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.

  • Review Article
  • Published:

Sex as a biological variable in stress and mood disorder research

Nature Mental Health volume 1, pages 453–461 (2023)Cite this article

Subjects

Abstract

In 2016, changes were mandated for basic research, including using sex as a biological variable. This policy change was due to the lack of research performed in female animals. This resulted in a mismatch between the sex of the subjects being used for drug development and the sex of the participants in subsequent clinical trials hampering the translational success of novel therapeutics, especially treatments for mood disorders. While it is now clear that sex differences exist, the field needs to move to the next frontier in sex-difference research. We need to start exploring why and how these sex differences exist. What are their functions? How do we harness this information to develop novel sex-specific treatments for mental illness? This Review will address what we have learned from using sex as a biological variable and how we can utilize these data to better understand and treat sex-based disparities in mental health.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Changes in the percentage of published studies using male and female subjects by year.
Fig. 2: Areas of the rodent brain that are different in males and females and respond to stress.
Fig. 3: SABV can contribute to novel treatments for mood disorders.

Similar content being viewed by others

References

  1. Gender Studies in Product Development: Historical Overview (FDA, 2018); https://www.fda.gov/science-research/womens-health-research/gender-studies-product-development-historical-overview

  2. Mastroianni, A. C., Faden, R. & Federman, D. Women and health research: a report from the Institute of Medicine. Kennedy Inst. Ethics J. 4, 55–62 (1994).

    Article  PubMed  Google Scholar 

  3. Rechlin, R. K., Splinter, T. F. L., Hodges, T. E., Albert, A. Y. & Galea, L. A. M. An analysis of neuroscience and psychiatry papers published from 2009 and 2019 outlines opportunities for increasing discovery of sex differences. Nat. Commun. 13, 2137 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Beery, A. K. & Zucker, I. Sex bias in neuroscience and biomedical research. Neurosci. Biobehav. Rev. 35, 565–572 (2011).

    Article  PubMed  Google Scholar 

  5. Mamlouk, G. M., Dorris, D. M., Barrett, L. R. & Meitzen, J. Sex bias and omission in neuroscience research is influenced by research model and journal, but not reported NIH funding. Front. Neuroendocrinol. 57, 100835 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Becker, J. B., Prendergast, B. J. & Liang, J. W. Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol. Sex Differ. 7, 34 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sensi, S., Pace Palitti, V. & Guagnano, M. T. Chronobiology in endocrinology. Ann. Ist. Super. Sanita 29, 613–631 (1993).

    PubMed  Google Scholar 

  8. Keck, M. E., Welt, T., Müller, M. B., Landgraf, R. & Holsboer, F. The high-affinity non-peptide CRH1 receptor antagonist R121919 attenuates stress-induced alterations in plasma oxytocin, prolactin, and testosterone secretion in rats. Pharmacopsychiatry 36, 27–31 (2003).

    Article  PubMed  Google Scholar 

  9. Binneman, B. et al. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am. J. Psychiatry 165, 617–620 (2008).

    Article  PubMed  Google Scholar 

  10. Coric, V. et al. Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder. Depress. Anxiety 27, 417–425 (2010).

    Article  PubMed  Google Scholar 

  11. Ising, M. et al. High-affinity CRF1 receptor antagonist NBI-34041: preclinical and clinical data suggest safety and efficacy in attenuating elevated stress response. Neuropsychopharmacology 32, 1941–1949 (2007).

    Article  PubMed  Google Scholar 

  12. Zobel, A. W. et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181 (2000).

    Article  PubMed  Google Scholar 

  13. Heinrich, J., Gahart, M. T., Rowe, E. J. & Bradely, L. Drug Safety: Most Drugs Withdrawn in Recent Years Had Greater Health Risks for Women (United States General Accounting Office, 2001).

  14. Arnegard, M. E., Whitten, L. A., Hunter, C. & Clayton, J. A. Sex as a biological variable: a 5-year progress report and call to action. J. Womens Health 29, 858–864 (2020).

