Familial aggregation of postpartum mood symptoms in bipolar disorder pedigrees
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Copyright ª Blackwell Munksgaard 2008
Bipolar Disorders 2008: 10: 38–44 BIPOLAR DISORDERS
Original Article
Familial aggregation of postpartum mood
symptoms in bipolar disorder pedigrees
Payne JL, MacKinnon DF, Mondimore FM, McInnis MG, Schweizer B, Jennifer L Paynea, Dean F
Zamoiski RB, McMahon FJ, Nurnberger Jr JI, Rice JP, Scheftner W, MacKinnona, Francis M
Coryell W, Berrettini WH, Kelsoe JR, Byerley W, Gershon ES, Mondimorea, Melvin G McInnisb,
DePaulo Jr JR, Potash JB. Familial aggregation of postpartum mood Barbara Schweizera, Rachel B
symptoms in bipolar disorder pedigrees. Zamoiskia, Francis J McMahonc,
Bipolar Disord 2008: 10: 38–44. ª Blackwell Munksgaard, 2008
John I Nurnberger, Jrd, John P
Ricee, William Scheftnerf, William
Objectives: We sought to determine if postpartum mood symptoms
and depressive episodes exhibit familial aggregation in bipolar I Coryellg, Wade H Berrettinih, John R
pedigrees. Kelsoei, William Byerleyj, Elliot S
Gershonk, J Raymond DePaulo, Jra
Methods: A total of 1,130 women were interviewed with the Diagnostic and James B Potasha
Interview for Genetic Studies as part of the National Institute of Mental a
Department of Psychiatry, Johns Hopkins School
Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative of Medicine, Baltimore, MD, bDepartment of
Study and were asked whether they had ever experienced mood Psychiatry, University of Michigan Medical School,
symptoms within four weeks postpartum. Women were also asked Ann Arbor, MI, cGenetic Basis of Mood and Anxiety
whether either of two major depressive episodes described in detail Disorders Unit, Mood and Anxiety Program and
occurred postpartum. We examined the odds of postpartum mood Laboratory of Clinical Science, National Institute of
symptoms in female siblings, who had previously been pregnant and had Mental Health, National Institutes of Health,
a diagnosis of bipolar I, bipolar II, or schizoaffective (bipolar type) Bethesda, MD, dInstitute of Psychiatric Research,
disorders (n ¼ 303), given one or more relatives with postpartum mood Indiana University School of Medicine,
symptoms. Indianapolis, IN, eDepartment of Psychiatry,
Washington University School of Medicine, St
Results: The odds ratio for familial aggregation of postpartum mood Louis, MO, fDepartment of Psychiatry, Rush
symptoms was 2.31 (p ¼ 0.011) in an Any Mood Symptoms analysis University Medical Center, Chicago, IL,
(n ¼ 304) and increased to 2.71 (p ¼ 0.005) when manic symptoms were g
Department of Psychiatry, University of Iowa
excluded, though this was not significantly different from the Any Mood School of Medicine, Iowa City, IA, hCenter for
Symptoms analysis. We also examined familial aggregation of Neurobiology and Behavior, Department of
postpartum major depressive episodes; however, the number of subjects Psychiatry, University of Pennsylvania School of
was small. Medicine, Philadelphia, PA, iDepartment of
Psychiatry, University of California at San Diego, La
Conclusions: Limitations of the study include the retrospective Jolla, CA, jDepartment of Psychiatry, University of
interview, the fact that the data were collected for other purposes and the California at San Francisco, San Francisco, CA,
inability to control for such factors as medication use. Taken together k
Department of Psychiatry, University of Chicago,
with previous studies, these data provide support for the hypothesis that Chicago, IL, USA
there may be a genetic basis for the trait of postpartum mood symptoms
generally and postpartum depressive symptoms in particular in women Key words: bipolar – genetics – postpartum
with bipolar disorder. Genetic linkage and association studies
incorporating this trait are warranted. Received 9 June 2006, revised and accepted for
publication 23 October 2006
Corresponding author: Jennifer L Payne, MD,
Johns Hopkins School of Medicine, 600 N Wolfe
Street, Meyer 3–181, Baltimore, MD 21287, USA.
Fax: +1 410 955 0152;
e-mail: jpayne5@jhmi.edu
JRK is a founder and holds equity in Psynomics, Inc. None of the other authors have any commercial associations that might pose a conflict of
interest in connection with this manuscript.
