ECNP Congress programme spotlight
Hormonal contraception and depression

Vibe Frokjaer is associate professor at the Department of Neurology and the Neurobiology Research Unit at the Copenhagen University Hospital, Rigshospitalet, and the Mental Health Services in the Capital Region of Denmark. Vibe’s scientific focus is the brain architecture of risk for neuropsychiatric disorders, in particular mood disorders. She runs an independent line in psychoneuroendocrinology. At the 36th ECNP Congress in Barcelona she will chair a session on ‘Hormonal contraceptives, brain function, and depression’. Here she speaks about the session to ECNP Press Officer, Tom Parkhill.

TP: You are chairing the session ‘Hormonal contraceptives, brain function and depression’ in Barcelona on Sunday 8 October. I used to work for a couple of organisations in endocrinology and fertility, so this is something I find personally interesting. It’s also important because of the huge number of women who regularly take oral contraceptives. According to the WHO, in 2019, approximately 1.1 billion women of reproductive age were in need of family planning services worldwide, with almost 50% of those women using various hormonal contraceptive methods (the rate of use is higher in Europe and North America). What’s the background to this session, where does your interest come from?
VF: I have been interested in finding ways to understand mechanisms affecting risk and resilience and how these impact chances of developing depressive episodes. There is a lot of evidence showing associations between sex hormone transitions and depressive symptoms and it is therefore potentially important to understand how the brain integrates steroid hormone information and if it matters for risk and robustness mechanisms. Specifically, there is a body of epidemiological work showing an increased risk for depression in women of reproductive age, in comparison to men. This is particularly true in phases of female life where we undergo quite dramatic changes in the sex hormone environment. This is where my interest arose, and looking for evidence meant working with naturally existing models where we can contrast some of these effects and that meant using large datasets, comparing women who use oral contraceptives with women who do not. This is a good opportunity to see if we can follow any brain biology or brain molecular links between users or non-users. There are now a few groups studying this, and it does now seem that a sub-group of women might be quite sensitive to these hormonal shifts. In terms of precision psychiatry, it would be helpful to understand who these women are who have more risk contribution from hormonal sensitivity. If we can understand that better, then maybe we can better target some of our preventive strategies and treatments according to reproductive states. At the same time, I also work with groups of women who are at high risk for developing perinatal depression and with pharmacological risk models in healthy individuals, where we have worked at manipulating the sex hormone environment with existing drugs which are used for reproductive care or infertility treatment.

I always find it instructive how sometimes medicine falls into silos. As I said, I used to work in fertility, perhaps 20 years ago, and the fertility specialists were very concerned at how these silos could box in someone’s life. A young woman might go into hospital for a cancer operation; the oncologists naturally tended to concentrate on the cancer, and zapping it with X-rays offered a cure. But they didn’t much consider how this treatment might affect that young woman if she wanted to have a baby. Do we see anything similar in this case? Are family doctors and reproductive specialists aware enough about mental health issues. And what’s the scale of the problem?
The scale is pretty large. We have a big public health problem, with depression on the rise. The WHO has pointed to depression as a major contributor to the global health burden. We need to identify and understand what options there are for preventing depressive episodes. Many young women are put on oral contraceptives on their doctor’s advice – or by their own wish – without sufficient information. There may be some room for improvement there. We do see women who get depressed after taking an oral contraceptive, and if that happens, we need to get them off as quickly as possible, we need to find alternative modes of contraception for them. We also need to understand if this risk is increased depending on when you start taking oral contraceptives. Does it matter if this disruption of the HPG axis starts before puberty, right at puberty, or further on into adulthood? There is some epidemiological evidence that it actually does matter. The younger the brain you have, the higher the risk of disruption, but we know too little about this. So maybe we should be looking to postpone when women begin taking oral contraceptive. You may not be aware, but a lot of young women are prescribed hormonal contraceptive without being sexually active. Hormonal contraceptives are, for example, prescribed for skin problems and pain with menstruation. These are certainly worth treating, but they can be treated with other strategies, if needed. Even just considering that proportion of women, maybe we can improve their quality of life, help them avoid developing depression.

