Facebook Live Event: The Menopause Transition and Depression

Transcript

PETER SCHMIDT: Welcome, everyone, and thank you for joining us today. I am Peter Schmidt. I'm a research physician in the section of behavioral endocrinology within the National Institute of Mental Health's intramural research program. Our lab focuses on mood disorders that occur during periods of reproductive hormone change, and in particular, we focus on questions of how reproductive hormones can trigger mood disorders. We try to understand why reproductive hormones would trigger mood disorders in only some women, whereas the same hormonal exposure has no effect in the majority of women. Finally, we also try to understand how or whether a better understanding of the underlying cause of these mood disorders can translate into alternative therapies that would be effective in women. Today, we're going to be focusing on depression that occurs during the menopause transition. I'm joined by two members of our lab. Dr. Sarah Rudzinskas, who is a molecular biologist and in collaboration with Dr. David Goldman at another institute, the National Institute of Alcohol Abuse and Alcoholism. She studies the underlying biology, at a cellular level, of mood disorders during the menopause transition. The second person is Sarah Spector, who is a nurse practitioner who has accumulated a wide expertise in women's health, both in the setting of a reproductive endocrine clinic for women, as well, most recently, in a behavioral health clinic for women. Sarah takes the lead on many of our studies examining mood disorders that are occurring during periods of reproductive endocrinology. So thank you both for joining us today.

SARAH RUDZINSKAS: Yeah, happy to be here. Thank you.

SARAH SPECTOR: Yes, thank you for having us.

PETER SCHMIDT: Great. Thanks for joining. So as I mentioned earlier, during the next half hour together, we'll discuss mood disorders linked to the perimenopause, or also called the menopause transition, and we will describe some of the signs and symptoms of depression during the menopause transition, we'll discuss the biology of the menopause transition, as well as some ongoing and recent research that we have performed in our research section. We'll also take maybe the last 5 to 10 minutes of this session to answer specific questions. Now, just on a program note, we're not able to answer specific questions on an individual basis about health-related issues, but you certainly can provide questions to us. And as well, if you're looking for-- you should be discussing these things with your own healthcare provider. And if you're in search of someone with that expertise, I would recommend that you go to visit the website sponsored by the NIMH. It is nimh.nih.gov/findhelp. If you know or if you or someone are in crisis, please call the National Suicide Prevention Lifeline  at 1800-273-TALK, T-A-L-K or 8255.

So let's begin. As we talked about, depression is-- or we will talk about, depression is a very important condition. It is one of the leading causes of disease-related disability worldwide. And that's measured by the number of days that someone with depression may not be able to work or experience some disability at work or in their personal relations and other personal life. In addition to being a leading cause of disability, it costs the US healthcare system millions of dollars both in terms of loss of work but also in terms of ongoing treatment. And not only is the pain of depression related to emotional pain that in some people is severe enough to lead them to try to take their life to end the pain, but it has also been established that it's associated with an increased risk for several medical conditions, including cardiovascular disease, metabolic syndrome, including insulin intolerance. So it is very important as a clinically relevant condition.

Now, depression affects many aspects of a person's brain function and their behavior. It impacts on a wide range of experiences that we have, including our memory, our ability to concentrate, and our attention span. It also impacts on how you feel about yourself, your self-worth. As well on the ability to enjoy certain events. So it impacts on the reward system that we have. And these all come to play in a persistent manner. So one of the features of depression is an inability to change mood state. So all of us may feel sad at some point or down in the dumps, and we'll try to do something that will make ourselves feel better. Whether it's going to the gym, work out, or having dinner with friends, or even talking to a close relationship. In depression, those abilities are dampened if not prevented, and so the negative mood state becomes persistent and starts snowballing in terms of its impact on your day-to-day life. In addition to affecting mood symptoms and cognition, depression will affect many behaviors, including sleep disturbance, appetite changes, as well as energy level. So it has wide-reaching impacts on those people. It's generally under-diagnosed and therefore under-treated. There is a sex difference, where women, really, worldwide demonstrate about a twofold increased risk of depression over their life history. Depression can manifest in several different ways and there may be different subtypes, even though the symptoms kind of overlap and are similar.

