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.

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Acknowledgements

This research was supported by Robert and Mary Jane Engman Foundation, Lynn and Edward Streim, Takeda-Sanford Consortium Innovation Alliance grant program (Takeda Pharmaceutical Company). KCV was supported by the Swiss National Science Foundation (SNSF) outgoing postdoctoral fellowship. Salk core facilities are supported by the Cancer center (NCI P30 CA014195). Patient enrollment and iPSC generation were funded by Minnesota Partnership Award for Biotechnology and Medical Genomics (YJ) and the 2012 Mayo Clinic Center for Regenerative Medicine (YJ). YJ was supported by the NIH-Mayo Clinic KL2 Mentored Career Development Award (NCAT UL1TR000135) and the Gerstner Family Mayo Career Development Award in Individualized Medicine. Patient recruitment and the laboratory aspects of the clinical trial were funded by NIH U19 GM61388 (PGRN) and NIH RO1 GM28157. The authors would also like to acknowledge the staff and investigators of the PGRN-AMPS study for their contributions, particularly the late Dr. David A. Mrazek, the former Principal Investigator of the PGRN-AMPS study within the Mayo Clinic NIH-PGRN (U19 GM61388). This research would not have been possible without Dr. Mrazek’s pioneering vision and dedication to antidepressant pharmacogenomics research. We also thank Dr. Manching Ku for help with RNA sequencing, Galina Erikson for help with sequencing data, and ML Gage for editorial comments on the manuscript.

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Affiliations

  1. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, USA

    • Krishna C. Vadodaria
    • , Apua Paquola
    • , Callie Fredlender
    • , Kelly J. Heard
    • , Yalin Deng
    • , Amy T. Le
    • , Sonia Dave
    • , Lianna Fung
    • , Xinyi Li
    • , Maria C. Marchetto
    •  & Fred H. Gage
  2. University of Utah School of Medicine, Salt Lake City, UT, USA

    • Yuan Ji
  3. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    • Yuan Ji
    • , Timothy Nelson
    •  & Richard Weinshilboum
  4. Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA

    • Michelle Skime
    •  & Daniel Hall-Flavin
  5. Lieber Institute for Brain Development, 855N Wolfe St, Ste 300, Baltimore, MD, USA

    • Apua Paquola

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The authors declare that they have no conflict of interest.

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Correspondence to Fred H. Gage.

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DOI

https://doi.org/10.1038/s41380-019-0363-y