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Bipolar Disorder: Update on Diagnosis and Treatment · Pediatrics Now: Cases Updates and Discussions for the Busy Pediatric Practitioner

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I'm Holly Wehment, and this is Pediatrics Now, cases, updates,
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and discussions for the busy pediatric practitioner.
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Today, I'm bringing you grand rounds. Let's listen in.
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Thank you very much, and thank you for inviting me to present this morning.
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We're going to spend the next 45 minutes or so talking about bipolar disorder
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in kids, talking about diagnosis, and then touching on some of the neurobiology and treatment.
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I wanted to disclose potential conflicts, mostly in the form of research support
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for a variety of companies that support some of the medications that we will be discussing.
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So first, we'll talk a little bit about the phenomenology and course of illness.
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We'll talk about treatment of the different phases of bipolar disorder,
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treatment of mania, treatment of depression associated with bipolar disorder,
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and then a little bit about maintenance treatment,
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early intervention, which is kind of a hot topic.
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How do you know when to treat for bipolar versus treating for other prodromal presentations?
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And then we'll talk a little bit about some of the metabolic adverse effects
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of the medications that are most effective to treat this illness.
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So just to kind of make sure we're all talking the same language,
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and this may be a review for some people, bipolar 1 disorder is defined by the
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presence of having at least one full-blown manic episode.
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And we'll talk about specifically what those criteria are.
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Bipolar 2 disorder is defined by having hypomanic episodes with depressive episodes.
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So for bipolar 1, you never have to have a depressive episode,
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although a majority, 80% will have a depressive episode sometime during the
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course of their illness.
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For bipolar II, you must have hypomanic episodes with depressive episodes.
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Cyclothymia, which is fairly common in kids compared to adults,
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and it may be an early presentation, is hypomanic and depressive symptoms that
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last over the course of a year.
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For kids, it's two years for adults.
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And then the most common diagnosis was historically bipolar,
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not otherwise specified.
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Now we have those divided into
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two different diagnoses, other specified bipolar and related disorders.
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That is actually when you want to specifically state why they don't meet full
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criteria for a manic episode and unspecified bipolar disorder.
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That's when they don't have the duration criteria or the number of criteria,
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but you don't really specify why they don't meet full criteria.
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Okay, so a manic episode. A manic episode is defined by the presence of elated,
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expansive, or irritable mood.
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You have to have one of those characteristic moods.
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And as we'll talk about, the problem is for kids, depression also.
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Irritability is a criteria.
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So sometimes when the mood is irritable, as we'll talk about,
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it can be very difficult to figure out what the underlying diagnosis is.
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So elevated, expansive, or irritable mood and an abnormally persistent goal-directed
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behavior with high energy lasting at least a week.
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And that's a new part of a criteria for a manic episode.
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The goal-directed behavior has to
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be increased energy that
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lasts at least a week it has to be present nearly every
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day and then depending on whether the mood
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is irritable elated or expansive you have to have three or four of the other
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criteria so it's increased grandiosity this is when the kids think they're better
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than the adults in their lives most kids think that but they act on it.
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They will tell their teachers, they know how to teach the class better than
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themselves, better than the teachers do.
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They will be very defiant, but to the point where they really believe that they
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have the ability to do things that they don't.
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They have a lot of grandiose ideas about the future, about where they fit into the future.
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They have decreased need for sleep, And it's not just poor sleep,
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it's poor sleep and high energy, increased pressured speech.
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Flight of ideas where their thoughts are jumping from idea to idea, distractibility.
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Increased goal-directed activity, and excessive involvement in high-risk activities,
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pleasurable high-risk activities, buying sprees,
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you know, purchasing a lot of things on the internet when they don't have the
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ability to do that financially.
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And then multiple sexual partners during a brief period or running away from home.
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These are all the kind of classic symptoms for a manic episode.
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Hypomanic episode, really the only difference between a manic episode and a
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hypomanic episode is that for a hypomanic episode.
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Four days, and it does not have as severe impairment.
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So the impairment for a manic episode is pretty severe.
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For a manic episode, it needs to last seven days, or you have to be hospitalized
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in the course of that manic episode.
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So it has to be pretty severe and functionally impairing.
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A hypomanic episode, it's not fewer criteria. It's all the same criteria,
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but it's not as much impairment.
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Major depressive episode, just everyone knows Siggy Capps, but it's more than
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or equal to five symptoms and depressed mood, anhedonia,
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failure to gain the weight they're supposed to or weight loss,
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decreased appetite, insomnia, psychomotor agitation or retardation,
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fatigue, loss of energy, worthlessness,
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suicidal ideation, and poor concentration.
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So any constellation of those symptoms, five or more, but you have to have the
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depressed or irritable mood or anhedonia.
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Okay, so the problem with DSM-5 was that for kids with bipolar disorder,
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we used to diagnose in the majority of kids a mixed episode,
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which is co-occurring mania and depression.
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In In DSM-5, there is no such thing as a manic or a mixed episode.
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What it typically ends up being is mania with mixed features.
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And you could have a depressed episode with mixed features as well.
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But there's no episode that is defined as a mixed episode any longer.
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Also, the change in energy level is emphasized,
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as we discussed in the manic episode definition, and
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because of that it's very hard sometimes
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with the differential and the comorbidity of
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ADHD that we'll talk about because that
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makes it even more difficult because you have to have the increased energy or
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culturacted activity and then as we mentioned there's no longer the BPNOS which
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a majority of kids were getting that diagnosis now it's other specified bipolar
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and related disorders as we talked about.
