Learning Objectives

After the webinar, clinicians should:

1. Be aware of common gender differences in the course of illness of bipolar disorder and schizophrenia

2. Know medication side effects that occur more commonly in female patients

3. Identify drug interactions with hormonal contraception

4. Summarize some of the current research findings in psychiatric treatment

[Transcript edited for clarity]

I will be speaking about frequently overlooked considerations in women's mental health. My name is Dr. Victoria Hendrick. I'm a clinical professor at the department of psychiatry at Olive View UCLA Medical Center and the Editor-in-Chief of The Carlat Hospital Psychiatry Report. I have no conflicts to disclose.

The objectives for this webinar are to be aware of common gender differences in the course of illness of bipolar disorder and schizophrenia, to know medication side effects that occur more commonly in female patients, to identify drug interactions with hormonal contraception, and to summarize some of the current research findings in psychiatric treatment relating to women's mental health.

Bipolar disorder: gender differences in course of illness

Beginning with bipolar disorder, some of the more notable gender differences are that women are more likely to experience rapid cycling. They also experience more time in depressive episodes; show more seasonal variations, with depressive episodes more likely to occur in the winter months and manic episodes more likely in summer months; and women are more likely to experience comorbid anxiety.

Reasons that have been proposed for why women might be more likely to have a rapid cycling course is that in general women are more likely to initiate antidepressants and if there's an underlying predisposition for bipolarity and a woman starts an antidepressant, that could set her off into a rapid cycling course.

A study by some colleagues at UCLA a few years ago found that the menstrual cycle phases were not associated with rapid mood cycling, so that's not the reason why we see more rapid mood cycling in women.

Gender differences in bipolar subtypes and comorbidity

Another important difference in bipolar disorder is that there appears to be an overrepresentation of women with the bipolar 2 subtype of bipolar disorder. And importantly, I wrote a paper about this a few years ago. Be careful not to mistake premenstrual dysphoric disorder (PMDD) for bipolar 2 disorder. In other words, don't overlook PMDD thinking that the patient might have bipolar 2 disorder when what's really going on is PMDD. They can look similar where a patient might have a rapid onset of dysphoria and irritability and the change in her mood can be quite sudden. With the onset of menses, a patient's symptoms might resolve very quickly, and it might look like a bipolar switch in her mood, but if you keep track of these mood changes and you and your patient notice they occur premenstrually every four weeks, then you're more likely dealing with PMDD. So, when you suspect there might be a monthly cycling in mood, have your patient keep a menstrual diary where she keeps track of how her mood changes in relation to her menstrual cycle.

Schizophrenia: gender differences

Moving on to schizophrenia: on average, the age of onset is later in women than in men. While typically young men might present at ages 18 or 19, in young women we're more likely to see that onset of symptoms in their early 20s. Women tend to have less severe symptoms and better outcomes. For example, they’re more likely to hold a job, to be in a relationship, to get married. They're also more likely to adhere to medication recommendations, so that might also be part of the reason male patients with schizophrenia are more likely to show negative symptoms like amotivation, flat affect, and more cognitive deficits. And very importantly, late-onset schizophrenia, occurring in mid-40s and above occurs far more often in women.

Interestingly, what do you see as women reach their late 40s? They're reaching the perimenopausal transition and there's extensive research showing a relationship between times of low estrogen in women's lives and a greater predisposition to psychotic illnesses. For example, we see the postpartum being a time of risk of psychosis.

These findings that have been reported for decades have led recently to the exploration of the use of estrogen as a potential adjunctive treatment for women with schizophrenia. This is one of several studies that have come out in the last few years. This study looked at a hundred women of childbearing age, median age 38 years old. They received estrogen patches or placebo for two months, and the positive and negative symptom scores showed significant improvement but only for women who were on estrogen patches and were older than age 38. So, the findings suggest that estrogen might be an effective add-on treatment for certain women with schizophrenia; in particular, women who are already at a low estrogen state as they're getting into their late thirties might be the ones most likely to benefit from supplemental estrogen.

