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Gender-Based Differences in the Treatment of Schizophrenia

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How does schizophrenia differ between men and women? And are there adjunctive treatments that can improve outcomes for female patients with schizophrenia? In this podcast, Dr. Kulkarni and I will tackle these questions. 

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Published On: 11/22/2021

Duration: 23 minutes, 16 seconds

Referenced Article: Sex-Based Treatment of Schizophrenia,” The Carlat Hospital Psychiatry Report, July 2021

Victoria Hendrick, MD, and Jayashri Kulkarni, MBBS, PhD, FAHMS, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.


Dr. Hendrick: How does schizophrenia differ between men and women? And are there adjunctive treatments that can improve outcomes for female patients with schizophrenia? In this podcast, Dr. Kulkarni and I will tackle these questions. Dr. Kulkarni is a professor of psychiatry at Monash University. She is also the Director at the Monash Alfred Psychiatry Research Center in Melbourne, Australia, and she is a Fellow of the Australian Academy of Health and Medical Science and a Member of the Order of Australia. Through her pioneering research in the use of estrogen and selective estrogen receptor modulators, or SERMs, for female patients with schizophrenia, she has helped expand treatment options for this population. After this podcast, you will have a better understanding on how to improve treatment outcomes for your female patients with schizophrenia.

Welcome to The Carlat Psychiatry Podcast

This is a special episode from The Carlat Hospital Psychiatry Report.

I’m Dr. Victoria Hendrick, the Editor-in-Chief of The Carlat Hospital Psychiatry Report, and a clinical professor at the David Geffen School of Medicine at UCLA. I’m also the director of inpatient psychiatry at Olive View — UCLA Medical Center.

Before we review promising new adjunctive treatments for women with schizophrenia, I’ll briefly cover the main sex-based differences. 

Compared to men, women with schizophrenia on average experience a more benign course of illness, including fewer psychiatric relapses and hospitalizations. They are more likely to be employed and married and to maintain interpersonal relationships. Also, women of reproductive age may experience premenstrual exacerbations of schizophrenia, even leading to a greater likelihood of psychiatric hospitalization in the week prior to menses.

A well-replicated finding is that the peak age of onset for men occurs at 18-24 years of age while for women this peak occurs about 5 years later. Women, but not men, have a second peak age of onset at age 45-50, around menopause. 

This second peak age of onset in perimenopausal women can be explained by the estrogen hypothesis of schizophrenia. Dr. Kulkarni, can you describe the estrogen hypothesis and how it influenced your research?

Dr. Kulkarni: Yes, so the estrogen hypothesis of schizophrenia really has several components to it. And I think it was phrased particularly well by Professor Heinz Hafner in Germany and also Professor Mary Seeman in Toronto in the 1990s. And they both described estrogen as a neuroprotective agent that did several things. Estrogen delayed the onset of early schizophrenia in women and, during menopause, declining levels of estrogen lead to schizophrenia relapse. Now their hypothesis and subsequent work on the hypothesis is based on several lines of evidence. 

So the first line of evidence was from animal studies where animal researchers showed, in fact, that estrogen has a significant impact on the dopaminergic and serotonergic receptor systems – the main chemicals involved in the development of schizophrenia. So the animal work showed that estrogen is protective. 

At the same time, Hafner and Anita Riecher-Rossler had done a lot of work looking at the public health side of things and looking up big databases and showing that, in fact, there was a difference in the age of onset with women developing schizophrenia about five to maybe even ten years later for their first episode. So that also led to an understanding that perhaps because women have rising estrogen in their brains due to puberty that that was protecting them from an early episode of schizophrenia. 

The third line of evidence globally is that clinical evidence that women were, in fact, often admitted for a relapse to hospital in the week prior to menstruation when their actual estrogen brain levels were low as well as the noted menopause relapse story across the world that women in their late 40s to early 50s had more hospitalizations and more difficulty containing the symptoms of schizophrenia. 

So all of these bits of evidence came together to form the estrogen protection hypothesis in schizophrenia. 

