University of Groningen

Hormones, monoamines and peripartum affective symptoms

Doornbos, Bennard

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Chapter 3

Sequential serotonin and noradrenalin associated

processes

involved in postpartum
blues
 Bennard Doornbos MD, Durk Fekkes PhD, M.A.C.Tanke
MSc, Peter de Jonge PhD, Jakob Korf PhD.

Published in Prog Neuropsychopharmacol Biol Psychiatry 2008 April

20;32:1320-5.

61
Chapter 3
Abstract
62 Objective: We investigated whether postpartum blues was related to changes in
parameters of noradrenergic and serotonergic functioning.
Methods: From 26 healthy pregnant women blood was collected at the end of pregnancy and five days
and six weeks postpartum. Serotonergic parameters were: platelet serotonin content; paroxetine binding
to platelet membranes as an index of SERT activity; the serotonin precursor tryptophan in proportion to
the large neutral amino acids, as an estimate of its cerebral influx. Noradrenergic indices were the
noradrenaline precursor tyrosine and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). The
Kennerly and Gath blues questionnaire was applied at day five postpartum.
Results: The incidence of postpartum blues was 30%. The tryptophan ratio and serotonin content of
platelets were decreased (p<0.01) at day five postpartum in all women. Bmax paroxetine at day five was
correlated with blues score (ß=0.460; p=0.031). MHPG levels at six weeks were increased in women with
blues (p<0.001). In a regression model MHPG at six weeks was related to blues score (ß=0.477;
p=0.002) and MHPG at day five (ß=0.550; p=0.001), explaining>50% of the variation (R2=0.588;
p<0.001).
Conclusions: A decreased serotonergic activity was found at the fifth day postpartum in all subjects.
Increased SERT activity, reflected by higher paroxetine binding to platelets might be involved in the onset
of blues. The elevated MHPG levels in women with blues are compatible with a higher stress sensitivity,
or a decreased stress coping in those and is suggested to be involved with the onset of depression.
Keywords: postpartum blues, postpartum depression, 3-methoxy-4-hydroxyphenylglycol, tryptophan,
tyrosine, large neutral amino acids, platelet 5-HT content, paroxetine binding to platelets
Acronyms: 5-HT = serotonin; MHPG = 3-methoxy-4-hydroxyphenylglycol; LNAA’s = Large Neutral Amino
Acids; tyr = tyrosine; phe=phenylalanine; SD= Standard Deviation; SERT= Serotonin Transporter
Sequential serotonin and noradrenalin associated processes involved in postpartum
blues

Introduction

Postpartum blues is a transient affective syndrome occurring in about half of the women
(15.3% – 84%) in the first week after delivery (Gitlin and Pasnau, 1989; Henshaw, 2003).
Symptoms of postpartum blues include crying, grief, anxiety, sadness, confusion, headache
and also exuberance (Yalom et al., 1968; Kennerley and Gath, 1989a; Henshaw, 2003).
Postpartum blues is considered as a risk factor for postpartum depression (Henshaw et al.,
2004; Bloch et al., 2005). In the etiology of postpartum blues much attention has been
given to the effects of the postpartum drop of estrogen and progesterone on
neurophysiology and behavior (Abou-Saleh et al., 1998; Bloch et al., 2003). But, only about
half of the women suffer from postpartum blues, and no consistent differences in hormone
levels have been found between women with and without blues (Hendrick et al., 1998;
Bloch et al., 2003). Indicating that other factors are involved in the etiology of postpartum
blues.

We hypothesized that differences in serotonin (5-HT) metabolism and neurotransmission

might be a factor underlying the individual risk for postpartum blues. Alterations in serotonin
metabolism and transmission have been associated with affective disorders (Owens and
Nemeroff, 1994; Kendler et al., 2005). In the peripartum the synthesis of both peripheral
and cerebral 5-HT is limited due to the decreased availability of tryptophan, caused by the
increased catabolism of tryptophan in the placenta during pregnancy (Schrocksnadel et al.,
1996; Munn et al., 1998), and the immune activation and increased liver metabolism
following delivery (Fuchs et al., 1996; Maes et al., 2002; Schrocksnadel et al., 2003a).
Changes in tryptophan concentration (Handley et al., 1977; Abou-Saleh et al., 1999; Kohl
et al., 2005; Bailara et al., 2006), tryptophan catabolism (Maes et al., 2000; Maes et al.,
2002) and platelet 5-HT content (Maurer-Spurej et al., 2007) have all been associated with
post partum blues. Moreover, postpartum depression has been associated with differences
in functioning of the serotonin transporter (SERT) as reflected by a decreased Kd of both
imipramine and paroxetine (Hannah et al., 1992b; Newport et al., 2004). During pregnancy
serotonergic activity is further modulated by estrogen, progesterone and some of their
metabolites (Bethea et al., 2002) resulting in a sudden change in the serotonergic
neurotransmission postpartum. All together, the early postpartum period is characterized by
a sudden change, mostly a reduction, of serotonergic activity and this condition may
contribute to the development of mood disorders.

