready to be triggered. Big reaction to small precipitants or virtually out of the blue. And then finally, this individual had a confirmed autism diagnosis, which just further compromises the course of an individual who has a mood disorder. And mood swings on a daily basis. And the daily mood swings, it's kind of like a changing Dr. Jekyll and Mr. Hyde, cycling within a day. Was that cycling or is it just changing symptoms? If you're euphoric and rageful, that's still mania, but it looks like a change to the parent. If you're euphoric and rageful and grouchy and cranky and hopeless and sad, well, that's a mixed state. It's not a cycle. These were the medications. So you can see at age five and six, they were very persistent in trying to treat that ADHD. Guanfacine, resulfenidate, mixed amphetamine salts. Kept going, bad reaction, okay, try another one. Bad reaction, okay, try another one. Wearing off fast, it'll give him a little booster. Bad reaction, try one more. Okay, they finally gave up by age six and seven. Let's try the antidepressants because this child looks pretty unhappy. Bupropion, this parent said psychosis, hallucinations, and actually said foaming at the mouth, which I haven't had a chance to ask exactly what was meant by that, but it sounds like a dramatic, awful, horrendous medicine reaction. Then fluoxetine, major positive mood reaction in one week. Yay, that sounds scary to me when you get such a dramatic improvement so quickly. It really makes me worry that it's causing a switch. And indeed, this child needed more and more dose because it was less and less effective. Finally, it was stopped because impulsivity was so increased. Guanfacine was given because of impulsivity, thinking it was ADHD. It sounds like this was kind of like a wild impulsivity though, like maybe a kind of reckless activities of mania. Hiding, running away, running away from home, running to neighbor's houses. And then duloxetine, worst of all the medicines, severely aggressive, hospitalized within the first week of starting. Lamotrigine, and now by the age of 12, they're thinking, okay, maybe we'll give an SGA. Place number two was the little girl who's six who's coming to me, banging her head, screaming. That's not a tantrum. Tantrum of childhood. Tantrums of childhood are annoying. Oh, my child really loses it. Yeah, that's annoying, it's difficult, and then you pick them up and you distract them, and as they get older, they develop more emotional control. This is self-harming and highly disruptive. Unpredictable outbursts. Also has this transitions difficult, sensory sensitivities. I'm thinking autism features in this child, but it's hard to convince the parents of that because she's funny and social and a leader in the class. Well, she is only four, but she's kind of a bright light for the party, which makes me think she's a little manic in class. Biting, scratching, throwing. You know, it's like my hitting, kicking, biting, spitting. Risky play. Loves to climb on high things, hang and jump. And this walking on eggshells. We don't know what's gonna set her off. We don't wanna set her off. Whatever happens, we don't wanna set her off. And then this disruptive high energy, this energy cycle. This last part, the more social the setting, the less there's a violent outburst. The parent says it happens more at home than at school. If she's in a violent tantrum and a neighbor comes over, the child stops. So some people will say, well, that can't be mania because that's just a wise kid who's kind of trying to get lollipops or something. But I hear this story a lot, and I can't say that it's volitional on the part of the child to have these tantrums because they're really quite regrettable afterwards. They're very remorseful, often remorseful, often ashamed, often embarrassed, often will say, I was out of control. But how could it be that they could change so quickly? Well, you can if you have some level of control still left, right? Like if you were in public and you were feeling super sad and you started to do the alphabet backwards, like do a cognitive task, it kind of takes your mind away from your tears. You're not using your emotional brain, you shift to your cognitive brain. And for children who are anxious, they kind of shift into anxious brain and away from moody brain when somebody comes over and sees them. Maybe at school, yeah, I wanted to do a study like putting these children in a fMRI scanner and hearing their teacher's voice, neutral, and then hearing mother's voice. We're having spaghetti, ah! And then they have tremendous emotional dysregulation. Their brain gets all stirred up. We all, your mother, your mother is somebody who's, you say mother, you think of mother. It puts you in a whole different emotional mindset. And if your problem is a problem of emotional dysregulation, if it's that part of the brain that regulates our emotions, mothers are going to bring out that type of response. And if you have any aberration, maybe it brings out the aberration. I don't know. I just know I hear it and I see it a lot. And one family advocacy group said, if you're gonna demand that this problem be constantly present in every setting all the time, you're gonna delay diagnoses for many, many children because this type of clinical picture is common. And I think a