- Email: [email protected]
Biological stress response in women at risk of postpartum psychosis: The role of life events and inflammation
Journal Pre-proof Biological stress response in women at risk of postpartum psychosis: the role of life events and inflammation Monica Aas, Costanza Vecchio, Astrid Pauls, Mitul Mehta, Steve Williams, Katie Hazelgrove, Alessandra Biaggi, Susan Pawlby, Susan Conroy, Gertrude Seneviratne, Valeria Mondelli, Carmine M. Pariante, Paola Dazzan
PII:
S0306-4530(19)31299-5
DOI:
https://doi.org/10.1016/j.psyneuen.2019.104558
Reference:
PNEC 104558
To appear in:
Psychoneuroendocrinology
Received Date:
16 September 2019
Revised Date:
10 December 2019
Accepted Date:
17 December 2019
Please cite this article as: Aas M, Vecchio C, Pauls A, Mehta M, Williams S, Hazelgrove K, Biaggi A, Pawlby S, Conroy S, Seneviratne G, Mondelli V, Pariante CM, Dazzan P, Biological stress response in women at risk of postpartum psychosis: the role of life events and inflammation, Psychoneuroendocrinology (2019), doi: https://doi.org/10.1016/j.psyneuen.2019.104558
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Monica Aas
Biological stress response in women at risk of postpartum psychosis: the role of life events and inflammation
Monica Aas1-2*, Costanza Vecchio1*, Astrid Pauls1, Mitul Mehta1, Steve Williams1, Katie Hazelgrove1, Alessandra Biaggi1, Susan Pawlby1, Susan Conroy1, Gertrude Seneviratne1, Valeria Mondelli1-3, Carmine M. Pariante1-3, Paola Dazzan1-3
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*Both contributed as first-author.
Institute of Psychiatry, Psychology and Neuroscience, Kings College London, UK.
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NORMENT K.G Jebsen Centre for Psychosis Research, Division of Mental Health and
Addiction, Oslo University hospital, Norway.
National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at
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South London and Maudsley NHS Foundation Trust and King’s College London, London, UK
*Corresponding Author:
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Dr Monica Aas, PhD, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London. De Crespigny Park, London SE5 8AF, UK.
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Email: [email protected]
highlights
Stress is an important factor in postpartum psychosis.
Women with postpartum psychosis have abnormal cortisol levels.
Our data suggest immune-HPA axis dysregulation in postpartum psychosis.
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ABSTRACT Background: Postpartum psychosis (PP) is the most severe psychiatric disorder associated with childbirth, and the risk is particularly high in women with a history of bipolar disorder, schizoaffective disorder or in those who have suffered previous episodes of PP. While studies in patients with psychosis not related to the puerperium have demonstrated that abnormalities in stress response are important risk factors for psychosis, it remains unknown whether this is
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also the case for PP. Methods: This study includes 30 postpartum women, assessed, on average, at postpartum week 14.8±10.1 either with a current episode of PP (n=14), or at-risk of PP because of a history of
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bipolar/schizoaffective disorder but who were well (n=16), and a group of healthy women (n=26). Details about recent stressful life events were obtained using the List of Threatening
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Experiences questionnaire, while perceived stress was evaluated using the Perceived Stress
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Scale. We estimated hypothalamic-pituitary adrenal (HPA) activity by measuring salivary cortisol at awakening; at 15, 30, and 60 minutes after awakening; at noon; and at 8 pm. An Area Under the Curve analysis was performed to assess the awakening response (AUCi) and cortisol
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levels during the day (AUCg). Immune markers, including high sensitivity C-Reactive Protein (hs-CRP) and Interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, Tumor Necrosis Factor
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(TNFa), Vascular Endothelial Growth Factor (VEGF), Interferon gamma (INFγ), Monocyte
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Chemoattractant Protein 1 (MCP-1), and Epidermal Growth Factor (EGF) were evaluated from peripheral blood samples. Results: Women with current PP reported more frequent recent stressful life events, and higher perceived stress than healthy women. They also showed an activation of the stress and immune response, with higher levels of cortisol AUCg and hs-CRP (but not of other inflammatory markers) than healthy controls. Women at-risk of PP who remained well had values on these
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measures that were intermediate between those of women with a current episode of PP and those of healthy women. Stress measures and markers of stress and immune response explained 78% of the variance of in group status between PP and healthy women, and 46% of variance of in group status between women at-risk and healthy women. Conclusion: These findings suggest that an immune-HPA axis dysregulation, together with current stress may represent an important underlying pathophysiological mechanism in the
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onset of psychosis after childbirth in vulnerable women.
Key words: Postpartum psychosis, cortisol, stressful life events, perceived stress, immune
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system, severe mental disorders
1. INTRODUCTION
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Postpartum, or puerperal, psychosis (PP) is a severe psychiatric disorder that typically manifests
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within days of childbirth in 1-2 every 1000 new mothers (Davies, 2017). PP is a psychiatric emergency that usually requires treatment in hospital, as the consequences can be devastating for both mother and child. These may include maternal suicide, neglect and increased risk of
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PP is crucial.
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harm to the infant (Sit et al., 2006). Hence, the ability to understand why some women develop
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Most episodes of PP occur within two weeks after delivery, and the single largest risk factor for PP is a personal or family history of bipolar disorder, schizoaffective disorder, or of previous postpartum psychosis episodes, which are reported in approximately 40%-50% of PP cases (Jones et al., 2014; Sit et al., 2006; Wesseloo et al., 2016). However, it remains to be established why only some women at-risk develop the disorder, while others do not. Interestingly, we recently showed for the first time that women with PP, but not those at-risk who remain well,
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show alterations in regional brain volumes and cortical areas similar to those seen in individuals with non-puerperal psychoses. These include smaller anterior cingulate gyrus, superior temporal gyrus and parahippocampal gyrus (Fuste et al., 2017). Investigating the biological risk factors for PP and their relationship with socio-environmental risk factors is crucial to advance our ability to identify the women most at-risk.
The synergistic role of both biological and socio-environmental risk factors has been integrated
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in the vulnerability-stress model, which proposes that a dysfunction of the HypothalamicPituitary-Adrenal (HPA) axis, the main system involved in the biological response to stress, as well as an underlying brain vulnerability, may increase the sensitivity of some individuals to
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stress and thus make them more likely to develop a psychotic episode under stressful circumstances. Relevant to psychosis, stressors such as childhood maltreatment, chronic stress,
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recent stressful events and perceived stress have all been found in excess in patients with these
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disorders (Mondelli et al., 2010). For example, patients with first-episode psychosis, and highrisk untreated individuals with attenuated positive symptoms, all show evidence of an activation of the biological response to stress, with higher levels of cortisol, the main hormone involved
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in the stress response. These findings suggest that a dysfunction of the HPA axis is already present at illness onset and may even precede the onset of symptoms (Andrade et al., 2016;
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Mondelli et al., 2010; Pruessner et al., 2017).
Several studies have also implicated an immune system dysfunction in psychotic disorders (Leboyer et al., 2016; Morch et al., 2016), and increased inflammatory markers (i.e., cytokines and C-reactive protein) have been consistently reported in patients with first-episode psychosis and with bipolar disorder, often together with HPA axis abnormalities (Hope et al., 2009; Mondelli et al., 2011; Mondelli et al., 2010; Potvin et al., 2008). Studying the role of the HPA
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axis in perinatal psychiatric disorders is challenging, as in pregnancy and in the postpartum period the HPA axis is normally suppressed. Still, while data on PP are lacking, evidence from studies on antenatal and postnatal depression suggest that an activation of the immune system and an inability to suppress the HPA axis play an important role in this disorder in the perinatal period ((Melon et al., 2018; Osborne et al., 2018); for a detailed review, please see, (for review (Bloch et al., 2003)). Interestingly, there is also some preliminary evidence on immune dysfunction in women with PP, who have been found to show an upregulated immune system-
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related gene expression profile, an excess of autoimmune disorders, and a failure to show the normal postpartum T cell elevation (Bergink et al., 2013; Kumar et al., 2017).
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To our knowledge this is the first study to report on the stress response in women with PP using multiple HPA axis and immune biomarkers, together with measures of life events and perceived
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stress. Based on evidence from work on psychoses unrelated to the puerperium, we
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hypothesized that: 1) women with PP would have higher cortisol levels than women at-risk who did not develop PP and healthy women in the same postpartum period; and 2) these higher cortisol levels would be associated with elevated pro-inflammatory markers and with symptom
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severity.
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2. METHODOLOGY 2.1. Design We recruited a group of 30 women with, or at-risk of, PP (see below for definition), from perinatal services of the South London and Maudsley (SLAM) NHS Foundation Trust and from the Central and North West London NHS Foundation Trust, as part of the Psychiatry Research and Motherhood Postpartum Psychosis study (PRAM-P). All women were between 18 and 41 years of age and they were all assessed in the postpartum period, on average at 14.8±10.1week
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postpartum. Women were identified as having PP (n=14, of which 4 had a history of Bipolar Disorder or previous Postpartum Psychosis) or being at-risk but well (N=16, of which 10 had a history of Bipolar Disorder, 2 of Schizoaffective Disorder (Manic type), and 4 had a family
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(n=1) or personal (n=3) history of PP. We also recruited a group of 26 healthy women (controls) from the Obstetric Services of King’s College Hospital, London, who did not have a current or
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previous history of a mental health disorder. Women with learning disabilities or those who
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were unable to communicate proficiently in English were excluded from the study. All participants were provided with detailed information about the study and written informed consent was obtained from all whom took part. The study was approved by the local Research
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Ethics Committee (10/H0807/14).