Another factor contributing to postpartum blues might be stress experienced during the
delivery and subsequent days. Stress and life events are well documented risk factors for
depression (Kendler et al., 1999). Virtually all kinds of stress induce activation of

63
Chapter 3
noradrenergic neurons of both peripheral (sympathetic) system and the cerebral
64

system, in particular that located in the locus coeruleus, leading to increased formation
of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) (Bremner et
al., 1996a; Bremner et al., 1996b). Therefore the impact of stress can to some extend
be assessed by measuring MHPG in the circulation.
Here we investigate if peripartum noradrenergic and serotonergic plasma parameters
are associated with postpartum blues. In contrast to most previous studies, we use a
longitudinal design and combine several peripheral measures of serotonergic activity.
Assessment of those parameters are limited to measurements in plasma. More direct
methods like CSF-analyses or PET scanning, are difficult to perform frequently, and
could be harmful for the fetus. These peripheral measures are frequently used in
psychiatric research, but their translation to central functioning is not straightforward,
and criticized in literature (Muller-Oerlinghausen et al., 2004).
Serotonergic activity was measured by 1.) The density and activity of 5-HT binding sites
of blood platelets, as assessed by platelet paroxetine binding, which is a measure for
activity of the serotonin transporter (SERT). The SERT has a key role in regulating
cerebral extracellular serotonin levels; 2.) The serotonin content of the platelets,
reflecting the recent serotonin production 3.) Plasma levels of the serotonin precursor
tryptophan in relation to the Large Neutral Amino Acids (LNAA’s), as factor linked to
central serotonin production. Noradrenaline activity was measured by plasma levels of
its precursor tyrosine in relation to LNAA’s and its metabolite MHPG.
The following hypotheses were tested: 1.) Postpartum blues is associated with a
decreased plasma tryptophan ratio and/or decreased platelet 5-HT levels; 2.) Serotonin
transporter capacity and functioning, as reflected by platelet paroxetine binding,
correlate with blues score; 3.) Women with postpartum blues experience more stress,
represented by increased MHPG levels.
Subjects, Materials and methods
Subjects and experimental protocol Twenty-six healthy pregnant women who visited
the maternity clinic of the Erasmus University Medical Center in Rotterdam participated
in this study, after they gave written informed consent. The protocol was approved by
the ethical committee of Erasmus Medical Center. Women, all Caucasian, and aged
between 21 and 35 years, were in good physical health and did not take any
medication. None of the subjects
Sequential serotonin and noradrenalin associated processes involved in postpartum
blues

suffered from affective disorders or other mental illnesses at baseline. Blood was collected
at the end of the third trimester (after 36 wk), and postpartum at day 5 and 6 weeks. The
following biochemical parameters were measured: the platelet serotonin content; the
paroxetine binding to platelet membranes; the plasma concentrations of the large neutral
amino acids (LNAA), i.e. tryptophan, tyrosine, phenylalanine, valine, leucine and isoleucine,
and the plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG). A Dutch version of the
Kennerley and Gath blues questionnaire was used at the fifth postpartum day (Iles et al.,
1989; Kennerley and Gath, 1989a). This questionnaire is the most used instrument for
measuring blues. According to this scale women have blues when the score was higher
than the mean of the whole group (Kennerley and Gath, 1989b). Because such a measure
is strongly influenced by outliers, and complicates the comparisons with other samples, we
use the widely used cut-off score of 12.

Biochemical analyses Blood (20 ml) was collected between 9:00 and 10:30 AM in
siliconated vacutainer tubes containing 0.15% K3-EDTA as anticoagulant. Platelet-rich
plasma was obtained by centrifugation of the blood at 90xg for 20 min at 20°C. A sample of
200 μl was frozen at – 80°C for the determination of 5-HT and platelets were counted in a
sample of 50 μl. The rest of the platelet-rich plasma was centrifuged at 2650xg for 20 min.
The supernatant (plasma) was frozen at –80°C for the determination of amino acids and
MHPG. The platelets were isolated from the pellet after two centrifugation runs, pooled and
washed in 10 ml buffer (Tris-HCl 50 mM, NaCl 150 mM, Na2-EDTA 20 mM, pH 7.35) and
finally frozen at –80°C for determination of paroxetine binding.

