ABSTRACT
Major depressive disorder (MDD) is a chronic, recurrent illness impacting 20.6% of the U.S. population,
causing significant disability and an economic impact of $326.2 billion annually. One of the largest risk factors
for depression chronicity and disability is inadequate antidepressant response, defined as less than a 50%
improvement in depressive symptoms after starting antidepressant treatment. Antidepressants are
recommended as a first-line depression treatment and taken by 70% of patients with depression. Inadequate
antidepressant response is experienced by 50-60% of patients starting an antidepressant and is responsible
for 47% of the economic impact and disability caused by MDD. As such, identifying risk for inadequate
antidepressant response early, during a patient’s first clinical presentation for a depressive episode, would be
an innovative, urgently needed first step towards preventing recurrent depressive episodes, reducing
depression chronicity and disability, and improving MDD outcomes. This step aligns with The National Institute
of Mental Health (NIMH) Strategic Plan Objective 3.2 to “develop strategies for tailoring existing interventions
(antidepressants) to optimize (depressive episode) outcomes.”
While previous studies identified separate predictors of antidepressant response, no study to date has focused
on integrating known and novel predictors of inadequate antidepressant response during a patient’s first
depressive episode. This knowledge gap exists as no large studies in diverse populations have integrated
comprehensive clinical, demographic, genetic, AND behavioral information in one model to predict inadequate
antidepressant response prior to first antidepressant treatment. Such information is crucial to improve patient
care, reduce depressive disorder chronicity and disability, and tailor existing patient interventions to optimize
MDD outcomes. Utilizing electronic health record data from three large, integrated healthcare systems
representing over 6.9 million members (Kaiser Permanente (KP) Northern California, KP Washington, and
HealthPartners), we aim to quantify inadequate antidepressant response risk at the time of a patient’s first
clinical presentation for a depressive episode by integrating clinical, demographic, genetic, and behavioral
information in one predictive model. To accomplish this aim, we will use translational machine learning and
predictive modeling, internal and external model validation and testing, prospective validation, and existing
genome-wide genotypic data. Further, we will examine barriers and facilitators to clinical applications of
predictive models for MDD to facilitate clinical translation and implementation of the predictive model, reducing
the time between research innovation and clinical application. Our long-term goal is to develop a clinical tool
informing decision making and promoting MDD treatment optimization.
