To understand the role of inflammation in depression, it's helpful to first review the normal physiologic response to stress. When faced with a threat, human bodies have a number of interdependent mechanisms in place designed to preserve our lives. The sympathetic nervous system responds by releasing catecholamines (norepinephrine, epinephrine, and dopamine). The hypothalamic-pituitary-adrenal (HPA) axis also responds: the hypothalamus releases corticotrophin releasing hormone (CRH), the pituitary releases adrenocorticotropin hormone (ACTH), and the adrenal cortex releases cortisol, a glucocorticoid. The immune system responds by increasing production of proinflammatory cytokines, which increase inflammation. Cytokines are proteins that regulate immune response. Proinflammatory cytokines help the body heal wounds and fight infection by stimulating an inflammatory response .
Maes and colleagues described the interrelatedness of these systems and noted that inflammation influences levels of serotonin and catecholamines, and has an impact on the HPA axis, which controls cortisol levels [7, 11]. Once inflammation starts, it triggers the HPA axis to release cortisol, and the release of more proinflammatory substances . Breastfeeding appears to attenuate these effects by lowering cortisol, ACTH, epinephrine and norepinephrine .
(1) Immune and HPA dysfunction in depression
Depression is also related to some distinct abnormalities in the immune system and HPA axis. I will describe the immune effects first. For many years, researchers considered depression to be primarily immunosuppressive in that they observed that depressed people had fewer lymphocytes and the natural killer cells (NK) had lower cytotoxicity [6, 13]. These are both indications of a suppressed immune system. More recent studies, however, indicate that depression causes an immune dysfunction, meaning that some aspects are suppressed, while other aspects are elevated [13, 14]. In depressed people, inflammation is increased, including high levels of proinflammatory cytokines and acute-phase proteins, such as C-reactive protein (CRP), which are a physiologic response to chronic distress [6, 12, 13]. Levels of inflammation can be 40% to 50% higher in depressed people than their non-depressed counterparts .
The proinflammatory cytokines that researchers identified most consistently as being elevated in depression are interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and more recently, interferon-γ (IFN-γ) . In the last trimester of pregnancy, levels of proinflammatory cytokines rise . When these cytokines are within normal levels, they are adaptive because they help prevent infection. When they are abnormally high, they increase the risk of depression. Proinflammatory cytokines cause a constellation of sickness behaviors in humans, which includes alterations in sleep, appetite, activity, mood, energy, sexual activity and socialization – all behaviors associated with depression . The relationship between inflammation and depression appears to be bidirectional: inflammation increases the risk of depression and depression increases inflammation.
Depression can also influence the systems that normally keep inflammation in check, such as the HPA axis. Cortisol is anti-inflammatory and is generally secreted when inflammation levels get too high. However, depressed people either have abnormally low levels of cortisol or they become less sensitive to cortisol. In either case, cortisol fails to restrain the inflammatory response. In one recent study of 72 women, depressed women had higher levels of IL-6 and TNF-α in response to an acute stressor than women who weren't depressed . Also they were less sensitive to glucocorticoids that normally terminate the inflammatory response system . The authors concluded that the depressed women had a blunted cortisol response to stress . Groër and Morgan in their study of 200 postpartum women also noted a down-regulation of the HPA axis and abnormally low levels of cortisol in depressed women at 4 to 6 weeks postpartum .
(2) Depression, inflammation and preterm birth
Depression poses another health risk to puerperal women – increased risk of preterm birth. Several researchers have noted that depression and posttraumatic stress disorder increase risk of preterm birth, and inflammation may explain why [16, 17]. In a study of 200 women at 4 to 6 weeks postpartum, depressed mothers had significantly smaller babies, more life stress, and more negative life events . These women also had abnormally low cortisol levels meaning that the inflammatory response was not restrained. Another study in Goa, India (n = 270) found that babies of mothers who were depressed during their third trimester of pregnancy were significantly more likely to have low birth weight babies than their non-depressed counterparts. Mothers who were most severely depressed were at highest risk (Odds Ratio, OR: 2.5); these findings were significant even after for controlling for maternal age, maternal and paternal education, and paternal income .
In a prospective cohort study of 681 women, the rate of spontaneous preterm birth for depressed women was more than twice that of women who were not depressed (9.7% vs. 4%; OR: 3.3) . The authors speculated on two possible pathways by which depression might lead to preterm birth. Depression can lead to elevated cortisol levels, which increases corticotrophin releasing hormone (CRH). CRH triggers parturition. The other possible mechanism they cited is activation of the proinflammatory cytokines and prostaglandin E2, which is secreted in response to cortisol and proinflammatory cytokines. Prostaglandin E2 plays a major role in uterine contractions .
