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The Future of Mental Health Research Examining the Interactions of The Hormones and Behavior 114 (2019) 104521 Contents lists available at ScienceDirect Hormones and Behavior journal homepage: www.elsevier.com/locate/yhbeh Review article Frank Beach Award Winner - The future of mental health research: Examining T the interactions of the immune, endocrine and nervous systems between mother and infant and how they affect mental health Jaclyn M. Schwarz University of Delaware, Department of Psychological and Brain Sciences, 108 Wolf Hall, Newark, DE 19716, USA ARTICLE INFO ABSTRACT Keywords: Pregnancy and the postpartum period are periods of significant change in the immune and endocrine systems. Women's health This period of life is also associated with an increased risk of mental health disorders in the mother, and an Peripartum mood disorders increased risk of developmental and neuropsychiatric disorders in her infant. The collective data described here Hormones supports the idea that peripartum mood disorders in mother and developmental disorders in her infant likely Cytokines reflects multiple pathogeneses, stemming from various interactions between the immune, endocrine and nervous Developmental disorders systems, thereby resulting in various symptom constellations. In this case, testing the mechanisms underlying Brain development specific symptoms of these disorders (e.g. deficits in specific types of learning or anhedonia) mayprovidea better understanding of the various physiological interactions and multiple etiologies that most likely underlie the risk of mental health disorders during this unique time in life. The goal here is to summarize the current understanding of how immune and endocrine factors contribute to maternal mental health, while simultaneously understanding the impact these unique interactions have on the developing brain of her infant. 1. Introduction and significance maternal and fetal medicine come to the forefront, because it is also now recognized that a lack of appropriate maternal-fetal care can increase the Maternal and fetal medicine are an important component of risk of negative mental health outcomes in both mother and infant. Women's Health, and this particular niche of medicine has continue to In 2013, Drs. Insel and Landis from the NIH wrote an important gain increased attention in recent years. In spite of that, maternal and perspective on our progress and future in mental health research (Insel fetal health outcomes have not improved in the United States in recent and Landis, 2013). They indicated that many neuropsychiatric dis- years. The Center for Disease Control (CDC) National Vital Statistics orders “begin early in life” and thus are the “chronic diseases of the young” Reports indicate an increased rate of pre-term births, which rose to that “have become the largest source of years lived with disability”. We nearly 10% of all births in 2017 (Centers for Disease Control, 2018). interpret “early in life” as the prenatal and the immediate neonatal or They also report an increase in the number of infants with significantly postpartum periods, and as such, these are sensitive periods of life for low birth weights for the third year in a row, rising to nearly 8.2% of all the infant and mother that should become an important consideration live births in 2017. They also report that only 75% of women in the in our understanding of the etiology of mental health disorders. For United States begin prenatal care in the first trimester, while nearly example, pregnancy and the postpartum period is associated with an 25% of women don't begin any form of prenatal treatment until the increased risk of depression and anxiety in 10–15% of mothers (Sherer second or third trimesters of pregnancy, if at all (Centers for Disease et al., 2018). Moreover, the prevalence of developmental disorders, Control, 2018). Ultimately, infant mortality in the United States is high including autism, schizophrenia, generalized pervasive developmental for a developed nation, as the CDC reports that 23,000 infants died in disorders, and even learning disabilities in the United States is 13.87% the United States in 2016 alone. These data clearly highlight that as a (Boyle et al., 2011; Scott et al., 2016). The primary risk factors for nation, we can do better. The goal of maternal and fetal medicine is that developmental disorders include inadequate prenatal care, complica- both mother and infant get the necessary assessment and care related to tions during pregnancy, maternal mental illness, early emotional de- nutrition, environmental factors, infection, stress, or other conditions privation, and in utero exposure to illness or toxins (Scott et al., 2016). that increase the health risks for mother and infant throughout gesta- Despite their