And today's focus of this Facebook live session will be on those depressions that occur during the menopause transition. The idea is that if these subgroups have different underlying causes or biologies, that they may then lead us to better identification of the risks in individual women but also the development of alternative therapies. So with that background, I wanted to lead it to Sarah Spector who is going to talk about some of the biology of the menopause transition in some of our studies.

SARAH SPECTOR: Yeah, so as Dr. Schmidt mentioned, perimenopause is the transition into menopause. It's a normal phase in women's life that can sometimes be challenging. Perimenopause is associated with ovarian aging, and the average age of menopause is 51. But that being said, there's tremendous variation in the onset of menopause age, let alone in the transition into menopause, which in some women can last 10 to 15 years. The range varies widely on an individual basis. So what does this look like? Signs of the transition that we see: menstrual irregularities, heavier periods, skipped periods, fewer ovulatory cycles. Up to 70% of women will experience hot flushes, possible vaginal dryness. The majority of women do not develop depression as they go through the transition. However, large community-based studies have identified increased risk for re-occurrence of depression, and most importantly, first onset of depression during this time in a woman's life. And as many as 10 to 20 percent of women will be affected by or may be affected by depression during this stage of their life.

We use the term depression as a categorical description, but many women, in addition to profound sadness, they experience irritability, anxiety, excessive worrying, tearfulness, loss of interest, or inability to enjoy things in their life. But regardless of the mosaic of symptoms with which these women present, what's consistent is that there's a persistent change in how they feel relative to how they felt four to five years before the perimenopause. And that impacts their ability to work, their family relationships, their ability to interact with others, and that's persistent. So it's that persistence and the disability with which we define the condition. And so our studies focus on this type of depression related to menopause.

PETER SCHMIDT: Thank you, Sarah. So an interesting recent study from the Center of Disease Control in the United States have identified that women at midlife, in their 40s, 50s, and 60s have experienced an increase and a much greater rate of being prescribed antidepressants compared with men and compared with previous years. Now, this may reflect a very effective messaging program that several, including the NIMH, have implemented over the years. Others have suggested that, in addition, it may suggest that, over the same period of time, because of results related to the side effects and the medical concerns about prescribing a woman hormone therapy, the increased rate of antidepressant use in this age group may reflect or parallel a decline, so a decrease, in prescriptions for hormone therapy. So that has led us to focus on some of the relationships between hormone therapy, in particular estrogen therapy, and perimenopausal depression. And Dr. Rudzinskas will provide you with some summary of some of the ongoing studies that we're focusing on in this area. Sarah?

SARAH RUDZINSKAS: Yeah, thank you, Dr. Schmidt. So first, I'd like to emphasize just a really critical point about the biology that we know today, and that is that many studies have demonstrated that there seems to be no abnormality in any of the core peripheral hormones that seems to distinguish a woman with perimenopausal depression from a woman without. And so this means there's no evidence that there's some imbalance of estrogen or progesterone, and there's also no evidence that there's any major deficiency. But what we do see clinically is that many perimenopausal women report this tremendous fatality, this restoration of their mood when they're given estrogen-based hormone therapies. So previously, Dr. Schmidt and others have tested these reports clinically. So the study that was done in 2015 showed that post-menopausal women who had perimenopausal depression compared to those who had never had depression-- so either in perimenopause or at other times in life. All these women were given estrogen. And after three weeks of estrogen, women were then switched to a placebo pill that contained no hormones for the final three weeks. And so women were reporting their mood symptoms throughout this entire six-week study. And what was demonstrated was that during the three weeks that estrogen was removed or withdrawn, women who had past perimenopausal depression reported a return of their mood and anxiety symptoms. But importantly, women who had never experienced perimenopausal depression, even though they underwent the same estrogen withdrawal, this estrogen removal did not see a significant change in their mood. And so what this study really did is it provides some of the first clinical evidence that this decline or this withdrawal of estradiol that occurs during perimenopause may play some direct role in triggering depression symptoms.

