Contrasting Neurobiological and Psychosocial Pathways in Postpartum Depression Treatment- Zuranolone Versus Exercise: A Comprehensive Narrative Review

Post- partum depression overview

PPD is a significant mental condition affecting women within the first year following birth. The physical and emotional health of women is severely harmed.^[9] Hormonal imbalance, neurochemical alterations, psychological stresses, and cultural influences are among the many factors that contribute to PPD. Prenatal anxiety, low mother self-efficacy, personal or family history of depression, and insufficient social support are the main risk factors. Evidence-based therapies comprise Edinburgh Postnatal Depression Scale (EPDS) -based screening, cognitive behavioral therapy, interpersonal psychotherapy, psychoeducation, and pharmaceutical medications such as brexanolone and zuranolone.^[10] As saying biomarkers from biological material in bodily fluids can aid in a less intrusive approach to estimate the risk of the condition, confirm the diagnosis and prognosis, and monitor the therapy of depression.^[9]

Despite substantial investigation into the underlying pathophysiology of major depressive disorder (MDD), the specific molecular malfunction underlying the ailment remains unknown. This problem derives from the complexity of MDD, which likely comprises numerous unique biological pathways that contribute to the presentation of severe depressive episodes.^[11] The primary distinction is that PPD is caused by postpartum-specific causes, such as biological and psychological ones. Among physiologic processes, inflammatory processes and hypothalamic-pituitary-adrenal dysfunction are the best markers of PPD risk. PPD is commonly treated with psychotherapy and antidepressants, but there has been great concern about the medications’ possible side effects, including decreased appetite, headaches, sleepiness, and dizziness.^[12]

The risk of MDD in both males and females is known to be influenced by environmental factors, including past negative life experiences, a history of anxiety and depression, sociocultural roles, psychological traits, and coping mechanisms. However, these factors may also contribute to the differences in incidence between males and females. Prenatal depression, prenatal anxiety, poor infant-mother relations, a lack of social support, financial and/or marital stress, and traumatic life events are among the many environmental risk factors for PPD that have been found. Recent studies on the role of stress have concentrated on life pressures during the peripartum period, which are positively correlated with depression severity ratings and predictive of postpartum depression. In mouse models, exogenous corticosterone during pregnancy or lactation is sufficient to induce behaviors similar to sadness and anxiety as well as impairments in parental care. Persistent stress during pregnancy not only results in deficiencies in mother care but also causes postpartum dams to exhibit depressive and anxious behaviors.^[13] A wide range of symptoms, such as melancholy, loss of interest, anhedonia, insomnia, tiredness, guilt, and suicidal or infanticidal thoughts, are connected with PPD. These symptoms have a detrimental effect on mothers’ and children’s well-being, leading to strained family relationships and poor maternal-infant bonding, which can eventually create a vicious cycle that impacts several generations. PPD is caused by a multitude of circumstances, including a history of depression, low socioeconomic status, limited social support, hormone levels, and genetic predisposition. Depression is mostly caused by immunological dysregulation and inflammation, and there is growing evidence that anti-inflammatory medications might lessen depressive symptoms. However, PPD can be predicted independently by two inflammatory markers during delivery: interleukin-6 (IL-6) and high-sensitivity C-reactive protein (Hs-CRP). However, because of the non-specificity of C-reactive protein and the short half-life of cytokines, immune cells have become a possible alternative for research or therapeutic purposes.^[14]

