Monday, September 25, 2023
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Editor's Note
Continued controversy surrounding the diagnosis, treatment, and management of pediatric and adolescent bipolar disorder (BD) may become a thing of the past as a result of emerging data from current trials. Medscape Scientific Director, Elizabeth Samander, PhD, interviewed Kiki Chang, MD, about the prospective results of these trials and what implications these results may have on clinical practice and the future management of children and adolescents with BD.
Medscape: The diagnostic criteria for adult bipolar disorder have been clearly defined in the DSM IV, but these diagnostic criteria have not clearly been defined in pediatric and adolescent populations despite an increase in the number of children and adolescents diagnosed with psychiatric disorders. What are the challenges of recognizing and diagnosing bipolar disorder in this population?
Kiki Chang, MD: I believe that there is a lot of perceived controversy around the diagnosis of bipolar disorder in childhood populations and I understand where the confusion is coming from. I think the confusion stems from 2 things: the first being that kids are very different from adults and so as you mentioned there are no child-specific criteria that have been developed yet. There should be, however, and hopefully those diagnostic criteria will be coming out soon. Second is that people seem to be confused about how we diagnose bipolar disorder. They seem to think that we already know exactly what bipolar disorder looks like and that we understand that it is 1 disorder and that either a person has bipolar disorder or they do not.
Medscape: So, this is really a spectrum disorder?
Dr. Chang: It is really a spectrum disorder that was defined according to DSM IV criteria and based on symptoms. So that is the way we defined it. It is similar to people stating that they can diagnose attention deficit-hyperactivity disorder (ADHD) using some test, but you cannot do that because the very core of the diagnosis is based on symptoms. You can diagnose cognitive impairment or specific working memory deficits based on tests, but you cannot diagnose ADHD because it is a syndrome composed of a cluster of symptoms. And that is the same diagnostic approach taken for bipolar disorder. We decided to call bipolar disorder this cluster of symptoms happening within a certain time frame. And as long as those children meet all those criteria, the same adult criteria for now, then by definition they have what we call bipolar disorder. Now does it mean that they have the exact same disorder as adults? Probably not, but they could. And does it mean that because children and adolescents meet all the criteria we should therefore jump in with the same treatment as adults? No, I don't think it means that. People often ask, "How can you be sure that child has bipolar disorder?" And I answer that it is because they meet the definition, and therefore by convention that is what they have. Until we define bipolar disorder a different way, say by brain imaging or genetics, then that is how kids are diagnosed.
Having said that, the main difficulty in diagnosing bipolar disorder in children and adolescents lies around the episodicity of it.
This difficulty is based on the fact that kids are different from adults in that they normally have a more rapid shift in emotion. If you think about a 4 year old or a 5 year old compared to a 32 year old, normal development would indicate that yes, the younger you are the more evident it is that there is a more rapid shift in emotions and over time it starts to become more stable. And in adolescence there is a little blip there where there is again a more rapid shift in emotion, but then again in young adulthood it becomes more stable. That is normal development. You can see that if a child, in addition to normal development, has problems with regulating their mood that they would have more of these rapid shifts, but it would go in the same direction as development, so as they get older these problems with their mood come to become more protracted moods. So in many adults it is easier to diagnose a manic episode because you have a longer period of time in which these symptoms are obviously present and causing impairment.
However, children may have 1- or 2-hour bursts of these kinds of manic activities, and therefore how can you say it lasts a whole week? So, what we do next is we go back and we say, was there ever a week when these symptoms were all present, more so than usual and were affecting the child. If they were, then you can count that week as a manic episode because clearly even for adults, people do not have manic symptoms 24 hours a day when they are in the middle of a manic episode. It just means during that time there is a predominant shift in mood along with the other required symptoms for mania.
Medscape: How do you distinguish between normal child development and prodromal symptoms of bipolar disorder?