The proinflammatory cytokines IL-6, IL-8, and TNF-α ripen the cervix before birth and these are also elevated when women are under stress. In a study of 30 pregnant women, Coussons-Read and colleagues found that TNF-α and IL-6 levels were significantly higher, and the anti-inflammatory cytokine IL-10 was significantly lower, in mothers who were stressed compared with mothers who weren't . The authors hypothesized that inflammation was the likely mechanism to explain the relationship between maternal stress and preterm birth. They noted that high levels of inflammation (particularly IL-6 and TNF-α) were associated with preeclampsia and premature labor. Infection also increases the risk of preterm birth and TNF-α is released in response to both viral and bacterial infections. They concluded that high levels of proinflammatory cytokines may in fact endanger human pregnancies .
Inflammation may also explain another set of findings regarding preterm birth. In a study of 291 low-income pregnant women, participants were randomly assigned to receive either DHA-enriched eggs or regular eggs that they were to consume daily during the last trimester of their pregnancy . This sample was predominantly African American (73%), a group generally at risk for preterm birth. DHA is a long-chain omega-3 fatty acid with anti-inflammatory effects (these effects are described in more detail in a subsequent section). Women who received the DHA-enriched eggs had an average increase in gestation of six days (SD = 2.3) . The DHA-enriched eggs may have increased gestation length by decreasing inflammation.
(3) Physical and psychological stressors
As described in the previous section, human bodies are designed to respond a certain way when they are threatened. These threats can be physical or psychological; the physiological response is the same. Moreover, some types of stressors have both physical and psychological elements. Three stressors – sleep disturbance, pain, and trauma – are particularly relevant to new mothers. Studies that examine these stressors with regard to inflammation are described below.
(a) Sleep disturbances and fatigue
Sleep disturbances and fatigue are physical and psychological stressors that increase the risk of depression. Fatigue and sleep problems are often overlooked or minimized because they are so common in new mothers. But fatigue is often of great concern to mothers, and quantity and quality of sleep can alter stress both immune function and emotional well-being . McEwen noted that short periods of disrupted sleep can wreck havoc on the physical health of even non-depressed people . Disrupted sleep elevates evening cortisol levels (suggesting dysregulation of the HPA axis), increases glucose and insulin levels, and increases insulin resistance. And disturbed sleep is nearly universal in the postpartum period. In addition, mothers of premature babies or babies with high-needs temperaments may wake frequently at night well beyond the postpartum period. Psychological trauma and current stress can also compromise sleep quality [21, 22]. All of these factors increase the risk of depression both directly and indirectly through sleep disturbance.
Sleep disturbance and depression are also mutually maintaining conditions: sleep disturbance can cause depression and depression causes sleep disturbances. Ross et al. noted that several factors suggest a relationship between sleep problems and depression in postpartum women [23
]. These are as follows.
Insomnia is a significant risk for new-onset depression;
Sleep disturbances are common in most psychiatric disorders;
Treatments that manipulate sleep and circadian rhythms can be used to treat mood disorders.
In a review of polysomnographic studies of postpartum women, Ross et al. noted that there are differences in REM latency for women at risk for postpartum depression or who have current postpartum depression – reduced REM latency, increased total sleep time during pregnancy and decreased total sleep time postpartum . REM latency refers to the time during the night when REM sleep becomes the predominant pattern. A pattern of reduced REM latency means that REM occurs earlier in the nightly sleep cycle, and is a symptom of depression. As a result of these sleep disturbances, women are more fatigued during the day. The authors noted that these changes may represent an underlying vulnerability to depression as they do with non-postpartum populations. They also noted that women with a history of affective disorders may be more sensitive to the normal physiologic changes of pregnancy.
Sleep disturbances and fatigue too are related to cytokine levels. When proinflammatory cytokine levels are high, fatigue increases. Moreover, the body experiences disturbed sleep as a physiological stressor . In a sleep study of 22 patients with major depressive disorder (MDD) and 18 age-matched controls, inflammation was associated with sleep disturbances . Prolonged sleep latency and REM density (two markers of disturbed sleep) were better predictors of IL-6 and ICAM (intercellular adhesion molecules – another inflammatory marker) than depressive symptoms. The authors concluded that sleep disturbances were at least the partial cause of elevated inflammation in depressed people .
Another study examined the role of the proinflammatory cytokine IL-1β in postpartum women . The researchers found that higher levels of IL-1β were related to fatigue in women at four weeks postpartum. The authors speculated that IL-1β may have an indirect link to postpartum depression through fatigue . Sleep deprivation is also a stressor that both activates the hypothalamic-pituitary-adrenal (HPA) axis and increases cytokine release in response .
