# 1/2 Genetics at an extreme: an efficient genomic study of individuals with clinically severe major depression receiving ECT

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $1,623,286

## Abstract

This proposal brings together investigators from around the world to carry out a genetic study of severe
major depressive disorder (MDD) treated with electroconvulsive therapy (ECT). These individuals are
among the most severely ill people seen by psychiatrists, and we anticipate that genetic studies will
have greater power. The driving goals of the proposal are to identify genetic variation that 1) is
associated with severe MDD and indicate which patients are candidates for ECT, and 2) influence
response to ECT and predict which patients may benefit from treatment. MDD is a leading cause of
disability worldwide, and up to a third of patients do not respond to first line therapies. The search to
find the right treatment may require a lengthy period of trial and error with multiple treatments during
which patients continue to suffer and remain at elevated risk for adverse outcomes, including suicide.
ECT is one of the more effective treatments for severe MDD that is refractory to first line therapies.
However, even with ECT between one-third to one-half of patients fail to achieve remission after acute
treatment, and cognitive impairments may emerge that limit its wider use. It is clear genetic factors
contribute to risk for MDD, and recent studies genome-wide association studies (GWAS) have identified
>100 susceptibility loci. However, MDD is a heterogeneous condition, and most of the cases in the
previous GWAS were of lesser severity. Studies have shown that severe/treatment refractory MDD is
a more heritable sub-type, highlighting the potential benefit of focusing on severe MDD by studying
those treated with ECT. Moreover, there is evidence that genetic factors may shape clinical response
to ECT, but this has not been studied genome-wide with sufficient sample sizes. To address these
limitations, the Genetics of ECT Consortium (GenECT, a PGC MDD subgroup) has brought together
ECT centers globally, including those in the National Network of Depression Centers (NNDC) in the US,
to carry out a genetic study with the following aims: 1) ascertain, broadly consent, consistently
phenotype, and biosample 25,000 patients with severe MDD treated by ECT; 2) conduct a GWAS
against age, sex and ancestry matched controls to identify genetic variants that contribute to risk for
severe MDD; and 3) conduct a GWAS of clinical response to ECT in a sub-sample of 10,000 cases with
prospective follow-up data to identify genetic variants associated with changes in measures of MDD or
occurrence of cognitive impairments. This proposal will advance our understanding of the genetic
etiology of severe MDD which, in turn, will motivate the development of new and more effective
treatment strategies for this burdensome and difficult to treat condition. In addition, it will identify genetic
factors that can help distinguish which patients are good candidates for ECT even before initiating
treatment.

## Key facts

- **NIH application ID:** 10215488
- **Project number:** 5R01MH121542-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Peter P. Zandi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,623,286
- **Award type:** 5
- **Project period:** 2019-09-23 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215488

## Citation

> US National Institutes of Health, RePORTER application 10215488, 1/2 Genetics at an extreme: an efficient genomic study of individuals with clinically severe major depression receiving ECT (5R01MH121542-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10215488. Licensed CC0.

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