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2.2. Clinical assessment
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All women completed a structured sociodemographic and physical health schedule postpartum, which included demographic information. Women with PP had to be clinically stable in order to undertake the assessment. Clinical diagnoses were obtained using the clinical version of the Structured Clinical Interview for DSM-IV Axis I Disorders (Clinician Version) (SCID-I CV), a semi-structured interview used for the formulation of the principle diagnosis on the Axis I of DSM IV (First, 2002) which allows applying the specifier “with postpartum onset”. Psychiatric
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symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). The PANSS consists of 30 items and the score is measured on a 7-points scale from 1 (absence of the symptom) to 7 (extreme degree). Current functioning was measured with the Global Assessment of Functioning scale (GAF) (Piersma and Boes, 1997).
Information about recent stressful life events was obtained using the List of Threatening Experiences questionnaire (Brugha and Cragg, 1990). This brief life event questionnaire
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examines the presence and the emotional impact of life stressors in the preceding six months, and includes illness or injury, death of a close friend or relative, unemployment, financial loss and loss of important relationships, measured on 3 point-scale from 1 (not too bad) to 3 (very
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bad). We measured perceived stress using the Perceived Stress Scale (Cohen, 1988). This is a self-rated questionnaire, which consists of 10-items and measures the degree to which situations
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in one's life, considering the preceding month, are appraised as stressful on a 5 point-scale,
2.3. HPA axis activity
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ranging from 0 (never) to 5 (very often true).
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We evaluated HPA activity measuring salivary cortisol. Subjects were instructed to collect saliva samples, using special Salivettes, consisting of sorbette arrows, at awakening, at 15, 30,
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and 60 minutes after awakening, at noon and at 8 pm. Subjects were instructed not to have
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breakfast or brush their teeth during the first hour of awakening, and in the 30 min before taking the sample at 12 pm and 8 pm. They were required to keep a record on a collection record form, including the time of the collection, if they had eaten or drunk before taking the sample or if they were experiencing any stressful circumstances or difficulties. Participants were required to store their samples in their domestic refrigerator and post them in a stamped addressed envelope on the following morning. On arrival at the laboratory the salivettes were frozen at
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−20 ° C. Cortisol levels were measured using ELISA. A sample tracking database for HTA purposes was completed by the researcher.
To limit the number of statistical comparisons, all HPA axis analyses were conducted using the Area Under the Curve (AUCg) of cortisol levels during the day (0 min, noon and 8 pm) and the AUC of the increase (AUCi) of cortisol levels after awakening (from 0 min to 15, 30, and 60 min after awakening). Both formulas for the calculation of the AUCs were derived from the
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trapezoid formula (Pruessner et al., 2003).
2.4. Inflammatory markers
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Blood samples were collected to measure inflammatory markers. The samples were collected into EDTA tubes and blood was processed between 30 minutes and 2 hours after venipuncture.
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Sub-aliquots of plasma were prepared for measurement of inflammatory markers. Aliquots of
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serum were immediately frozen at −80 °C pending analysis. Serum high sensitivity C-reactive protein (hsCRP) was measured using an ELISA kit supplied by PZ Cormay, Poland; the assay was analyzed in batches on the Cobas Mira (intra- and inter-assay CV were 2.96% and 3.85%
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respectively). Serum cytokine levels were measured using a cytokine chip array kit supplied by Randox Laboratories, UK; the kit employs a sandwich chemiluminescent immunoassay,
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described in our previous work (Di Nicola et al., 2013; Osborne et al., 2018). We analysed
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several immune and growth markers, including Interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL8, IL-10, Tumor Necrosis Factor (TNFa), Vascular Endothelial Growth Factor (VEGF), Interferon gamma (INFγ), Monocyte Chemoattractant Protein 1 (MCP-1), and Epidermal Growth Factor (EGF). We specifically evaluated differences in three proinflammatory markers (hs-CRP, TNFa, lL-6), and one anti-inflammatory cytokine (IL-4) that have been frequently
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reported as altered in psychoses (Leboyer et al., 2016), with a recent study reporting elevated IL-6 in women with PP (Sathyanarayanan et al., 2019)...
2.5. Statistical analyses Data were analysed using the Statistical Package for Social Sciences, Version 25.0 (SPSS 25.0). A one-way ANOVA was used to compare means of continuous variables between groups. Chisquare test was used to compare categorical variables. Correlational analyses were conducted
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using Pearson's or Spearman's correlation as appropriate, to examine the relationship between psychopathology in the postpartum, stress factors and biological measures (cortisol levels and inflammatory markers). A logistic regression model was then used to test for predictors of PP
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status. Biomarker analyses were adjusted for weeks after delivery, BMI and smoking status. The role of physical problems with pregnancy or delivery, and medications was also considered
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Bonferroni adjusted post hoc tests.
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in relation to biomarkers. The threshold for statistical significance was set at p≤0.05 with
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3. RESULTS Women with PP and women at-risk of PP did not significantly differ from healthy women (controls) in age, ethnicity, educational level or relationship status (Table 1). The mean number of weeks after delivery at the time of assessment was longer in women with PP than in women at-risk and controls; this could be accounted for by the fact that it was deemed appropriate to recruit and assess women with a current PP episode when clinically stable. Women with PP, women at-risk of PP and healthy women did not significantly differ in primiparity. There were
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no statistically significant differences in BMI or cigarette smoking between groups. Women with PP and women at risk were more likely to report physical problems with pregnancy or delivery (40% vs 50% vs 15% respectively), albeit at trend level. As expected, the severity of
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psychiatric symptoms from the PANSS was higher in women with PP and in women at-risk compared to controls, and the GAF scores were significantly lower in the women with PP and
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women at-risk compared with the healthy women (Table 1).
- Table 1 here-
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3.1. Life events and perceived stress
Details of recent stressful life events and perceived stress are shown in Table 1. Both women
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with PP and women at-risk reported more recent stressful life events compared to healthy
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controls, but the differences were larger, and statistically significant, for PP (p=0.007), while they only reached trend statistical significance for at-risk women (p=0.07) (Table 1). Both women with PP and women at-risk had significantly higher scores of perceived stress than healthy controls (p˂0.001), and again the women at-risk who remained well had scores that were intermediate between those of women with PP and the healthy controls.
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3.2. Salivary cortisol and immune markers Salivary cortisol levels during the day are shown in Figures 1 and 2, and the AUC values are presented in Table 1. An overall group difference in AUCg was observed (ANOVA, F2, 41=3.3, P=0.046), and post hoc analyses with Bonferroni correction revealed this was due to a higher AUCg in women with PP compared to the healthy controls (p=0.014) (Table 1, Fig. 1). Women at-risk who remained well had AUCg values intermediate between those of women with PP and healthy controls. As there was a difference in the number of weeks after delivery between the
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groups, we correlated the AUCg value with postpartum weeks at assessment and found that these were not correlated (r=0.03, p=0.86). We also repeated the ANOVA using weeks after delivery as a covariate, and we found that women with PP still had higher AUCg than the
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healthy controls, with the difference reaching an even higher level of significance (F1,32=5.54, p=0.026), while women at risk remained not significantly different from the controls (p=0.13).
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In addition, since women at risk and women with PP were more likely to report physical
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problems with pregnancy or delivery than healthy controls, we explored their role in explaining between-group differences in AUCg. We found that although reporting physical problems was associated with AUCg (F=4.50, P=0.046), the AUCg was still higher in women with PP than
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in women at-risk and in healthy women when physical problems were taken into account (F=4.52, p=0.017). Finally, we found no association between AUCg, and BMI, smoking, and
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use of medication (as Yes/No).
In contrast with what observed for the AUCg, we found no between-group significant differences in AUCi (Fig. 2). Of note, women with PP had higher cortisol peak levels at 30 minutes after awakening compared to healthy controls (F2,34=4.76, p=0.036), although this difference did not survive Bonferroni correction.
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- Figure 1 and Figure 2 here -
The analysis of immune markers revealed that more women with PP had a hs-CRP≥3, compared to women at-risk and healthy controls (46% vs 37% vs 15% respectively) (X2 2, 47=3.81, p=0.05). While mean levels of hs-CRP were not associated with weeks after delivery (r=0.05; p=0.73), when we included weeks after delivery in the between-group comparison of mean hs-CRP levels, women with PP still had higher hs-CRP levels than healthy women (p=0.059), with no
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difference between women at-risk and healthy women (p=0.14). We found no association between hs-CRP and BMI, smoking, physical problems with pregnancy or delivery, or
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medications.
Between-group comparisons showed no statistically significant difference between the groups
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in cytokine levels IL-4, IL-6, or TNFa (see Table 1), or in the additional immune and growth
Material, Table S1).
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markers IL-1a, IL-1b, IL-2, IL-8, IL-10, VEGF, INFγ, MCP-1, EGF (see Supplementary
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3.3. Logistic regression predicting group status
We then entered the factors that had shown between-group differences into a logistic regression
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analysis. This showed that recent stressful life events, perceived stress, and biomarkers of stress
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and immune response (AUCg and hs-CRP [dichotomized into below three or three and above]) explained 78% of the variance between PP and healthy controls, and 46% of the variance between women at-risk and healthy controls (see Table 2).
