7.5 Menopausal Psychosis and Hormone Therapy: Impact of Transitional Periods in Schizophrenia, Bipolar

[00:00:00] In this segment, Dr. Wood and I discuss hormonal transition periods in bipolar and schizophrenic females.

[00:00:08] First, we question what we were both taught in medical school and residency

[00:00:13] that there is a magical second peak of schizophrenia and bipolar disorder in females.

[00:00:20] Then we delve into several studies on hormonal transition periods in bipolar disorder females.

[00:00:27] Explore the relationship to postpartum symptoms.

[00:00:30] Then review several studies on hormonal transition periods in schizophrenic women.

[00:00:35] And finally, discuss whether there may be a role for prophylaxis in our patients

[00:00:41] as they go through hormonal transition periods. Hope you enjoy.

[00:00:48] Somebody get this guy some help!

[00:00:58] I wanted to talk a little bit about schizophrenia and bipolar disorder

[00:01:03] and transition periods in females, how that affects their symptoms.

[00:01:09] Probably the most common sense and most supportive pieces of evidence

[00:01:15] for the role of hormones in psychotic conditions. Both bipolar and schizophrenia,

[00:01:22] there's a big difference in the age of onset of the first episode.

[00:01:27] So the average age for men, the onset was 22 years old, whether it be bipolar or schizophrenia

[00:01:33] and the average age for women was 27 years old. That's a pretty significant difference

[00:01:41] when you're talking about conditions that have a lot of overlap otherwise.

[00:01:46] I've always kind of questioned the validity of this second peak of schizophrenia and bipolar

[00:01:53] disorder in females. People go through puberty and then all the sudden psychiatric disorders

[00:02:00] start to manifest, but in women it's later which just so happens to correspond with the fact that

[00:02:07] they start to produce a lot more estrogen and progesterone on a regular cyclical basis.

[00:02:14] So not only does it look like that pushes back the onset of severe psychiatric illnesses,

[00:02:23] but also they have this second peak when they lose that protective factor which is generally

[00:02:30] around 45 to 55. The same period of time that women go through menopause.

[00:02:36] So do you think that there is a real second primary peak of these illnesses or do you think that

[00:02:43] it's more of an organic cause of that second peak?

[00:02:47] Yeah, and the traditional teaching is that women also have this magical second peak and there was

[00:02:53] no real explanation for it but look out for it in your patients towards paramanopausal years

[00:02:59] in their 50s. Again, it's a little unclear if that's true or what that's related to,

[00:03:05] but that is something that's traditionally taught. I think it's been cited in literature before

[00:03:10] and also women with pre-existing schizophrenia have been found in multiple studies to have an

[00:03:16] increase in illness severity in midlife as well. And you really do not see either of those two

[00:03:23] patterns in men, that is something that has been pretty consistent in the literature.

[00:03:28] There's kind of a discrete pattern that really correlates with a lot of the hormone

[00:03:32] changes that we're seeing specifically the estrogen changes. And we do know that estrogen is

[00:03:37] actually neuroprotective in many different ways whether that's modulating inflammation pathways

[00:03:42] or working on various neurotransmitters and it really seems to have lots of downstream effects

[00:03:47] on things like serotonin, dopamine, GABA, NMDA. Lots of things that it seems like estrogen is

[00:03:54] protective with. So yes, there's a very strong argument to be made there for that second peak

[00:04:00] not being a primary type of schizophrenia but really more of a biologic entity.

[00:04:06] Yeah. And we know that estrogen has neuroprotective effects, we know that it's

[00:04:11] implicated in our ability to remember things and have adequate cognition. And that is something

[00:04:17] in schizophrenia that we see women tend to have more preserved cognition with their schizophrenia

[00:04:25] presentation versus men have generally more severe cognitive symptoms and negative symptoms.

[00:04:33] Is that because of some protective effect of estrogen? Men have estrogen as well, we do.

[00:04:42] But our hormones change so much more gradually throughout the course of our lives.

