WJ P World Journal of

Psychiatry
Submit a Manuscript: http://www.f6publishing.com World J Psychiatr 2017 June 22; 7(2): 77-88

DOI: 10.5498/wjp.v7.i2.77 ISSN 2220-3206 (online)

REVIEW

Understanding the pathophysiology of postpartum

psychosis: Challenges and new approaches

William Davies

William Davies, Medical Research Council Centre for Neuro­ Published online: June 22, 2017
psychiatric Genetics and Genomics and Division of Psychological
Medicine and Clinical Neurosciences, School of Medicine, Cardiff
University, Cardiff CF24 4HQ, United Kingdom

William Davies, School of Psychology, Cardiff University, Cardiff Abstract

CF10 3AT, United Kingdom Postpartum psychosis is a severe psychiatric condition
which affects 1-2 of every 1000 mothers shortly after
William Davies, Neuroscience and Mental Health Research childbirth. Whilst there is convincing evidence that the
Institute, Cardiff University, Cardiff CF24 4HQ, United Kingdom condition is precipitated by a complex combination of
biological and environmental factors, as yet the patho­
Author contributions: William Davies is the sole contributor to
physiological mechanisms remain extremely poorly
the article.
defined. Here, I critically review approaches that have
Supported by Medical Research Council Centre for Neuro­ been, or are being, employed to identify and characterise
psychiatric Genetics and Genomics, No. MR/L010305/1. such mechanisms; I also review a recent animal model
approach, and describe a novel biological risk model that
Conflict-of-interest statement: The author has no conflicts of it suggests. Clarification of biological risk mechanisms
interest to declare. underlying disorder risk should permit the identification
of relevant predictive biomarkers which will ensure that
Open-Access: This article is an open-access article which was “at risk” subjects receive prompt clinical intervention if
selected by an in-house editor and fully peer-reviewed by external required.
reviewers. It is distributed in accordance with the Creative
Commons Attribution Non Commercial (CC BY-NC 4.0) license,
Key words: CCN3 ; Immune system; Steroid sulfatase;
which permits others to distribute, remix, adapt, build upon this
work non-commercially, and license their derivative works on
Nephroblastoma-overexpressed; Mouse; Animal model;
different terms, provided the original work is properly cited and Risk factor
the use is non-commercial. See: http://creativecommons.org/
licenses/by-nc/4.0/ © The Author(s) 2017. Published by Baishideng Publishing
Group Inc. All rights reserved.
Manuscript source: Invited manuscript
Core tip: Postpartum psychosis is a severe psychiatric
Correspondence to: Dr. William Davies, School of Psychology, condition affecting a small proportion of women shortly
Cardiff University, Tower Building 70, Park Place, Cardiff CF10 after childbirth. The pathophysiological mechanisms
3AT, United Kingdom. [email protected] underlying risk for the condition are extremely poorly-
Telephone: +44-29-20870152 defined, but may include perturbed immune function,
Fax: +44-29-20874679
altered tryptophan metabolism and serotonergic
Received: November 7, 2016 dysfunction. Here, I critically review evidence underlying
Peer-review started: November 10, 2016 these assumptions, and discuss a novel model for
First decision: January 14, 2017 postpartum psychosis risk, involving maternal deficiency
Revised: February 8, 2017 for the enzyme steroid sulfatase, and overexpression of
Accepted: April 18, 2017 the CCN gene family, based upon emerging data from
Article in press: April 20, 2017 a recently-developed mouse animal model. Identifying

WJP|www.wjgnet.com 77 June 22, 2017|Volume 7|Issue 2|

 Davies W. Understanding the pathophysiology of postpartum psychosis

and characterising predictive biomarkers for postpartum A biological basis to risk?

psychosis risk will help to ensure prompt clinical inter­ The temporal proximity of PP onset to childbirth, its
vention if required. high relapse rate, and its relatively stable prevalence
and nature across societies and cultures, indicates that
risk for the condition may be substantially influenced
Davies W. Understanding the pathophysiology of postpartum [1,2]
by biological factors . The maternal body undergoes
psychosis: Challenges and new approaches. World J Psychiatr extreme physiological changes in the postpartum period,
2017; 7(2): 77-88 Available from: URL: http://www.wjgnet. notably a massive drop in circulating oestrogens upon
com/2220-3206/full/v7/i2/77.htm DOI: http://dx.doi.org/10.5498/ expulsion of the placenta. It has been suggested that
wjp.v7.i2.77
abnormal sensitivity to this endocrinological disturbance
[1,2]
may confer vulnerability to PP in some women , an idea
supported by the fact that oestrogen supplementation
[9,10]
may be beneficial to some patients . The fact that
INTRODUCTION PP is often responsive to antipsychotic treatment in­
What is postpartum psychosis? dicates that abnormal serotonergic and/or dopaminergic
Postpartum, or puerperal, psychosis (PP) is a severe function may play a role in its pathogenesis; there is
psychiatric disorder which typically manifests within days a well-established link between oestrogen levels and
[11]
of childbirth in a small proportion of women (1-2 in every serotonergic function . An increasing body of literature
[1,2]
1000 new mothers) . The main symptoms of PP include has implicated immune system dysfunction in psychotic
[12] [13]
hallucinations and delusions, cognitive disorganisation disorders in general and in PP specifically , whilst
[14]
[1,2]
and confusion, anxiety and sleep problems ; rarely, thyroid system abnormalities and other autoimmune
[15]
affected mothers may attempt to injure themselves or conditions have been reported in some cases of PP.
their child, with maternal suicide and infanticide observed Although the epidemiology, risk/protective factors,
in some cases. Pharmacological treatments are relatively and comorbid phenotypes associated with PP have
been systematically investigated and several have been
efficacious if administered promptly and in combination
[1,2] consistently replicated (albeit by a small number of
with psychotherapy and psychoeducation : These
research groups), the molecular, cellular and neural
include a range of typical and atypical antipsychotic drugs
pathophysiology of the condition is currently very poorly
and mood stabilisers (given that mood fluctuations,
understood. Below, I list some contemporary approaches
or bipolarity, may precede and/or be exacerbated by
aimed at addressing this issue and their successes
PP); prophylactic pharmacotherapy may also be used
[1,2] and limitations. Understanding the biological factors
judiciously in women at high risk of PP .
that confer PP risk will be important for identifying and
characterising novel drug targets for more efficacious,
Risk and protective factors less toxic, pharmacotherapy; however, given the re­
The single largest risk factor for PP is a personal, or asonable efficacy of currently available medications this
family, history of bipolar disorder or related psychotic is perhaps not the main goal. A more pressing aim once
[1,2]
disorder (seen in about 40%-50% of PP cases ). Other biological risk pathways have been identified will be to
risk factors that have been suggested as modulators of describe predictive biomarkers which may be used to
PP risk include: Primiparity, maternal age, stress levels classify individuals at risk of the condition early in their
[1-4]
in the puerperium, and maternal sleep problems ; pregnancy, and to ensure that they are closely monitored
in contrast to postpartum depression, adverse early- and have prompt access to appropriate clinical expertise
life events do not appear to significantly enhance risk and facilities if required.
[5]
of developing PP in women with bipolar disorder . The
condition is associated with obstetric complications,
[6]
notably pre-eclampsia , a potentially-damaging increase in CURRENT APPROACHES TO
maternal blood pressure. In common with other psychotic UNDERSTANDING POSTPARTUM
spectrum conditions such as schizophrenia, psychosis-
related phenotypes in the perinatal period seem to be PSYCHOSIS AND THEIR LIMITATIONS
higher in immigrant populations, possibly as a function There are a number of diverse approaches that have
of being exposed to new infections, or to high levels been employed in trying to understand the patho­
[7]
of stress . A recent intriguing study has tentatively physiology of PP. These investigational methods, and
suggested that women who smoke exhibit reduced their relative advantages and limitations are summarised
[8]
risk of developing PP , although the questions as to in Table 1.
whether this association is genuine, whether cigarettes
somehow confer biological protection, or whether the Clinical biochemistry
smoking and non-smoking groups differ on some other One conceptually-simple approach to understanding the
critical demographic, biological or psychological measure biology of PP is to compare the biochemistry of patients
unrelated to smoking remain to be directly addressed. diagnosed with PP with that of appropriate controls

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 Davies W. Understanding the pathophysiology of postpartum psychosis

Table 1 The advantages and limitations of methods for investigating biological risk factors in individuals with postpartum psychosis