That's a good question. I think it is very important to make a distinction between the 2 because we now realize that bipolar disorder most of the time is not something that suddenly appears when you are 18 or 26 or 32. That still happens sometimes, but in the majority of cases there appear to be early symptoms that predate this kind of onset and eventually becomes a full mood episode. What you have to do is determine if these early symptoms are affecting the functioning of the child. Because in normal childhood you are going to have some ups and downs and some mood problems and things like that; but when it gets to the point where it is really affecting the child, then you want to look for other things like a strong family history of bipolar disorder, for example, or of mood disorder in general. That would heighten your suspicion that these could be early symptoms of bipolar disorder, and those specifically include symptoms of ADHD such as inattention, hyperactivity, and symptoms of depression and irritability and general mood dysregulation. All of those symptoms in conjunction with family history should raise your suspicion that there is an early ongoing bipolar disorder. Now, that does not mean that it is absolutely going to become bipolar disorder, but it should raise your suspicion.
Medscape: In addition to not recognizing the prodromal symptoms of bipolar disorder in children and adolescents, do other issues, such as substance abuse, complicate early recognition and diagnosis?
Dr. Chang: Right, so why haven't we seen this frequency of bipolar disorder in children before? Because in the past we thought that this was something that happened with your first manic episode at age 16, 17, 18 or 25, 26, 27. And that still happens where we still do see patients who have this kind of very abrupt onset. But again, I think that is the exception rather than the rule. I think it is because we were missing the possibility that their mood problems might go into more substance abuse. For example, in an adolescent who is abusing substances, their mood symptoms may be blamed on that and that may lead to a missed diagnosis. There are many studies now that report that adults who have bipolar disorder often were misdiagnosed with something else first or they had these symptoms early on much before their first full manic episode that made the diagnosis obvious. But it is understandable because if you have not had a full manic episode yet, then how do you know some of these things are indicative of an impending bipolar episode? However, even children and adolescents who have had full manic episodes are sometimes misdiagnosed as having other disorders, such as ADHD or drug problems or behavioral problems. In most cases it takes about 10 years after the initial symptoms until a proper diagnosis is made. So I do think that there is still much misdiagnosis occurring.
Medscape: Research has documented the heritability of bipolar disorder through familial incidence. This suggests a strong genetic predisposition of bipolar disorder. Have any specific genes or gene regions been implicated in bipolar disorder?
Dr. Chang: There are. Although it may not be very useful to list them all at this point because most of the linkage studies which have implicated certain chromosomal regions as being involved in bipolar disorder have not been replicated. Now researchers are doing genome wide association studies using gene chips in which they can do a scan of the whole genome to see which areas are most likely involved with bipolar disorder. The problem with that kind of study is it takes thousands and thousands, about 5 to 10,000 patients, to really make a big difference and it's hard to recruit that many patients to be in a study. So another approach is studying genes that are likely to be involved based on what we know about bipolar disorder. There have been some of these "candidate genes" that have been identified such as brain-derived neurotrophic growth factor, serotonin transporter gene, or the GRK3 gene. These are genes that have a certain variant that likely have a small effect on increasing risk, but by themselves do not create large risk of developing bipolar disorder. We are still looking for more genes. It is clearly going to be a polygenic disorder, and we are going to find that there are very many genes involved and that they interact in complex ways to create susceptibility for bipolar disorder. But it makes sense that the more of these genes and gene variants that you have, the higher your risk for developing the disorder.
Medscape: In addition to genetic predisposition, what are the other triggers that would precipitate development of bipolar disorder?
Dr. Chang: We believe that in bipolar disorder, like most psychiatric illnesses, there is a gene-environment interaction. In essence, people are born with a certain genetic susceptibility to conditions, in this case mood problems, or problems regulating their mood. Eventually over time with certain triggers the full mood episode will develop. Now this is theoretical because it is based mostly on retrospective studies. But what we currently believe is that those triggers are largely environmental due to stress and the impact that stress has on the brain, on the hormones, on second messenger system, all of that, which then leads to developing mood symptoms that then becomes full mood episodes.
