Diverging effects of oxytocin treatment and
its implication for biologically distinct
subtypes of postpartum depression
Kim van Dijk (5817994)
Master Cognitive Neuroscience, University of Amsterdam
Literature Review
Supervisor: Dr. A. Witteveen
Co-assessor: Dr. A. Bakker
December 2014
Abstract
Postpartum depression (PPD) is of special interest in the field of neurobiological psychiatry since the onset of the disorder coincides with major psychological as well as biological changes. Currently, there is an ongoing debate about the possibility of oxytocin administration as a treatment option for PPD. It has long been proposed that the heterogeneity of symptoms and time of onset among PPD patients is due to distinct neurobiological subtypes of PPD. This review summarizes reports concerning the possibility of biologically distinct subtypes of PPD and the likelihood of successful treatment with oxytocin administration in these distinct groups. We hypothesize that oxytocin administration might only be therapeutic for postpartum distress with antenatal onset and under certain conditions in those with a history of early adversity. Postpartum women suffering from strictly antenatal depression might benefit from stimulating endogenous oxytocin levels. Pharmaceutical enhancement of oxytocin levels in postpartum women with hypofunction of the HPA axis (i.e. mothers with postpartum depression as defined in this review), women with a negative subjective interpretation of their current situation, and women with anxious attachment might result in adverse effects. Future studies should examine the possibility that there are important differences in the neurobiology underlying postpartum disorders in women with and without a history of childhood adversity, psychiatric disorders, or co-morbid anxiety and stress. The effects of oxytocin in individuals with and without childhood adversity should be examined in controlled settings where context and personal differences can be monitored. Studies on the clinical and biological differences between depressed and anxious postpartum profiles are recommended.
1. Introduction
Postpartum depression (PPD) is of special interest in the field of neurobiological psychiatry since the onset of the disorder coincides with major psychological as well as biological changes. Although pregnant women generally seem to benefit from protection against mood disorders (Vesga-López, O., et al. 2008), the postpartum period has been associated with increased risk of depression (Kessler, 2003) up to 5 months postpartum (Munk-Olsen et al., 2006). Postpartum women are found to be 1.6 times more likely to develop a depressive episode than non-postpartum women (Eberhard-Gran et al., 2002). Depression rates vary from 6.5% to 13% among pregnant and postpartum women (Gavin et al., 2005). Prenatal stress in pregnant women is known to strongly affect development of the baby as well as shorten pregnancy duration (O’Keane et al., 2011a). Women with PPD are at risk for subsequent episodes of major depressive disorder (MDD), another episode of PPD in subsequent pregnancies, and other mental disorders (Munk-Olsen et al., 2011; Wisner et al., 2002). PPD affects mother’s mood, thought processes, and her ability to parent (Campbell et al., 2007; Stein et al., 2012). Importantly, attachment with the infant is decreased (Campbell et al., 2004; Paulson et al., 2006), which is noticeable for the infant as early as 3 months of age (Cohn and Tronick, 1988). Not only does the infant adapt its behavior to the mothers’ depressed state (Jones, 2012), the child is also at risk of developing psychopathology and altered physiological stress regulation later in life (Feldman et al., 2009; Goodman, 2007; Halligan et al., 2004; Murray et al., 2011). Altogether, it is becoming increasingly clear that PPD not only affects the mother, but has long lasting consequences for the infant as well (Apter-Levy et al., 2013).
Despite numerous adverse effects of PPD on mother and child, only a quarter of women with PPD is treated (Bennett et al., 2004). According to the recently launched Diagnostic and Statistical Manual of Mental Disorders (DSM)-V, PPD is diagnosed similar to the criteria of MDD but with the addition that the onset occurs within 4 weeks following delivery (American Psychiatric Association, 2013). Noteworthy, since about half of postpartum depressions actually have an antenatal onset (Swendsen and Mazure, 2000), the current DSM-V also recognizes antenatal depression by adding MDD with an onset during pregnancy. Alongside depressive symptoms such as diminished interest or pleasure, changes in sleeping and eating patterns, feelings of worthlessness, and recurrent thoughts of death, PPD is known to coincide with symptoms of anxiety in at least half of the cases (Ross et al., 2003). The strongest predictors of PPD are antenatal depression and anxiety, occurrence of stressful events, low levels of social support, low self-esteem, and a history of either MDD or PPD (Beck, 2001; O’Hara, 2009; Robertson et al., 2004; Wisner and Wheeler, 1994). However, psychosocial risk factors for PPD do not account for all the observed variance in its profile. Biological factors surrounding pregnancy and birth are likely to have a big impact on the onset, symptoms, and treatment efficiency of PPD.
In order to facilitate parturition and adaptation to motherhood, several hormones rise gradually during pregnancy and then show a sharp drop following delivery (e.g. Carter et al., 2001). The gonadal hormones estradiol and progesterone play a big role in fetal development but also act on maternal brain regions such as the locus coereleus en the raphe nuclei. These areas are known to modulate mood through for example, interactions with the
serotonin system (Ostlund et al., 2003). In the third trimester of pregnancy, estradiol and progesterone levels rise by 50 to 100-fold and 10-fold respectively and return to normal in a matter of days after delivery (for reviews see Bloch et al., 2003; Hendrick et al., 1998). In vulnerable women these large hormonal changes can lead to psychopathology (e.g. Kammerer et al., 2006). Simulation of gonadal withdrawal elicits depressive symptoms in non-depressed women with a history of PPD, indicating an important role in PPD development for the sudden drop in gonadal hormones after delivery (Bloch et al., 2000). However, estradiol and progesterone levels in PPD women seem to be similar to that of non-depressed postpartum women (Bloch et al., 2003). As such, PPD might arise from differential central reactions to a normal change in hormone level rather than abnormal concentrations (Harris et al., 1994; Rubinow et al., 1998; Workman, Barha and Galea, 2012). Nevertheless, there are some indications that estradiol might be a treatment option for PPD (Gregoire et al., 1996; Ahokas, 2001) but evidence for a gonadal hormone cause of PPD is limited (Gentile, 2005, Zonana and Gorman, 2005). The relation between postpartum mood disturbances and a strong decline in gonadal hormones (O’Hara et al., 1991b; O’Keane et al., 2011b) is likely to be indirect and is possibly mediated by abnormalities in the fetal-maternal pituitary-adrenal system (Mesiano and Jaffe, 1997; Weintrob et al., 2006).