Investigational method Advantages of method Limitations of method

Clinical biochemistry or Direct assessment in patient or “at risk” Difficult to access central nervous system; peripheral changes may not reflect
gene expression analyses groups central functional abnormalities
Possibility of identifying peripheral Potential issues with obtaining consent for samples
biomarkers for PP risk Substantial fluctuation of markers with participant demographics, experiences
and treatments
Possible issues related to reverse causation, i.e., are abnormalities a cause or
consequence of the disorder?
Neuroimaging Direct assessment of brain structure, Cannot easily be performed during psychotic episodes
function or chemistry in patient or “at risk” Substantial exclusion criteria for procedure
groups Limited resolution; cannot provide information on most neurochemical,
cellular or molecular abnormalities
Substantial fluctuation of measures with participant demographics,
experiences and treatments
Possible issues related to reverse causation, i.e., are abnormalities a cause or
consequence of the disorder?
Genetics DNA can be readily obtained from patient Low power of genome-wide studies as a consequence of low prevalence of the
or “at risk” groups from peripheral tissues condition; possibility of false positives and negatives
DNA sequence is stable and unaffected by
variability in patient’s circumstances
Possibility of identifying biomarkers that
can predict risk at an early stage
Few issues with reverse causation
Porcine infanticide model Some degree of face validity Questionable relevance of animal behavioural phenotypes to PP symptoms
Direct access to brain tissue for detailed Difficult and expensive to breed and maintain
examination and DNA for genetic studies Not readily amenable to pharmacological studies; predictive validity unclear
Difficult to systematically assess all brain regions
STS-inhibition mouse model Some degree of face and predictive validity Questionable relevance of animal behavioural phenotypes to PP symptoms
Direct access to brain tissue for detailed Face and predictive validity require further confirmation
examination STS deficiency unconfirmed in PP cases, hence construct validity
Relatively cheap to breed and maintain unsubstantiated
Amenable to pharmacological and genomic
studies

PP: Postpartum psychosis; STS: Steroid sulfatase.

(either postpartum mothers without psychosis, or non- (CSF)] is very limited or impossible. Whilst this may not
postpartum females). Studies to date have focussed on be a major concern with regard to developing predictive
levels of tryptophan and its metabolites (i.e., precursors peripheral biomarkers, the relationship between any
[16] [13] [14]
of serotonin) , and the immune and thyroid systems, peripheral tissue changes and abnormal brain function
the latter two systems being in considerable flux during underlying behavioural phenotypes is difficult to chara­
pregnancy and in the perinatal period. The main findings cterise. Finally, biochemical measures can fluctuate
of these studies may be summarised, respectively, as: (1) substantially as a function of demographic variables,
deficient tryptophan breakdown, and lower kynurenine physiological and general health status, psychosocial
production, is evident in women with postpartum mood factors and drug regime; hence, identifying physiological
disorders; (2) abnormally low T cell numbers, and over- measures which definitively and reliably differentiate
activation of the monocyte/macrophage arm of the individuals with PP from healthy individuals, and esta­
immune system is evident in the postpartum period in blishing exactly how these measures correlate with
women diagnosed with PP; and (3) patients with PP have phenotype, is extremely challenging. Moreover, there
a higher prevalence of autoimmune thyroid disease than is the potential issue of reverse causation whereby it
controls. is difficult to establish unambiguously whether specific
Whilst this type of study undoubtedly provides clinically- biochemical differences between individuals with PP and
relevant knowledge about the abnormal biology asso­ healthy controls are a cause or a consequence of the
ciated with PP, it is limited in several key ways. First, it condition and its treatment.
is difficult to obtain biological samples from psychotic
patients, particularly where these patients lack capacity Neuroimaging
to consent to experimental procedures, and where The biochemical studies above are limited by their ability
they may be socially and geographically isolated from to directly assay brain function. The development of
individuals who can give consent on their behalf. Second, elegant neuroimaging techniques, including functional
the biological samples that can be obtained are peripheral magnetic resonance imaging (fMRI) and Diffusion Tensor
(typically blood or serum); accessibility to more relevant Imaging over the past couple of decades, has opened up
tissue from patients [brain, or even cerebro-spinal fluid the possibility of identifying neural substrates associated

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 Davies W. Understanding the pathophysiology of postpartum psychosis

with PP vulnerability. Neuroimaging studies in this area our existing knowledge, it seems likely that, in common
are scarce, presumably due to issues with participant with related mood and psychotic disorders, genetic risk
recruitment and testing. To date, no brain circuitry has for PP will be complex and polygenic; hence, genomic
consistently be shown to develop or function abnormally analyses in PP, even with several thousand cases, will be
in cases of PP. A recent case-control study has suggested limited by relatively low power.
that individuals developing PP have a reduced anterior Genetic studies that have been performed in PP to
[17]
cingulate cortex (ACC) volume . As the ACC plays an date have employed small sample sizes (< 1000 cases),
important role in cognitive and emotional processing, and hence their conclusions should be regarded with
including in impulse control, decision-making and cognitive caution: Low power implies a high rate of both false
organisation, it represents an interesting neural candidate positive and false negative findings. A seminal genetic
for further study. Rare cases with PP who have been (linkage) study in bipolar affective postpartum psychosis
[18]
imaged have reported altered ventricular morphology , suggested evidence for significant and suggestive risk
[19] [23]
abnormal orbitofrontal cortex reactivity and structural loci at 16p13 and 8q24 respectively ; the regions
[20]
abnormalities of the corpus callosum . implicated contained multiple genes, many of which
Imaging studies, like biochemical studies, are limited could theoretically have mediated PP risk. Efforts are
in several ways. First, for practical reasons, it is not currently underway to undertake a sufficiently-powered
possible to examine brain function during psychotic genome-wide association study (GWAS) in bipolar
episodes, and this has to be assessed in “recovered”, or affective postpartum psychosis, but as yet these have not
“at risk” participants - hence, the relevance of findings yielded significant findings. Candidate gene-led studies in
from, e.g., fMRI studies to psychotic experiences is PP have focussed upon serotonergic system genes given
questionable. Moreover, imaging measures, particularly the therapeutic efficacy of antipsychotics; one study
“snapshot” studies, may be confounded by a patient’s provided suggestive evidence for association within the
[24]
demography, life history and comorbid diagnoses, and serotonin transporter and serotonin 2A receptor genes .
current and previous medication regimes. Finally, whilst However, candidate gene association studies, which focus
neuroimaging can identify brain regions and circuits that upon genes of likely biological relevance to a condition,
may be of potential interest, and sophisticated techniques often have low replication rates and are inevitably
[25]
like magnetic resonance spectroscopy might identify biased by our very limited current knowledge base .
reasonably highly spatially-resolved changes in limited Other candidate gene association studies in PP have
brain neurochemistry, such approaches cannot identify examined a number of genes important in serotonergic
most changes in neurochemistry, nor altered cellular or and oestrogenic signalling, and the immune response,
molecular function. but, as yet, these have yielded mixed findings with little
[1]
consistent evidence for robust risk variants . Genomic
Genetics techniques such as exome, or even whole-genome, se­
Psychiatric genomics has recently come of age, with quencing are feasible in the relatively small number of PP
genetic risk variants associated with psychosis risk now samples available, but here again, low power will make
being reliably identified via genome screens in patients drawing any conclusions about the pathogenicity of any
with psychotic and mood disorders such as schizophrenia potentially-causal genetic variants difficult.
[21]
and bipolar disorder . Genetic studies offer two key Besides looking at the DNA sequence per se, insights
advantages over the above approaches: First, genomic into PP pathogenesis may be obtained by comparing the
material (DNA) can be reliably obtained from accessible epigenome or gene expression profiles in individuals with
tissues (typically saliva or blood), and DNA sequence is PP and controls. One such study focussed upon microRNAs
essentially conserved between these peripheral tissues known to regulate the immune response and demonstrated
and the brain. Second, genetic sequence is stable altered expression of miR-146a and miR-212 in patients
[26]
throughout life, and unlike biochemical or brain function with PP relative to healthy controls . However, whether
measures, is not affected by environmental, psychosocial these changes were a cause or consequence of the
or pharmacological influences. disorder (and associated medications) is unclear. Moreover,
The robust identification of common risk variants like with candidate gene association studies, expression
that increase risk of complex psychiatric disorders by a studies focussing on just a handful of pre-selected genes
small amount, or of rare variants that confer greater risk, provide limited information on the specificity of the changes
necessitates the use of large sample sizes (conceivably or on general risk pathways; for example, it could feasibly
up to 100000 cases to detect a high proportion of risk be the case that the expression of a large proportion of
variants). For relatively common psychiatric disorders microRNAs is perturbed in PP.
such as schizophrenia and bipolar disorder obtaining
this number of cases is feasible through collaborative The porcine infanticide model of PP
enterprises such as the Psychiatric Genomics Con­ A further approach towards understanding the biological
[22]
sortium . For rare disorders such as PP it is unlikely that basis of PP risk is through the use of animal models.
such large numbers of participants can be recruited, even Animal models permit a degree of experimental control
with extensive inter-institutional working. Based upon that cannot be achieved in clinical, or other human,