[00:04:47] Puberty is I wouldn't say it's too dissimilar in terms of our testosterone response but that drops off

[00:04:55] more linearly as we age versus falling off a cliff with menopause and females

[00:05:02] and to add to what you said in terms of the first episode of psychosis happening after the age of 40

[00:05:11] there's more than a two to one female to male ratio of people who are diagnosed with either one

[00:05:20] bipolar or schizophrenia. And the men who are diagnosed later tend to have less severe illnesses

[00:05:27] and decreased number of hospitalizations versus the women tend to have presentations that are

[00:05:35] justice severe as early onset. So I mean those are a few pieces of evidence that it's really hard

[00:05:44] to argue seeing this global picture and looking at trends. That's one that just shouts

[00:05:52] that female hormones have such an impact. Yes and I've seen that anecdotally in my own

[00:05:59] patients too it's been pretty striking just to see how much more women are affected in that way

[00:06:06] than my male patients. Maybe I wasn't listening in training, that's very possible but it was not

[00:06:14] really emphasized this basic fact of oh by the way your female patients are going to have

[00:06:22] later onset with a less severe presentation again depending on when they have their first period

[00:06:29] the earlier being the more protective but it's not emphasized and it's such an important piece

[00:06:35] of clinical information to consider. For bipolar disorder a couple of studies to review

[00:06:43] one was a large retrospective study of Paris women and that is not women from France,

[00:06:50] that is women who have had a baby. In women who experience postpartum psychosis that also had

[00:06:59] bipolar one disorder they had a 43% recurrence of having another episode of postpartum psychosis

[00:07:08] versus only a 10% recurrence rate in women with bipolar one disorder and a 2% recurrence rate

[00:07:16] in women with bipolar two disorder. Infocising the fact that the women who are affected in their

[00:07:24] first pregnancy have a much greater likelihood of being affected in their second pregnancy

[00:07:29] you could probably make the argument that maybe these are different types of bipolar disorder

[00:07:36] ones that are hormonally influenced and maybe ones that don't have a large hormonal influence.

[00:07:42] Another statistic that I found is that one in five women with bipolar will have a psychotic

[00:07:50] or manic episode postpartum and that's compared to one in 500 in the general population.

[00:07:56] Wow my studies that I came across found probably about similar rates but pretty significant differences.

[00:08:03] Yeah that is a massive difference when you're talking about one to two out of a thousand women

[00:08:09] who will get psychotic postpartum the vast majority of those are going to have a bipolar one diagnosis

[00:08:17] and a lot of the time for women that postpartum period may be the instigator or the first episode

[00:08:25] that indicates an underlying bipolar disorder. Another study showed a 22 times increase risk

[00:08:32] of psychosis or mood illness in bipolar disorder with a 35 times increase risk of a psych admission.

[00:08:40] It's comparing women with bipolar one after pregnancy to the entire period before that first

[00:08:46] pregnancy and to support the influence of estrogen in pregnancy that it is protective against a

[00:08:54] mood disturbance for women who had their mood stabilizer withdrawn during pregnancy.

[00:09:02] They had a 66% chance of developing postpartum depression versus if they stayed on their mood stabilizer

[00:09:11] a 23% risk so that period at the end of pregnancy when you have the rapid reduction in estrogen

[00:09:19] without treatment on top of it without a mood stabilizer which normally controls the symptoms

[00:09:26] of bipolar disorder. There are three times risk almost. The vast majority of postpartum depression

[00:09:34] and definitely postpartum psychosis patients ended up carrying a diagnosis at some point of

[00:09:42] bipolar disorder. There was a five year follow up by a guy named Weisner,

[00:09:47] Wisner who found that of the postpartum psychosis patients 95% ended up bipolar disorder.