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So those are some of the drawbacks of DSM-5 for kids.
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The criteria for a manic episode is no different between adults and kids at this point.
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So what is the epidemiology of bipolar disorder in kids?
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About 2% of kids will meet criteria for bipolar spectrum. That's bipolar 1,
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bipolar 2, or bipolar other specified.
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And so it's about 2%.
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50 to 60% of adults, when you ask them when their onset of bipolar or manic
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episodes or hypomanic symptoms were,
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most of them, two-thirds, up to two-thirds will say that they had it as early as during childhood.
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Irritability is one of the earliest symptoms of bipolar disorder when you do
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retrospective studies, but it's also very nonspecific.
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But most people who grow up to have bipolar diagnosis will tell you retrospectively
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that irritability was one of their earliest manifestations.
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And overall, we know that early-onset bipolar disorder is associated with poor
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outcome, increased risk for lifetime suicide compared with adult-onset bipolar disorder.
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And bipolar depression is more common than manic episodes.
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They spend more time in the depressed phase of bipolar after the onset of their
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manic episode when their onset is younger.
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So those are more the kind of characteristics or epidemiology of what early
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onset bipolar disorder looks like. We also know that there are very high rates of comorbidity.
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ADHD is almost ubiquitous when your onset of bipolar disorder is prepubescent. It's about.
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85% will have comorbid ADHD. That has been an area of our research interest. Is this real ADHD?
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That's like a whole other topic of a presentation.
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But regardless, they do meet criteria for ADHD about 50% when the onset is during adolescence.
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And other common comorbidities, conduct disorder, Anxiety is high rate of anxiety.
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Substance use disorders, about 40% who have their onset during adolescence will
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have co-occurring lifetime substance use disorders.
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But generally speaking, comorbidity is the rule rather than the exception.
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So irritability, as I mentioned, is nonspecific. It could be part of normal
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development. It can be part of cadre of diagnoses, and we consider it like a fever.
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It just tells you something is wrong, especially when they're getting to see
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as their chief complaint, whether it's us or pediatricians.
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When the chief complaint is irritability, it really is just a symptom,
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and it's our job to figure out what the underlying diagnosis is.
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Sometimes it's because they're being bullied at school, and we kind of diagnose
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that, generally speaking, as an adjustment disorder.
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Sometimes it's depression. Sometimes it's ADHD.
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About three-quarters of kids with ADHD present with irritability at different times.
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Anxiety disorders, irritability is very common. We'll talk in a minute about
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disruptive mood dysregulation disorder. That's a newer diagnosis that you may or may not have heard of.
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And oppositional defiant disorder, which I...
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Am a big advocate of never giving somebody oppositional defiant disorder as
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a diagnosis. It does not exist. It is irritability and defiance. It is a symptom.
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When you do epidemiologic studies,
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only a small, small number of kids will have just an ODD diagnosis.
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They always have it in conjunction with another diagnosis, ADHD.
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Mood disorders. And so it is very rare that a child will have ODD.
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We never give that diagnosis in isolation. There's always some reason they're irritable or defiant.
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Kids are not by nature irritable or defiant for the most part.
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Okay, so DMDD, you may have heard of this diagnosis.
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We typically do not give it at a reliable rate because the criteria are very complicated.
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But in most of the research studies that have examined DMDD.
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You can't have a manic episode and be diagnosed with DMDD.
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So it's kind of a diagnosis of exclusion.
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Some people will call it like having extreme temper tantrums.
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But it is basically a lot of the criteria for persistent depressive disorder.
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So generally the mood, and that's where it's listed in DSM, is under a mood
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disorder, but more under the depressive spectrum of disorders.
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So it's people who are very depressed and irritable as their predominant mood,
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but these are the specific criteria.
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Most of the people who give this diagnosis...
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Kids don't necessarily meet all these criteria. A lot of times they will have depression.
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When you do studies comparing what used to be severe mood dysregulation,
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now called DMDD, and basically the family history of bipolar is extremely unlikely.
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And so that is one of the criteria that we will use to differentiate.
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If somebody comes in and there is a family history of bipolar disorder,
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Those kids do not have DMDD.
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It is like less than 5%. And so that is really one of the biggest questions
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to ask about a family history of bipolar or manic-like behaviors.
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So again, if you have diagnosis of bipolar 1 or 2 in your family,
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you're not going to give them a diagnosis of DMDD.
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And if you have criteria for ever having a hypomanic or manic episode,
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again, typically they will not have DMDD.
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They will have bipolar disorder. This is an interesting study that was...
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Done or analysis that was done looking at all the different studies of DMDD.
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And in one study in particular, when you looked at who has just a diagnosis of DMDD without ADHD,
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ODD, or conduct disorder, out of almost 500 kids, only four did not have another diagnosis.
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And so we, again, like ODD, think of DMDD as it's a symptom of extreme irritability,
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temper tantrums, but we need to figure out what the underlying diagnosis is.
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A lot of times, it's ADHD in a majority of cases with extreme irritability,
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but again, using the criteria for a manic or hypomanic episode,
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you cannot have this diagnosis.
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And interestingly, when you look at the treatment studies of DMDD.
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They're kind of all over the place in terms of sometimes stimulants work,
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sometimes antidepressants work, sometimes second-generation antipsychotics work.
