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The Impact of a Single Nucleotide Polymorphism in SIGMAR1 on Depressive Symptoms in Major Depressive Disorder and Bipolar Disorder



Ample evidence suggested a role of sigma-1 receptor in affective disorders since the interaction of numerous antidepressants with sigma receptors was discovered. A recent study on Japanese subjects found a genetic variant within the encoding gene SIGMAR1 (rs1800866A>C) associated with major depressive disorder (MDD). We aimed to evaluate the same polymorphism in both MDD and bipolar disorder (BD) as well as its relationship to response to treatment with antidepressants and mood stabilizers.


A total of 238 MDD patients treated for an acute episode of depression, 132 BD patients in treatment with mood stabilizers for a manic or mixed episode, and 324 controls were genotyped for rs1800866. At discharge, response to treatments was evaluated in MDD and BD patients by the Hamilton Rating Scale for Depression (HRSD) and the Young Mania Rating Score (YMRS), respectively.


In our Korean sample, allele frequencies were different from those reported in other Asian and non-Asian populations. The CC genotype was associated with BD and, as a trend, with MDD. No significant effect was observed on response to antidepressants in MDD or mood stabilizers in BD, although the CC genotype was more frequent among BD patients experiencing a mixed episode.


The present findings are the first to propose the putative role of genetic variants within SIGMAR1 and sigma-1 receptor in BD. Sigma-1 receptor can modulate a number of central neurotransmitter systems as well as some other signaling pathways (e.g., neurotrophin and growth factor signaling) which are seemingly involved in BD and other mood disorders.

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  1. 1.

    Kourrich S, Su TP, Fujimoto M, Bonci A. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 2012;35(12):762–71.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Fujimoto M, Hayashi T. New insights into the role of mitochondria-associated endoplasmic reticulum membrane. Int Rev Cell Mol Biol. 2011;292:73–117.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Hayashi T, Rizzuto R, Hajnoczky G, Su TP. MAM: more than just a housekeeper. Trends Cell Biol. 2009;19(2):81–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Hayashi T, Su TP. Intracellular dynamics of sigma-1 receptors (sigma(1) binding sites) in NG108-15 cells. J Pharmacol Exp Ther. 2003;306(2):726–33.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Su TP, Hayashi T, Maurice T, Buch S, Ruoho AE. The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci. 2010;31(12):557–66.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Maurice T, Urani A, Phan VL, Romieu P. The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities. Brain Res Brain Res Rev. 2001;37(1–3):116–32.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Liang X, Wang RY. Biphasic modulatory action of the selective sigma receptor ligand SR 31742A on N-methyl-d-aspartate-induced neuronal responses in the frontal cortex. Brain Res. 1998;807(1–2):208–13.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Monnet FP, Debonnel G, Junien JL, De Montigny C. N-Methyl-d-aspartate-induced neuronal activation is selectively modulated by sigma receptors. Eur J Pharmacol. 1990;179(3):441–5.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Skuza G. Pharmacology of sigma (sigma) receptor ligands from a behavioral perspective. Curr Pharm Des. 2012;18(7):863–74.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 2007;131(3):596–610.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Hayashi T, Tsai SY, Mori T, Fujimoto M, Su TP. Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders. Expert Opin Ther Targets. 2011;15(5):557–77.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Minamino T, Kitakaze M. ER stress in cardiovascular disease. J Mol Cell Cardiol. 2010;48(6):1105–10.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Minamino T, Komuro I, Kitakaze M. Endoplasmic reticulum stress as a therapeutic target in cardiovascular disease. Circ Res. 2010;107(9):1071–82.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Bown C, Wang JF, MacQueen G, Young LT. Increased temporal cortex ER stress proteins in depressed subjects who died by suicide. Neuropsychopharmacology. 2000;22(3):327–32.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Fujimoto M, Hayashi T, Urfer R, Mita S, Su TP. Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse. 2012;66(7):630–9.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Kikuchi-Utsumi K, Nakaki T. Chronic treatment with a selective ligand for the sigma-1 receptor chaperone, SA4503, up-regulates BDNF protein levels in the rat hippocampus. Neurosci Lett. 2008;440(1):19–22.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Niitsu T, Iyo M, Hashimoto K. Sigma-1 receptor agonists as therapeutic drugs for cognitive impairment in neuropsychiatric diseases. Curr Pharm Des. 2012;18(7):875–83.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Moriguchi S, Shinoda Y, Yamamoto Y, et al. Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice. PLoS One. 2013;8(4):e60863.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Hashimoto K. Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship. Cent Nerv Syst Agents Med Chem. 2009;9(3):197–204.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Terada K, Izumo N, Suzuki B, et al. Fluvoxamine moderates reduced voluntary activity following chronic dexamethasone infusion in mice via recovery of BDNF signal cascades. Neurochem Int. 2014;69:9–13.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Shimizu H, Takebayashi M, Tani M, et al. Sigma-1 receptor concentration in plasma of patients with late-life depression: a preliminary study. Neuropsychiatr Dis Treat. 2013;8:1867–72.