Now subsequently, I took that hypothesis and thought well if it’s a protective agent, let’s see if it’s a useful treatment agent. And since then, since the early 1990s, have conducted a series of clinical trials showing indeed that, yes, estrogen is a positive treatment as an adjunct for women and men with schizophrenia.

Dr. Hendrick: As I said earlier, you’re a pioneer in this field of research. Can you tell us about your studies on adjunctive estrogen and SERMs, specifically raloxifene, for women with schizophrenia?

Dr. Kulkarni: Yes, so the very early studies we did, because again we were in uncharted territory as it were, and so we had to find what is the dose, what is the type of delivery of estrogen that might, in fact, help with actually getting across into the brain and therefore being useful as a treatment of schizophrenia. So they were the first studies that we did. We quickly dropped the oral estrogen – estradiol valerate because it’s a conjugated estrogen and doesn’t cross the blood-brain barrier, and went to a more pure form of estrogen that’s 17-beta-estradiol which is in the patch. So we worked on doses and came up with the optimal dose after a series of studies that have been published as 100 mcg of transdermal estradiol.

Then in about 2001, you’ll remember that the Women’s Health Initiative Studies gained a lot of public press. Now since then, of course, a lot of the data has been reanalyzed and people are viewing the role of estrogen and body issues differently. But back then the concern was that estrogen treatments were going to have a deleterious effect on breast or uterus or ovaries and create breast cancer in particular. That has actually been diminished and the data does not show a clear association, but back then that was an issue.

So here we were saying, “Well, look estrogen is good for the brain, and you know in schizophrenia it’s a useful adjunct because so many people do not respond that well to antipsychotics and there are side effects of antipsychotics.” So we were looking for a way of delivering estrogen but without the body effects. And that’s how I landed on the selective estrogen receptor modulators which were a new class of brain estrogens that had been developed. 

The first one was raloxifene and it was developed to treat osteoporosis in menopausal women. So I conducted the first pilot study of raloxifene in perimenopausal women with schizophrenia and found that, in fact, that was useful in terms of being a good adjunct – again treating the symptoms of schizophrenia. So we started with that particular pilot study, again having to find a dose. And we tried 60 mg of raloxifene, but it just wasn’t as effective as 120 mg of raloxifene per day as an adjunct to antipsychotics, and at that dose we saw quite a great control for the patient over her psychotic symptoms. So again we were very encouraged by this. And since then I’ve been continuing to look at the use of selective estrogen receptor modulators in men, in younger women – so reproductive age women, and also the different types of selective estrogen receptor modulators because there’s been development of subsequent medications. 

And the latest one that we’re trying at the moment is bazedoxifene which again is proving to be looking very promising.

Dr. Hendrick: Other research groups have also found significant benefits for postmenopausal women taking adjunctive raloxifene. A recent meta-analysis summarized the findings and concluded that, at doses of 60-120 mg/day, raloxifene appears effective and safe. The main side effects are hot flashes and leg cramping but these tend to diminish over the first few months of treatment.

Coming back to what you said about raloxifene being developed and FDA-approved to treat osteoporosis in menopausal women, when we are deciding whether to start or stop raloxifene, should we consider our patient’s risk for bone loss? It seems like raloxifene can kills two birds with one stone. It improves psychiatric symptoms and protects bone health. This is particularly relevant to our patients, since rates of osteomalacia and  porosis among women with schizophrenia appear to be higher than for the general population of women. 

Dr. Kulkarni: Absolutely. And often as you know we have patients who are on an antipsychotic and an antidepressant, and the SSRIs are also implicated in bone density changes as well. So there are several factors, and you add in smoking; you add in a poor lifestyle, poor nutrition, and all of these things lead to bone density problems and potential fractures and so on.

Dr. Hendrick: Are there any differences in the psychiatric benefits between estradiol and SERMs? For instance, do they have different effects on negative and positive symptoms, or does one improve cognition better than the other? 

