May 13, 2016
Approximately 2.5 percent of U.S. children under age 18 take antidepressant medications. The type of medication — most often a selective serotonin reuptake inhibitor (SSRI) — is based on symptoms and medical history and often involves a lengthy trial-and-error process.
Around 40 percent of pediatric patients show no response to a first SSRI, and only half of those respond to a second, with increasingly poor response rates with each subsequent medication. SSRIs are also associated with serious psychiatric side effects and other adverse events. Still, with no new drugs in development, attention is increasingly focused on doing better with existing ones.
One area of growing interest — and some controversy — is neuropsychiatric pharmacogenomic testing, which uses genetic information to predict responses to medications based on known gene-drug interactions. Both drug metabolism (pharmacokinetic) and mechanism of drug action (pharmacodynamic) genes play a role in variability of response and potential side effects.
For that reason, and because most psychiatric medications are metabolized by several cytochrome P450 enzymes, single-gene tests have shown limited clinical benefit. But a few studies suggest that testing a combination of gene interactions may provide information that improves medication decisions.
One open-label study, published in Pharmacogenetics and Genomics in 2013, looked at a multigene pharmacogenomic testing platform (GeneSight) for managing drugs used to treat major depression in adults. At eight weeks, participants whose treatment was based on testing demonstrated a greater improvement in depression scores and higher remission rates compared with controls.
No studies have looked at pharmacogenomic testing for children and adolescents, however. So investigators at Mayo Clinic's campus in Minnesota are enrolling pediatric patients with major depressive disorder in a trial using the same testing platform used in adult trials.
"These tests are expensive, and we need more data before ordering them on a routine basis," explains co-investigator Jennifer L. Vande Voort, M.D., a child and adolescent psychiatrist at Mayo Clinic's campus in Rochester, Minnesota. "Although the goal of the study is to evaluate the GeneSight platform, it is not intended to promote the technology, but rather to see whether it can improve response to treatment, minimize side effects and increase treatment adherence."
The randomized, double-blind, prospective study is ambitious, hoping to enroll a total of 276 patients, ages 13 to 18 years, with moderate to severe major depression. All will undergo GeneSight testing for the following genotypes:
- SLC6A4 and HTR2A (serotonin transporters)
- COMT and ADRA2A (may be important for ADHD medications)
Half the participants will then be randomized to a guided group, where the treating clinician will know the genetic results at baseline. The other half will be randomized to a treatment-as-usual group, where the treating clinician will not have the results until week eight. Patients, families and raters will also be masked until the end of the trial.
The primary outcome is a change from baseline to endpoint in the Children's Depression Rating Scale, Revised. Secondary outcomes include changes in depressive symptoms on clinician, patient and parent reports and global assessments as well as adherence to treatment based on concordance or nonconcordance of gene test results and clinical interventions.
"We would hope to see maximal benefit from any medication in three to six visits, but if patients aren't responding, genetic testing may help guide us to a better medication with a shorter response time," Dr. Vande Voort says.
For more information
Hall-Flavin DK, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenetics and Genomics. 2013;23:535.
Mayo Clinic. A PK/PD genetic variation treatment algorithm versus treatment as usual for adolescent management of depression (AMOD). ClinicalTrials.gov.