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Abstract

In comparison with the vast epidemiological literature on postpartum depression (PPD), relatively few studies have examined the biological aspects of the disorder. However, research into the biological mechanisms of PPD is a challenging task, as normal pregnancy and the postpartum period cause adaptive endocrine changes, which would otherwise be considered pathological in nonpregnant women. This review focuses on the adaptive changes of childbearing and nursing, which ultimately may put women at increased risk of PPD. In light of the normal physiology, the authors also attempt to describe the current evidence of the biological changes associated with the development of depression in the postpartum period, including ovarian steroids, the hypothalamic–pituitary–adrenal axis, the serotonergic neurotransmitter system, the thyroid system and inflammatory markers. In addition, current knowledge on candidate genes associated with PPD is reviewed.

Keywords

Cortisol estradiol genetic markers inflammatory markers postpartum depression progesterone serotonin thyroid

Postpartum depression (PPD) is a condition strictly defined in the psychiatric nomenclature as a major depressive episode beginning within the first 4 weeks after childbirth. Considering the fact that many women may start experiencing symptoms later in the postpartum period, the definition is often extended to include the entire first year of postpartum. As with other major depressive episodes, the depressive symptoms must be present for at least two consecutive weeks, and in addition to the core symptoms – depressed mood or loss of interest in normal activities – sleep and appetite disturbances, loss of energy, feelings of guilt and suicidal thoughts may be present. This makes the PPD diagnosis a challenging one, since fatigue, changes in sleep patterns and weight changes are often observed in the normal postpartum period.

In the past, many risk factors for PPD have been studied. The emphasis has historically been on psychosocial aspects, such as a personal history of psychiatric illness (previous PPD being a highly significant risk factor) [1], low socioeconomic status, low level of education, alcohol and drug abuse, and low levels of social or partner support [2,3]. In addition, obstetric factors such as unplanned pregnancy, pregnancy complications and delivery modes have been debated as potential risk factors [4]. However, while these risk factors are important for PPD, the main targets of this review are the biological risk factors associated with PPD.

Biological theories on the pathophysiology of PPD are, to some extent, similar to those of other psychiatric disorders. However, postpartum women represent a specific group, with both hormonal and psychosocial events that have no parallel in a woman's life time. Therefore, a direct comparison between depression related to pregnancy and childbirth, and depression at other times during a woman's life cannot always be made.

Neuropsychoendocrinology of normal pregnancy & the postpartum period

A normal pregnancy and postpartum period bring about large endocrine alterations, which represent adaptive changes in preparation for childbirth and nursing, but would be considered pathological in a nonpregnant woman. The physiological effects of these changes obviously include the suspension of ovulation and the development and growth of the uterus, the placenta and the fetus. In order to achieve this, readjustments of the maternal stress systems, immunology and metabolism are required. The changes involve hormones and neurotransmitters, which are known to have important roles in mental health and disease. Several of the hormonal alterations have been, perhaps rightfully, held responsible for impairing women's mental health during the postpartum period. However, it is important to bear in mind that this complex pattern of change obviously includes balancing elements, which do keep the majority of childbearing women in good health at a turbulent time in their lives.

A number of the endocrine changes follow a common pattern: a continuous increase in hormone plasma concentration through the 40 weeks of pregnancy, followed by a drastic drop at parturition. Estrogens, progesterone, testosterone, corticotropin-releasing hormone (CRH) and cortisol all essentially adhere to this temporal plasma profile [5 –9].

The long-term continuous increase of steroid hormones requires an uncoupling of the regular negative feedback systems. This is achieved by the feto–placental unit, which produces large amounts of estrogens, progesterone and CRH – among numerous other substances – to ultimately cause its own expulsion [10]. Instead of the negative feedback cortisol has on hypothalamic CRH production, cortisol has a positive feedback on placental CRH production [10]. Importantly, a substantial amount of cortisol is produced by the fetal adrenal gland during the very last weeks of gestation, probably as a signal for the maturation of fetal organs, as well as for the timing of parturition [10]. Elevated levels of placental CRH are thought to correlate with premature delivery, but also the start of labor in full-term pregnancies.

