madman
Super Moderator
Abstract
Postpartum depression (PPD) is a common major depressive episode surrounding childbirth, with estimated rates ranging from 5.5% to 23.5% of all live births across Europe and the USA based on the presence of key symptoms. PPD has been associated with significant impairments in both maternal functioning and mother-infant attachment and these impairments can have lasting effects on the emotional and cognitive development of children. Although the precise pathophysiology of PPD is unknown, preclinical findings suggest that large fluctuations in neurosteroid hormone levels can induce physiological plasticity in the expression of functional GABAA receptors during pregnancy and the postpartum period and that deficit in this plasticity may underpin a biological mechanism that contributes to the manifestation of depressive symptoms. Here, we review the controlled clinical trials to date that have assessed the efficacy of pharmacological treatments for PPD, including oestradiol, selective serotonin reuptake inhibitors, brexanolone (an iv formulation of allopregnanolone), and an investigational neuroactive steroid and GABAA positive allosteric modulator, zuranolone. Coupled with the GABAergic deficits implicated in major depressive disorder, these findings highlight not only the potential role of GABAA receptor plasticity in the pathophysiology of PPD but also the novel therapeutic approach of using positive allosteric modulators targeting GABAergic transmission to treat women affected by PPD.
1 | INTRODUCTION
Postpartum depression (PPD) is a major depressive episode (MDE) associated with pregnancy and childbirth. In the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), one of the specifiers of an MDE includes “peripartum onset” in recognition of the onset of symptoms that can occur during pregnancy or in the first 4 weeks following delivery.1 Expert opinion varies greatly regarding the timing of symptom onset that defines PPD, ranging from the early postpartum period to 12 months after delivery.2-5 In accordance with DSM-5 criteria, the diagnosis of depression requires the presence of 5 or more of the following symptoms: depressed mood, diminished interest or pleasure in all (or almost all) activities, significant weight loss or gain, insomnia, psychomotor agitation or slowing, fatigue or loss of energy, feelings of worthlessness or excessive inappropriate guilt, diminished ability to think or concentrate, or recurrent thoughts of death or suicidal ideation.1 Additionally, common PPD symptoms present as persistent sadness, anxiety, irritability, feelings of guilt, loss of interest, fatigue, trouble bonding with the baby, persistent doubts about the ability to care for the baby, or suicidal thoughts.6 The impact of PPD can also extend to the entire family, including children because several studies have implicated PPD as a negative factor affecting the cognitive and emotional outcomes of infants.7,8 Impairments in the quality of caregiving, mother-infant interaction, and attachment have also been identified as contributing factors to the burden of disease.9,10
PPD may be underdiagnosed because of a lack of disease awareness, barriers to access to care, and stigma11,12; therefore, many studies report rates of PPD based on the presence of key symptoms. In the USA, 9.7%-23.5% of women with a recent live birth experience symptoms of PPD.13 Across eight European countries, 5.5%- 13.5% of mothers are reported to experience PPD symptoms each year.14-21 Analyses that require a formal diagnosis of depression have reported PPD rates up to approximately 13%.12,14,22-27 The predicted costs of untreated perinatal mood and anxiety disorders, including PPD was estimated to be $14 billion in the USA in 2017 for affected mothers and their children.28 A similar UK study showed that perinatal mental illness could cost society over £8 billion per each 1-year birth cohort.29 Up until recently, there have been limited pharmacological treatment options for PPD; the first PPD-specific treatment, brexanolone (ZULRESSO®; Sage Therapeutics, Inc, Cambridge, MA, USA) was approved by the US Food and Drug Administration (FDA) in 2019.30 Brexanolone is an iv formulation of allopregnanolone that is administered as a continuous infusion for 60 hours.31 Traditional oral antidepressant treatments have been frequently used to treat these patients despite no specific indication for PPD; however, the literature has shown varied efficacy of such treatments, indicating that there remains a high unmet need among this population.32-35
2 | NEUROSTEROIDS AND PATHOPHYSIOLOGY OF PPD
3 | RANDOMISED CONTROLLED TRIAL S IN PATIENTS WITH PPD
4 | STUDIES OF NEUROACTIVE STERIODS THAT ARE GABAA POSITIVE ALLOSTERIC MODULATORS
5 | CONCLUSIONS
PPD is a common mood disorder that is associated with substantial implications for mothers and their families, including children. Although there is more work to be done to characterize the pathophysiology of PPD and how it is delineated from MDD, the available preclinical data suggest that, in the context of large neurosteroid level fluctuations, deficits in GABAA receptor plasticity during pregnancy and the postpartum period may confer biological vulnerability to depression. Controlled clinical trials with monoaminergic antidepressants have shown delayed improvements and variable outcomes. Brexanolone infusion, an iv formulation of ALLO, received the first regulatory approval for the treatment of PPD after demonstrating significant improvements in depressive symptoms within 60 hours. Collectively, these findings support further evaluation of the possible impact that neurosteroids may have as positive allosteric modulators of GABAA receptors for the treatment of PPD.
