Pharmacogenomic Profiling of Pediatric Patients

Background:

The Centers for Disease Control and Prevention estimate that 13-20% of children living in the
United States experience a mental disorder in a given year and an estimated $247 billion is
spent each year on childhood mental disorders. In the last 5 years, emergency departments
(ED) have been facing dramatic increases in the volume of pediatric patients presenting for
evaluation and treatment of mental and behavioral disorders, to the point where it has been
termed a national pediatric mental health crisis. Coincident with this increase has been the
exponential increase in the number of children, both children as young as 2 years of age and
adolescents, being prescribed 1 or more psychotropic medications—antidepressants (AD),
antipsychotics (AP), and medications for Attention Deficit Hyperactivity Disorder (ADHD)--
for various mental and behavioral disorders in the last 10 years. More intentional overdoses,
therapeutic errors, and/or adverse drug reactions (ADR) to these classes of medications are
being evaluated in our pediatric emergency department (PED), potentially attributable to the
increased number of children taking these medications. National Poison Data System (NPDS)
-reported exposures to these medication classes continue to increase in both children and
adolescents.

Numbers and rates of adverse drug event (ADE) emergency department visits involving
psychiatric medications among US adults are significant, although the numbers in children are
less well defined. The development of adverse medical conditions related to antipsychotic and
other psychotropic medication use in children and adolescents has been found to be
significantly associated with higher total costs of health care and to higher utilization of
outpatient, emergency, and inpatient services over time.

Interindividual differences of people's clinical responses to psychotropic drugs and adverse
drug reactions despite identical disease severity or etiology may be better explained by
genetic variation among patients than other various factors. We will determine if genetic
polymorphisms for genes coding for CYP450 drug metabolizing enzymes are associated with
therapeutic failures and/or toxicity using the GeneSight® buccal swab test. Multiple
published adult clinical studies have demonstrated that this combinatorial, multi-gene test
better predicts antidepressant treatment outcomes for patients with depression and their use
of health care resources, than any of the individual genes that comprise the test. One study
demonstrated 70% greater improvement in depressive symptoms when GeneSight® guided
physicians' treatment compared to unguided treatment, while another demonstrated a 67%
increase in total healthcare visits when medication plans did not match their genetic
profiles, contributing to significant increase in healthcare costs.19,20 Recent
recommendations from the Clinical Pharmacogenetics Implementation Consortium of the National
Institutes of Health Pharmacogenomics Research Network suggest that current data indicate
that genotypes for CYP2D6 and CYP2C19 can lead to specific treatment recommendations.

To the investigators knowledge, this study is one of the first to propose the use of
pharmacogenomic tests to study toxicity or treatment failure in pediatric patients using
psychotropic medications and assess its clinical utility in patients presenting in crises to
an ED. The results of this study are very likely to change clinical practice leading to
increased pharmacogenomic testing of children and adolescents at their point of care in
outpatient clinics, inpatient services, or PEDs. If successful, this project will lay the
groundwork for future prospective analyses of genotypic "match" versus "mismatch" and either
symptomatic or toxic adverse outcomes in this cohort presenting to a PED compared to a
control population in an outpatient setting.

Study population: Inclusion criteria: Two categories of PED patients on psychotropic
medications will be included in this trial: (1) Children/adolescents who present with
psychiatric/behavioral crisis or intentional overdose. This would include those referred for
psychiatric evaluation, who may have behavioral problems (aggressive behavior, violent
behavior), suicidal or homicidal thoughts, recent history of self-injury (with or without
suicidal intent), depression, psychosis, anxiety, altered mental status, or violence. 2)
Children/adolescents who present to the PED with a suspected adverse drug reaction to any of
the psychotropic/ADHD medications (toxicity)

Exclusion criteria: (1) Patients on the aforementioned medications who present to the PED
with a chief complaint other than those listed above. (2) Participants who present with acute
intoxication with alcohol or drugs of abuse. (3) Patients in Alabama Department of Human
Resources (DHR) custody. (4) Those with medical conditions that preclude participation. (5)
Those with previous pharmacogenomic testing.

Methods:

The investigators will enroll 100 patients 3-18 years of age who are taking 1 or more AD, AP,
and/or ADHD medication presenting to the PED at Children's of Alabama with mental
health/behavioral crisis and/or adverse drug reaction to one of these drugs. This would
include those referred for psychiatric evaluation, who may have behavioral problems, suicidal
or homicidal thoughts, recent history of self-injury (with or without suicidal intent),
depression, psychosis, anxiety, altered mental status, or violence.

The informed consent process will take place before any study-specific procedures are
initiated. Signed and dated written informed consent must be obtained from each
patient/parent/legal caregiver prior to enrollment into the study. Assent for patients 7-13
years of age will be obtained unless criteria for waiver is met.