- Table 2 here -
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3.4. Stressors, symptom severity and level of functioning We then performed an exploratory analysis of the relationship between stressors that differed between groups and symptom severity and level of functioning in the combined PP and at-risk groups. We found that more recent stressful life events (r=0.40, p=0.03), higher levels of perceived stress (r=0.43, p=0.02), and a higher AUCg (r=0.45, p=0.04) were all associated with more severe symptoms (see Table 3). Interestingly, higher perceived stress scores were particularly associated with higher scores on the PANSS positive symptoms subscale (r=0.40,
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p=0.03). In contrast, only a higher AUCg was associated with poorer level of functioning as measured by the GAF (r=-0.43, p=0.05; see Table 3). There were no differences in symptoms (from PANSS) or level of functioning (from GAF) in women with hs-CRP ≥3 compared to
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women with hs-CRP <3 (F1, 27=0.27, p=0.60, and F1,26=0.85, p=0.36 respectively).
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- Table 3 here -
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4. DISCUSSION This is the first study to report on stress, and both cortisol levels and immune markers of stress response in women with postpartum psychosis (PP) and in women at-risk of PP who remain well. Our main finding is that women with PP present an immune-HPA hyperactivation, with more frequent recent stressful life events, higher perceived stress and higher cortisol levels during the day, and a higher hs-CRP than women not at risk in the postpartum period. Interestingly, the women at-risk of PP who remain well have values for these factors that are
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intermediate between those of women with PP and healthy women. Together, these factors explained a large amount of variance in the risk of having an episode of PP, accounting for 78% of the variance in group status between PP and healthy women, compared to 46% of the
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variance between women at-risk and healthy women. Perhaps not surprisingly therefore, higher cortisol levels and current stress were associated with more severe symptomatology and poorer
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functioning, suggesting stress may represent an important underlying pathophysiological
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mechanism in the onset of PP. Although the small sample size of this study makes conclusion preliminary, the fact that women at-risk who did not develop PP also showed higher stress, and immune activation than healthy controls (albeit to a lesser degree than women with PP) suggest
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that these factors are possible markers for severe mental disorders that are exacerbated in the
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context of illness onset.
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The role of stress in psychiatric disorders, and in psychosis unrelated to the puerperium is well established, but studies of the biological response to stress in PP are less than a handful. The increase in cortisol levels during the day we found in women with PP is consistent with our previous findings in patients with a first-episode psychosis (Mondelli et al., 2011; Mondelli et al., 2015; Mondelli et al., 2010) and with our own finding of an increased pituitary volume in patients with first-episode psychosis (Pariante et al., 2005). An increase in cortisol levels during
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the day has also been reported in bipolar disorder, one of the strongest risk factor for the occurrence of PP (Cervantes et al., 2001). Interestingly, as discussed by Mondelli and colleagues (Mondelli, 2014), a hyperactivity of the HPA axis may be part of the biological vulnerability to psychosis, often predating the onset of psychosis (Aiello et al., 2012). This is further supported by evidence that higher cortisol levels as well as larger pituitary gland are found in individuals who experience attenuated psychotic symptoms, and to an even greater extent in those who subsequently develop psychosis (Garner et al., 2005). Supporting its role
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in the vulnerability to psychosis, an increased sensitivity to stress has been also reported in relatives of patients with psychotic disorders, who show increased emotional reactivity to daily life stress, increased ACTH in response to stress, larger pituitary volume and smaller
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hippocampal volume (Aiello et al., 2012). Indeed, previous studies have suggested that an abnormal sensitivity to the endocrinological disturbances of the puerperium may confer
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vulnerability to PP in some women (Jones et al., 2014; Sit et al., 2006). This would be consistent
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with what seen in women with antenatal and postnatal depression, in whom we and others have reported the presence of higher diurnal cortisol secretion (Bloch et al., 2003; Melon et al., 2018). Still, even in perinatal depression reports have been mixed, possibly because of different
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definitions of depression and different measurements of HPA axis, and at different time-points
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in the.
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Our data suggest that another component of the biological response to stress, the immune system, is also dysregulated in women with PP, as indicated by the elevated levels of hs-CRP we observed in the women with PP. We and others have reported an activation of the immune system in psychosis and in bipolar disorder, with higher levels of hs-CRP and markers of inflammation, such as TNF, IL-1 and IL-6 in patients with bipolar disorder or schizophrenia (Dieset et al., 2012; Hope et al., 2009). Our finding of a possible immune dysregulation in
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women with PP are consistent with evidence from Bergink and colleagues (Bergink et al., 2013) of a glucocorticoid receptor gene α/β expression ratio reduction, with immune activation correlates in women with PP. These authors showed elevated serum pro-inflammatory cytokine IL-1β in women with PP compared to healthy women in the postpartum period, as well as 17 upregulated immune related genes. Furthermore, they found that women with PP also had a reduction of the active glucocorticoid receptor gene α and an upregulation of the inactive glucocorticoid receptor gene β expression. This pattern of GR-α downregulation, GR-β
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upregulation, and the correlation patterns of this low GR α/β ratio to the expression level of inflammation-related genes together point to the presence of steroid resistance in PP. Our findings of elevated hs-CRP in conjunction with elevated cortisol levels during the day would
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provide further initial support to the notion of steroid resistance in PP, in other words that elevated cortisol levels may fail to downregulate the immune system, as for the higher hs-CRP
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we found in women with PP.
In contrast with the scarcity of evidence in PP, several lines of evidence support the inflammatory hypothesis in postpartum depression and in psychoses not related to the
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puerperium. First, elevated levels of inflammatory markers (i.e., C-reactive protein and cytokines) have been reported in patients with antenatal and postnatal depression, and with
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affective and non-affective psychoses (Guintivano et al., 2018; Leboyer et al., 2016; Liu et al.,
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2016; Osborne et al., 2018). Consistent with this, data from genome-wide association studies (GWAS) indicate that immune-related genes may represent susceptibility genes for schizophrenia, including the major histocompatibility complex (Ripke et al., 2013; Stefansson et al., 2009). Finally, proinflammatory cytokines have been associated with smaller hippocampal volume in patients with first-episode psychosis (Mondelli et al., 2011) and shown to predict progressive thinning of the prefrontal cortex in individuals at risk for psychosis who
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go on to develop the illness (Cannon et al., 2015). The mechanisms through which inflammatory cytokines may mediate the onset of psychosis include interaction with multiple pathways such as monoamine metabolism, neuroendocrine function and synaptic plasticity (Mondelli et al., 2015; Mondelli and Howes, 2014). While the exact biological mechanisms remain unclear, we have recently suggested that an imbalance between proinflammatory and immunosuppressive cells of the immune system in the postpartum period may be a trigger for the disorder (Dazzan et al., 2018). Replicating this preliminary evidence in larger samples of
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women at risk of, and with PP will help clarify the exact immune dysregulation profile that characterises the risk for this disorder.
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Consistent with the alteration in the stress system, is also our finding that women with PP were more likely to report brief stressful life events as well as higher perceived stress levels than
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healthy controls, although there was no difference between those with PP and those who were
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at-risk and remained well. This finding of increased stress is similar to what reported in patients with first-episode psychosis, in schizophrenia, and in bipolar disorder (Aas et al., 2016;
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Mondelli, 2014; Pruessner et al., 2017).
This study has a number of strengths. This is the first study to investigate both cortisol levels
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and immune markers in women with PP and in women at-risk of PP who remain well. All
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participants were assessed with detailed clinical and biological measures, providing a unique opportunity to study markers linked to the onset of PP. Furthermore, as we collected several cortisol samples during the day at specific time-points (morning, midday and evening), we were able to capture the diurnal pattern of cortisol levels throughout the day.
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Still, there are some important limitations that should be recognised. The main limitation is the relatively small sample size of this study, and we cannot exclude that some of the associations investigated did not reach statistical significance due to lack of power, or that some findings represented false positives. As such, these should be considered initial findings that could direct further research in larger samples. Also, inflammatory markers were measured in peripheral blood which is an indirect estimate of activity within the brain. However, there is accumulating evidence indicating communication across the blood brain barrier, and of a high correlation
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between biomarkers in the cerebro-spinal fluid and the periphery (Kipnis et al., 2012; Tomasik et al., 2016). The evaluation of stress-related biomarkers at a single time point prevents us to make inferences about causality. Also, while the fact we obtained data only on one day does
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not fully follow the Psychoneuroendocrinology criteria (Stalder et al., 2016), in one of our initial studies we compared one and two-day collection of cortisol, and found that values were
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highly correlated (Mondelli et al., 2010). Indeed, we have since used this method extensively
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in patients with a range of mental disorders and in individuals experiencing stress (Ciufolini et al., 2019; Mondelli et al., 2015; Osborne et al., 2018). Another important factor is that women in the PP group were later in their postpartum period (about twenty weeks compared to twelve
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and thirteen weeks in women at-risk and healthy women respectively). We cannot rule out that this may have influenced the immune and cortisol measures, since after delivery, the
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immunologically suppressed state of pregnancy needed to induce maternal tolerance toward the
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histo-incompatible fetus shows a rebound. Similarly, since there is central suppression of hypothalamic CRH secretion in the postpartum, which may last for about 12 weeks. While the longer interval between delivery and assessment in women with PP could potentially explain the higher diurnal cortisol levels and hs-CRP seen in this group, we found no relationship between weeks after delivery and hs-CRP or cortisol levels during the day. Even when this interval was included as a covariate, the between-group differences remained significant,
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suggesting that differences in time after delivery are unlikely to fully explain our results. Finally, we cannot rule out the potential role of socio-economic factors, which were not investigated in this study and that could play a role in stress perception and response.