lot of mental health people see it and say to the parents, she's fine at school and only doing this at home. Well, what are you doing to her at home? And that only adds a tremendous burden to the parent who already feels guilty, because that's parents feel guilty just because they're parents. Then there's the other thing the mother said. She keeps it together for so long, has to let it out. Well, I can appreciate that too. You could be at work all day and kind of be nice and smile to everybody if you're in a bad mood. Then you go home, who do you snap at? It's people you care about the most, but that's where you kind of let it all hang out. So one of my colleagues says like a dog, you teach to walk on two legs in the circus. You look at them and you say, look at those dogs on two legs. They can walk on two legs. They can do that so well. They can do that all the time. No, they can't do that all the time. They don't want to do that all the time. It's taken a lot of energy for them to do that all the time. Same for some of this containment, holding together their emotional responses. And then this child's medications. Atomoxetine, disaster. Methylphenidate, dexedrine. Tantrums escalated like a rabid dog or like she was possessed. I've heard many parents say both those things. There's a look in their eye. There's something kind of different. Went nuts. Oh, then guanfacine and sertraline were the next trials. And sertraline was started last May. These were both started last April, May. Sertraline increased to 50 milligrams in September. And guess when they started calling me, which was like just after that, November, December. Not getting any better. She's getting worse. Sertraline initially seemed like an improvement, right? Yay, it's an improvement, wins the battle. But then the problem started to come back again. And she's dampened, she's sleepy. Terrible side effects. It's just not working. Seems to maybe have triggered or maybe the disorder's evolving. More waves, the mother calls them. Sounds to me kind of like cycles of either extreme high energy levels or lethargy. Up for a few days, bouncing off the walls, then extremely tired and sleeping an unusual amount. These energy shifts are important to listen to. Okay, I think that's the end of my long presentation. Thank you so much for your kind attention. And we'll take questions, both from the audience. as well as from our online audience. Dr. Ambrose is going to help moderate those. All right. Can I go ahead? Yeah, hi. I'm Ray Sablatney. Sorry. Back microphone. So we'll do a little bit of a coordination because there are also questions online. So I'll call on folks alternating between. Feel free to just stand in line. And apologize ahead of time if we do not get to your questions pending time. I want to be sensitive to everyone's schedule. So back question. Thank you. I want to be very thoughtful about I have a question and a comment because I do find myself in that skeptical group as a child psychiatrist and also someone who's worked in children's mental health for 18 years in schools and in homes with families. So my question is when I have folks coming my way with emotional dysregulation as kind of like the chief complaint, I can't say that I've never felt like someone met criteria for bipolar disorder. I've definitely seen that in children and adolescents. But I would say it's more the exception than the rule. And what I have seen is that they kind of land into three camps. There's parents who are describing their kids as incredibly aggressive. But when you really ask them what that means, what they're really talking about is they're describing their kids that are just emotional. There's no physical aggression, property destruction, that kind of thing. And it's really more a family who kind of can't tolerate distress and doesn't really know what to do with emotional dysregulation. So there's kind of just like psychoeducation for that. And then there's autism and ADHD. And I saw that in your comorbidity and I felt like that was explained in a lot of ways. But then there's a third group that wasn't discussed today and I was hoping that maybe you could answer the question that I have, which is trauma. So I think that's a huge component of the third group that I see is that kids are experiencing pretty significant trauma and it might not rise to the level of having children's services remove them from their home. So they continue to live in these environments that are traumatic and incredibly activating. So I was hoping you could speak to that. And then my comment is with discussing the reason for pursuing the DMDD diagnosis. Correct me if I'm wrong. My understanding of that was not because we wanted to decrease the number of kids being diagnosed with bipolar disorder, but that there were significant concerns about the increase in use of atypicals in particular from pediatricians in using atypicals in the preschool age was what was being seen as there was more of a focus from child psychiatry in making sure we were recognizing pediatric bipolar disorder and that there were also concerns about the fact that research being done on pediatric bipolar disorder was connected financially to Johnson & Johnson who make Risperidone. And I bring that up because that was my understanding of why DMDD came about and I