Accepted Manuscript

Title: Bipolar affective disorder and borderline personality

disorder: Differentiation based on the history of early life
stress and psychoneuroendocrine measures

Authors: Angela Kaline Mazer, Anthony J. Cleare, Allan H.

Young, Mario F. Juruena

PII: S0166-4328(17)30363-7
DOI: https://doi.org/10.1016/j.bbr.2018.04.015
Reference: BBR 11381

To appear in: Behavioural Brain Research

Received date: 1-3-2017

Revised date: 30-3-2018
Accepted date: 11-4-2018

Please cite this article as: Mazer AK, Cleare AJ, Young AH, Juruena MF, Bipolar
affective disorder and borderline personality disorder: Differentiation based on the
history of early life stress and psychoneuroendocrine measures, Behavioural Brain
Research (2010), https://doi.org/10.1016/j.bbr.2018.04.015

This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. 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.
Bipolar affective disorder and borderline personality disorder: Differentiation

based on the history of early life stress and psychoneuroendocrine measures.

Angela Kaline Mazer1, Anthony J. Cleare2, Allan H. Young2, Mario F. Juruena1,2

1
Department of Neuroscience and Behavior, , University of Sao Paulo, Sao Paulo,

T
Brazil;

IP
2
Centre for Affective Disorders, Department of Psychological Medicine, Institute of

R
Psychiatry, Psychology and Neuroscience-King’s College London, London, UK

SC
Abstract
U
Introduction: Borderline Personality Disorder (BPD) and Bipolar Affective Disorder
N
(BD) have clinical characteristics in common which often make their differential
diagnosis difficult. The history of early life stress (ELS) may be a differentiating factor
A
between BPD and BD, as well as its association with clinical manifestations and
specific neuroendocrine responses in each of these diagnoses. Objective: Assessing
M

and comparing patients with BD and BPD for factors related to symptomatology,
etiopathogenesis and neuroendocrine markers.
Methodology: The study sample consisted of 51 women, divided into 3 groups:
ED

patients with a clinical diagnosis of BPD (n = 20) and BD (n = 16) and healthy controls
(HC, n = 15). Standardized instruments were used for the clinical evaluation, while the
history of ELS was quantified with the Childhood Trauma Questionnaire (CTQ), and
classified according to the subtypes: emotional abuse, physical abuse, sexual abuse,
PT

emotional neglect and physical neglect. The functioning of the hypothalamic-pituitary-

adrenal (HPA) axis was evaluated by measuring a single plasma cortisol sample.
Results: Patients with BPD presented with more severe psychiatric symptoms of:
E

anxiety, impulsivity, depression, hopelessness and suicidal ideation than those with
BD. The history of ELS was identified as significantly more prevalent and more severe
CC

in patients (BPD and BP) than in HC. Emotional abuse, emotional neglect and physical
neglect also showed differences and were higher in BPD than BD patients. BPD
patients had greater severity of ELS overall and in the subtypes of emotional abuse,
A

emotional neglect and physical neglect than BD patients. The presence of ELS in
patients with BPD and BP showed significant difference with lower cortisol levels when
compared to HC. The endocrine evaluation showed no significant differences between
the diagnoses of BPD and BD. Cortisol measured in patients with BPD was
significantly lower compared to HC in the presence of emotional neglect and physical
neglect. A significant negative correlation between the severity of hopelessness vs
cortisol; and physical neglect vs cortisol were found in BPD with ELS. The single
cortisol sample showed a significant and opposite correlations in the sexual abuse
diagnosis-related groups, being a negative correlation in BD and positive in BPD.
Discussion: Considering the need for a multi-factorial analysis, the differential
diagnosis between BPD and BD can be facilitated by the study of psychiatric
symptoms, which is more severe in the BPD patients with a history of early life stress.
The function of the HPA axis assessed by this cortisol measure suggests differences
between BPD and BP with ELS history.
Conclusion: The integrated analysis of psychopathology, ELS and neuroendocrine
function may provide useful indicators to differentiate BPD and BD diagnoses. These
preliminary data need to be replicated in a more significant sample with a better
assessment and multiple assessments of the HPA axis activity.

Key words: Borderline Personality Disorder; Bipolar Affective Disorder; Early Life

T
Stress; Hypothalamic-pituitary-adrenal (HPA) Axis; Cortisol; Abuse and Neglect

IP
Introduction:

R
SC
The concept of Borderline Personality Disorder (BPD), as defined in the DSM-III

U
in 1980, emerged from Gunderson and Singer´s review [1] that identified alleged
N
descriptors in the areas of dysphoric affect, impulsive action, interpersonal
A
relationships, quasi-psychotic cognitions and poor social adjustment. By 1994, when
M

DSM-IV was completed, more than 300 studies on BPD had been conducted and most

of the revisions in the diagnostic criteria represented refinements that were intended to
ED

increase the distinction between BPD and similar disorders, such as Bipolar Affective

Disorder (BD) and Narcissistic Personality Disorder [2]

PT

Nevertheless, the differentiation between BPD and BD remains a challenge in

E

the clinical setting, with the difficulty in establishing the differential diagnosis between
CC

these disorders mainly due to the clinical characteristics they have in common,

especially emotional instability and impulsivity [3, 4]. In addition, comorbidity is

A

common: approximately 20% of bipolar II patients are diagnosed with comorbid BPD,

compared to 10% of bipolar I patients [5,6]. Also, in this context, the concept of the

bipolar spectrum has been proposed to expand the BD diagnosis to include a wider

range of syndromes, notably BPD [7-9].

 To help determine the differential diagnosis between BPD and BD, the

relationship between these disorders has been analyzed under several aspects:

evaluation of co-occurrence, familial prevalence, response to medication,

phenomenology, longitudinal course and aetiology [10-13]. The results of these

studies provide sometimes controversial and inconclusive data, but recent evidence

indicates that biological factors and psychosocial factors may be more significant in

T
BPD than in BD [14].

R IP
SC
Association between early stress and BD and BPD diagnoses

U
Although we consider the aetiology of mental disorders generally as multi-factorial,
N
genetic factors and the occurrence of traumatic events in the life history of patients are
A

identified as the primary factors associated with vulnerability to developing a

M

psychiatric disorder [15-21]. Evidence from the literature demonstrates a positive

ED

association between early life stress (ELS) and the development of both BPD and BD

[22-25].In addition, many subsequent clinical and neurobiological changes have been
PT

linked to the occurrence of ELS. Suicidal behavior and hallucinations are linked with

ELS in both BPD [26,27] and BD [28-30]. Additionally, in BPD, a history of ELS is
E
CC

associated with changes in the function of the HPA axis [31], the volume of the

hippocampus and amygdala, as well as the cerebral blood flow in the recall of
A

traumatic memories [32]. In BD, the literature has highlighted associations with

changes in BDNF levels [33] and a worse clinical course, measured by

hospitalisations, rapid cycling, depressive episodes, and quality of life [34-37].

However, assessments of different types of early stress and their respective

associations with BD and BPD diagnoses are controversial and show conflicting
results. While some results indicate an association of sexual abuse history with the

development of BPD symptoms [18,38,39], other studies report that sexual abuse is

not significantly associated with an increased risk for BPD [40-42]. Additionally, other

studies have highlighted the role of emotional abuse, as a particular type of early

stress, finding a more consistent association with both diagnoses [26, 41,43].

Specifically considering BPD [38], reported borderline symptoms were significantly

T
correlated with physical abuse but not with neglect.

R IP
SC
Functioning of the hypothalamic-pituitary-adrenal axis and response to stress
U
The endocrine response to stress is characterised by the activation of the HPA
N
axis and associated with effects of cortisol; these are beneficial when related to an
A

acute action, but may have deleterious pathological consequences during chronic
M

activation [44, 45].

ED

Given these actions in response to stress, the link between trauma in childhood

and psychopathology in adulthood may be related to the HPA axis, which remains
PT

unstable, hyper-stimulated, vulnerable or dysfunctional after being hyperactive during

the development process, possibly due to the transcriptional/ epigenomic mechanisms

E
CC

that alter its functioning [46]. Thus, the occurrence of traumatic events in childhood

impacts the efficacy with which an individual can respond to stress in the long term, as
A

a result of the modifications observed within neuroendocrine circuits.