Now, in addition to environmental stress, there could be other triggers including drugs of abuse or even medications. One of our concerns, for example, is that antidepressants might be a similar trigger for kids who are at risk for bipolar disorder and precipitating the first manic episode.
Medscape: Would these specific genes and/or gene regions eventually serve as biological markers to differentiate between various psychiatric disorders?
Dr. Chang: We think so. We think that may help, certainly to identify risk and possibly even get a treatment and that is true with most biological markers, not just gene regions, but also findings from brain imaging studies. We think that we will be able to use this information to eventually help us identify if we are on the right track for a diagnosis and also to help us identify subtypes of bipolar disorder just as it might help for identifying subtypes of ADHD or subtypes of anxiety. These kinds of studies might cut through some of the heterogeneity we see in symptoms and get to biological subtypes that then have implications for treatment. In other words, the biggest advantage of these biological tests is that they may eventually guide more specific treatment that is more likely to work on the first try.
Medscape: When we talk about subtypes are we talking about differentiating between bipolar disorder I, bipolar disorder II, and bipolar disorder not otherwise specified?
Dr. Chang: I think we are talking about that, but also at an even finer level. In other words, eventually what I envision is that the subtypes will be based on things such as brain imaging and genes and each subtype will have a whole new categorical system of its own. For example, bipolar 2B6 might be 1 specific form where you have a certain constellation of genetic variance that leads to a certain constellation of brain imaging findings, which then leads to a certain constellation of behavioral patterns that emerge as mood symptoms and that specific profile is going to be known to respond better to 1 certain medication or 1 certain kind of environmental intervention, such as psychotherapy.
Medscape: How effective are psychosocial interventions as part of treatment management?
Dr. Chang: There are studies coming out that are beginning to demonstrate in a rigorous way that psychosocial intervention is essential as part of treatment management for both adults and now children and adolescents with bipolar disorder. Patients receiving these interventions have less relapse occurring and they stay well longer if they are taking their medications along with a psychosocial intervention. For example, David Miklowitz[1] is doing some groundbreaking work on family-focused therapy (FFT) for adolescents with bipolar disorder and he is getting ready to publish his results on a fairly large study of adolescents with bipolar disorder who received family therapy. We are collaborating with him now in modifying FFT for these children who we feel are high risk for bipolar disorder by virtue of having a first-degree relative with bipolar disorder and they themselves have some early symptoms that are creating functional problems for themselves and their families. So we are currently getting ready to study what we call FFT high-risk in these high-risk children in a more rigorous controlled study.
Medscape In the foreseeable future, are you of the opinion that these diagnostic tools will provide definitive evidence of bipolar disorder?
Dr. Chang: We are not there yet; it's going to be a long time. But, really in the past 10 years we have made a lot of progress towards that. So I'm pretty hopeful that we will get there eventually.
Medscape: The observed incidence of bipolar disorder in children may not only be a result of earlier recognition of symptoms, but also due to genetic anticipation. Is genetic anticipation implicated in bipolar disorder?
Dr. Chang: Genetic anticipation has not been proven in bipolar disorder. It represents a concept that a certain disease or a syndrome runs in a family and that with each generation the onset becomes earlier in age and also possibly more severe. In other words, the disease is more severe as well. This concept has been shown to exist in certain neurological disorders like spinal cerebellar ataxia, fragile X, even Huntington's, but it's only been partially shown to happen in some families with bipolar disorder. In 1993, Melvin McInnis[2] showed that 1 of his groups of patients with bipolar disorder had their onset much earlier than the previous generation had their onset and we are finding the same thing. In studies that we have not yet published, we are finding about a 5-five to 6-year difference in onset. That is, the children of parents who have bipolar disorder are developing their first manic episode about 5 to 6 years earlier than their parent did. We are defining onset as manic episode because that is what separates out bipolar disorder from other disorders, but as we talked about earlier, when does bipolar disorder really begin? Does it actually begin with the first onset of any problematic symptom like hyperactivity or any kind of mood symptom or the first depressive episode? So it is hard to determine exactly when it does begin, but we are using first manic episode because that is when it clearly becomes a bipolar disorder rather than another disorder.
