This interview took place on January 15, 2010 and was conducted by Norman Sussman, MD.
Disclosure: Dr. Chang is consultant to Bristol-Myers Squibb, Eli Lilly, and GlaxoSmithKline; is on the speaker’s bureaus of Bristol-Myers Squibb, Eli Lilly, and Merck; and receives research support from GlaxoSmithKline, the National Alliance for Research on Schizophrenia and Depression, and the National Institute of Mental Health.
Dr. Chang is associate professor of Psychiatry and Behavioral Sciences in the Division of Child Psychiatry at the Stanford University School of Medicine in California. He is director of the Pediatric Bipolar Disorders Clinic and Research Program, where he specializes in pediatric psychopharmacology and treatment of depression and bipolar disorder in children and adolescents. Dr. Chang’s research includes brain imaging, genetics, and medication and psychotherapy trials.
How is bipolar disorder diagnosed in children and adolescents?
Unfortunately, we are still using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition1 criteria because that is all we were given. We still do not have a good biological marker to help with early detection and diagnosis. That is the focus of my research, but in the meantime we are left with phenomenology and the DSM-IV. The biggest thing to remember in children is that they are not small adults and that, naturally in their developing brains, they have rapid mood shifts and rapid emotional changes; at each age, what is considered normal in development changes. A 3-year-old child is very normally going to have rapid mood shifts, and an adolescent is going to have fairly rapid mood shifts as well. Clinicians must remember that context when making a diagnosis in youths. In light of these rapid mood shifts, clinicians must realize that much of it is normal. Even if it is an abnormal mood, whether it is depression or mania, the child is not usually going to sit in the mood for the whole 2 weeks for depression or the full 1 week for mania. The crux of the whole diagnostic question always comes down to the episode: Can a child reach a full episode? Youths typically do not meet full episode criteria because their brains are not geared that way.
Since their brains are still developing, the criteria for bipolar disorder do not apply correctly to children. However, clinicians still try to make the diagnosis fit the criteria as much as possible, looking at the overarching episode as a distinct period of change in mood and not necessarily requiring that the child is in that mood state 24 hours a day.
How is that diagnostic process different than for an adult?
It is similar in that adults in mania are not necessarily manic 24 hours a day. Their moods do change throughout the day; it is just a predominant mood. However, a child’s mood fluctuation is definitely more extreme than in adults. When that normal developmental context is clear, a clinician can make a more appropriate diagnosis based on what is normal for a child.
The individual symptoms can be different as well, because the symptoms were originally developed for adults. Grandiosity in a 32-year-old does not look the same as grandiosity in a 7-year-old. Again, one has to be aware of what is normal versus abnormal grandiosity in a 7-year-old.
Do you think that bipolar disorder has become a default diagnosis in children and adolescents?
Yes, I think it has become one of the diagnoses, along with pervasive developmental disorders in children. A study2 examining the last 10 years in an Health Maintenance Organization sample found a 4,000-fold increase in community diagnoses of bipolar disorders in children. That does not mean that they really have bipolar disorder, rather that there has been a greater diagnosis in the community. I think it is a reflection of the fact that people do not know what it looks like. When behavioral problems occur, a diagnosis of bipolar disorder has become one of the first thoughts that people have. It is good in that at least we are not missing diagnosing children who have real bipolar disorders. However, clearly there are children also being incorrectly diagnosed and overdiagnosed. Thus, it is really important to get the accurate diagnosis.
Some people would argue that the increase in diagnosis is because there are now drugs approved for that diagnosis and that such drugs are being promoted.
Without just flat out saying that is complete lunacy, there is some concern about pharmaceuticals’ involvement to the extent where now pharma is reluctant to even market such drugs towards children, regardless of the indications for children, because of the fear of the backlash. If anything, I think that kind of backlash will be negative and that we are going to start missing diagnoses and missing treatment opportunities because people are so fearful that they may be looked upon as agents of the pharmaceutical industry.
Before the last 2 years, nothing was indicated for bipolar disorder in children other than lithium, and that was only down to age 12. There are still children who need treatment. I think it is a little bit of an incorrect kind of accusation.
Upon getting a history, even without seeing a child’s or adolescent’s symptoms, what would a clinician look for that would put a youth at high risk for bipolar disorder?
The first thing we always look at is family history. The more loaded the family history for mood disorder, particularly bipolar disorder, and the closer to the child (eg, a first-degree relative, like a sibling or a parent), the greater the risk.
Then, after that, we take a really close look at two main kinds of syndromes. First, unipolar depression: a child with depression who has a strong family history is at very high risk to go on to develop bipolar disorder, ie, possibly 30% to 50%. Second, attention-deficit/hyperactivity disorder (ADHD) plus mood dysregulation: if they have symptoms of ADHD at an early age and then go on to develop more mood problems and they have a family history of bipolar, that also puts them at higher risk.