Let me just say one thing about estrogen: much as we like the idea of using something natural like an estrogen patch, estrogen, nevertheless, can have some potential complications. It increases the risk of breast cancer and uterine cancer and thromboembolism, so we don't want to use it lightly. I'm not recommending that it be started in women of any age group, but I'm presenting this data to you because I believe in the future, we might find ways to use estrogen supplementation in a safe manner.

Another way to provide estrogen to women safely is through what are called selective estrogen receptor modulators or SERMs. Selective estrogen receptor modulators act similarly to estrogen on dopamine and serotonin receptors in the brain, but they don't have estrogen's negative effects on breast and uterine tissue.

So, there's been a lot of interest in SERM as an alternative to estrogen for women with schizophrenia. Much of the research has been done by Dr. Kulkarni in Australia. She has worked with postmenopausal women, randomized to SERMs like raloxifene, adjunctive to antipsychotics, and has found that women with the adjuvant raloxifene show significant improvement in positive symptoms and significantly faster recovery. And since SERMs seem safe, this supplementation might very well be a treatment that we can start offering our female patients.

Antiepileptic medications: drug interactions specific to women

Many antiepileptic drugs like carbamazepine are cytochrome P450 enzyme inducers. They're powerful inducers and they increase the metabolism and breakdown of hormones like estrogen, and as a result, they can reduce the efficacy of oral contraceptives and hormone replacement therapy.

These antiepileptic drugs include carbamazepine, topiramate, and oxcarbazepine. This is a very important drug interaction to be aware of. You could have a patient on a birth control pill and if you start her on carbamazepine, she might then become pregnant because the birth control pill is no longer effective.

And carbamazepine is a teratogenic medication. So that is a bad situation to be in. Make sure if you have a patient on carbamazepine or any other enzyme inducing agents, you're well aware of what they're using for contraception and if they're using oral contraceptives, recommend that they switch to some other form of contraception because hormonal contraceptives may very well be rendered ineffective due to this drug interaction.

And at later times in women's lives as they're it in the perimenopausal transition or postmenopausal, and they're receiving hormone replacement therapy for hot flashes and night sweats, If you start carbamazepine, they very well might start having hot flashes and night sweats again because the hormone replacement therapy will have been rendered less effective.

Keep those drug interactions in mind. Now, another drug interaction that works in a different manner is that estrogen, for example, estrogen in oral contraceptives, increases the breakdown of lamotrigine. You could have patients taking lamotrigine and then they start an estrogen containing oral contraceptive, and the lamotrigine might not be as effective because the levels will be reduced.

In fact, during pregnancy, when women are on lamotrigine, blood levels can be reduced drastically because of the high estrogen in pregnancy. Blood levels in pregnancy of lamotrigine can be reduced by 50%. But what do we do if you have a patient on an estrogen containing birth control pill and lamotrigine? What I recommend to these patients is to either not stop the oral contraceptive while they're taking lamotrigine or to stop the oral contraceptive before starting the lamotrigine or to use a progestin only contraceptive. You don't want to be in a situation where your patient is on lamotrigine and an oral contraceptive, and then they stop the oral contraceptive and then the lamotrigine levels might go up because they are no longer on the estrogen-containing birth control pill that was making the lamotrigine levels lower. Of course, the biggest risk for lamotrigine-induced Stevens Johnson syndrome is going up too fast on the lamotrigine dose. So, the best solution in my mind is for women to be consistent. If they're going to be on the lamotrigine and a birth control pill, just stay with a birth control pill the whole time. Or stop the birth control pill before starting lamotrigine and use a different form of contraception, or just stick with a progestin only contraceptive form of contraception.

Gender differences in side effects from mood stabilizers: lithium-induced hypothyroidism

We all know about lithium-induced hypothyroidism, but I just want to point out that hypothyroidism is far more common in women as a side effect of lithium than in men. So just be extra vigilant for your female patients on lithium in terms of checking their thyroid function tests. The risk of lithium-induced hypothyroidism is especially pronounced in women over the age of 50. One theory for why women are at greater risk for hypothyroidism than men on lithium is that we know women are at greater risk for autoimmune illnesses like lupus, myasthenia gravis; many forms of hypothyroidism are from autoimmune thyroid disease. If you have a female patient who is prone to an autoimmune illness like autoimmune thyroid disease, and you put her on lithium, which is an immunostimulant, that could throw her over the edge where she becomes frankly hypothyroid.

