Neurobiology of Postpartum Depression: Critical Aspects

INTRODUCTION Postpartum depression (PPD) is a prevalent, disabling but treatable condition that is primarily diagnosed in mothers. Perinatal depression affects 15%–20% of mothers and birthing people and is often cited as the most common complication of childbirth, with suicide being a leading cause of death in the 1st-year postpartum.1 It is well known that major depressive disorder (MDD) is twice as common in women as in men.2 Within the reproductive life cycle, time periods associated with hormonal change are known to precipitate mood symptoms in a subgroup of women including puberty depression, premenstrual dysphoric disorder, PPD, and perimenopausal depression. The antepartum and postpartum period is characterized by strong hormonal changes and obstetric circumstances, which, in conjunction with individual social and psychological factors can trigger the development of PPD.3 Affected women experience a depressive episode which might co-occur with anger and hostility toward the infant. The depressed mood, of which onset begins within 4 weeks of childbirth. It influences maternal caregiving behavior, resulting in inadequate responsiveness and disturbed attachment to the infant. It also affects the cognitive, emotional, and social development of a child. In its severest manifestation, it can lead to suicide, a major cause of maternal deaths in the 1st-year postpartum.4 This editorial discusses maternal PPD with its neurobiological underpinnings in the delivering mother. Perinatal depression may present as antenatal depression or as a postnatal condition and often yields long-term consequences for maternal mental health, maternal-child interactions, and child development.5 PPD is the most common psychological condition following childbirth and may have a detrimental effect on the social and cognitive health of the mother, child, and immediate family, especially the spouse. The likelihood of depressive episodes can be twice as high as during other periods of a woman's life and they often go undetected and untreated, wreaking havoc on partners as well as the emotional and cognitive growth of infants and adolescents.6 PPD can start at any time within the first few days after delivery and continue up to several years. There is no one consensus on the prevalence of PPD, different studies across different demographic regions report varied prevalence. This can be attributed to cultural variations and different perceptions of mental health, stigma related to mental health issues, diverse reporting practices, sample-specific findings, socioeconomic class differences and rate of poverty, poor social services and resource availability, and different study methods across temporal measures and biological factors.7 EPIDEMIOLOGY PPD is found in 17.22% of the world's population. Varied prevalence rates were noted in different geographic regions with the highest rate found in Southern Africa (39.96%). Of interest, was a significantly lower rate of PPD in developed countries or high-income countries or areas. Furthermore, the findings showed that there was a substantial difference in rates of PPD when marital status, educational level, social support, spouse care, violence, gestational age, breastfeeding, child mortality, pregnancy plan, financial difficulties, partnership, life stress, smoking, alcohol intake, and living conditions were considered in the pooled estimates. The study results indicated that one out of every five women experiences PPD which is linked to income and geographic development.7 FAILURE TO DETECT POSTPARTUM DEPRESSION Despite PPD being a major public health concern, about 50% of the cases go undetected, thus failing to receive evidence-based forms of treatment.8 The earliest stages of PPD are frequently overlooked due to the commonplace nature of baby blues (sudden feelings of sadness within the first few days postpartum), affecting up to 80% of new mothers. Another likely event linked to childbirth is adjustment disorder (AD), which is a maladaptive reaction to identifiable psychosocial stressors. While baby blues only last for a brief period of time and cease within the first few days of childbirth, AD can occur up to 3 months after exposure to psychosocial stressors. The symptom severity of AD does not meet the criteria for depression at any time point, distinguishing the condition from PPD. While neither AD nor baby blues have the debilitating effects of clinical depression, both should be regarded as important differential diagnoses of PPD.8 RISK FACTORS FOR POSTPARTUM DEPRESSION The major risk factors for PPD include the history of depression, presence of anxiety, lack of a partner, lack of social support, major transitional life events, poverty, substance use, previous abortion (s), unplanned pregnancies, family violence, and history of abuse.9,10 The strongest predictors of PPD are a history of mood or anxiety disorder, especially having active symptoms during pregnancy. Lack of support from the husband, poor relationship with the mother-in-law, marital conflict, and the birth of a female baby may also serve as sociocultural contributors.11,12 When it happens in the first pregnancy, it has been seen clinically that the risk of PPD happening in future pregnancies increases. PATHOPHYSIOLOGY OF POSTPARTUM DEPRESSION The pathophysiology of PPD is complex and not yet fully ascertained. However, there is evidence that biological factors, including hormonal factors, genetics, and immune function, may play a role. Rapid changes in the reproductive hormones estrogen and progesterone during pregnancy and immediately after delivery have long intrigued PPD researchers. When hormone levels in women are not fluctuating, such as during pregnancy and postmenopause, the risk of depression does