Medscape: Certain medications, for example, antidepressants, may precipitate the onset of the disorder in children, especially prior to the actual diagnosis of bipolar disease. How are treatments schemas being developed for treating childhood bipolar disorder?
Dr. Chang: I think overall we are doing an okay job. In some cases we are doing a good job and other cases we could be doing a better job. And I say "we" referring to the field in general. I think clinicians have a difficult time due to difficulties with diagnosing the disorder. So that often what happens is that you start treating symptoms. And if you see a child with depressive symptoms or an irritability that would represent depression, then one naturally might think well let us treat that with an antidepressant. But as I mentioned earlier, that's definitely not the best way to prescribe medications for children.
Medscape: The real controversy with childhood bipolar disorder is that of drug treatment. The crux of the problem seems to be that all of the available pharmacologic treatments, with the exception of the atypical antipsychotics risperidone and aripiprazole, are only indicated for adults with bipolar disorder, rather than children with bipolar disorder. Therefore, does the burden of controversy lie within the drug indications or the lack of long-term efficacy and safety data?
Dr. Chang: What we need are more of these rigorous controlled studies with large enough numbers of patients to make sense of the data. Unfortunately, we are slow in getting there. We are behind the adult bipolar research world in that we don't have as many placebo- controlled gold standard studies to refer to, but we are catching up.
So, hopefully by relying on these studies that clinicians can have a better understanding of how to approach both diagnosis and treatment of these kids.
Medscape: What is the first-line treatment for childhood bipolar disorder?
Dr. Chang: Currently, there are a lot of data about the atypical antipsychotics risperidone and aripiprazole, which have been approved to treat mania in children 10 years of age and older with bipolar disorder. Those approvals are probably coming down the plank for quetiapine, olanzapine, and ziprasidone as well. And overall it is looking like the atypical antipsychotics do have a favorable efficacy profile in treating mania. It appears that some of the anticonvulsants that were used in the past don't have much of a favorable profile, don't clearly differentiate themselves from placebo and, regarding lithium, we are still waiting to see if lithium will have as much as efficacy as we think it does. Clinically I think it does, but it hasn't been proven in a large scale study yet. But that study is underway currently.
Having said that, I just mentioned all the treatments that were being studied for mania, but not for the other forms of the disorder, so we need to study how to treat depression. If we are not going to use antidepressants, and I believe that we probably shouldn't, then we need to find other treatments for this. So pharmacologically, this raises the possibility that we then need better studies of lithium, quetiapine, aripiprazole, lamotrigine, or other agents that are not antidepressants that have been either shown or have been thought to be effective in adults with bipolar depression.
In addition, we also need more maintenance studies to determine what keeps kids well for the long run, not just for 4 weeks, which is the length of most studies. We need more long-term safety studies as well.
We also need combination studies because in the real world, most children are treated with combinations of medications, and this is where I think we are not doing such a good job. Out in the real world, kids are sometimes getting complex combinations that have no empirical support. I understand the need for the clinicians and the families to find a medication regimen that works for these severely ill children, but I also worry about the fact that we don't know what all these complex combinations do either positively or negatively to these children. Right now, though I do believe that most clinicians, at least those I interact with, are working on their best conscience to try to balance the risk and benefits, but clearly we need more data to evaluate this kind of treatment. Most children with bipolar disorder are taking at least 3 different medications.
Medscape: So, due to the lack of long-term studies, is it fair to say that we still have a limited understanding of the long-term side effects, such as metabolic risks?