The large neutral amino acids (LNAA) tryptophan, tyrosine, phenylalanine, valine, leucine
and isoleucine were analysed in the plasma samples by reversed phase high performance
liquid chromatography (HPLC) after pre-column derivatisation with o- phthaldialdehyde and
detected fluorometrically (Fekkes et al., 1995). The platelet 5-HT concentrations were
measured by a reversed phase HPLC method described previously (Fekkes et al., 1997).
Plasma free MHPG was measured by a reversed phase HPLC method after extraction
using a slightly modified published procedure (Moleman and Borstrok, 1982). In short, 0.5
ml plasma, 20 μl internal standard (2 μg iso-MHPG/ml) and 3 ml ethylacetate were added
to a seraclear tube containing 0.75 g NaCl and 0.1 g florisil. The tube was shaken for 20
min and centrifuged for 10 min at 2750 g. Two ml of the organic layer was evaporated to
dryness at 40°C under vacuum in a Buchler Vortex Evaporator (Lenexa, KS, U.S.A.) and
the residue was dissolved in 0.5 ml of the mobile phase. Ten or 20 μl samples were
injected onto a reversed phase column (ODS-Hypersil, 5

65
Chapter 3
μm particle size, 200 x 2.1 mm, Hewlett Packard) which was protected by a guard
66
column
(20 x 2.1 mm) of the same material. The mobile phase consisted of 50 mM
sodium phosphate and 0.67 mM disodium EDTA containing 1% isopropanol, pH 2.7.
The flow rate was set at 0.25 ml/min and the column temperature was 28°C. The
detection system consisted of a Model 5100A Coulochem detector equipped with a
5021 conditioning cell and a 5011 high sensitivity cell (ESA, Bedford, MA, U.S.A.). The
potentials for the conditioning cell and detectors 1 and 2 were +0.45, -0.05 and -0.43 V,
respectively. The gain was 15 x 100 and quantification was done by measuring peak
heights. The limit of detection at a signal to noise ratio of 2 was 10 fmol (approx. 2 pg)
MHPG per injection. The retention times of MHPG and iso-MHPG were 7.6 and 12.8
min, respectively. The intra- and inter-day coefficients of variation of duplicate analysis
of plasma samples were 2.6% (n=8) and 4.9% (n=18), respectively. The recovery of
iso-MHPG added to the plasma samples was 79 ± 4% (n=14). Paroxetine binding to

blood platelets was determined using 3H-paroxetine (New England Nuclear) as

radioligand and clomipramine as displacing agent to correct for nonspecific binding

(Klompenhouwer et al., 1990).
Calculations The tryptophan ratio indicated the tryptophan availability in the brain for
subsequent 5- HT synthesis. This ratio was computed with the formula: plasma
tryptophan x 100/ sum of the plasma LNAA minus tryptophan. The tyrosine ratio
indicated the tyrosine availability in the brain for subsequent dopamine and/or
noradrenaline synthesis. This ratio was computed with the formula: plasma tyrosine x
100/ sum of the plasma LNAA minus tyrosine. The tyrosine/phenylalanine (tyr/phe) ratio
was taken as index of peripheral tyrosine synthesis from phenylalanine. This ratio was
plasma tyrosine/ plasma phenylalanine.
Statistical analysis Data are presented as means with standard deviations (SD).
Statistical analyses were done with SPSS 12.0. Data were considered to have a normal
distribution when the Kolmogorov-Smirnov test was not significant. The significance
level was set at 0.05. The time course of the serotonergic and noradrenergic
parameters of the whole group was evaluated with repeated measures ANOVA with
time (end of third term, 5 days postpartum and six weeks postpartum) as a within
subject factor. Differences in the time course between blues and non-blues were
subsequently analyzed with blues and non-blues as a between subject factor.
Significant differences in the time course in the ANOVA test were further evaluated with
a post hoc test. The hypothesis that differences in SERT capacity, and functioning are
related to postpartum blues was
Table Sequential serotonin and noradrenalin associated processes involved in postpartum blues
investigated by correlating the Bmax and the Kd of paroxetine binding to platelets with
the blues score on day five postpartum. With two runs of logistic regression analyses
the factors contributing to blues and the stress during the puerperium (MHPG levels at
six weeks) were identified.
Results
Blues score Blues scores varied from 2 – 21. The average score was 9.0 ± 5.4. Eight
Participants (30%) had a score >12 and were considered to suffer from postpartum
blues.
Biochemical parameters of the whole group Data of the serotonergic and
noradrenergic activity of the whole group are summarized in table 1. All data were
normally distributed (with a z-score of the skewness and the kurtosis < 1.96 and a
non-significant Kolmogorov-Smirnov test) and were therefore analyzed with repeated
measures ANOVA. The tryptophan ratio decreased significantly postpartum (p<0.01)
and returned to prepartum levels after six weeks. The tyrosine ratio increased
significantly postpartum (p<0.05) and also returned to prepartum levels at six weeks.
The tyr/phe ratio increased significantly at day 5 (p< 0.05) and after six weeks, (p<0.01)
compared with pregnancy. MHPG levels decreased significantly postpartum i.e. five
days (p<0.05) and six weeks (p<0.01). The 5-HT content of platelets decreased at day
five postpartum (p<0.01), and increased to the prepartum levels after six weeks. 5-HT
content of platelets did not correlate with tryptophan ratio at any time. No changes were
found in Kd and Bmax of paroxetine-binding at the platelet membrane over time.
1. Biochemical parameters of all subjects (n=26) at the end of third trimester, 5 days postpartum, and six
weeks postpartum
Biochemical parameters of blues versus Third non blues
trimester 5 days postpartum 6 weeks
Subsequently, the biochemical data were analyzed with repeated measures postpartum
ANOVA Tryptophan with blues ratio and * non blues as between subject 8.99 ± 1.73 factor. a$
This 7.29 revealed ± 1.50 a between-subject
8.50± 1.41 a$ Tyrosine Tyrosine/phenylalanine platelet effect MHPG in Kd ratio levels paroxetine
MHPG * in the levels (nM) ratio non * (p<0.001). blues group Post six hoc 1.12 13.80 0.173
weeks analyses ± ± 0.13 ± 1.70 0.090 postpartum, a # a$ b# showed 0.148 15.20 1.30 while a ± ± ±
significant 0.18 0.067 2.05 in the 13.67 0.171 1.39 blues decrease ± ± ± 3.54 0.50
0.090 group
a#