Those are the two main pathways that my colleagues and I have been investigating in our research. We are pretty sure there are other pathways as well, including anxiety disorders, and even children who present with what we call bipolar not otherwise specified (NOS); the latter opens up a whole other can of worms, but is really important because probably most of these children in the community are being diagnosed with bipolar disorder NOS without really good, firm criteria to back up those diagnoses.
Does family history of alcoholism help predict whether there is a higher risk of bipolar disorder?
We have not seen alcoholism per se do that, but whenever we get a family history of alcoholism we examine more closely to see if there is a mood component. With family histories, we will go very closely and try to diagnose by proxy, asking the parents questions about their direct relatives (eg, “Did your brother have this? Did he have a manic episode? Did he have a depressive episode?”) Oftentimes, if the patient had a history of drug abuse or alcoholism, we will find either depression or sometimes even bipolar disorder. However, in the absence of that, we have not really seen a big increase in risk.
Do you think bipolar disorder is caught most of the time now, or is there still a ways to go in terms of recognition?
I think there is still a ways to go, depending on where you are. In the United States, certainly in major urban areas, there is probably the tendency towards overdiagnosis, but in other areas it is still being underdiagnosed. Clearly, the increase in incidence is due to better recognition and over-recognition, but it may also be due to an actual increase in incidence due to genetic and environmental reasons. The age of onset appears to be getting lower throughout the generations, so that would indicate that there are more children and adolescents with bipolar disorder now than there were in previous generations.
I think we have a long way to go in terms of catching bipolar disorder. The majority of children diagnosed in the community are diagnosed with NOS, but there are no firm criteria. We have been trying to develop criteria, along with other research institutions across the country so that we can speak the same research language, and that can be translated to better clinical recognition of bipolar NOS.
Currently, the way we are using NOS is that patients have to have the criteria A symptoms for the manic episode—which are elation, euphoria, or irritability—but they need one less criteria B symptom than they normally would, or their episodic duration needs only to be 4 hours rather than 4–7 days. However, during the 4 hours, the symptom has to be something that repeats itself on different occasions and does cause functional impairment.
It is a little controversial, but when this type of criteria is applied to children, many children are found to meet this diagnosis. This has been well-studied in the Course and Outcome of Bipolar Youth study in Pittsburgh.3 Those researchers have found that ~38% of these children with bipolar disorder NOS go on to develop full bipolar I or II disorder over 4 years.
Why are early recognition and intervention important in dealing with children and adolescents?
Detecting the manic episode early on is important to not only inform better treatment, but also to prevent future episodes from reoccurring. My colleagues and I are big believers in the kindling hypothesis, which proposes that with each subsequent mood episode, it becomes easier for the brain to flip into that mood episode. Preventing mood episodes is actually preventing recurrence of worse and worse mood episodes that become more difficult to treat.
Thus, it seems prudent to figure out which children are at the highest risk for developing bipolar disorder and intervene even before the first manic episode. Granted, there is much controversy with treating children who have not developed full bipolar disorder; however, as I mentioned, a lot of these states are already problematic, whether it is bipolar disorder NOS, depression, or ADHD plus mood symptoms. They are already usually being treated anyway in the community. If we can tailor that treatment and guide it more towards bipolar disorder prevention, we will be able to hopefully even stave off the first manic episode and prevent a whole life filled with morbidity.
Is there any new evidence that confirms or contradicts reports about there being specific polymorphisms associated with bipolar disorder?
What is new is that we are realizing the complexity involved with these genetic polymorphisms. For example, with brain derived neurotrophic factor or with the serotonin transporter gene, it does seem like certain polymorphisms confer perhaps a very small increased risk for developing bipolar disorder. Yet, the complexity we are realizing is that these polymorphisms then affect development of certain brain regions and brain activation patterns that then lead to problems with mood regulation. The future of understanding how these candidate genes help increase risk for major mood disorders, including bipolar disorder, is going to look at their effects on brain structure and function that then lead to these mood episodes. That is an area of research that my colleagues and I are actively engaged in.
In treating a child as opposed to a middle-aged adult, are there different considerations when choosing which medication to start with?
Absolutely. We used to base our treatment plans on adult data because there were no childhood data. In the last 4–5 years there has been an explosion of data, so that now we have many positive, placebo-controlled, large-scale trials for acute mania in children down to 10 years of age.
Unfortunately, some of those trials have been negative, as well—for example, with oxcarbazepine and, surprisingly, divalproex. This has somewhat changed the landscape of treatment choices in children in the community and probably also in academia, where now we are gearing a little bit more towards atypical antipsychotics because of their relatively positive data compared to anticonvulsants.
You seem to be referring to acute treatment. Does the answer change in regards to maintenance or long-term treatment?
Definitely, again because of our concerns with the side effects from the atypical antipsychotics, whether it be weight gain or metabolic problems. I refer to children who have even more weight gain than adults exposed to these medications. From a long-term standpoint, we are very careful when continuing medication doses at the doses that were used to get them stable.
