Portal de Periódicos da CAPES

Perinatal Depression: Embracing Variability toward Better Treatment and Outcomes

2019; Cell Press; Volume: 102; Issue: 1 Linguagem: Inglês

10.1016/j.neuron.2019.02.023

1097-4199

Liisa A.M. Galea, Vibe G. Frøkjær,

Child and Adolescent Psychosocial and Emotional Development

Perinatal depression (PND) is a heterogeneous disorder with differences in timing of onset of depression, which influences symptomology, severity, and treatment efficacy. Researchers must embrace the heterogeneity to bring fruition to a precision medicine approach for women in reproductive mental health care. Perinatal depression (PND) is a heterogeneous disorder with differences in timing of onset of depression, which influences symptomology, severity, and treatment efficacy. Researchers must embrace the heterogeneity to bring fruition to a precision medicine approach for women in reproductive mental health care. Depression is expected to be the number one burden of disease by 2030, according to the World Health Organization. Strikingly, depression affects twice as many women as men. Intriguingly, this disparity between the sexes starts from puberty and is most prominent during the reproductive years when women are in their 20s–50s. It is clear that in order to understand the etiology of disease and to build better animal or preclinical human models of disease, researchers should pay heed to the epidemiology of depression to emulate depression as it exists in its various forms. For women, the early postpartum is a time of high risk to develop a depressive episode for women (Munk-Olsen et al., 2006Munk-Olsen T. Laursen T.M. Pedersen C.B. Mors O. Mortensen P.B. New parents and mental disorders: a population-based register study.JAMA. 2006; 296: 2582-2589Crossref PubMed Scopus (504) Google Scholar). Perinatal depression (PND) is a distinct subtype of major depressive disorder that shares many similarities with major depressive disorder, although women with PND have greater levels of co-morbidity with anxiety, obsessive-compulsive symptoms, and thoughts of harm to their baby (Perani and Slattery, 2014Perani C.V. Slattery D.A. Using animal models to study post-partum psychiatric disorders.Br. J. Pharmacol. 2014; 171: 4539-4555Crossref PubMed Scopus (44) Google Scholar). So how can we exploit this information to understand and build better models of depression in females? A shocking 80% of women will experience a form of postpartum “blues,” while 15% of women will develop more severe PND. Perhaps due to the overwhelming number of women with low mood in the postpartum, diagnoses are often overlooked in postnatal visits and virtually ignored in the literature until recently. However, the postpartum period is the time of greatest risk to develop depression and/or anxiety disorders during a women’s lifetime. Worse yet, although the wellbeing of the mother is of paramount concern, as there is an increased risk of suicide at this time, there are both short- and long-term repercussion on the health of child. Mother-infant interactions are disrupted with PND, which affects many aspects of development. Children of depressed mothers are more likely to suffer from cognitive and antisocial behavioral issues and as teenagers suffer from depression themselves. Thus, it is of the upmost importance that the medical community understand the importance of early biomarkers and interventions not only for the health of the women but also for her child and family. Putting it mildly, pregnancy and the postpartum is a life-changing experience. During pregnancy, the woman’s body has to perform an intricate, physiologically challenging dance, together with the newly formed placenta, to ensure the survival and healthy development of the fetus. The placenta itself is complex, and demanding, as the new endocrine gland produces massive levels of hormones only seen during pregnancy. Furthermore, the placenta not only supports the growth of the fetus but also plays a role in shaping fetal brain development. Appropriate placental functioning has short- and long-term implications for the health of both the mother and the offspring. Indeed, the interplay between placenta, placental enzymes, inflammatory signaling, and hormones likely contributes to depression susceptibility in the mother and influences the fetus in ways we do not as of yet fully appreciate, including the child’s risk for psychiatric disease. To say hormone levels during pregnancy are elevated is to understate the matter. Progesterone, estriol, cortisol, allopregnanlone, and other hormones that are undetectable outside of pregnancy are at higher levels than