think it's a particularly kind of uncomfortable topic in child psychiatry but really highlights the fact that as child psychiatrists we have to be stewards of children's mental health because there aren't enough of us and so many pediatricians are doing this work and they're not well trained but they're desperate and they want to be helpful so when they hear things like we're missing pediatric bipolar you know they want to take action but what ended up happening was that there were a lot of kids being prescribed atypicals and I can't imagine that that actually represented that they were treating pediatric bipolar. So my question is about trauma as a comorbidity and then kind of speaking a little bit to the fact that this is it feels like a kind of controversial topic. Yes. Yes. I never know if someone's going to throw a tomato at me or give me a hug after these kind of talks for sure. And conflict of interests are true and real and we have to recognize them and they exist in all areas. But but in in I it's both directions inappropriate medication not medicating I agree we have to everybody has to be better trained and better at recognizing what's what especially if you're going to use a medicine that has significant serious side effects associated with it or annoying side effects even even just obesity which is a major problem. It's one of the reasons I started to do work with complementary and alternative treatments because they seem like safe and healthy and good for you and people felt okay about these over-the-counter treatments and I think that a lot of people are reluctant to see a psychiatrist because it's like they're going to give me some terrible medicine. Well if complementary and alternative treatments might be in the list of things that you might do to help I would hope that it would decrease the fear of seeking out the consultations for individuals and also give us something to use in people who have sub threshold cases it's gray. I don't think it's really there. It's not enough for me to want to prescribe an antipsychotic. So there's a number of reasons that we need to develop more of these treatments and opportunities. I guess I would say about comorbidity is that it's I my experience is that it's usually not productive to do an either or. It's usually a both this and this together. And so while you know autism and ADHD can bring some emotional dysregulation there's different levels of that but but again it comes back to this being trained in and understanding and being open to thinking about these different types of clinical pictures but yeah in a thoughtful way absolutely. I'm glad you mentioned the trauma question. All your questions are quite good and I didn't mention this at all here and you know people in trauma clinics see a lot of children who are very emotionally dysregulated. What I would say is by the same token plenty of people who are traumatized become more anxious and withdrawn and quiet or become depression and anxiety I think is a way more common outcome from trauma than than wild emotional dysregulation. So the question is where does where is your bone break when you stress it? What problem is going to emerge when you're stressed when you're in a terrible difficult situation? Do you become anxious? Do you become depressed? Do you rise to the occasion? Some people are resilient or do you show the signs of bipolar disorder? If you're traumatized and you're anxious afterwards absolutely take the child and the individual out of the traumatic environment if you can. Absolutely address the trauma but I'm going to treat their anxiety. If they're depressed I'm going to treat their depression along with it not ignore that they were traumatized but why leave them in a state of hopeless misery suicidal thinking unable to function if we have a pharmacologic intervention that can support them through it not take away the trauma at all. And if the symptoms look more bipolar then they should be treated with anti-manic or mood stabilizing agent. So it's not an either or. The other thing I would say about trauma is we looked at our cohort thinking okay so maybe these children are traumatized maybe they're traumatized we don't even know it but that's impossible what can you do there that's kind of you know we can't put cameras in their rooms or whatever but we did look for reported traumas and we did find a higher rate of trauma among the children we diagnosed with bipolar disorder but the interesting thing was that the traumas often occurred in time after the first symptoms of bipolar disorder which leads me to say to these families having bipolar disorder in your child is they're at risk to be traumatized. They're at risk to be traumatized because they're doing reckless things and they're not thinking. They're at risk to be traumatized because they attract the attention of nefarious adults. They're at risk to be traumatized because they may have relatives the familiality who aren't as good at monitoring and supervising. So I think that when we see a child who has trauma and emotional dysregulation it's important to think that both may be co-occurring. Yeah. All right. Front microphone. Okay. I'm an adult psychiatrist raised sublotny and I practiced for 35 years at Kaiser Permanente which is interesting because it meant that I followed many