Dr. Chang: Absolutely, metabolic risks, risks to other organ systems, and even effects on the brain. We do think that there are positive effects on the brain because of the positive behavioral effects and outcomes. In other words if mania improved, we would think that would be a positive effect on the brain, but structurally, chemically, functionally we haven't really shown that there's a positive effect because it is hard to do so. We can show that there is change in the brain, but how do you know that change is correlated with symptom improvement? Well, there are some studies that are beginning to look at that. We have some data, for example, that we published with lamotrigine showing that in a small set of adolescents with bipolar disorder, it does appear that they are having functional improvements in certain areas of the brain including prefrontal cortex and amygdala. But we can't be sure that this improvement was due to the medication alone. So it's very tricky to demonstrate positive brain changes due to medications, but I do believe that is also the future of research.
Medscape: Is there any evidence that early intervention can delay the progression, reduce the severity of the disease, or prevent the disease in children and adolescents?
Dr. Chang: Well, I believe that that is true. There is no clear cut evidence to support that currently. In other words we don't have good controlled long-term studies to prove that getting in early, either with a medication or a psychosocial intervention, such as family therapy or individual therapy, can reduce the likelihood of progressing to the full-blown presentation of bipolar disorder. There are some open studies that are suggestive of acute improvement in kids who are at high risk for bipolar disorder, but don't yet have it. For example we did a study with divalproex[3] suggesting acute mood improvement in these children, and Melissa DelBello[4] conducted an open study with quetiapine showing acute improvement. However, Bob Findling[5] did a placebo study with divaloproex that was a maintenance study in kids at high risk and it didn't matter if they were on divalproex or placebo; they both eventually needed further intervention at approximately the same time and at the same rate. So we need longer studies done that were similar to the one that was done by Dr. Findling with different agents as well as with psychosocial interventions.
But I want to argue strongly that even though there are no adequate prospective data, there are retrospective clinical data that would suggest that the earlier you get in and treat, the better your outcome is going to be. We can extrapolate to say even before the onset it would make sense that if we were to intervene and change the environment in some way, decrease the stress for example, increase the communication skills in the family and the coping strategies of the child and then if necessary introduce a medication that is going to help acutely, but also be protective in some way to prevent against the effects of both stress and having a mood disorder, I think those things can lead to neurobiological change. These changes may possibly include neurodegeneration or some other change in the "circuitry" to make the disorder worse. If these medications or these psychosocial interventions can get in there and prevent that from occurring, we think that we can also prevent the symptoms and the illness itself from getting worse or even becoming fully developed. Think about something terrible like Hurricane Katrina, representing mania. If before the storm those levies and dams were inspected and shored up properly, then they could have withstood the stress of the hurricane and flooding would not have resulted. I think of psychotherapeutic and pharmacologic early intervention as shoring up those dams.
Medscape: Bipolar disorder demonstrates a highly relapsing chronic course. Does the disease course worsen if patients are medication noncompliant?
Dr. Chang: That's a great question and as you can imagine it is very hard to design a rigorous study to answer that question. It's not really ethical to take kids off of medications that are helping and see what happens compared to kids staying on them. Although eventually we will need to do that because of so much concern about the negative side effects of medication. I am thinking back to 1 important study that was now done over 10 years ago by Michael Strober when at UCLA, in which they examined the outcomes of adolescents who had bipolar disorder and were treated with lithium. Among those children who stopped lithium on their own, over 90% of them at 18-month follow-up had a mood episode relapse. Whereas among those who continue to take their lithium, about a third of them had a mood relapse within 18 months; so two thirds of them didn't.
Now again, that is not a perfect study, but it would suggest that bipolar disorder has a highly relapsing chronic course. The question is if the children who stopped taking lithium now went back on it, would it work as well? We don't know that. My belief is that the more mood episodes you have, the more change you do to your brain to lead it to a state that is easier and easier to have more mood episodes. It's a never-ending spiral and you are just going down the bad path and so by preventing those episodes from happening at all we think that yes, you are more likely to then be responsive to the medication. Similarly, you are more likely to become responsive to psychosocial intervention, but the more episodes you have, you are less likely. There are data to suggest that people who have multiple episodes compared to people who have single episodes of mania, for example, have more changes in their brain including loss of cortical gray matter, and increase of ventricular size, which is another way of looking at loss of cortex, and one could make a little bit of a leap and say that perhaps it's due to the effects of having multiple mood episodes.
