The overall aim of this study is to investigate the pathophysiology of PPMD, and identify predictors of longitudinal outcome.Primary Objective: The primary objective is to investigate the underlying neurobiology of first-onset PPMD using…
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- Psychiatric disorders NEC
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Outcome measures
Primary outcome
The primary objective is to investigate the underlying neurobiology of
first-onset PPMD using longitudinal neuroimaging. Brain imaging will be
performed during both the acute episode (median 4 weeks postpartum) and after
full remission (12 months after onset). All MRI scans will be made by a trained
researcher and trained research assistant. The scanning protocol contains a
whole-brain structural MRI examination combined with Diffusion Tensor Imaging
(DTI), functional MRI (fMRI) scans and Magnetic Resonance Spectroscopy (MRS).
Because our previous research showed a possible auto-immune related cause of
postpartum mood disorders, we expect changes in white matter. Therefore our
primary measure will be white matter integrity, measured by the fractional
anisotropy (FA). Fractional anisotropy is the most-widely used DTI-based index
in brain research. Fractional anisotropy provides a gray-scale, 2D map,
enhancing diffusion anisotropy difference with intensity limits between zero
and one. In white matter, the anisotropy is high (approaching unity in most
ordered areas), reflecting fast diffusivity along the fibers and slow
diffusivity perpendicular to them. In gray matter and CSF, the anisotropy
approaches zero as the diffusivity is similar in all directions. White matter
abnormalities lead to a decrease in fractional anisotropy
Secondary outcome
Secondary endpoints include the longitudinal course of women with first-onset
PPMD and predictive factors for the longitudinal disease course (and thus for
the need for long-term maintenance therapy). Our main variable of interest is
relapse.
Relapse will be defined as the occurrence of any affective or psychotic
symptoms fulfilling DSM-IV-R criteria and severe enough to warrant treatment.
We will make a clear distinction of relapse after a subsequent pregnancy versus
a relapse outside the postpartum period, thereby enabling the distinction
between women with episodes of affective psychosis entirely limited to the
postpartum period (PPMD only) versus those with a lifelong mood disorder.
Our previous showed that overall relapse risk for women with only
postpartum-onset psychoses is 31% (95% CI=22, 42) as derived from 13 studies,
595 deliveries, and 528 patients. The risk of a postpartum episode (affective
psychosis, mania, mixed episode, or relapse requiring hospitalization) was
significantly higher in patients with a history of postpartum psychosis (29%,
95% CI=20, 41) compared to women with more chronic forms of bipolar disorder.
Further, in stark contrast to the high rates of relapse in women with bipolar
disorder during pregnancy, women with a history of psychosis limited to the
postpartum period are not at elevated risk of psychiatric episodes during
pregnancy.
We hypothesize that predictive factors for the longitudinal course might
include:
a. timing of onset
b. genetic vulnerability
c. immune related vulnerability
Timing of onset
The onset and severity of PPMD in the early postpartum period is not only of
diagnostic importance, but it may also well predict the likelihood of
subsequent conversion to a lifelong mood disorder. Several clinical experts in
the field have discussed the perspective that very early PPMD is more likely to
have a bipolar diathesis, especially if prominent manic symptoms are present.
In contrast, from a neurobiological perspective, a very early onset could be
suggestive for a favorable disease course (PPMD only), because the most
prominent physiological changes occur within the first week postpartum
(endocrine, immunological). Our Danish collaborators reported that primiparous
women had an increased risk of incident hospital admission with any mental
disorder through the first 3 months after childbirth, with the highest risk 10
to 19 days postpartum (relative risk [RR], 7.31; 95% confidence interval [CI],
5.44-9.81). This is consistent with our work; we found a median onset of
postpartum psychosis 8 days following delivery, (interquartile range 5-14) in
our clinical cohort. We will use the data of initial mental health contact as
date of onset. We hypothesize that an earlier onset will correspond to a more
favourable disease.