patients for 20 to 30 years because they don't change insurance and they continued. So lots of actually classic sounding bipolar ones you know psychotic mania at Dartmouth and then they go to Harvard for the MBA. They get hired by the Federal Reserve. They're great employees. They have great kids. After a few years they're down to once a year and then I volunteered the last 10 years after retirement in a bipolar clinic here at UCSF. I would say the majority of my patients had their first declaring episode whether it was depression or mania from 16 to 25. And then the whole spectrum which is kind of weird too. Why does someone have it at 38 and 45 and 55 like the patient of a brother sister bipolar patient I knew about. Are there different subtypes. I mean none of them describe what you describe in these children. I found it very interesting to listen to and and in my patients I mean I was trained when lithium became approved. I use lithium a lot. My colleague the other professor uses it and we see very good effects with stability breeding stability. So if you make that three years you're going to make six you might make nine you might make 12 or in 20 years you have one episode at the holidays where I give you a little Risperdal. So my question is do you. What do you think about subtypes. Yeah. So I guess I would say about insurance is that to have insurance you probably need a job or a spouse who has a job and kind of a stable life and a lot of the children who I treat end up in the Department of Mental Health type situations. So they may not end up in your cohort in that way. But yeah I think there are different subtypes of bipolar disorder but how do we figure how do we cleave them apart. I think we're in the realm of like if we in the old days if you were a general practitioner years ago and you had four patients come into your office vomiting you would just say oh you've got a you all have vomiting problem. I'm going to treat you all the same. But now we're going to say well maybe one had a concussion maybe one of them is pregnant maybe one of them has food poisoning. But now we just do that with psychiatry though. You've got these symptoms you all have those symptoms. I'm going to just think of you all in the same bucket. But I yeah I imagine there's all kinds of different neurobiological pathways to these symptoms that have different causes and may respond better to different treatments. Right now the only way we can tell if someone's going to respond to the treatment is you know give me the test for bipolar disorder. I'm going to ask you a lot of questions and hear the answers and give my best estimation. Give me the tell me if I'm going to respond to this medicine. I've got this gene test. That gene test doesn't tell me if you're going to respond to the medicine. I have to give you make my best guess about knowing what I know about psychiatry and your symptoms give you the medicine which I think is going to work but I have no it comes with no guarantees. You have to watch and see if it works for you and watch the side effects. So but this is the holy grail right knowing these subtypes and figuring it out. Yeah yeah. Yeah. Poor functioning. Yeah. More difficulty. Look downward drift. I would say you know. Difficulty functioning. Yeah. I think as I currently oversee a treatment resistant mood disorder to clinic and I think one of the things that was really instrumental in your teaching that I'm carrying forward in philosophy is like we expect patients to come in really neatly categorize DSM diagnosis and oftentimes they comments they are we try our hardest to configure what is the best possible option we can provide in that moment for them. So this question comes from the online folks is do you have any particular tips or guides in differentiating and treating kids who may have kind of intersectional DMDD and bipolar. How do you tease them out and how do you better approach the treatment DMDD getting I didn't show you all the different criteria and how you get there but all along the way if you have manic symptoms you kick out to mania. So I think it has to do a lot with how you construe the symptoms how you hear the symptoms. Is this irritability just irritability and in a family that can't tolerate emotional expression or is this really disturbing extreme and frightening irritability and in that way you may cure it as a manic symptom or you may not. So when I get DMDD I don't if you strictly go through it you end up looking more like you have ADHD ODD depression and a lot of the DMDD studies suggest stimulants and antidepressants so it's not that big a surprise. So I usually say well why do we need DMDD you've got depression depression presents with irritability depression and ADHD we've got those diagnoses so it leads us to that but a lot of people use DMDD because they don't want to say bipolar for whatever reason it holds more stigma I can't say that it doesn't you know all of our disorders do holds more stigma maybe they it means I have to be on medicines forever but I never said that I mean we're looking at longitudinal course of these kids some of them may grow out of it some may get better over time maybe early intervention means less medicines or no medicines later so there's a lot of reasons why people might not use the bipolar word and prefer