4.1. CONCLUSIONS Our findings provide initial evidence that stress and its biological response may play a role in the aetiology of PP and offer an interesting basis on which to conduct further investigations on
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the role of the stress and immune response in this neglected clinical population. As for other psychiatric disorders, interventions that specifically aim at stress-management, including cognitive behavioural therapy, and the development of new pharmacological approaches
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targeting the HPA axis and the immune system could also be beneficial to reducing the risk of
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postpartum psychosis in vulnerable women.
6. CONFLICT OF INTEREST
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None to declare.
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5.
7. CONTRIBUTORS
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All Authors contributed to the Manuscript.
ACKNOWLEDGEMENTS
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The research was supported by a NARSAD Independent Investigator Award to Professor P.
Dazzan. The research was also in part financially supported by the Psychiatry Research Trust, the Medical Research Foundation and the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily
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those of the NHS, the NIHR or the Department of Health. M. Aas is funded by a grant from the
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South-Eastern Norway Health Authority and a Narsad Young Investigator Award.
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Liu, H., Zhang, Y., Gao, Y., Zhang, Z., 2016. Elevated levels of Hs-CRP and IL-6 after delivery are associated with depression during the 6 months post partum. Psychiatry Res 243, 43-48.
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Melon, L.C., Hooper, A., Yang, X., Moss, S.J., Maguire, J., 2018. Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice. Psychoneuroendocrinology 90, 182-193. Mondelli, V., 2014. From stress to psychosis: whom, how, when and why? Epidemiol. Psychiatr. Sci, 14. Mondelli, V., Cattaneo, A., Belvederi, M.M., Di, F.M., Handley, R., Hepgul, N., Miorelli, A., Navari, S., Papadopoulos, A.S., Aitchison, K.J., Morgan, C., Murray, R.M., Dazzan, P., Pariante, C.M., 2011. Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: a pathway to smaller hippocampal volume. J Clin Psychiatry 72, 1677-1684. Mondelli, V., Ciufolini, S., Belvederi Murri, M., Bonaccorso, S., Di Forti, M., Giordano, A., Marques, T.R., Zunszain, P.A., Morgan, C., Murray, R.M., Pariante, C.M., Dazzan, P., 2015. Cortisol and Inflammatory Biomarkers Predict Poor Treatment Response in First Episode Psychosis. Schizophr Bull 41, 1162-1170.
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Monica Aas Mondelli, V., Dazzan, P., Hepgul, N., Di, F.M., Aas, M., D'Albenzio, A., Di, N.M., Fisher, H., Handley, R., Marques, T.R., Morgan, C., Navari, S., Taylor, H., Papadopoulos, A., Aitchison, K.J., Murray, R.M., Pariante, C.M., 2010. Abnormal cortisol levels during the day and cortisol awakening response in firstepisode psychosis: the role of stress and of antipsychotic treatment. Schizophr. Res 116, 234-242. Mondelli, V., Howes, O., 2014. Inflammation: its role in schizophrenia and the potential antiinflammatory effects of antipsychotics. Psychopharmacology (Berl) 231, 317-318. Morch, R.H., Dieset, I., Faerden, A., Hope, S., Aas, M., Nerhus, M., Gardsjord, E.S., Joa, I., Morken, G., Agartz, I., Aukrust, P., Djurovic, S., Melle, I., Ueland, T., Andreassen, O.A., 2016. Inflammatory evidence for the psychosis continuum model. Psychoneuroendocrinology 67, 189-197. Osborne, S., Biaggi, A., Chua, T.E., Du Preez, A., Hazelgrove, K., Nikkheslat, N., Previti, G., Zunszain, P.A., Conroy, S., Pariante, C.M., 2018. Antenatal depression programs cortisol stress reactivity in offspring through increased maternal inflammation and cortisol in pregnancy: The Psychiatry Research and Motherhood - Depression (PRAM-D) Study. Psychoneuroendocrinology 98, 211-221.
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Pariante, C.M., Dazzan, P., Danese, A., Morgan, K.D., Brudaglio, F., Morgan, C., Fearon, P., Orr, K., Hutchinson, G., Pantelis, C., Velakoulis, D., Jones, P.B., Leff, J., Murray, R.M., 2005. Increased pituitary volume in antipsychotic-free and antipsychotic-treated patients of the AEsop first-onset psychosis study. Neuropsychopharmacology 30, 1923-1931. Piersma, H.L., Boes, J.L., 1997. The GAF and psychiatric outcome: a descriptive report. Community Ment Health J 33, 35-41.
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Pruessner, M., Cullen, A.E., Aas, M., Walker, E.F., 2017. The neural diathesis-stress model of schizophrenia revisited: An update on recent findings considering illness stage and neurobiological and methodological complexities. Neurosci Biobehav Rev 73, 191-218.
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Ripke, S., O'Dushlaine, C., Chambert, K., Moran, J.L., Kahler, A.K., Akterin, S., et.al., 2013. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature genetics 45, 1150-1159. Sathyanarayanan, G., Thippeswamy, H., Mani, R., Venkataswamy, M., Kumar, M., Philip, M., Chandra, P.S., 2019. Cytokine alterations in first-onset postpartum psychosis-clues for underlying immune dysregulation. Asian J Psychiatr 42, 74-78.
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Sit, D., Rothschild, A.J., Wisner, K.L., 2006. A review of postpartum psychosis. J Womens Health (Larchmt) 15, 352-368.
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Stalder, T., Kirschbaum, C., Kudielka, B.M., Adam, E.K., Pruessner, J.C., Wust, S., Dockray, S., Smyth, N., Evans, P., Hellhammer, D.H., Miller, R., Wetherell, M.A., Lupien, S.J., Clow, A., 2016. Assessment of the cortisol awakening response: Expert consensus guidelines. Psychoneuroendocrinology 63, 414-432. Stefansson, H., Ophoff, R.A., Steinberg, S., Andreassen, O.A., Cichon, S., Rujescu, D., et.al., 2009. Common variants conferring risk of schizophrenia. Nature 460, 744-747. Tomasik, J., Rahmoune, H., Guest, P.C., Bahn, S., 2016. Neuroimmune biomarkers in schizophrenia. Schizophrenia research 176, 3-13. Wesseloo, R., Kamperman, A.M., Munk-Olsen, T., Pop, V.J., Kushner, S.A., Bergink, V., 2016. Risk of Postpartum Relapse in Bipolar Disorder and Postpartum Psychosis: A Systematic Review and MetaAnalysis. Am J Psychiatry 173, 117-127.
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Monica Aas FIGURE LEGENDS
Figure 1. Daily cortisol levels (AUCg) in women with postpartum psychosis, women at-risk for postpartum psychosis and healthy women. Figure 2. Cortisol awakenig response (AUCi) in women with postpartum psychosis, women at-risk for postpartum psychosis and healthy women. Figure 1. Daily cortisol levels (AUCg) in postpartum psychosis, women at-risk for postpartum psychosis and healthy women
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PP Women at- risk Healthy women
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AUCg= Area Under the curve in relation to ground. Mean and standard error. ANOVA, f=3.3. p=0.046.
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Posthoc tests revealed higher AUCg in PP than in HC (p=0.014). PP=postpartum psychosis.
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Figure 2. Cortisol awakenig response (AUCi) in postpartum psychosis, women at-risk for postpartum psychosis and healthy women
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PP
Women at-risk
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Healthy women
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Timepoint 15
Timepoint 30
Timepoint 60
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AUCi= Area Under the curve in relation to increase (also called the Cortisol Awakening Response,
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CAR). Mean and standard error.
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Monica Aas Table 1. Socio-demographic, clinical characteristics and stress markers in women with postpartum psychosis (PP), women at-risk who remained well (AR), and healthy controls (HC). PP n=14 34.1±3.9 43% 93% 64% 93% 20.5±12.4 79% 27.04±5 56%
AR n=16 32.1±5.4 25% 56% 56% 69% 12.3±5.8 50% 27.43±6 75%
HC n=26 34.4±4.7 46% 81% 77% 85% 13.2±9.8 65% 25.0±3 62%
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Age (mean±SD) Ethnicity (% White British) Educational level (% Higher Education) Employment status (% Employed) Relationship status (% In a relationship) Weeks after delivery (mean±SD) Parity (% Primiparity) BMI (mean±SD) Cigarette smoking, yes (%) Physical problems with pregnancy or 40% 50% 15% delivery, yes (%) PANSS total score (mean±SD) 39.9±5.2 36.7±7.7 30.8±1.8 GAF score 73.4±16.8 79.9±15.7 97.9±4.7 BLE score (mean±SD) 3.5±3.4 2.2±3.2 0.7±1.7 PSS score (mean±SD) 19.0±6.2 16.0±7.7 8.6±6.7 AUCg (mean±SD) 59.1±38.9 46.3±18.5 36.8±13.9 AUCi (mean±SD) 102.0±254.2 77.4±246.8 56.4±216.5 hs-CRP (mean±SD) 3.35±3.24 3.31±3.12 1.58±1.17 hs-CRP ≥3 (%) 46% 37% 15% TNFa (mean±SD) 2.03±0.90 2.16±0.69 1.75±0.63 IL-6 (mean±SD) 1.33±0.93 1.45±1.33 1.46±1.90 IL-4 (mean±SD) 3.01±1.93 2.71±1.12 2.45±0.53 PANSS: Positive and Negative Syndrome Scale; BLE: Brief Life Events; PSS: Perceived Stress Scale; AUCg: Area Under the curve in relation to ground (Daily cortisol levels); AUCi: Area Under the curve in relation to increase (also called Cortisol Awakening Response, CAR); BMI: Body Mass Index; TNF: Tumor Necrosis Factor; IL: InterLeukin; hs-CRP: High Sensitivity C-Reactive Protein. One woman with PP had missing data on PSS, and two had missing data for GAF. Four women with PP, 4 women at-risk and 4 healthy women had missing data on AUCg. Four women with PP, 4 women at-risk and 3 healthy women had missing data on AUCi. One woman with PP, 1 woman at-risk and 6 healthy women had missing data for CRP. Five healthy women had missing data on TNFa, IL-6 and IL-4. Bonferroni post-hoc analyses: a =P≤0.05. PP vs HC b = P≤0.05. AR vs HC c = P≤0.05. PP vs AR Table 2. Multiple Logistic Regression comparing women with postpartum psychosis (PP), women atrisk who remained well (AR) and healthy controls (HC).
