The Complex Role of Oxytocin in Major Depressive Disorder

Year 2022, Volume: 12 Issue: 2, 462 - 471, 30.06.2022

Angelos Halaris Jasleen Singh C. Sue Carter Hossein Nazarloo Brandon Hage

https://doi.org/10.33808/clinexphealthsci.975706

Cited By: 1

Abstract

Objective: One proposed mechanism to subclassify depressive illness relates oxytocinergic dysregulation, via its effect on social behavior and Hypothalamic-pituitary-adrenal (HPA) axis inhibition. To further investigate the role of oxytocin in Major Depressive Disorder (MDD), we compared plasma oxytocin levels in patients with MDD to healthy controls.
Methods: Plasma samples from 12 healthy controls and 33 MDD patients were collected at baseline, 8 weeks, and 12 weeks of treatment and oxytocin was measured by enzyme-immunoassay. Depression and anxiety scales were administered at screening, baseline, and at weeks 2, 4, 8, and 12 of treatment. Additionally, we investigated possible associations between blood concentrations of inflammatory biomarkers and oxytocin.
Results: The average baseline oxytocin level was 429 pg/ml in MDD patients and 392 pg/ml in healthy control subjects. A significant negative correlation was found between baseline oxytocin and BMI. Treatment responders had significantly lower baseline oxytocin levels than non-responders. After stratifying patients into low and high oxytocin groups based on a median split, within the high oxytocin group, patients with no prior depressive episodes had significantly higher baseline oxytocin levels. A Chi-square distribution test revealed that African American patients were more likely to belong to the high baseline oxytocin group while Caucasian and Hispanic patients were more likely to belong to the low baseline oxytocin group. We found significant correlations between oxytocin and Von-Willebrand Factor (VWF) and Epidermal Growth Factor (EGF), only within the high oxytocin subgroup. There were no other significant correlations between baseline oxytocin and any other biomarkers.
Conclusion: Within our limited patient cohort, our data adds to the mixed literature regarding the role of oxytocin in MDD. Oxytocinergic dysregulation and confounding factors may play a role for a subset of depressed patients.