During the third trimester, maternal cortisol levels reach approximately three-times that of nonpregnant levels [7]. While the basal levels of CRH, adrenocorticotropic hormone and cortisol are high, the acute hypothalamic–pituitary–adrenal (HPA) axis reactivity to stressful stimuli is dampened in late pregnancy [11]. Furthermore, while the baseline cortisol levels return to normal within a couple of days after parturition [12], the HPA axis' hyporesponsiveness lingers in breastfeeding women [13].

Besides the HPA axis, the hormonal changes of pregnancy and childbirth also affects the other major stress system – the sympathetic nervous system (SNS) – in a similar manner. In the third trimester, the basal skin conductance activity is increased, while the reactivity to stress is dampened [14]. This is further emphasized by the finding that the SNS reactivity to cold stress is lower in women with fewer days left to their actual delivery date [15]. In the postpartum period, SNS basal activity and reactivity seem to be continuously dampened [16]. The sympathetic tone and the sympathetic response to stress are lower in breastfeeding women compared with bottle feeding women and nonpostpartum controls [13,16].

Another approach to study psychophysiological effects of the endocrine changes during pregnancy and postpartum is measurement of the startle response, an innate reflexive twitch to sudden stimuli. In humans, the acoustic startle response is often measured by the eyeblink response to a sudden sound pulse, and can be enhanced or reduced by aversive and pleasant states, respectively, for example during viewing of emotional pictures. Studies in the present authors' laboratory have indicated a lack of effect of positively and negatively valenced pictures during both late pregnancy and 5 weeks into the postpartum period [17]. They also detected a significant postpartum reduction in startle modulation during the anticipation of viewing emotional pictures compared with late pregnancy, which may be indicative of decreased responsivity of the autonomous defense system postpartum [17].

Studies on neurotransmitter adaptations inside the CNS during pregnancy are rare, primarily due to a precautionary approach to the effects of imaging techniques on the fetus. However, women undergoing elective cesarian section have lower cerebrospinal fluid (CSF) levels of GABA, as well as the norepinephrine metabolite 3-methoxy-4-phenyl glycol compared with nonpregnant women [18]. A few imaging studies have been made at different stages of the postpartum period. For example, decreased cortical GABA concentrations in healthy women several months into the postpartum period have been demonstrated by magnetic resonance spectroscopy [19]. PET studies have revealed significantly increased monoamine oxidase A activity (i.e., increased breakdown of serotonin, norepinephrine and dopamine) throughout all analyzed brain regions in the early postpartum period of healthy women [20]. Studies on serum indicators of serotonergic activity in healthy women a few days after delivery strengthen the notion that the early postpartum is a state of serotonin deficiency [21,22], although the serotonergic indices seem to be restored to late pregnancy values at 6-weeks postpartum [22]. Indirect evidence of central nervous changes also include markedly decreased maternal serum levels of BDNF, both before and after delivery, and at both time points BDNF is correlated with decreased serotonin levels [23].

Allopregnanolone is another neuroactive substance, which increases approximately 40-fold in serum during pregnancy [24,25]. This progesterone metabolite enhances GABA_A receptor signaling, and thereby has a general inhibitory effect in the brain, as evidenced by its anxiolytic and sedative properties [26]. Based on rodent studies, it has been suggested that allopregnanolone, through upregulation of opioid signaling in the brainstem, is responsible for the reduced HPA axis activity during pregnancy [27]. After delivery, when allopregnanolone has fallen to very low levels, the increase in brain prolactin during lactation is thought to be responsible for the withheld HPA axis suppression [28,29].

Finally, the preparation of the mammary gland for lactation is an important goal for the endocrine changes during pregnancy. Prolactin, the key lactogen, starts increasing during early pregnancy [30], and at term, CSF and plasma levels of prolactin in pregnant women are approximately ten-times higher than in nonpregnant women [18]. When progesterone is withdrawn at parturition, the build-up of prolactin can induce milk production [30]. Furthermore, plasma prolactin crosses the blood–brain barrier, is involved in the inhibition of ovulation, and is responsible for decreasing postpartum stress increases, not only in the HPA-axis activity, but also in the oxytocin system [28,29].