in
platelet MHPG B max concentrations paroxetine (fmol/mg remained protein) at the same 1635 ±
level. 506 Data 1428 are ± depicted 432 in 1576 fig. ± 1. 751
No MHPG 5-HT * between-groups found Significant content (ng/ml) with time platelets repeated *
effect differences in (nmol/10repeated measures 9 platelets) measures in ANOVA.
the * ANOVA.
time-course 3.69 2.96 ± ± 0.91 1.01 of a # a$ b$ the serotonergic 3.29 2.19 ± ± 0.89 0.88
parameters 3.19 2.92 ± ± 1.16 0.85
were a$
a Differs significantly from 5 days postpartum. b Differs significantly from 6 weeks postpartum. # p<0.05. $

p<0.01.
67
The Bmax of platelet membrane paroxetine binding at day 5 correlated significantly with
68

blues score (Pearson. 0.460. p<0.05). The scatter plot is shown in fig 2. The Kd did not
correlate with the blues score (Pearson corr: 0.041, p=0.855).
Regression modeling indicated that the blues score was predicted by Bmax paroxetine at
day 5 postpartum (β=0.562) explaining 30% of the variance (R2 = 0.316; Adjusted R2 =
0.275) in a significant model (F(1,18)=7.840, p=0.012) . MHPG levels at six weeks were
related to MHPG levels at five days and blues score explaining more than 50% of the
variation (R2 of 0.588, adjusted R2 of 0.551) in a highly significant model (F(2,22)= 15.729,
p<0.001). Both models are shown in table 2. The temporal relations between the
different parameters indicated by the regression models are depicted in figure 3.
Discussion The present study indicates a decreased serotonergic activity in all
women during the first postpartum week, as illustrated by a decreased tryptophan ratio
and a decreased 5-HT content of platelets. The decrease in serotonergic activity was
not associated with the occurrence of postpartum blues. However, the significant
correlation between Bmax paroxetine-binding to platelets and blues scores suggests that
differences in serotonin transporter functioning might intensify the effect of those
changes in serotonergic metabolism thereby increasing the vulnerability for blues.
MHPG levels remain high in the women with blues, and depressive symptoms were
related to both blues scores and increased MHPG levels, indicative for persistent
activity of the sympathetic nervous system, the cerebral locus coeruleus or both in
women with blues.
Strong points of this study are the longitudinal design with the assessment of several
indices of both serotonergic and noradrenergic functioning and blues score. A serious
point of criticism is the uncertain relationship between peripheral and central parameters
of serotonergic and noradrenergic functioning (as summarized by (Muller-
Oerlinghausen et al., 2004)) However, a relation between peripheral and central
functioning has been reported for tryptophan ratio and central serotonergic functioning
(Russo et al., 2005); 5-HT platelet content and psychopathology (Mann et al., 1992;
Russo et al., 2005); and the amount of platelet 5-HT transporters (SERT) and central
SERT functioning (Rausch et al., 2005; Uebelhack et al., 2006) although the
correlations in these studies were low (0.3-0.6), and the relation was influenced by
several other factors, as for instance gender (the strongest correlations were found in
women.) Platelets have a circulating half life of 11 days. Therefore platelet data at 5
days postpartum do not fully represent the changes in this period. Summarizing: the
data on serotonergic metabolism of platelets should be interpreted with care.
Approximately about 35-60% of the peripheral MHPG has cerebral origin (Yoshimura et
al., 2004).
Chapter 3
Fig. 1. Plasma MHPG levels with SD.
Results show a significant group effect in repeated measures ANOVA (p<0,001). ○ women with blues
(n=8), ■ women without blues (n=18). # Represents a within-subject effect in the post hoc analyses in the
non- blues group: six weeks postpartum differed significantly from day 5 and the third trimester both with
p<0.001.
Peripheral MHPG may serve as index for stress responsiveness because both the
peripheral sympathetic nervous system and the central locus coeruleus are similarly
activated by stress.
Other limitations of the study concern 1) the single assessment of blues, limiting the
evaluation of the delivery induced changes in affective functioning; 2) the lactation
status was not assessed. Lactation status is associated with postpartum depression and
the lactation hormones prolactin and oxytocin influence stress reactivity and might thus
have influenced MHPG levels (Carter et al., 2001; Grattan, 2001);. 3) the sleep pattern
was not investigated. The sleep quality is disturbed during the puerperium (Ross et al.,
2005; Parry et al., 2006) what might lead to increased serotonergic activity or vice versa
(Adrien, 2002).These disturbances in sleep pattern have been associated with the onset
of depression (Ross et al., 2005; Parry et al., 2006).
Serotonergic parameters and blues Several authors have reported a reduced
puerperal tryptophan ratio (Schrocksnadel et al., 1996; Maes et al., 2001; Maes et al.,
2002; Schrocksnadel et al., 2003a; Kohl et al., 2005; Bailara et al., 2006), and a
correlation between the tryptophan ratio and postpartum blues or depression (Handley
