Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons

Krishna C. Vadodaria, Yuan Ji, Michelle Skime, Apua Paquola, Timothy J Nelson, Daniel Hall-Flavin, Callie Fredlender, Kelly J. Heard, Yalin Deng, Amy T. Le, Sonia Dave, Lianna Fung, Xinyi Li, Maria C. Marchetto, Richard M Weinshilboum, Fred H. Gage

Research output: Contribution to journalArticle

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StatePublished - Jan 1 2019

Fingerprint

Major Depressive Disorder
Serotonin Uptake Inhibitors
Serotonin
Neurons
Synaptic Transmission
Prosencephalon
Induced Pluripotent Stem Cells
Antidepressive Agents
Pharmacology
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. / Vadodaria, Krishna C.; Ji, Yuan; Skime, Michelle; Paquola, Apua; Nelson, Timothy J; Hall-Flavin, Daniel; Fredlender, Callie; Heard, Kelly J.; Deng, Yalin; Le, Amy T.; Dave, Sonia; Fung, Lianna; Li, Xinyi; Marchetto, Maria C.; Weinshilboum, Richard M; Gage, Fred H.

In: Molecular Psychiatry, 01.01.2019.

Research output: Contribution to journalArticle

Vadodaria, KC, Ji, Y, Skime, M, Paquola, A, Nelson, TJ, Hall-Flavin, D, Fredlender, C, Heard, KJ, Deng, Y, Le, AT, Dave, S, Fung, L, Li, X, Marchetto, MC, Weinshilboum, RM & Gage, FH 2019, 'Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons' Molecular Psychiatry. https://doi.org/10.1038/s41380-019-0363-y
Vadodaria, Krishna C. ; Ji, Yuan ; Skime, Michelle ; Paquola, Apua ; Nelson, Timothy J ; Hall-Flavin, Daniel ; Fredlender, Callie ; Heard, Kelly J. ; Deng, Yalin ; Le, Amy T. ; Dave, Sonia ; Fung, Lianna ; Li, Xinyi ; Marchetto, Maria C. ; Weinshilboum, Richard M ; Gage, Fred H. / Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. In: Molecular Psychiatry. 2019.
@article{5c1083fd9132419eae077448128044d1,
title = "Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons",
abstract = "Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30{\%} of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.",
author = "Vadodaria, {Krishna C.} and Yuan Ji and Michelle Skime and Apua Paquola and Nelson, {Timothy J} and Daniel Hall-Flavin and Callie Fredlender and Heard, {Kelly J.} and Yalin Deng and Le, {Amy T.} and Sonia Dave and Lianna Fung and Xinyi Li and Marchetto, {Maria C.} and Weinshilboum, {Richard M} and Gage, {Fred H.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41380-019-0363-y",
language = "English (US)",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons

AU - Vadodaria, Krishna C.

AU - Ji, Yuan

AU - Skime, Michelle

AU - Paquola, Apua

AU - Nelson, Timothy J

AU - Hall-Flavin, Daniel

AU - Fredlender, Callie

AU - Heard, Kelly J.

AU - Deng, Yalin

AU - Le, Amy T.

AU - Dave, Sonia

AU - Fung, Lianna

AU - Li, Xinyi

AU - Marchetto, Maria C.

AU - Weinshilboum, Richard M

AU - Gage, Fred H.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.

AB - Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed antidepressants. They regulate serotonergic neurotransmission, but it remains unclear how altered serotonergic neurotransmission may contribute to the SSRI resistance observed in approximately 30% of major depressive disorder (MDD) patients. Patient stratification based on pharmacological responsiveness and the use of patient-derived neurons may make possible the discovery of disease-relevant neural phenotypes. In our study from a large cohort of well-characterized MDD patients, we have generated induced pluripotent stem cells (iPSCs) from SSRI-remitters and SSRI-nonremitters. We studied serotonergic neurotransmission in patient forebrain neurons in vitro and observed that nonremitter patient-derived neurons displayed serotonin-induced hyperactivity downstream of upregulated excitatory serotonergic receptors, in contrast to what is seen in healthy and remitter patient-derived neurons. Our data suggest that postsynaptic forebrain hyperactivity downstream of SSRI treatment may play a role in SSRI resistance in MDD.

UR - http://www.scopus.com/inward/record.url?scp=85060917402&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060917402&partnerID=8YFLogxK

U2 - 10.1038/s41380-019-0363-y

DO - 10.1038/s41380-019-0363-y

M3 - Article

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

ER -