    Article  Google Scholar 

  15. Ernst, M. M., Kogan, B. A. & Lee, P. A. Gender identity: a psychosocial primer for providing care to patients with a disorder/difference of sex development and their families [individualized care for patients with intersex (disorders/differences of sex development): part 2]. J. Pediatr. Urol. 16, 606–611 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Rosenwohl-Mack, A. et al. A national study on the physical and mental health of intersex adults in the US. PLoS ONE 15, e0240088 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Salk, R. H., Hyde, J. S. & Abramson, L. Y. Gender differences in depression in representative national samples: meta-analyses of diagnoses and symptoms. Psychol. Bull. 143, 783–822 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Marcus, S. M. et al. Sex differences in depression symptoms in treatment-seeking adults: confirmatory analyses from the Sequenced Treatment Alternatives to Relieve Depression study. Compr. Psychiatry 49, 238–246 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Young, E. A. et al. Sex differences in response to citalopram: a STAR*D report. J. Psychiatr. Res. 43, 503–511 (2009).

    Article  PubMed  Google Scholar 

  20. Martin, L. A., Neighbors, H. W. & Griffith, D. M. The experience of symptoms of depression in men vs women: analysis of the National Comorbidity Survey Replication. JAMA Psychiatry 70, 1100–1106 (2013).

    Article  PubMed  Google Scholar 

  21. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed.) https://doi.org/10.1176/appi.books.9780890425596 (American Psychiatric Association Publishing, 2013).

  22. Labonte, B. et al. Sex-specific transcriptional signatures in human depression. Nat. Med. 23, 1102–1111 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Seney, M. L. et al. Opposite molecular signatures of depression in men and women. Biol. Psychiatry 84, 18–27 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Green, T., Flash, S. & Reiss, A. L. Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies. Neuropsychopharmacology 44, 9–21 (2019).

    Article  PubMed  Google Scholar 

  25. Engberg, H. et al. Increased psychiatric morbidity in women with complete androgen insensitivity syndrome or complete gonadal dysgenesis. J. Psychosom. Res. 101, 122–127 (2017).

    Article  PubMed  Google Scholar 

  26. Fliegner, M. et al. Sexual life and sexual wellness in individuals with complete androgen insensitivity syndrome (CAIS) and Mayer–Rokitansky–Kuster–Hauser Syndrome (MRKHS). J. Sex Med. 11, 729–742 (2014).

    Article  PubMed  Google Scholar 

  27. Jenkins-Jones, S. et al. Poor compliance and increased mortality, depression and healthcare costs in patients with congenital adrenal hyperplasia. Eur. J. Endocrinol. 178, 309–320 (2018).

    Article  PubMed  Google Scholar 

  28. Seney, M. L., Ekong, K. I., Ding, Y., Tseng, G. C. & Sibille, E. Sex chromosome complement regulates expression of mood-related genes. Biol. Sex Differ. 4, 20 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Seney, M. L. et al. The role of genetic sex in affect regulation and expression of GABA-related genes across species. Front. Psychiatry 4, 104 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Barko, K., Paden, W., Cahill, K. M., Seney, M. L. & Logan, R. W. Sex-specific effects of stress on mood-related gene expression. Mol. Neuropsychiatry 5, 162–175 (2019).

    PubMed  PubMed Central  Google Scholar 

  31. Post, C. & Leuner, B. The maternal reward system in postpartum depression. Arch. Womens Ment. Health 22, 417–429 (2019).

    Article  PubMed  Google Scholar 

  32. McCarthy, M. M., Arnold, A. P., Ball, G. F., Blaustein, J. D. & De Vries, G. J. Sex differences in the brain: the not so inconvenient truth. J. Neurosci. 32, 2241–2247 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kinnear, H. M. et al. A mouse model to investigate the impact of testosterone therapy on reproduction in transgender men. Hum. Reprod. 34, 2009–2017 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Dela Cruz, C. et al. A mouse model mimicking gender-affirming treatment with pubertal suppression followed by testosterone in transmasculine youth. Hum. Reprod. 38, 256–265 (2023).

    Article  Google Scholar 

  35. Lacasse, J. M., Gomez-Perales, E. & Brake, W. G. Modeling hormonal contraception in female rats: a framework for studies in behavioral neurobiology. Front. Neuroendocrinol. 67, 101020 (2022).

    Article  PubMed  Google Scholar 

  36. Skovlund, C. W., Morch, L. S., Kessing, L. V. & Lidegaard, O. Association of hormonal contraception with depression. JAMA Psychiatry 73, 1154–1162 (2016).

    Article  PubMed  Google Scholar 

  37. Rowniak, S., Bolt, L. & Sharifi, C. Effect of cross-sex hormones on the quality of life, depression and anxiety of transgender individuals: a quantitative systematic review. JBI Database System. Rev. Implement. Rep. 17, 1826–1854 (2019).