PP versus HC
AR versus HC
(R squared)
(R squared)
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0.26
0.12
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2 model: BLE+PSS
0.59
0.31
3rd model: BLE+PSS+AUCg
0.69
0.37
4th model: BLE+PSS+AUCg+hs-CRP
0.78
0.46
1 model: BLE
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Signific
F=1.3, p χ2= 7.0, p χ2=10.8, p χ2=4.2, p χ2=3.2, p F=3.4, p χ2=2.7, p F=1.6, p χ2=4.8, p
χ2=5.82, p
F=16.7, p F=21.2, p F=4.3, p= F=11.7, p F=3.3, p= F=0.1, p F=0.94, p χ2=3.81, p F=1.70, p F=0.50, p F=0.24, p
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BLE: Brief Life Events; PSS: Perceived Stress Scale; AUCg: Area Under the curve in relation to ground (Daily cortisol levels); hs-CRP: high sensitivity C-Reactive Protein dichotomized into <3 or 3.
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Monica Aas Table 3. Correlation between severity of symptoms and level of functioning, stress measures and hsCRP levels in women with PP and women at-risk who remained well.
Level of functioning (GAF)
Brief life events
r=0.40; p=0.03*
r=-0.33; p=0.09
Perceived stress
r=0.43; p=0.02*
r=-0.18; p=0.38
AUCi (cortisol awakening response)
r=-0.15; p=0.50
r=0.05; p=0.83
AUCg (daily cortisol)
r=0.45; p=0.04*
r=-0.43; p=0.05*
hs-CRP
r=-0.06; p=0.75
r=0.10; p=0.62
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Severity of symptoms (PANSS)
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GAF: Global assessment of Functioning Scale; PANSS: Positive and Negative Syndrome Scale; AUCg: Area Under the Curve in relation to ground (daily cortisol levels); AUCi: Area Under the Curve in relation to increase (also called Cortisol Awakening Response, CAR); hs-CRP: high sensitivity C-Reactive Protein. * Significance = p ≤ 0.05.
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PII:
S0306-4530(19)31299-5
DOI:
https://doi.org/10.1016/j.psyneuen.2019.104558
Reference:
PNEC 104558
To appear in:
Psychoneuroendocrinology
Received Date:
16 September 2019
Revised Date:
10 December 2019
Accepted Date:
17 December 2019
Please cite this article as: Aas M, Vecchio C, Pauls A, Mehta M, Williams S, Hazelgrove K, Biaggi A, Pawlby S, Conroy S, Seneviratne G, Mondelli V, Pariante CM, Dazzan P, Biological stress response in women at risk of postpartum psychosis: the role of life events and inflammation, Psychoneuroendocrinology (2019), doi: https://doi.org/10.1016/j.psyneuen.2019.104558
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.
Monica Aas
Biological stress response in women at risk of postpartum psychosis: the role of life events and inflammation
Monica Aas1-2*, Costanza Vecchio1*, Astrid Pauls1, Mitul Mehta1, Steve Williams1, Katie Hazelgrove1, Alessandra Biaggi1, Susan Pawlby1, Susan Conroy1, Gertrude Seneviratne1, Valeria Mondelli1-3, Carmine M. Pariante1-3, Paola Dazzan1-3
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*Both contributed as first-author.
Institute of Psychiatry, Psychology and Neuroscience, Kings College London, UK.
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NORMENT K.G Jebsen Centre for Psychosis Research, Division of Mental Health and
Addiction, Oslo University hospital, Norway.
National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at
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South London and Maudsley NHS Foundation Trust and King’s College London, London, UK
*Corresponding Author:
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Dr Monica Aas, PhD, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London. De Crespigny Park, London SE5 8AF, UK.
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Email: [email protected]
highlights
Stress is an important factor in postpartum psychosis.
Women with postpartum psychosis have abnormal cortisol levels.
Our data suggest immune-HPA axis dysregulation in postpartum psychosis.
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ABSTRACT Background: Postpartum psychosis (PP) is the most severe psychiatric disorder associated with childbirth, and the risk is particularly high in women with a history of bipolar disorder, schizoaffective disorder or in those who have suffered previous episodes of PP. While studies in patients with psychosis not related to the puerperium have demonstrated that abnormalities in stress response are important risk factors for psychosis, it remains unknown whether this is
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also the case for PP. Methods: This study includes 30 postpartum women, assessed, on average, at postpartum week 14.8±10.1 either with a current episode of PP (n=14), or at-risk of PP because of a history of
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bipolar/schizoaffective disorder but who were well (n=16), and a group of healthy women (n=26). Details about recent stressful life events were obtained using the List of Threatening
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Experiences questionnaire, while perceived stress was evaluated using the Perceived Stress
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Scale. We estimated hypothalamic-pituitary adrenal (HPA) activity by measuring salivary cortisol at awakening; at 15, 30, and 60 minutes after awakening; at noon; and at 8 pm. An Area Under the Curve analysis was performed to assess the awakening response (AUCi) and cortisol
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levels during the day (AUCg). Immune markers, including high sensitivity C-Reactive Protein (hs-CRP) and Interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, Tumor Necrosis Factor
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(TNFa), Vascular Endothelial Growth Factor (VEGF), Interferon gamma (INFγ), Monocyte
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Chemoattractant Protein 1 (MCP-1), and Epidermal Growth Factor (EGF) were evaluated from peripheral blood samples. Results: Women with current PP reported more frequent recent stressful life events, and higher perceived stress than healthy women. They also showed an activation of the stress and immune response, with higher levels of cortisol AUCg and hs-CRP (but not of other inflammatory markers) than healthy controls. Women at-risk of PP who remained well had values on these
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measures that were intermediate between those of women with a current episode of PP and those of healthy women. Stress measures and markers of stress and immune response explained 78% of the variance of in group status between PP and healthy women, and 46% of variance of in group status between women at-risk and healthy women. Conclusion: These findings suggest that an immune-HPA axis dysregulation, together with current stress may represent an important underlying pathophysiological mechanism in the
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onset of psychosis after childbirth in vulnerable women.
Key words: Postpartum psychosis, cortisol, stressful life events, perceived stress, immune
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system, severe mental disorders
1. INTRODUCTION
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Postpartum, or puerperal, psychosis (PP) is a severe psychiatric disorder that typically manifests
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within days of childbirth in 1-2 every 1000 new mothers (Davies, 2017). PP is a psychiatric emergency that usually requires treatment in hospital, as the consequences can be devastating for both mother and child. These may include maternal suicide, neglect and increased risk of
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PP is crucial.
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harm to the infant (Sit et al., 2006). Hence, the ability to understand why some women develop
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Most episodes of PP occur within two weeks after delivery, and the single largest risk factor for PP is a personal or family history of bipolar disorder, schizoaffective disorder, or of previous postpartum psychosis episodes, which are reported in approximately 40%-50% of PP cases (Jones et al., 2014; Sit et al., 2006; Wesseloo et al., 2016). However, it remains to be established why only some women at-risk develop the disorder, while others do not. Interestingly, we recently showed for the first time that women with PP, but not those at-risk who remain well,
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show alterations in regional brain volumes and cortical areas similar to those seen in individuals with non-puerperal psychoses. These include smaller anterior cingulate gyrus, superior temporal gyrus and parahippocampal gyrus (Fuste et al., 2017). Investigating the biological risk factors for PP and their relationship with socio-environmental risk factors is crucial to advance our ability to identify the women most at-risk.
The synergistic role of both biological and socio-environmental risk factors has been integrated
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in the vulnerability-stress model, which proposes that a dysfunction of the HypothalamicPituitary-Adrenal (HPA) axis, the main system involved in the biological response to stress, as well as an underlying brain vulnerability, may increase the sensitivity of some individuals to
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stress and thus make them more likely to develop a psychotic episode under stressful circumstances. Relevant to psychosis, stressors such as childhood maltreatment, chronic stress,
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recent stressful events and perceived stress have all been found in excess in patients with these
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disorders (Mondelli et al., 2010). For example, patients with first-episode psychosis, and highrisk untreated individuals with attenuated positive symptoms, all show evidence of an activation of the biological response to stress, with higher levels of cortisol, the main hormone involved
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in the stress response. These findings suggest that a dysfunction of the HPA axis is already present at illness onset and may even precede the onset of symptoms (Andrade et al., 2016;
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Mondelli et al., 2010; Pruessner et al., 2017).