normal, while estradiol reaches over 200% of pre-pregnancy levels. These high levels of hormones are maintained or escalate throughout the 40 weeks of human gestation and then plunge dramatically at parturition. While these changes prepare the brain for motherhood, they may also render a woman more biologically susceptible to depression, and recent studies highlight that some women navigate this hormonal rollercoaster less robustly than others (Frokjaer et al., 2015Frokjaer V.G. Pinborg A. Holst K.K. Overgaard A. Henningsson S. Heede M. Larsen E.C. Jensen P.S. Agn M. Nielsen A.P. et al.Role of serotonin transporter changes in depressive responses to sex-steroid hormone manipulation: a positron emission tomography study.Biol. Psychiatry. 2015; 78: 534-543Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). This information drew us early on to establish an animal model of depression based on withdrawal from a hormone-simulated pregnancy (for review, see Perani and Slattery, 2014Perani C.V. Slattery D.A. Using animal models to study post-partum psychiatric disorders.Br. J. Pharmacol. 2014; 171: 4539-4555Crossref PubMed Scopus (44) Google Scholar) and to determine whether sex-hormone fluctuations increased vulnerability to depressive symptoms in women by exposing them to ovarian hormone stimulation with subsequent profound withdrawal (Frokjaer et al., 2015Frokjaer V.G. Pinborg A. Holst K.K. Overgaard A. Henningsson S. Heede M. Larsen E.C. Jensen P.S. Agn M. Nielsen A.P. et al.Role of serotonin transporter changes in depressive responses to sex-steroid hormone manipulation: a positron emission tomography study.Biol. Psychiatry. 2015; 78: 534-543Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Notably, we and others have found that, following withdrawal from a hormone-simulated pregnancy, there is evidence of reduced neurogenesis and reduced expression of inhibitory neurotransmitter receptor GABAARα4 and brain-derived neurotropic factor (BNDF) in the hippocampus (reviewed in Eid et al., 2019Eid R.S. Gobinath A.R. Galea L.A.M. Sex differences in depression: Insights from clinical and preclinical studies.Prog. Neurobiol. 2019; (Published online February 2, 2019)https://doi.org/10.1016/j.pneurobio.2019.01.006Crossref PubMed Scopus (136) Google Scholar). In addition, ovarian steroid withdrawal or withdrawal from a modified hormone-simulated pregnancy in women increased gene expression of serotonin transporter (SERT) in the hippocampus and cortex and enhanced cortisol response in women with a history of postpartum depression (reviewed in Eid et al., 2019Eid R.S. Gobinath A.R. Galea L.A.M. Sex differences in depression: Insights from clinical and preclinical studies.Prog. Neurobiol. 2019; (Published online February 2, 2019)https://doi.org/10.1016/j.pneurobio.2019.01.006Crossref PubMed Scopus (136) Google Scholar). Findings reveal that withdrawal from estradiol affects critical domains of brain function in women who experience depressive-like symptoms, with compromised serotonin signaling in key brain regions known to be dysfunctional in major depressive disorder, and affects hippocampus functional connectivity (Frokjaer et al., 2015Frokjaer V.G. Pinborg A. Holst K.K. Overgaard A. Henningsson S. Heede M. Larsen E.C. Jensen P.S. Agn M. Nielsen A.P. et al.Role of serotonin transporter changes in depressive responses to sex-steroid hormone manipulation: a positron emission tomography study.Biol. Psychiatry. 2015; 78: 534-543Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). These findings complement other findings that the postpartum is associated with a number of epigenetic changes, which link estrogen signaling and sensitivity to estrogens to the core of PND pathophysiology (Guintivano et al., 2014Guintivano J. Arad M. Gould T.D. Payne J.L. Kaminsky Z.A. Antenatal prediction of postpartum depression with blood DNA methylation biomarkers.Mol. Psychiatry. 2014; 19: 560-567Crossref PubMed Scopus (112) Google Scholar). Based on these models, significant progress in understanding the mechanisms that make some women more vulnerable to depression in the early postpartum via the fluctuation of these hormones has been established. These studies also suggest that women who are more sensitive to hormone fluctuations, such as premenstrual dysphoric disorder, may be more at risk to develop a mood disorder in the early postpartum. One of the largest risk factors for depressive episodes in the perinatal period is depression prior to pregnancy, but it is important to acknowledge that 40%–60% of women with PND are experiencing depression for the first time in their life (Putnam et al., 2017Putnam K.T. Wilcox M. Robertson-Blackmore E. Sharkey K. Bergink V. Munk-Olsen T. Deligiannidis K.M. Payne J. Altemus M. Newport J. et al.Postpartum Depression: Action Towards Causes and Treatment (PACT) ConsortiumClinical phenotypes of perinatal depression and time of symptom onset: analysis of data from an international consortium.Lancet Psychiatry. 