appear to be elevated. There are many good reasons to suspect that reproductive hormones are etiologically important in PPD as they play important roles in emotion processing, arousal, cognition, and motivation. They also regulate various biological systems implicated in major depression, such as thyroid function, lactogenic hormones, the hypothalamic–pituitary–adrenal axis, the immune system, and genetic expression. Moreover, brain imaging studies have shown that reproductive hormones modulate the neurocircuitry involved in normal and abnormal affective states.13 As the diagnosis of PPD contains considerable variability in timing of onset, history of depression, pregnancy and infant factors, social conditions, genetic loading, and endocrine contributions, PPD may represent different depressive phenotypes. This variability complicates finding specific etiologic, including hormonal factors.14 Most studies of reproductive hormone levels in depressed and nondepressed postpartum women have failed to show an association with depression. Several studies have shown that peripartum changes in allopregnanolone, a major progesterone metabolite, may play a critical role in PPD.15 Allopregnanolone, a modulator of γ-aminobutyric acid (GABA) receptors, affects both anxiety and depression. Recent research has shown that the sudden decrease in allopregnanolone levels after childbirth may play an important role in triggering PPD through GABA receptors. FDA approved the first drug for PPD, Brexanolone which is a synthetic version of allopregnanolone.16 Studies have also shown lower pregnancy oxytocin is associated with higher levels of PPD.17 GENETICS OF POSTPARTUM DEPRESSION Genetic factors have also been implicated in the pathophysiology of PPD. Exciting evidence of genetic contribution has emerged from family and twin studies suggesting that PPD clusters in families. Candidate gene studies of PPD have identified several of the same polymorphisms found in nonperinatal depression, such as Val66Met polymorphism of brain-derived neurotrophic factor.18 Genome-wide linkage studies of >1200 women found genetic variations on chromosome 1q21.3–q32.1 and 9p24.3–p22.3 and in hemicentin-1 (HMCN1), which contains several estrogen-binding sites. All appear to increase susceptibility to PPD. Genome-wide linkage and association studies have found a variation in the areas of chromosomes 1 and 9.19 Estrogen-induced epigenetic DNA methylation changes have also been implicated in PPD. Candidate gene studies have implicated polymorphisms in several promising genes, including the serotonin transporter gene, the catechol-o-methyltransferase gene, and the estrogen receptor alpha.20 These findings need independent larger confirmatory studies to be corroborated. The one commonality across all these genetic studies is the issue of timing where results are often positive when symptoms are measured close to delivery but negative for depression that occurs later. This may indicate that there is a genetic basis for PPD only when the timing is clearly linked to the hormonal trigger of childbirth.21 IMMUNE FUNCTION The immune axis is regulated by estradiol, which fluctuates during the perinatal period. Anti-inflammatory cytokines responsible for immunosuppression are elevated in pregnancy to protect the fetus. However, following delivery, the immune system rapidly becomes proinflammatory and remains so for several weeks. Women with PPD, compared with those who are not depressed, appear to have different gene expressions that is functionally related to immunity. However, studies of several prenatal immune markers of PPD have reported contradictory findings, so the role of immune function in PPD remains unclear.22 SLEEP AND POSTPARTUM DEPRESSION It is well known that sleep can play a role in mental health and brain function, but little is known about the link between objective measures of sleep during pregnancy and depressive symptoms. There is a dire need for identifying and treating sleep troubles during pregnancy as a preventative measure against perinatal depression.23 EXTRACELLULAR MESSENGER RNA COMMUNICATION Extracellular RNA communication, which is a recently discovered mode of intercellular communication that is involved in a variety of important biological processes including pregnancy, is associated with PPD. Extracellular RNA communication is increased during pregnancy and is involved in embryo implantation, uterine spiral artery remodeling, parturition, preterm birth, immunity, and the inflammatory response. This analysis revealed that extravesicular (EV) messenger RNA (mRNA) levels during pregnancy and the postpartum period were extensively altered in women who went on to develop PPD. Gene set enrichment analysis revealed that mRNAs associated with autophagy were decreased in PPD cases. The extracellular RNA communication changes identified in the study suggest that women who develop PPD are unable to efficiently remove aging and defective cell components.24,25 NEUROBIOLOGICAL PATHWAYS OF POSTPARTUM DEPRESSION Imaging studies regarding PPD are rare and frequently underpowered, with only one imaging study to date including >14 patients and none pertaining to the structural changes in PPD.26 In addition, many of the resting-state studies included PPD patients within 8–12 weeks postpartum, thereby missing any early alterations with potential prognostic value and likely mixing up early- and late-onset cases, which are thought to represent different etiologies. The 4-week postpartum time frame is deemed to distinguish the so-called early-onset or hormone-sensitive phenotype of PPD from the later-onset phenotype, in which stress-inducing psychosocial factors are thought to play a more central role.27 Despite these limitations, functional abnormalities in PPD have been reported in the