# Ex vivo signature of psychosis and treatment response in patient-derived neurons

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $544,958

## Abstract

PROJECT SUMMARY
The efficacious treatment of psychotic disorders remains a significant challenge in psychiatry. Current
treatment approaches rely on compounds discovered serendipitously many decades ago and there is an
urgent need for new therapeutic approaches that target the neurobiology of psychosis. Postmortem studies of
schizophrenia and psychotic bipolar disorder suggest a significant role for dendritic spine abnormalities in the
prefrontal cortex (PFC) in psychosis. Brains of patients with psychotic disorders show well-replicated neuronal
abnormalities in dendritic spine density, specifically in upper-layer cortical pyramidal neurons. Additionally, in
animal models of psychosis, brain tissue show decreased dendritic spine synapses in the PFC, with a more
pronounced effect in the upper-layer cortical neurons. Furthermore, the decrease in spine synapses in these
animal models was reversed with antipsychotic treatment. In vitro studies of cultured rodent neurons show that
the antipsychotic clozapine modulates dendritic spines, with two independent studies showing increase in
dendritic spine density in rodent neurons with clozapine treatment. These studies provide a strong impetus to
test the hypothesis that dendritic spine biology plays an important role in the biology and treatment of
psychosis. The studies to date have focused on postmortem brains, animal models and rodent neuronal
cultures. To extend these findings, we seek to study cortical neurons generated from subjects with psychotic
disorders. We have reprogrammed induced pluripotent stem cells (iPSCs) from human subjects with
schizophrenia and bipolar disorder as well as from matched healthy controls. We have differentiated human
iPSCs along the forebrain lineage to generate mature cortical neurons. Based on our preliminary studies of
patient-derived neurons and of the effects of clozapine on dendritic spine density, we hypothesize that upper-
layer cortical neurons generated from subjects with psychotic disorders will show decreased dendritic spine
density compared to such neurons from healthy subjects. We further hypothesize that clozapine exposure in
vitro will have differential effects on dendritic spine density in neurons derived from patients who are clozapine
responders when compared to clozapine non-responders.

## Key facts

- **NIH application ID:** 9896850
- **Project number:** 5R01MH113858-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Rakesh Karmacharya
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $544,958
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896850

## Citation

> US National Institutes of Health, RePORTER application 9896850, Ex vivo signature of psychosis and treatment response in patient-derived neurons (5R01MH113858-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9896850. Licensed CC0.

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