Q&A: Potential Biomarkers of Postpartum Depression

Eric D. Achtyes, MD, MS, director of the Division of Psychiatry & Behavioral Medicine for the Michigan State University College of Human Medicine, was scheduled to present at this year’s American Psychiatric Association Annual Meeting on finding depression biomarkers. In this Q&A, Dr. Achtyes discusses possible biomarkers of postpartum depression, a study he and colleagues conducted on the topic, and future research in the area.

Q: Why did you choose to speak at the APA Annual Meeting on the topic of biomarkers of depression?

A: Our current constructs for understanding the pathophysiology of depression are incomplete, based on clusters of symptoms reported by patients over a distinct period of time. We need to gain a better understanding of the biological mechanisms underlying depressive illnesses. Because when someone is ill with an infection or another inflammatory condition, they display many of the same symptoms of depression (fatigue, altered sleep, low mood), we and others have hypothesized that some episodes of depression may have an underlying inflammatory cause. If shown to be true, then in cases of “inflammatory depression,” it may be possible that certain biomarkers of inflammation could be tracked over time, to show improvement with treatment or worsening if treatment isn’t effective (analogous to tracking HbA1c in a person with diabetes, for example). They may even be used to predict a future episode of depression.

Q: Please briefly describe the study you were going to present on women with postpartum depression (PPD) and inflammatory markers.

A: We measured serum biomarkers of interleukin-1 beta (IL-1b), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-a (TNF-a), tryptophan, serotonin, kynurenine, nicotinamide, quinolinic acid (QUIN), and kynurenic acid in 165 women with and without PPD within 6-12 weeks following delivery. We then looked for associations between levels of these markers and depression severity, measured using the Edinburgh Postnatal Depression Scale (EPDS) and suicidality using the Columbia Suicide Severity Rating Scale (C-SSRS).

Q: What led you to research this topic?

A: Previous research has shown that particular biomarkers related to the process of inflammation such as IL-6, white blood cell count (WBC), C-reactive protein (CRP), QUIN, and others, are elevated in the serum and cerebrospinal fluid (CSF) of depressed and suicidal people. The kynurenine pathway, in particular, is very active in the placenta of pregnant women to prevent rejection of the fetus by the mother’s immune system, and can lead to increased levels of inflammatory metabolites during pregnancy. We wanted to investigate whether increased levels of these markers might be detected in women with PPD, compared with nondepressed postpartum controls. PPD is a serious condition, occurring during pregnancy and up to 4 weeks following delivery and effecting 15-20% of postpartum women, with suicidal ideation effecting as many as 14% of postpartum women. Unrecognized and untreated, this can lead to significant morbidity (poor maternal-infant bonding, neglect), and even mortality (suicide or infanticide) in some cases.

Q: What were the key findings of the study?

A: There were 87 women with a DSM-5 diagnosis of PPD, who had a mean EPDS score of 18.5 +- 4.7 and 60 healthy controls who did not meet PPD criteria (mean EPDS 4.3 +- 2.6). There were also 18 women who had depression, but did not meet formal time criteria for PPD. They were included in the sensitivity analysis of EPDS score over the past 7 days only. There were 43 women with suicidal ideation in the past 7 days, and 13 who had active suicidal behavior during pregnancy or in the postpartum (11 suicide attempts and 2 with preparatory behavior).

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In the cross-sectional analysis, we found that increased postpartum plasma levels of IL-6 (OR=3.0, 95% CI 1.37-6.6) and IL-8 (OR=3.32, 95% CI 1.32-8.34) and reduced plasma levels of IL-2 (OR=2.34, 95% CI 1.35-4.05), QUIN (OR=4.48, 95% CI 1.41-14.25), and serotonin (OR=1.43, 95% CI 1.07-1.92) were associated with increased severity of depressive symptoms on the EPDS. We also found that low levels of serotonin were associated with increased suicidal attempt during pregnancy even when adjusting for EPDS score (OR=69.9% increase, 95% CI 2.1%-182.2%). We think this points to an increase in kynurenine pathway activity, shunting tryptophan away from serotonin production, and towards the production of kynurenine relative to serotonin.

These immunobiologic mechanisms warrant additional longitudinal study to better understand the dynamic fluctuations during and after pregnancy, and their relationship to peripartum and inflammatory depressions.

Q: Were any of the outcomes particularly surprising?

A: I think we were surprised to see that the neurotoxic metabolite QUIN was lower in this depressed sample, as it has been shown to be elevated in other depressed and suicidal patients. This could be due to the inclusion of only female patients, or the timing of the sample collection at 6-12 weeks postpartum. In unpublished data, we have seen QUIN rise during pregnancy and then fall in the postpartum period, again, reflecting the dynamic nature of these complex neurobiological processes.

Q: Are there any short-term clinical applications of the findings?

A: Although we had a relatively large sample in this study (n=165), replicating these findings in additional large, longitudinal samples prior to clinical application or routine testing would be recommended. As the mechanisms for PPD are elucidated, trials of novel medications designed to target these specific underlying biologic processes will then be needed as well.

Q: Are you conducting any more research in this area, and are there any other studies you feel are needed?

A: Yes, as a matter of fact we are. We are also analyzing hormone levels (estrogen and progesterone) in this same cohort, to try to understand the role hormonal fluctuations may play in the pathophysiology of PPD. We also have data during the three trimesters of pregnancy and are now analyzing longitudinal fluctuations in inflammatory biomarkers to learn whether changes in these markers might be used to predict future increases in depression severity. Finally, we are actively enrolling depressed-only and depressed/suicidal patients in another National Institute of Mental Health-funded longitudinal study to assess biomarker changes to assess their predictive ability over time.

Eric D. Achtyes, MD, MS, graduated from the University of Michigan Medical School in 2003 and completed his adult psychiatry residency training at the Massachusetts General Hospital/McLean hospital program in 2007. He is an Associate Professor and directs the Division of Psychiatry & Behavioral Medicine for the Michigan State University College of Human Medicine. He is also the Behavioral Health Medical Director for Network180, which provides the public mental health safety net for more than 640,000 people living in Kent County, Michigan. He has been an investigator on more than 40 clinical studies in schizophrenia and depression, including federally funded research and implementation projects from NIA, NIAAA, NICHD, NIDA, NIMH, CMS and SAMHSA. He treats patients at Pine Rest Christian Mental Health Services and Cherry Health, both in Grand Rapids, Michigan.

The Psychiatry and Behavioral Health Learning Network is providing readers coverage of content that was scheduled to be presented at the APA’s 2020 Annual Meeting, which is not taking place because of the COVID-19 pandemic.