Several studies have also implicated an immune system dysfunction in psychotic disorders (Leboyer et al., 2016; Morch et al., 2016), and increased inflammatory markers (i.e., cytokines and C-reactive protein) have been consistently reported in patients with first-episode psychosis and with bipolar disorder, often together with HPA axis abnormalities (Hope et al., 2009; Mondelli et al., 2011; Mondelli et al., 2010; Potvin et al., 2008). Studying the role of the HPA
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axis in perinatal psychiatric disorders is challenging, as in pregnancy and in the postpartum period the HPA axis is normally suppressed. Still, while data on PP are lacking, evidence from studies on antenatal and postnatal depression suggest that an activation of the immune system and an inability to suppress the HPA axis play an important role in this disorder in the perinatal period ((Melon et al., 2018; Osborne et al., 2018); for a detailed review, please see, (for review (Bloch et al., 2003)). Interestingly, there is also some preliminary evidence on immune dysfunction in women with PP, who have been found to show an upregulated immune system-
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related gene expression profile, an excess of autoimmune disorders, and a failure to show the normal postpartum T cell elevation (Bergink et al., 2013; Kumar et al., 2017).
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To our knowledge this is the first study to report on the stress response in women with PP using multiple HPA axis and immune biomarkers, together with measures of life events and perceived
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stress. Based on evidence from work on psychoses unrelated to the puerperium, we
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hypothesized that: 1) women with PP would have higher cortisol levels than women at-risk who did not develop PP and healthy women in the same postpartum period; and 2) these higher cortisol levels would be associated with elevated pro-inflammatory markers and with symptom
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severity.
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2. METHODOLOGY 2.1. Design We recruited a group of 30 women with, or at-risk of, PP (see below for definition), from perinatal services of the South London and Maudsley (SLAM) NHS Foundation Trust and from the Central and North West London NHS Foundation Trust, as part of the Psychiatry Research and Motherhood Postpartum Psychosis study (PRAM-P). All women were between 18 and 41 years of age and they were all assessed in the postpartum period, on average at 14.8±10.1week
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postpartum. Women were identified as having PP (n=14, of which 4 had a history of Bipolar Disorder or previous Postpartum Psychosis) or being at-risk but well (N=16, of which 10 had a history of Bipolar Disorder, 2 of Schizoaffective Disorder (Manic type), and 4 had a family
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(n=1) or personal (n=3) history of PP. We also recruited a group of 26 healthy women (controls) from the Obstetric Services of King’s College Hospital, London, who did not have a current or
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previous history of a mental health disorder. Women with learning disabilities or those who
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were unable to communicate proficiently in English were excluded from the study. All participants were provided with detailed information about the study and written informed consent was obtained from all whom took part. The study was approved by the local Research
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Ethics Committee (10/H0807/14).
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2.2. Clinical assessment
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All women completed a structured sociodemographic and physical health schedule postpartum, which included demographic information. Women with PP had to be clinically stable in order to undertake the assessment. Clinical diagnoses were obtained using the clinical version of the Structured Clinical Interview for DSM-IV Axis I Disorders (Clinician Version) (SCID-I CV), a semi-structured interview used for the formulation of the principle diagnosis on the Axis I of DSM IV (First, 2002) which allows applying the specifier “with postpartum onset”. Psychiatric
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symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987). The PANSS consists of 30 items and the score is measured on a 7-points scale from 1 (absence of the symptom) to 7 (extreme degree). Current functioning was measured with the Global Assessment of Functioning scale (GAF) (Piersma and Boes, 1997).
Information about recent stressful life events was obtained using the List of Threatening Experiences questionnaire (Brugha and Cragg, 1990). This brief life event questionnaire
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examines the presence and the emotional impact of life stressors in the preceding six months, and includes illness or injury, death of a close friend or relative, unemployment, financial loss and loss of important relationships, measured on 3 point-scale from 1 (not too bad) to 3 (very
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bad). We measured perceived stress using the Perceived Stress Scale (Cohen, 1988). This is a self-rated questionnaire, which consists of 10-items and measures the degree to which situations
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in one's life, considering the preceding month, are appraised as stressful on a 5 point-scale,
2.3. HPA axis activity
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ranging from 0 (never) to 5 (very often true).
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We evaluated HPA activity measuring salivary cortisol. Subjects were instructed to collect saliva samples, using special Salivettes, consisting of sorbette arrows, at awakening, at 15, 30,
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and 60 minutes after awakening, at noon and at 8 pm. Subjects were instructed not to have
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breakfast or brush their teeth during the first hour of awakening, and in the 30 min before taking the sample at 12 pm and 8 pm. They were required to keep a record on a collection record form, including the time of the collection, if they had eaten or drunk before taking the sample or if they were experiencing any stressful circumstances or difficulties. Participants were required to store their samples in their domestic refrigerator and post them in a stamped addressed envelope on the following morning. On arrival at the laboratory the salivettes were frozen at
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−20 ° C. Cortisol levels were measured using ELISA. A sample tracking database for HTA purposes was completed by the researcher.
To limit the number of statistical comparisons, all HPA axis analyses were conducted using the Area Under the Curve (AUCg) of cortisol levels during the day (0 min, noon and 8 pm) and the AUC of the increase (AUCi) of cortisol levels after awakening (from 0 min to 15, 30, and 60 min after awakening). Both formulas for the calculation of the AUCs were derived from the
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trapezoid formula (Pruessner et al., 2003).
2.4. Inflammatory markers
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Blood samples were collected to measure inflammatory markers. The samples were collected into EDTA tubes and blood was processed between 30 minutes and 2 hours after venipuncture.
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Sub-aliquots of plasma were prepared for measurement of inflammatory markers. Aliquots of
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serum were immediately frozen at −80 °C pending analysis. Serum high sensitivity C-reactive protein (hsCRP) was measured using an ELISA kit supplied by PZ Cormay, Poland; the assay was analyzed in batches on the Cobas Mira (intra- and inter-assay CV were 2.96% and 3.85%
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respectively). Serum cytokine levels were measured using a cytokine chip array kit supplied by Randox Laboratories, UK; the kit employs a sandwich chemiluminescent immunoassay,
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described in our previous work (Di Nicola et al., 2013; Osborne et al., 2018). We analysed
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several immune and growth markers, including Interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL8, IL-10, Tumor Necrosis Factor (TNFa), Vascular Endothelial Growth Factor (VEGF), Interferon gamma (INFγ), Monocyte Chemoattractant Protein 1 (MCP-1), and Epidermal Growth Factor (EGF). We specifically evaluated differences in three proinflammatory markers (hs-CRP, TNFa, lL-6), and one anti-inflammatory cytokine (IL-4) that have been frequently
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reported as altered in psychoses (Leboyer et al., 2016), with a recent study reporting elevated IL-6 in women with PP (Sathyanarayanan et al., 2019)...
2.5. Statistical analyses Data were analysed using the Statistical Package for Social Sciences, Version 25.0 (SPSS 25.0). A one-way ANOVA was used to compare means of continuous variables between groups. Chisquare test was used to compare categorical variables. Correlational analyses were conducted
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using Pearson's or Spearman's correlation as appropriate, to examine the relationship between psychopathology in the postpartum, stress factors and biological measures (cortisol levels and inflammatory markers). A logistic regression model was then used to test for predictors of PP
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status. Biomarker analyses were adjusted for weeks after delivery, BMI and smoking status. The role of physical problems with pregnancy or delivery, and medications was also considered
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Bonferroni adjusted post hoc tests.
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in relation to biomarkers. The threshold for statistical significance was set at p≤0.05 with
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3. RESULTS Women with PP and women at-risk of PP did not significantly differ from healthy women (controls) in age, ethnicity, educational level or relationship status (Table 1). The mean number of weeks after delivery at the time of assessment was longer in women with PP than in women at-risk and controls; this could be accounted for by the fact that it was deemed appropriate to recruit and assess women with a current PP episode when clinically stable. Women with PP, women at-risk of PP and healthy women did not significantly differ in primiparity. There were
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no statistically significant differences in BMI or cigarette smoking between groups. Women with PP and women at risk were more likely to report physical problems with pregnancy or delivery (40% vs 50% vs 15% respectively), albeit at trend level. As expected, the severity of
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psychiatric symptoms from the PANSS was higher in women with PP and in women at-risk compared to controls, and the GAF scores were significantly lower in the women with PP and
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women at-risk compared with the healthy women (Table 1).
- Table 1 here-
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3.1. Life events and perceived stress
Details of recent stressful life events and perceived stress are shown in Table 1. Both women
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with PP and women at-risk reported more recent stressful life events compared to healthy
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controls, but the differences were larger, and statistically significant, for PP (p=0.007), while they only reached trend statistical significance for at-risk women (p=0.07) (Table 1). Both women with PP and women at-risk had significantly higher scores of perceived stress than healthy controls (p˂0.001), and again the women at-risk who remained well had scores that were intermediate between those of women with PP and the healthy controls.
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3.2. Salivary cortisol and immune markers Salivary cortisol levels during the day are shown in Figures 1 and 2, and the AUC values are presented in Table 1. An overall group difference in AUCg was observed (ANOVA, F2, 41=3.3, P=0.046), and post hoc analyses with Bonferroni correction revealed this was due to a higher AUCg in women with PP compared to the healthy controls (p=0.014) (Table 1, Fig. 1). Women at-risk who remained well had AUCg values intermediate between those of women with PP and healthy controls. As there was a difference in the number of weeks after delivery between the
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groups, we correlated the AUCg value with postpartum weeks at assessment and found that these were not correlated (r=0.03, p=0.86). We also repeated the ANOVA using weeks after delivery as a covariate, and we found that women with PP still had higher AUCg than the
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healthy controls, with the difference reaching an even higher level of significance (F1,32=5.54, p=0.026), while women at risk remained not significantly different from the controls (p=0.13).
