A global mental health crisis is evolving. And at the forefront of the surging rates of mental health disorders globally are women, who are disproportionately affected when compared to men.

While men have higher rates of antisocial personality and substance use disorders, women are 20 to 40 per cent more likely to experience a mental health disorder.

A female doctor listens as a young woman talks about her symptoms. — Women are 20 to 40 per cent more likely to experience a mental health disorder. Picture: Getty Images

Women are twice as likely to be diagnosed with anxiety, depression, post-traumatic stress disorder and eating disorders.

And this issue is further complicated by the fact that mental health disorders that were historically more prevalent in men are converging between the sexes.

For example, alcohol use disorder.

While annual diagnosis rates in men increased by 35 per cent from 2001/2002 to 2012/2013 – during the same period, rates rose by 84 per cent in women.

A disparity in research

There are several factors that can influence the development, progression and persistence of mental health conditions. These include social, psychological, societal and neurobiological factors.

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The soaring rates of mental health disorders in women are particularly concerning – made worse by the fact that our knowledge of the biological drivers in women remains very limited.

This is especially true when it comes to understanding how the female brain might be altered in mental health disorders.

So, what’s the reason for our poor understanding?

The historical underrepresentation of females in medical research has created a significant gender knowledge and health gap.

Using mostly males in medical research stemmed from several ‘reasons’ (or excuses). These include the false belief that male bodies are the ‘norm’, along with concerns that female hormones can lead to variability in research outcomes.

In practice, this means research done on males is generalised and then applied to females.

A male patient sits on an exam table as a female nurse takes his blood pressure. — Research done on males is generalised and then applied to females. Picture: Getty Images

This is not an issue of the distant past. It’s been the standard until very recently in both human and animal studies.

For example, only 20 per cent of alcohol studies in animals between 2015 and 2019 included both sexes. And only 29 per cent of participants in clinical trials for alcohol use disorder between 2010 and 2019 were women.

This disparity in research representation means most drug treatments for mental health disorders are developed and trialled almost exclusively in males.

It also means important differences in the female biology are not taken into account.

The end result is poorer treatment outcomes for women, not only in terms of effectiveness, but also when it comes to safety and side effects.

So, there’s an urgent need for more personalised treatment options for mental health disorders, that at the very least account for differences in biological sex.

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Reducing the gender knowledge gap

One research tool that can greatly assist are translatable animal models. These models enable investigation of the brain at a level of depth and detail not easily possible in humans.

While animal models are not used to fully replicate the complexity of mental health disorders in people, they are useful in modelling specific aspects of these conditions.

These models – usually rodents – also offer a critical step in screening promising drugs to check their safety and efficacy before trialling them in humans..

Our lab’s recent study in Nature Communications uses a mouse model of binge drinking to reduce the gender knowledge and health gap.

Our study aims to show how the brain can drive alcohol drinking differently between the sexes.

A woman holds a glass of whiskey in her hands in front of a window — The research is looking at how the brain can drive alcohol drinking differently between the sexes. Picture: Getty Images

Binge drinking is defined as consuming alcohol that elevates blood alcohol concentration (BAC) to 0.08 per cent or greater. This roughly equates to five standard drinks in men and four standard drinks in women within two hours.

And binge drinking is the greatest predictor of future alcohol use disorder.

Females and the role of ghrelin

Our focus was on how the hormone ghrelin might influence alcohol drinking in both sexes.

Ghrelin, commonly referred to as the ‘hunger hormone’, is produced in the stomach and primarily acts in the brain to tell the body when to eat.

Interestingly, in both humans and rodents, females have more ghrelin circulating in their body than males.

Ghrelin’s role, however, extends beyond just eating and appetite. Preclinical and clinical studies have linked ghrelin with alcohol craving and consumption.

What’s less understood is where in the brain this hormone is influencing alcohol use, and whether this differs based on biological sex.

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Our team looked at ghrelin’s effect in the Edinger-Westphal nucleus.

This is a small brain region with the second highest expression of the ghrelin receptor (where ghrelin exerts its effect) and has been previously linked to drinking alcohol.

We found that reducing ghrelin receptor expression in the Edinger-Westphal nucleus decreased binge drinking in female mice compared to female mice with normal ghrelin receptor expression. But it had no effect in male mice.

Importantly, female sex hormones did not influence this reduction in female binge drinking.

After several follow-up studies, we identified exactly which ghrelin receptor cells in the Edinger-Westphal nucleus were responsible for regulating binge drinking specifically in females.

Our study highlights that the brain can drive alcohol drinking very differently between the sexes in very intricate ways.

Multiple MRI scans of human brains — Where in the brain is the hormone ghrelin influencing alcohol use? Picture: Getty Images

And we hope our work emphasises the importance of studying both sexes in mental health research.

If we had included only males in this study, as most historic studies have done, important findings like these would have been completely overlooked.

A shared and overarching goal

It’s imperative research improves understanding of how mental health conditions alter the brain in both women and men.

Many medical research bodies are beginning to recognise this for the issue it is.

For example, the US National Institutes of Health, the largest funder of medical research globally, now has policies to ensure the consideration of biological sex in funded research.

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While Australian research has lagged behind, in July 2024, the National Health and Medical Research Council (NHMRC) released a statement imploring researchers to consider sex and gender, a first step in correcting long-standing bias in medical research.

It’s critical that this is a shared and overarching goal of mental health research to address the gender knowledge and health gap.

Striving to change it has the potential to lead to the development of more personalised and targeted treatment options, resulting in improved health outcomes for everyone, especially women.

This article was first published on Pursuit. Read the original article.

Dr

Leigh Walker

Senior Research Fellow

Florey Department of Neuroscience and Mental Health

Dr

Leigh Walker

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