Postpartum depression (PPD) is a devastating condition, affecting somewhere between 11 and 20 percent of women who give birth. Yet it's complicated, and poorly understood.
Now, using mouse models, researchers have identified what could be an actual biological cause for the condition - at least in some patients. It all has to do with a pathway in the body that regulates stress.
When that pathway breaks down, the new study from Tufts University suggests that mothers are more likely to develop PPD.
PPD is distinct from the "baby blues," a low mood that may hang around for a few days after giving birth. Not only is it longer lasting, but it can deepen into a sense of worthlessness, fatigue, anxiety, inability to bond with the baby and even suicidal thoughts.
It doesn't just affect mothers either - postpartum depression correlates strongly with developmental and behavioural difficulties in infants.
Right now, up to 85 percent of mothers do not seek or receive help for PPD. This is partly because of the fact the condition is still so poorly understood.
But the discovery of a biological mechanism underlying postpartum depression could finally give scientists a better understanding of what causes some women to develop the condition and not others - and could also lead to more effective medication.
The new study revolves around a stress pathway in the body known as the hypothalamic-pituitary-adrenal (HPA) axis. This pathway is responsible for triggering the famous fight-or-flight response, but during pregnancy it's supposed to be suppressed to protect the foetus from stress.
One of the main drivers of this pathway is a hormone known as corticotropin-releasing hormone (CVH), which is released by the brain during times of stress.
Previous studies had shown a link between PPD, CVH, and the HPA axis, but until now no one had ever been able to figure out exactly how they all worked together.
The team used mouse models to show for the first time that when the HPA axis isn't functioning normally, it can actually trigger PPD-like behaviours in mice.
"Our new study provides the first empirical evidence supporting the clinical observations of HPA axis dysfunction in patients with postpartum depression," said one of the team, neuroscientist Jamie Maguire from Tufts University.
The first part of the experiment involved looking at a protein in the brain called KCC2. KCC2 is known to regulate how much CVN the brain releases, and therefore how much stress mice experience.
The team found that in virgin mice that were exposed to stress, KCC2 was suppressed, which indicated that CVN was unregulated.
But in stressed out pregnant and postpartum mice, KCC2 was active, which suggests it was stifling the stress response in the mothers.
Next, they developed mice that completely lacked KCC2, and compared these "knockout" mice with normal mice.
The knockout mice were much more stressed during pregnancy, and did not show a reduction in anxiety after giving birth, which would have been normal for the postpartum period. They also were more reluctant to mother their pups, approaching them more slowly, and spending less time with them.
To investigate further, the team then silenced the brain cells that usually secrete the stress-driving hormone CVN, and found that the mice without those active brain cells were less stressed and interacted more normally with their pups.
In other words, when CVN was blocked in pregnant mice through a number of different actions, mice were less likely to experience PPD-like symptoms.
This mechanism hasn't yet been demonstrated in humans, but there have been clinical observations of a dysfunctional HPA axis and postpartum depression, so it's definitely worth further investigation.
If the same link exists in humans, it could lead to a more effective way to treat the disease.
But, importantly, the researchers caution that the condition is highly complex and has several contributing mechanisms, so it's unlikely that one treatment would work across all women.
The researchers next hope they will be able to develop a biological marker that can identify women vulnerable to postpartum depression because of a dysfunctional stress axis.
"There is much more we need to learn, but we believe our model will be useful for testing novel therapeutic compounds for postpartum depression," Maguire said.
The research has been published in the journal Psychoneuroendocrinology.