Understanding and Treating Neuropsychiatric Symptoms of Pediatric Physical Illness

Depression is costly, worsens morbidity and mortality, and has detrimental effects on
disease course in physically ill populations. This research takes a novel multi-dimensional
approach to assess the neurobiological basis of depression in chronic pediatric physical
illness using inflammatory bowel disease (IBD) as a model. It also evaluates the efficacy of
a modified cognitive behavioral therapy (CBT) on emotional well-being, physical health,
economic costs, and neurobiological outcomes. These results will provide key building blocks
for a paradigm shift within medicine by integrating behavioral health into the comprehensive
medical care of physical illnesses.

Little is known about how the brain and body interact to increase depressive vulnerability,
particularly in youth. Adult studies identify disruptions in limbic and prefrontal brain
activity in the pathophysiology of depression. Cytokines secondary to inflammation and
exogenous treatment with steroids can cause mood and cognitive changes in these same brain
regions. It is important to understand the neuropsychiatric effects of IBD and its treatment
on underlying brain structures during adolescence, a critical developmental period for brain
maturation underlying emotional regulation and cognitive processing. More importantly,
neuronal plasticity during adolescence may still allow reversibility of disease-related
brain effects through teaching coping strategies for life-long illness management that could
change developmental trajectories and reduce vulnerability in adulthood.

Using translational neuroscience approaches, this research will examine: 1) brain regions
that underlie emotional and cognitive processing in youth with active IBD and depression
using brain functional magnetic resonance imaging compared to youth with IBD and no
depression, and normal controls; 2) the inter-relationship between depressive symptoms in
IBD and brain, immune, and gastrointestinal functioning; and 3) efficacy of a combined
CBT-physical illness narrative intervention targeting emotional and cognitive processing
compared to supportive non-directive therapy in the depressed IBD cohort with longitudinal
tracking of emotional, physical health, economic, and neurobiological outcomes.

Inclusion criteria for youths with IBD for Step 1 of Screening Process:

- Age 12 to 17 inclusive

- English-speaking

- Capable of completing CDI

- Meeting diagnostic criteria for IBD

- Absence of mental retardation by history

- Having at least one appointment at the GI clinic.

Criteria for Classification of IBD:

1. Presence of appropriate history: abdominal pain, chronic diarrhea, bloody diarrhea
(with or without extraintestinal symptoms) or, less commonly, a) primary
extraintestinal symptoms, b) growth retardation, c) peri-rectal abscess, or d) acute
abdomen.

2. Evidence of colitis, ileitis or granulomatous esophagitis, gastritis or duodenitis by
biopsy and/or small bowel strictures or fistulas by X-ray or multiple small
intestinal ulcerations by capsule endoscopy.

Eligibility Criteria For youths with IBD for Intervention Phase of the Comparison Study

Inclusion Criteria:

1. CDI or CDI-P > 10 at Step 1

2. CDRS-R > 34 at Step 2

3. Presence of at least one biological parent. Exclusion Criteria

1. History or current episode of bipolar disorder, eating disorder, or psychotic disorder
by DSM-IV criteria. 2. Recent suicide attempt (within 1 month of study entry) or
depression severity requiring acute psychiatric hospitalization within 3 months of study
entry. 3. Antidepressant medications within one month of assessment. 4. Substance abuse by
history within 1 month of study entry. 5. Current treatment with CBT or failure of
previous CBT trial for depression judged adequate by at least 12 treatment sessions over a
period of less than 1 year conducted by an appropriately trained mental health provider
using a manual. If currently receiving other psychotherapy modalities, willingness to
suspend treatment for 12-week acute treatment phase of study.

Physically Healthy Comparison Children

Inclusion Criteria:

- Age 12 to 17 inclusive

- English-speaking

- Capable of completing CDI

- Absence of mental retardation by history

Exclusion Criteria:

- self-report of a cold, flu or other infection within the past two weeks

- self-reported use of any antibiotics within the past 2 weeks

- score of 6 or more on the blood draw screening questionnaire

Screening process for youths with IBD: Participants will be recruited from the clinic
through a 2-step screening of all consecutive pediatric patients seen in the IBD clinic or
while medically hospitalized for an IBD flare-up at Children's Hospital of Pittsburgh, who
have confirmed IBD and who meet the other eligibility criteria as determined by medical
staff in IBD clinic (Tables 5 and 6). The medical diagnosis of IBD will be determined by a
GI physician using criteria below and will be confirmed in the medical record. Step 1:
administration of the CDI and CDI-P during the medical visit. Those subjects whose CDI
and/or CDI-P score of > 10 will be invited by phone to participate in Step 2: a face to
face interview. This cut-off score was chosen as it is consistent with an adjustment
disorder (Kovacs, 1992); it is consistent with sub-clinical levels of depression that are
not solely from neurovegetative symptoms and; because it still provided an adequate range
of scores to detect improvement in our preliminary work. Step 2 assessment will be
conducted within one week of Step 1 so that both CDI score and IBD severity ratings are
still valid from the Step 1 screen.

All subjects meeting eligibility criteria for Step 2 will be invited to participate in the
completion of neuropsychiatric questionnaires, blood draw, pupil measurements, and brain
functional magnetic resonance imaging within one week of Step 1.

All subjects meeting eligibility criteria after Step 2 (Table 7) will be invited to
participate in the treatment phase of the study. See Human Subjects Section for more
details about screening and consent procedures. All subjects who choose not to participate
or dropout of treatment for any reason will be referred for a psychiatric evaluation in
the Psychiatry Department. The face to face assessment in Step 2 will consist of
assessments both parent and child report. Subject and parent burden will be approximately
3-3.5 hours.

Normal controls (N=15) will be recruited from the Department of Pediatrics during
outpatient clinical office visits.