Underpinnings of Neuropsychiatric Disease: A Behavioral Health Research Q&A

A self-proclaimed “geeky student” in high school, Stewart Anderson, MD, a research psychiatrist at The Children’s Hospital of Philadelphia and associate professor of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania, always dreamed of being a scientist. He wandered through various fields — anthropology, archeology, geology, astronomy – before becoming fascinated with learning about the brain. In college, he majored in neuroscience and psychology, and shortly thereafter lived with a roommate who was diagnosed with schizophrenia and needed hospitalization. This experience led him to focus his research interest in understanding the biology of mental illness.

Cornerstone asked Dr. Anderson about ongoing research in the Department of Child and Adolescent Psychiatry and Behavioral Sciences (DCAPBS) that is oriented toward developing and optimizing the practical implementation of behavioral or neurochemical interventions that aim to advance care for the more than 20 percent of patients at CHOP who have a behavioral health condition.

When did you begin your lab, and what research problems do you hope to solve?

I started my independent lab at the Weill Cornell Medical School in New York City in 2001, where I also had a clinic devoted to treatment-resistant schizophrenia. As our knowledge of molecular determinants of forebrain development grew, so did my eagerness to move into a more translational environment. Schizophrenia, like many other neuropsychiatric illnesses, has neuropathological antecedents that precede the onset of symptoms.

CHOP and Penn have a tremendous environment for collaborative research involving brain imaging, genetics, and basic science work, so I moved here four years ago to immerse my lab in this atmosphere. By identifying the neuropathological antecedents to schizophrenia, we can use that knowledge to design interventions that halt the progression of pathology, preferably, in adolescents who are at high genetic risk, before symptoms begin.

Tell us how your research projects are revealing these molecular underpinnings behind neuropsychiatric disease.

I am very excited about a research project in which we are using stem cells derived from patients with schizophrenia and 22q11.2 deletion syndrome, a chromosomal abnormality occurring in about one in 4,000 births. CHOP has a world-renowned clinic for 22q11.2 deletion syndrome, and the children we treat frequently have a variety of neuropsychiatric challenges, including autism-associated symptoms, attentional problems, learning problems, and about 30 percent of them develop schizophrenia in the later adolescent years or as they move into young adulthood.

We take the stem cells made from tiny skin biopsies from 22q11.2 patients and healthy “controls,” then make them into forebrain like neurons in a dish, where we can watch and study their development. Based on the suspected functions of several of the genes missing (on one of the two chromosomes) due to the partial chromosome 22 deletion, we are focusing on mitochondrial function of these developing neurons. Mitochondria function as the “power plant” of cells, and are especially important in neurons since their firing to relay messages from one neuron to another requires a lot of cellular energy.

Thus far, we see evidence that mitochondria in neurons from patients with 22q11.2 deletion syndrome and schizophrenia are energetically stressed compared to those from healthy controls. We are applying for research funding that would allow us to study this deficit very closely, creating a platform for medication development targeting the problem, and extending the studies to patients with 22q11.2 deletion syndrome without schizophrenia, and schizophrenia without 22q11.2 deletion syndrome. Doug Wallace, PhD, one of the world’s leading mitochondria researchers and director of CHOP’s Center for Mitochondrial and Epigenomic Medicine, has been collaborating with us on these research projects.

Why is it important to foster such research collaborations in behavioral health?

CHOP is a wonderful setting where people engage in a kind of intense collegiality to move our fields forward. The faculty recognize that the challenge is much bigger than one lab or one ego, and real progress that translates into new and better ways to help the children in our care is made through synergistic interactions — such as the example above where a researcher like me with 80 publications on brain development and schizophrenia/epilepsy/autism is interacting with a more senior colleague such as Doug who has 400-plus publications on mitochondria.

Doug and I, together with a former CHOP colleague who moved to Harvard three years ago, recently published a paper showing that during prenatal development of the cerebral cortex, migrating excitatory neurons and migrating inhibitory neurons have different energy needs. The excitatory cortical neurons migrate by a far more energetically needy mechanism that renders them vulnerable to mitochondrial dysfunction and/or hypoxia. We believe this finding explains why prenatal hypoxia and also mitochondrial disorders sometimes cause symptoms in children that appear like problems of lack of inhibition (such as epilepsy/seizures).

Another quick example: We are learning how to make inhibitory interneurons out of human stem cells for the development of cell based therapy of severe, medication resistant, childhood epilepsy. This initiative involves my colleague Ethan Goldberg, MD, PhD, a CHOP pediatric neurologist and assistant professor of neurology at the Perelman School of Medicine at the University of Pennsylvania who runs a state-of-the-art epilepsy/electrophysiology lab next to mine.

What else is exciting in the field of behavioral health research for pediatrics at CHOP?

Personalized medicine is on the neurobiology front, whereby a child’s genetic variants are matched to treatment. Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP is leading this effort and interacting with faculty in DCAPBS, including its Executive Director and Chair Tami Benton, MD, psychiatrist-in-chief at CHOP.

In the Center for Autism Research (CAR), Robert Schultz, PhD, CAR director; Judith Miller, PhD, clinical training director for CAR; John Herrington, PhD, associate director of CAR’s Developmental Neuroimaging Program; and Benjamin Yerys, PhD, child psychologist, are using genetics, brain imaging, electrophysiology, and additional cutting-edge tools to discover new ways to understand, and to treat, autism.

On the behavioral intervention front, psychologist Ricardo Eiraldi, PhD, program director of the Behavioral Health in Urban Schools program at CHOP, and Tom Power, PhD, director of the Center for Management of ADHD, are determining how to teach teachers — and to quantify the success or failure of the effort — to optimize the learning of troubled students in under-resourced schools.

Psychologist Lamia Barakat, PhD, director of psychosocial services in Oncology and the section of Behavioral Oncology in the Center for Childhood Cancer Research, and Matthew Hocking, PhD, psychologist, are researching new ways to help childhood cancer survivors cope with special neurocognitive and social challenges they face as they grow up. Alix Timko, PhD, a CHOP assistant professor of psychology, and Robert Berkowitz, MD, an attending physician and director of CHOP’s Weight and Eating Disorders Research program, are studying the treatment of eating disorders and obesity, using both behavioral and medication-based approaches.

Unfortunately, stigma remains in our society that prevents some children and families from seeking behavioral health care. How can researchers take part in this very important conversation?

Researchers can take opportunities to engage the public and talk about the effectiveness of lifestyle adjustment and pharmacological treatments of major mental illnesses. There is much work left to do, but relative to treatment options a generation ago, there is much to be hopeful about.