    Article  PubMed  Google Scholar 

  38. Eliot, L., Ahmed, A., Khan, H. & Patel, J. Dump the “dimorphism”: comprehensive synthesis of human brain studies reveals few male–female differences beyond size. Neurosci. Biobehav. Rev. 125, 667–697 (2021).

    Article  PubMed  Google Scholar 

  39. Williams, C. M., Peyre, H., Toro, R. & Ramus, F. Neuroanatomical norms in the UK Biobank: the impact of allometric scaling, sex, and age. Hum. Brain Mapp. 42, 4623–4642 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  40. DeCasien, A. R., Guma, E., Liu, S. & Raznahan, A. Sex differences in the human brain: a roadmap for more careful analysis and interpretation of a biological reality. Biol. Sex Differ. 13, 43 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Liu, S., Seidlitz, J., Blumenthal, J. D., Clasen, L. S. & Raznahan, A. Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans. Proc. Natl Acad. Sci. USA 117, 18788–18798 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Joel, D. Beyond sex differences and a male–female continuum: mosaic brains in a multidimensional space. Handb. Clin. Neurol. 175, 13–24 (2020).

    Article  PubMed  Google Scholar 

  43. Kaczkurkin, A. N., Raznahan, A. & Satterthwaite, T. D. Sex differences in the developing brain: insights from multimodal neuroimaging. Neuropsychopharmacology 44, 71–85 (2019).

    Article  PubMed  Google Scholar 

  44. Ingalhalikar, M. et al. Sex differences in the structural connectome of the human brain. Proc. Natl Acad. Sci. USA 111, 823–828 (2014).

    Article  PubMed  Google Scholar 

  45. Abdallah, C. G. et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology 42, 1210–1219 (2017).

    Article  PubMed  Google Scholar 

  46. Arelin, K. et al. Progesterone mediates brain functional connectivity changes during the menstrual cycle—a pilot resting state MRI study. Front. Neurosci. 9, 44 (2015).

    PubMed  PubMed Central  Google Scholar 

  47. Cooke, B. M. & Woolley, C. S. Effects of prepubertal gonadectomy on a male-typical behavior and excitatory synaptic transmission in the amygdala. Dev. Neurobiol. 69, 141–152 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Cooke, B. M. & Woolley, C. S. Sexually dimorphic synaptic organization of the medial amygdala. J. Neurosci. 25, 10759–10767 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Estrada, C. M. et al. Estrogen signaling in the medial amygdala decreases emotional stress responses and obesity in ovariectomized rats. Horm. Behav. 98, 33–44 (2018).

    Article  PubMed  Google Scholar 

  50. Nordman, J. C. et al. Potentiation of divergent medial amygdala pathways drives experience-dependent aggression escalation. J. Neurosci. 40, 4858–4880 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Bangasser, D. A. & Shors, T. J. The bed nucleus of the stria terminalis modulates learning after stress in masculinized but not cycling females. J. Neurosci. 28, 6383–6387 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Dalla, C., Whetstone, A. S., Hodes, G. E. & Shors, T. J. Stressful experience has opposite effects on dendritic spines in the hippocampus of cycling versus masculinized females. Neurosci. Lett. 449, 52–56 (2009).

    Article  PubMed  Google Scholar 

  53. Salvatore, M. et al. Sex differences in circuits activated by corticotropin releasing factor in rats. Horm. Behav. 97, 145–153 (2018).

    Article  PubMed  Google Scholar 

  54. Bangasser, D. A. et al. Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Mol. Psychiatry 15, 896–904 (2010).

    Article  Google Scholar 

  55. Bangasser, D. A. & Valentino, R. J. Sex differences in molecular and cellular substrates of stress. Cell. Mol. Neurobiol. 32, 709–723 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Bittar, T. P. et al. Chronic stress induces sex-specific functional and morphological alterations in corticoaccumbal and corticotegmental pathways. Biol. Psychiatry 90, 194–205 (2021).

    Article  PubMed  Google Scholar 

  57. Hodes, G. E. et al. Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J. Neurosci. 35, 16362–16376 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Williams, E. S. et al. Androgen-dependent excitability of mouse ventral hippocampal afferents to nucleus accumbens underlies sex-specific susceptibility to stress. Biol. Psychiatry 87, 492–501 (2020).