Dr. Kulkarni: Yes, so with the estradiol studies, what we sort is the straight estradiol 17-beta-estradiol was very good in terms of quickly down turning the positive symptoms. So the first lot of symptoms we saw respond were particularly hallucinations and thought disorder and then a little bit later. We saw immediate effects within 48-72 hours. Then in about a week to ten days the delusional symptoms improved. Then by about two weeks we would start to see the cognitive improvement. I’ve had patients describe things like “wow, I suddenly felt like I went from having a calculator in my head to a supercomputer.” And I felt that that was a nice cognitive analogy that many women describe suddenly being able to multitask and suddenly having lots of memories. Now, of course, that can be bad because a lot of bad memories came back as well as good ones, but the memory and the new learning also increased, so that was really good.

With the SERMs we see the cognitive changes occurring first, but not in such a dramatic way. So it’s still taking a little bit longer, but there’s sort of a gradual improvement in cognition, and then accompanying that is also an improvement in again the positive symptoms first.

The negative symptoms, the biggest thing that people have described is an increase in energy, and with that increase in energy then they actually feel that they want to do more and can do more, which of course, is the heart of the negative symptoms, the amotivational states, and the poverty of thought and so on. So it is reflected in the patient’s description of “I’ve got more energy. What can I do?” So I think that’s how we’ve seen it and again, of course, I do caution that we haven’t got heaps and heaps of data yet. We are still collecting the data. In particular at the moment we’ve got a bazedoxifene trial that’s currently running for women and for men.

Dr. Hendrick: So these adjunctive therapies look promising, and their efficacy for improving outcomes in women with schizophrenia is pretty well established. But, personally, I have not seen any general increase in the prescribing of estradiol or SERMs for this population. It seems like we should be seeing an uptick in the prescribing of these drugs, however, I just haven’t seen it yet. Have you noticed anything similar, and, if so, what do you believe is impeding the use of these drugs in psychiatric clinical practice?

Dr. Kulkarni: Yes, and like you we’re not seeing it here and I think what is unfortunate is that specialists practice very much in a very siloed, blinkered kind of way. So the general psychiatrist will be very good at talking to patients about antipsychotics, antidepressants, benzodiazepines and all of the psychiatric drugs, but unfortunately the practice is not very inclusive of looking at other factors, and particular women’s physical health factors, I feel, are overlooked. 

And we see it in so many ways. We see it in this way that there isn’t the same knowledge base about the estrogen preparations or even about menopausal effects, for example, in the general psychiatry trainees and in the practicing psychiatrists. 

We also worry about it because they are not also particularly familiar with the oral contraceptive pill, for example, which is another form of estrogen that can be used in the younger woman as well. So I suspect that the practice, unfortunately, is not broad and inclusive; that’s one thing. I think women’s mental health and women’s health are not at the top of the health agendas and therefore these holistic approaches are really not considered very much. 

There is also I think – I mean we have a group that is published and there are several sporadic publications that come from around the world, but there are no other big centers that are producing this research as well, so it’s not done on a huge scale, although I’m very grateful to the Stanley Medical Research Institute in Washington which actually supported a lot of this research as well as the Australian National Health and Medical Research Council. But nonetheless, it’s not like some of the other branches of research where there are many, many centers and universities and hospitals around the world. So there’s some of the factors that I think are behind my same observation as yours, Dr. Hendrick, that in fact we are not taking this up and we should be.

Dr. Hendrick: I’m happy that you brought up oral contraceptives! We greatly emphasize the use of oral contraceptives where I work, because women with chronic mental illnesses are more likely to have unintended pregnancies when compared with women in general. You alluded to the fact that oral contraceptives can augment estrogen levels as well. Do you ever contemplate using birth control pills, not only as a contraceptive, but also for it’s potential psychiatric benefits as well?