The hypothalamic-pituitary-adrenal (HPA) axis undergoes massive changes in the course of gestation and parturition. Responsible for the physiological response to stress, the HPA axis prepares an organism for flight or fight. In response to stress, a cascade of events is brought on by release of corticotrophin releasing hormone (CRH) from the hypothalamus and paraventricular nucleus (PVN), a process under control of the hippocampus and the amygdala. CRH not only stimulates adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary, but also plays a vital role in behavioral and cognitive changes in reaction to stress by neuromodulatory and neuroregulatory effects in the brain. Released from the anterior pituitary, ACTH in turn stimulates secretion of cortisol by the adrenal cortex which is then releases into the bloodstream. By means of a negative feedback loop cortisol inhibits further CRH secretion from the hypothalamus and PVN. Also, cortisol can tune down HPA axis activity after a successful stress response by directly affecting the prefrontal cortex, amygdala, and hippocampus. During pregnancy, CRH, the driving hormone of the HPA axis, is also generated by the placenta and released into the maternal blood stream. CRH concentrations, that are otherwise not detectable in blood plasma, rise exponentially during pregnancy, reaching a 100-fold the start value in the weeks prior to delivery (Kalantaridou et al., 2003) and are thought to be an important trigger for parturition (McLean et al., 1995; Meltzer-Brody et al., 2011). Even though maternal CRH secretion is diminished during late pregnancy, cortisol levels still rise significantly in the course of gestation due to high placental CRH levels (Mastorakos and Ilias, 2000). Near parturition cortisol levels of pregnant women resemble those of patients with severe depression (for a review see Carter et al., 2001) and despite a sharp drop directly following birth, a complete return to baseline levels can take up to 8 weeks (Lommatzsch et al., 2006). Towards the end of pregnancy the rapidly developing child is protected against the toxic effects of maternal stress (Brunton and Russell, 2011) and the risk of preterm birth is reduced (Buss et al., 2010; Glynn et al., 2008) by a blunted HPA axis response following stress exposure (Kammerer et al., 2002; de Weerth and Buitelaar, 2005). Delivery of the placenta results in a rapid elimination of placental CRH and oestriol in the mothers’ bloodstream, a decline in maternal cortisol secretion, and a compensatory
increase in CRH production in the maternal brain (Mastorakos and Ilias, 2000; 2003). Recently it has been shown that ACTH levels also show an initial drop following parturition and start to climb again after three days (O’Keane et al., 2011). This finding is in line with an earlier study finding that placental CRH stimulates synthesis of maternal ACTH during pregnancy (Mastorakos and Ilias, 2003). Due to adrenal hypertrophy during pregnancy, as well as relatively high levels of the inhibitory neuropeptide oxytocin in the brain, the HPA axis shows a hypoactivation during the postpartum period (Magiakou et al., 1996; Mastorakos and Ilias, 2000). Consequently, postpartum women show less psychological and physiological response to stress (Glynn et al., 2004; 2001; Entringer et al., 2009; Owens et al., 1987).
Convincing evidence has been delivered to support the idea that the transition of HPA axis hyperfunction during pregnancy to a hypofunction following parturition is an important contributor to PPD development (Glynn et al., 2013; Kammerer et al., 2006; Mastorakos and Ilias, 2000). Postpartum blues, an important predictor of PPD at 8 weeks postpartum (Kendell et al., 1981; Adewuya, 2006; Glover et al., 1994), occurs in 30-35% of postpartum women and generally peaks at day 4-5 (O’Hara et al., 1991b; Okano and Nomura, 1992; Harris et al., 1994). These mood changes coincide and correlate with the dramatic decline in CRH and oestriol from pregnancy to early postpartum and the increase of maternal ACTH production in the days following delivery (O’Keane et al., 2011b). However, the clinical profile (i.e. time of onset and symptoms) of PPD patients varies and highlights distinct neurobiological underpinnings. For example, whereas antenatal depression is associated with hypercortisoleamia and increased CRH levels during the second trimester (O’Keane et al., 2011a; Rich-Edwards et al., 2008), depression in the postpartum period has been associated with HPA hypofunction (Jolley et al., 2007). Similarly, functional abnormalities in the HPA axis have long been known to underlie non-postpartum depression, but the exact results are mixed. A hyperactivated HPA axis has been associated with severe depression and is thought to reflect hypersecretion of CRH due to impaired negative-feedback at gluccorticoid receptor levels in the hypothalamus (Claes, 2009; Lightman, 2008). However, although hypercortisolaemia is commonly found in depression studies, CRH hypersecretion seems to only be associated with melancholic and not atypical depression (for a review see O’Keane et al., 2012). It has been proposed that atypical depression is the result of recurrent episodes of psychopathology and might reflect a complex system of stress vulnerability rather than a relatively simple neurochemical imbalance (O’Keane et al., 2012). Indeed, a majority of depressive episodes are preceded by a stressful life event that can potentially disclose HPA dysfunction (Parker et al., 2003). There has been much speculation about the importance of considering the birth of a child as a potential stressor (Hendrick et al., 1998) that could elicit depressive symptoms in these vulnerable women (Buist, 1998; O’Hara et al., 1991a; Swendsen and Mazure, 2000; Terry et al., 1996). Although involvement of the HPA axis in affective disorders is commonly accepted (Tsigos and Chrousos, 2002), controversy concerning the exact neurobiological underpinnings of PPD remains and different subtypes HPA axis dysfunction needs to be considered.
