CCPR: Dr. Pavuluri, please share with us your interest in pediatric bipolar disorder.
Dr. Pavuluri: i am the director of The pediatric Brain Research And Intervention (BraiN) center at the University of illinois at Chicago. I study the brains of children with bipolar disorder. I am interested in the brain’s plasticity in these patients and learning how to develop interventions capitalizing on the plasticity.
CCPR: What is so interesting about the brains of children with bipolar disorder?
Dr. Pavuluri: children with bipolar disorder give you a wonderful example of a brain that is impacted by cognitive and emotional problems, with impairment in many domains that are interrelated.
CCPR: In your research, you have found that kids with bipolar disorder understand things differently than kids without. What are some of these brain differences?
Dr. Pavuluri: We have mapped five main circuits in the brain so far. There is one circuit that modulates emotions, another that helps recognize facial emotions, another that shows immediate reaction to emotionally negative stimuli, another one that underlies impulse control, plus a circuit that connects the emotional/feeling and thinking regions. a quintessential clinical problem with bipolar disorder is that patients are excitable, irritable, and overly reactive, and these become problematic more so in the context of reactivity to perceived negativity. all of the five circuits are impaired and there is a complex problem with the wiring.
CCPR: How do you differentiate then between bipolar disorder and ADHD, since ADHD presents with impulsivity, emotional reactivity, and irritability, too?
Dr. Pavuluri: adhd, by diagnosis, is a disorder with attention problems and response inhibition. These kids are also emotional, though the emotionality arises from being frustrated. adhd presents predominantly with inattention, poor executive function, and poor impulse control. Bipolar disorder is predominantly an emotional wiring problem.
CCPR: Do all of these problems originate in the same part of the brain?
Dr. Pavuluri: impulse control and emotional control problems share the same hierarchical prefrontal cortex area of the brain called ventrolateral prefrontal cortex. It is the CEO that controls impulse control—with wiring shooting towards the caudate; and emotional control—with wiring shooting toward the amygdala. These two sets of wires are connected again at the subcortical level (in other words, caudate and amygdala). in some ways, if you pull one wire, it affects the other.
CCPR: Do you think this connection is why kids often are first diagnosed with ADHD when later it becomes clear that they have bipolar disorder?
Dr. Pavuluri: i think there are three reasons for that. The first reason is sometimes kids actually present with adhd first. in a young formative brain, there might be problems with adhd that spill into the bipolar spectrum over time. The second scenariois that people get it wrong because they may not recognize the emotional problems that indicate bipolar disorder. and the third reason is that one disorder may be present in full and the other disorder may be present in part, as i described earlier, due to entangled wiring problems across the brain. i want to point out that these are man-made labels. i believe that no matter what the disorder is, the labels are important only insofar as they help us communicate the larger picture.
CCPR: Knowing what you do about the brains of kids with bipolar disorder, how canwe better treat them?
Dr. Pavuluri: We should take a “double-pronged approach,” as I call it. In addition to treatingthe disorder, we need to focus on treating the domain dysfunction in the brain. executivefunction, impulse control, emotional control, emotional response, emotion processing,emotion recognition, perspective taking, concentration, attention, and memory are some ofthem. so we try to address any number of these difficulties that each child may be facing. it isthe predominant symptom structure that dictates the treatment plan.
CCPR: You did a really interesting study looking at two different medications and what they do functionally in the brain. Can you tell us about that?
Dr. Pavuluri: We have done a number of studies comparing risperidone (risperdal) and divalproex (depakote) (pavuluri M et al, J Am Acad Child Adolesc Psychiatry 2012;51(2):157–170). Risperdal is a serotonin dopamine antagonist—an atypical antipsychotic— that works in the subgenual cortex. and divalproex (depakote) is an anticonvulsant that works in the frontal and temporal regions of the brain to stabilize mood at the cellular level through calcium channels. risperdal moderates emotional regions such as the insula, amygdala, subgenual cortex, and the prefrontal cortex. depakote does similar things, but it works in regions that are slightly different, and works especially in the medial prefrontal cortex, which is the emotional evaluative area. Sometimes these drugs don’t work well at regulating emotions on their own as a single drug, but when they are given together to treat mood, they complement each other as they work on different regions of the brain.
CCPR: So a lot of us know combinations can work better than some drugs alone, but this explains why that is.
Dr. Pavuluri: yes, and this means that in the future we can develop new drugs, new treatments, and new techniques and tools using this knowledge and foster the brain’s ability to repair the dysfunctional circuits back to health.
CCPR: Do you think that there is a way to tell which kind of medication would be better based on the presentation ofa child?
Dr. Pavuluri: I would say: “sometimes.” If there is somebody who is very smart, and you really want to preserve cognition, lamotrigine (lamictal) is one mood stabilizer that i often prescribe along with, say, risperdal, because of the cognitive preservation that lamotrigine offers. Risperdal is a drug that offers response really quickly. So if someone is very sick it’s a good choice to get them feeling better fast. if someone has more depressive symptoms, then you might want to think about lithium, which is known to reduce suicidal symptoms a bit better (Baldessarini rJ et al, Pharmacological treatment of bipolar disorder throughout the life- cycle. in shulman Ki et al (eds): Bipolar Disorder Through the Life-Cycle. Wiley & Sons, New York, NY, 1996, pp 299–338). We just discovered that lithium changes genetic makeup that fosters nerve growth, which is why it may take longer for it to show its full effect! There are more drug studies done through clinical practice than through brain, so we are still trying to use brain studies to decode the drugs one by one.
CCPR: You mention cognitive preservation with lamotrigine. Do you find that kids with bipolar disorder have cognitive problems in addition to their issues interpreting emotional stimuli?
Dr. Pavuluri: emotional dysregulation is critical: even though these children are very smart, emotional dysregulation sometimes trumps their obvious intelligence. The brain shows complex impairment in bipolar disorder. To repeat, there are problems with executive function, attention, working memory, verbal memory, and impulse control.
CCPR: Do these problems improve with treatment?
Dr. Pavuluri: We have shown in bipolar disorder that over three years of follow-up, some get a little better, some get worse, and some stay the same over time, compared to their healthy peers (pavuluri et al, J Am Acad Child Adolesc Psychiatry 2009;48(3):299– 307). executive function and verbal memory either stay the same or get worse sometimes. attention problems, because we can treat them with stimulants, seem to respond a little better and quicker over time. Working memory also has been shown to improve with drugs that enhance the working memory and attention, such as lamotrigine and Focalin. lithium has a reputation for impairing cognition, but in our study lithium did not worsen it, but it did not fix the cognition, either (stevenson JM et al, J Pharm Prac 2012;25(2):274). sometimes, lithium helps cognition in part, via stabilizing emotional control.
CCPR: Sometimes people come into the office and say, “I want my kid tested for bipolar disorder!” How close do you think we actually are to being able to do that?
Dr. Pavuluri: i still think that clinical diagnostic assessment is the best option. We are developing more measures and more techniques to show exactly where “the (brain) engine” is not working. We have a long way to go to rely on these tools.
CCPR: Thank you, Dr. Pavuluri.
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