DMDD. So when I hear that diagnosis I don't know if I'm dealing with somebody who has strict DMDD which is probably going to be more like depression and ADHD and or ADHD or pseudo bipolar we're calling DMDD which means that we need to use mood stabilizers. So what do I do I I go back to the I go back to the specific symptoms of mania I go to that DSM checklist I ask the questions I listen to it and I say hmm does that sound like an extremely high level of irritability does that sound like the kind of high mood that I would call pathologically euphoric or elated I listen to the stories tell me more what how else do you see it does it happen every day give me if I had if you if I were in the room with you what would I see how would I see them doing these things so that I can get a sense of just which which symptom it is in the end you have to say DMDD doesn't have a particular specific treatment it looks like antidepressants and ADHD medicines because they also make criteria for ADHD and depression I guess is my answer I hope I answered that. All right back microphone. Great thank you so much for your presentation I have two I think fairly straightforward questions one is if you could comment on the cyclicity of bipolar symptoms in kids I remember your chart and there's so many comorbidities and there's so many different types of irritability that they overlap that I can understand it's hard for us to see the cycles distinctly is your theoretical understanding of bipolar in children that it still exists in cycles it's just that we can't see it clearly. Yeah the cycles though the way I see them and is that they don't go from completely fine to to worse they go from bad to worse to worser so it's better times and worse times and I can talk to parents parents can describe seasonal changes they can describe you know I can say anchor this in the worst time when was that oh that was last February when they were in the second grade Valentine's Day show I don't know they can anchor the worst periods there are worse times. It's almost as if they have a lower functioning baseline. Correct that's how I that's exactly how I think about it you're right. Okay great my second I'm actually going to defer to the gentleman in the front just in interest of time because we have a lot of folks have questions and there are like 20 questions. Thank you very much for a great presentation very informative but I tend to worry less about the diagnosis because as we understand the brain more and more the diagnosis can change so you know once we understand what part of the brains do what and better neurochemistry then what we call bipolar may be many different disorders and will be classified more specifically to what treatment is needed so what says worked for me with patients is rather their focus on what their diagnosis is is what their symptoms are so if I'm using psychopharmacology I would say well okay if you have a lot of mood swings irritability we will use a mood stabilizer if you have more depression without any necessarily evidence of bipolar I would use an antidepressant but if they start showing some many type of symptoms but more focus on the patient's symptoms as opposed to the diagnosis so my question is what do you think of that type of approach yeah yeah I totally agree I mean that's one of the reasons I mentioned the sub-threshold and these mixed states you don't have to count every symptom and say oh you don't meet criteria you're out of my office I I agree you need to to follow the symptoms and where it often comes up too is that somebody who's in partial treatment somebody comes in tremendously emotionally dysregulated with what I think is bipolar disorder probably comorbid with ADHD and anxiety and maybe autism who knows what I give them a mood stabilizer of some sort probably an SGA they settle down and now they're irritable but they're grouchy cranky whiny they're not so explosive is this depression that I need to now think about bipolar depression or is this residual mania so I need to increase this SGA is this the irritability that comes with somebody who's tremendously anxious and their parents are trying to push them out of the door to go to soccer and they get angry so a lot of it you get into these details of maybe this is the ADHD that hasn't been treated is it time to add a stimulant so the symptoms are really key more than the specific diagnoses and you we generally rank our treatments towards the most severe symptoms first but then you uncover then you're left with the next layer and the next layer and the next layer when we first did a look at a chart review of the SGA's we thought wow these SGA's are working great for these kids is back in the 1990s and so we had this blinded chart chart review that some of the residents did and it didn't show it the CGI's weren't improving and we're like this is so strange but when we looked we saw the chart notes would say things like no longer explosive and aggressive but teacher complaining that fidgety can't read da da da da da da da CGI very impaired but but they were much better if you did the symptom that symptom got better yeah after the app that's awesome well you always have to worry that what you're seeing is a side effect to what you've given them all right especially if you've given and when I say living