The posterior pituitary peptide oxytocin is responsible for the ejection of milk in response to suckling. Oxytocin levels are higher in plasma, but not in the CSF of pregnant women compared with nonpregnant women [18]. Average plasma oxytocin does not increase from pregnancy levels in the postpartum period [31], although it transiently rises at nursing [32]. On the other hand, a study on lactating rhesus macaques showed that oxytocin levels in the CSF seem to be independent of suckling, and that CSF levels and plasma levels are independent of each other [33]. There is also evidence that oxytocin does not cross the human blood–brain barrier [18].

Neuropsychoendocrinology of PPD

With the outlined changes that occur during a normal pregnancy and postpartum period, research into neuropsychoendocrine factors associated with PPD represents a true challenge for the scientist. Not only are relevant sample sizes and control groups needed, but assessments have to be made at strictly defined time frames of the postpartum period. In comparison with the vast epidemiological literature on PPD, relatively few studies have studied the biological aspects of the disorder.

Estradiol & progesterone

With estradiol and progesterone levels rapidly decreasing following parturition, it is not surprising that these hormones have attracted attention in PPD research. Hypoestrogenism at other times of a woman's life is associated with reduced well-being and estradiol treatment may potentially have beneficial effects in women with perimenopausal depression [34]. The hypoestrogenism of the postpartum period has been suggested as a contributing factor for PPD, especially since downregulation of endogenous hormone production in women with PPD history elicits depressive symptoms in more than 60% of cases [35]. Furthermore, estradiol treatment in relatively high doses has been shown to improve PPD [36,37]. However, as the study by Gregoire and colleagues was the only one to include a placebo control [37], these findings need replication. More recently, the concept of hypoestrogenism has also been challenged as women with major depression had higher estradiol serum concentrations than nondepressed mothers in the immediate postpartum period [38].

Progesterone and it's metabolite allopregnanolone, on the other hand, have mostly been associated with postpartum blues, as the peak in immediate postpartum depressive symptoms coincides with the most profound or rapid decline in progesterone levels [6], and as women with postpartum blues have lower allopregnanolone levels than controls [39]. In terms of PPD, findings are more inconsistent, with reports of unchanged [40] or increased [41,42] progesterone levels. Nevertheless, progestagen administration in the immediate postpartum period increased the risk of PPD [43].

The HPA axis

Hyper- or hypo-activation of the HPA axis has previously been associated with depressive states [44]. It has been hypothesized that depression during pregnancy and depression in the postpartum period may have different pathogeneses, the first being melancholic, with hyperactivity in the HPA axis, and the second atypical [45]. In seasonal affective disorder (SAD), atypical depression and PPD, the activity of the HPA axis is usually reduced, which could point to a similar pathologic mechanism in these three conditions [46]. Furthermore, the physiological excess production of CRH at the end of pregnancy leads to a transient downregulation of hypothalamic CRH postpartum, which could possibly lead to an elevated risk for depression [45]. Indeed, the hypothesis of PPD being related to hypoactivation of the HPA axis has been substantiated by a number of studies where women with PPD display lower baseline [40,47] or reduced HPA responsiveness [48,49] in comparison with controls, although conflicting data are available [23]. In addition, women with a history of PPD appear to have increased CRH-stimulated cortisol response during experimental conditions mimicking pregnancy [50] and PPD may also be predicted by increased stress-induced cortisol levels [51] or CRH levels [52] during pregnancy.

Oxytocin & breastfeeding

Oxytocin has been suggested to have a moodameliorating effect [53]. Pain, stress and anxiety are associated with diminished oxytocin release [54] and central, but not peripheral, oxytocin release is thought to functionally counteract the HPA axis [28]. However, decreased peripheral levels of oxytocin have been found in nonpregnant depressive patients and during pregnancy in women with high depression scores postpartum [55]. Notably, breastfeeding status does not influence basal plasma oxytocin at 1-month postpartum [56]. The literature also suggests that failed or discontinued lactation is associated with postpartum depressive symptoms. However, the direction of this association remains unclear. Studies show that women with negative early breastfeeding experiences [57] or those who stop breastfeeding early or are not breastfeeding are at an increased risk for PPD [58], and that breastfeeding self-efficacy predicts changes in postpartum depressive symptoms [59]. Other studies, on the contrary, have suggested that the appearance of depressive symptoms seems to promote discontinuation of breastfeeding [60,61].