And so it's that characteristic of estrogen that we're exploring now in our studies. And we're doing this in primarily two ways. So the first avenue of research that I'm more heavily involved in has been in collaboration with Dr. David Goldman, a neurogeneticist at the NIAAA. And so what these studies are doing is understanding whether there is the potential for a genetic basis as to why some women seem to experience depression from these changes in estrogen while some women don't. And so far, these studies have demonstrated that when you take cells from women with past perimenopausal depression compared to without, there seems to be this increased production of pro-inflammatory chemokines. And these are some of the same small molecules that have been linked to heart problems and stroke. And more interestingly, when you look at these cells and you add estrogen, you take it away, similarly to what was done in that clinic clinical study, these pro-inflammatory chemokines increase even more, but only in the women who have past perimenopausal depression. So what this is suggesting is that the lab work, the biology, it's adding up and it's matching the clinical findings. So essentially, what we are taking away from this is that some of these increased production of chemokines and some of this biology we're seeing may reflect some of the original findings of the Women's Health Initiative that showed the 50% increase in the risk for heart disease and stroke in women who had had even a minor episode of perimenopausal depression.

And the second major avenue of research has been clinically, and that's the estrogen receptor beta study. Sarah and Dr. Schmidt are going to tell you more about this, but essentially, estrogen, we think of it as a reproductive hormone, but it's also a major driver of neural activity in your brain. And the way it drives neural activity is primarily through two receptors: estrogen receptor alpha and estrogen receptor beta. So estrogen receptor alpha is found in the breasts, in the uterine lining, and in your brain. But estrogen receptor beta seems to be mostly concentrated in the brain and mostly concentrated in the regions that seem to be involved in mood and anxiety in preclinical studies. And so what we're wondering is, if we were to target specifically just the estrogen receptor beta with a compound like what we're using clinically, if we could help alleviate symptoms of perimenopausal depression without some of the side effects or some of the worries of hormone therapy. And so the hope is that someday, if these clinical studies check out, that this could be an alternative to hormone therapy for mood symptoms. But Sarah is going to tell you a little bit more about that.

SARAH SPECTOR: Yeah. So thank you, Sarah. So in this current study, we're using our previous estrogen withdrawal study design with the estrogen receptor beta compound. So all women are given estradiol to start, but then switch to either placebo or varying levels of the estrogen receptor beta compound to see if activating the estrogen receptor beta prevents recurrence of depression symptoms without the potential long-term side effects of traditional hormone therapy. Even though we're all blind to which medications women have been assigned to, either the placebo or the estrogen receptor beta compound, we're certainly seeing some women so far who have developed a full recurrence of their symptoms. So this is consistent with our initial estrogen withdrawal study and we're hoping means that they're on the placebo. But we're also finding some women who are feeling well-balanced, even-keeled, stable, with no recurrence of their mood symptoms. Some with hot flushes, some without. And we don't know for sure, but we're hopeful that in a year or so from now, when we've completed the study, that we'll see that these women have responded well to the estrogen receptor beta compound. So ideally, if this medication works, it would be great as an alternative to estrogen therapy for those who can't tolerate side effects or aren't able to be on estrogen due to medical history, or it could potentially be an alternative to antidepressant therapy for people with mood symptoms.