Another system receiving increasing attention in PPD literature is the oxytonergic system (for a recent review see Kim et al., 2014). Synthesized in the hypothalamus and secreted by the posterior pituitary, oxytocin can act as both a neurotransmitter and a neuromodulator in the brain and also has various peripheral effects. Oxytocin is of particular interest in PPD research since it is critically involved in uterine contractions during the birth
non-process (Zeeman et al., 1997), milk letdown for lactation (Brunton and Russell, 2008), and regulating maternal behavior (Ross and Young, 2009). Although extensive literature is lacking, oxytocin levels are thought to increase gradually during gestation and spike during birth and to a lesser degree during infant contact, in particular
lactation (see figure 1). Importantly, oxytocin is known to attenuate activation of the HPA axis (Smith and Wang, 2012; 2014) and its dysfunction is involved in MDD (for a review see McQuaid et al., 2014). Interestingly, mothers who report high levels of psychosocial stress, seem to be protected from developing depressive symptoms in the presence of high levels of the oxytocin (Zelkowitz et al., 2014), especially during lactation (Slattery and Neumann, 2010). Also, lower oxytocin levels during the first and third trimester are associated with less bonding postpartum and risk of PPD development respectively (Feldman et al., 2007; Levine et al., 2007; Skrundz et al., 2011). Oxytocin is often seen as an important stress-buffer with anxiolytic and anti-depressant properties (for reviews see Bakermans-Kranenburg and IJzendoorn, 2013; Bartz et al., 2011, but see also MacDonald and Feifel, 2014) and has been characterized as a potential miracle drug against a wide range of psychiatric symptoms (see Liu et al., 2012). However, varying effects depending on gender, personal history, personality, and social context have been reported. The diverging effects of exogenous oxytocin administration in psychiatric patients calls for a closer examination of the exact neurobiological underpinnings of important moderators (see also Kim et al., 2014).
To the best of our knowledge, only one study so far has examined oxytocin treatment in PPD, but showed unexpected and unfavorable results (Mah et al., 2013). Congruently, there has been an ongoing debate about the function of oxytocin as well as the biological underpinnings and classification of PPD. It has long been proposed that the of symptoms and time of onset among PPD patients is due to distinct neurobiological subtypes of PPD (e.g. Heim et al., 2008; Kammerer et al., 2006; Kim et al., 2014), but results concerning this matter are lacking or disappointing (Philips et al., 2010; Records and Rice, 2005). However, recent studies have highlighted several important moderators that are likely to influence the supposedly beneficial effects of oxytocin administration in women with PPD (see Guastella and MacLeod, 2012; Kim et al., 2014). It is our belief that these moderators interact with important biomarkers that distinguish biologically different subtypes of PPD.
This review summarizes reports concerning the possibility of biologically distinct subtypes of PPD and the likelihood of successful treatment with oxytocin administration in these distinct groups.
2. Subtypes of PPD
2.1 Antenatal or postpartum onset of PPD
Whereas half of PPD cases are triggered specifically by parturition, others start prepartum and are resolved by delivery. A third group has an antenatal onset of depression that
continues into the postpartum period. These clinical profiles are likely to have a different neurobiological profiles that underlie the onset of the depressive symptoms. Indeed, it has been proposed that antenatal and postpartum depression have distinct biological underpinnings similar to those of melancholic and atypical depression respectively (Kammerer et al., 2006). Whereas individuals with melancholic depression show a hyperactive HPA axis and abnormally increased cortisol levels (Meyer et al., 2001), sufferers from atypical depression display a HPA axis hypofunction and decreased cortisol levels (Brouwer et al., 2000; Gold et al., 2002; Gold and Chrousos, 2002 but see O’Keane et al., 2012). In agreement with this theory, decreased plasma cortisol levels have been found in postpartum depressed women 4-6 weeks after delivery (Groer and Morgan, 2007). Also, upon activation of the HPA axis, postpartum depressed women do not show the expected increase in cortisol despite of an increase in ACTH, indicating a persistent and dysfunctional suppression of normal HPA axis functioning (Jolley et al., 2007). In contrast, two studies have reported increased levels of cortisol, but they had either averaged prepartum (i.e. naturally high cortisol levels) and postpartum cortisol levels (Lommatzsch et al., 2006), or performed measurements days after parturition at which time point cortisol levels still reflect that of pre-partum levels (Okano and Moura, 1992). Thus, it is indeed likely that hypofunction of the HPA axis and decreased cortisol underlie PPD with a postpartum onset (see table 1, PPD subtype 1). Hyperfunction of the HPA axis and increased cortisol during pregnancy might underlie antenatal depression and is resolved by parturition (see table 1, PPD subtype 2). In addition, women who show relatively high levels of placental CRH or in whom placental CRH increases relatively fast during pregnancy are at risk for developing PPD at 2-3 months postpartum (Hahn-Holbroek et al, 2013; Yim et al., 2009). Prenatal placental CRH levels are shown to be related to postpartum HPA-axis dysregulation and PPD symptoms at 3 months postpartum (Glynn and Sandman, 2014). Although highly speculative, these findings may represent the subtype of PPD with a (subclinical) antenatal onset of depressive and anxious symptoms brought on by high cortisol levels, that continues into the postpartum period as a depression (Heron et al., 2004) simulated by withdrawal of cortisol (Kammerer et al., 2006). Considering the high predictive value of prenatal depression for PPD, this subtype is very common but sadly its neurobiology is poorly understood.