Genetic vulnerability
Information on the family history of both bipolar and postpartum episodes will
allow a unique look at the extent to which the genetic vulnerability for PPMD
and bipolar disorder are distinct or shared. It is well known that the
heritability for bipolar disorder is estimated to be up to 80%. In addition,
there is increasing evidence of a high heritability for postpartum episodes of
affective psychosis. Our Danish collaborators found that bipolar family
psychopathology represents a significant risk factor for the first onset of
psychiatric episodes in the postpartum period. It is very interesting to
investigate what the risk of a further bipolar disease course will be after
this first onset episode, if a family member suffers from bipolar affective
disorder. Moreover, within a larger consortium we will investigate genetic loci
that are associated with vulnerability to severe postpartum onset. Our
hypothesis is that bipolar family history is an important risk factor for a
bipolar disease course.
Immune related vulnerability
Interestingly, the pathophysiology of every non-psychiatric medical condition
known to have a postpartum flare pattern has been established to arise from
immune dysfunction, including rheumatoid arthritis, multiple sclerosis,
autoimmune thyroid dysfunction, autoimmune hepatitis, and myasthenia gravis.
Common characteristics of these pregnancy-related autoimmune diseases include
familial occurrence, progression from subclinical to clinical disease, a
cyclical exacerbation- remission pattern, and a high recurrence risk with
subsequent pregnancies. Remarkably, PPMD has shown to possess all of these
clinical features and we postulate that postpartum activation of the immune
system is central to the pathogenesis of these postpartum mood disorders. Our
previous work showed that patients with postpartum psychosis have significantly
elevated rates of autoimmune thyroiditis and pre-eclampsia, both of which have
established autoimmune etiologies. Recently, we showed that a very small
subgroup of patients suffered from undiagnosed autoimmune encephalitis. Lastly,
we observed abnormalities in monocyte activation, T cell function and
tryptophan breakdown in patients with postpartum psychosis during the acute
phase compared to postpartum controls,all suggestive for immune system
dysfunction. We intend to investigate if immune abnormalities are predictive
for the disease course.
Another secondary study parameter will be early child development.
Background summary
Childbirth has the highest relative risk of any vulnerability factor associated
with the onset of severe psychiatric illness. The three main conditions that
are associated with childbirth are the maternity blues, postnatal depression
and post-partum psychosis. Postpartum blues are mild mood changes that
commonly occur during the early postpartum period and these are not the focus
on this current protocol. In contrast, postpartum depression and psychosis are
serious clinical disorders, here called postpartum mood disorders (PPMD).
Postpartum depression is a clinical syndrome of moderate to severe
depressive symptoms that lasts longer than postpartum blues and has a greater
impact on the family. The prevalence of postpartum depression is about 10% and
occurs within 4 weeks of childbirth, according to the DSM-IV. However most
researchers suggests that it can occur within the first year postpartum. The
signs and symptoms of postpartum depression are generally indistinguishable
from those associated with major depression occurring at other times and
include depressed mood, anhedonia, low energy and guilty ruminations. There
are, however subtle differences, including: (a) difficulty sleeping when the
baby sleeps, (b) lack of enjoyment in the maternal role, (c) feelings of guilt
related to parenting ability.
Postpartum psychosis is the most severe form of pregnancy-related psychiatric
illness, with a prevalence in the general population of 0.1%. Postpartum
psychosis occurs most frequently in primiparous women without a psychiatric
history and generally manifests acutely within 4 weeks after delivery. The
relative risk for the first onset of affective psychosis such as mania or
psychotic depression is 23 times higher within 4 weeks after delivery, compared
to any other period during a woman*s life. The cardinal symptomatology is
affective and severe, including acute mania, depression, or a mixed state.
Psychotic symptoms almost exclusively occur within the setting of affective
instability. The initial clinical evaluation for postpartum psychosis requires
a thorough physical and neurological evaluation.
From a research perspective, PPMD is among the few psychiatric disorders in
which the etiological event is known. Childbirth is the responsible trigger for
PPMD, but there are many important unanswered questions regarding
pathophysiology and prognosis.