PETER SCHMIDT: Okay. Thank you both for providing us with that background and update. Maybe just as an aside, one of the concerns related to estrogen therapy that has come out maybe 20 years ago-- actually, exactly 20 years ago. And this was a study sponsored by the NIH. It was called the Women's Health Initiative Study, and it included a large number of women, over 300 women. And about half of them were placed on estrogen therapy, half of them were placed on placebo. Now, the age of these women was average of 65. So these were largely a group of older women who are post-menopause. So as Sarah Spector had mentioned, they would be up to 10 to 15 years after their last menstrual period. So they are not perimenopausal. They're postmenopausal women. And the estrogen therapy compared with the placebo treatment was associated with several important side effects, including an increased risk of breast cancer, which was anticipated, but also an increase, not a decreased, risk in heart disease, and an increased risk in clotting abnormalities that probably impacted and reflected an increased risk of all-cause dementia. So these were unique and remarkable and important findings because they suggested, in contrast to what we had previously thought, that in these women, estrogen therapy was associated with an overall negative effect on health outcomes.

Now, recently, there has been some review of these data, and I think the pendulum is somewhat swinging. Because maybe there is some evidence that in the younger perimenopausal women - so the women that we're referring to today, age 50s, late 40s - who have symptoms-- because only about 10% of the women in the Women's Health Initiative reported symptoms, and only that small group was included in the study. That these younger women, that hormone therapy or estrogen may have a very different effect both on improving symptoms, so kind of the efficacy as a treatment, but also a different long-term safety profile. So these are facts that are being explored. And certainly on an individual woman's basis, it's a conversation that you should either repeat with your care providers or seek out a possible treatment if you are experiencing these symptoms. So Sarah--

SARAH SPECTOR: Yeah, so just to concur with what you're saying and summarize, I think we're not saying that estrogen therapy is safe for everybody, but the world is changing and there are studies that are showing that estrogen may have better outcomes and be beneficial in a younger menopausal or perimenopausal woman with depressive mood symptoms. So if you have mood symptoms in menopause or antidepressants aren't working for you, it may be time to ask your provider about other options or any of your options. And as we already know, with treating psychiatric disorders, there's no one-size-fits-all treatment for everyone, so.

PETER SCHMIDT: Okay. So I think that kind of wraps up our talking, and maybe we can pause for the next few minutes to take some questions if they are-- yeah, so one question that's come up is what about suicide risk? And I had mentioned that in depression itself, because of the level of pain that people are experiencing, that-- and many people will try a range of activities to reduce the pain, but in some unfortunate and tragic situations, they have exhausted all possibilities and, really, ending one's life becomes their hope and leads to the tragedy of suicide. We don't know of the actual number of women with perimenopausal depression that would either feel in so much pain that they would consider taking their life or those who actually do take their life. There's no reason to believe that it would be different from depressions occurring at other times. The studies using large, community-based samples of women and men suggest that at midlife, in this age range, in both men and women, there has been an increase in suicidality. And so this is something that NIMH in particular is very much focused on, both in funding grants nationwide, but also within the intramural program. So this is a huge tragedy and it is a very important public health issue that is being taken very seriously.

So another question. Sarah Spector, do you want to tackle the other question about how kind of significant others can help in this situation?

SARAH SPECTOR: Yeah, absolutely. So I think there's a few ways, definitely. One, I think validating their experience as being real. I think a lot of times even the women themselves who are going through this tend to kind of brush it off as just the status quo, getting older. And we've established here that there is a biological basis for what these women are going through and some of the symptoms that they experience are very distressing. So definitely validating that their experience is real. And then I think advocating for them, with them-- I think I've seen a few times in-clinic where patients come in or women come in and their significant other acknowledged to them, "Hey, something isn't right. You don't seem like yourself." And sometimes it takes someone else mirroring or acknowledging that to you to understand really how severe it is. Because as we've discussed, there's a mosaic of symptoms, and it can happen gradually. And I think advocating for your significant other to receive or ask for help in these situations is really helpful.

