Perinatal depression: Heterogeneity of disease and in animal models
Introduction
The World Health Organization (WHO) identifies major depressive disorder (MDD) as the major leading cause of disability and a major contributor to the global burden of disease (Geneva World Health Organization, 2017). Major depressive disorder affects more females than males across all age-groups starting in adolescence (15–80+ years) (Seedat et al., 2009, Geneva World Health Organization, 2017). Aside from sex differences in disease prevalence, sex differences in symptom manifestation also exist (Silverstein, 2002, Marcus et al., 2008). For example, women diagnosed with MDD experience more ‘atypical’ symptoms such as hypersomnia and weight gain (Angst et al., 2002, Smith et al., 2008) and present with higher comorbidity for anxiety disorders (Lamers et al., 2011) than men diagnosed with MDD. The greater prevalence rate of depression in females compared to males is most salient during the reproductive years (i.e. 25–50 years of age) (Angst et al., 2002, Gutiérrez-Lobos et al., 2002). It is important to investigate unique experiences that occur during the reproductive years in females that may relate to greater susceptibility to depression. The perinatal period (during pregnancy and postpartum) is one timeperiod that deserves investigation as the risk for de novo onset of any mental disorder is heightened during the postpartum (Munk-Olsen et al., 2006).
Depression onset during pregnancy can be referred to as antepartum depression, whereas depression onset during the postpartum can be referred to as postpartum depression (PPD; World Health Organization, 2003, American Psychiatric Association, 2013). The timing of depression onset likely has different implications for disease etiology, given the differences in physiological characteristics between antepartum and postpartum. Unfortunately, both the DSM-V and the International Statistical Classification of Diseases tenth edition (ICD-10; World Health Organization, 2003) do not base their classification of perinatal depression (PND) on the recognition of the importance of the timing of onset of symptoms or by distinguishing PND as a de novo disorder. One major issue with the DSM-V definition is that, to be diagnosed with PND, there is a time restriction of occurrence between any time during pregnancy or up to the first four weeks postpartum. This generates an inability to distinguish between antepartum versus postpartum depression onset and negates any onset of depression after the first month postpartum (see Section 2). Additionally, the diagnosis can only be applied to the current or most recent depressive episode (American Psychiatric Association, 2013), which impedes retrospective analyses in determining whether there is a history of depression (Uher et al., 2014). People presenting with depression in the perinatal period who have had a previous history of depression versus those presenting with de novo antepartum or postpartum depression likely have a different etiology and possibly treatment needs. Thus, it is important to understand whether triggers and efficacy of treatment differ between de novo perinatal (antepartum or postpartum) onset versus a previous history of depression.
Research indicates that there is an underdiagnosis of PND within the general population by as much as 50%, suggesting, in part, that thiis may be due to a failure to identify PND using current diagnostic tools and/or relying on self-report (Woody et al., 2017, Cox et al., 2016). This underdiagnosis may be due to similarities between some symptoms of depression and the common side-effects of pregnancy/postpartum, leading patients and practitioners to dismiss depression symptoms as natural perinatal discomforts (Jolley and Betrus, 2007). Symptoms of pregnancy including changes in appetite, increases in body mass/weight gain, sleep dysregulation, increased fatigue and irritability, and decreased concentration (Yonkers et al., 2009, American Psychiatric Association, 2013) are also seen in MDD. Two specific self-report screening tools have been developed for PND, the Edinburgh Postnatal Depression Scale (EPDS) and the Postpartum Depression Screening Scale (PDSS). Although both are reliable screening tools when compared to structured clinical interviews for DSM-V (Tandon et al., 2012, Vogeli et al., 2018), the sensitivity of both screen tools could be improved by reducing the the cutoff scores, lowering the threshold for diagnoses, and including cultural appropriate measures (Chaudron et al., 2010, Tandon et al., 2012). For example, in low-income African American women, the sensitivity of major and minor depressive disorder screening tools was improved by reducing scale cutoff scores and thus lowering the threshold for diagnoses (Chaudron et al., 2010, Tandon et al., 2012). Overall, these data suggest a significant need for better screening and timeline inclusions for those diagnosed with PND. The ability to determine timing of depression onset is needed to gain an understanding of how timing of depression onset affects diagnosis, risk factors, and treatment barriers during these unique periods.