2.2 Peripartum distress: depression, anxiety, and stress
Although anxiety and depression commonly co-exist (Kessler et al., 2001; Matthey et al., 2003), especially in the postpartum period (Ross et al., 2003), peripartum symptoms of anxiety tend to be minimized or overlooked in absence of depression and are not included in the diagnostic criteria for postpartum disorders. Anxiety (and depression) levels normally diminish during the course of pregnancy (Heron et al., 2004) and are specifically alleviated by contact with the infant and breastfeeding (for a review see Lonstein, 2007). High antenatal anxiety increases the risk for PPD by 300% (Heron et al., 2004) and is shown to be a highly specific risk factor for adverse pregnancy outcomes such as preterm labour or prolonged labour (Dayan et al., 2001) as well as behavioral and emotional problems in the infant (O’Conner et al., 2002). Symptoms of anxiety are more prominent in depressive episodes in the postpartum period than in non-postpartum episodes (Hendrick et al., 2000; Misri et al., 2000; Stuart et al., 1998) and postpartum women are more likely to be anxious than to be depressed (Wenzel et al., 2005). Against advice of both researchers and clinicians, anxiety is
subsumed within the diagnoses of depression (Fisher et al., 2002; Matthey et al., 2003). It has been proposed to use the term ‘postpartum distress’, as opposed to PPD, to identify depression, anxiety, and stress in the postpartum period. The concept of postpartum depression might even have limited our understanding of postpartum distress (Green, 1998; Miller et al., 2006) which occurs in 30% of mothers (Johnsen et al., 1992). Twenty-nine percent of postpartum women show at least one of the classifications for depression, anxiety or stress. One study showed that 10% of postpartum women with significant postpartum distress are overlooked if only depressive symptoms are analyzed. Also, anxious-depressed mothers show higher levels of depressive symptoms compared to depressed mothers (Miller et al., 2006). Furthermore, anxious depression outside of the postpartum period is associated with more severe symptoms (Rivas-Vazquez et al., 2004), is more difficult to treat than separate anxiety or depression (Emmanuel et al., 1998), has a poorer outcome (Rivas-Vazquez et al., 2004), and increased risk for suicide (Fawcett, 1997). Importantly, anxiety and depression symptoms require specific treatment (Emmanuel et al., 1998). Anxiety might be the consequence of a maladaptive stress response (Heron et al., 2004). As mentioned before, stress levels and coping responses are linked to the development of depressive symptoms (Terry et al., 1996).
Since some postpartum women are anxiously-depressed but not all depressed mothers show symptoms of anxiety and not all anxious mothers are also depressed (Matthey et al., 2003), there seem to be three subtypes of postpartum distress that are clinically, and presumably neurobiologically, very different (see table 1, PPD subtype 3). To our knowledge, no studies so far have examined postpartum HPA axis functioning or stress response specifically in women who experience PPD with an antenatal onset.
2.3 Early experiences and psychiatric history
A considerable percentage of PPD patients has experienced earlier episodes of MDD (Meltzer-Brody et al., 2013) or posttraumatic stress disorder (PTSD; Cigoli et al., 2006; Maggioni et al., 2006), although the antenatal episode of depression is generally experienced as more severe than depression occurring in non-partum periods (Meltzer-Brody et al., 2013). Both a history of MDD and trauma-exposure or PTSD are thought to represent a risk for developing psychopathology in reaction to stress (Heim et al., 2002) and are known to greatly influence the stress responsivity system (e.g. Yehuda, 2006). In fact, childhood abuse, stressful life events, and depression have been shown to be the strongest predictors of ACTH responsiveness (Heim et al., 2000). Although melancholic depression is associated with hyperfunction of the HPA axis (Meyer et al., 2001), atypical depression and PTSD have been linked to hypofunction of the HPA axis (e.g. Gold and Chrousos, 2002; Griffin et al., 2005; Yehuda et al., 1990). In all three cases the stress brought on by earlier life events and the disorder itself are thought to have detrimental effects on hippocampus volume and function (Admon et al., 2013), which in turn affects the HPA axis drive (Frodl and O’Keane, 2013). The chances of stressful events to trigger a depression seem depend at least in part on the level of childhood adversity (Dougherty et al., 2004; Hammen et al., 2000; McQuaid et al., 2014), making individuals who experienced early abuse 5 times more likely to develop PPD up to 8 months postpartum (Records and Rice, 2009). Indeed, a high prevalence of abuse in women with PPD has been reported on several occasions (Chapman et al., 2004; Meltzer-Brody et al., 2011; Kendall-Tackett, 2007; Onoye et al., 2009; Silverman and Loudan, 2010). One
study showed that of the reported 63% of PPD women who experienced childhood trauma, 27% had endured childhood sexual abuse (Plaza et al., 2010), which represents a strong risk factor for PPD development (Meltzer-Brody et al., 2013). Importantly, women with a history of sexual abuse who develop PPD report higher depression and anxiety 3 years after delivery. Also, the disorder is more severe and longer lasting than in PPD women without history of abuse and general levels of life stresses in the abused group are higher (Buist and Janson, 2001).
Prevalence of childhood abuse among PPD women is similar to the prevalence of abuse among individuals with MDD (Galdstone et al., 2004). This indicates that women with PPD and a history of childhood abuse and possibly earlier MDD episodes might represent a different group than women who develop PPD in relation to changes in hormone levels. Indeed, women with a history of childhood abuse with a current depression show a 6-fold increase of ACTH in response to stress, accompanied by high levels of cortisol compared to controls and non-abused depressed women (Heim et al., 2000, see also table 1, PPD subtype 4). The same study showed that in absence of a depression abused women still show increased ACTH but lack abnormally high cortisol levels, indicating successful adaptation by the adrenal system. Interestingly, abused women without current depression show very low levels of cortisol and consequently display disinhibition of the HPA axis, resulting in maternal CRH hypersecretion and depressive symptoms (Heim et al., 2001). High levels of placental CRH during pregnancy mimics this CRH hypersecretion and therefore might elicit depressive symptoms in women who suffered abuse and are vulnerable to high levels of CRH. Hypothetically, the resulting anxiety and depression during pregnancy might carry on to the postpartum where are drop to already low cortisol levels occurs. Previously described neuroendocrine findings in depression and PPD are now thought to represent a vulnerability to stress due to childhood trauma and not the effects of the disorder itself. Importantly, this neuroendocrine profile is not present in those without a history of childhood abuse (Heim et al., 2008).