Previous literature has identified that the risk of psychopathology in adults is

related to a complex interaction of multiple factors associated with the HPA axis -

reflecting the range of individual vulnerability observed in response to various types of

stress impacting on the development of mental disorders. The identification of a stress

biomarker, such as cortisol, could provide useful information about the diagnoses of

BPD and BD, and aid in the distinction of etiopathogenic aspects related to the history

of early life stress, manifested by neuroendocrine changes. Thus, we evaluated and

compared patients with the diagnoses of BPD and BD, seeking to identify differential

indicators between these disorders related to the symptoms of anxiety, impulsivity,

depression, hopelessness, suicidal ideation and mania; the history of early life stress;

T
and the functioning of the HPA axis.

R IP
SC
Methodology

U
The methodology used a cross-sectional design, from a single psychometric and
N
neuroendocrine evaluation of 51 participants who either had a clinical diagnosis of
A
BPD (n=20) or BD (n=16), or were healthy control volunteers (n=15). Prior to
M

enrolment, participants underwent screening interviews by two Senior Psychiatrists

(AKM and MFJ) using the Structured Clinical Interview for DSM-IV Axis I Disorders
ED

(SCID-I) for the major DSM-IV diagnoses and the SCID-II for Personality Disorder
PT

diagnoses, to confirm diagnoses in accordance to the DSM criteria. The severity of

psychiatric symptoms, such as anxiety, depression, hopelessness and suicidal

E

ideation, and impulsivity, was assessed through Beck’s: Anxiety Inventory (BAI),
CC

Depression Inventory-II (BDI-II), Hopelessness Scale (BHS) and Suicidal Ideation

Scale (BSI) respectively. Additionally, the Young Mania Scale was used as a measure
A

for manic symptomology. The history of early life stress was investigated by the

Childhood Trauma Questionnaire (CTQ), and classified according to the subtypes:

emotional abuse, physical abuse, sexual abuse, emotional neglect and physical

neglect.
 The inclusion criteria specified patients aged between 18 and 60 years,

presenting with a clinical diagnosis of BD or BPD, according to DSM-IV-TR criteria and

currently receiving psychiatric treatment in the psychiatry services of the General

Hospital of School of Medicine of the University of Sao Paulo in Ribeirao Preto. All

eligible patients were clinically screened for comorbidities and general medical

conditions, according to the SCID-I and II. Both patients with BD and BPD were

T
evaluated whilst in a euthymic state, according to Young Mania Scale (YMS) and

IP
DSM-IV current episode.

R
The control group was composed of healthy volunteers (HC) with a minimum age of 18

SC
years, and without a diagnosed psychiatric disorder and no history of early life stress

(ELS). Many of the recruited HC participants included hospital staff, students and
U
members of the local community, and prior to enrolment had to complete a detailed
N
clinical history, in addition to a diagnostic evaluation, to exclude any psychiatric
A

disorders or use of psychotropic medications.

M

Exclusion criteria for patients were defined by: the presence of comorbidities
ED

with either BPD or BP, use of steroids, pregnancy or lactation, serious health

conditions or general medical conditions judged likely to underlie cognitive, emotional

PT

and behavioural changes. Additionally, patients were excluded if they were using

psychoactive substances not prescribed for psychiatric treatment in the last month. For
E
CC

ethical and practical reasons, it was not possible to evaluate patients in a medication-

free state.
A

For the control group, individuals with a diagnosis of a mental disorder or other

general medical condition that could present with psychiatric symptoms were excluded

from the study.

To measure endocrine activation, fasted blood samples were collected by

venipuncture n the early hours of the morning (8am), in order to measure plasma
basal cortisol. Participants were instructed avoid engaging in physical activities,

stressful situations, consuming large meals prior to the examination and, to the best of

their ability, respect the usual sleeping routine. The collected blood samples were

stored under appropriate laboratory conditions before being Plasma cortisol was

analyzed using a radioimmunoassay technique (RIA) standardized in the Laboratory of

Endocrinology of HC-FMRP-USP. The sensitivity of the assays and intra- and inter-

T
assay coefficients of variation were: 1.2 μg/dL, 2.8% and 10.4% respectively. Plasma

IP
cortisol measurements are expressed as mcg/ml within the results.

R
The analysis of data was performed using the SPSS software (Statistical

SC
Package for the Social Sciences, version 15.0). A p value of <0.05 was used to define

significance throughout.
U
The socio-demographic, clinical, psychometric and hormonal data were
N
analysed using descriptive statistics. Statistical analyses were performed using the
A

Student's t- test for continuous data and chi-square (2) for categorical data. T-test
M

and analysis of variance (ANOVA) followed by the Tukey's posthoc test was used for
ED

multiple comparisons in the groups.

PT

Results
E

The socio-demographic profile of the study sample was delineated from the
CC

identification of variables related to age, marital status, children, schooling and

employment status. Whereas, the clinical characterisation refers to severe medical

A

conditions, duration and forms of treatment (drug therapy and psychotherapy). This

data is presented in Table 1, distributed by the diagnostic groups, BD, BPD, and HC.

INSERT TABLE 1

Assessment of psychiatric symptomatology

 Borderline patients presented with more severe symptoms of depression (BDI),

suicidal ideation (BSI), hopelessness (BHS), anxiety (BAI) and impulsivity (BIS) in

comparison to the bipolar patients; however, manic symptoms (YMS) were higher in

patients with BD. Both patients with BD and BPD were evaluated in euthymia

according to YMS and DSM-IV current episode. See details in Table 2

T
IP
INSERT TABLE 2

R
SC
Assessment of the early stress history U
N
A
The assessment criteria defining the presence of a significant history of ELS was a
M

moderate to severe score according to the Childhood Trauma Questionnaire (CTQ). In

this way, the participants of each group were subdivided between those without ELS
ED

and with ELS. As can be seen in the figure 1, the presence of ELS predominated the

diagnostic groups, BD and BPD; however, it was not identified in the control group
PT

(HC).
E
CC

INSERT Figure 1
A

The comparison of the diagnostic groups, in relation to the presence of ELS,

revealed a greater occurrence in the BPD group (80%) compared to the BD (56%),

but without statistical significance (n = 36; x2= 2.36, df = 1, p = 0.124).

The quantitative assessment of the ELS history with the CTQ shows results that

differentiate BPD, BD and the HC group, as shown in Table 3.

 INSERT TABLE 3

The mean total and individual subtype CTQ scores across all three participant

conditions are presented in Figure 2.

These results suggest that within our sample, participants with BPD had

experienced a greater severity of ELS, with notably higher scores in emotional abuse,

T
IP
emotional neglect and physical neglect.

Additionally, we were able to observe, significant correlations in anxiety,

R
depression, and suicidal ideation with general early life stress, sexual abuse and

SC
physical neglect.

INSERT Figure 2
U
N
The severity of symptoms evaluated by the BAI, BDI and BSI scales in the BD
A
group were positively correlated with the severity of early stress in relation to sexual
M

abuse and physical neglect. We found a strong correlation between the measures of

anxiety and physical neglect (r = 0.979 ; p <0.001), depressive symptoms and early
ED

general stress (r = 0.770 ; p = 0.015); depressive symptoms and history of sexual

abuse (r = 0.911; p = 0.001); depressive symptoms and physical neglect (r = 0.750; p

PT

= 0.020); suicidal ideation and history of early general stress (r = 0.715; p = 0.030);
E

suicidal ideation and history of sexual abuse (r = 0.939; p <0.001) and suicidal ideation
CC

and physical neglect (r = 0.777; p = 0.014).

Other significant correlations between symptoms and the history of early life
A

stress were evaluated in the BD group. The severity of sexual abuse was positively

correlated with symptoms of depression (r = 0.851; p <0.001); sexual abuse and

suicidal ideation (r = 0.647; p = 0.007). Likewise, physical neglect had positive

correlations with depressive symptoms (r = 0.698; p = 0.003); and physical neglect

with anxiety symptoms (r = 0.954; p <0.001), in the BD group.

