Skip to main content

Thank you for visiting nature.com. 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.

  • Immediate Communication
  • Published:

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 fromĀ 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.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. http://www.who.int/mediacentre/factsheets/fs369/en/, http://www.nimh.nih.gov/health/statistics/prevalence/major-depression-among-adults.shtml, https://www.nlm.nih.gov/medlineplus/ency/article/000945.htm & http://www.dbsalliance.org/site/PageServer?pagename=education_statistics_depression

  2. Vigo D, Thornicroft G, Atun R. Estimating the true global burden of mental illness. Lancet Psychiatry. 2016;3:171ā€“8.

    ArticleĀ  Google ScholarĀ 

  3. Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. 2013;34:119ā€“38.

    ArticleĀ  Google ScholarĀ 

  4. Charney DS, Buxbaum JD, Sklar P, Nestler EJ. Neurobiology of mental illness. Oxford University Press: 2013.

  5. Breen G, et al. Translating genome-wide association findings into new therapeutics for psychiatry. Nat Neurosci. 2016;19:1392ā€“6.

    ArticleĀ  CASĀ  Google ScholarĀ 

  6. Levinson DF, et al. Genetic studies of major depressive disorder: why are there no genome-wide association study findings and what can we do about it? Biol Psychiatry. 2014;76:510ā€“2.

    ArticleĀ  Google ScholarĀ 

  7. Wray NR et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50:668ā€“81. https://doi.org/10.1038/s41588-018-0090-3

    ArticleĀ  CASĀ  Google ScholarĀ 

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

    ArticleĀ  CASĀ  Google ScholarĀ 

  9. Brennand KJ, et al. Modelling schizophrenia using human induced pluripotent stem cells. Nature. 2011;473:221ā€“5.

    ArticleĀ  CASĀ  Google ScholarĀ 

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

    ArticleĀ  CASĀ  Google ScholarĀ 

  11. 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;20:703ā€“17.

    ArticleĀ  CASĀ  Google ScholarĀ 

  12. Mertens J, et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015;527:95ā€“9.

    ArticleĀ  CASĀ  Google ScholarĀ 

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

    ArticleĀ  CASĀ  Google ScholarĀ 

  14. Drysdale AT, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28ā€“38.

    ArticleĀ  CASĀ  Google ScholarĀ 

  15. Woo YS, Wang HR, Bahk WM. Lurasidone as a potential therapy for bipolar disorder. Neuropsychiatr Dis Treat. 2013;9:1521ā€“9.

    CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  16. Ressler KJ, Mayberg HS. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci. 2007;10:1116ā€“24.

    ArticleĀ  CASĀ  Google ScholarĀ 

  17. McGrath CL, et al. Pretreatment brain states identify likely nonresponse to standard treatments for depression. Biol Psychiatry. 2014;76:527ā€“35.

    ArticleĀ  CASĀ  Google ScholarĀ 

  18. Mayberg HS, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651ā€“60.

    ArticleĀ  CASĀ  Google ScholarĀ 

  19. Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology. 2010;35:192ā€“216.

    ArticleĀ  Google ScholarĀ 

  20. Artigas F. Serotonin receptors involved in antidepressant effects. Pharmacol Ther. 2013;137:119ā€“31.

    ArticleĀ  CASĀ  Google ScholarĀ 

  21. Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry. 2010;15:473ā€“500.

    ArticleĀ  CASĀ  Google ScholarĀ 

  22. Hrdina PD, Du L. Levels of serotonin receptor 2A higher in suicide victims? Am J Psychiatry. 2001;158:147ā€“8.

    ArticleĀ  CASĀ  Google ScholarĀ 

  23. Anttila SA, Leinonen EV. A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Rev. 2001;7:249ā€“64.

    ArticleĀ  CASĀ  Google ScholarĀ 

  24. Knight AR, et al. Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiede Arch Pharmacol. 2004;370:114ā€“23.

    ArticleĀ  CASĀ  Google ScholarĀ 

  25. Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994;114:559ā€“65.

    ArticleĀ  CASĀ  Google ScholarĀ 

  26. Benekareddy M, Vadodaria KC, Nair AR, Vaidya VA. Postnatal serotonin type 2 receptor blockade prevents the emergence of anxiety behavior, dysregulated stress-induced immediate early gene responses, and specific transcriptional changes that arise following early life stress. Biol Psychiatry. 2011;70:1024ā€“32.

    ArticleĀ  CASĀ  Google ScholarĀ 

  27. Marek GJ, Carpenter LL, McDougle CJ, Price LH. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology. 2003;28:402ā€“12.

    ArticleĀ  CASĀ  Google ScholarĀ 

  28. Sarkisyan G, Roberts AJ, Hedlund PB. The 5-HT(7) receptor as a mediator and modulator of antidepressant-like behavior. Behav Brain Res. 2010;209:99ā€“108.

    ArticleĀ  CASĀ  Google ScholarĀ 

  29. Mullins UL, Gianutsos G, Eison AS. Effects of antidepressants on 5-HT7 receptor regulation in the rat hypothalamus. Neuropsychopharmacology. 1999;21:352ā€“67.

    ArticleĀ  CASĀ  Google ScholarĀ 

  30. Sowa-Kucma M, et al. Vortioxetine: a review of the pharmacology and clinical profile of the novel antidepressant. Pharmacol Rep. 2017;69:595ā€“601.

    ArticleĀ  CASĀ  Google ScholarĀ 

  31. 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.

    ArticleĀ  Google ScholarĀ 

  32. 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;59:493ā€“501.

    ArticleĀ  Google ScholarĀ 

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

  34. Dobin A, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15ā€“21.

    ArticleĀ  CASĀ  Google ScholarĀ 

  35. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923ā€“30.

    ArticleĀ  CASĀ  Google ScholarĀ 

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

    ArticleĀ  CASĀ  Google ScholarĀ 

  37. Santos R, et al. Differentiation of inflammation-responsive astrocytes from glial progenitors generated from human induced pluripotent stem cells. Stem Cell Rep. 2017;8:1757ā€“69.

    ArticleĀ  CASĀ  Google ScholarĀ 

Download references

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.Ā 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. Mrazekā€™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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fred H. Gage.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisherā€™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. Serotonin-induced hyperactivity in SSRI-resistant major depressive disorder patient-derived neurons. Mol Psychiatry 24, 795ā€“807 (2019). https://doi.org/10.1038/s41380-019-0363-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Quick links