Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression

Abstract

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.

Trial registration: ClinicalTrials.gov NCT04445792.

FIGURE 1

Design of the ADOPT‐PGx depression trial.

FIGURE 2

Process of interpreting CYP2D6 genotype with phenoconverting drug–drug interactions to produce a clinical CYP2D6 phenotype and clinical recommendation. Avoid refers to a recommendation to switch to a drug not predominantly metabolized by the listed drug metabolism enzyme. Paroxetine and fluoxetine are omitted from the phenoconversion list as dual‐SSRI therapy is rarely indicated and was not expected to be utilized for the trial participants.

FIGURE 3

Process of interpreting CYP2C19 genotype to produce a CYP2C19 phenotype and clinical recommendation. Dose reductions refer to starting dose of medication; Avoid refers to a recommendation to switch to a drug not predominantly metabolized by the listed drug metabolism enzyme. Per the FDA warning, the maximum recommended dose of citalopram in CYP2C19 poor metabolizers is 20 mg/day due to the risk of QT prolongation.

FIGURE 4

Example of an ADOPT‐PGx clinical decision support alert.