Endocrine evaluation

Morning plasma cortisol levels differed significantly between groups, with

T
IP
cortisol levels lower in both the BD and BPD groups in comparison to controls (Figure

3). However, there was no difference between the two patient groups. The BD group

R
showed the numerically lowest plasma cortisol levels and also showed lower variance

SC
(s.d.= 3.2), with a small mean difference (1.14 mcg / ml) in relation to the BPD group.

U
Conversely, the control group had the highest and most varied levels (s.d.= 9.9) of
N
plasma cortisol.
A
Figure 3 presents the results of cortisol compared to the average values
M

amongst the groups.

ED

INSERT Figure 3
PT

Correlations between psychometric measures and cortisol

E
CC

Correlations between psychometric measures and cortisol were calculated in

the whole BPD group for the severity of symptoms. We observed a strong negative
A

correlation between hopelessness, evaluated by BHS, and plasma cortisol (r = -0.716

and p <0.001), and a moderate negative correlation between suicidal ideation,

assessed by BSI, and cortisol (r = - 0.456 and p = 0.043).

 We found a strong negative correlation between the severity of Hopelessness

assessed by the BHS and dosage of plasma cortisol in Borderline Personality Disorder

patients with history of ELS (n=16. r=-0,709; p=0,002), see figure 4.

INSERT Figure 4

T
In the BD patients with a history of ELS, no significant correlation was seen between

IP
the psychometric measures (depression, hopelessness, anxiety, impulsivity and
suicide ideation) and cortisol.

R
SC
In order to explore if hormonal differences were observed in participants who

had experienced different subtypes of ELS, were further analysed these results
U
highlighting that in just one plasma sample, significant differences were observed
N
between cortisol levels when comparing the controls with the diagnostic groups (BD
A

and BPD). Additionally, the presence of ELS in patients with BPD and BP showed
M

significantly lower cortisol levels compared to controls.

ED

Moreover, we found a negative correlation between the severity of Physical Neglected

reported by the CTQ and dosage of plasma cortisol in borderline patients with history
PT

of ELS (n=16. r=-0,538; p=0,032), see figure 5.

INSERT Figure 5
E
CC

Cortisol measured in patients with BPD was significantly lower when compared

to the control group in the emotional neglect (p=0.04) and physical neglect (p=0.01)
A

subtypes.

The cortisol measured in patients with BD was significantly lower when

compared to control group in patients without experience of sexual abuse vs. controls

(p=0.04) and in BD without emotional (p=0.04) and without physical (p=0.04) neglect

vs controls; and in patients with BPD without sexual abuse (p=0.02) vs controls.
Regarding physical and emotional abuses, we did not find significant differences

(p>0.05) between patients in the diagnostic groups (BD or BPD) and healthy controls.

From the results obtained with the psychometric evaluations and cortisol levels

significant correlations were observed among BD and BPD and history of sexual

abuse.

In bipolar patients, the severity of the sexual abuse showed a moderate

T
negative correlation with the plasma cortisol (r = -0.509; p = 0.044). Sexual abuse and

IP
cortisol were positively correlated in patients with BPD (r = 0.467; p = 0.038), and are

R
represented in the Figures 6 and 7, respectively.

SC
INSERT Figure 6

U
We did not find significant correlations in either BD or BPD patients between
N
plasma cortisol level and other subtypes of early stress, including emotional abuse,
A
physical abuse, emotional neglect and physical neglect (p>0.05).
M

INSERT Figure 7
ED
PT

Discussion

Clinical diagnoses that rely solely on symptoms render themselves at risk for
E

misdiagnoses. A prime example is the common misdiagnosis between borderline

CC

personality disorder and bipolar disorder, due to the sharing of multiple similar clinical

features. However, as identified in the aforementioned results, the analysis of

A

psychopathology, ELS and neuroendocrine function, provides some clear

differentiating features that may be used to improve clinical diagnoses.

Through the measurement of basal cortisol, our findings suggest that there are

identifiable variations in the HPA axis functioning in patients with either BPD or BD and
histories of ELS; thus, supporting the previous literature associating ELS with

dysregulation of hormonal response(s).

The assessment of psychiatric symptoms in these patients indicates a higher severity

of depressive, suicidal ideation, hopelessness, anxiety and impulsivity symptoms in

Borderline Personality Disorder , thus suggesting that they are experiencing more

T
severe distress compared to bipolar patients. Another possibility for the more

IP
significant severity reported by the patients with BPD regardless of the stage or course

of the disease (which involves symptoms such as anxiety and depression [25,47,48],

R
SC
impulsivity [4,6,49], and suicidality [10]) is related to differences in treatment phase or

approach.

U
The prevalence of ELS was considered present if there was a moderate to severe
N
score obtained from the CTQ. For both diagnosis-related groups, the majority of
A
patients had a history of ELS according to this criterion. However, this was observed in
M

a higher proportion in the BPD group in comparison to the BD and HC groups, as also
ED

seen in previous literature suggesting a stronger association (60-80%) in patients with

BPD than BD (50%) [10, 50-55].

PT

Besides presenting higher prevalence, the group with BPD showed greater severity of
E

early life stress in general . Furthermore, emotional abuse, emotional neglect and
CC

physical neglect predominated in BPD, differentiating it from BD. There is currently no

similar literature comparing the history of different types of ELS between bipolar and
A

borderline personality disorder. Although it is suggested that there may be differences

between the subtype of trauma in childhood or vulnerability to such experience among

these diagnoses, the divergent evidence is clear in literature reviews [10, 56].
A comparative study between patients with BPD and Major Depressive Disorder

(MDD) observed no difference between the levels of reported physical abuse between

patients and a healthy control group and no difference in the severity of ELS was

observed between the two diagnoses assessed (BPD and MDD) [57]. Another study

evaluating patients with BPD and MDD found differences in regards to the emotional

abuse and emotional neglect subtypes, but not in the sexual abuse and physical

T
neglect scores [58].

IP
Within our BPD and BD sample, physical and sexual abuse were present only up to a

R
SC
moderate severity, with no difference between the diagnosis-related groups, and no

difference compared to the control group for sexual abuse. Thus, although these forms

U
of maltreatment during childhood are regarded as the most often recognized and
N
disclosed, they proved unrepresentative of the reality of early stress as a whole to
A
which patients were exposed. Instead, other aspects of early life stress seem to be
M

more significant: emotional abuse, emotional neglect and physical neglect [59].

Although it is reported that the sexual abuse is a factor associated with the
ED

development of several mental disorders, especially BPD and BD [38, 39, 60, 61], this

association is controversial and not supported by other studies [40-42, 62]. Similarly,
PT

there are disagreements about the role of physical abuse in the development of these
E

disorders [43, 63,64]. Therefore, it is important to emphasize the necessity of

CC

considering fully all types of ELS in mental health evaluations and developing a

perhaps less stereotypical view of childhood trauma, such as viewing violence in just a
A

sexual and/or physical form.

Although less studied, these other forms of abuse and emotional neglect are

suggested to significantly influence the development of the neuroendocrine systems

and the incidence of psychopathology. This is supported by rodent studies, where we

are able to observe sensitisation of the HPA axis in response to psychological stress,

but not in response to physical stress [65]. Moreover, comparative studies suggest

that, compared to other types of childhood trauma, emotional abuse and neglect are

the most significant predictors of psychopathology in adulthood [35]. Emotional abuse

is most frequently associated with personality disorders [56], whereas emotional

neglect has been associated with persistent effects on the psychological and

T
neurobiological constitution, such as low self-esteem, problems in interpersonal

IP
relationships, depressive and anxiety symptoms, all of which may imply a higher risk of

R
developing a personality disorder [56, 66-70] and in BD is also associated with a more

SC
unfavorable course [71].

U
By measuring plasma basal cortisol, we were able to obtain a measure of the
N
functioning of the HPA axis, with our results suggesting a more impaired functioning in
A
both BPD and BD in comparison to HC as seen in the lower cortisol concentrations
M

recorded. Regarding the cortisol profile in BPD, hypoactivity of the HPA axis, similar to

the results observed in our study, is reported in the literature [72,73]. On the other
ED

hand, elevated basal cortisol levels have also been observed, which has previously

been linked to a suppressed inhibitory feedback of the HPA axis [74], and comorbid
PT

depression [75].
E

Regarding BD, these results contrast with some parts of the literature that indicate
CC

hyperactivity of the HPA axis in bipolar patients, irrespective of their current mood

state [76-83]; history of suicidal behaviour [84]; and/or the age of onset of the first
A

episode [85]. These data suggested that these neuroendocrine changes may indicate

a genetic vulnerability factor (endophenotype) to BD [86-88].