Further distinction between PPD women with and without a history of early adversity is illustrated by the fact that individuals who experienced childhood abuse are less likely to respond to pharmacological treatment for depression (Hayden and Klein, 2001; Kaplan and Klinetob, 2000). Psychotherapy might be an essential element of treatment for depressed women with childhood trauma (Heim et al., 2008). This is not surprising since an important psychological factor brought on by disturbed attachment and interpretation of maternal care is thought to influence PPD in these women. They are more likely to be abusive or neglectful and show less sensitivity and responsivity to their babies needs (Krpan et al., 2005; Moehler et al., 2007). Negative parenting experiences are often transmitted from one generation to the next (Belsky et al., 2009; Neppl et al., 2009). Also, abused women tend to interpret relatively safe situations as threatening (e.g. see Records and Rice, 2009), which might influence the effectiveness of both pharmacological and psychotherapeutic interventions.
Table 1 – Proposed subtypes of postpartum depression. For each subtype the corresponding deviant cortisol patterns for non-pregnant time points (np), 30 weeks gestation (30w), birth, and 8 weeks postpartum (8w) are shown. Also, corresponding HPA axis function, stress response (if known), and symptoms are displayed. Finally, advices on treatment with oxytocin are listed per subtype.
PPD subtype Cortisol levels HPA axis function Stress response Symptoms Oxytocin treatment
1. Antenatal depression
Hyperfunction ? - Melancholic depression - Anxious - Loss of sleep & appetite
- Worse in the morning
- Oxytocin administration not possible - Raise endogenous oxytocin levels prepartum 2. Postpartum depression
Hypofunction - normal ACTH increase - blunted cortisol response - Atypical depression - Hypoaraoused - Weight gain - Interpersonal rejection sensitivity
- Worse in the evening
- Oxytocin administration not recommended
3. Postpartum distress with antenatal onset
Hyperfunction ? 3.1 Depressed subtype 3.2 Anxious subtype 3.3 Anxious-depressed subtype - Raise endogenous oxytocin levels prepartum - Postpartum oxytocin administration for anxiety 4. Postpartum distress with
antenatal onset and a history of early adversity
Mixed - increased ACTH response (even in absence of active depression)* - increased cortisol response * * as measured during MDD not PPD - Atypical depression - Interactions with attachment, stress, and maladaptive coping
- Psychotherapy (with oxytocin) targeting trauma and depression
2.5 Conclusion
Studies seem to support the idea that several subtypes with distinct biological underpinnings exist (see table 1). First, antenatal depression that resolves at parturition is likely associated with HPA axis hyperfunction. Cortisol levels during pregnancy as well as in response to stress are increased and symptoms resemble that of melancholic depression. Second, PPD with a postpartum onset has been linked to HPA axis hypofunction, including decreased cortisol levels at baseline and normal ACTH, but increased cortisol levels in response to stress. Symptoms are likely to resemble that of atypical depression. Third, postpartum distress with an antenatal onset is characterized by increased placental CRH during pregnancy, creating feelings of anxiety and possibly depression. Although prepartum anxiety symptoms are known to carry on as depressive symptoms postpartum, it remains unexplored what, if any, the exact role of the HPA axis plays in this subtype of postpartum distress. The symptoms of this particular subtype are known to be more severe than the type one and two, and maladaptive stress coping plays an important role. On a clinical level, three different groups within this type can be distinguished: depressed mothers, anxious mothers, and anxious-depressed mothers. Fourth, postpartum distress in women with a history of early adversity is subject to an underlying vulnerability to depression in response to stressor. Pre-existent low cortisol levels and CRH hypersecretion resemble high placental CRH levels and the parturition-related drop in cortisol that occur peripartum and elicit a distinct, and more complex, subtype of postpartum distress. Both ACTH and cortisol responses are shown to be abnormally high under stress, distinguishing this type of postpartum disorder from the ones previously mentioned.
3. Diverging effects of oxytocin
Because oxytocin has long been labelled as the pro-social hormone (Carter et al., 1992; Zak et al., 2004) with anxiolytic (Heinrichs et al., 2003) and anti-depressant effects (Scamtamburlo et al., 2011) it has been regarded as a promising candidate for treatment of several developmental, anxiety, and mood disorders. A recent meta-analysis by Bartz et al. (2011) however, showed that 43% of oxytocin administration studies demonstrated no effect and 63% demonstrated situational and/or individual difference moderators. Contrary to common expectations, a minority of studies even reported antisocial effects of oxytocin administration under certain conditions. Higher plasma oxytocin levels have been associated with trust, supportive communication, positive parenting styles, but also with perceptions of interpersonal distress and depressive symptoms (for a review see Liu et al., 2012). A complex network of moderators and interactions with other systems has been proposed to account for the diverging effects of exogenous oxytocin administration (Bakermans-Kranenburg and van IJzendoorn, 2013; Bartz et al., 2011; Graustella and MacLeod, 2012).
3.1 Oxytocin and depression
Although some studies have reported decreased plasma oxytocin levels in patients with MDD (Ozsoy et al., 2009) that are directly related to depressive symptoms (Scantamburlo et al., 2007), others found increased baseline oxytocin levels and greater oxytocin variability (Cyranowski et al., 2008; Holt-Lunstad et al., 2011; Parker et al., 2010; van Londen et al.,
1997). Studies examining CSF oxytocin have failed to find any abnormality (Demitrack and Gold, 1988; for a review see Slattery and Neumann, 2010).
The relation between endogenous oxytocin levels and PPD is not any less complex (Kim et al., 2014). Low plasma oxytocin levels during mid-pregnancy are found to predict PPD symptoms at 2 weeks postpartum (Skrundz et al., 2011). The authors of this study propose that stressful events after birth trigger an increased amygdala response due to low oxytocin levels and thus promote fear and insecurity (Skrundz et al., 2011). Also, lactation difficulties and PPD have frequently been associated (e.g. Watkins et al., 2011). A sudden increase of endogenous oxytocin during breastfeeding has been shown to reduce stress and negative mood (Mezzacappa and Katkin, 2002) and to lower PPD symptoms (Hatton et al., 2004). So far, only one study has directly investigated the role of oxytocin between lactation and PPD (Stuebe et al., 2013). Both antenatal and postpartum oxytocin levels were found to inversely correlate with depressive symptoms. Although cortisol levels normally decrease (Amico et al., 1994) and mood increases (Heinrichs et al., 2001) during breastfeeding, PPD women fail to show the expected increase in oxytocin and consequently improved mood during lactation (Stuebe et al., 2013).