Gender differences in side effects: lithium 

Some other side effects from lithium that we should be particularly vigilant with our female patients are hyperparathyroidism. In contrast to hypothyroidism, when it comes to the parathyroid gland, lithium can produce hyperparathyroidism.

We don't typically check calcium levels in our patients on lithium, but a lot of people think we should be doing that, and especially for female patients that might be at risk of osteoporosis because what happens with elevated parathyroid hormone? It causes the body to pull calcium from bones and it can exacerbate the risk of osteoporosis.

I'm always a bit wary about starting lithium on patients, male or female, for that matter, who might be prone to osteopenia or osteoporosis. For example, patients who are thin, who are smokers, white or Asian, or who have a family history of osteoporosis. Those might be patients that you might want to think twice about lithium use and you want to check their parathyroid hormone levels and calcium levels.

And then lastly as I mentioned earlier, lithium is an immunostimulant. If you have a patient with an autoimmune illness like psoriasis or lupus, which is more common in women, lithium's immunostimulating properties may very well exacerbate the symptoms. There's a wide literature on the exacerbation of autoimmune illnesses like psoriasis when patients are placed on lithium.

So just be mindful of that for male or female patients, keeping in mind that female patients are more prone to autoimmune illnesses.

Lithium: considerations of relevance to women

Another drug interactions of particular concern for female patients is that many female patients don't tell me if they're using over-the-counter non-steroidals or diuretics for premenstrual bloating or cramping. It's important to warn our patients that non-steroidals and many diuretics reduce lithium clearance and can produce lithium toxicity.

And for patients with eating disorders, which could be males or females, but we see these more frequently in female patients, lithium can be problematic because these patients, if they engage in frequent purging or using laxatives and diuretics, they can become lithium toxic, since Lithium has a narrow therapeutic window.

Polycystic ovary syndrome and valproate

I want to say some things about polycystic ovary syndrome (PCOS) and valproic acid or valproate. Several studies going back to the early nineties have found that valproic acid increases the incidence of menstrual disturbances in women compared to women on other antiepileptic drugs. To my knowledge, this study that I'm citing here was the very first one to report this finding, which came out in the New England Journal of Medicine in 1993. It found that women under the age of 20 were especially at high risk, and if patients switched to another antiepileptic drug, the menstrual cycle disturbances resolved. And it wasn't just menstrual cycle disturbances, but on lab testing, there was also evidence of elevated androgen levels.

Let me tell you about PCOS. It's defined by chronic anovulation—three or more months of no menstrual cycles—and symptoms of elevated androgens like hirsutism, obesity, acne. On labs you'll see elevated androgens. And a reason we worry about PCOS is that it increases the risk of insulin resistance and other forms of metabolic syndrome. The main reason women present to healthcare professionals for PCOS is they are trying to get pregnant, but we also worry about metabolic syndrome as a potential long-term consequence.

We do not want this to be happening to our patients. I'll tell you some interesting research that is believed to explain why valproic acid is linked to PCOS. Weight gain and insulin resistance or hyperinsulinemia are believed to play a role in the pathogenesis of PCOS. We know that elevated levels of insulin inhibit the enzyme that converts testosterone to estrogen. And if you have patients with elevated circulating androgens, that appears to initiate the reproductive dysfunction of PCOS.

PCOS and valproate

What do we know about valproic acid? We know that it increases the risk of insulin resistance and hyperinsulinemia, and so elevated insulin in a patient on valproic acid might be the trigger that prevents female patients from having their testosterone aromatized to estrogen. That is believed to be the pathogenesis for this relationship between valproic acid and PCOS. This leads me to think that any psychiatric medication that's linked with hyperinsulinemia could also produce reproductive dysfunction and PCOS, for example, olanzapine or clozapine.

I’m vigilant for menstrual disturbances across a wide number of psychiatric medications and make it a habit with my female patients to ask regularly if there have been any changes to their menstrual cycles or if they've noticed any signs of elevated androgens, like hirsutism. If I see any signs of elevated androgens, I get androgen levels: Testosterone, androstenedione, DHEA. And I also ask patients to keep a menstrual diary to see if they are having irregular menstrual cycles.