However, in a study to evaluate naïve patients experiencing their first manic episode,

reduced plasma cortisol levels were observed when compared to controls, which is
consistent with the findings of our sample. In this study, measurements of plasma

cortisol were correlated in diverse ways to mood state, with levels lower in the

presence of euphoria and increased in the presence of irritability [89]. Furthermore,

normal cortisol levels were reported in another study [90]. Additionally, similar finding

was identified in patients with BD without a history of suicidal behavior or earlier age of

onset [84,85].

T
IP
Correlational analysis between the types of ELS and cortisol presents enlightening

results. Thus, it was observed that plasma cortisol levels and sexual abuse were

R
SC
correlated in both diagnostic-related groups, but in opposite ways. Thus, in BPD, the

level of cortisol was positively correlated with sexual abuse, while the correlation was

U
negative in BD, i.e., higher levels of cortisol are associated with lower scores of sexual
N
abuse in this group. Thus, the results of our study indicate that in BPD patients, the
A
history of sexual abuse could stimulate the functioning of the HPA axis consistent with
M

reports in the literature [31]; while in patients with BD, a more inhibitory response is

observed. However, it is essential to consider that sexual abuse in borderline

ED

personality and bipolar patients was identified as mild or at minimal levels of severity,

as discussed earlier. This might indicate that even when the reported severity of
PT

sexual abuse is not severe, based on normative CTQ scores, it may still affect the
E

neuroendocrine profile of these subjects significantly.

CC

Some studies on the association between history of ELS, and the functioning

of the HPA axis, highlight the relevance of identifying the subtype of the stressor .
A

However, these studies show varying and inconsistent results, besides being not

specific to, and comparative between, the diagnoses of BPD and BD. There is

evidence to indicate an association of sexual abuse with hyperactivation of the HPA

axis [91], and emotional abuse with decreased cortisol reactivity [92], besides reports
of an association between emotional neglect and physical abuse and low cortisol

levels [91-93]. In relation to these data in the literature, our findings are in agreement

with the role of sexual abuse in the hyperactivation of the HPA axis in borderline

personality patients. Lee et al. conducted a study on BPD patients with a history of

ELS, using the same instruments used in our study, and identified a pattern of

reduced functioning of the HPA axis (decreased levels of cortisol) correlated with the

T
emotional neglect subtype [94,95].

IP
However, our data are preliminary and have some limitations and should be

R
SC
interpreted with caution. We have assessed a small sample of 51 subjects, with just 16

BD (31%), 20 BPD (39%) and 15 healthy controls (30%). This small sample size limits

U
the confidence with which we can conclude there is an opposite direction correlation
N
of cortisol and CTQ sexual abuse between the BPD and BP groups. Another aspect
A
that should be carefully considered is that only one sampling of plasma cortisol was
M

taken. A single cortisol measure has been described in some studies in the past as

correlating of HPA axis activity [96,97]; however, most studies have at least taken two
ED

or three samplings, or assessed on two or more days, in an attempt to get a more

reliable measurement of endogenous cortisol levels and HPA axis function [98, 99, for
PT

review see 100].

E

As mentioned before, the baseline functioning of the HPA axis could be influenced in
CC

several ways, and respond in different ways according to each subtype of ELS. In

addition, our results identified that HPA axis functioning, as measured by plasma
A

cortisol, also varies when comparing patients with BP and BPD. For instance, patients

with BD showed lower plasma cortisol as the severity of sexual abuse increased,

whereas the opposite pattern held in BPD patients. Additionally, a negative association

was identified between emotional neglect and physical neglect and plasma cortisol
levels in BPD patients. These differences suggest that with an understanding of a

patients’ specific ELS history, we could use biomarkers, such as cortisol, to further

support and improve the accuracy of either a BPD or BP diagnosis, due to these

unique and differential biological presentations. However, these findings are still

preliminary and, thus, would need further evaluation and replication, in a larger

sample, to further assess differences in HPA axis activity in BPD and BP before they

T
could be implemented in clinical settings.

R IP
Acknowledgements

SC
To editor, referees, Martha Bourne and Bartlomiej Pliszka for their review.
Funding: This work was supported by Academy of Medical Sciences/Royal
Society,UK (MF Juruena).
Conflicts of Interest: MF Juruena Honorary Consultant at South London and
U
Maudsley NHS Foundation Trust (SLaM-NHS UK) and at University of Sao Paulo.
Professor AH Young is the Director of the Centre for Affective Disorders and is
N
supported by the National Institute for Health Research (NIHR); Biomedical Research
Centre (BRC) at SLaM-NHS UK IoPPN, King's College London. Professor AJ Cleare is
A
supported by NIHR, BRC and SLaM-NHS UK.The views ex- pressed are those of the
authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
M

MF Juruena has within the last year received honoraria for speaking from GSK,
Lundbeck and Pfizer AJ Cleare has within the last 3 years received honoraria for
lectures or consulting from Astra Zeneca, Lundbeck, Livanova, Janssen & Allergan,
ED

and a research grant from Lundbeck. AH Young received honoraria for lectures and
advisory boards for all major pharmaceutical companies with drugs used in affective
and related disorders. Investigator-initiated studies from AZ, Eli Lilly and Lundbeck. A
PT

Mazer has no conflicts of interest to declare. Only the authors were involved in the
study design and preparation of this report.
E
CC
A
References

1. Gunderson, J.G.; & Singer, M.T. (1975). Defining borderline patients: an overview.
American Journal of Psychiatry, 132(1), 1-10.
2. Skodol, A.E.; Gunderson, J.G.; Pfohl, B.; Widiger, T.A.; Livesley, W.J.; & Siever, L.J.
(2002). The Borderline Diagnosis I: Psychopathology, Comorbidity, and Personality
Structure. Biological Psychiatry, 51, 936–950.
3. Coulston, C.M.; Tanious, M.; Mulder, R.T.; Porter, R.J.; & Malhi, G.S. (2012). Bordering
on bipolar: The overlap between borderline personality and bipolarity. Australian and
New Zealand Journal of Psychiatry, 46, 506-521.
4. Benazzi, F. (2006). A relationship between bipolar II disorder and borderline

T
personality disorder? Progress in Neuro-Psychopharmacology & Biological Psychiatry,

IP
38, 1022–1029.
5. Ruggero, C.J.; Zimmerman M.; Chelminski I.; & Young D. (2010). Borderline personality
disorder and the misdiagnosis of bipolar disorder. Journal of Psychiatric Research, 44,

R
405-8.

SC
6. Paris, J.; Gunderson, J.; & Weinberg, I. (2007). The interface between borderline
personality disorder and bipolar spectrum disorders. Comprehensive Psychiatry, 48,
145–154.
7. Angst, J.; & Gamma, A. (2002). A new bipolar spectrum concept: a brief review. Bipolar
Disorder, 4, 11-14.
U
N
8. Akiskal, H.S.; Chen, S.E.; Davis, G.C. et al. (1985). Borderline: an adjective in search of a
noun. Journal of Clinical Psychiatry, 46, 41-48.
A
9. Akiskal, H.S. (2004). Demystifying borderline personality: critique of the concept and
unorthodox reflections on its natural kinship with the bipolar spectrum. Acta
M

Psychiatrica Scandinavica, 110, 401-407.

