Antipsychotic Medications: Women are different from Men

Antipsychotic Medications: Women are different from Men

I am a psychiatrist working at the University Medical Center in Groningen, Netherlands and my research focuses on finding optimal treatments for schizophrenia-spectrum disorders. In this blog, I will specifically discuss the relationship between sex and antipsychotic treatment.

Although some patients prefer treatment without medication, acute psychosis (that is, the onset or relapse of disorders such as schizophrenia) is usually treated with antipsychotic medication, such as haloperidol and olanzapine. You can learn more about psychosis and antipsychotics in a previous InSPIre the Mind blog written by ITM Deputy Editor, Melisa Kose.

When the acute psychosis has passed, many patients are prescribed antipsychotics for a longer period of time to prevent a new psychosis (maintenance treatment). Classical antipsychotics such as haloperidol are still used, while second-generation antipsychotics such as olanzapine and amisulpride are often preferred because of their better balance of efficacy and side effects. In most countries, including the United Kingdom, antipsychotics are prescribed in a rather similar way to both men and women. That is, there is little difference in which antipsychotic is chosen and in what dose it is prescribed.

Recent research from Prof. Paola Dazzan and our group in the Netherlands, however, suggests that it is time to make a distinction. The female body is not the same as the male body. Also, the female brain is not the same as the male brain. Sex hormones, such as testosterone and estrogen, have a significant impact on our brains and behaviour. That is why in the Netherlands the Alliance Gender and Mental Health Care (GGZ) was founded in 2021 and supported by our Queen Maxima, which will put tailor-made treatment for men and women on the map.

For now, let’s focus on estrogens, the female hormones. Men also produce estrogens, but in women of reproductive age (between puberty and menopause) the production of estrogens is at least twice as high as in men. In these so-called “fertile years”, women generally have a menstrual cycle with a low estrogen period during menstruation and a high estrogen period in the other part of the menstrual cycle.

For people with psychotic disorders, these estrogens can be an important support. Estrogens are beneficial for mental health in general, and for psychotic disorders in particular. During periods of high estrogen production, women are relatively protected against negative symptoms (lack of energy and motivation) and intellectual problems (difficulty concentrating and remembering). This means that, during the menstrual period, these symptoms may become a bit more intense, as some women do notice.

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This also means that after menopause, the symptoms can worsen considerably because the protection by natural estrogens is then permanently lost. Indeed, the level of professional and social functioning of women with a psychotic disorder goes down on average after menopause.

But what does all this have to do with antipsychotics?

Well, actually, a lot.

The effects of antipsychotics on sex hormones

First, most antipsychotics are broken down by an enzyme in the liver called CYP1A2. This enzyme breaks down antipsychotics so that they are no longer active. With a few exceptions (quetiapine, amisulpride, paliperidone, and lurasidone), all antipsychotics depend on this enzyme for their breakdown and eventual clearance from the body.

However, estrogens slow down this enzyme. As a result, women during the fertile period will have a less active enzyme, which means that the breakdown of most antipsychotics is slower. Thus, when women in their fertile period receive a comparable amount of haloperidol, olanzapine, risperidone or most other antipsychotics as normally given to men, the concentrations in their bodies will become higher than in men. This can lead to side effects.

The way I approach this is that I measure the antipsychotic blood levels in women at least annually. That measurement must then be done in the fertile phase of the cycle, so not during menstruation. Sometimes, it turns out that the amount of medication in the blood is very high and the dose can be somewhat reduced. For women who are already receiving a very low dose, such measurements are not necessary.

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The role of prolactin

Many antipsychotics, such as risperidone, haloperidol, and amisulpride, increase another hormone called prolactin. This hormone is an important player after the birth of a baby as it enables breast development and milk production of the mother. Outside the postpartum period, however, the prolactin level should be quite low.

Unfortunately, many antipsychotics have the side effect of increasing the production of prolactin. Only the antipsychotics aripiprazole and brexpiprazole do not have this side effect. Quetiapine does cause some prolactin increase, but much less than most other antipsychotic drugs. In contrast, some of the older antipsychotics like haloperidol and risperidone, increase prolactin quite a lot.

What does high prolactin production mean? It may mean that the breasts feel a bit tense and become slightly larger. In some cases, there may even be a little milk production. But there’s another thing: you may have heard that breastfeeding women don’t get pregnant again easily? This is because prolactin inhibits the production of estrogens. That is a nice natural mechanism to ensure that a woman does not have the babies too quickly so that she can nurse them quietly.

But in women with psychotic disorders, these estrogens had such an important protective role! With the increase of prolactin by antipsychotics, the production of estrogens is inhibited. What you can notice in some of the women who take an antipsychotic, especially those that raise prolactin the most, is that menstruation does not occur, and that women no longer have regular menstrual cycles.

In addition, it can actually lead to a worsening of the symptoms that are kept at low levels by the estrogens, due to the reduced estrogens, such as the so-called “negative symptoms” (for example, motivation, and energy to get involved in work or social activities) and problems with thinking, concentration, and memory. This can lead to a greater need for in-patient care or for help with daily living.

What can we do about this?

Several things.

For women of childbearing age who are taking an antipsychotic for a longer period of time (i.e., years rather than months), it would be good to check blood levels of that antipsychotic from time to time. People who use clozapine already do this; the blood levels of that drug are in any case checked annually, as recently discussed in InSPIre the Mind, but we do not do that as standard for the other drugs.

With longer use of antipsychotics, it would also be good to use an antipsychotic that does not increase prolactin, or if that’s not possible for any reason, then to use an antipsychotic that causes minimal prolactin increase, such as aripiprazole, brexpiprazole or quetiapine. If someone is well on another antipsychotic, it may be helpful to take a low supplemental dose of aripiprazole, which will help get rid of the unwanted prolactin increase.

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We can also think of extra estrogens. This can be done via a contraceptive pill, such as the combination pill for women who are of childbearing age but do not want to have children. For women after menopause, Hormone Substitution Therapy is possible, which is the area of expertise of the gynaecologist. However, these hormone treatments come at a price, as they can increase the risk of blood clotting and even breast cancer alongside their benefits such as birth control and preventing a worsening of the psychotic disorder for postmenopausal women. An alternative is the drug raloxifene, of which we see favourable results in research, especially in women after menopause. This drug mimics the effect of estrogens but does not increase the risk of breast cancer. A gynaecologist is probably the most appropriate person to inform women about this and help them decide. Both psychiatrists and people with lived experience of psychosis should be more aware of the sex-specific differences in psychosis and its treatment, so as to optimize success and minimize side effects.