Serotonin

The pivotal role of the serotonergic system in the pathophysiology of mood disorders is now well established, with many pharmacological strategies targeting components of the system. The most solid evidence for a serotonergic involvement is the beneficial effect of selective serotonin reuptake inhibitors (SSRI) for the treatment of PPD, although some of the smaller studies have failed to demonstrate a beneficial effect in comparison with other types of interventions [62 –67]. It is also well documented that cortisol, progesterone and estradiol have regulatory effects on the serotonin (5-HT) system [68]. Additional findings to support the involvement of the 5-HT system include PET studies demonstrating a 20–28% reduced postsynaptic 5-HT_1A-receptor binding among PPD patients relative to controls, with the most significant reductions in the anterior cingulate cortex and mesio temporal cortex [69]. Numerous studies have used peripheral measures of serotonergic activity and the overall conclusion is that women with PPD have lower available tryptophan levels [70], lower platelet serotonin levels [23,71] and altered binding of platelet serotonin transporter sites [72,73].

Genetic variation of the serotonin transporter gene (5HTT) has been previously associated with susceptibility to depression [74]. The promoter region of the 5HTT gene (SLC6A4) contains a functional polymorphism (5HTTLPR) consisting of an insertion/deletion of 44 bp. The short allele of this polymorphism has been associated with reduced 5HTT transcriptional activity compared with the long allele [75]. This genetic variation has been associated with emotional and stress sensitivity differences in both humans and animal models [76]. The 5HTTLPR polymorphism has been investigated in PPD, but findings have been contradictory [77 –82] (see Table 1 [83 –88]). One large study found a main effect of the 5HTTLPR polymorphism together with STin2 VNTR, with the LL and 12.12 genotypes being the risk variants [82], while a smaller study found only a borderline significant main effect of the 5HTTLPR, with the LL as a risk variant [79]. The four subsequent studies did not find a main effect of the 5HTTLPR on PPD [77,78,80,81].

Table 1.

Genetic association studies on postpartum depression.

Study (year)	Ethnic background	n	PPD cases	Measure	Assessment time	Gene	Polymorphism	PPD risk variation	Ref.
Sun et al. (2004)	Taiwanese Han	114	28	CM-SADS-L + DSMI-V	Retrospective on peripartum	TPH1	rs7130929	T allele of rs2108977	[87]
							rs623580
							rs21105
							rs1800532
							rs2108977
Josefsson et al. (2004)	Swedish	145	100	EPDS	Week 35–36 prepartum, week 6–8 + week 26 postpartum	CYP2D6	CYP2D6^*1	UM variant of CYP2D6†	[85]
							CYP2D6^*3
							CYP2D6^*4
							CYP2D6^5 CYP2D6^UM
Sanjuan et al. (2008)	Spanish	1407	214	EPDS	Week 8 + week 32 postpartum	SLC6A4	5HTTLPR	Genotypes LL of 5HTTLPR together with 12.12 of STin2 VNTR	[82]
							STin2 VNTR
Lin et al. (2009)	Han Chinese	200	83	CM-SADS-L + CM-SADS-C	Week 36 prepartum, week 18 postpartum	TPH2	rs4570625	A allele of C2755A†	[86]
							rs11178997
							rs11178998
							C2755A
							rs11179003
Xie and Innis (2009)	Caucasian (majority)	69	8	EPDS	Week 36 prepartum, week 8 + week 26 postpartum	FADS1	rs174561	C allele of rs174575	[88]
						FADS2	rs498793
							rs174553
							rs99780
							rs174575
							rs174583
Doornbos et al. (2009)	Caucasian	89	n.i	EPDS	Week 16 +week 36 prepartum, week 6 + week 12 postpartum	MAOA	MAOA-uVNTR	LA genotypes of MAOA-uVNTR, Met/Met of rs4680, L allele of 5HTTLPR + rs25531‡; LA genotypes of MAOA-uVNTR by Met/Met of rs4680	[79]
						COMT	rs4680
						SLC6A4	5HTTLPR rs25531
Costas et al. (2010)	Spanish	1594	162	EPDS	Week 8 + week 32 postpartum	44 genes	388 SNPs	T allele of rs11924390 at KNG1‡	[83]
Figueira et al. (2010)	Brazilian	227	43	EPDS + MINIPLUS	Week 8 postpartum	BDNF	rs6265	n.s.	[84]
Comasco et al. (2011)	Caucasian	232	59	EPDS	Week 6 + week 26 postpartum	COMT	rs4680	Met allele of rs4680, LA genotypes of MAOA-uVNTR†‡; LA genotypes of MAOA-uVNTR by Met allele of rs4680	[78]
						MAOA	MAOA-uVNTR
						SLC6A4	5HTTLPR
Comasco et al. (2011)	Caucasian	219	n.i.	EPDS	Week 6 + week 26 postpartum	BDNF	rs6265	Met allele of rs6265‡	[77]
						SLC6A4	5HTTLPR
						PER2	SNP10870
Mitchell et al. (2012)	Black (majority)	1206	205	CIDI-SF	52-week postpartum	SLC6A4	5HTTLPR STin2 VNTR	n.s.	[80]
Mehta et al. (2012)	Caucasian	419	105	EPDS	Week 27–39 prepartum, week 1 + week 23–35 postpartum	SLC6A4	5HTTLPR	n.s.	[80]