2017; 4: 477-485Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). The criteria for PND diagnoses differ by organization, depending primarily on when the timing of depressive symptoms after pregnancy must occur, with the World Health Organization having identified the longest period after parturition at 12 months and the DSM-V identifying that depression must occur during pregnancy or within the first 4 weeks after giving birth. Unfortunately, most organizations do not fully appreciate that the variability in timing of onset of depression in a perinatal context has repercussions in the manifestation and outcome of PND on child outcomes and has implications for the treatment of PND. Studies have found that time of onset of depression has profound implications for severity, symptom cluster, chance of remission, and etiological factors. Interestingly, recent studies, which bridge animal and human data, highlight the intriguing hypothesis that estradiol, through induction of serotonin transporter expression in the brain, may compromise serotonin signaling and increase the risk for depressive symptoms in late pregnancy in certain susceptible individuals (Frokjaer et al., 2015Frokjaer V.G. Pinborg A. Holst K.K. Overgaard A. Henningsson S. Heede M. Larsen E.C. Jensen P.S. Agn M. Nielsen A.P. et al.Role of serotonin transporter changes in depressive responses to sex-steroid hormone manipulation: a positron emission tomography study.Biol. Psychiatry. 2015; 78: 534-543Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Other features, such as reduced hippocampal plasticity, may dominate the brain changes in women who are more vulnerable to the withdrawal phase (for review, see Galea et al., 2018Galea L.A.M. Qiu W. Duarte-Guterman P. Beyond sex differences: short- and long-term implications of motherhood on women’s health.Current Opinion in Physiology. 2018; 6: 82-88Crossref Scopus (16) Google Scholar). Indeed, some women experience severe and rapidly deteriorating depressive episodes in the early postpartum period (Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium, 2015Postpartum Depression: Action Towards Causes and Treatment (PACT) ConsortiumHeterogeneity of postpartum depression: a latent class analysis.Lancet Psychiatry. 2015; 2: 59-67Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar), leading to suicidal ideation and, tragically, infanticide. Notably, suicide is the leading cause of maternal deaths within a year from childbirth, which clearly calls for action. Numerous studies suggest that the endophenotypes of depression during the perinatal period are heterogeneous (Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium, 2015Postpartum Depression: Action Towards Causes and Treatment (PACT) ConsortiumHeterogeneity of postpartum depression: a latent class analysis.Lancet Psychiatry. 2015; 2: 59-67Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). First depressive episodes can occur during pregnancy (early or late) or the postpartum (early or late), and/or existing depression prior to pregnancy can also influence the development of depression during pregnancy and/or the postpartum. Depression with different timing onset (pregnancy or the postpartum, early or late) has a different constellation of symptoms and has variable etiologies and possibly prognosis. For example, women with gestational onset, or greater than 8 weeks postpartum onset, were more likely to have a history of depression and/or anxiety and have the most severe depression (Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium, 2015Postpartum Depression: Action Towards Causes and Treatment (PACT) ConsortiumHeterogeneity of postpartum depression: a latent class analysis.Lancet Psychiatry. 2015; 2: 59-67Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). Those women with a postpartum onset within the first 4 weeks were more likely to have pregnancy complications, present with greater anhedonia and anxiety symptoms (Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium, 2015Postpartum Depression: Action Towards Causes and Treatment (PACT) ConsortiumHeterogeneity of postpartum depression: a latent class analysis.Lancet Psychiatry. 