“Conceivably neglected:” risks of valproate

I want to say one more thing about valproic acid, because this is an important point. This was a study that came out in 2019 that found that, despite the robust evidence of teratogenic and neurodevelopmental risks of valproic acid in pregnancy, most patients we start on valproic acid are getting very little advice regarding these risks and getting very little advice about the importance of contraception if they're going to be on valproic acid.

What we do in the United States is very different from what you see in the United Kingdom and in France. For example, in the United Kingdom, the use of valproic acid is restricted for women of reproductive age. Their Medicines and Healthcare Products Regulatory Agency (MHRA), which is like our FDA, has banned the use of valproic acid for women of childbearing potential unless they're enrolled in a pregnancy prevention program where they have to sign acknowledgements saying that they're aware of the risks of valproic acid and pregnancy and they will use contraception before starting treatment. It’s an extremely highly teratogenic medication and it's teratogenic early in the pregnancy, often before a woman even knows she's pregnant. It's teratogenic in the first six weeks of gestation. Women often don't know they're pregnant till four weeks into the pregnancy.

The risks are of neural tube defects, like spina bifida, developmental delay and autism in children, so we want to do everything we can to avoid women of reproductive age unintentionally getting pregnant while they use valproic acid.

In the United Kingdom, valproic acid is prescribed in small package sizes with warning images of potential risks. They take this risk of teratogenicity very seriously in a way that I think we really should be doing ourselves. In France, there’s a partial ban on valproic acid for women and girls unless they're on a form of contraception.

Hyperprolactinemia and antipsychotic meds

We all know, of course, about hyperprolactinemia and first-generation antipsychotic medications and risperidone. I just want to point out a few things. Once prolactin levels reach 60 nanograms per ml, it's. likely women will experience amenorrhea or missed menstrual cycles. Why do we worry about missed menstrual cycles?

Because after a few weeks of missed menstrual cycles, women start to lose bone density. It's alarmingly fast, how quickly women lose bone density once they're in a low estrogen state. And there's an extensive literature showing that women on antipsychotic medications that produce hyperprolactinemia are at greater risk of osteoporosis and bone fractures. Imagine a female patient on an antipsychotic for years and all those years she's not been having a menstrual cycle and has been hypoestrogenic. You can clearly see how she's going to be at significant risk of osteoporosis, so, be vigilant about this side effect.

It's not just risperidone that's linked with hyperprolactinemia among the second-generation agents. Every second generation has been linked in at least one case report with hyperprolactinemia. Of course, some more than others. Risperidone is particularly likely as well, as well as paliperidone. But I've also seen reports with ziprasidone and olanzapine. So just be vigilant about asking your patients about missed menstrual cycles when they’re on any antipsychotic medication.

Medication-induced hyperprolactinemia

What do you do if you find your patient is doing very well on risperidone but you find her prolactin levels really elevated? You can try reducing the dose, but then she might have a relapse of symptoms. You can switch to another agent, but maybe it won't work so well for her.

I'll tell you the two tricks I like the most. One is to add a birth control pill. It kills two birds with one stone. There are a lot of unintended pregnancies among women with schizophrenia, so this helps reduce unintended pregnancies, and the nice thing about the birth control pill is it replenishes the estrogen, so it helps protect our patients’ bone health.

Another option is to use aripiprazole, a low dose, even as low as five milligrams a day. Aripiprazole is a partial dopamine agonist, so it can help reverse the hyperprolactinemia from dopamine antagonists. So adding a small dose of aripiprazole to risperidone, haloperidol, or whatever other antipsychotic medication your patient is on that's producing hyperprolactinemia, that can very well bring down the prolactin level and your patient will start having her menstrual cycles again. That can work very nicely and the effects are usually pretty quick. Within two to four weeks, you'll see that the prolactin levels come back down.

I really like using that as a strategy. It also works for male patients with gynecomastia. I've found many male patients don't want to take medications like risperidone that might be helping them, but they are embarrassed by the gynecomastia and the aripiprazole supplementation can help resolve that problem.