PETER SCHMIDT: Yeah, just as an addendum to that, there's two issues that we face in the clinic when women present. One is that, frequently, both the women, their family members, and their doctors see that this is something that-- depression, irritability, persistent anxiety, excessive worry, excessive tearfulness; that these symptoms may be a natural and normal experience in the menopause transition. Now, truth be told, the studies suggest, as we talked about, that that's not really the case and that the majority of women go through the perimenopause without any negative mood symptoms. So that's the first kind of flag. And if you're experiencing persistent symptoms, the second problem, actually, is that, in many cases, these symptoms are insidious and they happen slowly. So it's often not until we ask the women, "How do you feel relative to, say, five years ago?" that they will start establishing in their own mind that they've experienced a change in terms of either their productivity, their relationships with others. And so those are kind of cues that it may be time to talk to your provider and see what can be done. Both talking therapy and antidepressant therapy are shown to be effective in depression and they would be optional options for you as well. Or you can speak to your gynecologist.

So I think there's one last question. That's a very good question. The current recommendations-- and I'm not a gynecologist, so this will be something you should talk to your healthcare provider about. But the current thinking, which has largely been influenced by the recent Women's Health Initiative finding, is that estrogen should be taken for the shortest period of time and at the lowest dose. Now, that is switching. Many women have elected to stay on hormone or estrogen therapy because of its effect on symptoms. Others find that they can take estrogen for several months or several years around the perimenopause and around the last menstrual period, and then stop it effectively and not having a recurrence of symptoms. So these are questions that are really important, and on an individual woman's basis, it's a conversation you should have with your gynecologist if you are on estrogen therapy. But as we've said a couple of times - I don't mean to trivialize this - this is a decision on an individual woman's basis with her care providers.

So yes. And Sarah, maybe do you want to talk about some of your work and some of our other studies? Our longitudinal study, which is just being finished, that gets on that topic?

SARAH RUDZINSKAS: Sure, I could touch on this briefly. So the question is whether there's additional research being performed on the relationship between inflammation and depression. And then this question says specifically in menopausal women. So I can say wholeheartedly that there is a massive, massive tier of research going on right now with depression, inflammation more generally. And it seems very likely that the two are correlated, that there's brain chemistry that is altered in a way that shows increased inflammation in most cases. That does seem to correlate with depression symptoms in both men and women. Now, for perimenopausal depression specifically, I'd say this is some of the first research that's really getting at that specific biology. So with my studies, we've looked in cells, but as Dr. Schmidt just alluded to, we're actually doing a larger and longitudinal study clinically where we can look at women as they progress through the entire perimenopause, so pre, peri, and post. And what that's going to allow us to do is look at levels of these circulating inflammatory factors over time. And that will really help us get at some questions of cause and effect. Because I don't know if the research is quite there yet. But it's a really excellent question and we are certainly following up on it.

PETER SCHMIDT: Yes, I think one of the problems is the inflammatory system is an extremely complicated physiology and we're not sure whether the inflammation changes that we see and that others have seen represent compensation for some other, more fundamental change in biology, or whether it's the inflammation itself that is triggering the depression. So that awaits. But there's a lot of focus, as Sarah said. Now, we've run out of time. We'd love to stay longer, but we are limited. There is a couple of other questions that are still on the board, but we will get back to you with questions about that. Yes, there are some other treatment options that we can discuss. We'll get back to you about that.

PETER SCHMIDT: So to end the program, once again, reminder that if you have remaining questions, please send them in to us and we'll do our best to get back to you. Thank you all for joining us and to discuss this important topic. Please use the help website that I mentioned at the beginning of the broadcast. And we can send that link to you if you didn't get it. And as a reminder, if you know somebody or if you yourself are in crisis, please contact the National Suicide Prevention Lifeline that's posted in the comments. There's a 1800 number, 273-TALK, that's 273-8255. Now, finally, for more information on our studies, if you're interested in participating or just want to tell a friend, or for other studies at the NIMH that are focusing on depression and other conditions, please visit our website, which is www.nimh.nih.gov-- so that's www.nimh.nih.gov/joinastudy. So J-O-I-N-A-S-T-U-D-Y. So I want to thank you on all of our behalf for joining us, and we hope that this has been of some help to you. And again, if there are any further questions, don't hesitate to contact us.