†

Nonsignificant after correction for multiple testing.

‡

Borderline significant.

CM-SADS-C: Chinese modified version – Schedule for Affective Disorders and Schizophrenia –Current version; CM-SADS-L: Chinese modified version – Schedule for Affective Disorders and Schizophrenia – Lifetime version; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders – IV Edition; EPDS: Edinburgh Postpartum Depression Scale; LA: Low activity; MINIPLUS: Mini International Neuropsychiatric Interview – Plus; n.i.: Nonidentified, EPDS score used as a continuous variable; n.s.: Nonsignificant; PPD: Postpartum depression; SNP: Single nucleotide polymorphism; UM: Ultrarapid metabolizer.

The interaction effect between monoaminergic genes and environmental stressors is likely to contribute to vulnerability for PPD, however it has been investigated in only few studies [80,81]. The findings suggest an interaction effect between the low activity allele of the 5HTTLPR polymorphism and stressful life events or socioeconomic status on PPD. Two studies from the present authors' group have included stressful life events and postpartum maternal stressors, however, only one gene-by-environment correlation effect could be tested due to the limited sample size [77,78]. Psychiatric history, together with the 5HTTLPR polymorphism, has also been associated with PPD, however, with contradictory results and in different study set-ups [78,89]. Binder and colleagues found a higher risk for PPD symptoms among short allele carriers [89], while Comasco and colleagues found a higher risk for PPD symptoms among carriers of the long allele and the Met158 allele of catechol-O-methyltransferase [78]. Thus, epistatic effects between genes should also be considered.

BDNF

BDNF, which contributes to regulating neurogenesis and synaptic plasticity, has also been studied in relation to depression [90]. Furthermore, BDNF in interaction with the serotonin system has synergistic effects on the development and plasticity of neuronal circuits of relevance for affective disorders [90]. For instance, BDNF gene expression has been shown to be enhanced by SSRIs [90]. PPD is likely to be the results of an interaction effect between hormonal changes and these brain neurotransmitter systems [91]. Reduced BDNF and 5HTT gene expression has been associated with hormonal deprivation and with behavioral phenotypes relevant for PPD in rodents [92]. Variation of BDNF levels has also been associated with hormonal changes in humans [93 –95] and reduced BDNF levels have been found in women pre- and post-partum [23]. However, in comparison with healthy postpartum women, women with PPD reportedly have even lower BDNF levels [96]. In addition, hormonal status has been associated with circadian variation of BDNF levels in women [95]. A study from the present authors' group showed that season of delivery modulates the association between PPD and the Val66Met polymorphism of the BDNF gene, also after controlling for pre- and post-partum environmental risk factors. When delivery occurred during autumn/winter, women with the Met allele displayed the highest PPD symptoms [77].