    Google Scholar 

  22. 22.

    Ito K, Hirooka Y, Sunagawa K. Brain sigma-1 receptor stimulation improves mental disorder and cardiac function in mice with myocardial infarction. J Cardiovasc Pharmacol. 2013;62(2):222–8.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Matsuno K, Nakazawa M, Okamoto K, Kawashima Y, Mita S. Binding properties of SA4503, a novel and selective sigma 1 receptor agonist. Eur J Pharmacol. 1996;306(1–3):271–9.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Sabino V, Cottone P, Parylak SL, Steardo L, Zorrilla EP. Sigma-1 receptor knockout mice display a depressive-like phenotype. Behav Brain Res. 2009;198(2):472–6.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Ukai M, Maeda H, Nanya Y, Kameyama T, Matsuno K. Beneficial effects of acute and repeated administrations of sigma receptor agonists on behavioral despair in mice exposed to tail suspension. Pharmacol Biochem Behav. 1998;61(3):247–52.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Urani A, Roman FJ, Phan VL, Su TP, Maurice T. The antidepressant-like effect induced by sigma(1)-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test. J Pharmacol Exp Ther. 2001;298(3):1269–79.

  27. 27.

    Prasad PD, Li HW, Fei YJ, et al. Exon-intron structure, analysis of promoter region, and chromosomal localization of the human type 1 sigma receptor gene. J Neurochem. 1998;70(2):443–51.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Seth P, Leibach FH, Ganapathy V. Cloning and structural analysis of the cDNA and the gene encoding the murine type 1 sigma receptor. Biochem Biophys Res Commun. 1997;241(2):535–40.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Muglia P, Tozzi F, Galwey NW, et al. Genome-wide association study of recurrent major depressive disorder in two European case-control cohorts. Mol Psychiatry. 2008;15(6):589–601.

    Article  PubMed  Google Scholar 

  30. 30.

    Sullivan PF, de Geus EJ, Willemsen G, et al. Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo. Mol Psychiatry. 2009;14(4):359–75.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Garriock HA, Kraft JB, Shyn SI, et al. A genomewide association study of citalopram response in major depressive disorder. Biol Psychiatry. 2010;67(2):133–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Laje G, Allen AS, Akula N, Manji H, John Rush A, McMahon FJ. Genome-wide association study of suicidal ideation emerging during citalopram treatment of depressed outpatients. Pharmacogenet Genomics. 2009;19(9):666–74.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Kishi T, Yoshimura R, Okochi T, et al. Association analysis of SIGMAR1 with major depressive disorder and SSRI response. Neuropharmacology. 2010;58(7):1168–73.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Borowicz KK, Kleinrok Z, Czuczwar SJ. Influence of 3-PPP, a sigma receptor ligand, on the anticonvulsive action of conventional antiepileptic drugs. Pharmacol Res. 1999;40(6):509–16.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Wang Y, Guo L, Jiang HF, Zheng LT, Zhang A, Zhen XC. Allosteric modulation of sigma-1 receptors elicits rapid antidepressant activity. CNS Neurosci Ther. 2016;22(5):368–77.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Fabbri C, Hosak L, Mossner R, et al. Consensus paper of the WFSBP Task Force on Genetics: genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response. World J Biol Psychiatry. 2017;18(1):5–28.

