What we know about Postpartum Depression (PPD)

Postpartum Depression (PPD) is a serious mood disorder. It is estimated that, in the United States, depending on states, the incidence varies from 10 – 20%. PPD poses serious risk to the mother and the new born. PPD IS A MAJOR CAUSE OF MATERNAL MORTALITY. It affects maternal functioning and causes significant risk to the cognitive, behavioral and physical development of the infant and siblings. 

Currently the standard of care for PPD is the same treatment that is offered to manage Major Depressive disorder. Although SSRI are effective for Major depressive disorder, but it is not approved specifically for PPD. Therefore, there is a huge need for finding effective treatment for postpartum depression. 

Pathophysiology of Post-Partum Depression (cause of Post-partum of Depression): 

Fluctuation of hormones during the pregnancy period plays significant role in causing depression. Peripartum fluctuation in reproductive hormone (the major progesterone metabolite, allopregnanolone) have a pivotal pathophysiologic role in PPD.  

Most women experiences time limited and specific mood changes in the days after birth known as the maternity blues (BLUES). The maternal hypothalamic pituitary adrenal axis (HPA) undergoes gradual changes during pregnancy because of an increasing production of placental corticotropin releasing hormone (CRH).  Abrupt withdrawal of placental CRH at birth results in a re-equilibration of the maternal HPA axis in the days post-delivery.  These changes may be involved in the etiology of the blues given the central role of the HPA axis in the etiology of mood disorders in general and in perinatal depression. 

Concentration of CRH, ACTH, cortisol, progesterone and Oestriol were measured in 70 healthy women during the 3rd trimester of pregnancy and 1 - 6 post-delivery period by O’Keane et al.  Blues scores were evaluated during the postpartum days.  Progesterone and CRH levels fell rapidly from pregnancy up today 6 whereas cortisol levels fell modestly.  ACTH concentration declined from pregnancy to day 3 post-delivery and after that increased up to day 6.  Blues scores increased peaking on day 5 and were positively correlated with ACTH and negatively correlated with oestriol level during the postpartum days and with the reduction and CRH concentration from pregnancy. 

Ref: O’Keane V, Lightman S, et al. Changes in the maternal hypothalamic pituitary adrenal axis during the early PRP area may be related to the postpartum ‘blues’. J Neuroendocrinol. 2011 Nov;23(11):1149-55. 

Another study also suggests that during pregnancy the maternal hypothalamic pituitary adrenal axis undergoes dramatic alteration due to introduction of placenta.  Prenatal placentalhypothalamic pituitary adrenal axis dysregulation is predictive of postpartum depression.Greater elevations in the placental corticotropin releasing hormone are related to a disturbance in the sensitivity of the anterior pituitary to cortisol and also to decreased central corticotropin releasing hormone secretion.  There is secondary or tertiary adrenal insufficiency which emerge during the prenatal period may be predictive of an extended or more pronounced postpartum hypothalamic pituitary adrenal refractory.  Which in turn represents a risk factor for development of postpartum depression.  Elevated placental corticotropin releasing hormone with low level of ACTH at 3 months postpartum has also been seen in these patients.

Ref: Glynn LM, Davis EP et al, New Insights into the role of perinatal HPA – axis dysregulation in postpartum depression. Neuropeptides, 2013 Dec: 47 (6): 363 – 70. 

Allopregnanolone is a potent allosteric modulator of synaptic and extra synaptic, Ƴ- aminobutyric acid-ligand gated chloride channel (GABAA) receptors.  Plasma Allopregnanolone concentration rise in concert with progesterone throughout pregnancy, reaching the highest physiological concentration in the 3rd trimester.  After childbirth, these concentrations decrease abruptly.  Failure of GABAA receptors to adapt to these changes has been postulated to have a role in triggering postpartum depression. Maguire et al showed that alterations in delta GABAAR expression during pregnancy resulting brain region specific increases in neuronal excitability that are restored by the high levels of allopregnanolone under normal conditions but under pathological conditions may result in neurological and psychiatric disorder associated with pregnancy and postpartum.

Ref: Maguire J, Ferando I et al. Excitability changes related to GABAA receptor plasticity during pregnancy. J Neuroscience. 2009 Jul 29;29(30):9592-601.

Allopregnanolone (Investigational Products) Is an endogenous, naturally occurring neuroactive steroid formed in the corpus luteum of the ovary, adrenal cortex and central nervous system. Allopregnanolone is a metabolite of progesterone created by the action of 5-α reductase and 3-α hydroxy-steroid dehydrogenase.  Allopregnanolone is a potent allosteric modulator of both synaptic and extra-synaptic GABAA receptors. Higher dose than what is being used in the study causes sedation and has anesthetic effect. It has short half-life. It has moderate volume of distribution and higher levels in Cerebrum than plasma. To date, it has shown clinically meaningful improvement in depressive symptom.