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Tom: I have a background in communicating women’s health, and for me it’s always surprising to understand that so many drugs are not really tested on women.
Christina: I’m a pharmacist by training, but I have had a lot of influence from endocrinologists and from psychoneuroendocrinology, and I’m trying to integrate hormonal effect into my work; particularly in women, but also in men, it’s not only women who have hormones!

In clinical practice there is now more discussion about the influence of gender, but this is also true of preclinical research. This has increased since I did my PhD, around 20 years ago. Now there’s more awareness, especially in the States.

Why has this there been this delay? It seems obvious to me that you should be looking at the affected groups? Especially with psychiatric drugs.
Women have been included in clinical studies since 1993*^{See note below}. But despite this, there has been a lack of analysis based on sex. Depression is more common in women, so in fact it is easier to enrol women than men. The problem is that most preclinical research, mostly in mice, was largely carried out in male animals. And then the drug analysis was seldom broken down by sex, so we didn’t have any information on whether a drug was effective only in men or only in women. And to me the biggest problem arose from the mismatch between pre-clinical and clinical studies. I think that often the reason for this may simply have been ignorance. Many researchers were worried that studies in females would be more variable than studies in males, and some still tell me that they don’t know how to do studies in female animals. I get researchers who ask me to help with designing studies which take account of the oestrous cycle. It’s not so complex, but people have the impression that using females means we’d need to use more animals in research, and that using males would be simpler, easier… and so the female animals are ignored. But this is changing, there are new meta-analysis showing that the female rodent behaviour is not more variable than the male, even when we consider the hormonal cycle. Many tend to forget, for example, that mice also have testosterone, and are prone to form hierarchies and dominances. But we need to make sure we convince people of this necessity, at many different levels, funders, pharmaceutical companies, academia, researchers, etc.

I was familiar with this because it was my research. I think this was true for most people working in endocrinology. Other researchers probably felt it wasn’t important. Animal research can also be expensive, and this was a way of containing the costs. I think that we may have lost some important molecules because of this gender blindness. We may have saved money in the short term, but the final cost was much more. There’s also an ethical aspect. If we only experiment on half of the animals we breed, that gives us an ethical problem. In cases like this we are breeding animals simply to kill them.

Some drugs may not have been developed, but are there any drugs which are now being revisited with a more balanced view on gender difference?
We have recently written a detailed review on CRF antagonists. They affect the HPA-axis, and were very promising for depression, and other indications, especially in preclinical research in males, but then they all failed in clinical trials. Around 80% of the clinical trial participants were women. Now we are collaborating with some labs in the US, which are more aware of the sex differences. It may be that these drugs will be useful for men who have dysregulation of the HPA axis, or for other patients with stress-induced disorders. There’s also a lot of research being done on sex differences in pain research and many other areas.

I find it interesting that you work on aromatase inhibitors.
I started work with aromatase knockout mice a long time ago. When I started my own lab, I wanted to see if we could look at more targeted effects. We had seen epidemiological signs that aromatase inhibitors had effects on mood and cognition.

We are about to look at the GPR1 receptor, which is an oestrogen membrane receptor, and is responsible for the hormone’s rapid effect, and we think that this may be a target for depression treatment. It’s interesting that oestrogen is also found in male brains; it’s no longer considered a “female hormone”. So maybe by manipulating this receptor we can produce a therapeutic effect. We’re looking at depression and anxiety, but we don’t rule out an influence on other disorders.

I see that you are a consultant for the European Union’s Ethics and Research Integrity Unit. What can you tell me about that?
In the last three years I’ve had training to evaluate ethical aspects of research. This is mostly about animal welfare, but it also touches on clinical trial, personal data, etc. We’re all aware of the need to consider the ‘3 Rs’ – Replacement, Reduction and Refinement – in animal research. Animal welfare is often a balance, and we need to look in the long term. For example, sometimes reducing the number of animals in an experiment means that the results need to be confirmed multiple times, which can lead to using a greater number of animals in the long term.

I’m a member of the ECNP Preclinical Data Forum Network, and there are a couple of things which spring to mind as important. We certainly need to investigate both male and female animals and patients, but we need to make sure that we take account of our preconceptions in designing the research projects. There can be a sort of implicit bias in some research, so we need to question our ideas in designing experiments.

It seems to me that a lot of your career has been devoted to improving the way we do research.
Yes, I think that’s true. We’ve focused on female subjects being included in research, but we also need to look at how we can make research itself more inclusive, how can we include more women and diverse groups in research? In the past, research was largely conducted ‘by men, for men’, but we need more of a gender balance, both in terms of research subjects and researchers. This is improving, especially in the US. It’s improving in Europe too, but we can do more.

I’m in favour of making some efforts to include women in committees, research boards, and so on. This also applies to minority groups, such as racial minorities. It’s not a perfect way to do things, and I know that a lot of people would disagree, but I feel it would be a step in the right direction. We also need to make sure that we listen to the voices of patients, to understand what they and their caregivers get out of the treatment.

You are the president-elect of the Mediterranean Neuroscience Society.
I’m very happy about this position. The Society deals with the whole of the Mediterranean, including the countries in the Southern and Eastern Mediterranean, which are too often forgotten. It’s very important to create opportunities for researchers from North Africa. We’re currently organising conferences in Croatia and then in Egypt. I like the Society a lot because of the diversity; you can always learn something, and you can get a different perspective.

Symposium
S.02 Beyond neurosexism: sex and gender as crucial biological variables in brain disorders

Saturday 2 October 2021

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