et al., 1977; Abou-Saleh et al., 1999; Maes et al., 2002; Kohl et al., 2005; Bailara et al.,
2006). We confirmed the decreased puerperal tryptophan ratio, but did not find a
relation with blues scores. This could be due to the small sample size of this study, or to
the differences between the studies in the specific days that the blood samples were
collected. The reduced puerperal tryptophan ratio is most likely caused by the increased
immune activation in the first days post delivery, leading to activation of the tryptophan
catabolising enzyme Indoleamine deoxygenase (IDO) (Maes et al., 2002). However,
some other studies did not found a relation between immune activation and IDO activity
and suggested that the decreased tryptophan ratio is induced by hepatic tryptophan
pyrrolase (Schrocksnadel et al., 2003a; Schrocksnadel et al., 2003b) or the relatively
larger increase in the concentration of the other Large Neutral Amino Acids competing
for transport over the blood brain barrier (Bailara et al., 2006).
We found a decreased platelet 5-HT content at day 5 postpartum, which was not related
with the onset of blues. It has been recently reported that women with a postpartum
depression had a decreased platelet 5-HT content (Maurer-Spurej et al., 2007). The
reason they found a relation might be attributed to peculiar aspects of the latter study
namely, a different method for measuring the 5-HT content; the longer sampling time
Sequential serotonin and noradrenalin associated processes involved in postpartum blues
Figure 2. Scatter plot of Blues score an Bmax paroxetin on day 5 Pearson correlation 0,460, p= 0,031
69
Chapter 3
(inclusion in the study up to six months), and a different control group (ten healthy,
70

non-puerperal women).
Bmax of paroxetine binding to platelets in the first postpartum week correlated positively
with blues scores. Two studies (Newport et al., 2004); (Hannah et al., 1992a) reported
an association between postpartum depression and the Kd of impiramine or
paroxetine,,suggesting the presence of a different genetic SERT variant in women who
get depressed. In non-puerperal depressed patients a decreased number of SERT
binding sites has often been reported (as summarized by (Owens and Nemeroff, 1994)).
This may appear opposite to what we found. However, the changes in depressed
patients may reflect the end-stage of a long patho-physiological process, whereas the
Table present 2. changes Regression were models detected explaining at the beginning
blues score of and a transient MHPG levels affective at six syndrome.
weeks postpartum. The data on serotonergic functioning suggests that women with
blues have a relatively higher SERT activity, which might result in a low synaptic 5-HT
content. A decrease in Dependent brain tryptophan variable levels Predictors postpartum
might lead to a B further (SE) decrease β the synaptic Sig.
5-HT 1. content, Blues score thus impairing Constant serotonergic neurotransmission 0.245
(3.751) in women with blues 0.949
and increasing the vulnerability Bmax to paroxetin develop affective 0.007
symptomtomatology. (0.003) 0.562 The decrease 0.012*
in 2. serotonergic MHPG at six weeks metabolism Constant might also lead to a 0.487
decrease (0.474) in the serotonin 0.634
product melatonin, which is also Blues thought score to 5 be days involved pp in 0.074 the
onset (0.021) of depression.
0.477 0.002*
MHPG 5 days pp 0.540 (0.135) 0.550 0.001*
Model statistics: Model MHPG, Model We SE MHPG * significant = are standard 1: 2: the
22
levels blues RR first effect = = Error and 0.316; 0.588; in to cerebrospinal tyrosine
report Adjusted Adjusted data ratio
22
RRon fluid = = puerperal 0.275 0.551 (CSF) Model Model in course pregnant
statistics: statistics: of MHPG. women F(1,18)=7.840, F(4,21)=6.089, One (Altemus study
p=0.012 p=0.003
investigating et al., 2004) reported decreased MHPG levels when compared to non
pregnant women.
The previously reported increase in puerperal increase in tyrosine ratio’s (Abou-Saleh et
al., 1999; Maes et al., 2001; Bailara et al., 2006) might be the result of an increase of
intestinal absorption, protein breakdown and synthesis from hydroxylation of
phenylalanine. The latter was supported by the significantly increased tyr/phe ratio. The
relatively decreased tyrosine levels at six weeks with a constant tyr/phe ratio might point
to an increased utilization of tyrosine for synthesis of proteins, hormones (thyroxine and
triiodothyronine), or catecholamines. However MHPG levels, reflecting catecholamine
turnover, were apparently independent of tyrosine levels, as they did not Fig. correlate. 3.
Summary Presumably, of the regression tyrosine models levels explaining did not vary blues to
score an extend and
that they became rate- noradrenergic limiting for activity catecholamine at 6 weeks postpartum
synthesis (MHPG and (6wk)) most → likely Represents
also not for triiodothyronine significant synthesis. relationships.
Changes in synthesis both hormones have been associated with depression.
 Sequential serotonin and noradrenalin associated processes involved in postpartum
blues