Keywords

Depression, oxytocin, social behavior, HPA axis, inflammation

References

• REFERENCES Romano A, Tempesta B, Micioni Di Bonaventura MV, Gaetani S. From Autism to Eating Disorders and More: The Role of Oxytocin in Neuropsychiatric Disorders. Front Neurosci [Internet]. 2016 Jan 12;9. Available from: http://journal.frontiersin.org/Article/10.3389/fnins.2015.00497/abstract
• Scantamburlo G, Ansseau M, Geenen V, Legros J-J. Oxytocin: From milk ejection to maladaptation in stress response and psychiatric disorders. A psychoneuroendocrine perspective. Ann Endocrinol (Paris) [Internet]. 2009 Dec;70(6):449–54. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0003426609002649
• Slattery DA, Neumann ID. Oxytocin and Major Depressive Disorder: Experimental and Clinical Evidence for Links to Aetiology and Possible Treatment. Pharmaceuticals [Internet]. 2010 Mar 16;3(3):702–24. Available from: http://www.mdpi.com/1424-8247/3/3/702
• Cochran DM, Fallon D, Hill M, Frazier JA. The Role of Oxytocin in Psychiatric Disorders. Harv Rev Psychiatry [Internet]. 2013;21(5):219–47. Available from: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00023727-201309000-00001
• Keating C, Dawood T, Barton DA, Lambert GW, Tilbrook AJ. Effects of selective serotonin reuptake inhibitor treatment on plasma oxytocin and cortisol in major depressive disorder. BMC Psychiatry [Internet]. 2013 Dec 29;13(1):124. Available from: http://bmcpsychiatry.biomedcentral.com/articles/10.1186/1471-244X-13-124
• Lien Y-J, Chang HH, Tsai H-C, Kuang Yang Y, Lu R-B, See Chen P. Plasma oxytocin levels in major depressive and bipolar II disorders. Psychiatry Res [Internet]. 2017 Dec;258:402–6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0165178117301014
• Carter CS. The oxytocin-vasopressin pathway in the context of love and fear. Front Endocrinol (Lausanne). 2017;8(DEC):1–12.
• Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci [Internet]. 2012 Nov;35(11):649–59. Available from: https://linkinghub.elsevier.com/retrieve/pii/S016622361200152X
• Lang UE, Borgwardt S. Molecular mechanisms of depression: Perspectives on new treatment strategies. Cell Physiol Biochem. 2013;31(6):761–77.
• Halaris A, Hage B, Carter CS, Nazarloo HP, Singh J. Does Arginine Vasopressin Reflect HPA-axis Activation in Major Depressive Disorder? Clin Exp Investig [Internet]. 2020 Mar 30;1–8. Available from: https://www.sciencerepository.org/does-arginine-vasopressin-reflect_CEI-2020-2-101
• Ozden A, Michelle M, Edwin M, Angelos H. Efficacy and Tolerability of Quetiapine Extended Release (XR) as Monotherapy in the Treatment of Major Depressive Disorder. Int J Depress Anxiety [Internet]. 2019 Nov 25;2(2). Available from: https://www.clinmedjournals.org/articles/ijda/international-journal-of-depression-and-anxiety-ijda-2-017.php?jid=ijda
• Sue Carter C, Pournajafi-Nazarloo H, Kramer KM, Ziegler TE, White-Traut R, Bello D, et al. Oxytocin: Behavioral Associations and Potential as a Salivary Biomarker. Ann N Y Acad Sci [Internet]. 2007 Mar 1;1098(1):312–22. Available from: http://doi.wiley.com/10.1196/annals.1384.006
• MacLean EL, Wilson SR, Martin WL, Davis JM, Nazarloo HP, Carter CS. Challenges for measuring oxytocin: The blind men and the elephant? Psychoneuroendocrinology [Internet]. 2019 Sep;107:225–31. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0306453019302380
• Chu C, Hammock EA., Joiner TE. Unextracted plasma oxytocin levels decrease following in-laboratory social exclusion in young adults with a suicide attempt history. J Psychiatr Res [Internet]. 2020 Feb;121:173–81. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0022395619308726
• Saxbe D, Khaled M, Horton KT, Mendez AJ. Maternal prenatal plasma oxytocin is positively associated with prenatal psychological symptoms, but method of immunoassay extraction may affect results. Biol Psychol [Internet]. 2019 Oct;147:107718. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0301051118301017
• Ellis BJ, Horn AJ, Carter CS, van IJzendoorn MH, Bakermans-Kranenburg MJ. Developmental programming of oxytocin through variation in early-life stress: Four meta-analyses and a theoretical reinterpretation. Clin Psychol Rev [Internet]. 2021 Jun;86:101985. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0272735821000283
• Ozsoy S, Esel E, Kula M. Serum oxytocin levels in patients with depression and the effects of gender and antidepressant treatment. Psychiatry Res [Internet]. 2009 Oct;169(3):249–52. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0165178108002023
• Parker KJ, Kenna HA, Zeitzer JM, Keller J, Blasey CM, Amico JA, et al. Preliminary evidence that plasma oxytocin levels are elevated in major depression. Psychiatry Res [Internet]. 2010 Jul;178(2):359–62. Available from: https://linkinghub.elsevier.com/retrieve/pii/S016517810900362X