Data Collection

Buccal Swab: GeneSight uses a combinatorial psychiatric pharmacogenomics (CPGx) multi-gene
approach to produce a personalized interpretive report that categorizes psychotropic
medications into three groups (RED [use with increased caution and with more frequent
monitoring], YELLOW[use with caution], GREEN[use as directed) based on objective,
evidence-based gene-drug interactions. This decision support tool helps clinicians to make
informed, evidence-based decisions about proper drug selection, based on the testing for
clinically important genetic variants in multiple pharmacokinetic and pharmacodynamic genes
that affect a patient's ability to tolerate or respond to medications. It consists of a
cotton swab. GeneSight Psychotropic provides information on 38 FDA-approved antidepressant
and antipsychotic drugs. GeneSight® ADHD provides information on 100% of the FDA-approved
medications for ADHD.

Blood Sampling: Blood for measuring serum concentrations of the medications that the patient
is taking will be obtained (15-20 ml depending on how many medications the child is taking,
10 ml if the patient is < 14 kg). A small portion of this blood (5 ml) will also be banked
for future DNA genomic analyses. These blood volumes are all within accepted volumes for
patients in this age range.

Note: Blood samples are normally obtained in patients with drug overdose, suspected drug
toxicity as part of their standard evaluation as well as many patients being admitted to an
inpatient psychiatric facility.

12-lead Electrocardiogram: Rate, rhythm, QRS interval, QT, corrected QT interval (QTc),
terminal R wave in lead aVR will be recorded. The ECG is usually a standard part of the
evaluation for ingestions/overdose/suspected drug toxicity and sometimes for patients being
admitted to an inpatient psychiatric facility.

In addition to these tests we will also collect: (1) Demographics: age, sex/gender,
race/ethnicity, living situation, educational attainment. (2) Medication History: list of
current and past psychotropic medication treatments including name, doses, start and stop
dates, and estimated response. (3) All other medications. (4) Socioeconomic information,
including third party reimbursement. (5) Recall of healthcare utilization over the previous
12 months including hospitalization or ED visits. (6) Indication for psychotropic medication
(note that formal diagnostic interviewing will not be performed because of constraints of the
ED setting). (7) Reason for the current ED visit (e.g., anxiety, panic attack, intentional
self-injury including suicide attempt, suicidal ideation, homicidal ideation, medication
overdose, harm to persons or property, other aggression, psychosis, severe depression, other
psychiatric cause, adverse drug reaction). (8) Global Assessment of Function (GAF) scale,
Clinical Global Impression Scale (CGI-I), and Clinical Global Efficacy Index (CGI-E), all
validated scales used extensively in psychiatric research and (9) Clinical toxicity/adverse
drug reactions.

Note that the scales delineated in #8 ask for information that is usually part of the
physician's history and patient assessment: - self-assessment or the parent/caregiver's
assessment of the patient's overall functioning, drug tolerability, drug efficacy. This
information has been developed into validated scales.

The process is designed to be relatively brief to allow the study to proceed within the
workflow of the PED. Some information will be obtained from the electronic medical record
(drug names, duration of therapy, previous psychiatric diagnoses) if the patient, parent,
and/or caregiver is unsure or doesn't know.

Statistical Analyses:

- Descriptive statistics, specifically proportions, will be calculated for: Mismatch of
proportion of children presenting to PED with GeneSight RED or YELLOW categories and i.)
acute psychiatric/behavioral crisis ED visits; ii.) serum drug concentrations, high or
low; and iii.) overdose of drugs.

- Frequency of self-reported/caregiver-reported negative scores on GAF (score 5,6,7),
CGI-I (score 5,6,7), CGI-E scores

- Relationship between Mismatch(RED,YELLOW) and Match (GREEN) and self- and/or
care-reported GAF, CGI-I, CGI-E scores

- Descriptive statistics, specifically proportions will be calculated for: Mismatch of
proportion of children presenting to PED with GeneSight genotype RED or YELLOW
categories and adverse drug reactions

- Frequency of GeneSight genotype mismatch RED or YELLOW categories and specific adverse
reactions/clinical toxicity

Inclusion Criteria:

- Children taking 1 or more antidepressant, antipsychotic, and/or attention deficit
hyperactivity disorder medications.

- Children/adolescents who present with psychiatric/behavioral crisis or intentional
overdose. This would include those referred for psychiatric evaluation, who may have
behavioral problems (aggressive behavior, violent behavior), suicidal or homicidal
thoughts, recent history of self-injury (with or without suicidal intent), depression,
psychosis, anxiety, altered mental status, or violence.

- Children/adolescents who present to the PED with a suspected adverse drug reaction to
any of the psychotropic/ADHD medications (toxicity).

Exclusion Criteria:

- Patients on the aforementioned medications who present to the PED with a chief
complaint other than those listed in the inclusion criteria.

- Participants who present with acute intoxication with alcohol or drugs of abuse.

- Patients in Alabama Department of Human Resources (DHR) custody.

- Those with medical conditions that preclude participation.