[00:09:57] It would be interesting to have a little bit more insight into postpartum experiences in those

[00:10:02] patients who do develop perimenopausal psychosis. I didn't see anything going back retrospectively

[00:10:10] in saying what your postpartum episodes like. I did not find any literature about that and

[00:10:17] anecdotally just a lot of the patients I treat who have gone through perimenopausal depression

[00:10:24] for all of my female patients, I do tend to ask about hormone sensitivity,

[00:10:31] any kinds of mood changes or even anxiety around the onset of your first menstrual period

[00:10:39] and the luteal phase leading up to each menstrual cycle, surround birth and delivery. Then

[00:10:44] yeah it meant a lot to me. I tried to really get a good history there because I have found that

[00:10:48] there's quite a bit of overlap. This is all anecdotal and I did not really see this studied

[00:10:52] very thoroughly but there might be subpopulation of women out there who are just more sensitive

[00:10:57] to these hormonal changes and so are more susceptible to have things like postpartum depression,

[00:11:02] perimenopausal depression psychosis etc. I would agree with you. I think that there are certain people

[00:11:08] that are biologically predisposed to fluctuations. We talk about bipolar disorder,

[00:11:17] there are so many factors that go into the presentation or these people who maybe are on that spectrum

[00:11:25] but require that second-hit or second-insel to push them over the edge into symptomatic

[00:11:33] females vs males tend to have more depressive episodes, more rapid cycling and more mixed

[00:11:41] episodes. Having more depressive episodes if you have a monthly cycle makes sense along with

[00:11:48] rapid cycling it could just be related to hormone changes or at least in a proportion of women.

[00:11:55] I have a study here that was looking at age of menarchy with onset of bipolar one. It actually

[00:12:03] found that younger age predicted earlier onset of bipolar one but that's different from what

[00:12:08] you've read. It was, yeah 2017 study they looked at 1100 women who were in treatment at an Italian

[00:12:15] mood disorder center and basically they retrospectively asked the women to talk about their

[00:12:21] age at menarchy and then also their onset of bipolar one disorder and they did find that those women

[00:12:27] with earlier initiation of mencies and periods did have earlier onset of bipolar one disorder also.

[00:12:34] But how would that be reconciled with the fact that I mean and tell me how strong you feel about

[00:12:43] that data on the age of onset in men vs women of both bipolar and schizophrenia?

[00:12:50] Right, right. I mean that to me has a little bit more umph behind it. You know I think we've seen

[00:12:56] that play out on more studies and also in person too in real life so it's hard to say exactly what

[00:13:04] could be going on with that especially if there is a difference between timing of menarchy and

[00:13:08] onset of bipolar versus schizophrenia that doesn't make a lot of sense to me that one would be one

[00:13:13] direction and the other would be other. I think there was some thought in this paper that maybe

[00:13:18] earlier exposure to the fluctuations in estrogen perhaps were making young women more vulnerable

[00:13:26] to have an earlier onset of bipolar one disorder but again there wasn't a lot of specific evidence

[00:13:32] on how it could be working. And then bipolar disorder the first episode is almost always depressive

[00:13:39] episode. Right then having the monthly cycles I could see how when you have your first period it's

[00:13:48] not like you just jump right on board with monthly cycles. Right. There's a time period where

[00:13:53] your gonadal system is still developing and trying to get to a regular cycle so that would make

[00:14:00] sense that they would maybe be aware of their first depressive episode if they went two or three

[00:14:07] months between periods early on and there was a more prolonged period of estrogen deficiency there.

[00:14:15] That's just what I can come up with off top my head. Yeah and it is interesting just thinking about

[00:14:20] the role of estrogen and Dr. Griner probably has more to say about this too but I mean just looking

[00:14:26] at the physiology of the actual steroidal hormone itself you know it has pretty direct effects on

[00:14:33] things like neurotransmitter systems, serotonin, dopamine. However it also is able to penetrate

[00:14:39] into the nucleus of cells and altered gene transcription and we know that takes a lot longer than

[00:14:45] something that's more of a direct signal messenger system so I do wonder you know even when we're

[00:14:51] measuring serum levels of estrogen in a woman and correlating that with her symptomatology at the

[00:14:56] time what are we attributing in that too? Is estrogen working instantaneously and we can kind

[00:15:01] of correlate that directly or is it more the downstream longer term effects of these estrogen

[00:15:06] fluctuations both increases and decreases that is actually leading to these psychiatric symptoms?

