"There is a clear connection between changes in sex hormones in women and psychosis."

“I think it was quite early. I’m actually at the beginning of my career because I just finished my PhD. But I remember doing an internship with people with psychosis. Along with my PhD supervisor, we were working on a study looking at the role of selective estrogen receptor modulators—a type of drug that works similarly to estrogen—to see if they could improve the symptoms of psychosis. I remember the first time I heard about it, I thought, ‘That’s curious, why? Why would they do that? Why would they administer estrogen?’ That led me to investigate further how estrogen might have a protective effect on psychosis.”

I thought it was a very interesting approach and hypothesis because, obviously, I also have a personal awareness that hormones can have a big impact on how you feel as a woman—and perhaps as a man as well—but, as a woman, I had that experience myself. So I think that's what really drew me to investigate the impact of sex hormones, and specifically estrogen, on the cause of psychosis.

"Well, the first thing that interested me was the impact of hormones on the body and realizing that, since hormones have an impact on the whole body, they also have an impact on the brain. And then, as I delved deeper into that topic, I realized that not much is known about how psychosis affects women. The women with psychosis I've spoken to tell me, for example, that once they reach menopause , they have more symptoms. And that they can't really find a good way to resolve it, that changing medication doesn't work."

So I began to see that, on the one hand, we know the impact of estrogen and we say that estrogen is protective, which is good for women. But at the same time, we also see that we aren't providing them with treatment based on this knowledge. We really don't know what to do when estrogen declines. I've been able to see these effects, with severe episodes of psychosis in menopausal women, but also, in some cases, in women during their menstrual cycle.

How psychosis can alter the menstrual cycle

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"I think that, in general, we don't know enough about the female body and how to treat it. So the impact is twofold because it affects both general knowledge of the female body and mental health disorders."

It's a big problem. In the case of psychotic disorders, their early onset is more common in men, and most clinical trials with good results regarding the effectiveness of medications have been conducted with this group.

Most antipsychotics have been around for a long time and are still primarily tested on men. Although we now include women in clinical trials, these often focus only on women between the ages of 18 and 45. But the population of women over 50, who are much more prone to developing psychosis precisely because of the lack of estrogen, is excluded. Therefore, I think we are excluding not only women in general, but also a specific group of women over 50 who might respond differently .

The necessary gender perspective on psychosis

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"First, it's important to clarify that we shouldn't call estrogen 'female sex hormones.' It shouldn't be called that because men also have estrogen and women also have testosterone. It's simply that some are more predominant in one sex or the other: testosterone in men, and estrogen and progesterone in women."

Hormones are what we call "chemical messengers." They are present in the blood, can reach all organs, and have effects on all parts of the body. The same is true for progesterone and testosterone. As for estrogen , we know it has anti-inflammatory effects in the body. It reduces inflammation, and if we focus specifically on the brain, we know it can help decrease inflammation, but it can also influence gene transcription. In short, for healthy cell function, it could have neuroprotective effects . In the case of progesterone, we also know it has effects on the brain. These effects are less well-known, but the scientific community is now paying more attention to this area.

In the case of psychosis, the connection between estrogen and psychosis is clearer than with progesterone. This is also because most research has focused on estrogen and its neuroprotective effects, which are clearer for that hormone.

"The topics I will talk about are basically three:

• The protective effect of estrogen and what happens when estrogen levels decline. This could be due to menopause, but also to the use of certain medications. Part of the research I've conducted, which I'll be presenting, deals with what happens when estrogen levels are low in women and how this affects the progression and presentation of psychosis. Then there's a second, more detailed part, which focuses more on pharmacological treatment. What do we know about treating psychosis, and how might it differ between men and women? Are we administering the correct doses to women?
• What medications can have specific negative effects on women's health, but not on men's? Therefore, we will focus on treatments within the currently available options and a more thorough review of what we are currently doing and how we can improve it.
• And finally, based on the protective effect of estrogen and the consequences of its decline, and the gap in current antipsychotic treatments, what can we do? We're not doing well in this respect, so the third part will take a more positive tone about what we can do to improve treatment, for example, by increasing estrogen levels, but also by making adjustments to current treatment.

"We know the effects of estrogen, but we are not optimizing it enough ."