The anti-depressant effects of oxytocin in animals are well documented and are due to interactions between the oxytocin system and CRH (for a review see Neumann and Landgraf, 2012). Also, oxytocin release is thought to activate serotonergic system neurons in the raphe nuclei (Yoshida et al., 2009), which in turn elicit CRH and oxytocin release from the hypothalamus (Javed et al., 1999). This is hypothesized to be the neurobiological mechanism of anti-depressant SSRI’s (Emiliano et al., 2007). SSRIs increase plasma oxytocin, possibly explaining their effectiveness for reducing stress, depression, and anxiety. However, a linear relationship between depression en oxytocin is unlikely (for a review see Liu et al., 2012). Currently, exogenous oxytocin administration is not considered a suitable intervention for alleviating symptoms of MDD (McQuaid et al., 2014), but it may be used for treatment of particular aspects of depressive disorders (Baskerville and Douglas, 2010), such as stress and anxiety (Slattery and Neumann, 2010).
3.2 Oxytocin and anxiety
Decreased plasma oxytocin levels in patients with MDD (Ozsoy et al., 2009) have been found to relate to anxiety symptoms (Scantamburlo et al., 2007). Anxiety and a tendency to emotional-focused coping are influenced by oxytocin (Cardoso et al., 2012). In contrast to depression, anxiety has consistently been linked to the oxytonergic system in animals and humans including peripartum women (for a review see Lonstein, 2007). Another indication for involvement of the oxytonergic system in peripartum anxiety, is the fact that infant contact and breastfeeding (i.e. situations that increase endogenous oxytocin) are known to attenuate anxiety (Heinrichs et al., 2001; Stuebe et al., 2013) and reduce the risk for PPD development (Ystrom, 2012). A recent study has highlighted an important interaction between separation anxiety, postpartum oxytocin and depression. Based on the assumption that maternal separation anxiety might explain why mothers become very anxious during pregnancy, Eapen et al. (2014) showed that anxious attachment during pregnancy is negatively related to postpartum oxytocin levels. Furthermore, this relation is mediated by depression and separation anxiety. It is becoming increasingly clear that early adverse experiences in relation to parent-child interaction play a dramatic role in anxious attachment
styles that can leave a mother vulnerable for preoccupations with infant safety (Feldman et al., 1999), separation anxiety (Eapen et al., 2014), and symptoms of anxiety and depression in response to transition to motherhood. The fact that not all mothers who experienced negative care-giving relations in their past develop such symptoms is in part due to resilience of the oxytonergic system as well as to social support and positive experiences in adulthood (Meyers et al., 2014). For the mothers who do develop peripartum anxiety, it is likely that different attachment styles underlie distinct subtypes of anxiety (Bakermans-Kranenburg and IJzendoorn, 2013; Eapen et al., 2014) and therapeutic interventions should carefully consider the diverging effects of these subtypes.
Oxytocin administration diminishes the attentional bias towards negative stimuli (Ellenbogen et al., 2012) that is otherwise found in individuals with depressive symptoms. Oxytocin is thought to mainly reduce social anxiety and can modulate stress reactivity, but these effects are often qualified by features of the situation and/or person (for a review see Bartz et al., 2001). Also, individuals with high levels of anxious attachment remembered their mother as less caring and more distant after OT administration, whereas the opposite is true for individuals with low anxious attachment (Bartz et al., 2011).
The picture of oxytocin effects in women, and postpartum women especially, seems to be more complex than for men (for a review see Kim et al., 2014). Similar to studies in healthy men showing decreased stress and anxiety following oxytocin administration (Heinrichs et al., 2003), lactating women have displayed reduced HPA axis activity and diminished anxiety after a sudden endogenous increase of oxytocin as a result of breastfeeding (Heinrichs et al., 2001). Studies examining the amygdala response to fear after oxytocin administration have shown an interesting discrepancy. Fear related activation of the amygdala is shown to be attenuated in healthy males (Kirsch et al., 2005), increased in healthy females (Domes et al., 2010), and unchanged in postpartum women (Rupp et al., 2012) after oxytocin administration.
In conclusion, oxytocin administration may be anxiolytic and could facilitate the more positive mother-child relationships, but adverse personal history and attachment styles may interact with these potentially beneficial effects (Bakermans-Kranenburg and van IJzendoorn, 2013).