The longitudinal study design allows the modeling of the sequential changes in mood and
various biochemical parameters revealing a consistent relation between blues and
noradrenergic metabolism. This increased noradrenergic metabolism might be related to
depression at six weeks postpartum according to a personal observation of the clinician
who performed the study. He noted depressive symptoms in five women at six weeks
postpartum. All these women had blues. The women with blues and depressive symptoms
both had increased levels of MHPG. The apparent causality in this triangular relation can
have two forms: 1.) Women with blues experience more stress and thus have higher
MHPG levels. Due to this stress women develop subsequent depressive symptoms. The
relation between blues and MHPG levels is thus mediated by stress. 2.) Women with blues
are more vulnerable for depressive symptoms. Due to the depression women get stressed
(and get increased MHPG levels). So the relation between blues and MHPG levels is
primarily mediated by depression. The sequence of events has to be further clarified in a
study in which the temporal changes in mood and noradrenergic functioning are assessed
more frequently, for example on a weekly base, with a systematic assessment of
depressive symptoms at six weeks postpartum.

Conclusion

In summary, the present study indicates that: 1.) Individual differences in serotonin
transporter functioning together with a low plasma tryptophan ratio might synergistically
affect brain 5-HT function postpartum, which seems to increase the vulnerability for blues.
2.) Women with postpartum blues have increased noradrenergic activity at six weeks
postpartum which might be indicative for higher levels of perceived stress. This is
suggested to be either a causal factor or a consequence of later depression. 3.) Whether
these monoamine mediated effects are amplified by rapid hormonal fluctuations during the
postpartum period or by the stress experienced by the delivery or that their combination
contributes to labile affect postpartum (Halbreich, 2005) remains as yet to be elucidated.