Circadian rhythm

Patients with mood disorders are often characterized by circadian rhythm dysregulation, resulting mostly in disturbed sleep patterns and PPD is no exception. Sleep, or lack of it, is an issue most new parents struggle with, and lack of adequate sleep in the first months postpartum has been associated with both new-onset and recurrence of PPD [97 –99]. However, one must bear in mind that the assessment of sleep quality in the postpartum period is difficult, as it may be the cause [100], as well as the consequence, of depression [100 –102]. The best measure of circadian rhythmicity in humans is plasma melatonin. Melatonin is synthesized from serotonin under the rate-limiting influence of norepinephrine, and its secretion is regulated by the hypothalamic circadian pacemaker. Melatonin circadian rhythms have been described to be of lower amplitude in some depressed patients [103,104]. Thus far, only one study has been conducted in PPD women, suggesting that morning melatonin levels were significantly higher compared with controls [105]. Although it remains to be verified, it has also been suggested that melatonin may play a role in the increased risk of developing postpartum psychosis that women with bipolar disorder carry [106].

Seasonal effects

The seasonal differences in the prevalence of affective disorders are well documented [107]. SAD is more common among women than men, especially during the childbearing years [108]. Together with SAD, PPD has been classified, according to Chrousos and Gold, under the depressive states characterized by hypoactivation of the HPA axis [44]. It would therefore be plausible to speculate that seasonal variation would have an effect on its prevalence. There are few studies investigating this hypothesis. Although one American study found no effect of season on the risk of PPD [109], other studies have suggested an increased prevalence of depressive mood if delivery takes place during autumn and winter [110 –112]. In addition, the authors reported a significantly higher risk for depressive symptoms, at both 6-weeks and 6-months postpartum, among women delivering in the last quartile of the year [112]. The underlying mechanisms responsible for the relation between season and psychiatric illness have been speculated upon, and are thought to involve the change in certain climatic variables, such as daylight, which may affect cortical and subcortical serotonergic systems, as well as synthesis of vitamin D in the skin. It is well documented that serotonergic activity is lowest during autumn and winter, while other substances that follow seasonal patterns and may affect the risk for depressive symptoms include cortisol, melatonin and tryptophan.

Vitamin D

Vitamin D is metabolized either from dietary sources or manufactured in the epidermis when exposed to ultraviolet B sunlight. It is then metabolized in the liver into 25(OH)D and then to 1,25(OH)₂D. It is this active form of vitamin D that subsequently binds to receptors located in bone, brain and breast tissue, as well as in immune cells. Vitamin D has important actions in several organ systems. While the most important roles of vitamin D relate to bone metabolism, recent studies have, nevertheless, reported associations between vitamin D deficiency, inflammatory response [113,114] and mood disorders [115]. More specifically, studies report lower levels of 25(OH)D among women with major depressive disorder (MDD) compared with controls [116], as well as a positive association between vitamin D deficiency and presence of mood disorders [117]. Increase in 25(OH)D has also been shown to improve depression scores among SAD patients [118]. However, more recent studies have failed to demonstrate an association between active metabolites of vitamin D and mood disorders [119]. The biological mechanisms underlying the association between vitamin D levels and mood disorders are not clear, but as other patients with psychiatric disorders also have low levels, it has been hypothesized that socioeconomic differences and different nutritional habits may play a role [120,121]. Lower 1,25 (OH)₂ D levels have been found in postpartum women compared with pregnant women [122], but with regards to PPD, there is, so far, only one study in the literature, examining serum 25(OH)D levels postpartum in relation to Edinburgh Postpartum Depression Scale scores [123]. The study shows a significant association over time between low 25(OH)D levels and high depression scores postpartum. Thus far, only one randomized clinical trial has evaluated treatment with high doses of vitamin D in depressed subjects with promising results [124].