10. Basset, D. (2012). Borderline Personality Disorder and Bipolar Affective Disorder.
Spectra or Spectre? A Review. Australian and New Zealand Journal of Psychiatry, 46(4),
ED

327-39.
11. Renaud, S.; Corbalan, F.; & Beaulieu, S. (2012). Differential diagnosis of bipolar
affective disorder type II and borderline personality disorder: analysis of the affective
dimension. Comprehensive Psychiatry, 53(7), 952-61.
PT

12. Wilson, S.T.; Stanley, B.; Oquendo, M.A.; Goldberg, P.; Zalsman, G.; & Mann, J.J.
(2007). Comparing impulsiveness, hostility, and depression in borderline personality
disorder and bipolar II disorder. Journal of Clinical Psychiatry, 68, 1533-9.
E

13. Gunderson, J.G.; Weinberg, I.; Daversa, M.T.; Kueppenbender, K.D.; Zanarini, M.C.;
CC

Shea, M.T. et al. (2006). Descriptive and Longitudinal Observations on the Relationship
of Borderline Personality Disorder and Bipolar Disorder. American Journal of
Psychiatry, 163, 1173-1178.
14. Ghaemi S.N., Dalley S., Catania C., Barroilhet S. Bipolar or borderline: a clinical
A

overview. Acta Psychiatr. Scand. 2014;130(2):99–108

15. Mclaughlin, K.A.; Kubzansky, L.D.; Dunn, E.C.; Waldinger, R.; Vaillant, G.; & Koenen,
K.C. (2010). Childhood social environment, emotional reactivity to stress, and mood
and anxiety disorders across the life course. Depression and Anxiety, 27(12), 1087-94.
16. Neigh, G.N.; Gillespie, C.F.; & Nemeroff, C.B. (2009).The neurobiological toll of child
abuse and neglect. Trauma, Violence & Abuse, 10(4), 389-410.
17. Grover, K.E.; Carpenter, L.L.; Price, L.H.; Gagne, G.G.; Mello, A.F.; Mello, M.F.; et al.
(2007). The relationship between childhood abuse and adult personality disorder
symptoms. Journal of Personality Disorders, 21(4), 442-7.
18. Bandelow, B.; Krause, J.; Wedekind, D.; Broocks, A.; Hajak, G.; Ruther, E. (2005). Early
traumatic life event, parental attitudes, family history, and birth risk factors in patients
with borderline personality disorder and health controls. Psychiatry Research, 134,
169-179.
19. Cohen, P.; Brown, J.; & Smailes, E. (2001). Child abuse and neglect and the
development of mental disorders in the general population. Development and
Psychopathology, 13(4), 981-99.
20. Hecht, D.B.; & Hansen, D.J. (2001). The environment of child maltreatment contextual

T
factors and the development of psychopathology. Aggression and Violent Behavior, 6,

IP
433-457.
21. Heim, C.; & Nemeroff, C.B. (2001). The role of childhood trauma in the neurobiology of

R
mood and anxiety disorders: preclinical and clinical studies. Biological Psychiatry,
49(12), 1023-39.

SC
22. Fisher, H.; & Hosang, D. (2010). Childhood Maltreatment and Bipolar Disorder: a
critical review of evidence. Mind & Brain, The Journal of Psychiatry, 1(1), 1.
23. Ball, J.S. & Links, P.S. (2009). Borderline personality disorder and childhood trauma:

U
evidence for a causal relationship. Current Psychiatry Reports,11(1), 63-8.
24. Grandin, L.B.; Alloy, L.B.; & Abramson, L.Y. (2007). Childhood stressful life events and
N
bipolar spectrum disorders. Journal of Social and Clinical Psychology, 26(4), 460-478.
25. Zanarini, M.C.; Horwood, J.; Wolke, D.; Waylen, A.; Fitzmaurice, G.; & Grant, Bf. (2011).
A
Prevalence of DSM-IV borderline personality disorder in two community samples:
6,330 English 11-year-olds and 34,653 American adults. Journal of Personality
M

Disorders, 25, 607-19.

26. Kingdon, D.G.; Ashcroft, K.; Bhandari, B.; Gleeson, S.; Warikoo, N.; Symons, M.; et al.
(2010) Schizophrenia and borderline personality disorder: similarities and differences
ED

in the experience of auditory hallucinations, paranoia, and childhood trauma. Journal

of Nervous and Mental Disease, 198(6), 399-403.
27. Soloff, P.H.; Feske, U.; & Fabio, A. (2008). Mediators of the relationship between
PT

childhood sexual abuse and suicidal behavior in borderline personality disorder.

Journal of Personality Disorders, 22(3), 221-232.
28. Gao, K.; Tolliver, B.K.; Kemp, D.E.; Ganocy, S.J.; Bilali, S.; Brady, K.L.; Et Al. (2009).
Correlates of historical suicide attempt in rapid-cycling bipolar disorder: a cross-
E

sectional assessment. Journal of Clinical Psychiatry, 70(7), 1032-1040.

CC

29. Carballo, J.J.; Harkavy-Friedman, J.; Burke, A.K.; Sher, L.; Baca-Garcia, E.; Sullivan, G.M.;
et al. (2008). Family history of suicidal behavior and early traumatic experiences:
additive effect on suicidality and course of bipolar illness? Journal of Affective
Disorders,109(1-2), 57-63.
A

30. Hammersley, P., Dias, A., Todd, G., Bowen-Jones, K., Reilly, B., & Bentall, R.P. (2003).
Childhood trauma and hallucinations in bipolar affective disorder: preliminary
investigation. British Journal of Psychiatry, 182, 543-547.
31. Rinne, T.; De Kloet, E.R.; Wouters, L.; Goekoop, J.G.; Derijik, R.H.; & Van Den Brink, W.
(2002). Hyper responsiveness of hypothalamic-pituitary-adrenal axis to combined
dexamethasone/corticotropin-releasing hormone challenge in female borderline
personality disorder subjects with a history of sustained childhood abuse. Biological
Psychiatry, 52, 1102-12.
32. Schmahl, C.G.; Vermetten, E.; Elzinga, B.M.; & Douglas Bremner, J. (2003). Magnetic
resonance imaging of hippocampal and amygdala volume in women with childhood
abuse and borderline personality disorder. Psychiatry Research, 122(3),193-8.
33. Kauer-Sant’anna, M.; Tramontina, J.; Andreazza, A.C.; Cereser, K.; Da Costa, S.; Santin,
A.; et al. (2007). Traumatic life events in bipolar disorder: impact on BDNF levels and
psychopathology. Bipolar Disorder, 9 (Suppl. 1), 128-135.
34. Maguire, C.; Mccusker, C.G.; Meenagh, C.; Mulholland, C.; & Shannon, C. (2008).
Effects of trauma on bipolar disorder: the mediational role of interpersonal difficulties
and alcohol dependence. Bipolar Disorder, 10, 293–302.
35. Brown, G.R.; Mcbride, L.; Bauer, M.S.; & Williford, W.O. (2005). Impact of childhood
abuse on the course of bipolar disorder: A replication study in US veterans. Journal of

T
Affective Disorders, 89, 57-67.

IP
36. Garno, J.L.; Goldberg, J.F.; Ramirez, P.M.; & Ritzler, B.A. (2005). Impact of childhood
abuse on the clinical course of bipolar disorder. British Journal of Psychiatry, 186, 121-

R
125.
37. Leverich, G.S.; Perez, S.; Luckenbaugh, D.A.; & Post, R.M. (2002). Early psychosocial

SC
stressors: relationship to suicidality and course of bipolar illness. Clinical Neuroscience
Research, 2, 161-170.
38. Carlson, E.A.; Egeland, B.; & Sroufe, L.A. (2009). A prospective investigation of the

U
development of borderline personality symptoms. Development and Psychopathology,
21, 1311–34.
N
39. Bradley, R.; Jenei, J.; & Westen, D. (2005). Etiology of borderline personality disorder:
disentangling the contributions of intercorrelated antecedents. Journal of Nervous and
A
Mental Disease, 193(1), 24-31.
40. Widom, C.S.; Czaja, S.J.; & Paris, J. (2009). A prospective investigation of borderline
M

personality disorder in abused and neglected children followed up into adulthood.

Journal of Personality Disorders, 23(5), 433-46.
41. Bornovalova, M.A.; Gratz, K.L.; Delany-Brumsey, A.; Paulson, A.; & Lejeuz, W. (2006).
ED

Temperamental and environmental risk factors of borderline personality disorder

among inner-city substance use in residential treatment. Journal of Personality
Disorders, 20(3), 218-31.
PT

42. Golier, J.A., Yehuda, R., Bierer, L.M., Mitropoulou, V., New, A.S., Schmeidler, J., et al.
(2003). The relationship of borderline personality disorder to posttraumatic stress
disorder and traumatic events. American Journal of Psychiatry, 160(11), 2018-24.
43. Etain, B.; Mathieu, F.; Henry, C.; Raust, A.; Roy, I.; Germain, A.; et al. (2010).
E

Preferencial association between childhood emotional abuse and bipolar disorder.

