# Estrogen and Mechanisms of Psychotic-like Experiences in the Transition to Adolescence

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2024 · $225,621

## Abstract

PROJECT SUMMARY
Biological females develop psychotic disorders later than males. One leading theory that explains this
phenomenon is the estrogen hypothesis, which proposes that rising estrogen during the pubertal period may
impact mechanisms of psychosis onset until estrogens normatively decline (8-10 years later) and the risk for
psychosis is unmasked. The premorbid psychosis period, during the transition from childhood to adolescence,
is of high significance with regard to early mechanisms of psychosis as it marks a time where liability for
psychosis interacts with hormonal and brain development while subtle psychosis symptoms, i.e., psychotic-like
experiences (PLEs), emerge. This developmental period is also marked by the initiation and rising estrogen
levels in biological females which has a powerful impact on the hippocampus- increasing volumes,
connectivity, and improving hippocampal-related cognitive function- a region critically implicated in psychosis
vulnerability and course. However, the estrogen hypothesis has never been examined longitudinally in the
developmental context of the premorbid period. Instead, prior literature has often focused on late decreases in
estrogen or retrospective accounts of puberty in individuals along the psychosis spectrum. As a result, many
questions remain regarding the mechanisms of the estrogen hypothesis in adolescence. Individual variability in
late childhood and early adolescent development provides a natural experiment for testing the mechanisms
through which estrogen interacts with vulnerability to psychosis. This variability allows for the modeling of
changes in estrogen (in terms of rising levels and menarche), brain structure and function, cognition, and
course of symptoms both across and between biological females within their developmental context. This
approach has significant potential to provide an entirely new perspective on our mechanistic understanding of
psychosis. The proposed analyses will leverage the strengths of the ABCD study, capturing this rich variability
in estrogen in late childhood and early coupled with critical neural, cognitive, and symptom longitudinally within
biological females. This rich dataset will allow us to examine estrogen comprehensively within biological
females and whether there is sex specificity to the impact of estrogen levels on PLEs by examining biological
males for whom estrogen levels are available. Although not everyone with PLEs will transition to psychosis,
these symptoms do reflect underlying psychosis vulnerability in the premorbid period, and tracking changes in
PLE levels in the premorbid period may be informative in the early mechanism that may modulate vulnerability
related to formal psychotic disorders as a function of adolescent development. Understanding the mechanisms
of these estrogen effects within their developmental context will provide insights into how (structural, functional,
cognitive, direct clinical impact), when (timing/developm...

## Key facts

- **NIH application ID:** 10998688
- **Project number:** 1R21MH136408-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Katherine Steffen Filip Damme
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $225,621
- **Award type:** 1
- **Project period:** 2024-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998688

## Citation

> US National Institutes of Health, RePORTER application 10998688, Estrogen and Mechanisms of Psychotic-like Experiences in the Transition to Adolescence (1R21MH136408-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10998688. Licensed CC0.

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