In a study of women four to six weeks postpartum, Groër and colleagues found that mothers' fatigue levels correlated with their levels of stress and depression . They also found that fatigue, stress and depression increased the risk of infection for both mother and baby. Fatigue, stress and depression make the immune system less effective, which increases the risk of infection. Interestingly, the same study also found that mothers who were stressed, depressed and fatigued had lower levels of prolactin in both their serum and milk. These same mothers also had higher levels of melatonin in their milk, the hormone that regulates circadian rhythms .
In a more recent study of 200 women at 4 to 6 weeks postpartum, Groër and Morgan found that depressed mothers reported more fatigue and daytime sleepiness than non-depressed mothers . The depressed mothers had abnormally low levels of cortisol, which may also cause their fatigue. The authors describe how chronic fatigue syndrome, various chronic pain syndromes, and posttraumatic stress disorder are also associated with low cortisol levels. The depressed mothers also had more health problems since the baby was born and had more health-related events such as sprains, dental pain, and allergies. They had higher levels of perceived stress, anxiety and more negative life events. The serum IL-6 levels were three times higher in the depressed mothers, but this was not a significant difference because of measurement variability .
In summary, sleep disturbances and fatigue are physical stressors that increase the risk of depression. The relationship between sleep problems and proinflammatory cytokines appears to be bidirectional: sleep disturbances increase cytokines and cytokines increase sleep disturbance by delaying sleep onset, increasing daytime fatigue, and perpetuating the cycle of disturbed sleep and inflammation. Motivala and colleagues hypothesized that interventions that target disordered sleep may also lower inflammation, thereby lowering the risk of depression .
Pain is another physical and psychological stressor related to increased inflammation and the risk of depression. Pain and depression are highly co-morbid conditions and may have a common etiology . There are many types of pain that postpartum women are likely to experience. Pain can be the result of birth difficulties or breastfeeding difficulties. Pain can be caused by prior psychological trauma, which lowers the pain threshold so that normal sensations are perceived as painful . Pain can also be caused by autoimmune disease that may appear for the first time in the postpartum period .
The relationship between pain and inflammation also appears to be bidirectional. When a woman experiences pain, stress hormones and levels of proinflammatory cytokines increase. High levels of proinflammatory cytokines, in turn, increase pain. Cytokines (especially IL-1) are stimulated by Substance P. Substance P is the neuropeptide that is high in patients with pain. In one study, patients with major depression or posttraumatic stress disorder were compared to healthy controls (n = 101) . The patients with depression or PTSD had significantly elevated levels of Substance P in their cerebrospinal fluid. Moreover, the levels of Substance P rose significantly when the patients were presented with a laboratory-induced stressor that reminded them of their traumatic event. The authors concluded that Substance P was related to both depression and PTSD and responded to acute stress . High levels of Substance P are also related to lower levels of serotonin, which increases the risk of depression. In addition, cytokines increase prostaglandin synthesis, including the prostaglandin cyclooxygenase-2 (COX-2), which increases pain [24, 31–33]. In a study of mothers at eight weeks postpartum, a history of either violence or depression increased the risk of postpartum health problems including several types of postpartum pain .
Sleep disturbances can also increase pain. An example of the relationship between disrupted sleep and pain is in the chronic pain syndrome fibromyalgia. While this is a controversial diagnosis in some circles, researchers have noted that patients with fibromyalgia have a number of physiologic abnormalities that cannot be influenced by patient report. These include increases in Substance P (up to three times as much compared to healthy controls), decreases in serotonin and the serotonin metabolite 5-HIAA in the cerebral spinal fluid, abnormal brain activation patterns, and of relevance to the present discussion, abnormal sleep patterns . A pattern frequently found in patients with fibromyalgia is interrupted delta (slow-wave) sleep. Interrupted delta sleep means that patients' bodies do not make repairs to muscular micro-traumas that have occurred during the day. The net result is all-over body pain . Fibromyalgia has even been induced in the laboratory, where patients' sleep was monitored, and every time they went into delta sleep they were woken up. By the next morning, they had head-to-toe pain, which resolved once they had a normal night's sleep .
An interesting exception to the pain-sleep disturbance phenomenon is co-sleeping. Polysomnographic studies of breastfeeding mothers who are sleeping next to their babies for all or part of the night indicate that the mothers spend less time in deep sleep than mothers who are not co-sleeping. Despite significantly decreased slow-wave sleep, co-sleeping mothers do not appear to report an increase in body pain . Co-sleeping may be less stressful for mothers than needing to completely wake for night time feeding. Or the higher levels of prolactin that co-sleeping mothers have may have an impact decrease inflammation and pain. This issue has never been specifically addressed and would be an interesting topic for future research.
