Today we’ll bring you up to date on how to manage premenstrual dysphoric disorder and safe prescribing during pregnancy.

Learning Objectives:
After listening to this podcast:
1. Providers should know the safest drugs in breastfeeding and the ones that carry the highest risk.
2. Clinicians should be aware of minerals and vitamins that peak and drop during the various phases of the menstrual cycle.

Publication Date: 12/05/22

Duration: 13 mins, 00 seconds

CHRIS AIKEN: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. 

KELLIE NEWSOME: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

CHRIS AIKEN: Last month we attended the 9th annual Mood Disorders Summit. We tried to write down all the practice-changing nuggets they tossed into the virtual lecture hall, and we collected a lot from Anita Clayton. Dr. Clayton holds dual posts in the departments of psychiatry and OBGYN at the University of Virginia, where she is also the Chair of the department of psychiatry. She updated us on premenstrual dysphoric disorder, peripartum, and perimenopausal mental health. Here we’ll summarize those nuggets and expand on them.

KELLIE NEWSOME: First let’s clarify some lingo. Premenstrual dysphoric disorder is part of a broader syndrome called premenstrual syndrome. Both involve physical symptoms like bloating, fatigue, weight gain, breast tenderness, and headache. What makes premenstrual dysphoric disorder stand out is that the mood symptoms are more severe: irritability, anxiety, and depression. Both occur at the same time, during the luteal phase, which starts with ovulation and ends with the period. For most women, the luteal phase is 1-2 weeks before their period.

You know, it’s very rare for me to see premenstrual dysphoric disorder in practice because it’s hard to diagnose if the woman has another mood disorder – which most of mine do – the criteria requires that the “Disturbance” – I love that, these are not just symptoms – they are a “disturbance” “is not merely an exacerbation of another disorder.” 

CHRIS AIKEN: I can only recall one case of premenstrual dysphoric disorder. It was a young woman who had very distinct mood symptoms and irritability in the 2 weeks before her cycle. Otherwise she had no problems, but the “disturbance” was so severe that it was threatening her marriage. I did what the textbooks say – I prescribed an SSRI to take just during the luteal cycle – and she got worse.

KELLIE NEWSOME: How did that happen?

CHRIS AIKEN: She got manic on the antidepressant. It turned out the premenstrual symptoms were an early sign of bipolar disorder. This was in my first year of practice, and at the time all the messaging on premenstrual dysphoria was sponsored by the SSRI companies, and they left out an important fact: Premenstrual mood worsening is a soft sign of bipolarity. Around 30-75% of women with bipolar disorder experience worsening of their mood symptoms around their menses, and bipolar itself is 3-5 times more common in the PMDD population.

KELLIE NEWSOME: One thing I liked about Dr. Clayton’s lecture was that she didn’t over-emphasize the SSRIs. Not only is there the bipolar problem to worry about there, but many women with premenstrual symptoms prefer natural treatments. Dr. Clayton listed calcium, and there is also evidence for vitamin D. Both calcium and vitamin D levels drop in the luteal phase, and this drop is associated with premenstrual symptoms. The ovarian hormones that peak then, like estradiol, speed up the metabolism of vitamin D. Women whose diets are rich in calcium and vitamin D have fewer premenstrual symptoms. So the basic science is there, but what about clinical studies?

CHRIS AIKEN: Dr. Clayton recommended calcium (1200 mg/day) during the luteal phase, but did not mention vitamin D. And that’s with good reason, the studies in vitamin D are poor quality with a mix of positive and negative results. Calcium though is supported by a large randomized trial of over 400 women. All of the calcium studies involved premenstrual syndrome – not premenstrual dysphoric disorder, so calcium is a good place to start but may not be strong enough to treat the mood symptoms of genuine PMDD. We did find one study comparing calcium to fluoxetine/Prozac in premenstrual syndrome – which involves mood symptoms as well just not as severe – and the fluoxetine worked better.

KELLIE NEWSOME: Dr. Clayton also recommended Vitamin B6 100 mg/day, the doses were all over the place – from 50 to 600 mg daily in the studies – but it’s best to stay below 200mg/day as that is the most conservative cut off for potential toxic effects like neuropathy. Some studies used it daily throughout the month, and some prescribed it only during the luteal phase 2 weeks before menstruation. Most of the vitamin B6 studies are of small size and poor quality, but there are over a dozen of these controlled trials. Most were also in the milder premenstrual syndrome it seems that vitamin B6 has better effects on the mood than the physical symptoms. 

Other natural approaches include CBT, yoga, mindfulness, and just about any stress reduction method. A healthy diet may also work, and there’s a new study showing benefits with micronutrients – which are really just a healthy diet in a pill.

CHRIS AIKEN: Turning to medications, Dr. Clayton reminded us that only sertraline, fluoxetine, and paroxetine are FDA approved for premenstrual dysphoric disorder. Some women take them all month long, some during the luteal phase, and some simply raise the antidepressant during the luteal phase – that’s a good strategy if they have comorbid major depressive disorder. We recommend starting with fluoxetine because its long half life will prevent any withdrawal problems when it’s used for brief, 2-week spurts. Fluoxetine also has the lowest risk of weight gain among the SSRIs. Dr. Clayton recommended low doses, 10-20 mg/day. 