• Scantamburlo G, Hansenne M, Fuchs S, Pitchot W, Pinto E, Reggers J, et al. AVP- and OT-neurophysins response to apomorphine and clonidine in major depression. Psychoneuroendocrinology [Internet]. 2005 Oct;30(9):839–45. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0306453005000818
• Van Londen L, Goekoop JG, Van Kempen GMJ, Frankhuijzen-Sierevogel AC, Wiegant VM, Van Der Velde EA, et al. Plasma levels of arginine vasopressin elevated in patients with major depression. Neuropsychopharmacology [Internet]. 1997 Oct;17(4):284–92. Available from: http://www.nature.com/doifinder/10.1016/S0893-133X(97)00054-7
• Cyranowski JM, Hofkens TL, Frank E, Seltman H, Cai H-M, Amico JA. Evidence of Dysregulated Peripheral Oxytocin Release Among Depressed Women. Psychosom Med [Internet]. 2008 Nov;70(9):967–75. Available from: https://journals.lww.com/00006842-200811000-00003
• Massey SH, Backes KA, Schuette SA. Plasma Oxytocin Concentration and Depressive Symptoms: A Review of Current Evidence and Directions for Future Research. Depress Anxiety [Internet]. 2016 Apr;33(4):316–22. Available from: http://doi.wiley.com/10.1002/da.22467
• Rutigliano G, Rocchetti M, Paloyelis Y, Gilleen J, Sardella A, Cappucciati M, et al. Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis. Psychiatry Res. 2016;241:207–20.
• Yuen KW, Garner JP, Carson DS, Keller J, Lembke A, Hyde SA, et al. Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol. J Psychiatr Res [Internet]. 2014 Apr;51:30–6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0022395613003877
• Meynen G, Unmehopa UA, Hofman MA, Swaab DF, Hoogendijk WJG. Hypothalamic oxytocin mRNA expression and melancholic depression. Mol Psychiatry [Internet]. 2007 Feb 25;12(2):118–9. Available from: http://www.nature.com/articles/4001911
• Sue Carter C, Kenkel WM, Maclean EL, Wilson SR, Perkeybile AM, Yee JR, et al. Is oxytocin “nature’s medicine”? Pharmacol Rev. 2020;72(4):829–61.
• Tsai TY, Tseng HH, Chi MH, Chang HH, Wu CK, Yang YK, et al. The interaction of oxytocin and social support, loneliness, and cortisol level in major depression. Clin Psychopharmacol Neurosci. 2019;17(4):487–94.
• Massey SH, Schuette SA, Pournajafi-Nazarloo H, Wisner KL, Carter CS. Interaction of oxytocin level and past depression may predict postpartum depressive symptom severity. Arch Womens Ment Health [Internet]. 2016 Oct 8;19(5):799–808. Available from: http://link.springer.com/10.1007/s00737-016-0616-6
• Holt-Lunstad J, Birmingham W, Light KC. The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention. Psychoneuroendocrinology [Internet]. 2011 Sep;36(8):1249–56. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0306453011000965
• Beck AT, Steer RA, Carbin MG. Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clin Psychol Rev [Internet]. 1988 Jan;8(1):77–100. Available from: https://linkinghub.elsevier.com/retrieve/pii/0272735888900505
• Seay JS, Lattie E, Schneiderman N, Antoni MH, Fekete EM, Mendez AJ, et al. Linear and Quadratic Associations of Plasma Oxytocin With Depressive Symptoms in Ethnic Minority Women Living With HIV. J Appl Biobehav Res [Internet]. 2014 Mar;19(1):70–8. Available from: http://doi.wiley.com/10.1111/jabr.12016
• Bell CJ, Nicholson H, Mulder RT, Luty SE, Joyce PR. Plasma oxytocin levels in depression and their correlation with the temperament dimension of reward dependence. J Psychopharmacol [Internet]. 2006 Sep 9;20(5):656–60. Available from: http://journals.sagepub.com/doi/10.1177/0269881106060512
• Scantamburlo G, Hansenne M, Fuchs S, Pitchot W, Maréchal P, Pequeux C, et al. Plasma oxytocin levels and anxiety in patients with major depression. Psychoneuroendocrinology [Internet]. 2007 May;32(4):407–10. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0306453007000297
• Anderberg UM, Uvnäs-Moberg K. Plasma oxytocin levels in female fibromyalgia syndrome patients. Z Rheumatol [Internet]. 2000 Dec;59(6):373–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11201002
• Wang D, Ma Y. Oxytocin facilitates valence-dependent valuation of social evaluation of the self. Commun Biol. 2020;3(1):1–12.
• Scantamburlo G, Hansenne M, Geenen V, Legros JJ, Ansseau M. Additional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: An open trial. Eur Psychiatry [Internet]. 2015 Jan;30(1):65–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S092493381400162X
• De Magalhães-Nunes AP, Badauê-Passos D, Ventura RR, Da Silva Guedes D, Araújo JP, Granadeiro PC, et al. Sertraline, a selective serotonin reuptake inhibitor, affects thirst, salt appetite and plasma levels of oxytocin and vasopressin in rats. Exp Physiol [Internet]. 2007 Sep 1;92(5):913–22. Available from: http://doi.wiley.com/10.1113/expphysiol.2007.037358