CC

Journal of Traumatic Stress, 23(3), 376-83.

44. Tarullo, A.R.; & Gunnar, M.R. (2006). Child maltreatment and the developing HPA axis.
Hormones and Behavior, 50(4), 632-39.
45. Juruena, MF. Early-life stress and HPA axis trigger recurrent adulthood depression
A

Epilepsy & Behavior, 38, 148-59, 2014.

46. Faravelli, C.S.; Goriniamadei, F.; Rotella, F.; Faravelli, L. ; Palla, G. ; Consoli, V. et al.
(2010). Childhood traumata, Dexamethasone Suppression Test and psychiatric
symptoms: a trans-diagnostic approach. Psychological Medicine, 40, 2037–48.
47. Reich, D.B.; Zanarini, M.C.; & Fitzmaurice, G. (2012). Affective liability in bipolar
disorder and borderline personality disorder. Comprehensive Psychiatry, 53(3), 230-7.
48. Galione, J.; & Zimmerman, M. (2010). A comparison of depressed patients with and
without borderline personality disorder: implications for interpreting studies of the
 validity of the bipolar spectrum. Journal of Personality Disorders, 24(6), 763-72.
49. Henry, C.; Mitrapoulou, V.; New, A.S.; Koenigsberg, H.W.; Silverman, J.; & Siever, L.J.
(2001). Affective instability and impulsivity in borderline personality and bipolar II
disorders: similarities and differences. Journal of Psychiatric Research, 35, 307–312.
50. Alvarez, M.J.; Roura, P.; Osés, A.; Foguet, Q.; Solà, J.; Arrufat, F.X. (2011) Prevalence
and clinical impact of childhood trauma in patients with severe mental disorders.
Journal of Nervous and Mental Disease, 199(3), 156-61.
51. Daruy-Filho, L.; Brietzke, E.; Lafer, B.; Grassi-Oliveira, R. (2011). Childhood
maltreatment and clinical outcomes of bipolar disorder. Acta Psychiatrica
Scandinavica, 124(6), 427-34.
52. Fowke, A.; Ross, S.; & Ashcroft, K. (2012). Childhood maltreatment and i&nternalized

T
shame in adults with a diagnosis of bipolar disorder. Clinical Psychology &

IP
Psychotherapy, 19(5), 450-7.
53. Conus, P.; Cotton, S.; Schimmelmann, B.G.; Berk, M.; Daglas, R.; Mcgorry, P.D.; et al.

R
(2010).Pretreatment and outcome correlates of past sexual and physical trauma in 18
bipolar I disorder patients with a first episode of psychotic mania. Bipolar Disorder,

SC
12(3), 244-252.
54. Hyun, M.; Friedman, S.D.; & Dunner, D.L. (2000). Relationship of childhood physical
and sexual abuse to adult bipolar disorder. Bipolar Disorder, 2(2),131-5.

U
55. Herman, J.L.; Perry, J.C.; & Van Der Kolk, B.A. (1989). Childhood trauma in borderline
personality disorder. American Journal of Psychiatry, 146(4), 490-5
N
56. Carr, C.P.; Martins, C.M.; Stingel, A.M.; Lemgruber, V.B.; & Juruena, M.F. (2013). The
role of early life stress in adult psychiatric disorders: a systematic review according to
A
childhood trauma subtypes. Journal of Nervous and Mental Disease, 201(12), 1007-20.
57. Watson, S.; Bruce, M.; Owen, B.M.; Gallagher, P.; Hearn, A.J.; Young, A.H.; et al. (2007).
M

Family history, early adversity and the hypothalamic-pituitary-adrenal (HPA) axis:

Mediation of the vulnerability to mood disorders. Neuropsychiatric Disease and
Treatment, 3(5), 647–653.
ED

58. Carvalho-Fernando, S.; Beblo, T.; Schlosser, N.; Terfehr, K.; Otte, C.; Löwe, B.; et al.
(2012). Associations of childhood trauma with hypothalamic-pituitary-adrenal function
in borderline personality disorder and major depression. Psychoneuroendocrinology,
PT

37(10), 1659-68.
59. Chen, L.P.; Murad, M.H.; Paras, M.L.; Colbenson, K.M.; Sattler, A.L.; Goranson, E.N.; et
al. (2010). Sexual abuse and lifetime diagnosis of psychiatric disorders: systematic
review and meta-analysis. Mayo Clinic Proceedings, 85, 618-629.
E

60. Goldberg, J.F.; Garno, J.L.; & Harrow, M. (2005). Long-term remission and recovery in
CC

bipolar disorder: a review. Current Psychiatry Reports, 7, 456-461.

61. Zanarini, M.C.; Yong, L.; Frankenburg, F.R.; Hennen, J.; Reich, D.B.; Marino, M.F.; et al.
(2002). Severity of reported childhood sexual abuse and its relationship to severity of
borderline psychopathology and psychosocial impairment among borderline
A

inpatients. Journal of Nervous and Mental Disease, 190, 381-387.

62. Fossati, A.; Madeddu, F.; & Maffei, C. (1999). Borderline Personality Disorder and
childhood sexual abuse: a meta-analytic study. Journal of Personality Disorders, 13(3),
268-80.
63. Garno, J.L.; Gunawardane, N.; & Goldberg, J.F. (2008). Predictors of trait aggression in
bipolar disorder. Bipolar Disorder, 10, 285-292.
64. Kupka, R.W.; Luckenbaugh, D.A.; Post, R.M.; Suppes, T.; Altshuler, L.L.; Keck, P.E. Jr.; et
al. (2005). Comparison of rapid-cycling and non-rapid-cycling bipolar disorder based on
 prospective mood ratings in 539 outpatients. American Journal of Psychiatry, 162(7),
1273-1280.
65. Ladd, C.O.; Huot, R.L.; Thrivikraman, K.V. Nemeroff, C.B.; & Plotsky, P.M. (2004). Long-
term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and
negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal
maternal separation. Biological Psychiatry, 55(4), 367-75.
66. Tofoli, S M C; Baes, Cristiane V W; Martins, C M S ; Juruena,M . Early life stress, HPA
axis, and depression. Psychology & Neuroscience v. 4, p. 229-234, 2011.
67. Martins, CMS ; Tofoli, S M C ; Baes, C VW ; Juruena,MF Analysis of the occurrence of
early life stress in adult psychiatric patients: a systematic review. Psychology &
Neuroscience 4 (2), 219-27, 2011.

T
68. Baes, CVW; Tofoli, SMC; Martins, CM ; Juruena, MF .Assessment of the hypothalamic-

IP
pituitary-adrenal axis activity: glucocorticoid receptor and mineralocorticoidreceptor
function in depression with early life stress - a systematic review. Acta

R
Neuropsychiatrica , v. 24, 4-15, 2012.
69. Tunnard, Catherine, Rane, Lena J., Wooderson, Sarah C., Markopoulou, Kalypso, Poon,

SC
Lucia, Fekadu, Abebaw, Juruena, Mario, Cleare, Anthony J.The impact of childhood
adversity on suicidality and clinical course in treatment-resistant depression. Journal of
Affective Disorders, v.152, p. 122-130, 2014

U
70. Martins, CMS ; Baes, CVW; Tofoli, SMC and Juruena,MF Emotional Abuse In Childhood
is Differential Factor for the Development of Depression in Adults J Nerv Ment Dis.,
N
202, 774-82, 2014.
71. Dienes, K.A.; Hammen, C.; Henry, R.M.; Cohen, A.N.; & Daley, S.E. (2006). The stress
A
sensitization hypothesis: understanding the course of bipolar disorder. Journal of
Affective Disorders, 95, 43–49.
M

72. Walter, M.; Bureauc, J.F.; Holmesc, B.M.; Berthac, E.A.; Hollanderc, M.; Wheelise, J. et al.
(2008). Cortisol response to interpersonal stress in young adults with borderline
personality disorder: A pilot study. European Psychiatry, 23, 201–204.
ED

