Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic tool
Introduction Depression is a leading cause of disability worldwide despite dozens of approved antidepressants. There are currently no clear guidelines to assist the physician in their choice of drug, with existing tools limited to pharmacogenetics that have shown suboptimal response prediction outc...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Cambridge University Press
2023-03-01
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| Series: | European Psychiatry |
| Online Access: | https://www.cambridge.org/core/product/identifier/S0924933823002742/type/journal_article |
| _version_ | 1827753487276965888 |
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| author | S. Shohat Koren D. Kroitorou C. Albeldas A. Kugel N. Askari T. Cohen Solal D. Laifenfeld |
| author_facet | S. Shohat Koren D. Kroitorou C. Albeldas A. Kugel N. Askari T. Cohen Solal D. Laifenfeld |
| author_sort | S. Shohat Koren |
| collection | DOAJ |
| description |
Introduction
Depression is a leading cause of disability worldwide despite dozens of approved antidepressants. There are currently no clear guidelines to assist the physician in their choice of drug, with existing tools limited to pharmacogenetics that have shown suboptimal response prediction outcomes resulting in a subscription process that is largely a trial and error one. Consequently, the majority of depressed patients do not respond to their first prescribed antidepressant, with >30% not responding to subsequent drugs. We report here on molecular readouts from an in vitro-based platform that provides patient-specific information on antidepressant mechanisms using cortical neurons derived individually from each patient.
Objectives
To assess gene expression differences in prefrontal cortex neurons derived from responders and non-responders to two commonly used antidepressants, the selective serotonin reuptake inhibitor Citalopram and the atypical antidepressant Bupropion.
Methods
Patient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study with known response to Citalopram or Bupropion were reprogrammed and then differentiated to cortical neurons. Differential gene expression analysis was preformed to identify genes that are differentially expressed between drug responders and non-responders.
Results
Significant differential expression was shown in 359 genes between Bupropion responders and non-responders (Fig1A) and 12 genes between Citalopram responders and non-responders (Fig1B). Clustering on the differentially expressed genes showed high agreement with the known response to both drugs (Fig1). Functional enrichment analysis revealed biologically relevant pathways that differ between responders and non-responders in Bupropion versus Citalopram.
Image:
Figure 1.
Heatmap of the expression of genes that show significant differential expression between neurons derived from Bupropion (A) and Citalopram (B) responders and non-responders. Color is the scaled gene expression; lines are genes and columns are samples. Column side colors represent the known response of the patient. Colum and line dendrograms are unsupervised hierarchical clustering.
Conclusions
Gene expression patterns of neurons derived from patients with depression differ according to their response to two common antidepressants from different groups. The identification of distinct drug response dependent expression patterns in derived neurons can help elucidate mechanisms underlying antidepressant activity, supporting new drug development and response prediction.
Disclosure of InterestNone Declared |
| first_indexed | 2024-03-11T07:36:58Z |
| format | Article |
| id | doaj.art-6a0193bbcd1244e995bd5e5d4c7f7193 |
| institution | Directory Open Access Journal |
| issn | 0924-9338 1778-3585 |
| language | English |
| last_indexed | 2024-03-11T07:36:58Z |
| publishDate | 2023-03-01 |
| publisher | Cambridge University Press |
| record_format | Article |
| series | European Psychiatry |
| spelling | doaj.art-6a0193bbcd1244e995bd5e5d4c7f71932023-11-17T05:09:25ZengCambridge University PressEuropean Psychiatry0924-93381778-35852023-03-0166S92S9310.1192/j.eurpsy.2023.274Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic toolS. Shohat Koren0D. Kroitorou1C. Albeldas2A. Kugel3N. Askari4T. Cohen Solal5D. Laifenfeld6Genetika+, Tel Aviv-Yafo, IsraelGenetika+, Tel Aviv-Yafo, IsraelGenetika+, Tel Aviv-Yafo, IsraelGenetika+, Tel Aviv-Yafo, IsraelGenetika+, Tel Aviv-Yafo, IsraelGenetika+, Tel Aviv-Yafo, IsraelGenetika+, Tel Aviv-Yafo, Israel Introduction Depression is a leading cause of disability worldwide despite dozens of approved antidepressants. There are currently no clear guidelines to assist the physician in their choice of drug, with existing tools limited to pharmacogenetics that have shown suboptimal response prediction outcomes resulting in a subscription process that is largely a trial and error one. Consequently, the majority of depressed patients do not respond to their first prescribed antidepressant, with >30% not responding to subsequent drugs. We report here on molecular readouts from an in vitro-based platform that provides patient-specific information on antidepressant mechanisms using cortical neurons derived individually from each patient. Objectives To assess gene expression differences in prefrontal cortex neurons derived from responders and non-responders to two commonly used antidepressants, the selective serotonin reuptake inhibitor Citalopram and the atypical antidepressant Bupropion. Methods Patient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression (STARD) study with known response to Citalopram or Bupropion were reprogrammed and then differentiated to cortical neurons. Differential gene expression analysis was preformed to identify genes that are differentially expressed between drug responders and non-responders. Results Significant differential expression was shown in 359 genes between Bupropion responders and non-responders (Fig1A) and 12 genes between Citalopram responders and non-responders (Fig1B). Clustering on the differentially expressed genes showed high agreement with the known response to both drugs (Fig1). Functional enrichment analysis revealed biologically relevant pathways that differ between responders and non-responders in Bupropion versus Citalopram. Image: Figure 1. Heatmap of the expression of genes that show significant differential expression between neurons derived from Bupropion (A) and Citalopram (B) responders and non-responders. Color is the scaled gene expression; lines are genes and columns are samples. Column side colors represent the known response of the patient. Colum and line dendrograms are unsupervised hierarchical clustering. Conclusions Gene expression patterns of neurons derived from patients with depression differ according to their response to two common antidepressants from different groups. The identification of distinct drug response dependent expression patterns in derived neurons can help elucidate mechanisms underlying antidepressant activity, supporting new drug development and response prediction. Disclosure of InterestNone Declaredhttps://www.cambridge.org/core/product/identifier/S0924933823002742/type/journal_article |
| spellingShingle | S. Shohat Koren D. Kroitorou C. Albeldas A. Kugel N. Askari T. Cohen Solal D. Laifenfeld Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic tool European Psychiatry |
| title | Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic tool |
| title_full | Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic tool |
| title_fullStr | Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic tool |
| title_full_unstemmed | Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic tool |
| title_short | Patient iPSC-derived neurons reveal mechanisms underlying antidepressant response: a potential diagnostic tool |
| title_sort | patient ipsc derived neurons reveal mechanisms underlying antidepressant response a potential diagnostic tool |
| url | https://www.cambridge.org/core/product/identifier/S0924933823002742/type/journal_article |
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