2015; 2: 59-67Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar), and have their depression resolved within 12 months. As alluded to earlier, it is possible that women who exhibit first depressive symptoms shortly after parturition are more responsive to both effects of high hormone levels in late pregnancy and the subsequent withdrawal of placental and ovarian hormones such as estradiol and progesterone, which then most profoundly affects their neurobiology in the early postpartum. Indeed, on average, women will exhibit more depressive symptoms when exposed to a sudden withdrawal from ovarian hormones, with a subset of women showing even more endorsement (Frokjaer et al., 2015Frokjaer V.G. Pinborg A. Holst K.K. Overgaard A. Henningsson S. Heede M. Larsen E.C. Jensen P.S. Agn M. Nielsen A.P. et al.Role of serotonin transporter changes in depressive responses to sex-steroid hormone manipulation: a positron emission tomography study.Biol. Psychiatry. 2015; 78: 534-543Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). This suggests that women that are more vulnerable to these sudden changes may be more susceptible to PND with an onset in the early postpartum and may require different treatment than women who present with PND during pregnancy or in the later postpartum. In a study of 663 women with PND, approximately 70% of women show an onset of depressive symptoms during pregnancy (rather than the postpartum) (Putnam et al., 2017Putnam K.T. Wilcox M. Robertson-Blackmore E. Sharkey K. Bergink V. Munk-Olsen T. Deligiannidis K.M. Payne J. Altemus M. Newport J. et al.Postpartum Depression: Action Towards Causes and Treatment (PACT) ConsortiumClinical phenotypes of perinatal depression and time of symptom onset: analysis of data from an international consortium.Lancet Psychiatry. 2017; 4: 477-485Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). These women are more likely to have longer-lasting depression than those who show onset during the postpartum, although this varies by study and whether or not pre-existing depression was noted (Munk-Olsen et al., 2006Munk-Olsen T. Laursen T.M. Pedersen C.B. Mors O. Mortensen P.B. New parents and mental disorders: a population-based register study.JAMA. 2006; 296: 2582-2589Crossref PubMed Scopus (504) Google Scholar, Postpartum Depression: Action Towards Causes and Treatment (PACT) Consortium, 2015Postpartum Depression: Action Towards Causes and Treatment (PACT) ConsortiumHeterogeneity of postpartum depression: a latent class analysis.Lancet Psychiatry. 2015; 2: 59-67Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, Putnam et al., 2017Putnam K.T. Wilcox M. Robertson-Blackmore E. Sharkey K. Bergink V. Munk-Olsen T. Deligiannidis K.M. Payne J. Altemus M. Newport J. et al.Postpartum Depression: Action Towards Causes and Treatment (PACT) ConsortiumClinical phenotypes of perinatal depression and time of symptom onset: analysis of data from an international consortium.Lancet Psychiatry. 2017; 4: 477-485Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). These women likely have a different etiology of depression due to their predisposition or to complications during pregnancy. For example, women may be more susceptible during pregnancy given the rise in hormones or complications, such as preeclampsia or nausea, that may act as stressors and affect quality of life during pregnancy. Mothers who have PND during the later stages of the postpartum are more likely to have experienced stress such as complications with obstetrics and/or lack of social support, and indeed, there are indications that PND symptoms are related to higher levels of cortisol in either the early postpartum or later postpartum. Again, the difference in timing of depression not only has implications for differing etiology and symptoms of PND, but it is possible that PND later in the postpartum may require different treatment than those with PND earlier in the postpartum or during pregnancy. Given this diversity in maternal depression patterns, it is unfortunate that organizations classifying depression have not factored in the timing of depression in the perinatal context as an important indicator of type of PND. The community needs to embrace this heterogeneity to acknowledge that there are likely different mechanisms at play and, accordingly, different strategies needed for risk and disease management, which are yet to be exploited for these different phenotypes of PND. Clinical research efforts are needed in order to determine whether onset stratifiers should guide treatment choice in patients with PND and whether certain biomarkers, including gene transcript and/or epigenetic signatures, can identify women of such different subtypes of PND to allow for targeted and personalized clinical care. One of the neglected areas of research has been how motherhood changes the brain in both the short and long term. Natural postpartum changes within the brain likely contribute to the greater vulnerability to mental health disorders during this time. The postpartum is associated with reduced neuroplasticity in the hippocampus and dorsal raphe nuclei and greater immune signaling in the hippocampus (for review, see Galea et al., 2018Galea L.A.M. Qiu W. Duarte-Guterman P. Beyond sex differences: short- and long-term implications of motherhood on women’s health.Current Opinion in Physiology. 