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Lower Serotonin Transporter Binding Potential
in the Human Brain During Major Depressive Episodes
Ramin V. Parsey, M.D., Ph.D.
Ramin S. Hastings, B.S.
Maria A. Oquendo, M.D.
Yung-yu Huang, M.S.
Norman Simpson, B.S.
Julie Arcement, B.S.
Yiyun Huang, Ph.D.
R. Todd Ogden, Ph.D.
Ronald L. Van Heertum, M.D.
Victoria Arango, Ph.D.
J. John Mann, M.D.
Objective: CSF analysis, neuroendocrine
challenges, serotonin depletion studies,
and treatment studies implicate the serotonergic system in the pathophysiology
of major depressive disorder. On the basis of postmortem and imaging studies,
the authors hypothesized that subjects
with major depressive disorder in a major depressive episode have fewer serotonin transporter sites, compared with
healthy subjects.
Method: Serotonin transporter binding
potential (f1Bmax/Kd) was determined using positron emission tomography with
[11C]McN 5652 in six brain regions in 25
medication-free subjects with DSM-IV major depressive disorder during a major depressive episode and in 43 healthy volunteer comparison subjects. All subjects had
arterial lines placed to determine metabolite-corrected arterial input functions.
Results: Serotonin transporter binding
potential differed significantly by brain region and group. Post hoc analysis revealed
lower binding potential in subjects with
major depressive disorder, relative to the
comparison subjects, in the amygdala and
midbrain. The lower binding potential was
more pronounced in the depressed subjects who had never received antidepressants. No correlation was found between
binding potential in the midbrain and severity of depression or number of days
without medication. Binding potential did
not differ between suicide attempters and
nonattempters.
Conclusions: Subjects in a major depressive episode have lower serotonin transporter binding potential in the amygdala
and midbrain, compared to healthy
subjects.
(Am J Psychiatry 2006; 163:52–58)
S
erotonin (5-HT) transmission appears altered in major
depressive disorder (1–3). The serotonin transporter plays
a critical role in 5-HT transmission by terminating the action of 5-HT by reuptake into presynaptic neurons (4). Serotonin transporter binding is localized to serotonergic
neurons (5), and it can be regulated by drugs and by cellular mechanisms (6, 7). Serotonin transporter has been implicated in the pathophysiology of major depressive disorder (8) and is the target of most current antidepressants (5).
Findings from postmortem, lesion, and brain imaging
studies have suggested two main anatomical circuits involved in mood regulation (9–11). The first is a limbic-thalamic-cortical circuit that includes the amygdala, medialdorsal nucleus of the thalamus, and ventrolateral prefrontal cortex. The second is a limbic-striatal-pallidalthalamic-cortical circuit. Mood disorders may occur if there
is a disruption in the functioning of a component of either
circuit, both of which receive serotonergic innervation.
In addition to these circuits, the hippocampus and anterior cingulate also have serotonergic abnormalities in major depressive disorder. Female subjects with remitted depression have smaller hippocampal volumes (12), and
smaller hippocampal volume is negatively correlated with
the duration of lifetime depression (13) and is perhaps related to lower postmortem levels of serotonin transporter
(14). The anterior cingulate is implicated in the pathophys-
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iology of major depressive disorder, and there are reports of
lower blood flow and metabolism (15–18), smaller volume
(18), and lower postmortem serotonin transporter binding
(19) for this region. The dorsal and median raphe nuclei
supply all the serotonergic projections to the forebrain. An
in vivo single photon emission computerized tomography
study demonstrated 19% lower [123I]β-CIT serotonin transporter binding in the midbrain of subjects with major depressive disorder, compared with healthy subjects (20).
We used positron emission tomography (PET) with the
radiotracer [11C](+)-6β-(4-methylthiophenyl)1,2,3,5,6α,10β-hexahydropyrrolo[2,1-a]isoquinoline
([11C]McN 5652) to examine serotonin transporter binding potential in brain regions that have quantifiable serotonin transporter, are implicated in the circuits proposed,
and have 5-HT abnormalities—the amygdala, hippocampus, thalamus, putamen, anterior cingulate cortex, and
midbrain. Healthy volunteer subjects were compared with
medication-free subjects with major depressive disorder
during a major depressive episode. We hypothesized that
lower [11C]McN 5652 binding would be found in the selected regions in subjects with major depressive disorder.