Rationale primary objective
This will be the first neuroimaging study conducted in women with severe
postpartum psychiatric episodes. The primary aim is to investigate the
underlying neural mechanisms of PPMD, with a particular focus on white matter
integrity. Our previous research provided novel evidence for a central role of
the immune system in the pathogenesis of postpartum disorder. The postpartum
period is well established as a high-risk period for demyelinating autoimmune
central nerve system diseases, such as multiple sclerosis , neuromyelitis
optica, and radiologically isolated syndrome- the precursor of multiple
sclerose. In these demyelinating diseases, and highly similar to PPMD, the
postpartum period confers a dramatically increased risk of both first-onset and
relapse episodes. Interestingly, psychotic symptoms are not infrequently
observed in patients with multiple sclerose. Furthermore, clinical features of
demyelination are observed in a substantial proportion of patients with
anti-NMDA receptor encephalitis, for which psychosis is frequently observed,
including postpartum psychosis. White matter abnormalities are widely
demonstrated to be the central pathophysiological cause in multiple sclerose,
even in areas that appear normal on standard Magnetic Resonance Imaging (MRI).
A more subtle form of white matter pathology has previously been shown in
bipolar patients using both brain imaging and postmortem immunohistochemistry.
This has also been shown in patients with a unipolar major depression . Both
grey and white matter abnormalities have been shown to be present during the
early stages of bipolar disorder. They are of potential pathophysiological
significance in bipolar disorder as they are associated with a poor clinical
and functional outcome with cognitive decline, suicide attempts and treatment
resistance.
The development of modern neuroimaging techniques, such as diffusion tensor
imaging, has allowed white matter abnormalities and the resulting abnormal
functional connectivity to be investigated in greater detail. Therefore, to
identify the underlying neurobiology of first-onset PPMD, we will use a
longitudinal prospective design, with neuroimaging both during the first-onset
acute phase, as well as after complete remission. Specifically, we will examine
white matter volume (structural imaging), whole-brain and tract-based white
matter microstructure (diffusion weighted imaging), and functional connectivity
(resting state and passive viewing fMRI). Besides we will examine lithium
concentration in the brain with magnetic resonance spectroscopy (MRS). Our
overall hypothesis is that white matter integrity will be impaired in women
with PPMD, and potentially distinguishable between women with a lifelong mood
disorder versus those with a vulnerability limited to the postpartum period.
Rationale secondary objectives
In current clinical practice, most women with first-onset severe postpartum
episodes are given a diagnosis of a lifelong mood disorder, mostly bipolar
disorder, mainly because of these severe affective symptoms. With an adequate
treatment regime, nearly all women with PPMD achieve a full remission. After
complete remission of this first episode, women get the recommendation to use
long-term maintenance pharmacotherapy. The traditional rationale underlying the
recommendation for chronic pharmacotherapy is the prevention of subsequent
psychotic and affective episodes. Importantly however, retrospective studies
have documented that a substantial proportion of women with PPMD appear not to
be at increased risk for subsequent episodes outside the postpartum period.
These women do not develop a lifelong bipolar disorder, with the most
significant implication being that these women might be unnecessarily exposed
to the potentially severe side effects of medication. They have vulnerability
to a mood disorder that is limited to the postpartum period (PPMD only).
Together, women with PPMD have one of two disease courses:
- Lifelong mood disorder with episodes outside the postpartum,
- PPMD only
The distinction is of profound clinical relevance given that the current
practice of diagnosing all women with classical bipolar disorder following
postpartum psychosis of postpartum depression has likely led to a substantial
proportion of women receiving long-term pharmacotherapy without any potential
benefit.
Therefore, a secondary objective of our research is to describe the
longitudinal course of women with a first-onset PPMD. Based on previous
research, we hypothesize that 60% of women have classical bipolar disorder,
while 40% of women will exhibit a vulnerability to affective psychosis or
depression that is limited to the postpartum period (PPMD only). Our main
variable of interest is relapse.
Relapse will be defined as the occurrence of any affective or psychotic
symptoms fulfilling DSM-IV-R criteria and severe enough to warrant treatment.
We will make a clear distinction of relapse after a subsequent pregnancy versus
a relapse outside the postpartum period, thereby enabling the distinction
between women with episodes of affective psychosis entirely limited to the
postpartum period (PPMD only) versus those with a lifelong mood disorder.
Another secondary objective is to find predictive factors for the
longitudinal disease course (and thus for the need for long-term maintenance
therapy) of PPMD. Postpartum psychosis is a psychiatric condition with an
intrinsically defined onset wi
Study objective
The overall aim of this study is to investigate the pathophysiology of PPMD,
and identify predictors of longitudinal outcome.