Incidence and prevalence of post-partum depression

PPD is defined as a moderate-to-severe depressive episode that starts four weeks after childbirth and can persist up to twelve months according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).^[15] According to earlier research, up until 2017, the global incidence of PPD ranged from roughly 9.5% in high-income nations, 20.8% in middle-income nations, and 25.8% in low-income nations.^[16] Although prevalence rates vary significantly by country, a recent systematic review of 291 studies from 56 countries found the global PPD rate to be 17.7%. Singapore (3%), Nepal (7%), and the Netherlands (8%) had the lowest PPD rates, while Hong Kong (30%), South Africa (37%), and Chile (38%) had the highest rates.^[17] Therefore, PPD is a significant public health concern that affects 10% to 15% of women in developed nations and is a social health burden regardless of cultural identity and beliefs. The frequency of PPD in moms varies from 0.5% to 60.8% worldwide. According to current research, up to 30% of women may experience PPD, which typically ranges in severity from mild to severe in 50–80% of cases to intensive psychosis in less than 1% of cases.^[18] Additionally, there was a 40% chance of recurrence in either non-postpartum or subsequent postpartum cases.^[16] PPD epidemiology is significantly impacted by national development and income disparities.^[19] Other factors that have been shown to contribute to the higher prevalence of PPD include neighborhood underdevelopment, long-term exposure to air pollution, and high pre-pregnancy BMI.^[20] PPD was substantially correlated with marital status, with married mothers being less likely to develop PPD compared to single mothers.^[21] Younger mothers had a higher percentage of PPD than older mothers. This could be because younger mothers have less experience caring for newborns or managing depression, making them more likely to exhibit depressive symptoms in the postpartum period. These findings were in line with those of Rich-Edwards and Inandi, who discovered that women in the youngest age group had nearly twice the rate of depression scales in comparison to the other age groups.^[18] Compared to first-time mothers or mothers with two children, mothers with more than two children are likely to have higher levels of depression. This is consistent with nations such as Pakistan and Nepal, which are classified as low-income countries. Due to the financial and physical demands of childcare, multi-parity increases family stress and the likelihood of PPD.^[22] Additionally, it was found that the prevalence of PPD is influenced by a number of factors, which include educational attainment, partnership, stress in life, smoking, alcohol consumption, and housing conditions. Gender preference and newborn gender, on the other hand, did not significantly affect PPD.^[19] Five studies observed that PPD was negatively impacted by stress and/or anxiety brought on by traumatic events, perceived pain, low parenting skills, avoidant attachment style, and physical and mental illnesses. Conversely, PPD was found to be positively impacted by a variety of supports, including the frequency of maternal care received from medical professionals, financial support from family members, emotional support, and commute time to the health center.^[16] Inadequate mental health care appears to be a major contributing factor when societies do not emphasize postpartum mental wellness for women.^[18] PPD has been found to have detrimental effects on women’s physical and mental health, infants’ behavioral and emotional development, and relationships with spouses and other family members, in addition to its rising occurrence. It has been considered as one of the major worldwide public health concerns in the past ten years due to its high prevalence and negative effects [Figure 1].^[16]

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Figure 1: Prevalence of postpartum depression

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Zuranolone for managing PPD

PPD is a prevalent and impairing mood disorder that arises following childbirth, significantly impacting maternal well-being, infant growth, and family interactions. Traditional methods that include selective serotonin reuptake inhibitors (SSRIs) are limited by delayed onset of action and efficacy, underestimating the need for rapidly acting and targeted therapies. Zuranolone has become a new therapeutic choice of drug for PPD, providing a mechanism that directly targets the neurobiological alterations taking place during the postpartum phase.^[23,24] Zuranolone is a neuroactive steroid that is taken orally and acts as a positive allosteric modulator for the GABA receptor. It is a synthetic version of allopregnanolone, an endogenous neurosteroid produced from progesterone that is essential for mood regulation. Allopregnanolone levels rise significantly during pregnancy and then drop sharply after childbirth. This abrupt cessation is believed to interfere with GABAergic signalling, aiding in the emergence of postpartum mood disorders. In contrast to traditional antidepressants, which mainly affect the monoaminergic system, the action of zuranolone is directly on the inhibitory neurotransmission and provides a relatively quicker onset of the antidepressant effect. Articles show a decrease in depressive symptoms just a few days after the start of treatment, as evaluated in clinical studies, thus showing the efficacy of the drug in the acute phase of PPD.^[23,25]

Zuranolone is taken orally once a day for a fixed 14-day treatment course. Compared to traditional antidepressants, which usually need longer treatment duration and gradual dose increases, this time frame gives more advantage to the user. Zuranolone also offers a similar alternative to brexanolone, the first neurosteroid approved for PPD, which requires continuous intravenous infusion under clinical supervision. The oral route for giving zuranolone promotes its use in outpatient situations, boosting availability while lessening the load on healthcare systems.^[25,23] A randomized controlled trial conducted showed that zuranolone in women with moderate to severe PPD has consistently shown significant improvements in depressive symptom severity, as measured by standardized rating scales such as the Hamilton Depression Rating Scale (HAM-D). Improvements have been observed as early as Day 3, with sustained benefits through Day 15 and during follow-up after treatment is completed. These findings suggest that short-term neurosteroid treatment may cause a lasting neurobiological effect beyond the dosing period.^[24]