    Article  PubMed  Google Scholar 

  59. Dion-Albert, L. et al. Vascular and blood–brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue. Nat. Commun. 13, 164 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zhang, S. et al. Sex differences in the neuroadaptations of reward-related circuits in response to subchronic variable stress. Neuroscience 376, 108–116 (2018).

    Article  PubMed  Google Scholar 

  61. Jain, A., Huang, G. Z. & Woolley, C. S. Latent sex differences in molecular signaling that underlies excitatory synaptic potentiation in the hippocampus. J. Neurosci. 39, 1552–1565 (2019).

    PubMed  PubMed Central  Google Scholar 

  62. Tabatadze, N., Huang, G., May, R. M., Jain, A. & Woolley, C. S. Sex differences in molecular signaling at inhibitory synapses in the hippocampus. J. Neurosci. 35, 11252–11265 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Zer-Aviv, T. M. & Akirav, I. Sex differences in hippocampal response to endocannabinoids after exposure to severe stress. Hippocampus 26, 947–957 (2016).

    Article  PubMed  Google Scholar 

  64. Bollinger, J. L., Bergeon Burns, C. M. & Wellman, C. L. Differential effects of stress on microglial cell activation in male and female medial prefrontal cortex. Brain Behav. Immun. 52, 88–97 (2016).

    Article  PubMed  Google Scholar 

  65. Wohleb, E. S., Terwilliger, R., Duman, C. H. & Duman, R. S. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol. Psychiatry 83, 38–49 (2018).

    Article  PubMed  Google Scholar 

  66. Gandal, M. J. et al. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science https://doi.org/10.1126/science.aat8127 (2018).

  67. Gandal, M. J. et al. Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359, 693–697 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Setiawan, E. et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry 72, 268–275 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Kelly Barko, M. S. et al. Brain region- and sex-specific transcriptional profiles of microglia. Front. Psychiatry https://doi.org/10.3389/fpsyt.2022.945548 (2022).

  70. Barreto, G., Veiga, S., Azcoitia, I., Garcia-Segura, L. M. & Garcia-Ovejero, D. Testosterone decreases reactive astroglia and reactive microglia after brain injury in male rats: role of its metabolites, oestradiol and dihydrotestosterone. Eur. J. Neurosci. 25, 3039–3046 (2007).

    Article  PubMed  Google Scholar 

  71. Villa, A. et al. Sex-specific features of microglia from adult mice. Cell Rep. 23, 3501–3511 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Woodburn, S. C., Bollinger, J. L. & Wohleb, E. S. Synaptic and behavioral effects of chronic stress are linked to dynamic and sex-specific changes in microglia function and astrocyte dystrophy. Neurobiol. Stress 14, 100312 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Tsyglakova, M. et al. Sex and region-specific effects of variable stress on microglia morphology. Brain Behav. Immun. Health 18, 100378 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Menard, C. et al. Social stress induces neurovascular pathology promoting depression. Nat. Neurosci. 20, 1752–1760 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Dion-Albert, L. et al. Sex differences in the blood–brain barrier: implications for mental health. Front. Neuroendocrinol. 65, 100989 (2022).

    Article  PubMed  Google Scholar 

  76. Lorsch, Z. S. et al. Estrogen receptor alpha drives pro-resilient transcription in mouse models of depression. Nat. Commun. 9, 1116 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Devan, B. D., Tobin, E. L., Dunn, E. N. & Magalis, C. Sex differences on the competitive place task in the water maze: the influence of peripheral pool time on spatial navigation performance in rats. Behav. Processes 132, 34–41 (2016).

    Article  PubMed  Google Scholar 

  78. Mueller, B. R. & Bale, T. L. Early prenatal stress impact on coping strategies and learning performance is sex dependent. Physiol. Behav. 91, 55–65 (2007).

    Article  PubMed  Google Scholar 

  79. Gruene, T. M., Flick, K., Stefano, A., Shea, S. D. & Shansky, R. M. Sexually divergent expression of active and passive conditioned fear responses in rats. Elife https://doi.org/10.7554/eLife.11352 (2015).

  80. Maier, S. F. & Watkins, L. R. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci. Biobehav. Rev. 29, 829–841 (2005).

    Article  PubMed  Google Scholar 

  81. Dalla, C., Edgecomb, C., Whetstone, A. S. & Shors, T. J. Females do not express learned helplessness like males do. Neuropsychopharmacology 33, 1559–1569 (2008).