The immune system

One important function of the cortisol, progesterone and estradiol surges during pregnancy is immunomodulation [125]. As a fetus is perceived as nonself, the maternal immune system has to be tranquil to allow the fetus to thrive, but at the same time it must keep up the defense against pathogens. This is thought to be achieved through downregulation of the antigen-specific, T-cell mediated part of the immune system, while there is an upregulation of the generalized inflammatory response, (i.e., monocytes and granulocytes) [126]. Infection, injury and stress all trigger the innate immune system, which tries to limit tissue damage or the spread of an infection by the synthesis of proinflammatory (IL-β [IL-1β], IL-2, IL-6, TNF-α, IFN-α and IFN-γ) and anti-inflammatory (IL-4 and IL-10) cytokines. Release of proinflammatory cytokines initiates a systemic inflammatory response characterized by fever, hypersomnia, activity reduction, fatigue, decreased appetite and, in humans, depressed mood [127]. Indeed, changes in proinflammatory cytokines have been reported across the pregnant and postpartum states, with both pro- and anti-inflammatory cytokines being upregulated in the postpartum period [122,128,129].

In recent years, evidence that activation of the inflammatory response system may be involved in the pathophysiology of MDD and anxiety states, as well as PPD, has arisen [130 –134]. The cytokine hypothesis of depression suggests that prolonged or excessive activation of the proinflammatory immune response may be a mechanism for depression [135,136].

More specifically, in the case of PPD, it is suggested that for some women, PPD might represent a psycho–neuro–immunological disorder, which arises from exaggeration of the inflammatory response that normally accompanies labor and delivery, while the HPA-axis function is not adequately suppressed. Kendall-Tackett argues for a model for PPD, in which many previously identified risk factors (e.g., stress, sleep disturbances, pain, inflammation, psychological trauma and history of depression or trauma) all have inflammation as the underlying mechanism [131].

Increased serum concentrations of markers of the inflammatory response, for example IL-6, a proinflammatory cytokine with a variety of endocrine and metabolic actions, have now been shown to accompany major depression [137 –139]. IL-6 interacts with the HPA axis, and significantly higher serum levels in women with postpartum depressive symptomatology have been reported [133,140]. However, peripartal or postpartum IL-6 levels could not predict later development of PPD [98,141]. In addition, lower levels of the proinflammatory cytokine IFN-γ have been reported in women with PPD, whereas IL-10 did not differ from nondepressed postpartum controls [47].

The thyroid system

Thyroid function abnormalities appear to be associated with an increased frequency of psychiatric symptoms, with hyperthyroidism being related to anxiety, mania, restlessness, depression and cognitive deficits, while hypothyroidism is associated with memory deficits, lack of concentration, psychomotor slowing and depression [142]. The mechanism by which thyroid dysfunction may affect the risk of developing depression and vice versa remains to be established, but several theories have been expressed [143]. Furthermore, affective disorders and autoimmune thyroiditis are both clinical conditions well known to affect women in the puerperium. Abnormalities in thyroid function are more prevalent after delivery, with up to 7% of all new mothers experiencing thyroid dysfunction postpartum compared with a prevalence of 3–4% in the general population [142].

Normal thyroid balance is challenged during pregnancy. Levels of thyroid-binding globulin are increased secondary to increased estrogen levels, while there is a high production of several thyroid-stimulating factors by the placenta (mainly human chorionic gonadotropin) and a relative iodine deficiency. Although pregnancy may be associated with thyroid enlargement and increased total T3 and T4 levels, free T3 and free T4 usually remain within normal limits. Levels of thyroid-stimulating hormone (TSH), on the other hand, are decreased during the first trimester, in association with the increasing levels of human chorionic gonadotropin. After the initial decline, TSH levels rise again to prepregnancy levels and typically remain stable throughout the pregnancy [144]. Healthy women have significantly lower TSH levels 4 months after delivery than during the third trimester [145].