prevalence and severity, the etiology of these various tion and into the postpartum period. The Significance: It's time that disorders are not well understood. In our lab, we hypothesize that E-mail address: [email protected]. https://doi.org/10.1016/j.yhbeh.2019.04.008 Received 1 February 2019; Received in revised form 28 March 2019; Accepted 10 April 2019 Available online 18 April 2019 0018-506X/ © 2019 Elsevier Inc. All rights reserved. J.M. Schwarz Hormones and Behavior 114 (2019) 104521 interactions between the endocrine, immune and nervous system behavior”, a highly organized behavioral effect of the immune system of mother and infant have an important impact on the risk of that allows an organism to fight infection as efficiently as possible neural and psychiatric disorders in the offspring as well as the through the induction of various behaviors including listlessness, de- mother. Here we explore the evidence in support of this hypothesis creased appetite, sleepiness, reclusion, anhedonia, and malaise with the goal of increasing awareness of specific issues in the field of (Dantzer, 2006, Dantzer, 2001, Dantzer et al., 2011, Dantzer et al., mental health research that require further attention and additional 2008). Many researchers have noted the similarity of these sickness research. We also discuss possible criteria for effective diagnosis, as behaviors with the symptoms seen in major depression, and as a result well as mechanisms and risk factors associated with mental health it has been suggested that significant increases in circulating cytokines outcomes in the mother and infant. may be linked to the development of mood disorders, most notably major depressive disorder (Alesci et al., 2005; Brambilla and Maggioni, 2. Part 1. Pregnancy is a unique period of immunological change 1998; Capuron et al., 2004). In patients with major depressive dis- in mother that has been understudied in the context of mental orders, the production of specific cytokines (e.g. interferon, IL-6 and health monocyte chemotactic protein 1, tumor necrosis factor, and macro- phage inflammatory protein – 1a) can be exaggerated, correlating with During pregnancy, a mother's immune system undergoes a number an additional mental health pathologies, such as anxiety, in these in- of important changes that begin at the moment of conception and dividuals (Gaspersz et al., 2017). Moreover, immune molecules typi- continue through parturition. These changes in immune function are cally produced during infections, can induce major depression and even initiated by the cellular interactions at the placenta and the decidua of various forms of psychosis when injected directly into people or rodents the uterus. They are maintained by elevated levels of pregnancy hor- (Miller et al., 2009). This evidence is particularly important given that mones, including progesterone and estrogens, and they are tightly pregnancy and the postpartum period are associated with an increased controlled throughout pregnancy such that minor perturbations in im- risk of mood disorders, but also other pathologies including anxiety and mune function can affect the success of the pregnancy (Craenmehr psychosis (Goodman et al., 2016; M'baïlara et al., 2005; Pawluski et al., et al., 2016; Salamonsen et al., 2016; Song and Shi, 2014). The immune 2017; Seyfried and Marcus, 2003). system of the mother changes its function to accommodate the embryo A few studies indicate that perinatal depression is associated with for implantation, growth, development and maturation of the new in- alterations in cytokine production in the periphery, which would sug- fant, but this can also significantly contribute to the mother's health, gest that women diagnosed with perinatal depression are experiencing both pre- and postpartum (Estes and McAllister, 2016; Harmon et al., dysregulation of the immune system to some degree (Leff-Gelman et al., 2016; Moffett and Loke, 2006). As a result of these changes in immune 2016; Osborne and Monk, 2013). Alternatively, the naturally occurring function, the induction of classical (Th1/M1) pro-inflammatory im- changes in cytokine production that result from pregnancy and preg- mune molecules, such as Interleukin (IL)-1β or Tumer Necrosis Factor nancy hormones may induce subsequent vulnerability to mood and (TNF)-α, are decreased over the course of gestation while a unique anxiety disorders during pregnancy or the postpartum period. For ex- composition of alternate (Th2/M2) immune molecules are expressed in ample, a recent study found that circulating levels of IL-6, IL-15, and response to immune challenges (e.g. IL-4, IL-6, Arginase 1, and IL-10). CCL3 were significantly higher at a third trimester visit in depressed The difference between these classical (Th1/M1) and alternative (Th2/
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