Division of Mood Disorders, The University of British Columbia
Division of Schizophrenia, The University of British Columbia
Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Centre, Taipei, Taiwan
Division of Mood Disorders, The University of British Columbia
TRIUMF Positron Emission Tomography Programme, The University of British Columbia
Division of Mood Disorders, The University of British Columbia
TRIUMF Positron Emission Tomography Programme, The University of British Columbia, Vancouver, BC, Canada
Correspondence: Lakshmi N. Yatham, Associate Professor of Psychiatry, Director of Mood Disorders Clinical Research Unit, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 2A1. Tel: 1 604 822 0562; Fax: 1 604 822 7922; e-mail: yatham{at}unixg.ubc.ca
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ABSTRACT |
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Aims To determine the effects of RTD on brain 5-HT2 receptors using positron emission tomography (PET) and 18F-labelled setoperone.
Method Ten healthy women under went two PET scans. Each scan was done 5 h after the ingestion of either a balanced or a tryptophan-deficient amino acid mixture, and the two test sessions were separated by at least 5 days.
Results The RTD decreased plasma free tryptophan levels significantly but it had no significant effects on mood. Subjects showed a significant decrease in brain 5-HT2 receptor binding in various cortical regions following the RTD session.
Conclusions When taken with the evidence that antidepressant treatment is associated with a decrease in brain 5-HT2 receptors, these findings suggest that a decrease in 5-HT2 binding following RTD might be an adaptive response that provides protection against depressive symptoms.
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INTRODUCTION |
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METHOD |
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Positron emission tomography scanning and RTD protocol
All study subjects had a high-resolution magnetic resonance imaging scan of
the head to exclude cerebral pathology and facilitate localisation of brain
regions in PET images. The 18F-setoperone was prepared by a
modified method of Crouzel et al
(1988), as described by Adam
et al (1997). Each
subject was scanned on two separate days 5 h after the ingestion of amino acid
mixtures. The scanning on one day was preceded by the ingestion of a
nutritionally balanced mixture (15 amino acids and 2.3 g of L-tryptophan;
control session) and on the other day by the ingestion of a
tryptophan-deficient amino acid mixture (15 amino acid drink that contained
all the other amino acids but no tryptophan; RTD session). The composition of
the amino acid mixture was the same as that used by Delgado et al
(1999). The amino acid mixture
was flavoured with chocolate syrup and the unpleasant ingredients were given
in a capsule form. The administration of the amino acid mixture was done in a
randomised, counterbalanced protocol, with two test days separated by at least
5 days.
Subjects presented to the Mood Disorders Clinical Research Unit at 7 a.m. At 7.15 a.m., an intravenous cannula was inserted and a blood sample was drawn for free tryptophan levels. Behavioural ratings were completed prior to and 5 h after the ingestion of amino acid mixtures. Ratings included a 20-item Hamilton Rating Scale for Depression (HRSD) consisting of the 29-item HRSD (Williams et al, 1991) modified to exclude the nine items that could not be rated within the same day, such as sleep, eating (because patients were fasting), weight and diurnal variation. We also administered the Profile of Mood States (POMS; McNair et al, 1988) to detect subclinical mood changes. After subjects ingested the amino acid mixture, they stayed in a room for the next 5 h. During this period, subjects were allowed to read magazines. Approximately 5 h later, they had a second blood sample drawn for free tryptophan levels. Following this, the subjects were escorted to the PET suite.
Blood samples were centrifuged immediately for 30 min and an ultrafiltrate of plasma was obtained by additional centrifuge (2000 g) at room temperature for 30 min through a cellulose ultrafiltration membrane system (Amicon Co., Beverley, MA, USA) for assay of plasma free tryptophan levels. The ultrafiltrate samples were frozen at -70°C and later assayed using high-performance liquid chromatography with fluorometric detection (Anderson et al, 1981).
Subjects had a transmission scan done to correct PET images for attenuation. Following this, subjects were given 148-259 MBq of 18F-setoperone intravenously. The radioactivity in the brain was measured with the PET camera system ECAT 953B/31 (CTI/Siemens, Knoxville, TN, USA). The spatial resolution of images is about 5 mm. We performed 15 frame dynamic emission scans on each subject for a total of 110 min. The numbers and durations of the frames were as follows: 5 x 2 min (10 min), 4 x 5 min (20 min), 4 x 10 min (40 min) and 2 x 20 min (40 min). The subjects underwent the same protocol 5-7 days later, so that by the end of the second test session the subjects had 18F-setoperone scans preceded by an RTD session and control test sessions. At the end of each test session, subjects were assessed clinically. None had any substantial changes in mood.