[11C]McN 5652 binding in the prefrontal cortex is too low
to quantify reliably (21). We also explored the relationship
between [11C]McN 5652 binding and previous exposure to
Am J Psychiatry 163:1, January 2006
PARSEY, HASTINGS, OQUENDO, ET AL.
TABLE 1. Charactersistics of Healthy Comparison Subjects and Subjects With Major Depressive Disorder in a Study of
Serotonin Transporter Binding Potential in the Brain
Characteristic
Sex
Male
Female
Inpatient
Outpatient
Recent antidepressant use
Antidepressant naive
First-degree relative with major depressive disorder
Age (years)
24-item Hamilton Depression Rating Scale score
Beck Depression Inventory score
Global Assessment Scale score
Age at first major depressive episode (years)
Number of major depressive episodes
Healthy
Comparison Subjects
(N=43)
N
%
Subjects With Major
Depressive Disorder
(N=25)
N
%
Analysis
χ2 (df=1)
p
5.29
22
21
51
49
0
Mean
38.8
0.68
1.7
89.8
antidepressants (22), suicide attempt status, and clinical
measures of depression severity.
0
7
18
14
11
13
12
14
28
72
56
44
52
48
56
SD
Mean
SD
15.88
0.91
2.4
4.5
38.0
24.36
23.4
52.5
21.4
4.4
13.4
7.26
11.9
11.0
11.4
3.0
<0.03
t (df=66)
p
0.20
–21.95
–9.03
15.90
0.84
<0.001
<0.001
<0.001
cal response; they agreed to have their medications tapered and
discontinued for the study.
Radiochemistry
Method
Subjects
Twenty-five subjects who met the DSM-IV criteria for a current
major depressive episode and 43 healthy comparison subjects
were included in the study. Their demographic and clinical
characteristics are summarized in Table 1. Inclusion criteria for
subjects with major depressive disorder were 1) age 18–65 years;
2) fulfillment of the DSM-IV criteria for major depressive episode; 3) absence of any psychotropic medication use for at least
2 weeks before the PET scan (6 weeks for fluoxetine, 4 weeks for
oral neuroleptics), except for benzodiazepines, which were discontinued 3 days before the scan; 4) no current or lifetime history of alcohol or other drug abuse or dependence; 5) absence
of lifetime exposure to 3,4-methylenedioxymethamphetamine;
6) absence of significant current medical conditions; 7) absence
of pregnancy; and 8) capacity to provide informed consent. The
inclusion criteria for the comparison subjects were similar. In
addition, the comparison subjects were required to have no psychiatric history and no history of a mood or psychotic disorder in
their first-degree relatives. All subjects gave written informed
consent after explanation of the study. The Beck Depression Inventory (BDI) (23), Hamilton Depression Rating Scale (HAM-D)
(24), and Global Assessment Scale (GAS) (25) were used to assess
subjective and objective depression severity and functional impairment, respectively.
Seven depressed subjects met the criteria for melancholia, four
were experiencing their first episode of major depression, and
three had too many lifetime episodes to count reliably. Nine depressed subjects had made suicide attempts (mean=1.9 attempts,
SD=1.1, range=1–4). Comorbid disorders included posttraumatic
stress disorder (N=4), panic disorder (N=7), dysthymia (N=5), social phobia (N=4), generalized anxiety disorder (N=2), binge eating disorder (N=1), and simple phobia (N=1). Twelve subjects had
never received antidepressant medications. The mean medication-free interval (excluding benzodiazepines) in the remaining
subjects was 26.5 days (SD=13.2, median=21, range=14–58). The
subjects who were not medication naive had received medication
between 14 and 30 days before the study and had shown no cliniAm J Psychiatry 163:1, January 2006
[11C]McN 5652 was produced as previously described (26). The
injected radioactivity of [11C]McN 5652 differed between the comparison subjects (mean=11.9 mCi, SD=4.3) and the subjects with
major depressive disorder (mean=14.3 mCi, SD=3.9) (t=–2.29, df=
66, p<0.03), but the injected mass did not differ between groups
(comparison subjects: mean=82.2 µmol, SD=62.1; subjects with
major depressive disorder: mean=107.8 µmol, SD=156.6) (t=–0.95,
df=66, p=0.35).