Pain can be a potent trigger for depression in postpartum women. A common type of pain in the first few weeks after birth is nipple pain. A study of 113 breastfeeding women (48 with nipple pain, 65 without) demonstrated that women with pain were significantly more likely to be depressed than women without pain (38% vs. 14%) . Women in the pain group also had significantly higher scores on the Profile of Mood States questionnaire. Once the pain resolved, the scores on these scales dropped to normal levels .
Unfortunately, nipple pain appears to be common, even among educated, middle-class women – the group most likely to breastfeed. In one study in Minneapolis, Minnesota, an astonishing 50% of women had nipple pain at five weeks . Another study from Toronto, Canada had similar results; 52% of mothers reported cracked or sore nipples at two months postpartum .
In summary, postpartum pain is a common experience among women who have recently given birth . Addressing pain promptly, and providing mothers the means to cope with their pain can halt the cascade of stress hormones and proinflammatory cytokines, decreasing their risk of depression.
(c) Current trauma or history of trauma
Psychological trauma can also have an impact on depression and cytokine levels. Like depression, posttraumatic stress disorder (PTSD) is a dysregulation of a normal stress response. Cortisol levels can be abnormally high or low. Previous studies found that people with PTSD had abnormally low cortisol levels. When cortisol is not there to inhibit the inflammatory response system, people who have PTSD have increased cytokine activity [38–40]. Even if cortisol is elevated, the receptors can be less sensitive to cortisol and fail to restrain the inflammatory response [41, 42].
According to the Diagnostic and Statistical Manual , a traumatic event is one in which the person felt that death or serious injury was possible for themselves or a loved one, and the person responded with fear, helplessness or horror. In addition, there must be symptoms in each of these three clusters: 1) intrusion: frequent re-experiencing of the event via nightmares or intrusive thoughts, 2) avoidance: numbing or lack of responsiveness to or avoidance of current events that remind patients of their trauma, and 3) hyperarousal: persistent symptoms of increased arousal including jumpiness, sleep disturbances or poor concentration .
PTSD can be caused by a pre-existing trauma, such as sexual assault or natural disaster. Or it can be caused by the birth itself. In a review of the literature, Beck found that the rates of women who met full criteria for PTSD following birth ranged from 1.5% to 6% . The study with 1.5% excluded women with prior depression or PTSD – the very women who are most vulnerable. Even the highest percentage (6%) may seem relatively small. By way of comparison, in the weeks following the September 11th terrorist attacks in 2001, 7.5% of residents of lower Manhattan living near Ground Zero met full criteria for PTSD . It's shocking to realize that the percentage of women meeting full criteria for PTSD after birth is not substantially different than the rates following a terrorist attack. Moreover, even if women do not meet full criteria, they often have symptoms and these can be troublesome, interfere with their sleep and increase the risk of depression [1, 46].
1) The impact of highly stressful births on breastfeeding
Women may also have experiences that are highly stressful, while not leading to PTSD , can cause breastfeeding difficulties. Women who experience highly stressful births are likely to have abnormally high cortisol levels in the first few days postpartum. And elevated cortisol levels may cause problems. In a study from Guatemala, researchers measured the cortisol levels of 136 women before or after birth. For women with the highest levels of cortisol, lactogenesis II (the onset of copious milk supply) was delayed for several days .
2) Prior history of depression or trauma
A woman with a history of depression or trauma is often more vulnerable to current life stresses. One way that that vulnerability manifests is a more rapid inflammatory response to current stressors. This effect has been noted in both human and animal research. For example, in an animal study, prior exposure to a stressor (in this case, inescapable foot shock) led to a hypersensitivity of the inflammatory response system and more rapid release of proinflammatory cytokines when exposed to a subsequent stressor . This is consistent with human studies of childhood abuse that indicate that men and women who are abused in childhood have a significantly increased vulnerability when exposed to current life stressors. They may respond to these current situations with either depression of PTSD .
Kiecolt-Glaser and colleagues also noted that stress and depression appear to prime the inflammatory response so that it is more reactive to subsequent stressors . During the postpartum period, women experience a number of significant stressors, such a sleep deprivation and postpartum pain, that increase inflammation and the subsequent risk of depression [2, 5]. Women with prior histories of severe stress, depression and trauma are at increased risk of postpartum depression in part because of the way their bodies are primed to react to stress.