There ares some other techniques that I myself don't use, but just so you're aware of what's in the literature, an alternative strategy is to add metformin or a dopamine agonist, like bromocriptine.

I do want to point out, if you see a really high prolactin level, like over 100 ng/ml, you can't just assume it's a medication side effect. It could be something else; your patient could have a prolactinoma, a pituitary tumor that produces excess amounts of prolactin. You do want to get a consultation from an endocrinologist, especially if you switch your patient to another agent, and the prolactin levels still stay high.

So be vigilant about prolactinomas. Patients might present with headaches or vision changes if they have a pituitary tumor.

There are a few things I want to say about antiepileptic drugs and bone disease. Certain antiepileptic drugs increase the bone, the risk of bone disease by inducing the breakdown of vitamin D. For example, carbamazepine, being a potent enzyme inducer, can do this. It also interferes with intestinal absorption of calcium.

What I've seen in the neurologic literature, not so much in the psychiatric literature, is to counsel patients on antiepileptic drugs about good bone health practices like getting plenty of calcium and vitamin D; doing weight-bearing exercises; not smoking; and considering a bone mineral density measurement, a DEXA scan after five years of treatment or earlier if you've got any concerns in post-menopausal women on medications that could affect their bone density.

Menopause, hot flashes, and antidepressants

Another topic I want to touch on is that every major psychiatric illness worsens premenstrually for at least some women, including depression, anxiety disorders, schizophrenia, bipolar disorder. If your patient was doing fine with the treatment you were providing for her, but then she seems to have a monthly relapse of symptoms, ask where she is in her menstrual cycle before you assume the treatment's not working. If she's premenstrual, often just knowing that symptoms will resolve in a few days is enough for patients to think, “I'll just get through the next few days until the onset of menses.” If it's a distressing experience to have this recurrent worsening of symptoms premenstrually, you can go up on the dose of medications at mid cycle and then back to the previous dose with the onset of menses. That strategy often takes care of this premenstrual relapse.

And then just wrapping up with some comments about menopause. Keep in mind as women get into their late 40s and early 50s, if they're having hot flashes and night sweats, those could very well contribute to insomnia and anxiety. If you have patients presenting with insomnia and anxiety, ask if they're having hot flashes and night sweats. Not all women experience hot flashes during the menopausal transition, but most do—about 75%. And SSRIs and SNRIs have been found in some studies to reduce hot flashes and night sweats.

In fact, a few years ago, the FDA approved Brisdelle (paroxetine), as the first nonhormonal treatment for menopausal vasomotor symptoms. We saw that paroxetine, and for that matter, other SSRIs, were helping these vasomotor symptoms. We don't know why, but they seem to help. Especially if you have a patient who's experiencing depression and vasomotor symptoms, an SSRI could very well take care of both problems. Paroxetine has this FDA approval, but really any SSRI or even SNRI, like venlafaxine, seems helpful.

Reproductive-related mood changes?

Is there a correlation of depressive mood before menstruation during pregnancy in the postpartum and around menopause? An interesting retrospective study looked at women who were currently experiencing depressive symptoms during perimenopausal transition, and it found that depression around perimenopause was significantly associated with mood changes premenstrually, but not with depression at pregnancy or in the postpartum.

This, to me, makes sense. Depression in pregnancy and postpartum seems more linked with psychosocial stressors, like not having much support, or having more than one small child in the home, or conflict with the baby's father. These sorts of psychosocial stressors seem to be the biggest risk factors that predict depression perinatally.

But premenstrual and perimenopausal mood changes do seem to be more hormonal. And so, when you have a patient with PMDD or even with just premenstrual mood changes, you might want to warn her to watch out for mood changes as she goes through the perimenopausal transition and watch her a little more closely during that phase in her life.

Summary

Gender differences occur in the course of illness as we see with schizophrenia and bipolar disorder, as well as in medication side effects and drug interactions. There are some treatment options that work better for female patients. And female patients may experience exacerbations of mental illnesses at times of hormonal changes like premenstrually and at menopause, and then during pregnancy in the postpartum.

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