But SSRIs are not the only FDA approved option. The oral contraceptive Yaz is also approved – it’s a monophasic combo of ethinyl estradiol 20 mcg/drospirenone 3 mg – but most of us on the mental health side should defer to OBGYN for that prescription.

KELLIE NEWSOME: Next we turn to peripartum mood disorders, which used to be called postpartum back when doctors thought that the pregnancy glow would ward off all depression while the baby is in the womb. Not so. Depression is twice as common during pregnancy – at least by the time of the second trimester – as it is in the general population. 

And that brings us to the problem that can shake a clinician’s nerves: What to do with the medications when your patient becomes pregnant? There are risks on both sides, but it’s best to let go of your own anxieties around the issue and let the woman decide. Your job is to support her with the facts, and here they are.

• If she has mild, non-recurrent depression, the risk of relapse is not particularly elevated, according to a 2020 meta-analysis, so she may be able to taper off the antidepressant – we’d suggest a 2-week taper – and add in some antidepressant activity like light exercise, stress reduction, and healthy diet.
• If she has a history of more than 1 episode though – so recurrent depression – or a history of severe depression – then the risk of relapse during pregnancy is much higher – about double if she comes off the antidepressant.
• If she had a history of postpartum depression, the risks are even higher still.

And we have to weigh that against the risks that untreated depression poses to the infant. Most directly, they have higher rates of preterm delivery, low birth rates, and delayed developmental milestones. Then there are indirect risks, like women who have depression may be less likely to adhere to take care of themselves – we’re talking poor nutrition, substance abuse, alcohol, and nonadherence with prenatal care.

CHRIS AIKEN: In terms of the risks of medication, it’s the first trimester that we worry most about. That’s when the major organs are developing and teratogenic malformations can occur.  But only a few psych meds are associated with clear and relevant dangers that give us reason to avoid them in pregnancy; According to Dr. Clayton, those are: 

• Paroxetine (Paxil), valproate (Depakote), lithium, carbamazepine, tricyclic antidepressants, benzodiazepines, and stimulants like Ritalin and Adderall.

I agree with that list, and it’s one of the reasons I avoid paroxetine in practice, but it doesn’t give us much guidance for bipolar disorder where continued treatment is almost always needed to avoid the high risk of destructive episodes. Lamotrigine has the best safety evidence in pregnancy, and the atypical antipsychotics are surprisingly a close second, so I’ll try to continue patients on just these and discontinue the rest if they are planning pregnancy. But for about 1 in 3 people with bipolar disorder lithium is uniquely effective, and newer papers have suggested that the risks with lithium are not as bad as once thought. A new analysis from the American Journal of Psychiatry provides more accurate measures by pulling together multiple studies and comparing apples to apples: both groups of pregnant women had mood disorders, so the only difference between the two groups was that one took lithium. Only one risk stood out as significantly related to lithium: congenital anomalies, particularly cardiac abnormalities like Ebstein’s and atrioventricular septal defects. The paper also gives us usable numbers for those. The risk due to lithium for any congenital anomaly is 1 in 38, and the risk for cardiac anomalies is is 1 in 83. 

By congenital anomalies we’re talking about any structural defect, like neural tube defects where the spinal cord doesn’t close; or hypospadias in boys where the opening of the urethra is not located at the tip of the penis.

KELLIE NEWSOME: There are two ways to lower these risks with lithium. First, avoid exposure during the first trimester – that removed the risk of cardiac anomalies, though it didn’t completely eliminate the risk of all anomalies. Next, stick to the lowest dose of lithium that works, as the risk was dose dependent in this analysis. But Dr. Clayton emphasized that for other medications the risks are not dose-dependent, so you don’t gain anything – and do lose a lot – by lowering the dose of an antidepressant just to minimize the risks. Relapse rates are not as bad after lowering the dose as they are when women stop their antidepressant altogether; they are in the middle, about half way between staying on and stopping. And that puts these women into a whole new category – the ones who have depression despite taking an antidepressant. Outcomes for the infant were the worst for this group.

CHRIS AIKEN: The final thing you need to know about pregnancy is that doses may need to be adjusted in the third trimester. For one thing, the volume of distribution increases, diluting the medications in all that bloodflow. But pregnancy also increases the metabolism of some meds in the liver. For example lamotrigine may need to be as much as doubled during the third trimester. 

KELLIE NEWSOME: As we end this podcast let’s make a list of some of the key drugs to know in pregnancy. First, the meds with the highest risk in pregnancy: 

Paroxetine (Paxil), valproate (Depakote), lithium, carbamazepine, tricyclic antidepressants, benzodiazepines, and stimulants like Ritalin and Adderall. But benzodiazepine withdrawal is also harmful for the mother and possibly the developing fetus, so if you are stopping that it’s best to taper it off.

The safest antidepressant – or at least the one with the most robust safety data – is fluoxetine, but this one is not ideal for breastfeeding so if your patient plans to breastfeed and they have never been on an antidepressant before than sertraline (Zoloft) is your best choice.