2018; 6: 82-88Crossref Scopus (16) Google Scholar). However, it is important to note that other brain areas, notably the prefrontal cortex and the nucleus accumbens, show increased volume and activation in the postpartum (reviewed in Galea et al., 2018Galea L.A.M. Qiu W. Duarte-Guterman P. Beyond sex differences: short- and long-term implications of motherhood on women’s health.Current Opinion in Physiology. 2018; 6: 82-88Crossref Scopus (16) Google Scholar). The postpartum is also associated with reduced gray matter in many areas of the brain, including reductions in gray matter in the hippocampus seen in the early postpartum that are still present up to 2 years after parturition (reviewed in Galea et al., 2018Galea L.A.M. Qiu W. Duarte-Guterman P. Beyond sex differences: short- and long-term implications of motherhood on women’s health.Current Opinion in Physiology. 2018; 6: 82-88Crossref Scopus (16) Google Scholar). This is particularly intriguing as hippocampal gray matter loss is a key feature of depression. In rodents, reductions in hippocampal neurogenesis are seen in the immediate postpartum that last throughout the postpartum. Reductions in neurogenesis are also noted in major depressive disorder, and neurogenesis has been linked to the capacity of hypothalamic-pituitary-adrenal (HPA) axis responsiveness, which is also compromised in major depressive disorder (Eid et al., 2019Eid R.S. Gobinath A.R. Galea L.A.M. Sex differences in depression: Insights from clinical and preclinical studies.Prog. Neurobiol. 2019; (Published online February 2, 2019)https://doi.org/10.1016/j.pneurobio.2019.01.006Crossref PubMed Scopus (136) Google Scholar). Thus, alterations that occur during the postpartum period mimic those seen in major depressive disorder: reduced hippocampal volume/neurogenesis, compromised serotonin signaling, and dysregulated HPA responsiveness are all noted in the postpartum. Furthermore, research indicates that the postpartum brain shares many of the same genetic expression changes that are seen in depression, highlighting similarities and/or a predisposition to a depressive phenotype in the postpartum period. It is vitally important for researchers and clinicians alike to be aware that there are tremendous changes to the postpartum maternal brain that may contribute to the greater risk to develop depression. It is of small wonder that the postpartum is a time of greatest vulnerability to develop depression in a woman’s lifetime. Twenty years ago, there were no animal models of PND. However, the field has blossomed, now with multiple diverse models, including those that manipulate stress or stress hormones during or after pregnancy (Perani and Slattery, 2014Perani C.V. Slattery D.A. Using animal models to study post-partum psychiatric disorders.Br. J. Pharmacol. 2014; 171: 4539-4555Crossref PubMed Scopus (44) Google Scholar). The Galea laboratory was the first to develop a model based on withdrawal from a hormone-simulated pregnancy, although the hormone profile during pregnancy is different in rodents versus humans; in this model, high levels of estradiol were given for 21 days (unlike a rodent pregnancy but similar to human pregnancy) and then estradiol was withdrawn, similar to the profile during a human pregnancy. In this model, we see symptoms of depressive-like behaviors within 4 days after “parturition,” mimicking depression seen during the early postpartum. We subsequently developed another model based on high corticosterone during the postpartum to mimic depression occurring in the late postpartum after a normal pregnancy. We argue that each of the animal models of PND are advantageous in demonstrating different subtypes of PND. Rather than to say one model is superior than the others, it is important to detail how these models differ, what symptoms they manifest, and when these symptoms (early or late pregnancy or postpartum) are seen. It is equally important to acknowledge that the heterogeneity in animal modeling can help us understand the heterogeneity in human disease and, as discussed below, possibly lead us to treatment that is more efficacious based on etiology of symptoms. Understanding the etiological risk factors using animal models will lead us to understand the mechanisms required to provide the best treatment or prevention during the time of risk for PND within the model (reviewed in Eid et al., 2019Eid R.S. Gobinath A.R. Galea L.A.M. Sex differences in depression: Insights from clinical and preclinical studies.Prog. Neurobiol. 