Data analysis
A multipurpose imaging tool (Pietrzyk
et al, 1994) was used to draw regions in frontal,
temporal and parietal cortex and cerebellum. When time-activity curves were
plotted, they showed that the cortex/cerebellum ratio was constant between 70
and 110 min, indicating the occurrence of pseudo-equilibrium during this time
period for the tracer. Hence, the PET data obtained during this period were
used for comparing the differences in binding between the RTD and control
sessions.
If it is assumed that there is no specific binding to 5-HT2
receptors in the cerebellum and, furthermore, that non-specific binding is the
same in cerebellum as in cortex, the ratio of binding in cortex (Cx)
to cerebellum (Cb) is given by:
![]() | (1) |
![]() | (2) |
![]() | (3) |
An alternative approach would be to employ a change in the ratio of regional to mean global cortical setoperone concentration to obtain a value that is proportional to the change in local binding potential between conditions (see Yatham et al, 1999), for details). This method has the advantage of circumventing the uncertainty surrounding the differences in non-specific binding between cortex and cerebellum. This method, however, is only valid provided that the mean global binding potential does not vary substantially between conditions. Our data suggest that the mean (s.d.) global binding potential was significantly lower in the RTD session (1.56965 (0.38850)) than in the control session (1.64726 (0.35139)) (P<0.01) and hence this method cannot be used to compare the differences in binding between the sessions.
We therefore employed the method based on the ratio of cortical to
cerebellar binding to derive a measure of change in 5-HT2 receptor
binding potential for each voxel from the measured change in cortex/cerebellum
ratio (employing Equation (3)), assuming that the non-specific binding in
cortex and cerebellum did not vary significantly between the RTD and control
sessions. Furthermore, it should be noted that the quantity that is determined
for each subject is not the change in binding potential itself, but is
f2cb(Bmax/Kd).
None the less, under the assumption that non-specific binding is not affected
by tryptophan depletion, this quantity can be regarded as a measure of change
in binding potential.
Statistical Parametric Mapping (SPM96) software (Friston et al, 1991, 1995) was used to align PET images, co-register them to magnetic resonance images and transform the magnetic resonance images (and PET images) into the standard coordinate frame used for templates in SPM96. Then an 18F-setoperone binding image was created by dividing each pixel in the RTD and control session realigned normalised mean images by that image's average cerebellar value. A mean activity value from two large regions of interest (one on the right and one on the left) drawn on three contiguous cerebellar slices was used as that image's average cerebellar value. The binding images were smoothed by applying a 12-mm full width at half-maximum (FWHM) isotropic Gaussian filter to improve the signal-to-noise ratio.
Statistical analysis
Statistical parametric mapping (SPM96) software was used to determine the
change in cortex/cerebellum ratio (hereafter referred to as the
5-HT2 binding potential: 5-HT2BP) between the RTD and
control sessions. The grey matter threshold was determined using a
multipurpose imaging tool (Pietrzyk et
al, 1994) and was set at 1.3 times the mean global cerebral
image intensity, to exclude non-grey matter voxels in the analysis. For each
voxel, the Z value corresponding to the t statistic for the
difference in 5-HT2BP between the RTD and control sessions was
computed. We also computed the Z value for each voxel for the difference in
5-HT2BP between the first and second scans for each subject to
examine the order of scanning effects. In estimating the significance of
change in individual voxels, the method developed by Worsley
(1994) as implemented in SPM
was used to correct for multiple comparisons, taking into account the
correlation between voxels. In addition, we also computed the significance of
change in clusters of contiguous voxels exceeding a threshold of Z = 2.33, as
implemented in SPM96 based on the method of Poline et al
(1997).
Behavioural and plasma free tryptophan data were analysed using paired and unpaired t-tests and repeated-measures analysis of variance (ANOVA) with time and session as intrasubject factors. Data are presented as mean (s.d.) and all tests were two-tailed, with significance set at P<0.05. All analyses were performed on a personal computer using the Statistical Package for Social Science (SPSS) software, version 7.5 (SPSS, 1996).