Image Analysis and Modeling
PET and magnetic resonance imaging data acquisition, analysis, and measurement of arterial input indices were previously described (21). After a 10-minute transmission scan, [11C]McN 5652
was injected intravenously, and emission data were acquired for
130 minutes. After radiotracer injection, 12 arterial samples were
collected at 10-second intervals over 2 minutes, the next six samples were collected at 20-second intervals over 2 minutes, and the
remaining 13 samples were collected at longer intervals, for a total
of 31 samples. The first 18 samples were collected with an automated sampling system, and the remaining samples were manually drawn. Six samples (collected at 2, 20, 50, 80, 110, and 130
minutes) were further processed by high-pressure liquid chromatography to measure the fraction of plasma activity representing
unmetabolized parent compound. Regions of interest were traced
by using brain atlases (27, 28) and published reports (29, 30). A
neuroanatomist (V.A.) verified the regions of interest. Derivation
of [11C]McN 5652 regional distribution volume (VT) was performed
with likelihood estimation in a graphical approach (31–33). VT is
the sum of the specific (V3) and nondisplaceable (free plus nonspecific binding) (V2) distribution volumes. Binding potential
(BP′) was calculated as follows: VT – V2, equivalent to f1Bmax/Kd,
where f1 is the free concentration of the radiotracer in plasma,
Bmax is the maximum number of binding sites, and Kd is the dissociation constant. V2 was measured in a 12.1-cm3 (± 1.5 cm3) sample of the cerebellum.
Statistical Analysis
Data were analyzed by using linear mixed-effects models, with
region and diagnostic group as fixed effects and subject as the ranhttp://ajp.psychiatryonline.org
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SEROTONIN TRANSPORTER AND DEPRESSION
FIGURE 1. Serotonin Transporter Binding Potential in Healthy Comparison Subjects and Subjects With Major Depressive
Disorder Who Had Never Been Treated With Antidepressants or Who Had Been Recently Treated With Antidepressantsa
45
Mean (±SD) Binding Potential (ml/g)a
Comparison subjects (N=43)
40
Depressed subjects who had never received antidepressant medication (N=12)
Depressed subjects who had recently received antidepressant medication (N=13)
35
30
25
20
15
10
5
0
Midbrainb
Putamen
Amygdalac
Thalamus
Hippocampus
Anterior
Cingulate
a Significant effect of region and group (F=2.23, df=10, 325, p<0.02).
b Significantly lower binding potential in the depressed subjects who
c
had never received antidepressants, relative to the comparison subjects
(t=–2.37, df=323, p<0.02).
Significantly lower binding potential in the depressed subjects who had never received antidepressants, relative to the comparison subjects
(t=–2.93, df=323, p=0.003).
dom effect. To stabilize variance and satisfy modeling assumptions, natural log-transformed data were used in the analysis after
a quantity was added to all measures to ensure positive values. The
reported p values were not adjusted for multiple comparisons.
Results
The group with major depressive episode included a
greater proportion of female subjects, relative to the comparison group (Table 1), but no effect of sex was found in
the mixed model (F=0.26, df=1, 63, p=0.62). Across the six
regions of interest, BP′ differed significantly by diagnostic
group (F=2.82, df=5, 330, p<0.02). In post hoc tests examining the effect of diagnostic group on BP′ in each region in
the mixed model, significantly lower BP′ was found in the
amygdala (t=–2.29, df=329, p<0.03) and midbrain (t=–2.22,
df=329, p<0.03) in the subjects with major depressive disorder, relative to the comparison subjects.
Effect of Previous Exposure to Antidepressants
Selective serotonin reuptake inhibitors are cleared from
the brain about 2 weeks after discontinuation (34), and
therefore, residual drug should not occupy the serotonin
transporters after that period. However, medication may
have long-term effects such as suppression of gene expression (35), although this possibility is controversial (22,
36). To rule out effects of prior treatment with antidepressants, data for 13 subjects with major depressive disorder
who had been medication free for at least 14 days were
compared to data for 12 subjects who had never received
antidepressants and to data for the comparison subjects.