Primary Objective:
The primary objective is to investigate the underlying neurobiology of
first-onset PPMD using longitudinal neuroimaging.
Our overall hypothesis is that white matter integrity will be impaired in women
with PPMD, and potentially distinguishable between women with classical bipolar
disorder versus those with a vulnerability limited to the postpartum period.
Secondary Objective(s):
Secondary objectives are to describe the longitudinal course of women with
first-onset PPMD and to find predictive factors for the longitudinal disease
course (and thus for the need for long-term maintenance therapy).
We hypothesize, based on previous studies, that women with PPMD will emerge
into two primary subgroups; women for whom post-partum psychosis or depression
represents the onset of a lifelong course of bipolar disorder (60%) and women
in which episodes of affective psychosis or depression are entire limited to
the postpartum period (40%) (1-6). Our main variable of interest is relapse,
which will be defined as the occurrence of any affective or psychotic symptoms
fulfilling DSM-IV-R criteria and severe enough to warrant treatment. We will
make a clear distinction of relapse after a subsequent pregnancy versus a
relapse outside the postpartum period, thereby enabling the distinction between
women with episodes of affective psychosis entirely limited to the postpartum
period (PPMD only) versus those with a lifelong mood disorder.
Also we hypothesize that predictive factors for the longitudinal course might
include:
(a) timing of onset
(b) genetic vulnerability
(c) immune related vulnerability
Another secondary objective will be the assessment of early child development.
Study design
Design: Longitudinal naturalistic prospective cohort study
Duration: This is an ongoing prospective cohort study
Follow-up: 4 years
Setting: This is a multicenter prospective cohort study in the Netherlands in
which three mental health institutions collaborate: Erasmus Medical Center
Rotterdam, St. Antonius Ziekenhuis, Utrecht and Leiden University Medical Center
This study will be a longitudinal clinical cohort study examining white matter
integrity through MRI to identify the underlying neurobiology of PPMD (primary
objective). Subjects will be enrolled through the Onderzoeksprogramma
Postpartum Psychiatry Erasmus MC Rotterdam (OPPER) study. Additionally a
healthy control group of women from the normal population matched on
demographics and postpartum interval at the time of neuroimaging will be
included. The longitudinal design of this study with matched postpartum
controls is the ideal approach for both within-subject and between-group
comparisons.
*
Study burden and risks
The design of the study is non-therapeutic. The risks of participation are
minimal. No side effects of MRI are known. In addition, no contrast agents,
sedation, or X-rays are needed. The burden for participants will be the time of
scanning. The burden for the healthy control group will mainly be the actual
visits to the Erasmus MC and the time of the research. Benefit of participation
is an assessment of the early development of their child and appropriate care
if necessary. The information letter for participants discusses the possible
advantages and disadvantages of the study.
Important benefit of the proposed study is that it has the potential to both
advance our understanding of PPMD, as well as to identify risk and protective
factors guiding clinical decision-making.
's Gravendijkwal 230
Rotterdam 3015CE
NL
's Gravendijkwal 230
Rotterdam 3015CE
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in the OPPER study, a subject must meet
all of the following criteria (inclusion criteria OPPER study):, Inclusion
criteria patients:
• Age: 18-45
• Postpartum onset psychosis, mania or severe depression
• Written informed consent, Also, parents will be asked for consent to include
their children in our study (between the age of 2 and 5 years). , Inclusion
criteria healthy control:
• Age: 18-45
• No history or current DSM-V diagnosis
• Written informed consent
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in the OPPER study (exclusion criteria OPPER study):
• Patients whom are incapable to understand the information and to give
informed consent. And patients whom are unable to read or write.
• Drug/ alcohol dependence last 3 months
• Mental retardation (IQ < 80)
• Serious medical illness, Additional exclusion criteria for MRI scanning phase
Women will be excluded from the scanning phase of the study if they have any
contraindications for MRI scanning such as metal-containing implants. Before
the MRI scan all participants need to fill out a questionnaire to screen for
contraindications (see Annex F1a).
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL58913.078.16 |