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In addition, since women at risk and women with PP were more likely to report physical
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problems with pregnancy or delivery than healthy controls, we explored their role in explaining between-group differences in AUCg. We found that although reporting physical problems was associated with AUCg (F=4.50, P=0.046), the AUCg was still higher in women with PP than
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in women at-risk and in healthy women when physical problems were taken into account (F=4.52, p=0.017). Finally, we found no association between AUCg, and BMI, smoking, and
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use of medication (as Yes/No).
In contrast with what observed for the AUCg, we found no between-group significant differences in AUCi (Fig. 2). Of note, women with PP had higher cortisol peak levels at 30 minutes after awakening compared to healthy controls (F2,34=4.76, p=0.036), although this difference did not survive Bonferroni correction.
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- Figure 1 and Figure 2 here -
The analysis of immune markers revealed that more women with PP had a hs-CRP≥3, compared to women at-risk and healthy controls (46% vs 37% vs 15% respectively) (X2 2, 47=3.81, p=0.05). While mean levels of hs-CRP were not associated with weeks after delivery (r=0.05; p=0.73), when we included weeks after delivery in the between-group comparison of mean hs-CRP levels, women with PP still had higher hs-CRP levels than healthy women (p=0.059), with no
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difference between women at-risk and healthy women (p=0.14). We found no association between hs-CRP and BMI, smoking, physical problems with pregnancy or delivery, or
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medications.
Between-group comparisons showed no statistically significant difference between the groups
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in cytokine levels IL-4, IL-6, or TNFa (see Table 1), or in the additional immune and growth
Material, Table S1).
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markers IL-1a, IL-1b, IL-2, IL-8, IL-10, VEGF, INFγ, MCP-1, EGF (see Supplementary
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3.3. Logistic regression predicting group status
We then entered the factors that had shown between-group differences into a logistic regression
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analysis. This showed that recent stressful life events, perceived stress, and biomarkers of stress
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and immune response (AUCg and hs-CRP [dichotomized into below three or three and above]) explained 78% of the variance between PP and healthy controls, and 46% of the variance between women at-risk and healthy controls (see Table 2).
- Table 2 here -
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3.4. Stressors, symptom severity and level of functioning We then performed an exploratory analysis of the relationship between stressors that differed between groups and symptom severity and level of functioning in the combined PP and at-risk groups. We found that more recent stressful life events (r=0.40, p=0.03), higher levels of perceived stress (r=0.43, p=0.02), and a higher AUCg (r=0.45, p=0.04) were all associated with more severe symptoms (see Table 3). Interestingly, higher perceived stress scores were particularly associated with higher scores on the PANSS positive symptoms subscale (r=0.40,
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p=0.03). In contrast, only a higher AUCg was associated with poorer level of functioning as measured by the GAF (r=-0.43, p=0.05; see Table 3). There were no differences in symptoms (from PANSS) or level of functioning (from GAF) in women with hs-CRP ≥3 compared to
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women with hs-CRP <3 (F1, 27=0.27, p=0.60, and F1,26=0.85, p=0.36 respectively).
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- Table 3 here -
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4. DISCUSSION This is the first study to report on stress, and both cortisol levels and immune markers of stress response in women with postpartum psychosis (PP) and in women at-risk of PP who remain well. Our main finding is that women with PP present an immune-HPA hyperactivation, with more frequent recent stressful life events, higher perceived stress and higher cortisol levels during the day, and a higher hs-CRP than women not at risk in the postpartum period. Interestingly, the women at-risk of PP who remain well have values for these factors that are
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intermediate between those of women with PP and healthy women. Together, these factors explained a large amount of variance in the risk of having an episode of PP, accounting for 78% of the variance in group status between PP and healthy women, compared to 46% of the
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variance between women at-risk and healthy women. Perhaps not surprisingly therefore, higher cortisol levels and current stress were associated with more severe symptomatology and poorer
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functioning, suggesting stress may represent an important underlying pathophysiological
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mechanism in the onset of PP. Although the small sample size of this study makes conclusion preliminary, the fact that women at-risk who did not develop PP also showed higher stress, and immune activation than healthy controls (albeit to a lesser degree than women with PP) suggest
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that these factors are possible markers for severe mental disorders that are exacerbated in the
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context of illness onset.
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The role of stress in psychiatric disorders, and in psychosis unrelated to the puerperium is well established, but studies of the biological response to stress in PP are less than a handful. The increase in cortisol levels during the day we found in women with PP is consistent with our previous findings in patients with a first-episode psychosis (Mondelli et al., 2011; Mondelli et al., 2015; Mondelli et al., 2010) and with our own finding of an increased pituitary volume in patients with first-episode psychosis (Pariante et al., 2005). An increase in cortisol levels during
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the day has also been reported in bipolar disorder, one of the strongest risk factor for the occurrence of PP (Cervantes et al., 2001). Interestingly, as discussed by Mondelli and colleagues (Mondelli, 2014), a hyperactivity of the HPA axis may be part of the biological vulnerability to psychosis, often predating the onset of psychosis (Aiello et al., 2012). This is further supported by evidence that higher cortisol levels as well as larger pituitary gland are found in individuals who experience attenuated psychotic symptoms, and to an even greater extent in those who subsequently develop psychosis (Garner et al., 2005). Supporting its role
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in the vulnerability to psychosis, an increased sensitivity to stress has been also reported in relatives of patients with psychotic disorders, who show increased emotional reactivity to daily life stress, increased ACTH in response to stress, larger pituitary volume and smaller
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hippocampal volume (Aiello et al., 2012). Indeed, previous studies have suggested that an abnormal sensitivity to the endocrinological disturbances of the puerperium may confer
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vulnerability to PP in some women (Jones et al., 2014; Sit et al., 2006). This would be consistent
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with what seen in women with antenatal and postnatal depression, in whom we and others have reported the presence of higher diurnal cortisol secretion (Bloch et al., 2003; Melon et al., 2018). Still, even in perinatal depression reports have been mixed, possibly because of different
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definitions of depression and different measurements of HPA axis, and at different time-points
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in the.
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Our data suggest that another component of the biological response to stress, the immune system, is also dysregulated in women with PP, as indicated by the elevated levels of hs-CRP we observed in the women with PP. We and others have reported an activation of the immune system in psychosis and in bipolar disorder, with higher levels of hs-CRP and markers of inflammation, such as TNF, IL-1 and IL-6 in patients with bipolar disorder or schizophrenia (Dieset et al., 2012; Hope et al., 2009). Our finding of a possible immune dysregulation in
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women with PP are consistent with evidence from Bergink and colleagues (Bergink et al., 2013) of a glucocorticoid receptor gene α/β expression ratio reduction, with immune activation correlates in women with PP. These authors showed elevated serum pro-inflammatory cytokine IL-1β in women with PP compared to healthy women in the postpartum period, as well as 17 upregulated immune related genes. Furthermore, they found that women with PP also had a reduction of the active glucocorticoid receptor gene α and an upregulation of the inactive glucocorticoid receptor gene β expression. This pattern of GR-α downregulation, GR-β
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upregulation, and the correlation patterns of this low GR α/β ratio to the expression level of inflammation-related genes together point to the presence of steroid resistance in PP. Our findings of elevated hs-CRP in conjunction with elevated cortisol levels during the day would
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provide further initial support to the notion of steroid resistance in PP, in other words that elevated cortisol levels may fail to downregulate the immune system, as for the higher hs-CRP
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we found in women with PP.
In contrast with the scarcity of evidence in PP, several lines of evidence support the inflammatory hypothesis in postpartum depression and in psychoses not related to the
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puerperium. First, elevated levels of inflammatory markers (i.e., C-reactive protein and cytokines) have been reported in patients with antenatal and postnatal depression, and with
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affective and non-affective psychoses (Guintivano et al., 2018; Leboyer et al., 2016; Liu et al.,
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2016; Osborne et al., 2018). Consistent with this, data from genome-wide association studies (GWAS) indicate that immune-related genes may represent susceptibility genes for schizophrenia, including the major histocompatibility complex (Ripke et al., 2013; Stefansson et al., 2009). Finally, proinflammatory cytokines have been associated with smaller hippocampal volume in patients with first-episode psychosis (Mondelli et al., 2011) and shown to predict progressive thinning of the prefrontal cortex in individuals at risk for psychosis who
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go on to develop the illness (Cannon et al., 2015). The mechanisms through which inflammatory cytokines may mediate the onset of psychosis include interaction with multiple pathways such as monoamine metabolism, neuroendocrine function and synaptic plasticity (Mondelli et al., 2015; Mondelli and Howes, 2014). While the exact biological mechanisms remain unclear, we have recently suggested that an imbalance between proinflammatory and immunosuppressive cells of the immune system in the postpartum period may be a trigger for the disorder (Dazzan et al., 2018). Replicating this preliminary evidence in larger samples of
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women at risk of, and with PP will help clarify the exact immune dysregulation profile that characterises the risk for this disorder.
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Consistent with the alteration in the stress system, is also our finding that women with PP were more likely to report brief stressful life events as well as higher perceived stress levels than
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healthy controls, although there was no difference between those with PP and those who were
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at-risk and remained well. This finding of increased stress is similar to what reported in patients with first-episode psychosis, in schizophrenia, and in bipolar disorder (Aas et al., 2016;
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Mondelli, 2014; Pruessner et al., 2017).