PPD has been associated both with overt thyroid dysfunction [146,147] and with the mere presence of thyroid antibodies [148,149], even during early pregnancy [150]. However, postpartum thyroxin treatment of women with positive thyroid antibodies during pregnancy failed to decrease their rate of depression or depression scores [151]. Low – although within normal range – late gestational levels of free T4 and free T3 have been associated with increased incidence of mood disturbances in the first postpartum week [152] and depressive mood later in the postpartum period [153,154]. However, postpartum free T4 levels (immediately or 4-weeks postpartum) have, in most cases, not been associated with PPD [155,156]. Reports on TSH levels and PPD are more inconclusive. TSH concentrations measured on admission for delivery have been associated with increased depression scores within the first postpartum week [152,155]. Women with maternity blues have higher TSH levels [157] and women with higher, albeit still normal, TSH levels (measured 4 weeks after delivery) tended to have higher depression scores at 4-weeks postpartum [156]. In addition, the authors reported a positive association between subclinical hypothyroidism at delivery and the development of self-reported depressive symptoms at 6 months postpartum [158].

Leptin

Leptin, a protein synthesized in the adipose tissue and coded by the obese gene, has been studied recently with regards to depression. Leptin is involved in the regulation of food intake and energy expenditure and is also thought to affect reproductive function in healthy women [159]. Leptin is reported to rise during pregnancy, fall after delivery and subsequently increase during the first 6-months postpartum [160,161]. The effects of leptin on depression are inconclusive in previous studies, with leptin levels being unaltered, increased or decreased in different groups of depressed patients [162]. A study by the authors showed that higher leptin levels at delivery conferred protection against depressive symptoms at 5-days, 6-weeks and 6-months postpartum [141]. This protective effect may be explained by either a slower decrease of hormones, such as cortisol and estrogens, during late pregnancy due to leptin, or by direct upregulation of the HPA axis by leptin, in order to compensate for the withdrawal of glucocorticoids and estrogens. Alternatively, one could consider that higher leptin levels induced serotonergic activity, which is shown to protect against depressive states.

Conclusion & future perspective

Whereas efforts to investigate psychosocial and epidemiological background of PPD have been extensive, the genetic risk factors underlying PPD essentially remain unknown. Familiarity of PPD has been preliminarily pointed out, with increased odds of PPD among siblings of probands with PPD [163]. A twin study including 838 parous female twin pairs has suggested a genetic basis for self-reported PPD, with genetic factors explaining 38% of variance in PPD [164]. A recent genome-wide linkage study, followed by single nucleotide polymorphism association analyses, suggested the 1q21.3–1q32.1 and 9p24.3–9p22.3 regions, as well as the HMCN1 and METTL13 genes as loci of interest for PPD susceptibility [165]. It is expected that this field of research will have expanded greatly in the coming 10 years.

In addition, accumulating evidence suggests that activation of the inflammatory response system is involved in the pathophysiology of MDD and anxiety states [130 –134]. Owing to the immunomodulatory effects of pregnancy and the fact that as many of the psychosocial risk factors of PPD may well be mediated by inflammatory responses, continued research in this area may open up new treatment alternatives. Vitamin D supplementation, previously known to improve inflammatory response [113,114], as well as mood [124], is a promising candidate for PPD intervention.

Financial & competing interests disclosure

I Sundström Poromaa has, over the past 3 years, received compensation as a consultant and lecturer for Bayer Schering Pharma, MSD and Lundbeck A/S. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Numerous biological pathways may act in concert to increase the risk of postpartum depression (PPD), and it is also reasonable to assume that different biological mechanisms may come into play in individua

Overt thyroid dysfunction, subclinical hypothyroidism or even the mere presence of thyroid antibodies have been associated with higher risk for PPD. Based on these findings, it is important that thyroid function is assessed in all women seeking care fo

Continued research on PPD is needed to broaden the treatment alternatives in affected women. Important areas in this respect include further studies on estrogen supplementation and treatments that may have beneficial effects on inflammatory response, vitamin D being one o

The genetic risk factors underlying PPD remain to be defined and this route of research may open up for better prevention, early diagnosis and new treatment options.

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The first genome-wide association study of PPD.

Biological Aspects of Postpartum Depression

Abstract

Keywords

Neuropsychoendocrinology of normal pregnancy & the postpartum period

Neuropsychoendocrinology of PPD

Estradiol & progesterone

The HPA axis

Oxytocin & breastfeeding

Serotonin

BDNF

Circadian rhythm

Seasonal effects

Vitamin D

The immune system

The thyroid system

Leptin

Conclusion & future perspective

Financial & competing interests disclosure

References