In this review, we will highlight the differences between antepartum versus postpartum depression onset within PND in the clinical and animal literature. We review the evidence that de novo depression onset during pregnancy versus during the postpartum should be considered two different presentations of PND with possibly different treatment efficacy. We then focus on physiological changes that occur during pregnancy and the postpartum and compare animal models of PND. Our review focusses on conveying differences in PND that depend on whether the onset of symptoms was during pregnancy or in the postpartum and whether depression was de novo as these have implications for etiology, severity, and possibly treatment.
Section snippets
Heterogeneity of Perinatal Depression
The greatest risk factor for PND is a previous history of depression (Tebeka et al., 2016, English et al., 2018, Altemus et al., 2012, Flynn et al., 2006, Records and Rice, 2007, Bunevicius et al., 2009). Interestingly, 43% of women with MDD relapsed during pregnancy, the majority of whom (68%) had discontinued their medication during pregnancy (reviewed in Cohen et al., 2006). Although researchers have attempted to dissociate PND based on timing of onset and differences in symptom risk, many
Considerations for Pharmacological Antidepressants and Non-Pharmacological Treatments
A comprehensive review identified that only 13–16% of women receive treatment of those diagnosed with PND and of these women, only half received adequate treatment, defined as six weeks of continued pharmacological or psychological treatment (Cox et al., 2016). Furthermore, perhaps most disturbingly, only about 3–5% of those that received adequate treatment reached remission (Cox et al., 2016). Interestingly, the authors also found lower treatment and remission rates for PPD compared to those
Physiology of Motherhood and Depression: A Perfect Storm
During pregnancy and the postpartum, there are several physiological changes that occur which mirror the changes seen in depression. These changes may contribute to the greater susceptibility to depression, creating the “perfect storm” for depression (see Galea and Frokjaer, 2019). We outline changes across pregnancy and the postpartum in steroid and peptide hormones, immune signalling, serotonergic tone, and associated serotonerigic metabolic factors (typtophan-kynurenine pathway), brain
Rodent Models of Perinatal Depression
Different models of PND may be used to illustrate different etiology and timelines of depression onset. Hormonal withdrawal paradigms may be used to model the subset of women who are particularly sensitive to sudden hormonal changes that occur with childbirth (Bloch et al., 2000, Galea et al., 2001, Green et al., 2009). Gestational stress paradigms may be used to model depression onset that would occur during pregnancy and early postpartum, whereas postpartum corticosterone exposure would model
A Call to Arms for Researchers, Clinicians, Funders and Policy Makers
PND is a heterogeneous disorder where timing and history of previous depression are critical in understanding etiology and the best treatment options for the mother. Researchers and clinicians must recognize and harness this heterogeneity to reap the potential important contributions of these factors to discovery research. We call on researchers (basic and clinical) to disaggregate data, build new models of disease, and by considering timing of onset and history of MDD to propel the field
Conclusions
Several lines of evidence suggest that PND is a heterogeneous disease. We argue that to enhance the understanding of the etiology of PND, increase treatment efficacy, and improve overall health outcomes, researchers need to harness this heterogeneity. We highlighted various physiological changes that occur during pregnancy and the postpartum period that may contribute towards distinct PND etiopathology. Although not part of our review, it is important to acknowledge that social economic
Acknowledgements
Financial support for this research was provided by an operating grant from the Canadian Institutes for Health Research (CIHR- MOP142308) to LAMG. WQ is supported by a 4-year Fellowship granted by the University of British Columbia, Faculty of Medicine, Graduate Program in Neuroscience, and the University of British Columbia Institute of Mental Health Marshall Scholars Program in Mental Health, Department of Psychiatry. TEH is supported by the University of British Columbia Institute of Mental
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