The following antidepressants are not as well studied, but we at least don’t know of any major risks with them: bupropion, trazodone, mirtazapine, and all the SSRIs/SNRIs.

When it comes to pregnancy, we worry about teratogenicity as the organs develop, but when it comes to breastfeeding the risks are very different. There we worry about how much the medication passes into the breast milk and what the risks of toxicity are. Those toxicity risks are similar for adults as they are for infants – so manly we’re worried about sedation and depressing respiration. 

The safer drugs in breastfeeding are: Sertraline, bupropion, the atypical antipsychotics, buspirone, and – surprisingly – the z hypnotics, particularly zaleplon (Sonata) which has a favorable L2 rating – probably because of its short half life..

The riskier drugs in breastfeeding are:

• Benzodiazepines: We worry about sedation
• The tricyclics: Worry about constipation and – with doxepin – sedation 
• Nefazodone and trazodone – sedation
• Some atypical antipsychotics – particularly quetiapine (Seroquel) and ziprasidone (Geodon) – which can be sedating
• Lithium – we worry about lithium toxicity
• Valproate and carbamazepine: Potential hepatotoxicity or blood dyscrasia
• And a controversial one is lamotrigine. Dr. Clayton was concerned about the risk of a rash in the infant, but many women with epilepsy have breastfed on lamotrigine and we’ve found no cases of serious rash in the literature. We asked Dr. Clayton about this and she conjectured that lamotrigine is probably safe as long as the infant was exposed to it in the womb – because they are not likely to develop an allergic reaction if they are already accustomed to it – but that it could be risky to start lamotrigine in a breastfeeding mother. Lamotrigine levels do pass into the breastmilk, and in the baby lamotrigine reaches levels that are about 30% that of the mother.

CHRIS AIKEN: And just as with pregnancy, we have to educate women that avoiding breastfeeding comes with risks of its own. Formula has not replaced the significant health benefits of breastfeeding, such as greater immunity, and protection against asthma, obesity, diabetes, and sudden infant death syndrome (SIDS). Breastfed babies also have higher IQs, which reminds me of one of my favorite studies: the Neurodevelopmental Effects of Antiepileptic Drugs study. This international study followed 177 women with epilepsy for 6 years after giving birth. The study was not randomized, but about half of the women chose to breastfeed while taking an anticonvulsant and the other half chose to bottle feed. They were taking a variety of antiepileptics - carbamazepine, lamotrigine, phenytoin, and valproate.

That last one scared me: valproate (Depakote), because it is probably the riskiest psych med during pregnancy. Not only can it cause neural tube defects, but children exposed to valproate in the womb grow up to have 10 points lower on their IQ. So I would not feel comfortable about giving a breastfeeding woman valproate. And this study did confirm that fetal exposure to valproate resulted in a lower IQ, but when it came to breastfeeding the results were flipped. At age 6, the children who were breastfed on valproate had higher IQs than those whose mothers bottle fed them while taking valproate to avoid any risks with the med. 

The finding of greater development and IQ when breastfeeding on the meds was true for all the antiepileptics, and particularly significant for valproate. 

KELLIE NEWSOME: Managing meds in the peripartum is not about knowing which meds to use and which ones to avoid. There are risks on all sides in this business, and the hard part is in helping your patients understand that reality. Patients are often focused on the medications, as though each one is a jagged pill taking aim at their developing child. Not so. Babies are exposed to far more chemicals than what’s in their pill box – air pollution, caffeine, alcohol –the average package of processed foods has more chemicals on than your patients medlist – and most of them untested. The bottom line is that a healthy mother leads to a healthy baby – and mental health is part of that. Focus your patient on what they can do to improve their health during pregnancy. Are they taking a prenatal vitamin? Avoiding alcohol? Limiting caffeine? Are they keeping away from the kitty litter with its well-known risk of toxoplasmosis? Reducing stress and getting good sleep, exercise, and a healthy diet? Any one of those is going to make a bigger difference for the baby’s health than stopping or starting the average psych med. With the possible exception of the big 7 – the meds with known risks in pregnancy. Let’s call them out one more time:

•Paroxetine (Paxil), valproate (Depakote), lithium, carbamazepine, tricyclic antidepressants, benzodiazepines, and stimulants like Ritalin and Adderall.

If you missed the Mood Disorders Summit,  catch it next September where they’ll return to a real, in-person conference in Scottsdale, Arizona. The conference will also be simulcast for a virtual audience, and admission is free for all attendees.

Earn your CME for this episode through the link in the show notes, and we hope you will join us in two weeks when we pick up on the 10 Psychopharm Commandments with #6: Honor thy MAOI interactions. In the meantime, follow Dr. Aiken on twitter or LinkedIn – his handle is @chrisaikenmd - where he has posted a new finding every day for the past 6 months. Today’s study closes the door on a once promising trend. After an initial success, the novel antipsychotic pimavanserin/Nuplazid failed to deliver in two randomized controlled trials of antidepressant augmentation. 

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The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.