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RESULTS |
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Effects of RTD on brain 5-HT2 receptors
The 5-HT2BP was decreased significantly following the RTD
session compared with the control session. Analysis with SPM showed an
extensive cluster of voxels embracing frontal, temporal, parietal and
occipital cortical regions (Fig.
2). The reduction in 5-HT2BP in this cluster was highly
significant even after correcting for multiple comparisons
(P<0.0001) (Table
1). The cluster included 28 106 voxels and this corresponds to
about 39% of the volume of grey matter that was in the field of view. The mean
reduction in 5-HT2BP was 7.9% for the entire cluster. There were
134 voxels within this cluster that satisfied the criteria for significance
for individual voxels.
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The location and Z value for change in 5-HT2BP at local maxima where Z exceeded 4.00 (P<0.025 after correction for multiple comparisons) are given in Table 1). The areas that showed the most significant decrease in 5-HT2BP included the left fusiform gyrus, left insula, left superior temporal gyrus and left superior frontal gyrus (Table 1 and Fig. 3).
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There was no difference in 5-HT2BP between first and second scans, indicating that scanning order had no systematic effect on 5-HT2BP.
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DISCUSSION |
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A potential source of artefactual result must be considered before
ascribing the decrease in 5-HT2BP to a true decrease in
5-HT2 receptor density. The estimates of 5-HT2BP might
have been confounded by changes in endogenous 5-HT levels that would have
occurred following RTD. Several studies in recent years have suggested that
the in vivo measurement of neurotransmitter receptors is affected by
changes in the levels of endogenous neurotransmitter. This has been
demonstrated very elegantly in the case of D2 receptors by
manipulating endogenous dopamine levels
(Breier et al, 1997;
Laruelle et al,
1997). These studies have shown that increasing the synaptic
dopamine concentration with amphetamine or methylphenidate reduces, whereas
decreasing the synaptic dopamine concentration with dopamine synthesis
inhibitor -methyl-p-tyrosine (AMPT) increases, the striatal
D2 receptor binding as measured with 11C-raclopride
(Breier et al, 1997) or 123I-iodobenzamide (IBZM)
(Laruelle et al,
1997). It is, therefore, conceivable that the changes in
endogenous 5-HT levels could affect the estimates of 5-HT2 receptor
binding with PET. However, RTD is expected to decrease rather than increase
brain 5-HT levels. This should leave a greater number of 5-HT2
receptors unoccupied. In such a situation, one would expect to see an increase
in 5-HT2BP as measured with 18F-setoperone. Because we
found a decrease in 5-HT2BP, this is unlikely to be due to a
confounding effect of a decrease in brain 5-HT levels.
Is the decrease in 5-HT2BP due to a change in
5-HT2 receptor affinity or density?
The methods used in this study provide a semi-quantitative estimate of
5-HT2BP but do not permit an independent determination of
Bmax (density) or Kd (affinity).
Therefore, we cannot tell whether the decrease in 5-HT2BP observed
in the study subjects following RTD was due to a decrease in
Bmax or an increase in Kd. However,
most (Peroutka & Snyder,
1980; Kellar & Stockmeier,
1986; Paul et al,
1988; Mason et al,
1993; Klimek et al,
1994; Hensler & Truett,
1998), although not all
(Blackshear & Sanders-Bush,
1982), studies that examined the acute or chronic effects of
antidepressants or electroconvulsive shock on various 5-HT receptors in rats
reported an alteration in Bmax and not
Kd; this would suggest that pharmacological or somatic
interventions commonly lead to changes in Bmax and not
Kd. Hence, the decrease in 5-HT2BP observed in
our study subjects is more likely to be due to a decrease in
Bmax than to an increase in Kd.
Could 5-HT2 receptors down-regulate rapidly?
