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

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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


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)
Pages (from-to)795-807
Number of pages13
JournalMolecular Psychiatry
Issue number6
StatePublished - Jun 1 2019

ASJC Scopus subject areas

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


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