2019; (Published online February 2, 2019)https://doi.org/10.1016/j.pneurobio.2019.01.006Crossref PubMed Scopus (136) Google Scholar). In modeling depression with onset in the postpartum by giving high corticosterone during this time period, we see disruptions in maternal care and increased depressive-like behavior, as assessed by increased passive coping beginning mid-postpartum that lasts until the time of weaning, which models postpartum depression that is manifested later in the postpartum (Perani and Slattery, 2014Perani C.V. Slattery D.A. Using animal models to study post-partum psychiatric disorders.Br. J. Pharmacol. 2014; 171: 4539-4555Crossref PubMed Scopus (44) Google Scholar). Using this model, no enhanced anxiety-like behavior is observed. However, gestational stress, which models PND that initiates antenatally, increases passive coping, disrupts maternal care, and enhances maternal anxiety (for review, see Perani and Slattery, 2014Perani C.V. Slattery D.A. Using animal models to study post-partum psychiatric disorders.Br. J. Pharmacol. 2014; 171: 4539-4555Crossref PubMed Scopus (44) Google Scholar). Intriguingly, these models do not just differ in terms of the timing of initiation of depressive symptoms and symptom expression, but also in the efficacy of selective serotonin reuptake inhibitors (SSRIs) to alleviate these behaviors. Preclinical models using gestational stress indicate that SSRI treatment is efficacious in the postpartum to offset behavioral outcomes and restore reduced hippocampal plasticity (reviewed in Eid et al., 2019Eid R.S. Gobinath A.R. Galea L.A.M. Sex differences in depression: Insights from clinical and preclinical studies.Prog. Neurobiol. 2019; (Published online February 2, 2019)https://doi.org/10.1016/j.pneurobio.2019.01.006Crossref PubMed Scopus (136) Google Scholar). However, using a postpartum corticosterone model, SSRI treatment is not efficacious to reverse the effects on either passive coping or reduced neurogenesis in the hippocampus. These findings suggest that different exposure times to SSRIs, and possibly different etiology of PND, may influence the efficacy of SSRIs. While we have focused on the biological mechanisms, there is no denying that psychosocial factors, particularly those imposing more stress, play a role in vulnerability to antenatal and postpartum depression. We know that factors such as a social support, socioeconomic status, parity, and an unwanted pregnancy can play a role in manifestation of PND. Furthermore, fathers can also get “postpartum depression,” which may well have physiological as well as psychological components, as fathers have a reduction in testosterone and increased body mass associated with birth of the child. However, strikingly the father’s severe adverse mental health responses manifest more than 12 months postpartum, much later than those seen in the mother (Munk-Olsen et al., 2006Munk-Olsen T. Laursen T.M. Pedersen C.B. Mors O. Mortensen P.B. New parents and mental disorders: a population-based register study.JAMA. 2006; 296: 2582-2589Crossref PubMed Scopus (504) Google Scholar). This emphasizes qualitative differences between mothers and fathers in the nature of postpartum/parenthood transition and its mental health consequences. As mentioned earlier, complications during pregnancy or at birth can also increase risk to develop PND in the mother, and these may have biological as well as psychosocial considerations in the mother. In sum, both psychosocial and biological factors will clearly play a role in PND. Overall, more attention is being paid to PND, and recently, a drug developed by SAGE Therapeutics using an allopregnanolone derivative has shown clinical efficacy in PND (Meltzer-Brody et al., 2018Meltzer-Brody S. Colquhoun H. Riesenberg R. Epperson C.N. Deligiannidis K.M. Rubinow D.R. Li H. Sankoh A.J. Clemson C. Schacterle A. et al.Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials.Lancet. 