73. Carrasco, J.L.; Diaz-Marsa, M.; Ignacio, P.; Molina, R.; Brotons, L.; & Horcajas, C. (2003).
Enhanced suppression of cortisol after dexamethasone in borderline personality
disorder. A pilot study. Actas Espanolas de Psiquiatria, 31, 138-41.
PT

74. Lieb, K.; Rexhausen, J.E.; Kahl, K.G.; Schweiger, U.; Philipsen, A.; Hellhammer, D.H. et
al. (2004). Increased diurnal salivary cortisol in women with borderline personality
disorder. Journal of Psychiatric Research, 38(6), 559-65.
75. Wingenfeld, K. (2010). HPA axis and neuroimaging in BPD. Psychoneuroendocrinology,
E

35, 154-170.
CC

76. Deshauer, D.; Duffy, A.; Alda, M.; Grof, E.; Albuquerque, J.; & Grof, P. (2003). The
cortisol awakening response in bipolar illness: a pilot study. Canadian Journal of
Psychiatry, 48, 462–466.
77. Cassidy, F.; Murry, E.; Forest, K.; & Carroll, B.J. (1998). Signs and symptoms of mania in
A

pure and mixed episodes. Journal of Affective Disorders, 50, 187–201.

78. Schmider, J.; Lammers, C.H.; Gotthardt, U.; Dettling, M.; Holsboer, F.; & Heuser, I.J.
(1995). Combined dexamethasone/corticotropin-releasing hormone test in acute and
remitted manic patients, in acute depression, and in normal controls. Biological
Psychiatry, 38, 797–802.
79. Linkowski, P.; Kerkhofs, M. ; Van Onderbergen, A. ; Hubain, P. ; Copinschi, G.;
L'hermite-Baleriaux, M. Et Al. (1994). The 24-hour profiles of cortisol, prolactin, and
growth hormone secretion in mania. Archives of General Psychiatry, 51, 616–624.
80. Daban, C.; Vieta, E.; Mackin, P.; & Young, A.H. (2005). Hypothalamic-pituitary-adrenal
axis and bipolar disorder. The Psychiatric Clinics of North America. 28, 469–480.
81. Watson, S.; Gallagher, P.; Ritchie, J.C.; Ferrier, I.N.; & Young, A.H. (2004).
Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. British
Journal of Psychiatry, 184, 96–502.
82. Swann, A.C.; Stokes, P.E.; Casper, R.; Secunda, S.K.; Bowden, C.L.; Berman, N.; et al.
(1992). Hypothalamic-pituitary-adrenocortical function in mixed and pure mania. Acta
Psychiatrica Scandinavica, 85, 270-274.
83. Evans, D.L.; & Nemeroff, C.B. (1983). The dexamethasone suppression test in mixed
bipolar disorder. American Journal of Psychiatry, 140, 615–617.
84. Kamali, M.; Saunders, E.F.; Prossin, A.R.; Brucksch, C.B.; Harrington, G.J.; Langenecker,

T
S.A.; et al. (2012). Associations between suicide attempts and elevated bedtime

IP
salivary cortisol levels in bipolar disorder. Journal of Affective Disorders, 136, 350-358.
85. Manenschijn, L.; Spijker, A.T.; Koper, J.W.; Jetten, A.M.; Giltay, E.J.; Haffmans, J.; et al.

R
(2012). Long-term cortisol in bipolar disorder: Associations with age of onset and
psychiatric co-morbidity. Psychoneuroendocrinology, 37(12), 1960-8.

SC
86. Duffy, A.; Lewitzka, U.; Doucette, S.; Andreazza, A.; & Grof, P. (2012). Biological
indicators of illness risk in offspring of bipolar parents: targeting the hypothalamic-
pituitary-adrenal axis and immune system. Early Intervention in Psychiatry, 6(2), 128-
37.
U
87. Ellenbogen, M.A.; Hodgins, S.; Linnen, A.M.; & Ostiguy, C.S. (2011). Elevated daytime
N
cortisol levels: a biomarker of subsequent major affective disorder? Journal of
Affective Disorders, 132, 265-269.
A
88. Aydin, A.; Selvi, Y.; Besiroglu, L.; Boysan, M.; Atli, A.; Ozdemir, O.; Kilic, S.; Balaharoglu,
R. (2013). Mood and metabolic consequences of sleep deprivation as a potential
M

endophenotype in bipolar disorder. Journal of Affective Disorders,150(2), 284-94.

89. Valiengo, L.L.; Soeiro-De-Souza, M.G.; Marques, A.H.; Moreno D.H.; Juruena M.F.;
Andreazza, A.C.; et al. (2012). Plasma cortisol in first episode drug-naïve mania:
ED

Differential levels in euphoric versus irritable mood. Journal of Affective Disorders, 138,
149–152.
90. Schlesser, M.A.; Winokur, G.; & Sherman, B.M. (1980). Hypothalamic-pituitaryadrenal
PT

axis activity in depressive illness. Its relationship to classification. Archives of General

Psychiatry, 37, 737–743.
91. Carpenter, L.L.; Carvalho, J.P.; Tyrka, A.R.; Wier, L.M.; Mello, A.F.; Mello, M.F.; et al.
(2007). Decreased adrenocorticotropic hormone and cortisol responses to stress in
E

healthy adults reporting significant childhood maltreatment. Biological Psychiatry,

CC

62(10), 1080-7.
92. Carpenter, L.L.; Tyrka, A.R.; Ross, N.S.; Khoury, L.; Anderson, G.M.; & Price, Lh. (2009).
Effect of childhood emotional abuse and age on cortisol responsivity in adulthood.
Biological Psychiatry, 66, 69-75.
A

93. Flory, J.D., Yehuda, R.; Grossman, R.; New, A.S.; Mitropoulou, V.; & Siever, L.J. (2009).
Childhood trauma and basal cortisol in people with personality disorders.
Comprehensive Psychiatry, 50(1), 34-7.
94. Lee, R.J.; Hempel, J.; Tenharmsel, A.; Liu, T.; Mathé, A.A.; & Klock, A. (2012). The
neuroendocrinology of childhood trauma in personality disorder.
Psychoneuroendocrinology, 37(1), 78-86.
 95. Lee, R.; Geracioti, T.D.; Kasckow, J.W.; & Coccaro, E.F. (2005). Childhood trauma and
personality disorder: positive correlation with adult CSF corticotropin-releasing factor
concentrations. American Journal of Psychiatry, 162, 995–997.
96. O’Keane, V., Dinan, T.G., 1991. Prolactin and cortisol responses to d-fenfluramine in
major depression: Evidence for diminished responsivity of central serotoninergic
function. Am. J. Psychiatry 148, 1009–1015.
97. Orsel, S., Karadag, H., Turkcapar, H., Kahilogullari, A.K., 2010. Diagnosis and
Classification Subtyping of Depressive Disorders: Comparison of Three Methods.
Klin.Psikofarmakol. Bül.-Bull. Clin. Psychopharmacol. 20 (1), 57–65.
98. Lamers, F., Vogelzangs, N., et al., 2012. Evidence for a differential role of HPA-axis
function, inflammation and metabolic syndrome in melancholic versus atypical

T
depression. Mol. Psychiatry 18 (6), 692–699.

IP
99. Joseph-Vanderpool, J.R., Rosenthal, N.E., et al., 1991. Abnormal pituitary-adrenal
responses to corticotropin-releasing hormone in patients with seasonal affective

R
disorder: clinical and pathophysiological implications. J. Clin. Endocrinol. Metab. 72(6),
1382–1387.

SC
100. Juruena MF, Bocharova M, Agustini B, Young AH, Atypical depression and non-atypical
depression: Is HPA axis function a biomarker? A systematic review, Journal of Affective
Disorders, online 6 Oct 2017, ISSN 0165-0327, https://doi.org/ 10.1016/j.jad.2017.09.
052
U
N
A
M
ED
E PT
CC
A
 25

20
Without 20%
15 Without 44%
ELS With Without
10
ELS 80%
With 100%
5 56%
ELS

0
BD BPD HC

T
IP
Figure 1- Distribution of the subjects of the diagnostic BD and BPD(n = 36) and
control (n = 15) groups classified as having early life stress (with ELS) or without early

R
life stress (without ELS).

