Disrupted serotonergic neurotransmission has long been implicated in major depressive disorder (MDD), for which selective serotonin reuptake inhibitors (SSRIs) are the first line of treatment. However, a significant percentage of patients remain SSRI-resistant and it is unclear whether and how alterations in serotonergic neurons contribute to SSRI resistance in these patients. Induced pluripotent stem cells (iPSCs) facilitate the study of patient-specific neural subtypes that are typically inaccessible in living patients, enabling the discovery of disease-related phenotypes. In our study of a well-characterized cohort of over 800 MDD patients, we generated iPSCs and serotonergic neurons from three extreme SSRI-remitters (R) and SSRI-nonremitters (NR). We studied serotonin (5-HT) biochemistry and observed no significant differences in 5-HT release and reuptake or in genes related to 5-HT biochemistry. NR patient-derived serotonergic neurons exhibited altered neurite growth and morphology downstream of lowered expression of key Protocadherin alpha genes as compared to healthy controls and Rs. Furthermore, knockdown of Protocadherin alpha genes directly regulated iPSC-derived neurite length and morphology. Our results suggest that intrinsic differences in serotonergic neuron morphology and the resulting circuitry may contribute to SSRI resistance in MDD patients.

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This research was supported by the Robert and Mary Jane Engman Foundation, Lynn and Edward Streim, and a Takeda-Sanford Consortium Innovation Alliance grant program (Takeda Pharmaceutical Company). KCV was supported by the Swiss National Science Foundation (SNSF) outgoing postdoctoral fellowship. Patient enrollment and iPSC generation were funded by the 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 and ML Gage for editorial comments on the manuscript.

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

    • Krishna C. Vadodaria
    • , Apua C. Paquola
    • , Kelly J. Heard
    • , Callie Fredlender
    • , Yalin Deng
    • , James Elkins
    • , Komal Dani
    • , Amy T. Le
    • , 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 C. 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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