10 facts every psychiatrist should know about Premenstrual Dysphoric Disorder

Premenstrual Dysphoric Disorder (PMDD) is a uniquely interesting psychiatric disorder, about which most psychiatrists know little. It’s important both because it is chronic and disruptive for sufferers but also because it gives us clues to the underlying pathophysiology of affective disorders more generally.

Despite many years of research into PMDD, it has only been officially recognised as a (mental) disorder by DSM-5 and as a (gynaecological) disorder by ICD-11 in the last decade.

Unlike most mental disorders, it is the timing of symptoms that’s crucial to make a diagnosis. Symptoms have to be present in the week before menstruation (i.e. the premenstrual week) and minimal or absent in the week after. Typical affective symptoms include dysphoria, irritability, lability and tension while other supporting symptoms are include poor concentration, lethargy, and disturbances in sleep and appetite.

Symptoms have to be severe enough to interfere with daily life and can’t just be an exacerbation of another mental disorder. A similar condition, Premenstrual Syndrome (PMS), is a generally milder form, with patients only having to experience at least one symptom in the premenstrual week.

Sometimes to the frustration of patients, psychiatrists don’t get much training in hormone-related disorders like PMDD. I think this is a pity because we know more about the pathophysiology and treatment of PMDD than most psychiatric diagnoses.

This is in the wider context of mental health research largely ignoring the role of sex and gender, and even many animal studies using males exclusively. Hopefully the tide is beginning turn but there is still a reluctance in many quarters around female-specific health research.

PMDD is the archetypal menstrual disorder and a great example of how to study the complex effects of hormones. Here are 10 facts that every psychiatrist should know.

1. PMDD can be objectively diagnosed

For almost all psychiatric diagnoses, a psychiatrist will interview a patient, ask about symptoms, observe behaviour and then fit this to an appropriate diagnosis. It is inherently subjective and the agreement between psychiatrists interviewing the same patient is less than we might hope.

By contrast, PMDD is diagnosed prospectively, tracking symptoms over two menstrual cycles. This is crucial because retrospective timing of PMDD symptoms does not correspond to tracking symptoms over time.

Symptom ratings can be operationalised, self-reported and accurately timed - resulting in a valid and reliable diagnosis of PMDD that is not dependent on an assessing clinician categorising patterns of symptoms.

2. The prevalence of PMDD in a population can be accurately measured

Following on from objective diagnosis, it is possible to obtain a population sample and accurately measure who in that sample is experiencing PMDD during a certain time-period. Some researchers have done this, and in the biggest community samples the prevalence of PMDD may be as low as 1.2% of menstruating females.

This leads onto another point - PMDD is not an attempt to pathologise women. A tiny proportion meet the strict criteria for PMDD and even the more liberal criteria for PMS applies only to a minority. It also hints at the underlying pathophysiology: an abnormal vulnerability to the normal cyclical fluctuations in female hormones.

3. PMDD goes away during pregnancy

As you might expect, during pregnancy (when there are no monthly fluctuations in female sex hormones) PMDD is absent. Patients typical feel well and have high circulating levels of female sex hormone until giving birth when both progesterone and oestrogen fall precipitously…

4. PMS is the most robust risk factor for postpartum depression

If you are following this, you probably won’t be surprised that women who are vulnerable to PMS/PMDD are also vulnerable to postpartum depression - in fact, this is the biggest risk factor identified in a recent umbrella review (a review of reviews).

5. Fluctuating hormonal levels cause the symptoms of PMDD

Again, this one seems obvious. However, unlike most psychiatric disorders we can definitively say what causes PMDD symptoms. As they are cyclical and we can experimentally stabilise hormone levels, we can measure the impact of hormone fluctuations on symptoms.

In an elegant series of experiments, Peter Schmidt and David Rubinow gave participants a medication (leuprolide) that suppresses oestrogen and progesterone. This eliminated PMDD symptoms. Whats more, when they reintroduced either oestrogen or progesterone, symptoms returned.

But this was only for women already affected by PMDD - in healthy females, either suppressing or adding back oestrogen and progesterone had no effect. Harking back to my earlier point that most women are minimally affected by hormonal fluctuations.

6. Adding back female hormones provokes symptoms…but only for one month

In a follow-up study, they suppressed hormones with leuprolide before adding them back. This time, they followed up participants for three months. Again, suppressing hormones relieved symptoms and adding-back provoked them. However, after one month…symptoms miraculously disappeared again!

What does this tell us? Symptoms of PMDD are minimal when levels of oestrogen and progesterone are either steadily high or steadily suppressed, it is the fluctuation in hormone levels that is key.

7. Blocking allopregnanolone production reduces symptoms

Scott Alexander recently did a fantastic summary of allopregnanolone-based medications for postpartum depression and Major Depressive Disorder (MDD). Well allopregnanolone, a progesterone metabolite and positive allosteric modulator of the GABA-A receptor, is also thought to be a key culprit in PMDD. An RCT (n=206) of isoallopregnanolone (sepranolone) in PMDD did not beat placebo for the primary outcome. However, blocking allopregnanolone production with the 5α-reductase inhibitor dutasteride does seem to work, in a small RCT at least.

8. We have a range of evidence-based treatments

We have treatments for PMDD that work! And a relatively logical rationale for choosing which treatment to try in which order.

First-line are SSRIs, which have specific mechanism of action in PMDD I’ll describe later.

The other treatment strategy is to suppress the cyclical fluctuation in hormones. This can be done in a step-wise fashion:

• Combined oral contraceptive pill (containing drospirenone as the older synthetic progesterones can negatively impact mood)

• Transdermal oestrogen plus micronised progesterone

• Gonadotrophin releasing hormone analogues (such as leuprolide) with hormone addback

• Surgical treatment (usually this involves removal of the uterus and ovaries and is reserved for the most severe cases)

9. Antidepressants do not work like antidepressants in PMDD

Antidepressants for PMDD work differently than in MDD. For one, the effect size in PMDD (SMD - 0.6) is bigger than the typical effect size in MDD (SMD - 0.3).

SSRIs work much faster in PMDD, typically within a few hours, peaking at 48 hours, compared to a few weeks for MDD. As a result, SSRIs can be prescribed intermittently, only during symptomatic days. When SSRIs are stopped in PMDD, relapse happens immediately in the next cycle.

As there has been much speculation about the delayed onset of SSRIs in MDD, in PMDD there is speculation about the immediate onset of action. One hypothesis is through increasing the conversion of progesterone to allopregnanolone.

10. PMDD can be present in the absence of menstruation

Surgical removal of the ovaries is the last line treatment for PMDD. However, if the uterus alone is removed (for a variety of reasons), the patient can still experience PMDD symptoms in the absence of uterine bleeding. This is because the cause of the symptoms are ovarian hormone fluctuations which still happen if the ovaries are in place.

You might be thinking - if PMDD diagnosis is based on the timing of symptoms, how can you time this without menstrual bleeding? One way is through the cyclical changes of basal body temperature that are occur, with temperature dipping before ovulation and rising afterward. From this, premenstrual days can be calculated and symptoms tracked.

Conclusions

PMDD is a cyclical affective disorder, caused by abnormal vulnerability to the normal cyclical fluctuations in female sex hormones . It can be objectively diagnosed, we have a good understanding of the underlying mechanisms and a range of effective treatments.

So why don’t more psychiatrists (particularly those with a mechanistic or biological mindset) know or care about this disorder? I think partly it’s a condition that falls between psychiatry, gynaecology and primary care. I think it’s too easily dismissed as ‘women’s issues’, not seen as mainstream and faces the bias against research into sex-specific problems.

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