At the same time, we need to make sure that we don’t scare women unnecessarily. We know that there are very strong benefits to having good access to reliable contraception, but it’s not candy, it does have brain effects at least for some women. If we can identify a smaller group of women who do not tolerate this as well as others, we would be better off counselling on the use of contraceptives. I sometimes meet what I think is relevant resistance: people mention the importance of avoiding unwanted pregnancies, prioritising sexual health and female rights, and I completely agree. But nevertheless, if some don’t tolerate a drug very well, we should be able to recognise this, and advise them on other strategies. So we need to think about how we communicate this.

You also asked me if it is a big problem. There are a lot of women using oral contraceptives. In Scandinavian countries it’s about half of women of childbearing age. Likewise, around half of women who get depressed some time in their life also are on hormonal contraceptives – even though their depression does not seem to be caused by oral contraceptives since they had been using it for a long time before becoming depressed. Therefore, another thing to consider is how we can best treat a depressive episode, depending on whether you are on a hormonal contraceptive or not. That’s a question which we will not directly address in the symposium, but it’s super important. One reason we did this symposium is that there have been some discrepant results in register-based conclusions. In the Danish register work the conclusion is that there is indeed an increased risk of developing a depressive episode across all hormonal contraceptions. But there were some Swedish studies, performed in slightly different ways, which questioned whether this link was real or not. We want this to be discussed in some depth at the ECNP session. And then we also want to touch on the translational work – can we understand the mechanisms?

You are right, you don’t want to scare women away from taking contraceptives. I’m reminded of the Women’s Health Initiative which came out 20 years ago, which showed some of the problems associated with taking menopausal hormone therapy, but didn’t offer women much in the way of alternatives; it gave them nowhere to go. And this resulted in women gradually edging back to take hormone therapy and feeling guilty about it. 
That’s the same dilemma as here. The message should be that not everyone is sensitive to this higher risk of developing depression after starting a hormonal contraceptive. But that doesn’t mean that we can’t inform those who are at risk. We need to be able to embrace this complexity. I think our patients can deal with this, our patients are smarter than we sometimes give them credit. We don’t want to be overprotective in terms of giving patients information, even though the information may not be so simple. And, of course, if people understand the issues, it becomes easier for them to accept that they need to change track and react or seek advice if they find they have problems.

I don’t know if you are aware of a JAMA psychiatry paper we published, where we looked at the whole concept of a subgroup of women where hormonal contributions matter more for their risk of developing a depressive episode than in other women. What we see in that paper is an overlap between women who have had a depressive episode following initiation of oral contraception and women who later develop a perinatal depressive episode. So it seems as if there are similar biologies popping up in different phases of reproductive life. We are not saying that hormonal contraceptive leads to a later depressive episode, we are wondering more if it unmasks a tendency. And again, we need to be careful in communicating these things. We all want to find ways to stratify depressive episodes and facilitate precision psychiatry, and one way may be to say that there are groups where the hormone contributions matter more than others. And these women may need different types of prevention and treatment.

There are different types of contraceptive pills. Have the registries been able to pick out which types carry a greater association with subsequent depression?
No, but it’s not only the pill, it’s also intra-uterine devices or contraceptive methods containing hormones. So maybe we should be thinking about any hormonal contraceptive. We also need to understand – along the lines of providing alternative contraceptives – whether there are any dosage or type of synthetic hormone effects. Is it safer to take a low dose or a higher dose contraceptive? We don’t have enough data on that yet. But these are relevant questions, since we need to be able to provide advice on alternative contraceptive methods if someone has some bad side-effects. This I think is quite urgent, and very important. We hope that this symposium will be able to support the momentum needed to keep this work moving forward, to support the networks working on this. If we are going to understand more and to develop targeted prevention strategies and treatments, we need to stay curious about these mechanisms.

Vibe Frokjaer, Denmark, will chair the session S07 — Hormonal contraceptives, brain function and depression on Sunday 8 October 2023 at 11.15-12.35 CEST (Central European Summer Time).

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