Now, people who have multiple mood episodes may also have more problems with substance abuse or leading to these brain changes, that's possible as well too. But in our model we do think that the more mood episodes you have the more likely you are to have these kind of neural effects long term and therefore you are probably less likely to respond to medications and you have more symptoms consistent with rapid cycling. For example, if your prefrontal cortex ends up becoming less and less functional over time because you are losing neuronal cells, glial cells, or general gray matter and you are losing the connection that helps regulate your mood and regulate your subcortical system, then you are just not able to regulate as well and then you may not even be as responsive to some of these medications that may act on the prefrontal cortex, and now you don't even have a prefrontal cortex that is healthy enough to respond to these medications. So theoretically and in the model it makes sense. It's just difficult to prove these kinds of theories, but we are working on it.
Medscape: As a follow-up, is there evidence that early pharmacological treatment of children and adolescents with bipolar disorder become treatment-resistant when they enter adulthood?
Dr. Chang: While it is so controversial in some areas that we are treating young children, and I understand that there is a concern about side effects, on the other hand what happens to these kids over time? We don't know yet. There is some possibility that we are getting it early enough that we may be able to reverse or prevent some of these brain changes from occurring and that maybe by the time they are 26 or 27 they will no longer have mood dysregulation. Or they won't have bipolar disorder and be able to come off all their medications. That really has not been the case over the past 20 to 30 years. You rarely see patients who are able to come off their medications and become relatively stable, euthymic, and high functioning. There is a very small percentage of the population that has bipolar disorder that can do that. But, there is a potential with early intervention that we could be getting it early enough that maybe, as we follow these children to adulthood, we will be seeing more of those patients who do well and won't need medication.
There is an excellent textbook written by Robert Post and Gabrielle Leverich[6] that has many case histories of individual patients and life charts that show exactly how their illness progressed over time and what the relationship of taking the appropriate medications vs medications that weren't appropriate as to their cycling pattern. And from those histories it is very clear that untreated or mistreated bipolar disorder leads to a more treatment-resistant outcome. Again, it's hard to prove, but it's an excellent book to refer to for that kind of impression about how patients become more likely to experience rapid cycling and treatment-resistance the longer they go without treatment.
Medscape: Are there any closing remarks you would like to make?
Dr. Chang: I think we have enough data currently that we can make some clinical recommendations, and what I usually tell mental health care professionals who are on the front line of treating children and adults with these disorders is that if you are treating an adult with bipolar disorder who say is 46 years old, ask them if they have children and see what's going on with their children and their relatives and how they are all doing psychiatrically. Are they having early problems with mood and behavior and is it affecting the children are functioning and the family's functioning? Have they seen somebody who has some particular expertise in teasing out what is normal childhood and what is not, and what may be risk factors for bipolar disorder? I think it is important to be aware of it, but not paranoid and jumping on symptoms and calling them bipolar when they are really not. Rather, be educated and open to the idea that these symptoms could be ones to monitor, and if mild, then making psychosocial interventions first. I think that might be very important for clinicians to do.
If the clinician doesn't feel comfortable with this approach or the diagnosis, then go ahead and refer the family to either a child psychiatrist or a therapist or someone who understands childhood development so they can help the family prevent an impending bipolar disorder. I have spoken to so many parents, who have bipolar disorder, who say that they would do anything to prevent bipolar disorder in their children and they also see their children going through some of the same early stages of the disorder that they went through themselves. And so that is what drives our research: to be able to say eventually that we were able to go in and prevent this devastating disorder from happening in millions of children.
This activity is supported in part by an unrestricted educational grant from Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc.
