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Psychiatric Research Suffering From Legacy of Ignoring Sex Differences, Say Neuroscientists

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Research into developing treatments for psychiatric illness is missing out vital data from female animals, producing drugs that aren’t optimized for women and contributing to the failure of clinical trials, said a panel of neuroscientists today at FENS Virtual Forum of Neuroscience.

In a press conference, Professor Christina Dalla from the National and Kapodistrian University of Athens, Dr Debra Bangasser from Temple University and Professor Mohammed Milad at New York University Grossman School of Medicine spoke of the impacts of the inequitable use of female animals on their research areas.

Dalla reviewed the targeting of the hypothalamic–pituitary–adrenal (HPA) axis using antidepressants. The HPA axis is a major neuroendocrine system that regulates responses to stress and many other bodily processes. Dysfunctions in the HPA axis have long thought to be a factor in the onset of depression, but drugs targeting this axis have roundly failed in clinical trials. Dalla proposed that this failure may partly be the result of pre-clinical studies using male animals, followed by clinical trials that often recruit more women than men. Bangasser and Milad respectively showed how responses to stress and fear also vary between male and female mice.

The Forum, held online for the first time, has extensively addressed the representation of women in the field in its program, opening with a Mini-Conference led by the Cajal Club that celebrated the impact of women in the development of neuroscience.

Psychiatric burden is not evenly balanced

The burden of mood disorders falls far more heavily on women than men. Depression and anxiety disorders are twice as prevalent in women, but in large swathes of pre-clinical brain research, female animals are a rarity. For every neuroscience study on female animals, there are five studies using males only.

The explanation historically given by researchers for this disparity has been the proposed “variability” of female animals due to their estrous cycle, which sees hormone levels fluctuate. That theory has been thrown into doubt by recent reviews, but cultural changes in science are often slow to take hold.

Efforts to correct for this imbalance have already begun. The US National Institutes of Health (NIH) has mandated both male and female animal subjects in all funded research projects since 2015. The process of bringing more female animals into research is, nevertheless, a balancing act. Whilst the influence of the estrous cycle may have been overblown in previous studies, male and female animals do differ at baseline and in their response to certain environmental factors, such as stress or administration of drugs. A serious consequence of the failure to include both sexes in pre-clinical research, says Bangasser, is that researchers simply don’t understand the neurobiology of female animals as well as they do males: “We need at the pre-clinical level to include females in our research and start to understand their biology, which […] has been largely ignored. so we can make sure that drugs work well for men and women.”

Sex differences behind the failure of clinical trials

The researchers are clear that they are not suggesting these differences be ignored, but rather that they be better understood. The impact of the estrous cycle on brain function is a clear example. Far from having a blanket effect on behavior as was once thought, the cycle’s influence will “depend on the circuit,” says Bangasser. “Where the field needs to go is we need to first look at males and females, importantly, and then, if there’s evidence that the estrous cycle plays a role from other papers, certainly consider that as a factor, but not let that dissuade us from studying females, period.”

Dalla proposes that changes across the clinical process are needed. She outlines an approach that would involve studying both male and female animals in pre-clinical studies. If sex differences are identified, the clinical research stage should reflect this by separating participants by sex and studying drugs’ effects on the groups independently. If no differences are seen, mixed-sex trial groups would be suitable.

The focus on male animals in preclinical studies has ultimately lead to a system that impacts both women and men, as drugs that are designed to be effective in male bodies then fail to pass female-majority clinical trials, whilst women rely on drugs and dosing regimens that may be metabolized differently by their bodies. Rates of adverse drug effects in women are higher than that seen in men. The impact of the failure by the field to address this earlier, in terms of cost and model animal lives, is likely to be immense.

Stamping out bias in research

So why has it taken so long to identify a factor that so greatly impacts medical research? Is it down to sexist bias at an institutional level in the field? The panel gives varying answers. “I really don’t think that there is an element of sexism in what we do in science. We are all in search for the truth, that’s what scientists, and science, is about,” says Milad. He says that the fault lies with communication issues between different disciplines within neuroscience that have led to these issues being ignored.

Bangasser’s view differs. “I think the focus on only using males and excluding females from basic research is influenced, in part, by sexism.” She identifies the assumption that females are complicated by their hormones and therefore not worthy of inclusion as an “exclusive tradition”, especially given that males have hormones that vary as well. “No one seemed to be bothered by that,” Bangasser points out.

“There is also the element of the subconscious bias,” says Dalla. “Even if, as scientists, we hope we are very good at what we are doing, still we might have some ideas or some theories that could influence our results or our experimental designs.”

But ultimately, the panel are hopeful that new innovations to take account of these biases, such as more careful blinding. can improve practices, experimental designs and ultimately lead to more objective and accurate science.

The movement towards ending male-exclusive pre-clinical research in gaining pace. A special issue of the European Journal of Neuroscience reviews the importance of including sex as a variable in neuroscience studies and Dalla, who edited the issue, commented, “If you end up making drugs that are suitable for only half the population and you do not even know about it, that is unethical. It’s a waste of money and resources.”