# 2/5-Clozapine Response and Biomarker Correlates in Low-IEA Biotype-1

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $364,500

## Abstract

Project Summary
Treatment advances in psychosis are limited by the use of phenomenology-defined diagnoses based on
symptomatic outcomes, rather than by neurobiological constructs monitored by quantitative characteristics.
The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) uses biomarkers to define
psychosis subgroups with the goal of testing the advantages of B-SNIP biomarkers for diagnostic and
therapeutic decisions, consistent with principles in the NIMH Strategic Plan (NSP). With >3000 phenotyped
psychosis probands, relatives and healthy controls (HC), B-SNIP has a multilevel biomarker library for
psychosis and used that library to re-conceptualize psychosis subgroups as biomarker-defined Biotypes (B1,
B2, B3), where B1 and B2 are the low cognition/high symptom groups and B3 shows lower symptoms and
relatively normal cognition. We replicated Biotypes in a new sample, “forging a future where measures of an
individual's … neural and physiological state will form the basis of an increasingly specific and informative
diagnosis” (NSP). In this grant we propose that B1, with its low cognition and low cortical activity, will respond
uniquely to clozapine, a drug which will generate active cortical attractor networks in B1 to support
symptomatic improvement.
Clozapine is the most effective antipsychotic drug (APD) with unique clinical efficacy. It is the least used APD
because its side effects are serious (neutropenia, myocarditis, seizures) and its administration complex. A
predictive biomarker would allow targeting of cases most likely to respond and improve prognosis in psychosis.
B-SNIP has shown that clozapine is associated with increases in EEG measures of alpha/theta power, and we
identify this increase in time periods without stimulus processing requirements as intrinsic EEG activity (IEA),
across all Biotypes. Because B1 cases express low IEA, clozapine's action to increase EEG power will be
normalizing for this psychosis subgroup, with increased cortical attractor states. Because B2 express
accentuated IEA, clozapine is associated with more deviant IEA in B2. We propose to test B1 psychosis cases
with clozapine vs. risperidone (n=40/group clinical trial completers), over a 6 week cross-titration (to
therapeutic plasma levels) and a 9 week stable dose extension, predicting that the B1/clozapine group will
respond significantly better, as measured with total PANSS, than the B1/risperidone group and also better than
either B2 group. It is our hypothesis that the cortical attractor networks will be normalized and their function
increased by the increase in intrinsic EEG activity.

## Key facts

- **NIH application ID:** 10397395
- **Project number:** 5R01MH124804-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Elliot S Gershon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397395

## Citation

> US National Institutes of Health, RePORTER application 10397395, 2/5-Clozapine Response and Biomarker Correlates in Low-IEA Biotype-1 (5R01MH124804-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10397395. Licensed CC0.

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