[00:15:13] Yeah or what is the role of empty estrogen receptors?

[00:15:19] Right. It is because and I can't speak with any confidence to this but I have seen some of the

[00:15:26] stuff that I've read talks about the estrogen receptors and if a receptor is not filled for long

[00:15:33] enough they will start to catabolize or eat themselves or destroy themselves because they're not

[00:15:39] needed. Yeah. Is there something about the ratio of the amount of estrogen to the amount of

[00:15:45] receptors that are unoccupied that contributes? Oh one other interesting study I came across looked

[00:15:52] at the risk of new onset bipolar disorder in perimenopause and they found that particularly in

[00:15:58] women who had symptomatic menopausal transition meaning things like night sweats hot flashes

[00:16:06] they were actually more likely than women who did not have those symptomatic signs to have

[00:16:12] new onset bipolar disorder. It does make me wonder if women are having visa motor symptoms of

[00:16:18] menopause. Perhaps the hormonal fluctuations are impacting them on a higher level for whatever

[00:16:23] reason and therefore could be contributing to a higher likelihood of psychiatric symptoms as well.

[00:16:28] Is there a direct correlation between the vasomotor symptoms and the

[00:16:34] psychotic or depressive symptoms? Right and there have been some thoughts that maybe it's just

[00:16:40] the vasomotor symptoms that are so miserable that people are getting depressed and not sleeping

[00:16:44] and then becoming psychotic or manic but that at least in my investigation has not really played out

[00:16:50] in the literature it doesn't seem like we can really attribute just the discomfort of vasomotor

[00:16:56] symptoms to causing the psychiatric disturbances. You don't sleep you feel like shit yeah

[00:17:02] and then if you don't sleep for long enough you can get psychotic I don't think I've ever had a

[00:17:06] patient who just wasn't sleeping and just developed psychosis from that. Right there's-

[00:17:13] I haven't slept a lot in the last two years and I'm not psychotic yet that I know of yeah maybe

[00:17:18] a little grandiose you know thinking anybody's gonna listen to this but psychotic and delusional?

[00:17:26] No but yes anytime I have seen sleep disturbance affect someone to that degree they have had an

[00:17:32] underlying predisposition for bipolar disorder to begin with. To add a little bit more and look at

[00:17:39] female schizophrenia related to the regular menstrual cycle study that showed that the psychosis was

[00:17:47] more likely in the PMS phase which is right around menstruation and then also a 20 times increased

[00:17:55] risk of psychosis in schizophrenia women after they deliver their baby. This one was really interesting

[00:18:02] too that even though as you get older you metabolize medications more poorly women with schizophrenia

[00:18:11] these are women who have been diagnosed they've had symptoms their whole life when they go through

[00:18:17] menopause they actually require higher doses of their anti psychotic to manage their symptoms of

[00:18:25] schizophrenia. I think that's fascinating actually I was reading that too and that was really striking

[00:18:31] there was a study on estradiol 200 schizophrenic women at the age of 30 to 50 or something

[00:18:40] a hundred of them are given an estrogen replacement and a hundred of them are given a placebo

[00:18:47] and they measure the change in the pan score or the positive and negative symptoms of schizophrenia

[00:18:54] just to standardize scale to assess the degree of impairment or the degree of psychotic symptoms.

[00:19:03] Overall the study showed a one point greater reduction in the estrogen group versus the placebo

[00:19:09] group but when they sub stratified it and they looked at the age of the women they got a two point

[00:19:15] a twice the reduction in symptoms for women over the age of 38 and we already know that women with

[00:19:22] schizophrenia go through menopause earlier than women without schizophrenia so when they actually

[00:19:28] looked at those women who are much more likely to be perimenopausal they are the ones who responded

[00:19:36] even more to the estrogen. There's an interesting study way back to 1958 by a guy named Mal I could not

[00:19:44] find the original study but I found that referenced in multiple other papers he studied 167 women

[00:19:52] with schizophrenia and he actually did a 24 hour urine estrogen excretion and a cytology.