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So it kind of really is not very homogeneous diagnosis. It's a lot of different
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diagnosis with extreme irritability and temper tantrums.
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So what are outcome predictors of kids with bipolar disorder?
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Well, non-adherence is very common, especially in adolescents.
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Most of the kids will not be fully adherent with their medications during the
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course of their initial diagnosis.
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But so non-adherence is obviously a predictor of poor outcome.
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Comorbidity makes the diagnosis more difficult to treat.
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Girls have a worse outcome. They remain more symptomatic and.
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Being prescribed stimulants and antidepressants in conjunction is often associated
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with poor outcome, and we'll talk a little bit more about that later.
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Having co-occurring substance use, independent of non-adherence,
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although substance use comorbidity is more prevalent in those who have poor
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adherence, substance use by itself is a predictor of poor outcome.
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Having no psychotherapy.
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And this has been in a variety of studies, interestingly, and it doesn't matter
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what type of psychotherapy, but having any type of psychotherapy is predictive
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of having a good outcome.
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Socioeconomic status is lower socioeconomic status is predictive of poor outcome.
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And having a lack of maternal warmth, and maternal warmth could be paternal
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warmth, It's just having a
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caregiver that is participating in the child's care on a day-to-day basis.
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So basically, a lack of maternal warmth is associated with poor outcome.
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It doesn't mean it causes the illness, but it is associated with poor outcome.
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And then in some of the largest studies, we know that kids who have a diagnosis
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of bipolar 2 disorder or bipolar NOS in prior studies,
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most of them will go on to have bipolar 1 or bipolar 2 if they have NOS.
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And if they have bipolar 2, about a quarter will go on to have bipolar 1.
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This is during about five years of, on average, follow-up. So bipolar NOS and
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bipolar II will often progress. Now, what about.
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Kids who have family histories of bipolar disorder.
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The BIOS study is a multi-site study that was done predominantly in Pittsburgh,
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but it is a study, and the only study we have,
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that compares kids who have parents with bipolar disorder, and bipolar disorder
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is one of the most familial illnesses we have in psychiatry.
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If you have a parent with bipolar disorder, the child has a 30% chance of having bipolar disorder.
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One parent with bipolar, the other with a mood disorder.
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If it's depression or bipolar disorder, it has ranged from 70 to 85% of those
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kids will have bipolar diagnosis.
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So it's very familial diagnosis. But this study looked at offspring of parents
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with bipolar disorder and compared them to control offspring who had parents
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without any psychopathology,
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but then uniquely compared them to also kids who had parents with other psychopathology
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other than bipolar disorder. So we have three groups.
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So it's one of the only studies that has looked at it that way.
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And what this study found is that across the board, kids who have parents with
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bipolar disorder are at higher risk for, of course, having a bipolar spectrum illness.
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And the middle column is compared to those who have a non-bipolar diagnosis in the parents.
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So another, you know, population or sample that has psychopathology in the parents.
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And there's nine times the risk of having a bipolar spectrum diagnosis, but also the.
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Four times the risk of having any mood disorder in the kids.
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And across the board, most diagnoses are higher in the kids compared to the
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kids of parents who have other psychopathology.
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Compared to kids who have control parents who don't have psychopathology,
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the risk is even higher of any mood disorder.
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It's about 20 times the risk.
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So again, it's a familial illness. Other risk factors that are associated with
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having a parent with bipolar disorder and the kid themselves having a diagnosis
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of bipolar is having younger parental age at the child's birth.
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Of course, we mentioned having both parents have bipolar disorder.
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And if you have a parent who had early onset bipolar disorder during childhood
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or adolescence, the child themselves is at more risk for having early onset bipolar disorder.
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And then in the child themselves, if you have a parent with bipolar disorder,
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if the child has depression or anxiety,
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mood liability, if they have exposure to antidepressants or stimulants,
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if they have anxiety or disruptive behavior disorders in themselves,
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they are longitudinally more at risk for developing bipolar disorder.
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So those are kind of what we consider maybe quadronal presentations of bipolar
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disorder in offspring of parents with bipolar disorder.
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So we kind of characterize the development of bipolar disorder into different stages.
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And depending on the stages, and we'll talk a little bit about how treatment
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plays a role here, but there's stage one, which is having risk factors.
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So as we mentioned, having a first-degree relative, number one risk factor.
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But these are other well-established risk factors for having a bipolar diagnosis.
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In the more risk factors you have, the more likely you are to go on to have a bipolar diagnosis.
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For those of you who are interested, Pittsburgh has developed a predictive scale
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that looks at what it takes a child.
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And it's not been validated in a lot
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of different samples, but it has been validated in more than one sample.
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And it looks at the risk factors that a child has and predicts the potential
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for them to go on to develop bipolar disorder.
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So if you're interested, it's worth at least looking at and knowing that it exists.
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And then there's the prodromal clinical features. All of these diagnoses have
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been established to be risk factors for going on to have bipolar 1 disorder.
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So that's kind of how we think about it in terms of staging.
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We also think about the increased stage that you're at,
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the more likely you are to go on to have more significant intervention or need
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a more significant intervention.
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So earlier on, you might be treated with omega-3 fatty acid,
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for example, or some type of therapy, Whereas you progress on to stage two and stage three.
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Particularly stage three, that's where you would need a mood stabilizer or antipsychotic.
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What about neuroimaging and what do we know about brain development in these
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kids? So I'm only going to briefly touch on this.
