# Developmental pathways model of depression heterogeneity

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $793,914

## Abstract

Depressive disorders are a leading cause of disability, their first onsets peaks between ages 14-24, and
they are a major concern in adolescent and emerging adult mental health. Although the majority of people
with depression quickly recover with few, if any, recurrences, many suffer from a protracted and highly
impairing illness. These time-limited depression (TLD) and chronic-intermittent depression (CID) groups
appear to differ in developmental etiology, outcome, and treatment response, yet are rarely distinguished in
research, gravely confounding the literature. To make progress in reducing depression burden, it is critical
to delineate the developmental pathways and adult outcomes of these groups. We propose to test a dual
developmental pathways model that hypothesizes that TLD results from severe life stressors. In contrast,
CID develops from a familial liability to low reward responsiveness and childhood adversity, which produce
blunted reward system functioning. Reward functioning may deteriorate further as the illness progresses.
No study to date has examined whether exposure to severe life events and reward responsiveness prior to
the first-onset of depression differentiate between these subtypes, which is essential to evaluating their role
in etiology. Moreover, research has not traced the trajectory of reward function after CID onset to
determine if it continues to worsen. We will build on an ongoing longitudinal study that has followed 550
young women (the high-risk demographic subgroup) from age 14 to 21 years, with > 85% retention. We
propose to follow the cohort through age 26 (2 years beyond the highest-risk period) to accurately
distinguish CID, TLD, and no depression groups. This will allow us to test the dual developmental pathways
model. We also will trace trajectories of reward responsiveness assessed using self-report,
electrophysiology, and a novel magnetic resonance imaging measure of dopamine signaling. Moreover, we
will assess young adult outcomes (occupational and relationship functioning, suicidality, and mental health
service utilization) to evaluate the public health significance of these subtypes. In addition, we will test the
feasibility of developing a predictive algorithm for CID using a comprehensive battery of premorbid risk
factors. Most research on depression to date conflates two markedly different populations, CID and TLD.
We will test a model of their development and etiology by closely following a large sample from early
adolescence to young adulthood, thus starting before and ending after the highest-risk period for
depression onset. No previous study that begun prior to the risk period for depression has charted the
course of depressive disorders at the level of resolution needed to distinguish CID from TLD. Delineation of
these groups can greatly reduce the diagnostic heterogeneity that plagues depression research and
treatment, which will increase the statistical power and interpretability of studies...

## Key facts

- **NIH application ID:** 10879538
- **Project number:** 1R01MH133652-01A1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Daniel N Klein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $793,914
- **Award type:** 1
- **Project period:** 2024-05-22 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879538

## Citation

> US National Institutes of Health, RePORTER application 10879538, Developmental pathways model of depression heterogeneity (1R01MH133652-01A1). Retrieved via AI Analytics 2026-06-15 from https://api.ai-analytics.org/grant/nih/10879538. Licensed CC0.

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