Dr. Kulkarni: Yes, absolutely, and also for contraception, so it’s killing two birds with one stone as it were. However, there is a difficulty with some of the oral contraceptive pills because the progestin in the oral contraceptive pills can be depressive, and that’s another branch of our work that we’ve looked at the impacts of the OCP (oral contraceptive pill) on depression. And there have been some rather big studies, Scovlund study that was published in JAMA Psychiatry in 2016 in a big database, a million women showed that there was a significant correlation between the use of progesterone only contraception and depression, and also certain types of oral contraceptives with certain types of progestins and depression. 

So we have, over time, in our clinical trials discovered that really nomegestrol as a progestin is really the best in terms of being mood neutral in the pill. 

And many other types of progesterone can actually precipitate depression particularly in the vulnerable women, and of course, our patients with schizophrenia would fall into that category. So yes we do use the OCP, but over time we’ve learned that all pills are not the same.

Dr. Hendrick: Now that we know more about the safety of transdermal estradiol, and how it’s not as problematic as we used to think it was, would you recommend transdermal estradiol over a SERM like raloxifene?

Dr. Kulkarni:  I think it always ends up as a case by case final decision because you have to weigh out all the risk factors. And certainly in a woman who has a family story of breast cancer with a mother or an aunt or a sister, we always worry about the use of estradiol anyway in that population. Yes, transdermal has much less risk. But if she’s a smoker, for example, if she has a sedentary lifestyle, if she has diabetes, if she has hypertension, these are escalating risk factors for cardiovascular or stroke disease, so we always have to weigh out the risks and benefits as we all do in clinical practice. 

And so therefore it’s useful to know that you have a repertoire that you can actually call upon if the patient needs an adjunct because she’s not responding to standard antipsychotic medications. But, yes, of course, the transdermal is less of a risk in terms of both the cancer risks as well as the thromboembolic lamina that we worry about. So we have got a repertoire. 

Dr. Hendrick: Additionally, estradiol might be a better choice than a raloxifene for a menopausal patient with schizophrenia who is experiencing vasomotor symptoms like hot flashes.

We should also complete some screening before we start our patients on raloxifene. We should check for a past history of deep venous thrombosis or pulmonary embolism and measure Factor V Leiden (a genetic mutation that increases the risk for blood clots) because raloxifene slightly increases the risk of deep venous thromboses and other thromboembolic events — but, these are rare side effects, with an absolute risk difference of 0.9 per 1000 woman-years. 

Dr. Hendrick: To summarize, we should consider using estrogen or SERMs as adjunctive treatments for female patients with schizophrenia, especially postmenopausal women who are not fully responding to antipsychotic medications and who are primarily experiencing positive symptoms. 

For women of reproductive age, oral contraceptives can be helpful. For post-menopausal women, adjunctive raloxifene 120 mg is helpful. Alternatively, transdermal estradiol is another option and should be prescribed with a progestin if the patient has a uterus. Transdermal estradiol is particularly helpful for women with schizophrenia who also report vasomotor symptoms, like hot flashes. These appear to be safe adjunctive treatments for schizophrenia. 

Dr. Kulkarni, is there anything else you’d like to add about the effects of these adjunct treatments on improving women’s mental health?

Dr. Kulkarni: I mean I like to think that women’s mental health agenda is to have health and mental health together as an approach for our patients. And if we think about what we’ve just talked about with the pill or with the HRT, so the menopause treatment, hormones – they are all about health and mental health. So I think it’s a different agenda that we would like to see psychiatrists and mental health systems focus on as well for women.

Dr. Hendrick: I totally agree! These treatments can improve our patient’s overall health and their schizophrenia symptoms. 

And if we do not feel comfortable prescribing these agents ourselves, we can work with our patients’ primary care physicians to help patients get started on these adjunctive treatments and get followed for any adverse sequelae. As long as patients are screened and monitored appropriately, raloxifene and transdermal estradiol appear to be safe and effective adjunctive treatments for schizophrenia in women.

The print version of this interview is available for subscribers to read in The Carlat Hospital Psychiatry Report. This newsletter article also contains a handy table detailing which adjunctive hormone treatments should be used in patients younger or older than 45 years old. It also includes the cautions/contraindications associated with each adjunct, and the optimal dose of each treatment.

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