3.4 Oxytocin and early adversity
The stress-protective effects of oxytocin may be profoundly impacted by negative experiences, especially in the caregiver-child relationship. A growing number of studies shows the potency of early life experiences to have long lasting effects on behavior and neuropeptide systems such as the oxytocin system (Ahern & Young, 2009; Bales et al, 2007; Carter et al., 2008a,b; Lukas et al., 2010). Early life experiences such as handling, family structure, and stress levels have been found to alter oxytocin receptor expression and regulation in rodents (for a review see Bales & Perkeybile, 2012). Importantly, reduced handling in the first postpartum week for female prairie voles has been shown to lead to up-regulation of oxytocin receptors in the nucleus accumbens, lateral septum, and bed nucleus of the stria terminalis (Bales et al., 2011). However, offspring receiving high maternal care also show this up-regulation of oxytocin receptors (Champagne & Meaney, 2007; Francis et al., 2000, 2002). Despite of similar neuropeptide profiles, only the voles that experienced high maternal care show normal social behavior in adulthood. It has been hypothesized that
the up-regulation for those receiving low maternal care reflects a compensatory mechanism of decreased oxytocin production due to a lack of stimulation (Bales & Perkeybile, 2012). Likewise, nursery rearing, as opposed to receiving nurturing attention from a mother, has been shown to lead to persistently reduced oxytocin levels in cerebral spinal fluid (CSF) but not plasma of male rhesus monkeys (Winslow et al., 2003). These lower oxytocin levels were found to relate to less favorable social behavior, independent of rearing conditions. Interestingly, lower urinary oxytocin levels have also been found in human orphans (Fries et al., 2005), although the validity of this study has been questioned due to serious methodological concerns (Anderson, 2006). However, other reports of lower oxytocin levels in individuals who experienced early adversity exist. One study showed lower CSF oxytocin concentrations in women with a history of emotional abuse (Heim et al., 2009). Based on this study alone it cannot be excluded that the dysfunctional oxytocin system was due to prenatal stress and not to maltreatment or inadequate parent-infant contact per se. The authors however note that the relation between emotional abuse, rather than other forms of abuse, and low oxytocin levels is most likely due to the detrimental effects of perceived rejection and lack of support from caretakers. Interestingly, women’s CSF oxytocin levels are related to severity and duration of abuse and neglect experienced in childhood (Heim et al., 2009). Reduced levels of plasma oxytocin have been found in individuals who received low levels of parental care (Feldman et al., 2011; Gordon et al., 2008). Decreased CSF oxytocin levels in women with childhood traumas supposedly leads to decreased social attachment and diminished resilience against stress and anxiety (Heim et al., 2008). Women who experienced childhood sexual abuse show decreased oxytocin levels and suppressed HPA axis activation in response to stress (Pierrehumbert et al., 2010) as opposed to hyperactivation of the HPA axis and decreasing oxytocin levels during stress found in a similar abused group but with current depression (Heim et al., 2000).
Despite promising effects of oxytocin administration in healthy adults as well as certain groups of psychiatric patients (for a review see Liu et al., 2012), results for individuals who experienced abuse, neglect, loss (Meinlschmidt and Heim, 2007), harsh parenting experiences (Bakermans-Kranenburg et al., 2012), or parental love-withdrawal (Riem et al., 2013; van IJzendoorn et al., 2011) seem to be disappointing. Alterations in oxytocin receptors brought on by early caregiving experiences might underlie a reduced sensitivity for exogenous oxytocin (Champagne, 2008; Meaney, 2001; Bakermans-Kranenburg and van IJzendoorn, 2013). Early adversity affects the endogenous oxytocin system through changes on the oxytocin receptor level, since differences are seen even in absence of social cues (Bakermans-Kranenburg and IJzendoorn, 2013; Slattery and Neumann 2010). These experiences may alter experience-dependent methylation of genetic areas regulating the oxytocin system. Also, variants in the oxytocin receptor gene determine the effect of early adversity on PPD (Jonas et al., 2013).
Effects of oxytocin administration are also moderated by attachment style (for a review see Bakermans-Kranenburg and IJzendoorn, 2013), which is most likely related to personality (Noftle and Shaver, 2006). After oxytocin administration, individuals with low anxiety have more positive childhood memories (vs placebo treatment), but high anxious individuals remember their mother as less caring and more distant (Bartz et al., 2011). A recent study by Pierrehumbert et al. (2012) was able to show clearly how attachment style are associated with very different neurobiological profiles in response to stress. Low
psychosocial stress in autonomous attached individuals was shown to be related to moderate HPA axis activation in response to stress and high plasma oxytocin levels. Although individuals with either dismissing or pre-occupied attachment styles showed moderate psychological response to stress, only pre-occupied attachment style was associated with low levels of oxytocin in plasma and moderate HPA axis activation. Individuals with a dismissing attachment style showed high HPA activation in response to stress with moderate oxytocin plasma levels. Lastly, individuals with unresolved attachment, and a high prevalence of childhood trauma, showed high levels of psychological stress, low activation of the HPA axis, and moderate oxytocin levels in response to stress. Importantly, this study shows that the relation between HPA axis, oxytocin levels, and earlier experiences/attachment styles is complex. Based on large differences in endogenous oxytocin levels in both baseline and stressful conditions, it cannot be expected that oxytocin administration in a population with varying attachment styles and earlier experiences will produce similar effects.
Lastly, the context in which oxytocin is administered seem to be of paramount importance. Despite of its known pro-social effects, oxytocin increases non-cooperation with a partner that is perceived as a potential threat. Oxytocin administration effects are absent or mixed when the partner is unknown. Perception of others (friend vs threat) may depend on early care giving experiences (Bakermans-Kranenburg and van IJzendoorn, 2013). It has been proposed that oxytocin makes social conditions more salient, making both positive and negative events more intense (Averbeck, 2010; Cardoso et al., 2014). This finding is of great importance when administrating oxytocin to populations that are known to have negative interpretations of the current situation or stressor.
3.5 Conclusion
Although the oxytonergic system is thought to be involved in the development and maintenance of depressive symptoms, it is not likely that oxytocin administration will successfully alleviate these symptoms. Contrary, there are indications that under the right circumstances, oxytocin administration can reduce stress and anxiety. The diverging effects of exogenous administered oxytocin seem to depend, at least in part, on early experiences that shape the sensitivity of the oxytonergic system as well as attachment styles. Also, personal interpretation of the context surrounding administration has a great influence on the effect of exogenous oxytocin.