amygdala, the insula, and the orbitofrontal and dorsomedial prefrontal cortices. Studies assessing structural alterations suggest that there are reductions in overall gray matter volume. Task-based functional MRI studies have also identified altered activity in response to an infant's cry or images of an infant, with the greatest evidence for the amygdala, prefrontal cortex, cingulate cortex, and insula.28 Results from radiolabeling and positron emission tomography studies in women suggest that serotonin receptors implicated in depression are affected by female gonadal hormones and cycles. However, with respect to both MDD and PPD, it is still unclear if the reported structural and functional alterations are present early in the disease course, potentially preceding the clinical symptoms, or if they develop because of the disease. An understanding of these time courses is essential to establish the diagnostic and prognostic value of the respective neuroimaging alterations.29 NEUROPLASTICITY Estradiol, as a neurotransmitter, promotes neuronal survival, decreases oxidative stress, improves neuronal energetics by increasing mitochondrial respiratory efficiency, increases both dendritic spine density and synaptic plasticity, and increases cell in response to a variety of toxic insults (for example, hypoxia, inflammation, excess glutamate, decreased glucose). The female brain undergoes dynamic neuroplastic processes during pregnancy and the postpartum period with decreases in gray matter volume in a number of brain regions (e.g. hippocampus, cingulate cortex, medial orbitofrontal cortex, and insula) which have been shown to play key roles in social processes, emotion regulation, stress processing, as well as being linked to the development of depression. While these changes are thought to be adaptive, preparing new mothers for their new role, their possible contribution to the development of mental disorders cannot be ruled out as the changes in brain structure and the development of postpartum psychiatric disorders co-occur in time.30,31 NEURAL NETWORKS Neural networks are structurally and dynamically connected brain regions whose coordinated activity enables effective and efficient responses to the environment. Evidence exists for the dysfunction of each of these networks, namely, default mode network, which mediates internal-based thought (daydreaming and reflecting) and permits recall of the past and imagining of the future; social cognition network, which enables one to "read" the intentions of others (theory of mind); reward Network, which permits the assignment of affective valence (positive or negative) to events, thoughts, and experiences and is critical for decision-making; affective regulation network, which regulates the interplay between more cognitive (dorsolateral prefrontal cortex); and more "affective" (limbic, amygdala) brain regions and Central Executive Network, critical for mediating executive functions like a cognitive appraisal, results in depression.32,33 HORMONE THERAPY FOR POSTPARTUM DEPRESSION The use of transdermal estrogens is recommended to suppress ovulation in women with premenstrual syndrome or in correcting the profound estrogen decrease with PPD. As compared to oral estrogens, transdermal estrogens are preferable because they do not invoke hepatic coagulation factors and are not associated with the higher rates of venous thromboembolism of oral estrogens. However, such therapy does not exclude combined therapy with antidepressants.34 ANTIDEPRESSANT TREATMENT FOR POSTPARTUM DEPRESSION Several studies suggest that reproductive depression may be specifically responsive to selective serotonin reuptake inhibitors (SSRIs). These observations argue for a specific mechanism involving serotonergic pathways underlying the pathophysiology of PDD that is distinct from the mechanisms underlying MDD that is unrelated to the reproductive cycle. Endogenous estrogen levels play a permissive or augmentation role in the setting of an SSRI. In studies of women with PPD, preliminary evidence suggests that women with PPD may respond preferentially and more rapidly to SSRIs than to tricyclic antidepressants (TCAs).35 CERTAIN OTHER CRITICAL POINTS: There is a huge need for awareness to be created about PPD. Not many mothers and families are aware of PPD and there is a need for collaboration between obstetricians and mental health professionals to screen and create awareness about PPD in pregnant mothers and their families There is a need for indianized screening tools for PPD which are multilingual and can help create awareness about the same. There is a need for rating scales that are multilingual and those that are validated in Indian populations There is a need for clinical consensus and guidelines for the management of PPD in Indian settings considering that post-delivery situations in India vary considerably from the West It would be interesting to look at research where after identifying high-risk individuals for PPD, we could start them on prophylactic antidepressant therapy and watch whether the severity and intensity of PPD when it develops is controlled or lesser compared to a group where this intervention was not done Any female patient with a history of MDD is at risk for PPD and must be monitored for PPD even though remission of MDD has occurred. The same is true for females who have had childhood or adolescent depression or a family history of depression In conclusion, integrating preexisting psychosocial risk factors with the measurement of neurobiological changes during pregnancy could improve the ability to detect women and families at greatest risk and in need of early intervention. In addition, longitudinal research mapping the trajectories and timing of these alterations across pregnancy, and the postpartum period is necessary.