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 Davies W. Understanding the pathophysiology of postpartum psychosis

studies and allow procedures that would be ethically

PATHWAYS TO PROGRESS
prohibited in humans to be conducted; however, there is
some resistance to the use of animals, and particularly Despite decades spent studying the illness, and the
non-primate species, for modelling complex psychiatric availability of cutting-edge experimental techniques and
phenotypes characterised by deficits in “uniquely- research hardware, we are still far from understanding
human” aspects of behaviour and cognition. The first the biological and psychological risk factors underpinning
published animal model for PP is the infanticidal sow pig, PP and hence how to identify women at greatest risk for
which exhibits several epidemiological, behavioural and the condition. Below, I briefly outline what I believe is
endocrinological traits associated with the condition .
[27] required in order to make progress in this area over the
An early quantitative trait locus (QTL) study in this next decade.
model identified four possible genomic loci of interest Perhaps the main factor hindering progress in PP
on chromosomes 2, 10 and X, corresponding to human research is sample size. It is now well recognised in
chromosomal loci 5q14.3-15, 1q32, Xpter-Xp2.1, and psychiatry that groups from around the world must
[27]
Xq2.4-Xqter respectively ; an independent linkage collaborate in order to generate an adequately-powered,
study confirmed an association between X-linked loci and consistently and deeply-phenotyped cohort of patients
maternal aggression, and suggested regions of interest (and their affected and non-affected relatives) in which
[28]
on chromosomes 2, 6, 14 and 15 . Examination of genetic, biochemical and neuroimaging analyses can be
hypothalamic gene expression in the maternal infanticide undertaken; such a large sample will permit factors such
model identified multiple genes, the expression of which as drug treatment, demography and symptomatology to
was altered in pigs showing aberrant behaviour; several be covaried for, and hence for robust genotype-biology-
of these mapped to the previously-implicated QTL phenotype correlations to be ascertained. There are
regions [of particular note were the HTR2C (serotonin ongoing collaborative efforts in the field of PP research
receptor 2C), DRD2 (dopamine receptor 2) and PRL involving centres of excellence across Europe and the
(prolactin) genes, the first two encoding antipsychotic drug United States, and these should soon begin to bear fruit.
[29]
targets ]. A genome-wide association study in this model One research area that has been relatively neglected
indicated candidate regions on porcine chromosomes 3, to date is deciphering the fundamental psychological
4 and 15, syntenic with human chromosomal regions processes that distinguish mothers who develop PP from:
implicated in bipolar disorder and postpartum psychosis (1) those who have bipolar disorder and do not develop
[30]
(including 16p13) , whilst a candidate gene association the condition; or (2) from healthy mothers. Specifying
study suggested preliminary evidence for association how “at risk” women differ from “protected” women
with oestrogen receptor (ESR1), excitatory amino acid on measures of behaviour and cognition, may feasibly
transporter 2 (EAAT2) and dopamine receptor 1 (DRD1) permit the development of a simple screening test to be
genes, but not HTR2C .
[31]
applied prior to childbirth, and may provide clues as to
The fact that the pig model described above shows underlying neurobiology.
some superficial phenotypic similarities to patients with Even with larger numbers of cases available for
PP (“face validity”), and that it indicates genomic regions, genome-wide genetic analyses, there is a strong possibility
and specific gene candidates, of possible functional that only a handful of polymorphisms or mutations
relevance, suggests that it may represent a reasonable associated with PP risk will be identified, and that many
model for PP. However, it should be acknowledged will not reach genome-wide levels of significance after
that the model is compromised in a number of ways the requisite stringent multiple testing corrections.
which may limit its utility. First, there is a relatively poor Hence, there may still be a role for sensible candidate
correlation between the clinical and animal behavioural gene association studies comparing variant frequency
profiles, in that the vast majority of women with PP are in cases and controls, where higher levels of alpha (as a
not aggressive, and even those who are aggressive consequence of reduced multiple testing) are more likely
will not attempt infanticide. Second, this large animal to give rise to statistically significant findings. However,
model is difficult and expensive to breed, maintain, and as discussed above, traditional candidate gene studies
analyse experimentally. Of particular note, it is difficult based upon theoretical causal or therapeutic mechanisms
to test whether the infanticide phenotype is sensitive have frequently been shown to be irreproducible, or to
to antipsychotic administration - hence it is difficult give rise to findings of a much smaller magnitude than
[25,32]
to determine the extent to which this phenotype is initially suspected . Moreover, genome-wide association
analogous to PP, and to assess whether or not the model studies have repeatedly demonstrated that genetic
has any degree of predictive validity. Another main issue variants robustly associated with disorder risk are often
is that, because the brain of the pig is relatively large, poorly-annotated and have unknown effects on biology,
it is difficult to investigate all regions where abnormal and hence would not have been prioritised in candidate-
[32]
activity may be observed; whilst previous work has led approaches . Bearing in mind these caveats,
understandably focused on the hypothalamus given its proposals for candidate PP genes should be supported by
known role in maternal behaviour, there is, as yet, little multiple converging lines of evidence, and should ideally
convincing evidence for impaired hypothalamic function exhibit both positional and functional relevance. In the
in PP cases. following section, I describe a candidate gene backed by

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 Davies W. Understanding the pathophysiology of postpartum psychosis

[40]
such evidence. placenta, uterus, brain ) and hence its dysfunction may,
There is also clearly a need for more experimentally- a priori, be expected to impact upon normal reproductive
tractable animal and cellular models, in which molecular, physiology. Recently, placental mis-expression of the STS
[41]
cellular and circuit mechanisms that may influence PP gene has been implicated in pre-eclampsia risk . It is
risk can be characterised. In terms of animal models, plausible that in STS-deficient mothers, where baseline
[42]
ideally these should be available to be tested in large, oestrogen levels may already be low , expulsion of the
well-defined batches, be neurobiologically-amenable, oestrogenic placenta precipitates psychosis vulnerability.
and exhibit some degree of face, construct and predictive There is also some evidence that women who are carriers
validity (the latter in contrast to the porcine infanticide for STS mutations, and who are STS-deficient, are at
model). In terms of cellular models, the advent of induced increased risk of psychological abnormalities (unpublished
pluripotent stem cell technology technology now means results) and of delayed, or prolonged labour, and related
[43]
that “pathological” samples such as brain cell cultures obstetric complications ; such complications, and the
can ultimately be generated from patient fibroblast, or accompanying psychological stress, may be one pre­
[33]
other peripheral, cells . Any data generated from in vitro cipitant of postpartum psychiatric distress, although a
[1,44]
studies in which derived-brain cells are examined in specific link to PP remains unconfirmed .
isolation, should be extrapolated cautiously given that In the developing and adult brain, STS is expressed in
PP risk, in common with the risk of related psychiatric regions implicated in postpartum psychosis. Specifically,
conditions such as schizophrenia and depression, is likely to it is highly expressed in the thalamus (involved in the
be modulated by complex ongoing interactions between integration and usage of sensory information) and through­
[45,46]
a multitude of intra-brain and extra-brain (e.g., hormonal, out the cortex (including the cingulate cortex) ; it is
[34]
placental or immune system) factors . also highly expressed in the hypothalamus, and outside
[45,46]
the brain in the thyroid gland . Hence, its absence
may feasibly give rise to abnormal hypothalamic-pituitary-
A NEW CANDIDATE GENE adrenal or hypothalamic-pituitary-thyroid function, con­
I have previously proposed, based upon numerous lines sistent with notions of an abnormal stress response, or
of clinical and basic scientific evidence, that maternal thyroid pathology, in cases of PP.
deficiency for the enzyme steroid sulfatase, encoded by Parallel clinical and animal model studies have demon­
the X-linked STS gene, may represent one candidate risk strated that STS deficiency (or genetic variation within
[35]
mechanism for PP . The STS enzyme cleaves sulfate STS) gives rise to behavioural phenotypes of relevance to
groups from a variety of steroid hormones, notably dehy­ PP including psychosis, cognitive disorganisation, anxiety,
droepiandrosterone sulfate (DHEAS), thus allowing them depression and, rarely, aggression (unpublished results
[46-49]
to be used as precursors for a variety of androgens and and ref. ). Moreover, there is a positive correlation
oestrogens; hence it is a key modulator of the steroid between serum levels of DHEAS and psychoticism (anxiety,
hormone axis. There are a number of criteria that candi­ paranoia, psychosis) in healthy women and women ex­
[50,51]
date genes and pathways for PP may be expected to hibiting postpartum psychiatric distress . Data from
meet based upon our existing knowledge; the STS gene genetic and pharmacological rodent models suggest that
and the processes which it modulates meet many of deficiency for STS may impact upon neurochemistry
these. of relevance to psychosis vulnerability including altered
One might expect the candidate system to be in levels of hippocampal serotonin (and Htr2c receptors)
[52,53]
flux in the postpartum period, and to influence immune and acetylcholine .
function at this time; in mice, and perhaps also in man, Finally, STS was explicitly suggested as a candidate
brain levels of STS are elevated specifically shortly after gene underlying significant X-linked QTLs in the porcine
[36] [27]
giving birth . In healthy women, reduced levels of maternal infanticide model of PP .
serum DHEA in the postpartum period are associated
[37]
with activation of the immune system ; conceivably,
in STS-deficient women, abnormally low levels of post­ INSIGHTS FROM A NEW MOUSE MODEL
partum DHEA (as a consequence of impaired DHEAS The only existing animal model for PP, the porcine ma­
desulfation) may result in hyperactivation of the immune ternal infanticide model, is sub-optimal. We have recently
system. attempted to develop a more experimentally-tractable
The steroid hormone axis has repeatedly been im­ mouse model for the condition, based upon the idea that
plicated in the pathogenesis of PP given the sudden drop maternal steroid sulfatase deficiency is a putative risk
[54]
in circulating oestrogen levels in the mother following factor .
birth, and the suspected protective effects of oestrogens Briefly, we showed that pharmacological inhibition
[38]
against psychosis ; indeed, early candidate gene of the steroid sulfatase enzyme in new mouse mothers
association studies focussed upon those regions of the resulted in behavioural, endocrinological and genetic
[39]
genome thought to be regulated by oestrogens . STS phenotypes partially mirroring those seen in PP (“face
is a key player within this axis. STS is highly expressed validity”). Whilst STS inhibition did not affect gross health,
in key reproductive tissues (testis, mammary gland, maternal behaviours or activity, it did have subtle effects on

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 Davies W. Understanding the pathophysiology of postpartum psychosis

exploration of the elevated plus maze (increased rearing dysregulation of the CCN gene family arising down­stream
and reduced latency to enter the exposed open arms) and of dysfunction of the STS axis may be implicated in PP
the startle response (reduced with enzyme inhibition); risk. Is this a reasonable concept? If so, can this evaluation
a reduced startle response is a feature of patients with suggest molecular, cellular and neural pathways that could
[55]
bipolar disorder . These observations support the notion be perturbed in PP and that could feasibly be targeted
of STS as a modulator of postpartum maternal behaviour. via re-purposing of existing drugs, or through developing
STS inhibition did not seem to influence levels of the new drugs?
main stress hormone corticosterone in mice, consistent The CCN gene family encodes a number of secreted
with data indicating that women with PP show normal extracellular matrix-associated proteins that are highly-
[56]
cortisol levels . [58]
expressed in the brain ; impaired function of the ex­
Previous work had suggested that a small genomic tracellular matrix, and the subsequent abnormal cell-
region on mouse chromosome 15 harboured a QTL cell interactions, have recently received attention as a
influencing rearing and open arm latency measures in the possible pathophysiological mechanism in a number of
[57]
elevated plus maze ; excitingly, this region of chromo­ [59]
mood disorders . This gene family is also known to be
some 15 was syntenic with human chromosome 8q24, important in female reproductive function , exhibits
[60]

[23]
a region implicated in PP pathogenesis by linkage . dynamic brain expression throughout pregnancy and the
Expression screening of the small number of genes within [61]
puerperium , and modulates Notch and Wnt signalling
the mouse chromosome 15 interval revealed just one, pathways
[57]
that are disrupted in bipolar disorder
[62]

Nov/Ccn3, whose expression was significantly altered and cases of postpartum psychiatric disturbance .
[63]

(upregulated) in STS-inhibited brain; the expression of Interestingly, the expression of CCN family members may
two other genes from the Ccn family (Ctgf/Ccn2 and also be altered by the administration of substances that
Wisp1/Ccn4), as well as genes whose products may be induce psychosis-like states
[64,65] [66]
, by social stress and
co-regulated with Nov/CCN3 (Arhgdig, Adcy8 and Ccl2) by small molecules including cytokines and serotonin
[67]
[54]
was also increased in STS-inhibited brain tissue . suggesting these members as possible mediators of
An advantage of the mouse model is that it is possible analogues of psychosis.
to test whether putative PP-relevant behavioural and CCN3 is of particular interest as a candidate modulator
molecular features are sensitive to antipsychotic admini­ of PP risk given the location of the associated gene directly
stration, i.e., to test whether it has potential predictive under the 8q24 linkage peak. There is also emerging evidence
validity. We showed that administration of clinically- from a study in human female (cervical cancer) cells that
relevant doses of the atypical antipsychotic ziprasidone STS and DHEA can directly influence the expression of the
reverses the deficient startle response, and tempers the [68]
integrin β1 molecule , a known interactor with CCN3 in
over-expression of Nov/Ccn3 in the STS-inhibited mouse, the brain and a putative mediator of CCN3-induced effects
indicating that these facets of the model may be relevant on cytokine secretion .
[69]
[54]
to psychotic pathophysiology . The CCN3 protein exhibits a variety of additional
Although the STS-inhibited mouse shows some degree features that strengthen its candidacy. First, it regulates
of promise as a model for PP, its face validity needs to be intracellular calcium signalling
[70]
a process that goes
defined more thoroughly. For example, does it show the [71] [72]
awry in both bipolar disorder and PP . Second, it is highly
abnormalities in the tryptophan-kynurenine pathways expressed in the brain’s cortex and limbic system , and
[58]

and immune system that have been reported in PP its expression is dampened by circulating oestrogens .
[73]

cases? One limitation of the current pharmacological It is apparently a regulator of axonal outgrowth of callosal
model is that steroid sulfatase is solely inhibited in the [74]
projection neurons , a finding of interest in light of possible
postpartum period - if STS deficiency is truly a risk factor corpus callosum abnormalities in cases of PP . The fact
[20]

for PP, it would likely be genetic in origin, and operate that CCN3 modulates placental angiogenesis , that the
[60]

throughout life (including pregnancy and the postpartum associated gene is located 70kb from a GWAS hit for
period). Hence, it would be useful to examine the [75]
hypertension and that it, and its family members, are
behaviour and physiology of new mouse mothers that regulated by thyroid hormone derivatives in the cortex of
lack one (or both) functional STS alleles, and hence have [76]
the brain , is consistent with the epidemiological studies
reduced constitutive STS expression; such knockout
showing overlap between PP, pre-eclampsia and thyroid
mice have historically proved difficult to generate due to
abnormalities. Given the preliminary findings regarding
the complex genomic architecture around the STS locus,
a potential attenuation effect of smoking on PP risk, it
but this difficulty may potentially be overcome with new
is interesting to note that the CCN3 gene lies close to a
genetic engineering technologies such as CRISPR.
single nucleotide polymorphism nominally associated
[77]
with smoking cessation , and that in female mouse
A NEW PATHWAY TO PATHOLOGY AND tissues Ccn3 expression is reduced upon exposure to
[78]
cigarette smoke . The protein DDR1 is a putative
TREATMENT? receptor mediating CCN3 signalling ; there is some
[79]

The new mouse model described above indicates, on evidence suggesting association of genetic variants within
[80,81]
the basis of analyses agnostic to gene function, that DDR1 with psychotic illness .

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 Davies W. Understanding the pathophysiology of postpartum psychosis

Abnormal behaviour in postpartum period

Hallucinations, delusions, anxiety, cognitive disorganisation, mood problems. Possible suicidal or infanticidal ideation, and completed suicide or
infanticide

Environmental risk factors in

Placental dysfunction postpartum period
Aberrant secretion of signalling molecules E.g. , psychosocial stressors, sleep
such as oestrogens and placental lactogens disruption

"At risk" personality and psychological traits

including bipolar disorder

Altered brain anatomy and physiology Altered function of CCN gene family members
Abnormal development of multiple brain regions including thalamus, and interactors in brain and other tissues (e.g. ,
cortex, corpus callosum and hypothalamus placenta)
Disruption of serotonergic and cholinergic systems Disrupted extracellular matrix function, and
abnormal signalling to cytoplasm via , e.g. ,
Notch and integrin pathways

Dysfunction of endocrine organs

Aberrant secretion of signalling molecules such
as oestrogens and thyroid hormones

Baseline genetic and environmental risk factors

Possession of multiple genetic risk variants and exposure to general environmental risk factors

Figure 1 A revised model for postpartum psychosis risk. We suggest that multiple genetic risk variants (potentially influencing STS and CCN family member
function), in combination with environmental risk factors, adversely affect the function of multiple endocrine organs (notably placenta and thyroid gland) and increase
expression of CCN family members in brain and placenta, to elicit functional changes in brain architecture and neurochemistry which predispose to postpartum
psychosis risk. This risk may be further exacerbated by acute environmental risk factors acting within the postpartum such as psychosocial stressors (plausibly also
acting via CCN-mediated pathways). Putative and well-characterised protective factors such as smoking and antipsychotic administration respectively could potentially
exert their effects via normalisation of CCN family member function.

Finally, converging evidence from a genetic mouse dysfunction, and disruption to CCN family members
model is consistent with the notion that Ccn3 over­ based upon current knowledge is presented in Figure
expression is associated with abnormal maternal be­ 1. This model may be updated and refined as new data
haviour. Specifically, wildtype mouse mothers carrying emerge from avenues including larger genomic screens,
pups with genetic modifications which affect placental hypothesis-free gene expression screens in model
(spongiotrophoblast) function exhibit abnormal maternal systems, and physiological measurements in patients
and anxiety-related behaviours in the postpartum period with PP. The model makes several readily-testable clinical
and significantly increased hippocampal Nov/Ccn3 gene predictions for PP cases relative to control subjects: (1)
[54,82]
expression ; this finding is intriguing as it suggests the there will be an excess of genetic variants that reduce STS
possibility that the secretion (or lack thereof) of one or function and enhance CCN3 expression; (2) there will be
more circulating factors from the placenta can indirectly an increased DHEAS:DHEA tissue ratio; and (3) there will
affect brain expression of Nov/Ccn3, and subsequently be elevated levels of CCN3 in accessible fluids including
[86]
maternal behaviour. The spongiotrophoblast is involved serum, cerebrospinal fluid and urine . In parallel to these
in the synthesis and secretion of multiple compounds clinical studies, we could potentially demonstrate whether
which have been shown to influence maternal behaviour or not CCN3 contributes significantly to abnormal maternal
in rodent models and which may plausibly mediate this behavioural phenotypes in mice by administering an
effect (e.g., placental lactogens and pregnancy-specific STS inhibitor to wildtype mice and readily-available Ccn3
[83] [87]
glycoproteins ). Interestingly, in humans, placental knockout mice , with the prediction being that wildtype
lactogen is secreted by the syncytiotrophoblast of the mice would exhibit behavioural abnormalities whereas
[84] [85]
placenta , a site of high STS expression . knockout mice would not.
An integrated model showing how PP risk may Should CCN family member over-expression be
conceivably be influenced by STS deficiency, placental confirmed as a PP risk factor by future clinical and basic

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 Davies W. Understanding the pathophysiology of postpartum psychosis

studies, it may be amenable to pharmacological ameliora­ psychosis. J Womens Health (Larchmt) 2006; 15: 352-368 [PMID:
tion by, amongst other approaches, antibody-targeting 16724884 DOI: 10.1089/jwh.2006.15.352]
[88] 3 Di Florio A, Jones L, Forty L, Gordon-Smith K, Blackmore ER,
or knockdown strategies ; such interventions may have
Heron J, Craddock N, Jones I. Mood disorders and parity - a clue
therapeutic benefits and offer an alternative to more to the aetiology of the postpartum trigger. J Affect Disord 2014;
conventional mood stabiliser and antipsychotic approaches. 152-154: 334-339 [PMID: 24446553 DOI: 10.1016/j.jad.2013.09.034]
4 Lewis KJ, Foster RG, Jones IR. Is sleep disruption a trigger for
postpartum psychosis? Br J Psychiatry 2016; 208: 409-411 [PMID:
CONCLUSION 27143002 DOI: 10.1192/bjp.bp.115.166314]
5 Perry A, Gordon-Smith K, Di Florio A, Forty L, Craddock N, Jones
Numerous features of postpartum psychosis (notably L, Jones I. Adverse childhood life events and postpartum psychosis
its low prevalence, its high degree of heterogeneity, its in bipolar disorder. J Affect Disord 2016; 205: 69-72 [PMID:
relative unpredictability and a lack of relevant animal and 27420133 DOI: 10.1016/j.jad.2016.06.061]
cellular models) make understanding its pathophysiology 6 Bergink V, Laursen TM, Johannsen BM, Kushner SA, Meltzer-
difficult. Whilst research to date has provided tantalising Brody S, Munk-Olsen T. Pre-eclampsia and first-onset postpartum
psychiatric episodes: a Danish population-based cohort study.
hints at pathways and systems that may be perturbed in
Psychol Med 2015; 45: 3481-3489 [PMID: 26243040 DOI:
the condition, the questions as to whether or not they are 10.1017/S0033291715001385]
truly pathogenic remains to be addressed. Undoubtedly, 7 MacKinnon AL, Naguib M, Barr HJ, Levinsson A, Robins S,
there are many more risk pathways to be discovered. Feeley N, Hayton B, Zelkowitz P, Gold I. Delusional ideation during
To make meaningful progress in understanding the the perinatal period in a community sample. Schizophr Res 2017;
179: 17-22 [PMID: 27670238 DOI: 10.1016/j.schres.2016.09.027]
molecular, cellular, neural and psychological mecha­
8 Di Florio A, Morgan H, Jones L, Forty L, Gordon-Smith K,
nisms underlying PP risk it will be necessary to adopt Craddock N, Jones I. Smoking and postpartum psychosis. Bipolar
a converging experimental approach comprising large- Disord 2015; 17: 572-573 [PMID: 26241192 DOI: 10.1111/bdi.12314]
scale genetic (association, copy number variations and 9 Balaraman Y, Schmetzer AD. Hormonal replacement therapy
sequencing), gene expression and genetic neuroimaging in postpartum affective disorders. Ann Clin Psychiatry 2011; 23:
studies, clinical studies correlating behavioural phenotypes 71-72 [PMID: 21318198]
10 Huang MC, Wang YB, Chan CH. Estrogen-progesterone com­
with phy­siological markers of immune, neurochemical bination for treatment-refractory post-partum mania. Psychiatry Clin
and neuro­endocrine dysfunction, and animal (pig and Neurosci 2008; 62: 126 [PMID: 18289153 DOI: 10.1111/j.1440-
mouse) and cellular (e.g., induced pluripotent stem cells) 1819.2007.01782.x]
model studies, bearing in mind the many caveats raised 11 Barth C, Villringer A, Sacher J. Sex hormones affect neurotran­
above. Importantly, hypothesis-free approaches such smitters and shape the adult female brain during hormonal
transition periods. Front Neurosci 2015; 9: 37 [PMID: 25750611
as the genomic and animal/cellular model approaches
DOI: 10.3389/fnins.2015.00037]
may identify non-obvious risk pathways which can then 12 Leboyer M, Oliveira J, Tamouza R, Groc L. Is it time for im­
be followed up in more focussed clinical analyses. The munopsychiatry in psychotic disorders? Psychopharmacology
prioritisation of candidate pathways may be informed by (Berl) 2016; 233: 1651-1660 [PMID: 26988846 DOI: 10.1007/
work examining the physiology of related conditions and s00213-016-4266-1]
13 Bergink V, Burgerhout KM, Weigelt K, Pop VJ, de Wit H,
behaviours including bipolar disorder, other postpartum
Drexhage RC, Kushner SA, Drexhage HA. Immune system
mood disorders, pre-eclampsia and smoking. dysregulation in first-onset postpartum psychosis. Biol Psychiatry
A main goal in PP research is to identify biomarkers 2013; 73: 1000-1007 [PMID: 23270599 DOI: 10.1016/j.biopsych.
within easily accessible tissues that can be sampled 2012.11.006]
before, or during, pregnancy (e.g., blood, saliva) that 14 Bergink V, Kushner SA, Pop V, Kuijpens H, Lambregtse-van
can accurately predict risk, a substantial challenge for den Berg MP, Drexhage RC, Wiersinga W, Nolen WA, Drexhage
HA. Prevalence of autoimmune thyroid dysfunction in postpartum
such a rare condition; early identification of “at risk” psychosis. Br J Psychiatry 2011; 198: 264-268 [PMID: 21343331
individuals should facilitate rapid access to appropriate DOI: 10.1192/bjp.bp.110.082990]
facilities and medical care (including close monitoring, 15 Bergink V, Armangue T, Titulaer MJ, Markx S, Dalmau J,
administration of psychological or pharmacological treat­ Kushner SA. Autoimmune Encephalitis in Postpartum Psychosis.
ments, and counselling). The experimental analyses Am J Psychiatry 2015; 172: 901-908 [PMID: 26183699 DOI:
10.1176/appi.ajp.2015.14101332]
proposed above are likely to result in the identification
16 Veen C, Myint AM, Burgerhout KM, Schwarz MJ, Schütze
and characterisation of such biomarkers. G, Kushner SA, Hoogendijk WJ, Drexhage HA, Bergink V.
A recent study has shown that the expression of Tryptophan pathway alterations in the postpartum period and in
Nov/Ccn3 in rat tissues is sensitive to the administration acute postpartum psychosis and depression. J Affect Disord 2016;
of the mood-stabilising drug lithium which has clinical 189: 298-305 [PMID: 26454336 DOI: 10.1016/j.jad.2015.09.064]
[89] 17 Fuste M, Pauls A, Reinders S, Mehta M, Simmons A, Williams
efficacy in some cases of PP .
S, Pariante C, Dazzan P. Anterior cingulate cortex abnormalities
in postpartum psychosis: a structural MRI study. Early Interv
Psychiatry 2014; 8 (Suppl 1): 35 [DOI: 10.1111/eip.12186]
REFERENCES 18 Lanczik M, Fritze J, Hofmann E, Schiulz C, Knoche M, Becker
1 Jones I, Chandra PS, Dazzan P, Howard LM. Bipolar disorder, T. Ventricular abnormality in patients with postpartum psychoses.
affective psychosis, and schizophrenia in pregnancy and the post- Arch Women Ment Health 1998; 1: 45-47 [DOI: 10.1007/s0073
partum period. Lancet 2014; 384: 1789-1799 [PMID: 25455249 70050005]
DOI: 10.1016/S0140-6736(14)61278-2] 19 Fahim C, Stip E, Mancini-Marïe A, Potvin S, Malaspina D.
2 Sit D, Rothschild AJ, Wisner KL. A review of postpartum Orbitofrontal dysfunction in a monozygotic twin discordant for

WJP|www.wjgnet.com 85 June 22, 2017|Volume 7|Issue 2|

 Davies W. Understanding the pathophysiology of postpartum psychosis

postpartum affective psychosis: a functional magnetic resonance Pharmacol 2013; 8: 900-920 [PMID: 23645137 DOI: 10.1007/
imaging study. Bipolar Disord 2007; 9: 541-545 [PMID: 17680927 s11481-013-9462-8]
DOI: 10.1111/j.1399-5618.2007.00404.x] 35 Davies W. Does steroid sulfatase deficiency influence postpartum
20 Udaya SC, Chauhan BN, Philip VJ. Bright splenium of a psychotic psychosis risk? Trends Mol Med 2012; 18: 256-262 [PMID:
mind. Ann Indian Acad Neurol 2015; 18: 80-83 [PMID: 25745318 22475435 DOI: 10.1016/j.molmed.2012.03.001]
DOI: 10.4103/0972-2327.145287] 36 Mortaud S, Donsez-Darcel E, Roubertoux PL, Degrelle H. Murine
21 Neale BM, Sklar P. Genetic analysis of schizophrenia and bipolar steroid sulfatase gene expression in the brain during postnatal
disorder reveals polygenicity but also suggests new directions for development and adulthood. Neurosci Lett 1996; 215: 145-148
molecular interrogation. Curr Opin Neurobiol 2015; 30: 131-138 [PMID: 8899734 DOI: 10.1016/0304-3940(96)12944-X]
[PMID: 25544106 DOI: 10.1016/j.conb.2014.12.001] 37 Tagawa N, Hidaka Y, Takano T, Shimaoka Y, Kobayashi Y,
22 Network and Pathway Analysis Subgroup of Psychiatric Amino N. Serum concentrations of dehydroepiandrosterone and
Genomics Consortium. Psychiatric genome-wide association dehydroepiandrosterone sulfate and their relation to cytokine
study analyses implicate neuronal, immune and histone pathways. production during and after normal pregnancy. Clin Chim Acta
Nat Neurosci 2015; 18: 199-209 [PMID: 25599223 DOI: 10.1038/ 2004; 340: 187-193 [PMID: 14734211]
nn.3922] 38 Grigoriadis S, Seeman MV. The role of estrogen in schizophrenia:
23 Jones I, Hamshere M, Nangle JM, Bennett P, Green E, Heron J, implications for schizophrenia practice guidelines for women. Can
Segurado R, Lambert D, Holmans P, Corvin A, Owen M, Jones J Psychiatry 2002; 47: 437-442 [PMID: 12085678]
L, Gill M, Craddock N. Bipolar affective puerperal psychosis: 39 Jones I, Craddock N. Searching for the puerperal trigger: mo­
genome-wide significant evidence for linkage to chromosome 16. lecular genetic studies of bipolar affective puerperal psychosis.
Am J Psychiatry 2007; 164: 1099-1104 [PMID: 17606662 DOI: Psychopharmacol Bull 2007; 40: 115-128 [PMID: 17514190]
10.1176/ajp.2007.164.7.1099] 40 Unigene. Available from: URL: https://www.ncbi.nlm.nih.gov/
24 Kumar HB, Purushottam M, Kubendran S, Gayathri P, Mukherjee unigene
O, Murthy AR, Ghosh S, Chandra P, Reddy YC, Benegal V, 41 Gratton AM, Ye L, Brownfoot FC, Hannan NJ, Whitehead C,
Brahmachari SK, Jain S. Serotonergic candidate genes and puerperal Cannon P, Deo M, Fuller PJ, Tong S, Kaitu’u-Lino TJ. Steroid
psychosis: an association study. Psychiatr Genet 2007; 17: 253-260 sulfatase is increased in the placentas and whole blood of women
[PMID: 17728663 DOI: 10.1097/YPG.0b013e3280ae6cc3] with early-onset preeclampsia. Placenta 2016; 48: 72-79 [PMID:
25 Munafò MR. Candidate gene studies in the 21st century: meta- 27871476 DOI: 10.1016/j.placenta.2016.10.008]
analysis, mediation, moderation. Genes Brain Behav 2006; 5 Suppl 42 Lykkesfeldt G, Bennett P, Lykkesfeldt AE, Micic S, Møller S,
1: 3-8 [PMID: 16417611 DOI: 10.1111/j.1601-183X.2006.00188.x] Svenstrup B. Abnormal androgen and oestrogen metabolism in
26 Weigelt K, Bergink V, Burgerhout KM, Pescatori M, Wijkhuijs men with steroid sulphatase deficiency and recessive X-linked
A, Drexhage HA. Down-regulation of inflammation-protective ichthyosis. Clin Endocrinol (Oxf) 1985; 23: 385-393 [PMID:
microRNAs 146a and 212 in monocytes of patients with post­ 3864567 DOI: 10.1111/j.1365-2265.1985.tb01096.x]
partum psychosis. Brain Behav Immun 2013; 29: 147-155 [PMID: 43 Fernandes NF, Janniger CK, Schwartz RA. X-linked ichthyosis:
23295264 DOI: 10.1016/j.bbi.2012.12.018] an oculocutaneous genodermatosis. J Am Acad Dermatol 2010; 62:
27 Quilter CR, Blott SC, Wilson AE, Bagga MR, Sargent CA, Oliver 480-485 [PMID: 20080321 DOI: 10.1016/j.jaad.2009.04.028]
GL, Southwood OI, Gilbert CL, Mileham A, Affara NA. Porcine 44 Meltzer-Brody S, Maegbaek ML, Medland SE, Miller WC,
maternal infanticide as a model for puerperal psychosis. Am J Sullivan P, Munk-Olsen T. Obstetrical, pregnancy and socio-
Med Genet B Neuropsychiatr Genet 2007; 144B: 862-868 [PMID: economic predictors for new-onset severe postpartum psychiatric
17503476 DOI: 10.1002/ajmg.b.30529] disorders in primiparous women. Psychol Med 2017: 1-15 [PMID:
28 Chen C, Guo Y, Yang G, Yang Z, Zhang Z, Yang B, Yan X, Perez- 28112056 DOI: 10.1017/S0033291716003020]
Enciso M, Ma J, Duan Y, Brenig B, Huang L. A genome wide 45 Platia MP, Fencl MD, Elkind-Hirsch KE, Canick JA, Tulchinsky
detection of quantitative trait loci on pig maternal infanticide behavior D. Estrone sulfatase activity in the human brain and estrone sulfate
in a large scale White Duroc x Erhualian resource population. Behav levels in the normal menstrual cycle. J Steroid Biochem 1984; 21:
Genet 2009; 39: 213-219 [PMID: 19130209 DOI: 10.1007/s10519- 237-241 [PMID: 6492790]
008-9252-x] 46 Stergiakouli E, Langley K, Williams H, Walters J, Williams NM,
29 Quilter CR, Gilbert CL, Oliver GL, Jafer O, Furlong RA, Blott SC, Suren S, Giegling I, Wilkinson LS, Owen MJ, O’Donovan MC,
Wilson AE, Sargent CA, Mileham A, Affara NA. Gene ex­pression Rujescu D, Thapar A, Davies W. Steroid sulfatase is a potential
profiling in porcine maternal infanticide: a model for puerperal modifier of cognition in attention deficit hyperactivity disorder.
psychosis. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: Genes Brain Behav 2011; 10: 334-344 [PMID: 21255266 DOI:
1126-1137 [PMID: 18361432 DOI: 10.1002/ajmg.b.30734] 10.1111/j.1601-183X.2010.00672.x]
30 Quilter CR, Sargent CA, Bauer J, Bagga MR, Reiter CP, 47 Chatterjee S, Humby T, Davies W. Behavioural and Psychiatric
Hutchinson EL, Southwood OI, Evans G, Mileham A, Griffin Phenotypes in Men and Boys with X-Linked Ichthyosis: Evidence
DK, Affara NA. An association and haplotype analysis of porcine from a Worldwide Online Survey. PLoS One 2016; 11: e0164417
maternal infanticide: a model for human puerperal psychosis? Am [PMID: 27711218 DOI: 10.1371/journal.pone.0164417]
J Med Genet B Neuropsychiatr Genet 2012; 159B: 908-927 [PMID: 48 Milunsky J, Huang XL, Wyandt HE, Milunsky A. Schizophrenia
22976950 DOI: 10.1002/ajmg.b.32097] susceptibility gene locus at Xp22.3. Clin Genet 1999; 55: 455-460
31 Chen C, Yang Z, Li Y, Wei N, Li P, Guo Y, Ren J, Ding N, Huang [PMID: 10450863 DOI: 10.1034/j.1399-0004.1999.550610.x]
L. Association and haplotype analysis of candidate genes in five 49 Trent S, Dennehy A, Richardson H, Ojarikre OA, Burgoyne PS,
genomic regions linked to sow maternal infanticide in a white Humby T, Davies W. Steroid sulfatase-deficient mice exhibit
Duroc × Erhualian resource population. BMC Genet 2011; 12: 24 endophenotypes relevant to attention deficit hyperactivity disorder.
[PMID: 21303561 DOI: 10.1186/1471-2156-12-24] Psychoneuroendocrinology 2012; 37: 221-229 [PMID: 21723668
32 Farrell MS, Werge T, Sklar P, Owen MJ, Ophoff RA, O’Donovan DOI: 10.1016/j.psyneuen.2011.06.006]
MC, Corvin A, Cichon S, Sullivan PF. Evaluating historical can­ 50 Marrs CR, Ferraro DP, Cross CL. Hormones and mood across the
didate genes for schizophrenia. Mol Psychiatry 2015; 20: 555-562 first postpartum year. Eur J Obstet Gynecol Reprod Biol 2010; 149:
[PMID: 25754081 DOI: 10.1038/mp.2015.16] 121-122 [PMID: 20022686 DOI: 10.1016/j.ejogrb.2009.11.006]
33 O’Shea KS, McInnis MG. Neurodevelopmental origins of bipolar 51 Marrs CR, Ferraro DP, Cross CL, Rogers SL. A potential role for
disorder: iPSC models. Mol Cell Neurosci 2016; 73: 63-83 [PMID: adrenal androgens in postpartum psychiatric distress. Eur J Obstet
26608002 DOI: 10.1016/j.mcn.2015.11.006] Gynecol Reprod Biol 2009; 143: 127-128 [PMID: 19181432 DOI:
34 Gibney SM, Drexhage HA. Evidence for a dysregulated immune 10.1016/j.ejogrb.2008.12.008]
system in the etiology of psychiatric disorders. J Neuroimmune 52 Rhodes ME, Li PK, Burke AM, Johnson DA. Enhanced plasma

WJP|www.wjgnet.com 86 June 22, 2017|Volume 7|Issue 2|

 Davies W. Understanding the pathophysiology of postpartum psychosis

DHEAS, brain acetylcholine and memory mediated by steroid of Integrin Signaling by Steroid Sulfatase in Human Cervical
sulfatase inhibition. Brain Res 1997; 773: 28-32 [PMID: 9409701] Cancer Cells. Biomol Ther (Seoul) 2016; 25: 321-328 [PMID:
53 Trent S, Cassano T, Bedse G, Ojarikre OA, Humby T, Davies W. 27956712 DOI: 10.4062/biomolther.2016.155]
Altered serotonergic function may partially account for behavioral 69 Le Dréau G, Kular L, Nicot AB, Calmel C, Melik-Parsadaniantz
endophenotypes in steroid sulfatase-deficient mice. Neuropsy­ S, Kitabgi P, Laurent M, Martinerie C. NOV/CCN3 upregulates
chopharmacology 2012; 37: 1267-1274 [PMID: 22189290 DOI: CCL2 and CXCL1 expression in astrocytes through beta1 and
10.1038/npp.2011.314] beta5 integrins. Glia 2010; 58: 1510-1521 [PMID: 20648642 DOI:
54 Humby T, Cross ES, Messer L, Guerrero S, Davies W. A phar­ 10.1002/glia.21025]
macological mouse model suggests a novel risk pathway for 70 Lombet A, Planque N, Bleau AM, Li CL, Perbal B. CCN3 and
postpartum psychosis. Psychoneuroendocrinology 2016; 74: calcium signaling. Cell Commun Signal 2003; 1: 1 [PMID:
363-370 [PMID: 27728876 DOI: 10.1016/j.psyneuen.2016.09.019] 14606958 DOI: 10.1186/1478-811X-1-1]
55 Giakoumaki SG, Bitsios P, Frangou S, Roussos P, Aasen I, 71 Harrison PJ. Molecular neurobiological clues to the pathogenesis
Galea A, Kumari V. Low baseline startle and deficient affective of bipolar disorder. Curr Opin Neurobiol 2016; 36: 1-6 [PMID:
startle modulation in remitted bipolar disorder patients and their 26210959 DOI: 10.1016/j.conb.2015.07.002]
unaffected siblings. Psychophysiology 2010; 47: 659-668 [PMID: 72 Riley DM, Watt DC. Hypercalcemia in the etiology of puerperal
20233338 DOI: 10.1111/j.1469-8986.2010.00977.x] psychosis. Biol Psychiatry 1985; 20: 479-488 [PMID: 3986256]
56 Epperson CN, Ballew J. Postpartum depression: a common 73 Vendrell JA, Magnino F, Danis E, Duchesne MJ, Pinloche S,
complication of childbirth. In: Hendrick V, ed., Psychiatric disorders Pons M, Birnbaum D, Nguyen C, Theillet C, Cohen PA. Estrogen
in pregancy and the postpartum: Principles and treatment. Humana regulation in human breast cancer cells of new downstream gene
Press: New York, 2006; 61-81 targets involved in estrogen metabolism, cell proliferation and
57 Henderson ND, Turri MG, DeFries JC, Flint J. QTL analysis of cell transformation. J Mol Endocrinol 2004; 32: 397-414 [PMID:
multiple behavioral measures of anxiety in mice. Behav Genet 15072547]
2004; 34: 267-293 [PMID: 14990867 DOI: 10.1023/B: BEGE.000 74 Park M, Baek IJ, Kim H, Woo DK, Park YJ, Shim S. CCN3 over­
0017872.25069.44] expression inhibits growth of callosal projections via upregulation
58 Malik AR, Liszewska E, Jaworski J. Matricellular proteins of the of RAB25. Biochem Biophys Res Commun 2015; 461: 456-462
Cyr61/CTGF/NOV (CCN) family and the nervous system. Front [PMID: 25871796 DOI: 10.1016/j.bbrc.2015.04.016]
Cell Neurosci 2015; 9: 237 [PMID: 26157362 DOI: 10.3389/ 75 Slavin TP, Feng T, Schnell A, Zhu X, Elston RC. Two-marker
fncel.2015.00237] association tests yield new disease associations for coronary artery
59 Lubbers BR, Smit AB, Spijker S, van den Oever MC. Neural disease and hypertension. Hum Genet 2011; 130: 725-733 [PMID:
ECM in addiction, schizophrenia, and mood disorder. Prog Brain 21626137 DOI: 10.1007/s00439-011-1009-6]
Res 2014; 214: 263-284 [PMID: 25410362 DOI: 10.1016/B978-0- 76 Berbel P, Navarro D, Román GC. An evo-devo approach to
444-63486-3.00012-8] thyroid hormones in cerebral and cerebellar cortical development:
60 Winterhager E, Gellhaus A. The role of the CCN family of proteins etiological implications for autism. Front Endocrinol (Lausanne)
in female reproduction. Cell Mol Life Sci 2014; 71: 2299-2311 [PMID: 2014; 5: 146 [PMID: 25250016 DOI: 10.3389/fendo.2014.00146]
24448904 DOI: 10.1007/s00018-014-1556-9] 77 Argos M, Tong L, Pierce BL, Rakibuz-Zaman M, Ahmed A, Islam
61 Ray S, Tzeng RY, DiCarlo LM, Bundy JL, Vied C, Tyson G, T, Rahman M, Paul-Brutus R, Rahaman R, Roy S, Jasmine F,
Nowakowski R, Arbeitman MN. An Examination of Dynamic Kibriya MG, Ahsan H. Genome-wide association study of smoking
Gene Expression Changes in the Mouse Brain During Pregnancy behaviours among Bangladeshi adults. J Med Genet 2014; 51:
and the Postpartum Period. G3 (Bethesda) 2015; 6: 221-233 [PMID: 327-333 [PMID: 24665060 DOI: 10.1136/jmedgenet-2013-102151]
26596646 DOI: 10.1534/g3.115.020982] 78 Gueugnon F, Thibault VC, Kearley J, Petit-Courty A, Vallet A,
62 Pedroso I, Lourdusamy A, Rietschel M, Nöthen MM, Cichon S, Guillon A, Si-Tahar M, Humbles AA, Courty Y. Altered expression
McGuffin P, Al-Chalabi A, Barnes MR, Breen G. Common genetic of the CCN genes in the lungs of mice in response to cigarette
variants and gene-expression changes associated with bipolar smoke exposure and viral and bacterial infections. Gene 2016; 586:
disorder are over-represented in brain signaling pathway genes. Biol 176-183 [PMID: 27080955 DOI: 10.1016/j.gene.2016.04.022]
Psychiatry 2012; 72: 311-317 [PMID: 22502986 DOI: 10.1016/ 79 Ricard AS, Pain C, Daubos A, Ezzedine K, Lamrissi-Garcia I,
j.biopsych.2011.12.031] Bibeyran A, Guyonnet-Dupérat V, Taieb A, Cario-André M. Study
63 Pantoni L, Pescini F, Inzitari D, Dotti MT. Postpartum psychiatric of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo
disturbances as an unrecognized onset of CADASIL. Acta Psychiatr skin. Exp Dermatol 2012; 21: 411-416 [PMID: 22507556 DOI:
Scand 2005; 112: 241; author reply 242 [PMID: 16095483 DOI: 10.1111/j.1600-0625.2012.01473.x]
10.1111/j.1600-0447.2005.00595.x] 80 Roig B, Franco-Pons N, Martorell L, Tomàs J, Vogel WF, Vilella E.
64 Sakuma K, Komatsu H, Maruyama M, Imaichi S, Habata Y, Expression of the tyrosine kinase discoidin domain receptor 1 (DDR1)
Mori M. Temporal and spatial transcriptional fingerprints by in human central nervous system myelin. Brain Res 2010; 1336:
antipsychotic or propsychotic drugs in mouse brain. PLoS One 22-29 [PMID: 20380825 DOI: 10.1016/j.brainres.2010.03.099]
2015; 10: e0118510 [PMID: 25693194 DOI: 10.1371/journal.pone. 81 Roig B, Virgos C, Franco N, Martorell L, Valero J, Costas J,
0118510] Carracedo A, Labad A, Vilella E. The discoidin domain receptor
65 Ito T, Hiraoka S, Kuroda Y, Ishii S, Umino A, Kashiwa A, Yamamoto 1 as a novel susceptibility gene for schizophrenia. Mol Psychiatry
N, Kurumaji A, Nishikawa T. Effects of schizo­phrenomimetics on 2007; 12: 833-841 [PMID: 17440435 DOI: 10.1038/sj.mp.4001995]
the expression of the CCN1 (CYR 61) gene encoding a matricellular 82 Creeth H, McNamara G, Tunster S, Eddy J, Isles A, John R.
protein in the infant and adult neocortex of the mouse and rat. Int J Programming of maternal behaviour by the placenta: A novel
Neuropsychopharmacol 2007; 10: 717-725 [PMID: 17608974 DOI: animal model. Psychoneuroendocrinology 2015; 61: 4 [PMID:
10.1017/S1461145707007882] 26383283 DOI: 10.1016/j.psyneuen.2015.07.397]
66 Stankiewicz AM, Goscik J, Majewska A, Swiergiel AH, 83 Tunster SJ, Creeth HD, John RM. The imprinted Phlda2 gene
Juszczak GR. The Effect of Acute and Chronic Social Stress on modulates a major endocrine compartment of the placenta to
the Hippocampal Transcriptome in Mice. PLoS One 2015; 10: regulate placental demands for maternal resources. Dev Biol 2016;
e0142195 [PMID: 26556046 DOI: 10.1371/journal.pone.0142195] 409: 251-260 [PMID: 26476147 DOI: 10.1016/j.ydbio.2015.10.015]
67 Chen PC, Cheng HC, Yang SF, Lin CW, Tang CH. The CCN 84 Fujimoto S, Hamasaki K, Ueda H, Kagawa H. Immunoelectron
family proteins: modulators of bone development and novel targets microscope observations on secretion of human placental lactogen
in bone-associated tumors. Biomed Res Int 2014; 2014: 437096 (hPL) in the human chorionic villi. Anat Rec 1986; 216: 68-72
[PMID: 24551846 DOI: 10.1155/2014/437096] [PMID: 3767004 DOI: 10.1002/ar.1092160112]
68 Ye DJ, Kwon YJ, Shin S, Baek HS, Shin DW, Chun YJ. Induction 85 Salido EC, Yen PH, Barajas L, Shapiro LJ. Steroid sulfatase

WJP|www.wjgnet.com 87 June 22, 2017|Volume 7|Issue 2|

 Davies W. Understanding the pathophysiology of postpartum psychosis

expression in human placenta: immunocytochemistry and in situ Osteoarthritis Cartilage 2015; 23: 607-615 [PMID: 25541297
hybridization study. J Clin Endocrinol Metab 1990; 70: 1564-1567 DOI: 10.1016/j.joca.2014.12.012]
[PMID: 2347893 DOI: 10.1210/jcem-70-6-1564] 88 Jun JI, Lau LF. Taking aim at the extracellular matrix: CCN
86 Burren CP, Wilson EM, Hwa V, Oh Y, Rosenfeld RG. Binding proteins as emerging therapeutic targets. Nat Rev Drug Discov
properties and distribution of insulin-like growth factor binding 2011; 10: 945-963 [PMID: 22129992 DOI: 10.1038/nrd3599]
protein-related protein 3 (IGFBP-rP3/NovH), an additional 89 Marti HP, Jeffs A, Scherer A, Leader J, Leader C, Bedford J,
member of the IGFBP Superfamily. J Clin Endocrinol Metab 1999; Walker R. Renal Fibrosis mRNA Classifier: Validation in Experi­
84: 1096-1103 [PMID: 10084601 DOI: 10.1210/jcem.84.3.5577] mental Lithium-Induced Interstitial Fibrosis in the Rat Kidney. PloS
87 Roddy KA, Boulter CA. Targeted mutation of NOV/CCN3 in mice One 2016; 11: e0168240 [PMID: 28002484 DOI: 10.1371/journal.
disrupts joint homeostasis and causes osteoarthritis-like disease. pone.0168240]

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