This study has a number of strengths. This is the first study to investigate both cortisol levels
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and immune markers in women with PP and in women at-risk of PP who remain well. All
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participants were assessed with detailed clinical and biological measures, providing a unique opportunity to study markers linked to the onset of PP. Furthermore, as we collected several cortisol samples during the day at specific time-points (morning, midday and evening), we were able to capture the diurnal pattern of cortisol levels throughout the day.
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Still, there are some important limitations that should be recognised. The main limitation is the relatively small sample size of this study, and we cannot exclude that some of the associations investigated did not reach statistical significance due to lack of power, or that some findings represented false positives. As such, these should be considered initial findings that could direct further research in larger samples. Also, inflammatory markers were measured in peripheral blood which is an indirect estimate of activity within the brain. However, there is accumulating evidence indicating communication across the blood brain barrier, and of a high correlation
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between biomarkers in the cerebro-spinal fluid and the periphery (Kipnis et al., 2012; Tomasik et al., 2016). The evaluation of stress-related biomarkers at a single time point prevents us to make inferences about causality. Also, while the fact we obtained data only on one day does
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not fully follow the Psychoneuroendocrinology criteria (Stalder et al., 2016), in one of our initial studies we compared one and two-day collection of cortisol, and found that values were
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highly correlated (Mondelli et al., 2010). Indeed, we have since used this method extensively
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in patients with a range of mental disorders and in individuals experiencing stress (Ciufolini et al., 2019; Mondelli et al., 2015; Osborne et al., 2018). Another important factor is that women in the PP group were later in their postpartum period (about twenty weeks compared to twelve
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and thirteen weeks in women at-risk and healthy women respectively). We cannot rule out that this may have influenced the immune and cortisol measures, since after delivery, the
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immunologically suppressed state of pregnancy needed to induce maternal tolerance toward the
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histo-incompatible fetus shows a rebound. Similarly, since there is central suppression of hypothalamic CRH secretion in the postpartum, which may last for about 12 weeks. While the longer interval between delivery and assessment in women with PP could potentially explain the higher diurnal cortisol levels and hs-CRP seen in this group, we found no relationship between weeks after delivery and hs-CRP or cortisol levels during the day. Even when this interval was included as a covariate, the between-group differences remained significant,
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suggesting that differences in time after delivery are unlikely to fully explain our results. Finally, we cannot rule out the potential role of socio-economic factors, which were not investigated in this study and that could play a role in stress perception and response.
4.1. CONCLUSIONS Our findings provide initial evidence that stress and its biological response may play a role in the aetiology of PP and offer an interesting basis on which to conduct further investigations on
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the role of the stress and immune response in this neglected clinical population. As for other psychiatric disorders, interventions that specifically aim at stress-management, including cognitive behavioural therapy, and the development of new pharmacological approaches
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targeting the HPA axis and the immune system could also be beneficial to reducing the risk of
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postpartum psychosis in vulnerable women.
6. CONFLICT OF INTEREST
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None to declare.
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5.
7. CONTRIBUTORS
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All Authors contributed to the Manuscript.
ACKNOWLEDGEMENTS
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The research was supported by a NARSAD Independent Investigator Award to Professor P.
Dazzan. The research was also in part financially supported by the Psychiatry Research Trust, the Medical Research Foundation and the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily
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those of the NHS, the NIHR or the Department of Health. M. Aas is funded by a grant from the
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South-Eastern Norway Health Authority and a Narsad Young Investigator Award.
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Monica Aas FIGURE LEGENDS
Figure 1. Daily cortisol levels (AUCg) in women with postpartum psychosis, women at-risk for postpartum psychosis and healthy women. Figure 2. Cortisol awakenig response (AUCi) in women with postpartum psychosis, women at-risk for postpartum psychosis and healthy women. Figure 1. Daily cortisol levels (AUCg) in postpartum psychosis, women at-risk for postpartum psychosis and healthy women
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AUCg= Area Under the curve in relation to ground. Mean and standard error. ANOVA, f=3.3. p=0.046.
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Posthoc tests revealed higher AUCg in PP than in HC (p=0.014). PP=postpartum psychosis.
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Figure 2. Cortisol awakenig response (AUCi) in postpartum psychosis, women at-risk for postpartum psychosis and healthy women
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PP
Women at-risk
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Healthy women
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Timepoint 15
Timepoint 30
Timepoint 60
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AUCi= Area Under the curve in relation to increase (also called the Cortisol Awakening Response,
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CAR). Mean and standard error.
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Monica Aas Table 1. Socio-demographic, clinical characteristics and stress markers in women with postpartum psychosis (PP), women at-risk who remained well (AR), and healthy controls (HC). PP n=14 34.1±3.9 43% 93% 64% 93% 20.5±12.4 79% 27.04±5 56%
AR n=16 32.1±5.4 25% 56% 56% 69% 12.3±5.8 50% 27.43±6 75%
HC n=26 34.4±4.7 46% 81% 77% 85% 13.2±9.8 65% 25.0±3 62%
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Age (mean±SD) Ethnicity (% White British) Educational level (% Higher Education) Employment status (% Employed) Relationship status (% In a relationship) Weeks after delivery (mean±SD) Parity (% Primiparity) BMI (mean±SD) Cigarette smoking, yes (%) Physical problems with pregnancy or 40% 50% 15% delivery, yes (%) PANSS total score (mean±SD) 39.9±5.2 36.7±7.7 30.8±1.8 GAF score 73.4±16.8 79.9±15.7 97.9±4.7 BLE score (mean±SD) 3.5±3.4 2.2±3.2 0.7±1.7 PSS score (mean±SD) 19.0±6.2 16.0±7.7 8.6±6.7 AUCg (mean±SD) 59.1±38.9 46.3±18.5 36.8±13.9 AUCi (mean±SD) 102.0±254.2 77.4±246.8 56.4±216.5 hs-CRP (mean±SD) 3.35±3.24 3.31±3.12 1.58±1.17 hs-CRP ≥3 (%) 46% 37% 15% TNFa (mean±SD) 2.03±0.90 2.16±0.69 1.75±0.63 IL-6 (mean±SD) 1.33±0.93 1.45±1.33 1.46±1.90 IL-4 (mean±SD) 3.01±1.93 2.71±1.12 2.45±0.53 PANSS: Positive and Negative Syndrome Scale; BLE: Brief Life Events; PSS: Perceived Stress Scale; AUCg: Area Under the curve in relation to ground (Daily cortisol levels); AUCi: Area Under the curve in relation to increase (also called Cortisol Awakening Response, CAR); BMI: Body Mass Index; TNF: Tumor Necrosis Factor; IL: InterLeukin; hs-CRP: High Sensitivity C-Reactive Protein. One woman with PP had missing data on PSS, and two had missing data for GAF. Four women with PP, 4 women at-risk and 4 healthy women had missing data on AUCg. Four women with PP, 4 women at-risk and 3 healthy women had missing data on AUCi. One woman with PP, 1 woman at-risk and 6 healthy women had missing data for CRP. Five healthy women had missing data on TNFa, IL-6 and IL-4. Bonferroni post-hoc analyses: a =P≤0.05. PP vs HC b = P≤0.05. AR vs HC c = P≤0.05. PP vs AR Table 2. Multiple Logistic Regression comparing women with postpartum psychosis (PP), women atrisk who remained well (AR) and healthy controls (HC).
PP versus HC
AR versus HC
(R squared)
(R squared)
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0.12
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2 model: BLE+PSS
0.59
0.31
3rd model: BLE+PSS+AUCg
0.69
0.37
4th model: BLE+PSS+AUCg+hs-CRP
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0.46
1 model: BLE
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Signific
F=1.3, p χ2= 7.0, p χ2=10.8, p χ2=4.2, p χ2=3.2, p F=3.4, p χ2=2.7, p F=1.6, p χ2=4.8, p
χ2=5.82, p
F=16.7, p F=21.2, p F=4.3, p= F=11.7, p F=3.3, p= F=0.1, p F=0.94, p χ2=3.81, p F=1.70, p F=0.50, p F=0.24, p
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BLE: Brief Life Events; PSS: Perceived Stress Scale; AUCg: Area Under the curve in relation to ground (Daily cortisol levels); hs-CRP: high sensitivity C-Reactive Protein dichotomized into <3 or 3.
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Monica Aas Table 3. Correlation between severity of symptoms and level of functioning, stress measures and hsCRP levels in women with PP and women at-risk who remained well.
Level of functioning (GAF)
Brief life events
r=0.40; p=0.03*
r=-0.33; p=0.09
Perceived stress
r=0.43; p=0.02*
r=-0.18; p=0.38
AUCi (cortisol awakening response)
r=-0.15; p=0.50
r=0.05; p=0.83
AUCg (daily cortisol)
r=0.45; p=0.04*
r=-0.43; p=0.05*
hs-CRP
r=-0.06; p=0.75
r=0.10; p=0.62
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Severity of symptoms (PANSS)
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GAF: Global assessment of Functioning Scale; PANSS: Positive and Negative Syndrome Scale; AUCg: Area Under the Curve in relation to ground (daily cortisol levels); AUCi: Area Under the Curve in relation to increase (also called Cortisol Awakening Response, CAR); hs-CRP: high sensitivity C-Reactive Protein. * Significance = p ≤ 0.05.
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