Another issue that needs to be considered before ascribing the decrease in
5-HT2BP to a decrease in Bmax and hence to a
decrease in 5-HT2 receptor density is whether receptor density
could change within a 6-7 h time period following an intervention. Indeed,
animal studies have shown that 5-HT2 receptor density was
significantly reduced 48 h after a single dose of mianserin
(Blackshear & Sanders-Bush,
1982; Hensler & Truett,
1998). Similarly, rats that received injections of
5-HT2 agonist DOM (4-methyl-2,5-dimethoxyphenylisopropylamine)
every 8 h showed a significant decrease in 5-HT2 receptors in
frontal cortex following the second injection
(Leysen & Pauwels, 1990). Other studies have shown that treatment with imipramine, amitriptyline and
desipramine for 2-7 days also led to a reduction in 5-HT2 receptor
density (Paul et al,
1988; Mason et al,
1993). A single dose of fluoxetine decreases 5-HT1A
receptor density within a 24-h period
(Klimek et al, 1994),
therefore it is feasible that RTD could lead to a rapid reduction in
5-HT2 receptor density.
Should tryptophan depletion cause an up-regulation rather than a
down-regulation of 5-HT2 receptors?
In general, neurotransmitter receptors upregulate following depletion of a
neurotransmitter or administration of an antagonist, and down-regulate
following the administration of an agonist. However, it is well known that the
regulation of brain 5-HT2 receptors does not follow the classical
receptor regulation model because both 5-HT2 agonists as well as
antagonists consistently down-regulate 5-HT2 receptors
(Leysen, 1990). Also, some
animal studies have shown that experimentally induced 5-HT neuronal lesions
that deplete 5-HT cause either no change
(Butler et al, 1990)
or a decrease in brain 5-HT2 receptors
(Leysen et al, 1982).
These studies indicate that the regulation of 5-HT2 receptors is
peculiar and cannot be predicted based on the classic receptor regulation
model. Thus, the finding of a decrease in 5-HT2BP following RTD is
consistent with what is known about the regulation of this receptor and with
the findings of previous animal studies.
Could a change in 5-HT2 receptor density determine whether
or not a subject experiences depressive symptoms following RTD?
Our finding of no mood changes in healthy volunteers following RTD is
consistent with the findings of previous studies in healthy volunteers (see
Lam et al, 2000, for
a review). Could a decrease in 5-HT2 receptor density in our
subjects following RTD explain the lack of mood changes? A number of animal
studies have indeed shown that most, but not all, antidepressant medications
down-regulate 5-HT2 receptors
(Peroutka & Snyder, 1980;
Blackshear & Sanders-Bush,
1982; Cross & Horton,
1988; Paul et al,
1988; Hrdina & Vu,
1993; Klimek et al,
1994). Furthermore, we have shown recently in a PET study that
patients with depression show a significant decrease in brain 5-HT2
receptors following treatment with desipramine
(Yatham et al, 1999).
Taken together, these observations may indicate that reduced 5-HT2
receptor density may be potentially a critical event in the prevention and
relief of depressive symptoms.
If this were true, only those subjects that fail to down-regulate their brain 5-HT2 receptors following RTD or those that do not have down-regulated 5-HT2 receptors should show a transient relapse of depressive symptoms. Animal studies have shown that desipramine (an NRI) consistently down-regulates 5-HT2 receptors (Peroutka & Snyder, 1980; Goodnough & Baker, 1994), whereas SSRIs such as fluoxetine do not appear to have consistent effects on 5-HT2 receptors (Peroutka & Snyder, 1980; Hrdina & Vu, 1993). The fact that patients treated with NRIs do not relapse following RTD is in keeping with this hypothesis because these patients already would have down-regulated 5-HT2 receptors. This hypothesis would predict that patients treated with SSRIs would be vulnerable to RTD-induced depression because they would not be expected to have down-regulated 5-HT2 receptors. However, only 50% of SSRI-treated patients relapse following RTD; possibly these are the patients that cannot down-regulate their 5-HT2 receptors to prevent relapse of symptoms. There are no PET studies to date that measured the effects of RTD on brain 5-HT2 receptors in patients with depression. However, a recent PET study that examined brain glucose metabolism reported a decrease in the middle frontal gyrus, orbitofrontal cortex and thalamus in those patients who relapsed following tryptophan depletion but not in those who did not relapse (Bremner et al, 1997). This would support the argument that some SSRI-treated patients may be able to mount a compensatory mechanism to prevent the relapse of depressive symptoms. This hypothesis, however, needs to be tested in patients with recently remitted depression before any firm conclusions can be drawn.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication June 23, 2000. Revision received November 1, 2000. Accepted for publication November 2, 2000.
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