38Familial aggregation of postpartum mood symptoms
Postpartum depression is a serious syndrome
which occurs in up to 10–20% of all mothers in Methods
the year following delivery (1, 2). While the
Sample
etiology of postpartum depression is unknown, it
is likely to be multifactorial with psychological The sample consisted of women who participated
factors, biological factors including hormonal in a multi-site genetics study of BD which was
changes, and social factors all playing a role. The collected for the National Institute of Mental
risk for postpartum depression is increased in Health (NIMH) Genetics Initiative Bipolar Disor-
women with a history of major depression (3, 4), as der Collaborative project. Johns Hopkins was part
well as in women with a history of postpartum of a 10-site collaboration that collected this sample
depression following prior pregnancies (5, 6). from 1999 to 2003. The additional sites were
In women with bipolar disorder (BD), the risk of Indiana University, Washington University in
postpartum mood episodes (depression or mania) St. Louis, the NIMH Intramural Program, the
has been reported in up to 25–40% (7) and the risk University of California, San Diego, University of
of postpartum psychosis in particular (a syndrome Iowa, University of Pennsylvania, University of
resembling mania with psychotic features) in Chicago, Rush-Presbyterian Medical Center, and
women with bipolar I disorder (BD I) has been University of California, Irvine. Inclusion criteria
reported to be 20–30% (8–10). There have been focused on BD I probands with at least one sibling
fewer studies specifically examining the rates of with BD I. A total of 53% of the affected subjects
postpartum depressive episodes in women with were female (18, 19). The sample was primarily
BD. Freeman et al. (11) found that 67% of 30 Caucasian, with African-Americans comprising
women with BD experienced a postpartum mood 5.5% of the total and Hispanics 1.9%.
episode within one month of childbirth, the Subjects were recruited through various means,
majority of which were depressive episodes. Fur- including newspaper, magazine and radio ad-
ther, in eight of these women who had more than vertising, as well as from clinical settings. After a
one child, the recurrence rate of a postpartum complete description of the study had been given to
depressive episode was 100% in women who the subjects, written informed consent was ob-
experienced postpartum depression after the birth tained. Diagnoses were based upon an interview
of their first child (11). conducted using the Diagnostic Interview for
The evidence that postpartum mood syndromes Genetic Studies (DIGS; see below) (20). Collateral
may have a genetic basis is supported by several information from family informants and medical
studies. Treloar et al. (12) interviewed 838 parous records was obtained whenever possible. Final
female twin pairs and concluded that genetic diagnoses were made at each site by two clinicians
factors explained 38% of the variance in postnatal who reviewed all available data using a best-
depression. There have been several family studies estimate diagnosis procedure based on the DSM-IV.
of postpartum psychosis. These studies support the The final sample included 303 women derived
idea of a genetic susceptibility to a postpartum from a total of 1,130 women. In the total sample,
trigger, as well as an overlap in genetic factors 105 had a diagnosis of major depressive disorder
predisposing to postpartum psychosis and bipolar (MDD), 666 had BD I, 64 had bipolar II disorder
illness (13, 14). Dean et al. (15) suggested a higher (BD II), 24 had schizoaffective disorder, bipolar
risk of postpartum mood illness in relatives of type (SABP), 123 had a non-affective diagnosis
probands with postpartum psychosis. We recently (e.g., an anxiety disorder) and 147 were relatives
reported familial aggregation of postpartum as who had never been mentally ill. A total of 81.5%
well as perinatal depressive symptoms in families (n ¼ 922) of the sample had had a previous
with recurrent early onset major depression (16). pregnancy. Thus, there were 591 women with a
Similarly, Forty et al. (17) have shown that the diagnosis of BD I, BD II or SABP, and a previous
trait of postpartum depression (with onset in pregnancy. Of these 591 women, we excluded 217
£4 weeks postpartum) exhibited familiality in ped- women whose families did not have another
igrees with recurrent major depression. To our woman with BD who had also been pregnant and
knowledge there has been no study of familial 71 women who were non-siblings, leaving 303
aggregation of postpartum depressive episodes in individuals from 139 families.
families with BD.
In this study, we sought to determine if post-
Interview
partum mood symptoms generally, and postpar-
tum depressive episodes in particular, show The DIGS 3.0 version (20) was used as part of the
familial aggregation in BD pedigrees. diagnostic process. Inter-rater reliability has been
39Payne et al.
shown to be 0.85–0.96 for mood disorders (20). As history of postpartum mood symptoms positively
part of the Medical Section, every woman was predicting postpartum mood symptoms in the
asked questions about mood symptoms during and individual. A positive family history of postpartum
after pregnancy. Specifically, each woman was mood symptoms was defined as having another
asked: ÔHave you ever had any severe emotional member or members of the family who also gave a
problems during a pregnancy or within a month of history of postpartum mood symptoms or depres-
childbirth?Õ Clinicians were allowed flexibility in sion, while a negative family history was defined as
their interview in order to obtain enough informa- having no family members who gave a history of
tion to accurately answer the questions. Af- postpartum mood symptoms or depression by
firmative answers allowed for a designation that direct interview using the DIGS. For each analysis
included during pregnancy only, both during and described below, the same criteria were used to
after pregnancy, and after pregnancy only. Since assign a positive family history and to assign a
we were interested in mood symptoms that may positive individual history. We also examined
have been specifically triggered by the hormonal rates, comparing: (i) the number of women who
changes that occur during and after childbirth, we had postpartum symptoms and a family history of
counted as positive for our analyses those women postpartum symptoms, divided by the total num-
who answered Ôafter pregnancy onlyÕ, excluding ber of women with a family history of postpartum
others who answered Ôboth during and after symptoms; and (ii) the number of women who had
pregnancyÕ. A description of the types of symptoms postpartum symptoms and NO family history of
that were experienced was included. In addition, postpartum symptoms divided by the total number
each subject was asked to describe two major of women without a family history of postpartum
depressive episodes – the most severe episode and a symptoms. In these analyses, we used general
second well-remembered episode. As part of this family history of postpartum mood history to
Depression Section of the interview, women were predict postpartum mood symptoms rather than
asked whether the described episode had occurred proband history, since many of the probands in the
during or after pregnancy. In addition, the month family were either male or had never been
and year of the onset of the major depressive pregnant. All analyses were carried out using
episode and the month and year of the childbirth STATA 9.0.
were collected. These dates again allowed us to We completed two sets of analyses. The first
include as positive for our analyses only those used information from the Medical Section exam-
women whose depressive episode began at or after ining the familiality of postpartum mood symp-
delivery of their child. toms. This analysis has the advantage of being
broadly inclusive, i.e., women indicated in this part
of the interview if they had ever experienced Ôsevere
Statistical analysis
emotional problemsÕ during or after pregnancy.
We examined demographics using either the two- The disadvantages of this analysis are that there is
tailed Student’s t-test or the chi-square test when no information as to whether depressive symptoms
indicated. We used the two-tailed Student’s t-test met criteria for a major depressive episode, and
to compare the mean age of interview, age of onset that some of the episodes may have been manic or
of BD, number of major depressive episodes, mixed. The second analysis used information from
number of manic episodes, longest depressive the Major Depression Section, in which two major
episode (in days), number of pregnancies, number depressive episodes were described. The advantage
of live births and years of education in the sample of this analysis is that we can be sure that the
of women with and without a history of post- episode described met criteria for a major depres-
partum mood symptoms. Similarly, we used the sive episode; however, many postpartum episodes
chi-square test to compare the percentage of may be missed since each subject only described 2
women currently depressed and currently married of an average of about 20 episodes in their lifetime.
in women with and without a history of post- Based on the Medical Section, we completed two
partum mood symptoms. analyses: (i) ÔAny Mood SymptomsÕ, in which the
We used the generalized estimating equation women included in the analysis were siblings (n ¼
(GEE) (21) to examine familial aggregation of the 303, 139 families) and were scored positive for
trait of postpartum mood symptoms. This ap- answering yes to having postpartum mood symp-
proach uses logistic regression but also takes into toms; and (ii) ÔDepression OnlyÕ, in which women
account potential correlation between observations who experienced manic symptoms (as detailed in
when multiple members of the same family are the Description field) were scored as negative for
considered. We examined the odds of family the trait of postpartum depressive symptoms. We
40Familial aggregation of postpartum mood symptoms scored as negative for postpartum symptoms by the Medical Section in the entire sample (n ¼ women whose description included the words 303). There were no significant differences between ÔmaniaÕ or ÔhypomaniaÕ. One woman was also women with and without these symptoms except scored as negative for a description of increased for the number of live births and age at interview. bulimic symptoms postpartum. Women with postpartum mood symptoms had For the Major Depression Section, dates of the significantly more live births compared to women childbirth and onset of the described major depres- without these symptoms and were also significantly sive episode were compared and women were older. Clinical characteristics such as age of onset, scored as positive for a postpartum depressive number of major depressive and manic episodes, episode if the date of the childbirth preceded or and current depression did not differ significantly coincided with the onset of the depressive episode. between the two groups. Because the dates were not exact (month and year Table 2 shows the results of the familiality only), we completed three sets of analyses: (i) analyses based on the Medical Section. Since there One Month, in which episodes were scored as was a significant difference in the number of live positive if the month of childbirth and the month births and age at interview between women with of the onset of depressive episode were the same; and without postpartum mood episodes, we con- (ii) Two Months, in which episodes were scored as trolled for both these factors in the odds ratio positive if the childbirth took place the month analyses. The rate of women with postpartum before the onset of depression; and (iii) Three symptoms and a positive family history of post- Months, when the month of childbirth and the partum symptoms (30.43%) was higher than the onset of depression were £2 months apart. In this rate of women with postpartum symptoms and a analysis, £3 months passed from the onset of negative family history of postpartum symptoms delivery to the onset of the major depressive (14.53%). This was reflected in a significant odds episode. Note that the Two-Months analysis ratio of 2.31 (p ¼ 0.011) for postpartum mood included women who scored positive in the One- symptoms of any type in the Any Mood Symptoms Month analysis and, similarly, the Three-Month analysis. The odds ratio increased to 2.71 (p ¼ analysis included women who scored positive in 0.005) when manic symptoms were excluded, the One-Month and Two-Months analyses. This though this was not significantly different from allowed us to examine familial aggregation based the Any Mood Symptoms analysis. on the DSM definition of
Payne et al.
Table 2. Familiality of postpartum mood symptoms in women with bipolar disorder
Postpartum symptoms Postpartum symptoms
and positive family and negative family
history of postpartum history of postpartum
symptomsa, n (%) symptomsb, n (%) Odds ratioc p-value 95% CI
Any mood symptom 21/69 (30.43) 34/234 (14.53) 2.31 0.011 1.21–4.40
Depression only 17/58 (29.31) 29/245 (11.84) 2.71 0.005 1.35–5.47
a
Numerator equals number of women who had postpartum symptoms and a family history of postpartum symptoms. Denominator
equals total number of women with a family history of postpartum symptoms.
b
Numerator equals number of women who had postpartum symptoms and NO family history of postpartum symptoms. Denominator
equals total number of women without a family history of postpartum symptoms.
c
All odds ratio analyses were controlled for number of live births.
CI ¼ confidence interval.
Table 3. Familiality of postpartum depressive episodes in women with bipolar disorder
PDE and positive family PDE and negative family
history of PDEa n (%) history of PDEb n (%) Odds ratioc p-value 95% CI
Within 1 month 2/14 (14.29) 8/289 (2.77) 5.79 0.038 1.100–30.39
Within 2 months 2/16 (12.50) 10/287 (3.48) 3.96 0.094 0.789–19.89
Within 3 months 2/16 (12.50) 10/287 (3.48) 3.96 0.094 0.789–19.89
a
Numerator equals number of women who had postpartum depressive episodes and a family history of postpartum depressive epi-
sodes. Denominator equals total number of women with a family history of postpartum depressive episodes.
b
Numerator equals number of women who had postpartum depressive episodes and NO family history of postpartum depressive
episodes. Denominator equals total number of women without a family history of postpartum depressive episodes.
c
All odds ratio analyses were controlled for number of live births.
PDE ¼ postpartum depressive episode; CI ¼ confidence interval.
within one month postpartum had an odds ratio evidence for a familial basis for mood symptoms
for familial aggregation of 5.79 (p ¼ 0.038), which with onset in the postpartum period in women with
became non-significant when episodes occurring up mood disorders.
to three months postpartum were included (odds There are a number of possible interpretations of
ratio 3.96, p ¼ 0.094). Note that the number of our findings. The familiality of these symptoms
women who met the criteria for the Two-Months may reflect a genetic vulnerability, though envi-
analysis was only two more than for the One- ronmental influences are also possible. For exam-
Month analysis and no additional women met the ple, a familial history of severe postpartum mood
criteria for the Three-Months analysis. The rate of symptoms could influence the personal interpre-
women with postpartum depressive episodes and a tation of the very common experience of postpar-
positive family history of postpartum depressive tum blues, particularly in a woman with a
episodes was again higher than the rate of women pre-existing mood disorder. We were not able to
with postpartum depressive episodes and a neg- distinguish between postpartum blues or more
ative family history. severe postpartum depression in the Medical Sec-
tion of our data. Other non-genetic or environ-
mental factors that have been proposed to be
Discussion
involved in the development of at least some
To our knowledge this is the first study to examine episodes of postpartum depression include sleep
the familiality of postpartum mood symptoms deprivation (22–24), the stress of becoming a
generally, as well as postpartum depressive epi- mother (25–28), and alterations in the hypotha-
sodes particularly, in women with BD. We found lamic–pituitary–adrenal (HPA) axis triggered by
evidence that these symptoms and these episodes labor and delivery (29–32). On the other hand,
do aggregate in families. Our findings build on and even these seemingly environmental etiologies
extend previous work demonstrating similar clus- could have genetic components. For example, sleep
tering of postpartum depression in MDD (16, 17) deprivation could trigger postpartum depressive
pedigrees and of postpartum psychosis in BD episodes in women who are genetically vulnerable
pedigrees (13, 15). Our results provide additional to this type of stressor. The stress of labor, delivery
42Familial aggregation of postpartum mood symptoms
and taking care of a young infant could trigger There are several important limitations to
depression in those with a vulnerability conferred consider when interpreting our findings. First,
by, for example, one or two copies of the short the sample was originally collected for other
allele of the serotonin transporter gene (33). purposes and thus the interview was not focused
Alterations in the HPA axis after labor and on obtaining the maximum level of detail about
delivery might trigger depression in those with the relationship between childbirth and mood
susceptibility variants in cortisol-related genes. symptomatology. Thus, in the Major Depression
Another genetic mechanism of interest is the Section, our analyses were limited to the small
effect of estrogen on gene transcription in the brain number of women who described in detail a
(34). Estrogen is known to act through two different postpartum depressive episode. While the women
intracellular estrogen receptors, ER-a and ER-b, in the study had had an average of 20 lifetime
that reside in the nuclei of cells. These receptors are major depressive episodes, only 2 were described
able to influence genomic transcription, which then in any detail for our interview. Further, the
directs or modulates the synthesis of enzymes, interview did not contain a question about
receptor proteins, and signal transduction enzymes. whether manic or hypomanic episodes had their
Recent work by Jones et al. (13), however, indicates onset during or after pregnancy. A second limi-
no association between two polymorphisms in the tation was the retrospective nature of the inter-
ER-a gene and postpartum psychosis. Nonetheless, view. A number of studies have found that the
it remains unclear whether alterations in other reliability of retrospective recall of mood-related
genes that are influenced by estrogen are involved in symptomatology, such as premenstrual symptoms,
the genetic basis of postpartum mood syndromes, is questionable (37–39). One issue with these
as well as whether the underlying mechanism(s) for studies is that they were, in general, attempting
postpartum psychosis, are the same as those for to confirm both timing and frequency of symp-
postpartum depressive episodes. toms in order to make the retrospective diagnosis
Our finding that limiting positive episodes to of premenstrual dysphoric disorder. To our
depressive symptoms results in a larger odds ratio knowledge, there have been no such studies
is difficult to interpret. The odds ratio improved; examining the reliability of retrospective recall
however, the confidence intervals overlap with for postpartum mood episodes. One important
those of the more general analysis. One possibility difference between the recall of a postpartum
that remains to be explored is that familial aggre- episode and other types of mood symptoms,
gation of postpartum manic or psychotic episodes including premenstrual symptoms, is that the first
is separate from the familial aggregation of post- involves a momentous event, the birth of a child,
partum depressive episodes, indicating a different the date of which is remembered and to which
underlying mechanism. We cannot draw that other events, such as mood symptoms, can be
conclusion from the data presented here, however. tied. Nonetheless, prospective studies would likely
We chose to focus on symptoms and episodes provide more reliable data with which to address
which began explicitly after labor and delivery. the familiality of postpartum mood symptoms.
Recent evidence indicates that that some episodes We were also not able to control for such factors
of ÔpostpartumÕ depression actually begin during as medication use during and after pregnancy
pregnancy (35). Mood episodes which begin during (since these data were not collected), which may
pregnancy or several months postpartum may have influenced our results. Finally, we performed
conceivably have a very different biological basis multiple comparisons and did not correct for this
than mood episodes which appear to be triggered statistically.
shortly after the hormonal changes that occur In summary, these findings indicate that there
during labor and delivery. The DSM-IV designates may be a genetic basis for the trait of postpartum
the use of the term ÔpostpartumÕ as mood episodes depressive symptoms in women with BD. Future
which occur within four weeks of labor and genetic linkage and association studies will be
delivery. Although this time period remains con- needed to test molecular hypotheses about the
troversial since the exact period of biological biological underpinnings of this trait.
consequences secondary to hormonal withdrawal
remains unknown (36), it is a reasonable starting
Acknowledgements
point when attempting to examine more homoge-
neous ÔtypesÕ of postpartum mood episodes, since This study was supported by a NARSAD Young Investigator
mood episodes which begin within a month of Award and the Passano Family Clinician Scientist Award. The
authors wish to gratefully acknowledge Dr Peter J Schmidt for
labor and delivery are more likely to be associated his careful reading of the manuscript and helpful suggestions.
with concurrent hormonal changes.
43Payne et al.
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