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This is also an area that we do a lot of research in, but there have been pretty
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consistent findings in terms of prefrontal connectivity with subcortical and amygdala regions.
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The uncinet fasciculus has been pretty well-established and consistent finding
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in imaging studies that there are alterations.
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And if you think about adolescence as a time where prefrontal amygdala connectivity
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is very much being established, there's a lot of pruning going on,
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and there's a lot of.
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These pathways that are being developed, but they don't seem to develop normally
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in kids who have bipolar disorder, and particularly ventral prefrontal,
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anterior stingulate insula, and amygdala.
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Those connectivity, those regions
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have been consistently shown to not develop normally in these kids.
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This is just an example of one study that looked at the amygdala and structural
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findings that showed that at baseline, kids with bipolar disorder,
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ADHD, and control kids all kind of look the same.
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So it's not like amygdala structural abnormalities are present prior to the onset.
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But during the first year of illness, you can see that there's normally during
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adolescence an increase in amygdala volume.
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That's been consistently shown in a lot of studies. But in the bipolar kids,
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both the left and right amygdala seems to not increase in size and in some cases
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decreases in size or stays the same.
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And so the development of amygdala volume, probably as a result of connectivity
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with prefrontal regions, does not seem to develop normally.
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And again, just to highlight the regions that have been studied most have also
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shown the most effect of pharmacologic intervention, and we'll talk a little bit more about that,
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but some of the studies have shown that there is changes as a result of intervention
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with specific medications that normalizes development.
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So we'll talk a little bit more about that.
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So we're going to switch gears now and talk about treatment.
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And these are the FDA-approved medications for the different phases of illness.
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So during acute mania for kids, the medications listed are the ones that are
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evidence-based that there have been placebo-controlled studies.
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Historically, lithium was grandfathered in by the FDA, but more recently,
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we do have data to support its efficacy for mania.
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For acute bipolar depression, which is probably, in my opinion,
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the more severe phase of illness because that's when kids are most at risk for
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attempting suicide, we only have two options.
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Olanzapine-fluoxetine combination, otherwise known as Symbiax,
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which is very rarely used.
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We'll talk about because of the side effects.
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And lorazodone, which is the first and only monotherapy we have for bipolar depression.
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And then for long-term treatment, we only have lithium and aripiprazole that
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are FDA-approved for use.
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And we'll talk about the evidence for that. So we really have an unmet need
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in terms of acute bipolar depression and maintenance or long-term use.
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This just looks at some of the effect sizes and the scale that we use for rating
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manic symptoms is a clinician-administered scale called the Young Mania Rating Scale.
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And it's an instrument that basically clinicians will interview the parent, the kid, and the
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observe behavior, and rate this instrument. And that is the main outcome measure
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for manic episodes in kids.
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What we see here is the effect size of these different medications.
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These are mood stabilizer medications like Divalpro-X, lithium,
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oxcarbacicine, and topiramate.
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And you can see here that unlike adults with bipolar disorder or manic episode,
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Divalpro-X has not been very effective.
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The effect size is 0.28 compared to other effect sizes. Lithium is 0.37.
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Generally speaking, for efficacy, you want it to be about 0.4 to 0.5 for mania.
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That's what the FDA is in general, you know, required for approval.
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To pyramid is kind of an interesting story because it was studied in adults
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with bipolar disorder for mania, but it was found in multiple studies to be
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ineffective for adult mania.
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And then the one study that was done in kids was stopped with only a quarter
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of the subjects that were to be enrolled who were enrolled.
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And then when it was looked at, the effect size was 0.5, but no other study
30:00
has been done really looking at efficacy.
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So we're kind of left with an open question about topiramate.
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When you look at second-generation antipsychotics, across the board,
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these medications have been shown to be effective for manic symptoms.
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And really, the effect sizes are fairly similar across the different antipsychotics.
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But when you directly, there's only a handful of studies directly comparing
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second-generation antipsychotic to a mood stabilizer.
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This is the TEAM study, Treatment of Early-Aged Mania, that was done,
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that was ranged in age from 6 to 15-year-olds. and risperidone was compared
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to lithium and Divalpro-X.
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And you can see here that only a quarter of the patients on Divalpro-X responded.
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In general, the studies that have looked at Divalpro-X compared to placebo have
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found that placebo responses are generally higher than Divalpro-X.
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And this study, again, is fairly consistent. Lithium has a response rate of
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about 35%, and risperidone, very consistent with the other SGAs,
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is about 70% response rate.
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And looking at side effects, though, as we'll talk about, wheat gain was the
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most significant with risperidone.
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Prolactin elevation was more significant than with lithium or Divalpro-X, as expected.
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And so the side effects are greater. However, the discontinuation rate was greatest
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for lithium in this study.
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So that is one of the only studies we have comparing the two.
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We've done a study actually comparing quetiapine to lithium.
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And this was double-blinded, double-dumied study where patients were taking
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pills for both the lithium and the quetiapine.
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And we were yoking it in terms of increases, decreases, because we wanted to,
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lithium has to be titrated to a therapeutic level.
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And here in this study was a six-week
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study of acutely manic early course adolescents with bipolar disorder.
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And you can see that lithium and quetiapine at the end of six weeks were similar
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in efficacy, although quetiapine did have the slight edge.
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Quetiapine resulted in greater weight gain than lithium, although lithium was not weight neutral.
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And those with family history of bipolar were in general in the lithium group
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more likely to respond than those without a family history of bipolar.