    Article  PubMed  Google Scholar 

  82. Morrison, K. E. et al. Preadolescent adversity programs a disrupted maternal stress reactivity in humans and mice. Biol. Psychiatry 81, 693–701 (2017).

    Article  PubMed  Google Scholar 

  83. Zucker, I. & Prendergast, B. J. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biol. Sex Differ. 11, 32 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Kornstein, S. G. et al. Gender differences in treatment response to sertraline versus imipramine in chronic depression. Am. J. Psychiatry 157, 1445–1452 (2000).

    Article  PubMed  Google Scholar 

  85. Sramek, J. J., Murphy, M. F. & Cutler, N. R. Sex differences in the psychopharmacological treatment of depression. Dialogues Clin. Neurosci. 18, 447–457 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Damoiseaux, V. A., Proost, J. H., Jiawan, V. C. & Melgert, B. N. Sex differences in the pharmacokinetics of antidepressants: influence of female sex hormones and oral contraceptives. Clin. Pharmacokinet. 53, 509–519 (2014).

    Article  PubMed  Google Scholar 

  87. Hodes, G. E., Hill-Smith, T. E., Suckow, R. F., Cooper, T. B. & Lucki, I. Sex-specific effects of chronic fluoxetine treatment on neuroplasticity and pharmacokinetics in mice. J. Pharmacol. Exp. Ther. 332, 266–273 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Alvarez, J. C., Bothua, D., Collignon, I., Advenier, C. & Spreux-Varoquaux, O. Determination of fluoxetine and its metabolite norfluoxetine in serum and brain areas using high-performance liquid chromatography with ultraviolet detection. J. Chromatogr. B 707, 175–180 (1998).

    Article  Google Scholar 

  89. Ferguson, J. M. & Hill, H. Pharmacokinetics of fluoxetine in elderly men and women. Gerontology 52, 45–50 (2006).

    Article  PubMed  Google Scholar 

  90. Carrier, N. & Kabbaj, M. Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology 70, 27–34 (2013).

    Article  PubMed  Google Scholar 

  91. Freeman, M. P. et al. Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression. J. Psychiatr. Res. 110, 166–171 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Ponton, E., Turecki, G. & Nagy, C. Sex differences in the behavioral, molecular, and structural effects of ketamine treatment in depression. Int. J. Neuropsychopharmacol. 25, 75–84 (2022).

    Article  PubMed  Google Scholar 

  93. Anderson, G. D. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J. Womens Health 14, 19–29 (2005).

    Article  Google Scholar 

  94. Pinna, G., Costa, E. & Guidotti, A. Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake. Psychopharmacology 186, 362–372 (2006).

    Article  PubMed  Google Scholar 

  95. Dalla, C., Pitychoutis, P. M., Kokras, N. & Papadopoulou-Daifoti, Z. Sex differences in animal models of depression and antidepressant response. Basic Clin. Pharmacol. Toxicol. 106, 226–233 (2010).

    Article  PubMed  Google Scholar 

  96. Berkley, K. J. Vive la difference! Trends Neurosci. 15, 331–332 (1992).

    Article  PubMed  Google Scholar 

  97. Lin, H. et al. The prevalence and factors associated with anxiety-like and depression-like behaviors in women with polycystic ovary syndrome. Front. Psychiatry 12, 709674 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Wang, Z. et al. Mapping global prevalence of depression among postpartum women. Transl. Psychiatry 11, 543 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Freeman, E. W. Associations of depression with the transition to menopause. Menopause 17, 823–827 (2010).

    Article  PubMed  Google Scholar 

  100. Mirin, A. A. Gender disparity in the funding of diseases by the US National Institutes of Health. J. Womens Health 30, 956–963 (2021).

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by National Institute of Mental Health grant no. R56MH124930 (G.E.H.). Figures 2 and 3 were created using https://BioRender.com.

Author information

Authors and Affiliations

  1. School of Neuroscience, Virginia Tech, Blacksburg, VA, USA

    Georgia E. Hodes & Dawson R. Kropp

Authors
  1. Georgia E. Hodes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dawson R. Kropp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Georgia E. Hodes.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Mental Health thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hodes, G.E., Kropp, D.R. Sex as a biological variable in stress and mood disorder research. Nat. Mental Health 1, 453–461 (2023). https://doi.org/10.1038/s44220-023-00083-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44220-023-00083-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing