(Stroke. 1998;29:1293-1298.)
© 1998 American Heart Association, Inc.
Diminished Serotonin-Mediated Prolactin Responses in Nondepressed Stroke Patients Compared With Healthy Normal Subjects
Rajamannar Ramasubbu, MD, MRCPsych, FRCPC;
Alastair Flint, MB, FRCPC, FRANZCP;
Gregory Brown, MD, PhD, FRCPC;
George Awad, MD, FRCPC;
Sidney Kennedy, MD, MRCPsych, FRCPC
From the Department of Psychiatry, University of Ottawa, Royal Ottawa
Hospital (R.R.), Ottawa, Canada; the Department of Psychiatry, University of
Toronto, the Queen Elizabeth Hospital and the Toronto Hospital (A.F.); and the
Clarke Institute of Psychiatry, University of Toronto (G.B., G.A., S.K.),
Toronto, Canada.
Correspondence and reprint requests to Dr Ramasubbu, Royal Ottawa Hospital, 1145 Carling Avenue, Ontario, K1Z 7K4, Canada.
 |
Abstract
|
|---|
Background and Purpose—The purpose
of this study was to use hormonal responsiveness to
d-fenfluramine (d-FEN) challenge as a
measure of central serotonin (5-HT) function in a
comparative evaluation of serotonergic abnormalities between stroke
patients and healthy elderly normal subjects to test the hypothesis
that stroke may be associated with diminished serotonergic
functioning.
Methods—Eight nondepressed medically stable stroke patients and
12 healthy volunteers completed a single-blind, placebo-controlled,
fixed-order, crossover design challenge test with 30 mg of oral
d-FEN. Baseline prolactin (PRL) and cortisol (CORT) and
hormonal responses to d-FEN and placebo were measured at
hourly intervals over a 4-hour period. Cardiovascular
responses (pulse and blood pressure) and behavioral responses were also
recorded at the same time points.
Results—The 2 groups were comparable in demographics, body
weight, plasma drug concentration, and behavioral and CORT responses. A
3-way ANOVA for repeated measures showed group differences for baseline
adjusted PRL responses (change of scores from baseline). Peak PRL
responses (maximal PRL change from baseline scores after treatment with
d-FEN) in nondepressed stroke patients were attenuated
compared with healthy elderly subjects, suggesting diminished
serotonergic responsiveness in stroke patients.
Conclusions—The demonstrated serotonergic hypofunctioning
poststroke may contribute to the high incidence of depressive disorders
in stroke patients. Serotonergic agents may have a role in augmentation
of stroke recovery.
Key Words: hormones • serotonin • stroke
|
Introduction
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There is evidence
from preclinical and clinical studies that brain vascular lesions
induce abnormalities in serotonergic
functioning.1 2 3 4 5 Excessive release of 5-HT from
ischemic neurons during the acute phase of infarction and the
diminished monoamine synthesis due to enzyme inhibition of enzymes
during ischemia have been postulated to account for depletion
of 5-HT after cerebral infarction.1 5-HT has been
implicated in the regulation of mood,6 sleep, and
appetite,7 as well as in the expression of
brain-derived neurotrophic factor.8 Therefore,
diminished serotonergic functioning associated with vascular brain
lesions may contribute to emotional and physical consequences of
stroke.
Most of our knowledge concerning serotonergic abnormalities associated
with vascular lesions is derived from animal
experiments1 2 3 and CSF studies involving stroke
patients.4 5 These studies could be criticized on
a number of methodological grounds. Animal models of stroke involved
very young animals without any chronic diseases such as hypertension or
genetic predisposition to such diseases.9
Furthermore, there is considerable variation among species in neuronal
and biochemical responses to cerebral ischemia. Hence, animal
models of stroke may have limited relevance to humans. CSF studies are
limited by the fact that metabolite concentration ratios in CSF
obtained from lumbar puncture may not be representative
of central 5-HT activity.10
The neuroendocrine challenge paradigm provides a better measure of net
physiological responsiveness of the central 5-HT
system in comparison to platelet and early positron emission
tomography studies that are used to study specific 5-HT receptors.
Neuroendocrine challenge tests have been designed on the basis of
abundant evidence substantiating the stimulatory role of 5-HT in the
release of PRL, adrenocorticotrophic hormone, and CORT in animals and
humans.11 12 FEN is an anorectic drug that
enhances 5-HT function by both increasing release and inhibiting
reuptake. A direct action on 5-HT receptors has also been
reported.13 14 The racemic compound of FEN
(d,l-FEN) is a mixture of d and l
isomers. Because the l isomer has
dopamine-antagonist properties,15 the
d isomer has been reported to be more specific to the 5-HT
system than d,l-FEN. Hence, PRL and CORT responses induced
by d-FEN might be assumed to be mediated solely by specific
activation of the 5-HT system. d-FEN induces a
dose-dependent increase in plasma PRL levels that has been shown to be
attenuated by pretreatment with the 5-HT2A/2C
receptor antagonist ritanserin16 or
the 5-HT1A receptor antagonist
pindolol,17 suggesting that this response is
mediated by a serotonergic mechanism.
Another advantage of using oral d-FEN as a 5-HT probe is
that 30 mg of oral d-FEN is well tolerated in healthy normal
subjects without any spontaneously reported adverse
effects.18 Furthermore, d-FEN is
considered to be an appropriate probe to study net presynaptic and
postsynaptic serotonergic activity because serotonergic agents that act
primarily on receptors indicate receptor responsiveness and may not
necessarily reflect the net functional activity of the
system.19 5-HT precursors such as tryptophan and
5-hydroxytryptophan (5-HTPP) are not specific to 5-HT
neurons,20 and side effects of
intravenous clomipramine, such as nausea and
vomiting,21 and the development of early
tolerance to the PRL-releasing effect of
fluvoxamine22 reduce their practical utility as
5-HT probes.
The purpose of this study was to examine net central serotonergic
function in stroke patients by comparing PRL and CORT responses to oral
d-FEN in nondepressed stroke patients and healthy normal
subjects to test the hypothesis that stroke may be associated with
diminished serotonergic functioning.
|
Subjects and Methods
|
|---|
This study represents part of a larger investigation
examining serotonergic function in stroke patients with and without
depression and in healthy elderly subjects. Eight nondepressed stroke
patients (4 women, 4 men) with a mean age of 73±7.56 years and 12
healthy volunteers (9 women, 3 men) with a mean age of 71.08±6.78
years participated in a single-blind, fixed-order, placebo-controlled
d-FEN challenge test.
Subject Selection
Stroke patients were recruited from the stroke rehabilitation
unit of the Queen Elizabeth Hospital, Toronto, and from the
community through local distribution of posters and media
advertisements. The diagnosis of stroke was confirmed by clinical
examination by a qualified neurologist and by CT scan findings. A
minimum of 1 month had elapsed since onset of the stroke and inclusion
of subjects into the study. Stroke includes thrombotic or embolic
infarct or cerebral hemorrhage. These patients were screened
for the presence of a depressive disorder by using the Center for
Epidemiological Studies of Depression Scale, a self-report
instrument.23 Stroke subjects who scored 15 or
less on the Center for Epidemiological Studies of Depression Scale were
considered to be nondepressed and were included in this
analysis. The Barthel Index was used to assess functional
abilities of stroke patients,24 and cognitive
deficits were evaluated using the Mini-Mental State
Examination.25 CT scan findings pertaining to
laterality and location of lesions were obtained from the
radiologist's report. Physical examination and laboratory tests were
performed to rule out any other major neurological and medical
diseases.
Exclusion criteria were as follows: (1) inability to speak or
understand English, (2) severe cognitive deficits as determined by the
Mini-Mental State Examination (scores <15), (3) severe impairment in
comprehension and expressive language, (4) severe essential
hypertension (diastolic blood pressure 
120
mm Hg),26 (5) uncontrolled diabetes mellitus,
(6) myocardial infarction within the past 2 months, (7) hypothyroidism,
(8) other neurological illnesses, (9) a history of alcohol or drug
abuse, (10) schizophrenia or other psychosis, (11) a lifetime history
of depressive disorder, or (12) the use of medications known to produce
changes in the 5-HT system or PRL concentrations, including ketanserin,
methyldopa, estrogen, glucocorticoids, thyroid supplementation,
metoclopramide, cimetidine, antipsychotic, and antidepressive
medications.
Healthy normal subjects were recruited by media advertisements and word
of mouth. An honorarium was provided for participating in the study.
Normal control subjects were screened for severe mental disorders,
substance abuse, and also for a family history of mental disorders,
using a semistructured interview. Appropriate laboratory tests and a
physical examination were performed to rule out any severe medical
illnesses. These subjects were not receiving any medications that could
alter 5-HT function or PRL secretion as mentioned above. Signed
informed consent as approved by the local ethics committee was obtained
from all subjects who participated in the study.
Challenge Tests
Identical challenges with single-dose placebo and
d-FEN were carried out under single-blind conditions
separated by a consistent interval of 24 hours. In all cases
d-FEN, which has a long carryover effect, was administered
second, although both rater and patient were kept blind to the order.
Challenge tests were conducted at the Clinical Investigation Unit of
The Toronto Hospital. Participants remained fasting from
midnight on the night before testing. They attended the test center at
8 AM. A breakfast low in tryptophan (apple sauce, jello,
orange juice) was served to prevent hormonal changes due to
hypoglycemia. They were not allowed to take caffeine or nicotine, and
they remained awake during the test sessions. A cannula was inserted
into the anterior cubital vein, and a physiological
saline drip was begun. Blood samples were taken 30 minutes after that
(zero time) before the oral administration of d-FEN or
placebo and at hourly intervals for 4 hours postchallenge. A fixed dose
of 30 mg of oral d-FEN was used because it is considered to
be equivalent to the dose of d isomer in 60 mg oral
d,l-FEN.27 The sampling period was
limited to 4 hours postchallenge on the basis of the fact that peak PRL
response occurs at 4 hours after oral administration of
d-FEN.28 The blood sample drawn at 3
hours after administration of d-FEN was selected for
determination of d-FEN and d-nor-FEN levels
because the pharmacokinetics of oral d-FEN show a maximal
plasma level of its active metabolites d-FEN and
d-nor-FEN 2 to 4 hours after treatment with
d-FEN.29 Vital signs (blood pressure
and pulse) and self-rated behavioral responses (drowsy, anxious, sad,
or high) were also recorded at these time points using a visual
analogue scale.
Assays
Each blood sample was centrifuged, and plasma was stored
at –25°C before assays. Each sample was assayed for PRL and CORT by
quantitative enzyme immunoassay using transferable solid-phase
technology. The kits were supplied by Sychron Enzyme Linked
Immunosorbent Assay (SYNELISA-USA). The mean intra- and interassay
coefficients of variation for plasma PRL were 5.0% and 7.8%,
respectively, and sensitivity was 2 mg/mL. The intra-assay and
interassay coefficients of variation for plasma CORT were 5.2% and
7.1%, respectively, and sensitivity was 0.5 mg/mL. Levels of
d-FEN and d-nor-FEN were determined by gas liquid
chromatography using a nitrogen selective detector
according to the methods of Kerbs et al (1984) with minor
modifications.30 The intra- and interassay
coefficients of variation for FEN at 15 mg/mL were 2.7% and 2.7%,
respectively, and for nor-FEN at 15 mg/mL were 3.7% and 5.4%,
respectively. The lower detection limit was 2 mg/mL.
Data Analysis
PRL and CORT responses were calculated for 2 outcome measures:
(1) mean baseline-adjusted net changes (change scores from baseline)
and (2) peak hormonal responses (baseline values subtracted from the
maximum increase in after treatment with d-FEN).
Baseline-adjusted net changes in PRL and CORT concentrations in placebo
and drug conditions were compared between 2 groups using 3-way ANOVA
for repeated measures. -AUC for hormonal responses to d-FEN
was calculated using the trapezoid rule. Intergroup differences in AUC
values between each of the time point were compared using the Student
t test. Peak hormonal concentrations between groups were
compared using Student t tests. Comparisons of continuous
and categorical variables were performed using Student's
t tests and 
2 tests, respectively.
Statistical significance of all tests was set at P
0.05
(2-tailed). Data were analyzed using Statistical Program for
the Social Sciences (SPSS, Inc).
|
Results
|
|---|
Sample characteristics of 8 nondepressed stroke patients are
summarized in Table 1
. As shown in Table 2, stroke patients did not significantly
differ from healthy normal subjects in age (t-0.59,
df=18, P=0.56), sex
(2=1.31, df=1, P=0.25),
body weight (t=1.64, df=18, P=0.12),
or plasma concentration of d-FEN or d-nor-FEN
(t=0.77, df=15, P=0.45). The mean of
baseline PRL concentration in both drug and placebo conditions
(t=1.24, df=18, P=0.23) and the mean
of baseline CORT in both drug and placebo conditions (t=70,
df=18, P=0.49) were comparable between
groups.
PRL Responses
Baseline-adjusted net PRL responses to d-FEN and
placebo over 240 minutes are shown in Figure 1. A 3-way ANOVA revealed a main effect
of drug (F=4.47; df=1,18; P=0.043),
time (F=5.65; df=3,54; P=0.002), a
drug-time interaction (F=5.36; df=3,54;
P=0.003), and group-time interaction (F=8.90;
df=3,54; P=0.005), suggesting an increase in PRL
concentration in response to d-FEN and also intergroup
differences in PRL responses. A 2-way ANOVA was performed to determine
whether the observed group-time interaction was caused by different PRL
responses to placebo or to d-FEN. Group-time interaction was
significant for baseline-adjusted PRL responses to d-FEN
(F=5.49; df=3,54; P=0.002) but not for
baseline-adjusted PRL responses to placebo (F=1.25;
df=3,54; P=0.30). AUC analysis of PRL
responses from time points 180 to 240 minutes after the administration
of d-FEN demonstrated significantly higher values in healthy
normal subjects than in nondepressed stroke patients
(t=2.43, df=18, P=0.026). Similarly,
peak PRL responses to d-FEN in healthy normal subjects were
significantly higher than in nondepressed stroke patients
(t=2.26, df=12.04, P=0.043),
suggesting blunted PRL responses in nondepressed stroke patients.
CORT Responses
Figure 2 summarizes the CORT
responses to d-FEN and placebo. For baseline-adjusted CORT
changes, ANOVA showed a main effect of drug (F=24.29,
df=1,18, P=0.00), but there was no group effect
(F=0.31; df=1,18; P=0.59), group-time
interaction (F=0.29; df=3,54; P=0.83),
group-drug interaction (F=0.21; df=1,18;
P=0.65), or group-time-drug interaction (F=0.96;
df=3,54; P=0.42), indicating an absence of
intergroup differences in CORT responses. Furthermore, there were no
differences in peak CORT responses between the 2 groups
(t=0.63, df=18, P=0.54).
Cardiovascular and Behavioral Responses
None of the stroke patients or the healthy normal subjects
experienced unpleasant side effects or reported any change in mood
state or alertness after treatment with d-FEN. There were no
significant differences in heart rate (group-drug-time interaction:
F=0.62; df=4,56; P=0.65),
systolic blood pressure (group-drug-time interaction:
F=1.36; df=4,56; P=0.26), or
diastolic blood pressure (group-drug-time interaction:
F=0.83; df=4,60; P=0.51).
|
Discussion
|
|---|
This study demonstrates a blunted PRL response to the acute
administration of 30 mg of oral d-FEN in medically stable
nondepressed chronic stroke patients compared with healthy normal
subjects. Since PRL responsiveness to d-FEN reflects brain
5-HT function, the blunted PRL responses observed suggest diminished
serotonergic function in stroke patients. However, it could be argued
that the blunted PRL responses observed in stroke patients might be
mediated by nonserotonergic mechanisms. Ischemic damage to the
hypothalamopituitary axis resulting in decreased biosynthesis, storage,
or release of PRL, poor sensitivity of the pituitary lactotroph to
PRL-releasing factor, enhanced dopamine
activity,31 or
hypercortisolism32 could contribute to blunted
PRL responses. When one considers the fact that PRL responses with
placebo reflect baseline PRL synthesis, storage, and release in the
normal resting state, the comparable PRL responses to placebo
administration in both groups suggest that the diminished PRL
responsiveness in stroke patients is not because of any anatomic or
functional deficit in the hypothalamopituitary axis. In addition there
is no firm evidence in the literature to suggest an alteration in
sensitivity of pituitary lactotroph to PRL-releasing factor as a remote
effect of brain vascular lesions. Furthermore, 5-HT activation has been
reported to be associated with a reduction in dopamine function, and
basal PRL concentrations, which may be under tonic control of dopamine
system,33 were comparable between stroke patients
and healthy normal subjects. It is also unlikely that PRL responses are
blunted due to stroke-related hypercortisolism because there were no
intergroup differences in either basal CORT concentrations or CORT
responses to placebo or d-FEN. Hence, it is reasonable to
think that attenuation of PRL responses to d-FEN challenge
in stroke patients might be directly related to diminished serotonergic
functioning. Previous CSF studies reported an increased CSF-5H1AA
content in the first few days after the onset of
stroke.4 5 This increased CSF-5H1AA content is
considered to be a reflection of increased release of 5-HT in the
affected area leading to depletion of 5-HT. When one takes into account
these considerations in combination with our findings of serotonergic
hypofunction in chronic stroke patients, it might be suggested that the
association between diminished serotonergic function and stroke may be
independent of time since stroke in at least some stroke patients.
Several mechanisms could be postulated to explain the diminished
serotonergic responsiveness in nondepressed stroke patients. Focal
vascular lesions may alter the serotonergic functioning of anatomically
intact and distant brain structures. In this study, 1 patient had a
pontine lesion and 7 patients had frontal lesions. A pontine lesion may
have damaged serotonergic projections from the dorsal and median
raphe to the hypothalamus, resulting in diminished PRL release to 5-HT
activation. Frontal lesions may have caused direct retrograde changes
in 5-HT cell bodies of the raphe nuclei,2 which
in turn could alter serotonergic responsiveness at the hypothalamus.
The other possibility is that frontal lesions may have caused
disruption of efferent pathways from the orbitofrontal cortex to
serotonergic raphe nuclei or to the hypothalamus. The preponderance of
left-sided lesions in our stroke sample, and the observation of
diminished serotonergic functioning, is consistent with
previous studies reporting right-left asymmetry in serotonergic
functioning in healthy normal subjects and stroke patients. There is
evidence that the right frontal cortex has a significantly higher
number of imipramine-binding sites than the left frontal
cortex.34 Furthermore, patients with right-sided
lesions have been found to have greater cortical
5-HT2 receptor binding than patients with
left-sided lesions 16 months poststroke.35 Hence,
it is possible that left-sided lesions may cause greater depletion than
right-sided lesions, because of failure in upregulation of 5-HT
receptors after left-sided lesions35 and also
because of a relative increase in 5-HT binding sites in the right
hemisphere compared with the left hemisphere.
The effect of lesions on the 5-HT system may also depend on the
volume of the infarcted area. We did not repeat the CT head scans at
the time patients entered the study. As a result we could not
accurately assess the relationship between lesion volume and
serotonergic responsiveness, since lesion volume may have changed
between the time of the stroke (when the CT scans were performed) and
the time of the study. Another important issue is that, besides stroke
lesions, comorbid diseases such as diabetes mellitus and hypertension
may influence serotonergic function in stroke
patients.36 37 Prolonged psychosocial stress
associated with physical and cognitive impairment in stroke patients
may lead to downregulation of 5-HT1A
receptors.38 We did not quantify cognitive and
physical functioning in the healthy control subjects so we are unable
to determine whether impairment-related stress may have contributed to
PRL differences between the groups. A reduction in precursor supply due
to poor intake of tryptophan or inhibition of tryptophan uptake or
tryptophan hydroxylase due to brain
ischemia39 may result in decreased 5-HT
synthesis. Unfortunately, we did not have measures of these
variables to compare between the 2 groups. Hence, factors other
than the stroke lesion may also have contributed to diminished
serotonergic responsiveness in the group of stroke patients.
In contrast to PRL responses, CORT responses failed to distinguish
between the nondepressed stroke group and the healthy control group.
This might be explained by the fact that d-FEN–induced PRL
and CORT responses might involve different 5-HT receptor subtypes or
mechanisms. Some studies suggest that PRL and CORT responses are
mediated by 5-HT1A17 and
5-HT2A/C,40 41
respectively. Hence, it is possible that blunted PRL response in stroke
patients might be caused by selective vulnerability of
5-HT1A receptors to ischemic neuronal
damage because the hippocampus, a brain structure that is selectively
vulnerable to ischemia, has a high density of
5-HT1A receptors.42
However, 5-HT2A/5-HT2C
receptors also have been implicated in PRL
secretion,43 and d-FEN used in this
study is not specific to any receptor subtype. It is not possible to
determine from this experiment which receptor subtypes are affected in
stroke patients. Van de Kar et al (1985) proposed that cortisolemic
effect of d,l-FEN might be due to direct stimulation of the
adrenal gland or d,l-FEN–induced hypoglycemia in addition
to serotonin activation.44
Precautions were taken to minimize hypoglycemic effects of
d-FEN during the challenge test by providing a light
breakfast at the beginning of the study. However since corticotropin
and corticotropin-releasing factor responses were not examined, it is
not possible to rule out peripheral mechanisms involved in
the mediation of CORT responses in this study. Hence, normal CORT
responses in contrast to diminished PRL responses to d-FEN
in stroke patients compared with normal subjects might be due to
selective involvement of 5-HT subtypes and or direct stimulation of the
adrenal gland.
We recognize that this study has methodological shortcomings that
limit the validity of inferences beyond the sample analyzed.
First, the stroke patients participating in the study cannot be
considered to be a random sample. Second, the sample size is small and
heterogeneous in lesion characteristics, with a
preponderance of left-sided lesions and also a variation in time since
stroke. Third, there are several possible differences between stroke
patients and healthy subjects such as comorbid physical illnesses and
tryptophan status, which were not measured but which may have affected
the results. Hence, the findings of the study should be considered
preliminary.
Despite these shortcomings, this study has several implications. To the
best of our knowledge, this is the first study to examine central
serotonergic responsiveness in stroke patients. The findings of
serotonergic hypofunction in stroke patients may explain why a
significant proportion of stroke patients develop major depressive
illnesses and emotional lability, which are believed to be associated
with central 5-HT deficiency.45 46 Furthermore,
when one takes into account the efficacy of specific 5-HT reuptake
inhibitors in the treatment of poststroke
depression47 and the demonstrated
mood-independent serotonergic hypofunction in stroke patients, this
abnormality may be considered both a trait and state marker of
poststroke depression. The observed diminished serotonergic function in
stroke patients may have adverse consequences on stroke recovery
because recent studies suggest that the 5-HT2A
receptors may play a role in the expression of brain-derived
neurotrophic factor and neuronal survival8 and
that 5-HT1A receptors may limit neuronal damage
after cortical ischemia.48 Furthermore,
fluoxetine, a selective 5-HT reuptake inhibitor, was found
to be superior to maprotaline, an 
-adrenergic antidepressant, in
augmentation of functional recovery in poststroke hemiplegic patients
undergoing rehabilitation therapy.49 Therefore
the role of specific 5-HT reuptake inhibitors and
5-HT1A agonists in augmentation of neurological
and functional recovery in stroke patients are the potential areas for
future investigations.
|
Selected Abbreviations and Acronyms
|
|---|
| AUC |
= |
area under response curve |
| CORT |
= |
cortisol |
| CSF |
= |
cerebrospinal fluid |
| FEN |
= |
fenfluramine |
| 5-HT |
= |
serotonin |
| nor-FEN |
= |
norfenfluramine |
| PRL |
= |
prolactin |
|
|
Acknowledgments
|
|---|
This research was supported by a grant from the Canadian
Psychiatric Research Foundation. The authors thank Drs Hajek and
Ruderman and the staff of the stroke unit at The Queen Elizabeth
Hospital and the staff of the Clinical Investigation Unit, The
Toronto Hospital, for their cooperation and assistance in
recruitment and performance of challenge tests. We would also
like to thank Servier for supplying d-fenfluramine and
placebo capsules. Dr David Streiner provided statistical consultation
and Mr Paul Miceli assisted with statistical analysis. We also
acknowledge Thomas Cooper, Nathan Kline Institute of Psychiatric
Research, New York, NY, for measuring levels of
d-fenfluramine and d-nor-fenfluramine and
Sangeetha Ramasubbu for technical assistance.
Received November 4, 1997;
revision received April 9, 1998;
accepted April 9, 1998.
|
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Abstract
Introduction