In addition to the relief of symptoms, zuranolone could provide an even larger benefit for maternal function. Early and quick relief from symptoms of depression could enable earlier recovery from functional impairment, enhance bonding between mother and infant, and mitigate risks to development when PPD goes untreated. It is clear that PPD is very prevalent and difficult for women to treat over for a long term. A new treatment with immediate relief and lasting only for 14 days offers enormous progress for the treatment paradigm.^[26] Regarding safety and tolerability, zuranolone has demonstrated a largely positive profile. The most frequently seen side effects include drowsiness, light-headedness, sedation, tiredness, and headaches, aligning with its GABAergic mode of action. The majority of adverse events were mild to moderate and subsided without requiring any intervention. Significantly, clinical trials did not show a notable rise in suicidal thoughts or major safety issues. However, it is advised to exercise caution with activities that necessitate alertness while undergoing treatment.^[23]

Even though these advantages are present, a number of limitations must be taken into consideration, which include long-term safety data that are still limited, and additional studies are required to fully evaluate relapse rates, durability of response, and optimal integration with psychotherapy and other supportive interventions. Future studies are needed regarding the use during breastfeeding and in various populations. In conclusion, zuranolone is a novel treatment for PPD since it targets neurosteroid dysregulation, a feature of the postpartum phase. For women with PPD, it is a potential alternative due to its quick onset of effect, short treatment duration, and oral administration. Zuranolone been found to have the potential to alter postpartum mental health care and improve outcomes for mothers and their families.^[24]

Zuranolone mechanism of action

Zuranolone, first found as SAGE-217. It is an orally bio-accessible positive allosteric modulator that targets both the intrasynaptic and extrasynaptic GABAA receptors.^[26] Similar to brexanolone, zuranolone is an allopregnanolone analogue that is used to treat postpartum depression. It is a neuroactive GABA receptor modulator that functions similarly to allopregnanolone. Although benzodiazepines have long been known to modulate GABA receptors, their effects are limited to synaptic GABA receptors that are largely composed of the Ψ subunit. Zuranolone affects both synaptic and extrasynaptic GABA receptors, which sets it apart from benzodiazepines. The activity of zuranolone is not entirely dependent on the Ψ subunit carrying GABA receptors because the extrasynaptic GABA receptors are mainly composed of the δ subunit.^[27]

Research on mouse brain slices has shown that zuranolone increases the GABA-A receptors’ tonic and phasic conductance, which is consistent with the receptors’ increased surface expression. Furthermore, in multiple in vivo models, zuranolone showed a significant positive allosteric modulator (PAM) of the GABA-A receptors.^[28] These receptors serve as inhibitory neurotransmitter receptors, and when they are stimulated, neuronal excitability is reduced, which has calming and relaxing effects.^[29] GABA neurons are located in regions linked to motivation, pleasure, memory, emotions, and decision-making. Neuroactive steroids (NAS) can influence pain and mood regulation by acting on GABA neurons and even serotonin receptors.^[30]

It is the only oral drug that the US Food and Drug Administration (FDA) has approved for the treatment of PPD in adult females. The cyanopyrazole ring at carbon 21 sets it apart from brexanolone. Zuranolone offers the convenience of once-daily, evening dosage at home due to its oral bioavailability.^[31] Additionally, it might re-establish the equilibrium of GABA receptor activity, which is altered by the rapid decrease in allopregnanolone following childbirth.^[32] Downregulation of both GABA and NAS is linked to psychiatric conditions like major and postpartum depression, as well as neurodegenerative and inflammatory brain illnesses like Alzheimer’s.^[33] The CYP3A4 enzyme is mainly responsible for the liver’s metabolism of zuranolone. It is improbable that circulating metabolites will be beneficial. Zuranolone has a mean apparent clearance of 33 L/h and a terminal half-life of roughly 19.7 to 24.6 hours. Following oral dosing, 41% of radio-labeled zuranolone is excreted in the feces, and 45% is recovered as metabolites in the urine. Unaltered medication accounts for less than 2% of total fecal clearance [Figure 2].^[29]

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Figure 2: Zuranolone mechanism of action. GABA-A: Gamma-aminobutyric acid Type A

