Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons


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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.

    Article  Google Scholar 

  2. Levinstein MR, Samuels BA. Mechanisms underlying the antidepressant response and treatment resistance. Front Behav Neurosci. 2014;8:208.

    Article  Google Scholar 

  3. Andersen J, et al. Mutational mapping and modeling of the binding site for (S)-citalopram in the human serotonin transporter. J Biol Chem. 2010;285:2051–63.

    Article  CAS  Google Scholar 

  4. Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan. Lancet. 1997;349:915–9.

    Article  CAS  Google Scholar 

  5. Sharp T, Cowen PJ. 5-HT and depression: is the glass half-full? Curr Opin Pharmacol. 2011;11:45–51.

    Article  CAS  Google Scholar 

  6. Cowen PJ. Serotonin and depression: pathophysiological mechanism or marketing myth? Trends Pharmacol Sci. 2008;29:433–6.

    Article  CAS  Google Scholar 

  7. Vadodaria KC, Stern S, Marchetto MC, Gage FH. Serotonin in psychiatry: in vitro disease modeling using patient-derived neurons. Cell Tissue Res. 2018;371:161–70.

    Article  Google Scholar 

  8. Baker KG, Halliday GM, Tork I. Cytoarchitecture of the human dorsal raphe nucleus. J Comp Neurol. 1990;301:147–61.

    Article  CAS  Google Scholar 

  9. Wray NR & Sullivan PF. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50:668–81.

  10. Soliman MA, Aboharb F, Zeltner N, Studer L. Pluripotent stem cells in neuropsychiatric disorders. Mol Psychiatry. 2017;22:1241–9.

    Article  CAS  Google Scholar 

  11. Brennand KJ, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011;473:221–5.

    Article  CAS  Google Scholar 

  12. Mertens J, et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015;527:95–99.

    Article  CAS  Google Scholar 

  13. Marchetto MC, et al. Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry. 2017;22:820–35.

  14. Yoon KJ, et al. Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell stem Cell. 2014;15:79–91.

    Article  CAS  Google Scholar 

  15. Madison JM, et al. Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry. 2015;20:703–17.

    Article  CAS  Google Scholar 

  16. Robicsek O, et al. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol Psychiatry. 2013;18:1067–76.

    Article  CAS  Google Scholar 

  17. Mrazek DA, et al. Treatment outcomes of depression: the pharmacogenomic research network antidepressant medication pharmacogenomic study. J Clin Psychopharmacol. 2014;34:313–7.

    Article  CAS  Google Scholar 

  18. Vadodaria KC, Marchetto MC, Mertens J, Gage FH. Generating human serotonergic neurons in vitro: methodological advances. Bioessay News Rev Mol Cell Dev Biol. 2016;38:1123–9.

    Article  CAS  Google Scholar 

  19. Vadodaria KC, et al. Generation of functional human serotonergic neurons from fibroblasts. Mol Psychiatry. 2016;21:49–61.

    Article  CAS  Google Scholar 

  20. Kiyasova V, Gaspar P. Development of raphe serotonin neurons from specification to guidance. Eur J Neurosci. 2011;34:1553–62.

    Article  Google Scholar 

  21. Albert PR, Vahid-Ansari F, Luckhart C. Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression. Front Behav Neurosci. 2014;8:199.

    Article  Google Scholar 

  22. Sundstrom E, et al. Neurochemical differentiation of human bulbospinal monoaminergic neurons during the first trimester. brain Res Dev brain Res. 1993;75:1–12.

    Article  CAS  Google Scholar 

  23. Katori S, et al. Protocadherin-alpha family is required for serotonergic projections to appropriately innervate target brain areas. J Neurosci. 2009;29:9137–47.

    Article  CAS  Google Scholar 

  24. Chen WV, et al. Pcdhalphac2 is required for axonal tiling and assembly of serotonergic circuitries in mice. Science. 2017;356:406–11.

    Article  CAS  Google Scholar 

  25. Keeler AB, Molumby MJ, Weiner JA. Protocadherins branch out: Multiple roles in dendrite development. Cell Adh Migr. 2015;9:214–26.

    Article  CAS  Google Scholar 

  26. Vadodaria KC, Amatya DN, Marchetto MC, Gage FH. Modeling psychiatric disorders using patient stem cell-derived neurons: a way forward. Genome Med. 2018;10:1.

    Article  Google Scholar 

  27. Albert PR, Benkelfat C, Descarries L. The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos Trans R Soc Lond Ser B Biol Sci. 2012;367:2378–81.

    Article  CAS  Google Scholar 

  28. Rush AJ, et al. An evaluation of the quick inventory of depressive symptomatology and the hamilton rating scale for depression: a sequenced treatment alternatives to relieve depression trial report. Biol Psychiatry. 2006;59:493–501.

    Article  Google Scholar 

  29. Lu J, et al. Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol. 2016;34:89–94.

    Article  CAS  Google Scholar 

  30. Dobin A, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  Google Scholar 

  31. Liao Y, Smyth GK, Shi W. FeatureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

    Article  CAS  Google Scholar 

  32. Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11:R106.

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Fred H. Gage.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vadodaria, K.C., Ji, Y., Skime, M. et al. Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons. Mol Psychiatry 24, 808–818 (2019).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links