Biological Sex in Mental Health Research
Written by Sara Price
For decades, neuroscience research has disproportionately studied male subjects, often treating findings as though they apply equally to everyone. Yet we know that mental health conditions do not affect everyone in the same way. The Australian Bureau of Statistics (2020-2022) highlighted that depression and anxiety disorders are significantly more frequent in females, while substance use disorders are over twice as prevalent in males (1). Even when people experience the same mental health condition, their symptoms, underlying biology, and responses to treatment can differ (2).
Today is World Mental Health Day, an opportunity to raise awareness of mental health issues and start conversations about the work still needed in this space. We want to highlight why understanding these differences matters and how new neuroscience research is helping us ask better questions about mental health.
As neuroscientists, we often work behind the scenes, uncovering the biological basis of mental health conditions and the treatments that target them. With more than 2 in every 5 Australians having experienced a mental disorder at some point in their life (1), understanding the biological factors that contribute to mental health conditions is an urgent priority.
But what if some of the biological differences that matter most have been overlooked? We can observe that mental health conditions look and respond differently from person to person, but we still know little about why. And because research has so often centred on males or omitted sex altogether, we have a limited understanding of how sex, a fundamental biological variable, plays a role.
Sex matters in mental health research
Mental health is shaped by a complex interaction of biological, psychological and social factors. Gender roles, expectations and lived experiences influence our mental health, but biology is also critical. Biological sex involves a range of characteristics, including chromosomes, hormones and reproductive structures. These factors can influence how the brain develops and functions, potentially contributing to differences in vulnerability to mental health conditions and responses to treatment (3, 4). Understanding these influences is not about reducing mental health to biology. It's about ensuring we don't overlook an important part of the picture. Yet, there is a stark gap in the research addressing this. Back in 2017, only 6% of neuroscientific research in some of the top journals included both males and females and considered sex (5). This means some of our understanding of the brain has been built on research that may or may not fully reflect biological differences.
The upside is that policy shifts are attempting to address this gap, such as the mandate that sex be included in research funded by the Australian National Health and Medical Research Council (NHMRC) from the beginning of 2026 (6). However, the field is required to sufficiently address sex in its research, not just a “tick box” exercise. Although more researchers continue to incorporate both sexes in their studies, simply including sex is not enough. Even when both sexes are included, presenting only their combined results can mask important findings. Without sex-stratified analyses, real differences and sex-specific effects can go unnoticed.
Why sex matters for serotonin
The brain’s serotonin system offers a clear example of what we can learn when sex is properly considered. Serotonin, a chemical messenger in the brain, regulates mood alongside many other functions, and its dysfunction is notable in research on mental health. The system is a major target of psychiatric treatments, including commonly prescribed antidepressants. Including sex as a biological variable has transformed our understanding of this system and how it may contribute to sex-based vulnerabilities in depression and anxiety, as well as responses to treatments (7, 8).
At the Dehorter lab, we are researching how sex differences emerge in the brain’s serotonin system and the molecular processes that may contribute to these differences. This work is especially crucial as serotonin can also play a critical early role in brain development. By understanding how these differences develop, we hope to identify biological mechanisms that have previously been overlooked. These discoveries could help us better understand why some individuals are more vulnerable to particular mental health conditions and ultimately inform more targeted approaches to treatment.
Our research, alongside the growing body of literature, emphasises that a one-size-fits-all approach cannot sufficiently address the biological basis of the growing burden of mental health conditions. Understanding the influence of sex can also go beyond benefiting the binary female and male comparisons, as biomedical research into mental health in populations with variations in sex development, sex chromosomes, or hormonal states, including those undergoing gender-affirming hormone treatment, also requires further investigation. This can provide further opportunities to understand which sex-related biological factors can impact mental health, with the hope of translating these findings into clinical insights.
As we mark World Mental Health Day, it’s important to recognise who this research is meant to benefit. This work is for the many people living with mental health conditions and the better outcomes they deserve. By addressing sex, a factor that has been overlooked for so long, we hope to build a clearer and more holistic understanding of mental health and ultimately improve the lives of the people we do this work for.
References:
Australian Bureau of Statistics. National Study of Mental Health and Wellbeing, 2020–2022. 2023 Oct 5. Available from: https://www.abs.gov.au/statistics/health/mental-health/national-study-mental-health-and-wellbeing/2020-2022
Singh, K., & Wendt, F. R. (2024). Effects of sex and gender on the etiologies and presentation of select internalizing psychopathologies. Translational Psychiatry, 14(1), 73. https://doi.org/10.1038/s41398-024-02730-4
Cahill, L. (2006). Why sex matters for neuroscience. Nature Reviews Neuroscience, 7(6), 477-484. https://doi.org/10.1038/nrn1909
Hodes, G. E., & Kropp, D. R. (2023). Sex as a biological variable in stress and mood disorder research. Nature Mental Health, 1(7), 453-461. https://doi.org/10.1038/s44220-023-00083-3
Mamlouk, G. M., Dorris, D. M., Barrett, L. R., & Meitzen, J. (2020). Sex bias and omission in neuroscience research is influenced by research model and journal, but not reported NIH funding. Frontiers in Neuroendocrinology, 57, 100835. https://doi.org/https://doi.org/10.1016/j.yfrne.2020.100835
Australian Government Department of Health, Disability and Ageing; National Health and Medical Research Council. Embedding sex and gender considerations in research for better medical outcomes. 2025 Nov 27. Available from: https://www.health.gov.au/resources/publications/embedding-sex-and-gender-considerations-in-research-for-better-medical-outcomes
Donner, N. C., & Lowry, C. A. (2013). Sex differences in anxiety and emotional behavior. Pflügers Archiv - European Journal of Physiology, 465(5), 601-626. https://doi.org/10.1007/s00424-013-1271-7
Palacios-Avendaño, N., Rojas, P. S., Alarcón-Mardones, M., & Fiedler, J. L. (2026). Sex-dependent serotonergic signaling across development: molecular mechanisms shaping vulnerability to neurodevelopmental and mental disorders. Frontiers in Pharmacology, Volume 17 - 2026. https://doi.org/10.3389/fphar.2026.1800447
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