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So family history was predictive of lithium response.
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And in the lithium group, those
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without prior stimulant treatment or five times more likely to respond.
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And that was only predictive of lithium response.
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The response was quicker in the quetiapine group.
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So there have been a couple of systematic reviews and network meta-analyses.
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We won't go into detail either of these, but they've been published in the past
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couple of years, and they're worth at least knowing about and looking at if you're interested.
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They both summarize a little bit differently the literature.
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This is a systematic meta-analysis that looked at 18 studies of acute manic
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adolescence, and basically performed a network meta-analysis,
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did not look at dosing within the studies combined.
33:44
If a study had two different dosings of the medication versus placebo.
33:49
It only looked at the two different doses as one dose.
33:55
And what you can see here in terms of efficacy, and this is just the top and
34:00
the bottom are just different definitions of response.
34:03
The top is change in or continuous change in improvement in manic symptoms as
34:10
measured by the Young Mania Rating Scale.
34:13
And then the other was dichotomous, 50% or greater response or improvement in
34:19
the Young Mania Rating Scale.
34:20
Regardless, risperidone, elanspene, or piprazole were generally the most effective.
34:26
And then valproic acid, as you can see here, either definition was no more effective than placebo.
34:33
So it's a way of combining the different studies to kind of rank which is most effective.
34:39
And in general, when they looked at mood stabilizers versus second-generation
34:45
antipsychotics, you can see here that, again, second-generation antipsychotics
34:51
as a group are more effective than mood stabilizers.
34:55
In general mood stabilizers, don't seem to be very effective.
34:59
And that is in contrast to adults with bipolar disorder, where SGAs and mood
35:05
stabilizers have very similar efficacy.
35:09
This is a second meta-analysis which looks at dosing specific.
35:14
So a lot of the second-generation antipsychotic studies had two different dosing
35:20
of the treatment versus placebo, and it actually just kind of gives you a better
35:26
sense of what dosing is most effective.
35:29
I think it's most helpful, actually, for risperidone and erpiprazole.
35:33
For risperidone, the lower dose
35:36
is more effective and the higher dose just gives you more side effects.
35:41
So for risperidone, we will rarely go above 2.5 milligrams because we don't
35:47
get, in general, better efficacy. We get more side effects.
35:51
And eripiprazole, we do tend to need to push the dose to get better efficacy.
35:57
So this just breaks it down by dose, but it's similar findings to the other meta-analysis.
36:03
We did meta-analysis for bipolar depression, and in bipolar depression,
36:09
there have been four studies,
36:11
two with quetiapine, which you may or may not know is approved for bipolar depression
36:16
in adults, and then the olanzapine-fluoxetine combo med and lorazodone.
36:22
And you can see here that a lower ranking is better.
36:26
And so lorazodone, in terms of efficacy outcomes, is the most effective.
36:33
In terms of side effects, olanzapine-fluoxetine combination has the worst profile.
36:40
And quetiapine was found to be ineffective in both of those studies,
36:45
And so both of the studies of quetiapine.
36:49
So lorazodone really in terms of efficacy and outcome safety seems to be the
36:56
best in terms for bipolar depression.
37:00
Okay, so talking for a couple of minutes, there aren't very many maintenance
37:05
studies or long-term studies. We have one with lamotrigine, and these studies are very hard to do.
37:12
This was a randomized withdrawal study, so patients were stabilized,
37:17
if they could be stabilized, on adjunctive lamotrigine.
37:21
So lamotrigine was added on to whatever they were on.
37:25
They could have been on up to two conventional mood stabilizers,
37:29
and they had up to 18 weeks to stabilize, and there were specific definitions of stabilization.
37:36
And then they were randomized to placebo or lamotrigine. They were allowed to,
37:41
again, continue on whatever medication.
37:43
These studies, you would imagine, once the patient's stabilized,
37:46
it's very hard to justify and continue these patients and risk the randomization to placebo.
37:55
So there is a large dropout, even of patients who stabilize for people who don't
38:01
want to take the risk of randomizing.
38:03
So they're very difficult. And this was an adjunctive study.
38:06
So what this study found was that in the older age, 13 to 17,
38:12
there was an advantage, these are survival curves, of being treated with lamotrigine,
38:19
whereas in the younger age, the 10 to 12-year-olds,
38:23
there was no difference between staying on lamotrigine or placebo.
38:27
So again, for the older age, they were less likely to need any other intervention
38:34
if they were on lamotrigine versus placebo.
38:38
There's been another study with erpiprazole that is erpiprazole versus placebo
38:44
monotherapy after stabilizing on monotherapy of erpiprazole.
38:50
And this was a smaller study where 96 people were allowed to give in the opportunity
38:56
to stabilize, 60 did, and they were randomized to erpiprazole or placebo for up to 72 weeks.
39:05
And reason for discontinuation, any reason was considered not surviving in this study.
39:12
And again, as you can see here, a lot of people rapidly discontinue because
39:18
they are worried, and in this study even more so, that they were only on placebo
39:24
after stabilizing on aripiprazole.
39:26
And despite that, aripiprazole was more effective than placebo long-term.
39:32
If you stayed on aripiprazole, you did stabilize and maintain stabilization
39:38
after the initial, what we call a nocebo effect, where they drop out because
39:44
they could be on placebo.
39:46
There has been one small study called the Colt study.
39:52
This were people who responded to lithium and then randomized to lithium or
39:58
placebo for up to 28 weeks.
40:01
And you can see here that for maintenance purposes, lithium was highly more
40:08
effective than placebo. The dropout in placebo was fairly high.
40:14
Okay, long-term lorazodone, just to briefly mention, this is a study that was
40:21
open-label lorazodone after stabilizing.
40:25
This was either they were depressed coming into the study, but they could have
40:28
been in the open label part coming in with any phase.
40:32
And because we don't have a placebo, we don't really know.
40:36
But looking at trajectories for kids who, you know, over the course of two years
40:41
are going to gain weight, you see here that on lorazodone during the course of two years,
40:47
the weight gain was exactly what was predicted for over the course of two years.
40:53
So lorazodone is probably the only second-generation antipsychotic that is generally
41:01
weight neutral. Not always, but generally.
41:05
Just want to briefly mention a couple of other medications that are being studied
41:09
for bipolar depression.
41:12
At this point, cariprazine is medication. The advantage of cariprazine is that
41:19
it has a very long half-life, and it is being studied for bipolar depression.
41:25
In kids at this point, it's approved in adults for depression,
41:30
mania, and schizophrenia.
41:33
Lumetepiron is another medication that works a little bit differently.
41:37
It's a 5-HT2A antagonist, and we know that historically some of the best antidepressants
41:44
have been 5-HT2A antagonists,
41:47
and this medication is approved in adults for bipolar depression and schizophrenia.
41:54
It's approved for bipolar I and bipolar II, and it is now being studied in kids.
42:00
So I just wanted to mention, these are other potential treatments in the future
42:05
for kids with bipolar depression.
42:08
Just to touch on kids who have a family history of bipolar disorder,
42:14
they present with ADHD, with anxiety, with mood symptoms.
42:19
And one of the biggest dilemmas in child psychiatry is how do we treat these
42:24
kids without making them accelerate their progression to bipolar disorder?
42:30
We do know that a lot of these kids, when they are treated with antidepressants,
42:36
will have significant adverse effects.
42:39
So having a bipolar family history and being treated with an antidepressant,
42:45
age is one of the strongest predictors.
42:48
So if you're age eight and you have a parent with bipolar disorder and you're
42:52
treated with an antidepressant, almost all of those kids will have a severe adverse reaction.
43:01
So suicidality, psychosis, ending up in the emergency room in this study.
43:06
And on average, if you're about 14, that's the average age, about 50% will go
43:13
on to have a bad side effect.
43:16
The older you are, the more likely you are to tolerate an antidepressant,
43:21
probably because you've passed through some of the risk of accelerating the
43:27
onset of bipolar disorder.
43:29
Again, other studies have shown this, that if you're treated with an antidepressant,
43:35
and you in general are treated with an antidepressant, and you have a bipolar
43:41
spectrum illness, so you're at risk, about a third of those kids will have new onset suicidality.
43:49
Okay, so there have been a whole bunch of studies looking at kids who have parents
43:56
with bipolar, but they themselves don't have bipolar.
43:59
And they have been open-label studies that have shown some effectiveness.
44:06
Double-blind studies of Divalpro-X show that only if you have a multi-generational
44:12
family history of bipolar will it be effective.
44:16
There has been a study that has shown it's effective for high-risk kids.
44:25
But at this point, really trying to avoid an antidepressant is probably,
44:30
or getting away with the lowest dose possible,
44:34
is probably the best strategy if they're presenting with depression,
44:38
but monitoring them very carefully,
44:41
particularly in the very young kids.
44:43
And, of course, screening very carefully for manic symptoms.
44:47
I also just want to mention non-pharmacologic evidence-based interventions.
44:53
Family-focused therapy, which is David Miklowitz's therapy, which is to reduce
45:01
stress conflict in the family,
45:04
affective arousal, and it involves the family or caregiver and the patient,
45:10
and And that's been shown to be very effective compared to an enhanced care
45:15
treatment and mindfulness-based cognitive therapy,
45:19
particularly for anxiety in high-risk kids.
45:23
So kids who have parents with bipolar has been shown to be effective.
45:28
Okay, so just want to end with mentioning the adverse effects of antipsychotics.
45:34
And of course, we have wheat gain as the primary adverse effect that most people are familiar with.
45:42
Up to 70% of kids will gain wheat with antipsychotics, with second-generation antipsychotics.
45:50
Unfortunately, those are the medications that are most effective for acute mania, at least.
45:57
And there are some side effects that kids are at lower risk for.
46:03
So it's tardive dyskinesia, developing full-blown diabetes.
46:07
That tends to occur more in adults who are on antipsychotics.
46:12
But in kids, they're more at
46:14
risk for prolactin elevation and for the dyslipidemia and the weight gain.
46:21
So again, this is part of that meta-analysis that looked at olanzapine as probably the worst,
46:28
acinapine, quetiapine, and it just kind of gives you erpiprazole,
46:32
probably one of the better second-generation antipsychotics.
46:37
And this is from the other study. As you may or may not know,
46:41
topiramate is used adjunctively for the weight gain oftentimes.
46:46
And you can see here, again, And olanzapine is the highest risk for weight gain
46:51
and quetiapine, acinapine.
46:54
And we talked about how olanzapine-fluoxetine combination is particularly problematic
47:02
for the metabolic side effects and for weight gain.
47:06
And just looking at some of the other metabolic parameters, risperidone is high
47:12
risk for increasing glucose as well as triglycerides as well as quetiapine and the other SGAs.
47:22
We have done a study with topiramate, adjunctive to olanzapine,
47:26
and it doesn't completely neutralize it, but it halves the weight gain.
47:31
And looking at it, whether you define it with change in BMI or change in weight,
47:36
it halves the weight gain when used adjunctively compared to placebo.
47:42
I want to spend the last couple of minutes talking about metformin.
47:46
There are now pretty strong recommendations if you are treating kids with a
47:52
second-generation antipsychotic that has a moderate or greater potential for weight gain,
47:59
then you should always treat them with metformin.
48:03
And this is based on several studies.
48:05
Dr. Klein, who was an endocrinologist in Cincinnati,
48:09
did one of the first studies that showed metformin can plateau the weight gain
48:14
versus placebo that is associated with second-generation antipsychotics.
48:21
So some kids lose weight, but most of them don't continue to gain weight.
48:27
There's been the IMPACT study, which is more of a controlled study that looked at three groups.
48:33
It compared three groups who were treated with second-generation antipsychotics
48:39
and had significant weight gain from them over the past three years.
48:44
And they were ages 8 to 19. There were three randomized arms of the study.
48:51
They obviously were not blinded, but continuation with the SGA they were on
48:57
plus a healthy lifestyle intervention.
48:59
Continuation with the SGA plus addition of metformin and a healthy lifestyle
49:05
intervention, or switching to eripiprazole, or if they were on eripiprazole,
49:10
switching to perfenacine plus the healthy lifestyle intervention.
49:14
So three treatment arms and.
49:18
What was found was that switching to a lower propensity antipsychotic for weight
49:23
gain and adding metformin were both effective compared to just a healthy lifestyle
49:30
intervention at decreasing BMIZ score.
49:34
And then, unfortunately, switching to a different antipsychotic was associated
49:40
with increased risk for mood instability.
49:44
So aggression, impulsivity, anger, irritability was very high in the switch
49:51
group compared to the metformin, and the control group was similar to the switch group.
49:57
So it's not to say metformin helps with that, but it actually doesn't destabilize these kids.
50:05
And so we did a study that was a pragmatic trial that involves sites from all
50:13
over the country, including Texas.
50:15
And this was a study that patients in clinic settings who were overweight or
50:22
obese were randomized to a lifestyle intervention or a lifestyle intervention plus metformin,
50:29
and they had to have a bipolar spectrum diagnosis.
50:33
If you're interested, you can visit our website. There is a healthy lifestyle video on there.
50:39
It's a seven-minute video that was done by HealthWorks, which is our.
50:45
Weight loss intervention program by our pediatrics department.
50:49
And it's based on the traffic light, low glycemic, high glycemic,
50:54
moderate glycemic diet.
50:56
And that is the intervention that was done in mobility, the study.
51:01
And this was the recommended titration by our pediatric endocrinologists.
51:07
And again, kids were 8 to 18 in the study.
51:12
1,500 kids were randomized. average age of about 14.
51:17
Most had been on an SGA for at least a year, so about 50 percent.
51:23
We did have some SGA-naive kids and skipped to the main findings in the interest of time,
51:31
but metformin plus a lifestyle intervention resulted in a decrease in BMI Z-score for up to 24 months.
51:41
And then compared to a healthy lifestyle intervention, which month six,
51:47
which was one of our primary outcome, they were weight neutral,
51:50
a little bit increase in weight.
51:52
And then at month 24 had some weight decrease, but less than metformin.
51:59
And so the people who reached 1500 with metformin had more weight loss or BMI
52:07
Z-score loss than those who didn't get to 1500.
52:11
So based on this study, we recommend 1500 milligrams per day.
52:17
Rates of suicidality were half as much in the group that got metformin.
52:23
Again, I'm not saying that metformin is effective for the mental health But
52:28
because of the weight loss, these kids generally did better in terms of peer relationships,
52:38
in terms of self-esteem.
52:41
GI side effects were the primary side effects that we saw.
52:45
We advised people to switch to the extended release.
52:50
And again, with the titration, we told people to go decrease the dose and go
52:56
in the lower dose for a longer period of time. It was a pragmatic study.
53:01
But again, based on this and based on the guidelines that have recently been
53:07
released, kids who are prescribed SGA that has moderate or more potential for weight gain.
53:16
And the guidelines actually suggest they don't have to be overweight or obese,
53:22
but the studies we've done have been overweight or obese.
53:25
But they suggest if you're going to prescribe an SGA, they should be on metformin as well.
53:32
So with that, I know we're kind of out of time. I will stop and maybe we have
53:37
a couple of minutes for questions.
53:39
Thank you, Dr. Revello, for that wonderful presentation on bipolar disorder.
53:44
There are two questions already in the chat box. Should all children with ADHD
53:48
symptoms and family history of bipolar be referred to child psychiatry?
53:55
I think, you know, there's the reality of how hard it is to get people,
53:59
at least here, into child psychiatry, but I think probably, I think they should
54:06
be monitored very closely for symptoms of a mood disorder.
54:13
These kids tend to have really bad rebound if they're using short acting or
54:20
if you're using long acting in the evening. It tends to be very difficult for these kids.
54:26
And so I do think if you're going to try a stimulant, use the lowest dose possible.
54:33
And instead of titrating quickly by weight, as we would do for a kid who does
54:38
not have a family history, you know, you can try them and start them on one
54:43
while you're waiting for them to get in to see a child psychiatrist.
54:48
Thank you, Dr. Another question by Dr. Lopez. who should prescribe metformin?
54:54
Are they referred to endocrinologists?
54:56
Yeah, that's a great question. We've had a lot of debate about this.
55:02
And, you know, I advocate that, and this is what we've done in Cincinnati for
55:09
years, is, you know, talk with the pediatrician as a child psychiatrist.
55:15
Talk with the pediatrician. If you are a pediatrician, then you should be prescribing
55:20
it if you're prescribing the SGA, but if we're as psychiatrists or as nurse
55:26
practitioners in mental health,
55:29
If we were to prescribe an SGA and somebody were to have a dystonic reaction,
55:34
it would be standard of care for us to give them cogetin or Benadryl.
55:40
Like, we would not withhold that.
55:42
So if we're prescribing an SGA and they are gaining weight from the SGA as a side effect.
55:50
Or they are overweight or obese to begin with, and we're prescribing a medication
55:55
that has the potential to make it worse, I think it is our obligation to,
56:02
after at least talking with the pediatrician, to prescribe it.
56:06
But we really can't get caught in, is it the endocrinologist?
56:10
There aren't enough endocrinologists to go around. And I can tell you,
56:14
our endocrinologist here in Cincinnati does not want to see every child who
56:19
has gained weight on an SGA.
56:22
But I think pediatricians and family docs should absolutely be prescribing metformin.
56:30
And, you know, the American Academy of Pediatric Guidelines,
56:35
the new guidelines that came out are fairly aggressive about pharmacologic intervention
56:41
for weight gain in obese and overweight kids.
56:45
And it's just worse in kids who have bipolar disorder.
56:49
The comorbidity is because of lots of different reasons and we're just making it worse.
56:55
And so I do think it is 100% pediatricians and family docs that should be prescribing it.
57:04
It is, I think, a continuation of what about training more pediatrician or family
57:09
docs to diagnose and manage bipolar disorder?
57:12
Would this increase medication, endurance, and treatment? Sure.
57:17
I think so. I think that would be great. It's hard because I know,
57:22
you know, most pediatricians have to, you know, see a lot of patients in a quick amount of time.
57:29
And so I think if you have the time, absolutely.
57:35
Dr. Hundon, you have raised your hand. Can you ask your question, please?
57:40
You're here to unmute. We cannot hear you, Dr. Hundon. Thank you. Okay. Okay.
57:49
I've noticed that some of these kids get diagnosed as borderline personality disorder.
57:55
They have, you know, explosive episodes. But if you look at it,
58:00
the episode will occur over five, maybe seven days.
58:05
And these things will last and they've been treated with all kinds of things.
58:10
I was just wondering, if you look at the family situations, a lot of those kids
58:15
have been prenatally exposed to alcohol.
58:19
And I mean, you know, you look at the South African studies.
58:22
I mean, you just see hundreds of thousands of people who've been prenatally
58:26
exposed to alcohol and have inhibitory behavior problems.
58:33
Yeah, there are a lot of kids, and I kind of call them a phenocopy of ADHD.
58:39
The kids who have been exposed to alcohol and other substances in utero,
58:46
they look more like ADHD kids that don't respond to regular doses of medications.
58:54
They oftentimes need higher doses of stimulants, whereas the kids with bipolar
59:00
don't do well with higher doses of stimulants.
59:04
Generally, that kind of mood destabilizes them. And there's usually more developmental issues.
59:10
Most of the time, there's some developmental issues. And those kids tend to
59:16
like need a lot of OT, PT, speech intervention.
59:20
And so they kind of seem more like a phenocopy of severe ADHD rather than bipolar disorder.
59:28
Going back to your borderline disorder,
59:31
we tend to not give kids the diagnosis of borderline and try and stabilize their
59:38
mood with as much structure and caregiving as we possibly can and hope that
59:44
they won't have a long-term personality disorder.
59:49
Thank you, Doctor. There's one question by Dr. Williams. When a strong family
59:54
history, there is a nature or genetic component, but there is also nurture component,
59:59
which is role modeling of behavior that is normalized in that family,
1:00:04
but behaviorally are poor interpersonal behaviors.
1:00:07
What is done in therapy and family therapy to address this aspect?
1:00:11
Yeah, I think that's why family-focused therapy is highly effective.
1:00:16
And again it reduces
1:00:20
the conflict in family it increases the
1:00:23
structure and it kind of
1:00:26
kind of gets into not not giving into the kids and to like set limits and it's
1:00:34
okay and how the kids deal with those emotions so family focused therapy that
1:00:40
that's why i think it's the most effective I encourage you, if you're interested, Dr.
1:00:46
Miklowitz has written several books on family-focused intervention.
1:00:51
And Mary Freistad is the other psychologist whose books I would recommend.
1:00:56
She's done more group therapy, psychoeducation with kids.
1:01:02
Pediatrics Now is brought to you by the Department of Pediatrics at UT Health
1:01:07
San Antonio and University Health's new Women's and Children's Hospital.
1:01:12
Thank you so much for listening to that fascinating talk.
1:01:16
Don't forget to click on the link. Our sister podcast is Pediatrics Now for Parents.
1:01:23
Pediatrics Now for Parents can be found wherever you get your podcasts,
1:01:27
or the web address is pediatricsnowforparents.com.
1:01:32
Thank you so much for listening. I'm Holly Wehment. I'll see you next week.