Post-Partum Depression: Progesterone “Withdrawals” and the Issue with SSRIs

“Congratulations, it’s a boy!” Or a girl! Or twins!

With the birth of a child, a new happy family is formed, but it isn’t always as smooth of a transition as we’d like to pretend — especially for the new mother. A rarely discussed topic for new mothers is post-partum depression, a form of depression that presents itself in mood swings, concerns about the baby, excessive crying or sadness, and in extreme cases, thoughts of death and suicide after the birth of a child. PPD affects about 15-20% of new mothers [3], and is different from Major Depressive Disorder (clinical “depression”) in that PPD is sparked by the birth of the baby [1]. Hormonal imbalance, breastfeeding, and the pressure of being a good mother are all factors that increase anxiety in new moms, creating a state of depression that is often dismissed or ignored. Most PPD resolves in about three months [2], but there are no preventive measures or standard pharmaceutical treatments in place to treat PPD specifically.

PPD patients are sometimes prescribed Selective Serotonin Reuptake Inhibitors (SSRIs), which are antidepressant medications that were developed for MDD patients. Though they may alleviate some of the depressive symptoms of PPD, their exact mechanisms are unknown, and they were not made with safety for nursing women in mind [4]. Figure 1 is an illustration showing the fMRI (functional MRI) activity in different regions of the brain for PPD and MDD patients. There are some clear differences in which regions of the brain are activated between the two diagnoses, such as in the subfrontal gyrus, interior frontal gyrus, and posterior cingulate gyrus [2], suggesting that different pathways involved for the two forms of depression — for this reason, PPD and MDD cannot necessarily be pharmacologically treated the same way.

1-postpartumde — Figure 1: Differences in fMRI activation patterns between patients with postpartum depression and patients with major depressive disorder and general anxiety disorder. Credit: Maayan Harel (maayanillustration.com/) [Image Link]

Several regions of the brain are disturbed in PPD patients, and current research by Rupprecht, Rainer et al. suggests that neuroactive metabolites play a significant role [1]. As allosteric modulators of different receptors, neuroactive steroids can decrease neuronal excitability by increasing the receptors’ inhibitory effects, and, when in disequilibrium, may cause the mood changes exhibited by PPD patients [2]. Figure 2 is a diagram showing some of the targets that neuroactive metabolites bind to, causing dysregulation of several intracellular processes that lead to a downstream of effects.

Figure 2: Neuroactive steroids and their intracellular targets. [Image Link]

Progesterone is the neuroactive steroid of particular interest. During pregnancy, a woman’s progesterone levels increase by about 10 times the normal levels. The hypothalamic–pituitary–adrenal axis (HPA axis), a major neuroendocrine system, will adapt to accommodate the new elevated levels of hormones [3], but women may still experience a “withdrawal” of progesterone during the puerperium (post-partum) period, triggering the development of PPD. In Figure 3 below, we can observe a sharp drop-off of progesterone levels after the baby is born. Unsurprisingly, the puerperium period, during which the woman’s body returns to its non-pregnant condition, is the time during which women have the highest risk of developing PPD.

progesterone-placenta — Figure 3: Progesterone Levels before and after Pregnancy. Image taken from “High Progesterone Level Causes” by SheCares.com. [Image Link]

In addition, Rupprecht, Rainer et al. found that 3α,5α-THP and 3α,5α-THDOC, precursors of progesterone, were lower in PPD patients compared to the ante-partum levels [1]. Non-PPD patients had elevated levels of these progesterone metabolites for 7 weeks post-partum before normalization, allowing them to be “weaned” off the progesterone. In contrast, PPD patients had normalized progesterone metabolite levels within as short as 7 days post-partum, further suggesting a correlation between PPD development with relative levels of the neuroactive metabolites 3α,5α-THP and 3α,5α-THDOC [1].

Though we still don’t definitively know exactly what causes postpartum depression, new information is continuously being discovered that can hopefully lead to the development of effective preventive measures and treatments. Unfortunately, because of its short duration, pharmaceutical companies have little incentive to develop treatments specific to PPD. Known to resolve within a few months, PPD is not a big priority for drug developers because there isn’t much profit to be made from the 15-20% of mothers who would only require the treatment for a short time. The severity of hormone fluctuations during and after pregnancy also varies by person, making it difficult to develop effective universal treatments.

I hope that pharmaceutical companies will take the need for preventative PPD treatments seriously despite PPD’s short duration and small affected population relative to other disorders. The experience of depression after an infant’s birth has a huge effect on the mother’s relationship with the infant, and will most likely negatively alter her perception of motherhood. SSRI medications prescribed to affected women were not designed to treat PPD, nor were they developed to ensure that mother’s breastmilk would be unaffected. Treatments designed to prevent PPD, rather than mitigating its effects after development would be ideal, enabling women to transition to motherhood without suffering from depression that could mar the first impressions of her relationship to the newborn. Treatment that regulates progesterone and its precursors, effectively preventing post-partum progesterone “withdrawals,” would also allow new mothers to enjoy the experience of having a child without being hindered by PPD, resulting in overall better relationships to their babies.

Alternatively, just don’t have a baby.

References:

Rupprecht, Rainer et al. “Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives” Trends in Neurosciences, Volume 22, Issue 9, 410 – 416.
Trends in Neurosciences, Pawluski, Lonstein, and Fleming: “The Neurobiology of Postpartum Anxiety and Depression” http://www.cell.com/trends/neurosciences/fulltext/S0166-2236(16)30177-1
Fiorelli M, Aceti F, Marini I, et al. “Magnetic Resonance Imaging Studies of Postpartum Depression: An Overview. Behavioural Neurology.” 2015;2015:913843. doi:10.1155/2015/913843.
Misri, S. & Kostaras, X. “Benefits and Risks to Mother and Infant of Drug Treatment for Postnatal Depression” Drug-Safety (2002) 25: 903.

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