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The role of exercise in PPD

A substantial body of research shows that physical activity performed during pregnancy, during the combined pregnancy–puerperium period, or exclusively during the postpartum period contributes to a measurable reduction in postpartum depressive symptoms. Evidence indicates that engaging in physical activity enhances mental well-being not only through reducing depressive symptoms but also by improving quality of life and diminishing fatigue among postpartum women.^[34]

Preventive exercise during pregnancy

One randomized controlled trial demonstrated the effectiveness of a completely face-to-face supervised fitness intervention during pregnancy in the prevention of postpartum depression. The primary analysis revealed no significant differences between the groups. However, limited compliance with the exercise routine, particularly among young and less educated women, may have resulted in an underestimation of the benefit of exercise using the full case method. The effect of attending ≥70% of exercise sessions, rather than being allocated to the intervention or control group, was greater than the primary analysis estimates. Importantly, while PPD was not decreased in this study, the program resulted in a substantial reduction in prenatal depressive symptoms, which is consistent with the larger evidence demonstrating that exercise during pregnancy has mental health benefits.^[35] A dose-response meta-analysis further reinforces a preventive effect by showing that accumulating at least 90 minutes of physical activity per week is sufficient to reduce the risk of postpartum depression.^[36]

Another study focusing on individuals with overweight or obesity during pregnancy found that meeting the recommended 150 minutes of moderate-to-vigorous physical activity weekly was associated with lower odds of probable depression at six months postpartum [Table 1].^[37]

Postpartum exercise interventions

Yoga-focused interventions have demonstrated meaningful improvements in depressive symptoms, with a recent meta-analysis concluding that yoga significantly improves EPDS scores and can therefore serve as a viable therapeutic option.^[38] Physical activity significantly improves maternal depression, anxiety, and fatigue, underscoring its role as a practical, accessible, and impactful approach to enhancing overall well-being across the perinatal period. Exercise is thus an important nonpharmacological component of complete maternal health care [Table 1].^[39]

Types of exercise interventions associated with reduced postpartum depression

Aerobic exercise therapies, particularly walking-based programs, have always been linked to a decrease in PPD symptoms. A Bayesian network meta-analysis of exercise modalities found that Pram walking performed better than other types of exercise and ranked first, followed by supervised mixed exercise, yoga, and usual care. Mixed exercise was included as a distinct intervention category and demonstrated favorable effect estimates compared with usual care. Subgroup analyses further showed that supervised exercise interventions produced larger reductions in depressive symptoms than unsupervised programs.^[40] The beneficial physiological benefits of aquatic exercise, which are produced by thermal dissipation, may enhance venous return and blood circulation as well as reduce oedema brought on by pregnancy. Because it works all of the major muscles and incorporates breathing, relaxation, and stretching techniques, aerobic exercise can also be beneficial. Women can socialise and engage emotionally by working out in a group.^[41] Exercise interventions that are offered digitally have become popular choices for postpartum women who have trouble participating in in-person activities. When compared to a non-exercise control group, a contactless online Pilates program significantly reduced PPD symptoms, perceived stress, and back pain in a randomized controlled experiment.^[42]

Determinants of effectiveness of exercise interventions for postpartum depression

Evidence indicates that the effectiveness of exercise interventions for PPD varies according to program characteristics rather than exercise participation alone. A meta-analysis of exercise interventions within the first six months postpartum demonstrated significant reductions in depressive symptoms, with effect sizes differing based on supervision status, timing of initiation, and exercise intensity.^[43]

Supervision

A crucial factor in determining the success of interventions has been repeatedly found to be supervision. According to the same meta-analysis, supervised exercise significantly affects depressive symptoms in Edinburgh Postnatal Depression Scale scores compared to unsupervised exercise. This implies that group support is probably responsible for the exercise intervention benefit that has been observed [Table 1].^[43]

Timing

The timing of exercise initiation also influences outcomes. Subgroup analyses demonstrated that exercise programs initiated within the first three months postpartum achieved larger effect sizes than those beginning between three and six months after delivery. This suggests that early postpartum exercise may confer greater mental health benefits than later initiation.^[43]