4. Oxytocin treatment of PPD
4.1 Treatment of PPD with oxytocin administration
Mah et al., 2013 was the first, and so far the only, study to examine the effect of oxytocin administration in PPD patients. Although PPD mothers report the relationship with their baby as more positive after oxytocin administration versus placebo, they also report a more negative opinion about their child. A disturbing finding in this study was that PPD mothers reported their mood as poorer after receiving oxytocin administration. The authors rightfully suggest taking caution in administrating oxytocin to individuals with low mood since oxytocin might increase the intensity of the pre-existing (negative) mood (see also Bartz et al., 2011). According to Mah et al. (2013) a more positive report about the mother-child relationship
after oxytocin administration was due to increased trust in the interviewer making the mothers more candid about their situation. Although probably not intended as such, this finding supports an important hypothesis in oxytocin literature. Since increased oxytocin levels are known to facilitate feelings of trust (De Dreu et al., 2010), it has been proposed to be a suitable adjunct agent to trauma therapy where success depends on the candor of the patient (Olff et al., 2010). Mah et al. (2013) did not find any mediation of childhood abuse on the relation between oxytocin administration and expressed mood. It should be noted however, that only physical abuse at the age of 13 was analyzed in this study. Considering the relatively large role of emotional and sexual abuse on the development of the oxytonergic system, it still remains to be examined if those types of early adversity moderate the relation between oxytocin administration, expressed mood, and possibly depressive symptoms. 4.2 Treatment of the proposed PPD subtypes with oxytocin administration
The proposed subtypes of PPD addressed in this paper have never been experimentally compared and some authors have doubted the existence of distinct subtypes of PPD (Philips et al., 2010; Records and Rice, 2005). Although we believe the data discussed in this paper points towards biologically different profiles in postpartum disorders, it should be noted that the proposed subtypes of PPD are not completely mutually exclusive and do not represent a full model of PPD. The proposed effectiveness of oxytocin treatment in each of these subtypes is hypothetical and warrants further investigation rather than implying a definite conclusion about the matter.
4.2.1 Antenatal depression
Antenatal depression that is resolved by parturition is proposed to be associated with HPA axis hyperfunction and hypersecretion of cortisol. The response to stress the HPA axis is likewise expected to show disinhibition. Since oxytocin increases are known to increase HPA axis suppression (Cohen et al., 2010), this type of depression is likely to benefit from oxytocin administration. However, due to the increased risk for uterine contraction, oxytocin cannot be administered during pregnancy. We hypothesize that depressive symptoms, due to HPA axis hyperactivation (i.e. of the melancholic type without a history of childhood adversity), should benefit from psychological interventions aimed at increasing endogenous oxytocin concentrations. For example, interventions such as engaging in social or romantic relationships, physical contact with a loved one, or massage are known to be potent in stimulating the oxytonergic system.
4.2.2 Postpartum depression
Postpartum depression that finds its onset during the sharp drop of cortisol levels after parturition is characterized by hypofunction of the HPA axis and relatively low cortisol concentrations. In response to stress, the normal increase in cortisol is absent. Psychological symptoms of postpartum depression are thought to reflect that of atypical depression. In our opinion, there is no reason to expect favorable results from administrating oxytocin to women with this subtype of postpartum depression. Since cortisol levels are already low, oxytocin increases might enhance the depressed mood by further reducing cortisol levels. 4.2.3 Postpartum distress with antenatal onset
Postpartum distress with antenatal onset appears to be preceded by relatively high levels of placental CRH and cortisol in the mother during pregnancy. Symptoms will commonly be prepartum anxiety and postpartum depression, although 3 different combinations of anxiety and depression can be distinguished postpartum (i.e. depressed, anxious, and anxious-depressed). The exact functioning of the HPA axis and the oxytonergic system in this subtype of postpartum disorders is unknown. However, since prepartum oxytocin levels are known to predict postpartum depressive levels, we suggest that stimulation of endogenous oxytocin levels during pregnancy might reduce some of this risk. Also, anxiolytic effects of oxytocin might alleviate some of the anxiety symptoms postpartum. Special attention should be paid to the contribution of maladaptive stress coping in women with this type of postpartum disorder.
4.2.3 Postpartum distress with antenatal onset and a history of early adversity
Postpartum distress with antenatal onset in women with a history of early adversity represents a heterogeneous and complex population. The impact of underlying biological mechanisms, clinical profile, and response to treatment depends strongly on the nature of the experienced adversity, genetic profile, and potential compensating circumstances/experiences. However, disinhibition of the HPA axis due to chronic low cortisol levels has been reported for individuals with a history childhood adversity. Although increasing oxytocin levels in these individuals might stimulate a process to counter CRH hypersecretion, results of oxytocin administration has proven to be somewhat unpredictable in individuals with negative early experiences. Like others, we propose that psychotherapy should aim to encourage positive interactions between mother and child by changing negative attitudes based on previous experiences (for a review see Miniati et al., 2014). Depressive symptoms might be partially alleviated by targeted trauma-therapy that could potentially benefit from short term oxytocin administration. However, increasing oxytocin levels in situations that are interoperated as potentially harmful by mothers with negative parental experiences is likely to lead to counterproductive results.
4.3 Conclusion
We hypothesize that oxytocin administration might only be therapeutic for postpartum distress with antenatal onset and under certain conditions in those with a history of early adversity. Postpartum women suffering from strictly antenatal depression might benefit from stimulating endogenous oxytocin levels. Pharmaceutical enhancement of oxytocin levels in postpartum women with hypofunction of the HPA axis (i.e. mothers with postpartum depression as defined above), women with a negative subjective interpretation of their current situation, and women with anxious attachment might result in adverse effects.
Research into the neurobiology underlying postpartum disorders has come a long way, but probably has an even longer way to go. Although several neuroendocrine factors have been shown to play a crucial role in development and maintenance of PPD symptoms, translational studies so far have failed to come up with a conclusive model of effective treatment options. Considering the complex mechanisms influencing mothers’ wellbeing in the postpartum, this is not surprising.
To our knowledge this is the first review to come up with a detailed hypothesis of biologically distinct subtypes of PPD, including proposals for the most efficient treatment options. Oxytocin administration in women with postpartum depressive or anxiety symptoms warrants for much more investigation. Future studies should examine the possibility that there are important differences in the neurobiology underlying postpartum disorders in women with and without a history of childhood adversity, psychiatric disorders, or co-morbid anxiety and stress. The effects of oxytocin in individuals with and without childhood adversity should be examined in controlled settings where context, and personal differences can be monitored. Studies on the clinical and biological differences between depressed and anxious postpartum profiles are recommended.
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