Acknowledgements

We thank Dr. J.L. Klompenhouwer for recruiting the subjects in this study and Mrs. A van
Dalen for expert performance of the biochemical assays.
 71
Chapter 3
72
Sequential serotonin and noradrenalin associated processes involved in postpartum
blues
73
Chapter 3
Reference List
1. Abou-Saleh MT, Ghubash R, Karim L,
74 Krymski M, Anderson DN (1999). The role of pterins and
related factors in the biology of early postpartum depression. Eur Neuropsychopharmacol; 9; 295-300
2. Abou-Saleh MT, Ghubash R, Karim L,
Krymski M, Bhai I (1998). Hormonal aspects of postpartum depression. Psychoneuroendocrinology; 23;
465-475
3. Adrien J (2002). Neurobiological bases for
the relation between sleep and depression. Sleep Med Rev; 6; 341-351
4. Altemus M, Fong J, Yang R, Damast S,
Luine V, Ferguson D (2004). Changes in cerebrospinal fluid neurochemistry during pregnancy. Biol
Psychiatry; 56; 386-392
5. Bailara KM, Henry C, Lestage J, Launay
JM, Parrot F, Swendsen J, Sutter AL, Roux D, Dallay D, motes-Mainard J (2006). Decreased brain
tryptophan availability as a partial determinant of post-partum blues. Psychoneuroendocrinology; 31;
407-413
6. Bethea CL, Lu NZ, Gundlah C, Streicher
JM (2002). Diverse actions of ovarian steroids in the serotonin neural system. Front Neuroendocrinol; 23;
41-100
7. Bloch M, Daly RC, Rubinow DR (2003).
Endocrine factors in the etiology of postpartum depression. Compr Psychiatry; 44; 234-246
8. Bloch M, Rotenberg N, Koren D, Klein E
(2005). Risk factors associated with the development of postpartum mood disorders. J Affect Disord; 88;
9-18
9. Bremner JD, Krystal JH, Southwick SM,
Charney DS (1996a). Noradrenergic mechanisms in stress and anxiety: I. Preclinical studies. Synapse;
23; 28-38
10. Bremner JD, Krystal JH, Southwick SM,
Charney DS (1996b). Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse; 23;
39-51
11. Carter CS, Altemus M, Chrousos GP
(2001). Neuroendocrine and emotional changes in the post-partum period. Prog Brain Res; 133; 241-249
12. Fekkes D, Timmerman L, Pepplinkhuizen
L (1997). Effects of clomipramine on plasma amino acids and serotonergic parameters in panic disorder
and depression. Eur Neuropsychopharmacol; 7; 235-239
13. Fekkes D, van Dalen A, Edelman M, Voskuilen A (1995). Validation of the determination of amino
acids in plasma by high-performance liquid chromatography using automated pre-column derivatization
with o-phthaldialdehyde. J Chromatogr B Biomed Appl; 669; 177-186
14. Fuchs D, Schrocksnadel H, Baier-Bitterlich G, Dapunt O, Wachter H (1996). Activated cellular
immunity and decreased serum tryptophan in healthy pregnancy. Adv Exp Med Biol; 398; 149-153
15. Gitlin MJ, Pasnau RO (1989). Psychiatric
syndromes linked to reproductive function in women: a review of current knowledge. Am J Psychiatry;
146; 1413-1422
16. Grattan DR (2001). The actions of
prolactin in the brain during pregnancy and lactation. Prog Brain Res; 133; 153-171
17. Halbreich U (2005). Postpartum disorders:
 multiple interacting underlying mechanisms and risk factors. J Affect Disord; 88; 1-7
polymorphism in the prediction of episodes of
18. Handley SL, Dunn TL, Baker JM, major depression: a replication. Arch Gen
Cockshott C, Gould S (1977). Mood changes in Psychiatry; 62; 529-535
puerperium, and plasma tryptophan and 27. Kennerley H, Gath D (1989a). Maternity blues.
cortisol concentrations. Br Med J; 2; 18-20 I. Detection and measurement by questionnaire. Br
J Psychiatry; 155; 356-362
19. Hannah P, Adams D, Glover V, Sandler M
(1992a). Abnormal platelet 5-
blues. III. Associations with obstetric,
hydroxytryptamine uptake and imipramine
psychological, and psychiatric factors. Br J
binding in postnatal dysphoria. J Psychiatr Res;
Psychiatry; 155; 367-373
26; 69-75
29. Klompenhouwer JL, Fekkes D, van Hulst
20. Hannah P, Adams D, Lee A, Glover V,
AM, Moleman P, Pepplinkhuizen L, Mulder PG
Sandler M (1992b). Links between early post-
(1990). Seasonal variations in binding of
partum mood and post-natal depression. Br J
3H-paroxetine to blood platelets in healthy
Psychiatry; 160; 777-780
volunteers: indications for a gender difference.
Biol Psychiatry; 28; 509-517
21. Hendrick V, Altshuler LL, Suri R (1998).
Hormonal changes in the postpartum and 30. Kohl C, Walch T, Huber R, Kemmler G,
implications for postpartum depression.
Neurauter G, Fuchs D, Solder E,
Psychosomatics; 39; 93-101
Schrocksnadel H, Sperner-Unterweger B
(2005). Measurement of tryptophan,
22. Henshaw C (2003). Mood disturbance in
kynurenine and neopterin in women with and
the early puerperium: a review. Arch Women without postpartum blues. J Affect Disord; 86;
Ment Health; 6 Suppl 2:S33-42. Epub@2003 135-142
Aug 9.; S33-S42
31. Maes M, Lin AH, Ombelet W, Stevens K,
23. Henshaw C, Foreman D, Cox J (2004). Postnatal
Kenis G, De Jongh R, Cox J, Bosmans E (2000).
blues: a risk factor for postnatal depression. J
Immune activation in the early puerperium is
Psychosom Obstet Gynaecol; 25; 267-272
related to postpartum anxiety and depressive
symptoms. Psychoneuroendocrinology; 25;
24. Iles S, Gath D, Kennerley H (1989). 121-137
Maternity blues. II. A comparison between
post-operative women and post-natal women. 32. Maes M, Ombelet W, Verkerk R, Bosmans
Br J Psychiatry; 155; 363-366 E, Scharpe S (2001). Effects of pregnancy and
delivery on the availability of plasma tryptophan
25. Kendler KS, Karkowski LM, Prescott CA (1999). to the brain: relationships to delivery-induced
Causal relationship between stressful life events and immune activation and early post-partum
the onset of major depression. Am J Psychiatry; 156; anxiety and depression. Psychol Med; 31;
837-841 847-858