you give an antidepressant for sure yeah a lot of folks asked about this but would you mind commenting on the chronology of the the child's development like under six years old six to say 12 years old and 12 into adolescence are there different approaches pharmacologically that you consider for both the manic and depressed state I just combined like six questions one don't think anybody's ever done a study of response based on age there have been some studies to show that because the FDA approvals go down to age 10 for those STA's number of studies have looked at that longer younger age group and even preschoolers in clinic samples and basically the conclusion is they look a lot like the older kids they respond a lot of like the older kids they have the side effects like the older kids do it's um you know I think that using medications and preschoolers is scary because their brains are developing and so we don't understand that and don't know what what's happening but I like to think that when we choose the right treatment and match it they're setting somebody on the better developmental trajectory there's something's already gone awry with development if they're in one of our offices so I don't think that we do think differently about about the about the treatments in those different age groups I you know if somebody has like a conduct disorder that onsets in adolescence you don't all of a sudden become sociopathic out of nowhere you start out with conduct disorder when you're younger and if all of a sudden people are doing sociopathic things in their 13 or 14 I'm thinking there might be manic because they're reckless and impulsive and making bad decisions for themselves so I sometimes think of the symptoms differently in these different age groups for sure and then in the adolescence I always worry that they're complicated by substance use and I always get a drug screen on everybody even the ones who look like innocent good citizens because I've been fooled so many times all right last question back microphone thank you I'm a child and adolescent psychiatry fellow and this makes so much sense just coming from the inpatient unit like wow amazing thank you but I was hoping to hear a little bit about a comorbidity that I you haven't mentioned which is borderline personality disorder because that right we see it a lot it's a good question yeah I was once asked to be in a forum that way they were going to do is it borderline or is it bipolar and I was supposed to say it was bipolar and I said no I'm not going to do that because again it's hardly ever either or you can be borderline and have depression you can be borderline and be bipolar you know you could be borderline I think we tend to see the most disruptive borderlines in our clinic it's kind of like the traumatized kids the ones who filter in have everything but that level of emotional dysregulation is not a core feature of borderline personality disorder you have emotional instability but if you're having things that look like they're manic level rages or euphoric episodes or depression and hopelessness and suicidality you're going to treat those symptoms with the matched medications whether it's an antidepressant for depression or whether it's mood stabilizer for bipolar disorder there's a kind of a small literature on the medication pharmacotherapy of borderline personality disorder and it's interesting it's a lot of mood stabilizers but I think that's because they are most severe you know individuals enrolled in those trials and you could see that that once you settled down the emotionality they seem to do better in their interpersonal ways I tend to think of when you're if you're asking me is it borderline it's it's like talking a little bit of a different language than the axis one it's I thinking about axis one being phenomenologic what symptoms do you have how much when and what are they like and access to I'm thinking more like how do you interact with others do you use different what defense mechanisms do you employ protective a medic identification is it if they're splitting that's those are that's a different way to think about someone's thinking feeling and behavior and some of the bipolars I treat I think are have borderline features but many of them don't and I imagine in borderline personality disorder it's the same thing like I remember in the borderline clinics they often all looked like they might have bipolar disorder but I have neighbors who are borderline I can tell you for sure they're not nearly I gave you lots of stories but I can tell you that they don't have that level of emotional dysregulation so it's not an sine qua non it doesn't automatically give you borderline it's not again not either or both and they both need a little bit of different treatment although it's interesting that DBT is good for both right these are all such great questions and I appreciate everybody bringing them to me and listening and I always think that it just leads us to more interesting research studies that we might do to parse it all out thank you

pediatric bipolar disorder

diagnosis

treatment

Dr. Janet Wozniak

comorbidities

ADHD

second-generation antipsychotics

mood stabilizers

borderline personality disorder

trauma

alternative treatments

pediatric mood disorders

early intervention