SC
U
N
A
M
ED
E PT
CC
A
 60

CTQ Average Score

BD BPD HC
50

40

30

20

10

0
Total Emotional Physical Sexual Emotional Physical

T
Abuse Abuse Abuse Neglect Neglect
Early Stress Type

IP
Figure 2. Distribution of scores of early stress and its subtypes compared between the

R
diagnosis-related groups.

SC
U
N
A
M
ED
E PT
CC
A
 Average of the cortisol

25 *
*
20
dosage mcg/dl

15

10

T
0

IP
BD BPD Control

Figure 3 Distribution of the average dosage of basal cortisol among the groups

R
SC
ANOVA Test. F = 5.8; df 2; p = 0.005
BD vs. BPD p=0,869
*BD vs. Healthy Controls p=0,008
*BPD vs. Healthy Controls p=0,019

U
N
A
M
ED
E PT
CC
A
 T
R IP
SC
Figure 4. A negative correlation between the severity of Hopelessness assessed by
the BHS and dosage of plasma cortisol in Borderline Personality Disorder patients with

U
history of Early life Stress (n=16. r=-0,709; p=0,002)
N
A
M
ED
E PT
CC
A
 T
R IP
SC
Figure 5. A negative correlation between the severity of Physical Neglected reported
by the CTQ and dosage of plasma cortisol in borderline patients with history of Early
life Stress (n=16. r=-0,538; p=0,032)
U
N
A
M
ED
E PT
CC
A
 Bipolar Disorder

18

16
Cortisol dosage (mcg/ml)

14

12

10

T
4

IP
2

0
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

R
CTQ Scores for Sexual Abuse

SC
n= 16. r=-0.509; p=0.044

Figure 6. Negative correlation between the severity of sexual abuse reported by the
CTQ and dosage of plasma cortisol in bipolar patients (n= 16. r=-0.509; p=0.044) U
N
A
M
ED
E PT
CC
A
 Borderline Personality Disorder
Cortisol dosage (mcg/ml)
35

30

25

20

15

T
10

IP
5

R
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

SC
CTQ scores for Sexual Abuse

n=20. r=0.467; p=0.038

U
N
Figure 7. Positive correlation between the severity of sexual abuse reported by the
CTQ and dosage of plasma cortisol in Borderline Personality Disorder patients (n= 20
A
r=-0.467; p=0.038)
M
ED
E PT
CC
A
Table 1- Demographic and clinical characteristics of the groups (n=51)

BD BPD Control
n =16 n=20 n=15 P
(31%) (39%) (30%)
37.3 28.40 30.8
Age, years (± sem) 0,014
(±10.3) (±8.8) (±7.11)
Marital status, n (%) 0.641
Never-married 9 (56) 9 (45) 8 (53)
Married 5 (31) 8 (30) 5 (40)
Separated/divorced 2 (13) 5 (25) 1 (7)

T
Children, n 0.93 0.90 0.46
0.305
(±sem) (±0.99) (±0.96) (±0.43)

IP
Yes 8 (56) 11 (55) 4 (27)
No 7 (44) 9 (45) 11 (73)

R
Education, n (%) 0.049
≤ 4 years 0 (0) 1 (5) 0 (0)

SC
5-8 years 1 (6) 1 (5) 0 (0)
9-12 years 7 (44) 10 (50) 1 (7)
Undergraduate 5 (31) 4 (20) 3 (20)
Graduate
Post-graduation
3 (19)
0 (0)
4 (20)
0 (0) U
9 (60)
2 (13)
N
Employment status, n (%) 0.035
Employed 8 (50) 11 (55) 15 (100)
A
Unemployed 2 (13) 1 (5) 0 (0)
Certificate of health to take
M

time off work 5 (31) 8 (40) 0 (0)

Retired 1 (6) 0 (0) 0 (0)
Severe Medical
0.173
ED

Ilness, n (%)
Yes 6 (38) 3 (15) 2 (13)
No 10 (62) 17 (85) 13 (87)
Duration of treatment, 10.68 3.71 0
PT

<0.001
years (±SEM) (±10.4) (±6.2) (0)
Medication, n (%) <0.001
Yes 16 (100) 18 (90) 0 (0)
E

No 0 (0) 2 (10) 15 (100)

Psychotherapy, n (%) 0.645
CC

Yes 7 (44) 11 (55) 6 (40)

No 9 (56) 9 (45) 9 (60)
Note: sem: standard error of the mean
A
Table 2 Psychiatric symptomatology in Borderline Personality Disorder (BPD),
Bipolar Disorder (BD) and Healthy Control (HC) samples (n=51)

Scales BPD BD HC
n=20 n=16 n=15 P
BAI, mean (sem) 30.4 (±9,25) 16.43 (±15,18) 4.26 (±2,49) <0,001
BIS, mean (sem) 82.80(±3,04) 62.15 (±5,29) 55.83 (±2,66) <0,001
BDI, mean (sem) 30.15 (±10,87) 16.12 (±9,30) 3.86 (±3,66) <0,001

T
BHS, mean (sem) 12.45 (±4,04) 7.99 (±3,88) 0 (±1,60) <0,001

IP
BSI, mean (sem) 17.5 (±11,33) 4.81 (±7,62) 0.00 (±0,00) <0,001
YMS, mean (sem) 1.06 (±2,91) 1.8 (±1,43) 0.00 (±0,00) 0,039

R
BAI: Beck Anxiety Inventory
BIS: Barratt Impusivity Scale

SC
BDI: Beck Depression Inventory
BHS: Beck Hopelessness Scale
BSI: Beck Suicide Ideation
YMS: Young Mania Scale
ANOVA, between groups

Posthoc Tukey test: U

N
BAI. BD vs. BPD p=0,001; BD vs. HC p=0,006; BPD vs. HC p<0,001
BIS. BD vs. BPD p<0,001; BD vs. HC p=0,022; BPD vs. HC p<0,001
A
BDI. BD vs. BPD p<0,001; BD vs. HC p=0,001; BPD vs. HC p<0,001
BHS. BD vs. BPD p<0,001; BD vs. HC p=0,244; BPDvs. HC p<0,001
M

BSI. BD vs. BPD p<0,001; BD vs. HC p=0,251; BPD vs. HC p<0,001

YMS. BD vs. BPD p= 0,519; BD vs. HC p=0,310; BPD vs. HC p=0,030
ED
E PT
CC
A
Table 3. Comparisons among groups in terms of early stress and their subtypes
(n = 51)

BD BPD Control
n=16 n=20 n=15 P
Total CTQ 43.50 58.00 30.13 <0.001
(±15,44) (±16,20) (±3,39)
Emotional Abuse 11.68 15.75 6.60 <0.001
(±4.70) (±5.46) (±1.54)
Physical Abuse 7.18 9.60 5.26 0.004
(±3.42) (±4.84) (±0.45)

T
Sexual Abuse 6.25 7.7 5.00 0.082
(±3.54) (±4.52) (±0.00)

IP
Emotional Neglect 10.84 14.75 7.80 <0.001
(±5.21) (±4.67) (±1.85)
Physical Neglect 7.21 10.50 5.46 <0.001

R
(±2.38) (±3.69) (±1.60)
ANOVA Test among the groups.

SC
Posthoc Tukey test:
CTQ total. BD vs. BPD p = 0.007; BD vs. Control p = 0.022; BPD vs. Control p <0.001
Emotional abuse. BD vs. BPD p = 0.023; BD vs. Control p = 0.007; BPD vs. Control p <0.001

U
Physical abuse. BD vs. BPD p = 0.125; BD vs. Control p = 0.310; BPD vs. P = 0.003 Control
Sexual abuse. BD vs. BPD = p=0,432; BD vs. HC p=0,579; BPD vs. HC p=0,068
Emotional neglect. BD vs. BPD p = 0.023; BD vs. Control p = 0.126; BPD vs. Control p <0.001
N
Physical neglect. BD vs. BPD p = 0.002; BD vs. Control p = 0.187; BPD vs. Control p <0.001
A
M
ED
E PT
CC
A