"My research so far has focused primarily on menopause, but also on the menstrual cycle and premenopausal women, and how estrogen levels can also be low in premenopausal women due to antipsychotic use. I won't be addressing the postpartum period in relation to psychosis at this conference, but it is clearly a relevant topic and, in fact, something I am researching."

Periods of low estrogen levels can also occur at different stages of a woman's life. We need to ask ourselves questions… For example, is a woman who has experienced an episode of postpartum psychosis more likely to develop a more severe episode during menopause? We don't know this connection scientifically, but we have observed it.

"Well, currently there are no specific treatment guidelines for each sex because there isn't enough research, but I think that, with the knowledge we already have, professionals could be more careful or more aware when prescribing to women. My field isn't clinical practice, but I have the feeling that menopause isn't usually considered to have such a significant impact ."

For example, if they are aware that a lower dose or specific adjustments might be needed, or if they should consider specific side effects that affect the menstrual cycle or menstrual health, and then choose one treatment over another. Women begin to experience a decline in estrogen levels around age 40 or 45. Healthcare professionals should be more aware of women's specific hormonal transition phase, as it could influence how they feel and the progression of their condition.

Although the end of their menstrual cycle shouldn't be a cause for concern for women, it's important that they are informed and able to discuss psychosis with their healthcare providers. Treatments that could help improve psychosis, for example, during menopause, include menopausal hormone therapy. I'm not saying it should replace antipsychotics, but it's a treatment with a long track record and is relatively safe. Therefore, it can already be used in clinical practice when treating a woman in menopause and adjusting the antipsychotic dosage isn't possible. Sometimes, when adjustments are needed, we have to think beyond antipsychotics.

"We conducted a study to investigate how to prevent increased prolactin levels , a common side effect of many antipsychotics . This hormone's primary function is to stimulate milk production in breastfeeding women. In women who have not given birth, it is typically at a low level. However, antipsychotics can increase prolactin production, even in men. By increasing prolactin production, estrogen production can be suppressed. Therefore, a common negative side effect of these medications is that they can cause menstrual dysfunction."

If estrogen levels are suppressed, the natural menstrual cycle, during which estrogen is supposed to fluctuate, is suppressed, silenced. This results in menstrual dysfunction and, for example, breast pain. It is also observed what influence this has on long-term problems such as infertility or osteoporosis.

In men it can have more generalized effects, but the effects in women are particularly harmful, since levels rise more easily (women already have higher levels of prolactin per se ), but they are also more sensitive to side effects.

Furthermore, we were interested in investigating whether these medications are associated with higher prolactin levels and lower estrogen levels, given that we know estrogen also has a neuroprotective effect on the brain. Do these women also experience a negative effect on the severity of their symptoms? This study was very specific and had a small sample size, so we really need more research on this. In any case, we found a negative correlation between symptoms. We discovered that the greater the severity of the symptoms, the lower the estrogen level.

" More studies, whether epidemiological or clinical, are needed to determine whether hormone therapy for menopause or other available estrogen-based treatments can improve health. "

This, of course, also applies to women with psychosis during menopause . I say this because we know that hormone therapy and other estrogen-based medications are already available. And I believe it would be an easily achievable goal. We conducted a cohort study in Finland where we demonstrated that hormone therapy for menopause was associated with a lower risk of developing psychosis during menopause. Therefore, I believe that, building on that work, further clinical studies would provide more evidence, if any exists.

Evidence that these therapies could be beneficial for these women might convince professionals to prescribe them. So it's a more clinical and more feasible goal.

On the other hand, we are trying to understand the mechanisms by which estrogen affects the risk of psychosis and perhaps other mental vulnerabilities , but specifically in the case of psychosis. We read a lot that estrogen is neuroprotective and that it might affect dopamine neurotransmission, and dopamine is the main neurotransmitter that is altered in psychosis, but we don't really understand how it works or whether it might also act through other neurotransmitters. Therefore, it is crucial to understand what happens, what factors influence it... If we know this, perhaps we can also better understand how we can intervene or how we can prevent this increased vulnerability.

"To achieve true gender equality in the care of psychosis, it is necessary to offer a differentiated approach for men and women. It is not enough to treat them in the same way as men; we must recognize and take advantage, in the case of women, of the protective role of their endogenous estrogen production ."