New Research: Identifying the Pathophysiology of Postpartum Psychosis

Updated: Oct 29, 2020

While the etiology of postpartum psychosis is still in question, efforts are underway to identify biological factors that contribute to risk for or the onset of the disorder. Postpartum psychosis (PP) affects 1-2 of every 1,000 mothers and generally presents shortly after childbirth. The disorder is characterized by a range of symptoms, often starting with depressive or manic symptoms and progressing to psychotic symptoms such as confusion or delirium, hallucinations, paranoia, and delusions. Pharmacological interventions including both typical and atypical antipsychotics and mood stabilizers have been shown to be effective especially if they are administered early and in conjunction with psychotherapy and psychoeducation.

Several approaches have been used in attempt to elucidate the cause of PP including clinical biochemistry or gene expression analyses, neuroimaging, genetics, and animal models. The results of these efforts have helped to uncover potential risk factors and propose pathophysiological mechanisms for PP, but there are drawbacks to each method, and none of the results have been able to definitively determine the cause of PP.  Additionally, due to its low prevalence, variability of symptoms and presentations across cases, relative unpredictability, and lack of adequate animal and cellular models, postpartum psychosis is particularly difficult to study. In his review of the current findings from and approaches to studying the disorder, William Davies outlines what we know and where we are heading with regards to our knowledge about PP.

Studies employing clinical biochemistry have largely looked at the levels of an amino acid, tryptophan, and its metabolic products (which act as precursors in the biosynthesis of the neurotransmitter serotonin). Additionally, the thyroid and immune systems have been of interest as they are particularly active and changeable during pregnancy. Findings have indicated decreased breakdown of tryptophan and lower levels of kynurenine (a metabolite of tryptophan) in women with postpartum mood disorders. One drawback to clinical biochemistry as a method for understanding PP is the difficulty of obtaining samples of blood, serum, or cerebrospinal fluid from patients experiencing psychosis. Additionally, it is difficult to directly associate changes in peripheral tissue to central functioning. It is also important to consider how demographic, psychosocial factors, and general health might influence biochemical measures, making it difficult to effectively differentiate between patients with PP and controls.

While there has been some success with using neuroimaging as an investigational method in studying many psychiatric disorders, no consistent brain region has been found to be associated with PP. Using techniques such as fMRI, researchers have suggested the involvement of some areas such as the anterior cingulate cortex, an area associate with cognitive and emotional processing. However, findings in this area are preliminary and cannot be considered absolute. There is the added challenge of assessing brain activation and function while a patient is experiencing a psychotic episode, which has proven to be difficult.

Another approach to studying PP has been through analysis of genomic risk variants. This is accomplished through genome screening of patients with the disorder and can provide valuable information that may point to a genetic predisposition for PP. The genetic approach to studying PP has generated some promising results that implicate serotonin transporter and receptor genes as well as genes that are important to serotonergic and oestrogenic signaling pathways. Genetic risk screening has also uncovered some evidence for the role of the immune system and its regulatory elements. However, these results will likely be limited by several factors including the low prevalence of postpartum psychosis and the probability that PP will, like many psychiatric disorders, have a complex and polygenic genetic risk.

One gene, the STS gene encoding the enzyme steroid sulfatase, has recently been proposed as a mechanism for postpartum psychosis. The enzyme it encodes is involved in cleaving sulfate groups from steroids which allows them to be used as oestrogen and androgen precursors. STS cleaves a sulfate group from the steroid hormone dehydrepiandrosterone sulfate (DHEAS) to form dehydrepiandrosterone (DHEA). STS seems to be a key player in the steroid-hormone axis, which is in considerable flux during pregnancy and birth. In patients with PP, the cleaving mechanism of STS seems to be lacking which leads to multiple downstream effects including pre-eclampsia risk, immune system hyperactivation, and abnormal stress response related to the hypothalamic-pituitary-adrenal or hypothalamic-pituitary-thyroid axes. The implications of abnormal or mis-expression of the STS gene are still being investigated, but it does show promise as a candidate genetic risk factor.

Animal models can provide valuable insight into human diseases. However, it is difficult to find models that can effectively model complex psychiatric disorders. One model that has been used to model PP is the porcine infanticide model, which has been shown to exhibit many similarities to PP in humans. Upon genetic screening of these infanticidal sow pigs, there were several genomic regions and candidate genes of interest identified that could be functionally relevant. While this animal model may be useful in learning more about the causes of PP, there are significant barriers to its efficacy including the poor correlation with human PP symptoms (most women with PP are not aggressive and very few harm their children) and underlying differences in brain structure and chemistry between pigs and humans. A relatively new animal model that has shown some promise is a mouse model that has provided valuable insights on genetic components that parallel those seen in humans with PP.

While the research developments and future directions described by Davies in his review are exciting and will hopefully begin to uncover some of the causes of PP, it is difficult to account for the heterogeneity of the disorder. The variety of symptoms experienced, and the complexity of most psychiatric disorders, make it difficult to study PP in a controlled manner and to generalize findings to all cases of the disorder. If you are interested in learning more about the breadth of lived experiences of mothers who have experienced postpartum psychosis, read our Survivor Stories.

Research summary compiled by Nicola Roux.

Davies, W. (2017). Understanding the pathophysiology of postpartum psychosis: Challenges and new approaches. World Journal of Psychiatry,7(2), 77-88.