Intensity, dose, and delivery mode

Exercise dosage and intensity have a big impact on results. Moderate-intensity exercise reduces depressed symptoms more than low-intensity programs, according to subgroup studies.^[43] This dose–response meta-analysis demonstrated that accumulating approximately 90 minutes of physical activity per week was sufficient to significantly reduce the risk of postpartum depression.^[35] The mode of delivery also influences efficacy. When compared to non-exercise controls, a 16-week contactless online Pilates program significantly reduced postpartum depressive symptoms and perceived stress in a randomized controlled trial. This program addressed metabolic dysregulation, which often arises after delivery, particularly in circumstances of social isolation brought on by the pandemic.^[42]

Comparison - non-pharmacological and medicine for PPD

Zuranolone is the second medication in its category to be sanctioned by the FDA for addressing PPD. The use of zuranolone results in a notable enhancement of depressive symptoms and is generally well accepted by patients enduring PPD. Zuranolone serves as an alternative to brexanolone for managing moderate to severe PPD. Its oral form and the absence of an FDA Risk Evaluation and Mitigation Strategy (REMS) program make it a more appealing option for treating these patients. The most frequently reported treatment-emergent adverse events (occurring in 5% or more of patients in either group) included somnolence, dizziness, sedation, headache, diarrhea, nausea, upper respiratory tract infections, and COVID-19 infection. Zuranolone shows the possibility of drug interactions, requiring a thorough review of medications prior to starting treatment. Taking it alongside central nervous system depressants or alcohol can intensify sedative effects, which may result in disrupted cognitive function and psychomotor coordination. Adjustments in dosage are required for individuals with impaired liver or kidney function. For those with severe liver impairment (Child–Pugh C), a reduced dosage of 30 mg per day for 14 days should be administered.^[28] Zuranolone has shown improvement in the key symptoms of depression, as assessed by HAMD-17 scores, in women experiencing PPD and has generally been well tolerated. At present, none of the monoaminergic antidepressants, such as SSRI, serotonin-norepinephrine reuptake inhibitors, or atypical antidepressants, have specific approvals for treating PPD.^[44] Barriers to adherence with pharmacotherapy remain, as patients often decline treatment due to misconceptions about teratogenicity, safety during lactation, and other concerns. Additionally, PPD often occurs alongside bipolar affective disorder and shares similar symptoms, making diagnosis more challenging. This difficulty can result in inappropriate medication strategies, where choosing the incorrect drug may worsen depressive symptoms and escalate severity.^[45]

Cognitive-behavioral therapy (CBT) and interpersonal psychotherapy are effective in reducing symptoms of depression.^[46] Factors that increase the risk of developing PPD include having a personal or family history of depression or anxiety, experiencing a difficult pregnancy, giving birth to multiples, facing relationship or financial challenges, lacking social support, and undergoing an unplanned pregnancy. For those with mild to moderate PPD, psychotherapy, particularly cognitive behavioral therapy, should be the first line of treatment. CBT assists patients in recognizing their triggers for depression and anxiety while providing coping strategies to help them respond to situations in a healthier way.^[28]

Non-pharmacological treatments for PPD are increasingly popular among patients, with options such as psychotherapy, walking with a pram, yoga, music therapy, and acupuncture being embraced as either standalone or complementary methods. These non-drug approaches have several advantages: they typically result in fewer side effects. Non-drug methods provide various advantages: they typically have fewer adverse effects, making them particularly appropriate for breastfeeding mothers; psychotherapy helps in addressing negative emotions and builds lasting psychological resilience. The combination of exercise and psychotherapy is ranked as the most effective. Non-drug interventions have been shown to significantly enhance anxiety symptoms. The use of yoga and psychological counselling for first-time mothers experiencing PPD not only greatly reduced depressive symptoms but also improved mental health, aided in recovering postpartum body shape and restoring pelvic floor function, and elevated the overall quality of life for patients. However, the findings should be viewed with caution due to differences in methodologies and limited long-term follow-up [Table 2].^[45]

Authors’ contributions:

RRK: Conceptualization, methodology, writing - original draft, writing - review and editing, supervision, visualization; JRJ, AAK: Methodology, writing original draft, writing review and editing, visualization; PP: Methodology, visualization, writing review and editing, writing original draft; WM: Supervision, visualization, writing original draft, writing - review and editing; JBG: Methodology, writing review and editing, writing original draft; AS: Methodology, writing review and editing, visualization; HJG: Methodology, visualization, writing review and editing; SYB: Methodology, supervision, writing - review and editing.