2018; 392: 1058-1070Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar); however, notably, at the same time, a large placebo effect was observed. Allopregnanolone, an allosteroic modulator of GABAARs, is elevated during pregnancy and reduced in the postpartum, and lower serum levels in the early postpartum have been linked to the postpartum blues. It is telling that this breakthrough originated from an animal model of PND from work by Jamie Macguire, leading to the possibility that more therapeutics may be developed successfully using carefully thought-out animal modeling. Early detection and treatment of PND will be important in successful interventions, which is why many have searched for biomarkers. In addition, there appears to be limited efficacy of SSRIs during the perinatal period and often a reluctance of the mother to take pharmaceutical interventions during pregnancy, and thus, alternative treatments are actively sought. Such treatments have targeted the microbiome, and there is some room for optimism as early trials suggest that probiotics targeting tryptophan may offset postpartum blues in women (Dowlati et al., 2017Dowlati Y. Ravindran A.V. Segal Z.V. Stewart D.E. Steiner M. Meyer J.H. Selective dietary supplementation in early postpartum is associated with high resilience against depressed mood.Proc. Natl. Acad. Sci. USA. 2017; 114: 3509-3514Crossref PubMed Scopus (20) Google Scholar). These data are exciting, as we have found that serotonin transmission is compromised by a reduction in signaling in the hippocampus, dorsal raphe, and other regions early in the postpartum and even more so in a corticosterone-induced animal model of postpartum depression. Probiotic treatment may be more palatable for women who do not want to take pharmacological treatments while pregnant or breastfeeding. Our preclinical work also suggests that exercise reduces depressive-like behavior and increases neurogenesis in the hippocampus in our corticosterone-induced model of postpartum depression when SSRIs are not effective to mitigate against the negative repercussions in the long term (reviewed in Eid et al., 2019Eid R.S. Gobinath A.R. Galea L.A.M. Sex differences in depression: Insights from clinical and preclinical studies.Prog. Neurobiol. 2019; (Published online February 2, 2019)https://doi.org/10.1016/j.pneurobio.2019.01.006Crossref PubMed Scopus (136) Google Scholar). In addition, epigenetic markers of estrogen sensitivity hold promise as predictors of PND (Guintivano et al., 2014Guintivano J. Arad M. Gould T.D. Payne J.L. Kaminsky Z.A. Antenatal prediction of postpartum depression with blood DNA methylation biomarkers.Mol. Psychiatry. 2014; 19: 560-567Crossref PubMed Scopus (112) Google Scholar) but have not yet been evaluated in clinical trials to capitalize on personalized approaches to prevent and treat PND. Clearly the heterogeneity of PND, including time of onset and etiology, points to a window of opportunity for developing distinct preventive and treatment approaches to optimize perinatal mental health. Studies that evaluate precision medicine strategies hold promise for targeting alternative treatment to women with perinatal onset of depression, when traditional pharmacological treatment is not efficacious. Thus, the postpartum period, with dramatic fluctuations in hormones and reduced neuroplasticity, is a perfect storm for depression onset. The medical community needs to have in place standards of care to ensure that all women are screened for mental health issues and that those most vulnerable get timely and efficient treatment or, ideally, preventative care, as recently recommended by the U.S. Preventative Services Task Force. Such efforts will be paramount for protecting mental health for both mother and infant lifelong and secure optimal neurocognitive development of the infant. These studies further reinforce that motherhood does change physiology, including neural functioning and brain architecture, which lead to a number of candidate risk factors during pregnancy and early postpartum that challenge maternal brain health. Lastly, it is vital that the field acknowledge and record that other factors during the pregnancy, including fetal sex, obesity, parity, and inflammation, may be contributing to PND. It is our hope that clinicians and researchers acknowledge and embrace heterogeneity in the field toward discovery of personalized treatment or prevention tactics based on this heterogeneity in order to have the best impact on the wellbeing of mother and her children. The research from L.A.M.G. was sponsored by Canadian Institutes of Health Research (CIHR) grants MOP-142308 and IGO-103692 and a NARSAD Independent Investigator award. V.G.F. is supported by grant from The Danish Council for Independent Research and The Capital Region of Denmark Foundation for Health Research. V.G.F. declares that she has received honorarium as consultant from Sage Therapeutics.