It becomes a different issue. Unfortunately, there are very little maintenance data in children. There are a couple studies being conducted now in that area, but only with a couple agents, so we need a lot more data before being able to understand what is the best for efficacy. However, for long-term side effects profile, we are concerned about continuing atypical antipsychotics. Thus, we will be very active in treating the acute symptoms. Once we get things under control, we are also very active in trying to pare down the medication regimen so that the children do not have these side effects, because very little is known about the adverse effects on the developing brain and body of these children.
Are risks of side effects greater in children, as opposed to adults, taking medications to treat bipolar disorder?
Yes, the risks become much greater when dealing with children. Many are psychological risks because clinicians are afraid to impact children more so than they are afraid to impact adults, as children are in a more vulnerable position. They cannot consent for themselves, but can only give assent. It is a little bit trickier.
Still, when it comes to a major mood disorder like bipolar disorder that carries great morbidity and a great suicide rate, it becomes clear to these families that some of these unknown side effects can be handled down the road. My colleagues and I believe endocrine effects, such as polycystic ovarian syndrome, are somewhat reversible. Maybe not the kidney effects—almost nothing is known about that in children in long term.
The idea is to try to stabilize a child and improve his or her functioning and prevent the suicidality now because that is the most important thing. Then we will worry about the other kinds of side effects down the road after the child has been stabilized.
Is there any evidence that the early use of antidepressants or stimulants to treat either depression or ADHD has led to an increase or a worsening of bipolar disorder when used in a vulnerable child?
Clinicians are much more aware of this possibility now than they were 10 years ago. However, time and time again, we still see patients who are exposed to these medications that have manic episodes, and we wonder if it is completely due to these medications or not. We used to be very concerned about stimulants and that they may promote kindling in these vulnerable children, but more and more data have come out that suggest that, overall, stimulants are probably not a problem. In fact, they may be beneficial in some children.
Tillman and Geller4 followed children with ADHD. Approximately 25% of them developed bipolar disorder, eventually experiencing a manic episode. Those children treated with stimulants were less likely to develop mania than children who were not treated with stimulants, almost suggesting that there may be some protective effects of improving a child’s psychosocial and school functioning as well as against developing a mood disorder. Even with stimulants currently, once in a while a child still may have a manic reaction. Of course, that child should probably not be on this class of medications. Still, overall, it appears stimulants may actually be beneficial in these children and not speed up the process of bipolar disorder.
Antidepressants are a different story. A lot of retrospective evidence suggests that antidepressants are much more problematic in causing manic episodes in children who otherwise may not have developed mania. My colleagues and I are examining that area very closely. The conversion from unipolar depression to mania often coincides with giving a child an antidepressant.
Again, we look very carefully at family history and other early signs of hypomania that might indicate that this child really has underlying bipolar brain chemistry, and then in those children we are very careful before starting antidepressants. We still feel that some of them will be fine, but there is a certain proportion—probably significant somewhere on the order of 30% to 40% of children who have strong family histories of bipolar disorder and depression—who may respond adversely to antidepressants. I am very careful before using them, and if we do use them, we start very low and go very slowly, and ask the parents to really closely monitor for any manic symptoms.
The alternatives, though, are the mood stabilizers lithium and lamotrigine, which have not been well studied yet in this population. Some parents will opt to go that direction rather than risk having a manic episode. There are more side effects associated with those medications, so we are very careful to explain all the risks and benefits to the family members.
People tend to ask whether there is some kind of imaging or other diagnostic test that will help confirm the diagnosis. What are your thoughts on this?
I tell parents, family members, and patients that right now the general consensus among all researchers in the field is that bipolar disorder or most psychiatric disorders cannot be diagnosed using any kind of brain imaging. In fact, at this point brain imaging does not inform diagnosis or treatment selection, particularly for bipolar disorder.
I do tell them there are private enterprises that use brain imaging more as a clinical gestalt tool because most of their data have not been published and have not been rigorously analyzed to figure out what are signs associated with specific diagnoses or specific treatment response. A clinician involved in such enterprises might see that the last five people treated with a certain medication who had a certain symptom complex did really well on a specific drug. The clinician will then continue that drug. It is almost as if they are using this tool in the same manner, saying, “The last five people we saw with this brain pattern responded well to this medication profile, so we will use this.” Some have received positive results but some have not. I just caution them to be completely aware of the possible pitfalls of that approach.
That is all a long-winded way to say that we really have no idea or evidence that these things work at all. I do not recommend obtaining brain imaging for diagnostic purposes at this time, but it is an excellent research tool, and we are getting close to making it useful clinically. PP
1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2. Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9):1032-1039.
3. Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal course of children and adolescents with bipolar spectrum disorders: the Course and Outcome of Bipolar Youth (COBY) study. Am J Psychiatry. 2009;166(7):795-804.
4. Tillman R, Geller B. Controlled study of switching from attention-deficit/hyperactivity disorder to a prepubertal and early adolescent bipolar I disorder phenotype during 6-year prospective follow-up: rate, risk, and predictors. Dev Psychopathol. 2006;18(4):1037-1053.