From Breakthroughs, 2010

Kiki Chang, M.D., and Tara Peris, Ph.D., study and treat mental illness in children. In the clinic, Dr. Chang, a NARSAD Independent Investigator, is using psychotherapy to see whether, by changing family dynamics, he can forestall illness or reduce symptoms in children believed to be at risk for bipolar disorder. In the lab, he is searching for clues to better predict the risk. Dr. Peris, a NARSAD Young Investigator, is testing a form of therapy she has adapted specifically for families with children with obsessive compulsive disorder (OCD).

The work of these two scientists — one at mid-career and one starting out — represents a major conceptual turnabout in neuropsychiatric research. Childhood mental illness was once considered virtually nonexistent. Today, scientists believe that many if not most psychiatric disorders begin early in life, “and the younger the age of onset, the worse the outcome,” Dr. Chang says.

Dr. Chang founded and directs the Pediatric Bipolar Disorders Program at Stanford University and has been the recipient of three NARSAD awards over the past decade. Dr. Peris, whose NARSAD grant was awarded in 2008, is an assistant professor in the department of psychiatry and biobehavioral sciences at UCLA . For both, NARSAD funding has been the path to more substantial federal support as they strive to improve the lives of families in crisis.

Finding predictors of bipolar disorder in children

Like many if not most mental illnesses, bipolar disorder is thought to arise from the interaction of genetic susceptibility and environmental stress. The search for genes, and genetic or biological markers as diagnostic tests or predictors of bipolar illness, is a major, long-term goal of Dr. Chang’s lab. But it has been complicated by the large number of genes believed to be involved. At present, the identification of children at risk is based on family history.

Of the two poles of bipolar disorder, depression and mania, depression usually strikes first. But treating bipolar depression with common antidepressants can inadvertently trigger mania and rapid mood cycling and incite one of the greatest dangers of bipolar disorder: suicide.

While the search for genes and brain markers goes on, Dr. Chang is hoping that a concurrent project will have a nearer-term payoff. He is collaborating in a study with David Miklowitz, Ph.D., of UCLA, who developed the use of family-focused therapy (FFT) with adults with bipolar disorder to ease symptoms and prevent relapse. Trials at Stanford and UCLA are testing the potential of the therapy to delay or prevent the onset of illness in children at high-risk for bipolar disorder by educating the family about symptoms and about available help and medications and providing coping mechanisms to reduce family stress.

Imaging the bipolar brain to identify if and how psychotherapy helps

Chang’s latest NARSAD research includes pre- and post-therapy brain imaging, which he says has rarely been done with psychotherapy studies. When he began his studies, it was known that adults with bipolar disorder had abnormal levels of a chemical called N-acetyl aspartate, NAA, in the prefrontal cortex, a brain area associated with mood regulation. With his first NARSAD grant, he found abnormal NAA levels in children with bipolar disorder, which led him to wonder whether the it was an effect of the disorder or preceded it. If it were the latter, it might then be a marker of impending illness.

Under a second NARSAD grant, in 2002, he looked at NAA in children believed at risk who had not yet developed bipolar disorder. “We didn’t find what we had hoped to; their NAA levels were normal, indicating that NAA levels don’t drop until after having the full illness.” But subsequent studies, by Chang and others, succeeded in uncovering important aspects of bipolar mechanisms involving interactions between the prefrontal cortex and the amygdala, a structure within the primitive, limbic region of the brain critical to emotional behavior.

“If you experience some very emotional event,” Chang explains, “your amygdala fires. It’s like pressing down on the gas pedal when you’re driving. The prefrontal cortex then acts like the brake pads to control the gunning from the amygdala. But if you press the gas pedal too hard or if your brake pads are failing, it can lead to trouble.

In children with bipolar disorder, the amygdala is smaller than normal but abnormally active. “Since we’ve found this occurring in other mood disorders as well, we can’t use it as a diagnostic test specifically for bipolar disorder, but it does tell us more about why these children are having problems. For example, in studies comparing fearful or angry faces to neutral faces, kids with bipolar disorder show heightened amygdala activation. We’re following these kids, measuring their amygdala volumes over time to see what happens to them. As for the prefrontal cortex — the brake pads — it does appear they’re wearing down with repeated mood episodes.”

Chang expects to see changes in amygdala reactivity and in prefrontal structures. “While it’s not as simple as just increasing the brakes and letting up on the gas pedal, we’ve begun to find some prefrontal areas that do increase in activation, and other areas that decrease. Different brain circuits are coming on line and others are not as active as before, which we think and hope might be a sign children are using a ‘healthier’ emotional circuit as the result of this therapy.”

Projecting both urgency and optimism, Chang states: “ With bipolar disorder it can be years between the onset of symptoms and diagnosis, years in which a lot of bad stuff can happen, which is why my lab is all about early identification and prevention. We want to get to kids before they reach full-blown bipolar disorder. We’re getting closer.”

A promising therapy for pediatric OCD

The kids Peris treats already have full-blown obsessive-compulsive disorder. Like the nine-year-old who stopped eating solid food for fear of choking and repeatedly asked his parents for reassurance that he wouldn’t die. Or the boy who gets up in the middle of the night to shower for hours on end. Or the one who wears socks on his hands so as not to touch the doorknob. In each of these cases and many more like them, distressed, confused families of these children are drawn into the child’s OCD rituals and may inadvertently contribute to maintaining the cycle of illness.

In a small pilot study supported by NARSAD, Peris is testing an approach called positive-family interaction therapy, PFIT, that she has developed as a supplement to traditional child-focused treatment. She is examining whether the PFIT family treatment module can decrease family conflict, increase cohesion and help families disengage from the rituals and aberrant behaviors that may maintain or worsen OCD. PFIT and the treatment being used by Chang both derive from cognitive behavioral therapy, developed by Aaron Beck

“In the study, we looked for very distressed families who might have a hard time supporting their children in traditional treatment.” These families tend to be less stable and less organized and to have high levels of conflict and blame. The program, which Peris designed with her UCLA postdoctoral mentor, John Piacentini, Ph.D., places emphasis on getting parents to acknowledge and manage their own emotions and incorporates a number of well-established techniques to help them set realistic goals and carry them through, step by very small step.

Peris hesitates to speculate about clinical outcomes, but says so far around 60 percent of the PFIT families appear to be responding to treatment versus 40 percent of those in usual care. She reports that the little boy who would only take liquids has started trying solid foods again, and is working on chewing in a normal, non-ritualistic way. His parents are learning to stay calm and supportive during difficult moments.