Postpartum depression (PPD) is a common major depressive episode surrounding childbirth, with estimated rates ranging from 5.5% to 23.5% of all live births across Europe and the USA based on the presence of key symptoms. PPD has been associated with significant impairments in both maternal functioning and mother-infant attachment and these impairments can have lasting effects on the emotional and cognitive development of children. Although the precise pathophysiology of PPD is unknown, preclinical findings suggest that large fluctuations in neurosteroid hormone levels can induce physiological plasticity in the expression of functional GABAA receptors during pregnancy and the postpartum period and that deficit in this plasticity may underpin a biological mechanism that contributes to the manifestation of depressive symptoms. Here, we review the controlled clinical trials to date that have assessed the efficacy of pharmacological treatments for PPD, including oestradiol, selective serotonin reuptake inhibitors, brexanolone (an iv formulation of allopregnanolone), and an investigational neuroactive steroid and GABAA positive allosteric modulator, zuranolone. Coupled with the GABAergic deficits implicated in major depressive disorder, these findings highlight not only the potential role of GABAA receptor plasticity in the pathophysiology of PPD but also the novel therapeutic approach of using positive allosteric modulators targeting GABAergic transmission to treat women affected by PPD.
1 | INTRODUCTION
Postpartum depression (PPD) is a major depressive episode (MDE) associated with pregnancy and childbirth. In the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), one of the specifiers of an MDE includes “peripartum onset” in recognition of the onset of symptoms that can occur during pregnancy or in the first 4 weeks following delivery.1 Expert opinion varies greatly regarding the timing of symptom onset that defines PPD, ranging from the early postpartum period to 12 months after delivery.2-5 In accordance with DSM-5 criteria, the diagnosis of depression requires the presence of 5 or more of the following symptoms: depressed mood, diminished interest or pleasure in all (or almost all) activities, significant weight loss or gain, insomnia, psychomotor agitation or slowing, fatigue or loss of energy, feelings of worthlessness or excessive inappropriate guilt, diminished ability to think or concentrate, or recurrent thoughts of death or suicidal ideation.1 Additionally, common PPD symptoms present as persistent sadness, anxiety, irritability, feelings of guilt, loss of interest, fatigue, trouble bonding with the baby, persistent doubts about the ability to care for the baby, or suicidal thoughts.6 The impact of PPD can also extend to the entire family, including children because several studies have implicated PPD as a negative factor affecting the cognitive and emotional outcomes of infants.7,8 Impairments in the quality of caregiving, mother-infant interaction, and attachment have also been identified as contributing factors to the burden of disease.9,10
PPD may be underdiagnosed because of a lack of disease awareness, barriers to access to care, and stigma11,12; therefore, many studies report rates of PPD based on the presence of key symptoms. In the USA, 9.7%-23.5% of women with a recent live birth experience symptoms of PPD.13 Across eight European countries, 5.5%- 13.5% of mothers are reported to experience PPD symptoms each year.14-21 Analyses that require a formal diagnosis of depression have reported PPD rates up to approximately 13%.12,14,22-27 The predicted costs of untreated perinatal mood and anxiety disorders, including PPD was estimated to be $14 billion in the USA in 2017 for affected mothers and their children.28 A similar UK study showed that perinatal mental illness could cost society over £8 billion per each 1-year birth cohort.29 Up until recently, there have been limited pharmacological treatment options for PPD; the first PPD-specific treatment, brexanolone (ZULRESSO®; Sage Therapeutics, Inc, Cambridge, MA, USA) was approved by the US Food and Drug Administration (FDA) in 2019.30 Brexanolone is an iv formulation of allopregnanolone that is administered as a continuous infusion for 60 hours.31 Traditional oral antidepressant treatments have been frequently used to treat these patients despite no specific indication for PPD; however, the literature has shown varied efficacy of such treatments, indicating that there remains a high unmet need among this population.32-35
2 | NEUROSTEROIDS AND PATHOPHYSIOLOGY OF PPD
3 | RANDOMISED CONTROLLED TRIAL S IN PATIENTS WITH PPD
4 | STUDIES OF NEUROACTIVE STERIODS THAT ARE GABAA POSITIVE ALLOSTERIC MODULATORS
5 | CONCLUSIONS
PPD is a common mood disorder that is associated with substantial implications for mothers and their families, including children. Although there is more work to be done to characterize the pathophysiology of PPD and how it is delineated from MDD, the available preclinical data suggest that, in the context of large neurosteroid level fluctuations, deficits in GABAA receptor plasticity during pregnancy and the postpartum period may confer biological vulnerability to depression. Controlled clinical trials with monoaminergic antidepressants have shown delayed improvements and variable outcomes. Brexanolone infusion, an iv formulation of ALLO, received the first regulatory approval for the treatment of PPD after demonstrating significant improvements in depressive symptoms within 60 hours. Collectively, these findings support further evaluation of the possible impact that neurosteroids may have as positive allosteric modulators of GABAA receptors for the treatment of PPD.