    Article  PubMed  Google Scholar 

  37. 37.

    First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition. (SCID-I/P). New York: Biometrics Research, New York State Psychiatric Institute; 2002.

  38. 38.

    Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Young R, Biggs J, Ziegler V, Meyer D. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–35.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Sackeim HA. The definition and meaning of treatment-resistant depression. J Clin Psychiatry. 2001;62(Suppl 16):10–7.

    CAS  PubMed  Google Scholar 

  41. 41.

    Dew RE, Kramer SI, McCall WV. Adequacy of antidepressant treatment by psychiatric residents: the antidepressant treatment history form as a possible assessment tool. Acad Psychiatry. 2005;29(3):283–8.

    Article  PubMed  Google Scholar 

  42. 42.

    StatSoft I. STATISTICA per Windows: StatSoft Italia srl; 1995.

  43. 43.

    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated acid. Nucleic Acids Res. 1988;16:1215.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Lin PI, Vance JM, Pericak-Vance MA, Martin ER. No gene is an island: the flip-flop phenomenon. Am J Hum Genet. 2007;80(3):531–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Ohi K, Hashimoto R, Yasuda Y, et al. The SIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(5):1309–15.

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Watanabe Y, Nunokawa A, Kaneko N, Shibuya M, Egawa J, Someya T. Supportive evidence for the association between the Gln2Pro polymorphism in the SIGMAR1 gene and schizophrenia in the Japanese population: a case-control study and an updated meta-analysis. Schizophr Res. 2012;141(2–3):279–80.

    Article  PubMed  Google Scholar 

  47. 47.

    McIntyre RS, Yoon J. Efficacy of antimanic treatments in mixed states. Bipolar Disord. 2012;14(Suppl 2):22–36.

    Article  PubMed  Google Scholar 

  48. 48.

    Ishima T, Fujita Y, Hashimoto K. Interaction of new antidepressants with sigma-1 receptor chaperones and their potentiation of neurite outgrowth in PC12 cells. Eur J Pharmacol. 2014;727:167–73.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Perneger TV. What’s wrong with Bonferroni adjustments. BMJ. 1998;316(7139):1236–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Nakagawa S. A farewell to Bonferroni: the problems of low statistical power and publication bias. Behav Ecol. 2004;15(6):1044–5.

    Article  Google Scholar 

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This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number : HC15C1405).

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.


Laura Mandelli, Sheng-Min Wang, Changsu Han, Soo-Jung Lee, Ashwin A. Patkar, Prakash S. Masand, Chi-Un Pae, and Alessandro Serretti declare no personal, financial, commercial, or academic conflicts of interest.

Compliance with Ethics Guidelines

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. All the patients were informed in detail about the aims and the procedures of the study and they signed an informed consent prior to inclusion into the study. The protocol and the informed consent were approved by the local ethical committee (approval number HC10TISI0031).

Data Availability

The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request. All authors presented no conflicts of interest to disclose.

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Correspondence to Chi-Un Pae.

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Mandelli, L., Wang, SM., Han, C. et al. The Impact of a Single Nucleotide Polymorphism in SIGMAR1 on Depressive Symptoms in Major Depressive Disorder and Bipolar Disorder. Adv Ther 34, 713–724 (2017).

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  • Antidepressants
  • Bipolar disorder
  • Major depressive disorder
  • Mood stabilizers
  • Psychiatry
  • Sigma-1 receptor