• De Cagna F, Fusar-Poli L, Damiani S, Rocchetti M, Giovanna G, Mori A, et al. The role of intranasal oxytocin in anxiety and depressive disorders: A systematic review of randomized controlled trials. Clin Psychopharmacol Neurosci. 2019;17(1):1–11.
• Hesketh S, Jessop DS, Hogg S, Harbuz MS. Differential actions of acute and chronic citalopram on the rodent hypothalamic–pituitary–adrenal axis response to acute restraint stress. J Endocrinol [Internet]. 2005 Jun;185(3):373–82. Available from: https://joe.bioscientifica.com/view/journals/joe/185/3/1850373.xml
• Eisenberg Y, Dugas LR, Akbar A, Reddivari B, Layden BT, Barengolts E. Oxytocin is lower in African American men with diabetes and associates with psycho-social and metabolic health factors. Rosenfeld CS, editor. PLoS One [Internet]. 2018 Jan 4;13(1):e0190301. Available from: https://dx.plos.org/10.1371/journal.pone.0190301
• Engstrom G, Hedblad B, Stavenow L, Lind P, Janzon L, Lindgarde F. Inflammation-Sensitive Plasma Proteins Are Associated With Future Weight Gain. Diabetes [Internet]. 2003 Aug 1;52(8):2097–101. Available from: http://diabetes.diabetesjournals.org/cgi/doi/10.2337/diabetes.52.8.2097
• McCormack SE, Blevins JE, Lawson EA. Metabolic Effects of Oxytocin. Endocr Rev [Internet]. 2020 Apr 1;41(2):121–45. Available from: https://academic.oup.com/edrv/article/41/2/121/5658523
• Lawson EA, Olszewski PK, Weller A, Blevins JE. The role of oxytocin in regulation of appetitive behaviour, body weight and glucose homeostasis. J Neuroendocrinol [Internet]. 2020 Apr 28;32(4). Available from: https://onlinelibrary.wiley.com/doi/10.1111/jne.12805
• Arletti R, Benelli A, Bertolini A. Oxytocin inhibits food and fluid intake in rats. Physiol Behav [Internet]. 1990 Dec;48(6):825–30. Available from: https://linkinghub.elsevier.com/retrieve/pii/003193849090234U
• Sabatier N, Leng G, Menzies J. Oxytocin, Feeding, and Satiety. Front Endocrinol (Lausanne) [Internet]. 2013;4. Available from: http://journal.frontiersin.org/article/10.3389/fendo.2013.00035/abstract
• Zhang G, Bai H, Zhang H, Dean C, Wu Q, Li J, et al. Neuropeptide Exocytosis Involving Synaptotagmin-4 and Oxytocin in Hypothalamic Programming of Body Weight and Energy Balance. Neuron [Internet]. 2011 Feb;69(3):523–35. Available from: https://linkinghub.elsevier.com/retrieve/pii/S089662731001086X
• Qian W, Zhu T, Tang B, Yu S, Hu H, Sun W, et al. Decreased Circulating Levels of Oxytocin in Obesity and Newly Diagnosed Type 2 Diabetic Patients. J Clin Endocrinol Metab [Internet]. 2014 Dec;99(12):4683–9. Available from: https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2014-2206
• Grewen KM, Light KC, Mechlin B, Girdler SS. Ethnicity is associated with alterations in oxytocin relationships to pain sensitivity in women. Ethn Health [Internet]. 2008 Jun;13(3):219–41. Available from: http://www.tandfonline.com/doi/abs/10.1080/13557850701837310
• Carter C. Sex differences in oxytocin and vasopressin: Implications for autism spectrum disorders? Behav Brain Res [Internet]. 2007 Jan 10;176(1):170–86. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0166432806004827
• Lee H-J, Macbeth AH, Pagani J, Young WS. Oxytocin: The Great Facilitator of Life. Prog Neurobiol [Internet]. 2009 Apr 10; Available from: https://linkinghub.elsevier.com/retrieve/pii/S030100820900046X
• Uhl-Bronner S, Waltisperger E, Martínez-Lorenzana G, Condes Lara M, Freund-Mercier MJ. Sexually dimorphic expression of oxytocin binding sites in forebrain and spinal cord of the rat. Neuroscience [Internet]. 2005 Jan;135(1):147–54. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0306452205005816
• Garforth B, Degnbol H, Terris ET, Zak PJ, Winterdahl M. Elevated plasma oxytocin levels and higher satisfaction with life in young oral contraceptive users. Sci Rep [Internet]. 2020;10(1):1–7. Available from: http://dx.doi.org/10.1038/s41598-020-64528-w
• Wouters E, Hudson CA, McArdle CA, López Bernal A. Central role for protein kinase C in oxytocin and epidermal growth factor stimulated cyclooxygenase 2 expression in human myometrial cells. BMC Res Notes [Internet]. 2014;7(1):357. Available from: http://bmcresnotes.biomedcentral.com/articles/10.1186/1756-0500-7-357
• Müller N. COX-2 Inhibitors, Aspirin, and Other Potential Anti-Inflammatory Treatments for Psychiatric Disorders. Front Psychiatry [Internet]. 2019 May 31;10. Available from: https://www.frontiersin.org/article/10.3389/fpsyt.2019.00375/full
• Halaris A, Cantos A, Johnson K, Hakimi M, Sinacore J. Modulation of the inflammatory response benefits treatment-resistant bipolar depression: A randomized clinical trial. J Affect Disord [Internet]. 2020 Jan;261:145–52. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0165032719321809