26. Kendler KS, Kuhn JW, Vittum J, Prescott 33. Maes M, Verkerk R, Bonaccorso S,
CA, Riley B (2005). The interaction of stressful Ombelet W, Bosmans E, Scharpe S (2002).
life events and a serotonin transporter
Depressive and anxiety symptoms in the early which is related to immune activation. Life Sci;
puerperium are related to increased degradation 71; 1837-1848
of tryptophan into kynurenine, a phenomenon
Sequential serotonin and noradrenalin associated processes involved in postpartum
blues

28. Kennerley H, Gath D (1989b). Maternity

75
 34. Mann JJ, McBride PA, Anderson GM,
76 Mieczkowski TA (1992). Platelet and whole blood serotonin
content in depressed inpatients: correlations with acute and life- time psychopathology. Biol Psychiatry;
32; 243-257
35. Maurer-Spurej E, Pittendreigh C, Misri S (2007). Platelet serotonin levels support depression scores
for women with postpartum depression. J Psychiatry Neurosci; 32; 23-29
36. Moleman P, Borstrok JJ (1982). Analysis of
urinary 3-methoxy-4-hydroxyphenylglycol by high-performance liquid chromatography and
electrochemical detection. J Chromatogr; 227; 391-405
37. Muller-Oerlinghausen B, Roggenbach J,
Franke L (2004). Serotonergic platelet markers of suicidal behavior--do they really exist? J Affect Disord;
79; 13-24
38. Munn DH, Zhou M, Attwood JT,
Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL (1998). Prevention of allogeneic fetal rejection
by tryptophan catabolism. Science; 281; 1191-1193
39. Newport DJ, Owens MJ, Knight DL,
Ragan K, Morgan N, Nemeroff CB, Stowe ZN (2004). Alterations in platelet serotonin transporter binding
in women with postpartum onset major depression. J Psychiatr Res; 38; 467-473
40. Owens MJ, Nemeroff CB (1994). Role of
serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem; 40;
288-295
41. Parry BL, Fernando Martinez L, Maurer EL, Lopez AM, Sorenson D, Meliska CJ (2006). Sleep,
rhythms and women's mood. Part I. Menstrual cycle, pregnancy and postpartum. Sleep Med Rev
Chapter 3
42. Rausch JL, Johnson ME, Li J, Hutcheson J, Carr BM, Corley KM, Gowans AB, Smith J (2005).
Serotonin transport kinetics correlated between human platelets and brain synaptosomes.
Psychopharmacology (Berl); 180; 391-398
43. Ross LE, Murray BJ, Steiner M (2005).
Sleep and perinatal mood disorders: a critical review. J Psychiatry Neurosci; 30; 247-256
44. Russo S, Kema IP, Haagsma EB, Boon JC,
Willemse PH, den Boer JA, de Vries EG, Korf J (2005). Irritability rather than depression during interferon
treatment is linked to increased tryptophan catabolism. Psychosom Med; 67; 773-777
45. Schrocksnadel H, Baier-Bitterlich G,
Dapunt O, Wachter H, Fuchs D (1996). Decreased plasma tryptophan in pregnancy. Obstet Gynecol; 88;
47-50
46. Schrocksnadel K, Widner B, Bergant A,
Neurauter G, Schennach H, Schrocksnadel H, Fuchs D (2003a). Longitudinal study of tryptophan
degradation during and after pregnancy. Life Sci; 72; 785-793
47. Schrocksnadel K, Widner B, Bergant A,
Neurauter G, Schrocksnadel H, Fuchs D (2003b). Tryptophan degradation during and after gestation. Adv
Exp Med Biol; 527; 77-83
48. Uebelhack R, Franke L, Herold N, Plotkin M, Amthauer H, Felix R (2006). Brain and platelet serotonin
transporter in humans- correlation between [(123)I]-ADAM SPECT and serotonergic measurements in
platelets. Neurosci Lett; 406; 153-158
49. Yalom ID, Lunde DT, Moos RH, Hamburg
DA (1968). "Postpartum blues" syndrome. A description and related variables. Arch Gen Psychiatry; 18;
16-27
Sequential serotonin and noradrenalin associated processes involved in postpartum
 blues

50. Yoshimura R, Nakamura J, Shinkai K,

Ueda N (2004). Clinical response to
antidepressant treatment and 3-methoxy-4-
hydroxyphenylglycol levels: mini review. Prog
Neuropsychopharmacol Biol Psychiatry; 28;
611-616
77
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