[00:20:00] The conclusion of his paper was females in the hypo-filicular phase with psychotic conditions are

[00:20:09] easily treated with estrogen and he made this distinction between the hypo-filicular phase

[00:20:15] and the hypo-filicular phase which 70 years later I couldn't figure out what that meant.

[00:20:22] Can you imagine what hypo-filicular versus hyper-filicular phases?

[00:20:28] He wasn't just talking about pre-menopause and post-menopause right?

[00:20:32] No he was talking about the specific phase of their monthly cycles.

[00:20:36] Like just like oh yeah okay yeah I mean the only thing I can think of is in the

[00:20:41] filicular phase the first half you are developing your follicles growing getting ready for

[00:20:46] egg release and then in the luteal phase the follicle has already released and burst if you will

[00:20:52] so you're not actively growing that but I don't know if that's what he meant it's a little

[00:20:56] unclear. Strong conclusion and it would be nice to know a little bit more about that because

[00:21:02] if there was a way to substratify women in knowing okay this is the time period that

[00:21:09] you're going to need this and we can treat it prophylactically or preventatively that'd be really

[00:21:15] beneficial. Yes yes and I think that's actually one of the core issues and questions that

[00:21:22] this topic brings up is you know is there a role for prophylaxis? Should we be screening or

[00:21:26] our female patients particularly ones who we know have known hormone sensitivities

[00:21:31] and should we be upping their antidepressant, upping their mood stabilizers during these

[00:21:35] more vulnerable transition times? It's a really interesting question and something again I don't

[00:21:41] know if there's enough evidence to say exactly one way or the other but something I would alter my

[00:21:46] practice to do. Would you alter it to the degree of doing that on a monthly basis? Well that is

[00:21:54] yeah that's a good question and I don't know about the practicality of that I think a lot of

[00:22:00] patients might have a hard time honestly every month kind of increasing a dose than going back

[00:22:05] down, keeping track of that you know any kind of potential side effects that they also might have

[00:22:10] which again it would probably be well tolerated but if it's worth the benefit I think it could be.

[00:22:17] Yeah and I think ideally you'd have a situation where initially maybe they wouldn't be capable

[00:22:24] of managing that themselves but if they had enough structure in their environment or family

[00:22:30] or social support then hopefully after doing that for a few cycles they would also recognize

[00:22:36] the benefit of treating it prophylactically. Yes and I will say I have utilized that strategy with some

[00:22:42] of my female patients who have had pre-menstrual dysphoric disorder they will just for a week and their

[00:22:49] luteal phase will take an antidepressant just literally for seven days and then stop once

[00:22:54] months he's begin don't take anything and then the same month they do it over again and for

[00:22:59] those folks who are generally stable and yeah pretty well able to keep track of medications it has

[00:23:04] been effective. It takes me back to Katarina Dalton some of her work with a progesterone and since I

[00:23:12] think all the way back to the 50s she was working on the role of hormones she did studies on incarcerated

[00:23:20] women and found that the strong majority of them committed different crimes of aggression and

[00:23:29] violence within a couple of days on either side of their mencise. Wow yeah she testified in court

[00:23:38] cases and tried to help women out who had committed crimes and really was a proponent for using

[00:23:46] progesterone in the period around your period to prevent bad outcomes. What I want to see is a study

[00:23:54] of women who have had the onset of a change in their menstrual cycles and have the presence of some

[00:24:01] symptoms why can't we just study this in just that population? Yes we get better data. Yeah isolated

[00:24:09] really track those women particularly and I think we could measure hormone levels too a lot of

[00:24:14] these studies unfortunately did not measure any kind of hormone level or what stage of menopausal

[00:24:19] transition they were in before actually making any of these conclusions you know it's just kind

[00:24:24] of all surmised and they're all lumped together in a group. Somebody get this guy some help!

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