Postpartum depression (PPD) affects between 10 and 20% of women in the general population, but the risk is much higher in women with a history of major depression (MDD) or bipolar disorder (BP) with at least 30% developing PPD (Payne et al, 2007). There is evidence that women with a history of PPD are affectively susceptible to hormonal change: Bloch et al (2000) demonstrated that women with a history of PPD developed mood symptoms in response to a blinded withdrawal of supraphysiological levels of estrogen and progesterone compared to none of controls.
We used a cross-species translational design to identify estrogen-mediated epigenetic changes associated with PPD (Guintivano et al, 2013). DNA methylation profiles were generated from whole blood using methylation microarrays in a sample of PPD high-risk women who were followed prospectively through pregnancy and after delivery. These profiles were cross-referenced with syntenic locations, which demonstrated murine hippocampal DNA methylation changes in response to long-term treatment with 17β-estradiol (E2). Initially, we investigated only DSM-4 defined PPD where women suffered a major depressive episode within 4 weeks of delivery. Using this group, we identified two biomarker loci at HP1BP3 and TTC9B, which predicted PPD with an area under the receiver operator characteristic curve (AUC) of 0.87. In a replication analysis, these biomarkers also functioned to segregate PPD status in women who developed depression during the antenatal period with 88% accuracy; however intriguingly, the prediction was in the opposite direction. There is controversy in the literature as to whether PPD as defined by DSM-4 is a unique entity from depression that begins during pregnancy and continues postpartum. In light of previous reports demonstrating depression-associated changes in white blood cell type compositions (Lutgendorf et al, 2008), we compared the two groups and found a decrease in the ratio of monocytes to lymphocytes and granulocytes in the antenatally depressed women that correlated with HP1BP3 DNA methylation status. Incorporation of cellular composition into the model enabled a prediction of PPD status with an AUC of 82% independent of antenatal depression status.
Our results further suggested that there is an enhanced sensitivity to estrogen-based DNA methylation reprogramming in the hippocampus in those at risk for PPD, independent of antenatal depression status. Our findings are consistent with the hypotheses of hormone sensitivity-mediated PPD risk put forth by Bloch et al, as well as previous work implicating an increased sensitivity of the stress system with antenatal depression (Katz et al, 2012).
As estrogen is closely tied to both the hypothalamic pituitary adrenal (HPA) axis as well as inflammation, it is conceivable that our findings represent a first step in unifying the disparate definitions of PPD into a common etiology of estrogen sensitivity and possibly a continuum of vulnerability to its downstream consequences. Whether our identified biomarkers represent a mere proxy of estrogen sensitivity or are involved in PPD pathophysiology will require further study. TTC9B may be linked to regulation of AMPA receptor levels, which in turn have been shown to be associated with resilience or vulnerability to stress (Schmidt et al, 2010). If the molecular changes exhibited by the biomarkers indicate a biological vulnerability, these may interact with stress occurring in the postnatal period and ultimately lead to depression. The use of animal models to either alter brain biomarker expression or to simulate hormone sensitivity differences may be used to test these mechanistic hypotheses. Further research will be needed to determine whether the identified biomarkers will display PPD predictive alterations at periods of low circulating estrogen in non-pregnant women; however, as high estrogen levels are a feature of normal pregnancy, these biomarkers are capable of early screening for PPD during pregnancy independent of whether they represent trait or state biological variation.
In conclusion, we have identified biomarkers for postpartum mood status that correctly identify whether or not a woman will be depressed during the postpartum time period, regardless of whether or not she is depressed during pregnancy. Future work is needed to confirm these findings and to determine whether identification of women at risk will allow successful prevention of PPD.
FUNDING AND DISCLOSURE
ZK and JP co-inventors listed on a patent application for DNA methylation at biomarker loci related to PPD. In the past year, JP has conducted consulting work for Astra Zeneca and Johnson and Johnson. JP also has a grant from Corcept Pharmaceuticals.
Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR (2000). Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 157: 924–930.
Guintivano J, Arad M, Gould TD, Payne JL, Kaminsky ZA (2013). Antenatal prediction of postpartum depression with blood DNA methylation biomarkers. Mol Psychiatry (advance online publication, 21 May 2013).
Katz ER, Stowe ZN, Newport DJ, Kelley ME, Pace TW, Cubells JF et al (2012). Regulation of mRNA expression encoding chaperone and co-chaperone proteins of the glucocorticoid receptor in peripheral blood: association with depressive symptoms during pregnancy. Psychol Med 42: 943–956.
Lutgendorf SK, Lamkin DM, DeGeest K, Anderson B, Dao M, McGinn S et al (2008). Depressed and anxious mood and T-cell cytokine expressing populations in ovarian cancer patients. Brain Behav Immun 22: 890–900.
Payne JL, Roy PS, Murphy-Eberenz K, Weismann MM, Swartz KL, McInnis MG et al (2007). Reproductive cycle-associated mood symptoms in women with major depression and bipolar I disorder. J Affect Disord 99: 221–229.
Schmidt MV, Trumbach D, Weber P, Wagner K, Scharf SH, Liebl C et al (2010). Individual stress vulnerability is predicted by short-term memory and AMPA receptor subunit ratio in the hippocampus. J Neurosci 30: 16949–16958.
This work was funded in part by a NARSAD 2010 Young Investigator Award to ZK and K23 MH074799-01A2 to JP.
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Kaminsky, Z., Payne, J. Seeing the Future: Epigenetic Biomarkers of Postpartum Depression. Neuropsychopharmacol 39, 234 (2014). https://doi.org/10.1038/npp.2013.238
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