We found a significant effect of region and medication sta-
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tus (F=2.23, df=10, 325, p<0.02) (Figure 1). Post hoc testing
revealed significantly lower BP′ in the amygdala (t=–2.93,
df=323, p=0.003) (Figure 2) and midbrain (t=–2.37, df=323,
p<0.02) for the antidepressant-naive subjects, relative to
the comparison subjects. When the data for the comparison subjects were excluded from the analysis, there was no
difference in BP′ between the antidepressant-naive and
recently medicated groups across all brain regions (F=
0.71, df=1, 23, p=0.41), although the interaction of region
and medication status approached significance (F=2.24,
df=5, 115, p=0.055). The 12 antidepressant-naive subjects
did not differ from the 13 recently treated subjects in demographic and clinical characteristics, except that the recently treated subjects were more likely to be inpatients
(Table 2). No correlation was found between the time
since discontinuation of antidepressants and BP′ in any
region of interest (data not shown), although the previously medicated subjects had a median time of only 21
days since discontinuation of antidepressants.
Effect of Suicide Attempt Status
A group-by-region interaction was found in the comparison of BP′ in the subjects with major depressive disorder who had a history of at least one suicide attempt, the
subjects with major depressive disorder who had never attempted suicide, and the comparison subjects (F=1.12,
df=10, 325, p<0.05). Post hoc analysis revealed that this
difference was due to differences in BP′ in the amygdala
and midbrain between the comparison subjects and the
subjects with major depressive disorder who had never attempted suicide. No differences in BP′ were found beAm J Psychiatry 163:1, January 2006
PARSEY, HASTINGS, OQUENDO, ET AL.
tween the suicide attempters and nonattempters or between the attempters and the comparison subjects (data
not shown).
Correlation Between BP′
and Depression Severity
FIGURE 2. Serotonin Transporter Binding Potential in the
Amygdala in Healthy Comparison Subjects and Subjects
With Major Depressive Disorder Who Had Never Been
Treated With Antidepressants or Who Had Been Recently
Treated With Antidepressants
40
No significant correlation was found between the BP′ in
any region of interest and the measures of depression severity, including the BDI and HAM-D scores, age at first major
depressive episode, number of previous major depressive
episodes, or length of current major depressive episode.
Binding Potential (ml/g)a
35
Discussion
We found lower midbrain and amygdala [11C]McN 5652
BP′ in major depressive disorder and found that this effect
was more pronounced in depressed subjects who had
never received antidepressants. There was no correlation
between BP′ and depression severity. There was no difference in BP′ between the major depressive disorder subjects with a history of suicide attempt and those with no
history of suicide attempt.
30
25
20
15
10
5
0
Comparison
Subjects
(N=43)
Never received
Recently received
antidepressant
antidepressant
medication (N=12) medication (N=13)
Depressed Subjects
Comparison to Previous In Vivo Imaging Studies
Our finding of a 20% lower BP′ in the midbrain in subjects with major depressive disorder, compared to healthy
volunteers, is in agreement with that of Malison et al. (20),
who found a 19% lower [123I]β-CIT binding in subjects with
major depressive disorder, but is at odds with the findings
of Ichimiya et al. (37), who reported no difference in midbrain [11C]McN 5652 V3′′ (V3′′ is defined later in the Discussion section) and higher V3′′ in the thalamus of depressed
subjects. It should be noted that the study by Ichimiya et
al. 1) included euthymic subjects; 2) used data from 90minute scans; 3) used age as a covariate (we could detect
no age-related changes in BP′ in the midbrain); 4) used the
graphical method of Logan, which is reported to have
noise-dependent bias (38); and 5) had a smaller number of
depressed subjects (N=13). Our data are also consistent
with the results of a previous PET study with the transporter radioligand [ 11 C] N,N-dimethyl-2-(2-amino-4cyanophenylthio)benzylamine ([11C]DASB) in which no
difference in striatal V3′′ was found between depressed
subjects and healthy comparison subjects (39). We found a
20% lower BP′ in the amygdala in subjects with major depressive disorder, compared to healthy subjects; to our
knowledge, this finding has not been reported previously.
Interpretation of Findings
We interpret the lower [11C]McN 5652 BP′ (f1Bmax/Kd) in
the subjects with major depressive disorder to reflect lower
Bmax, or lower total number of available serotonin transporter binding sites. Several outcome measures are used in
PET studies, including BP (B max /K d =V T – V 2 /f 1 ), BP′
(f1Bmax/Kd=VT – V2), and V3′′ (f2Bmax/Kd=BP′/V2), where VT
is the total volume of distribution in an region of interest,
V2 is a measure of the free and nonspecifically bound
Am J Psychiatry 163:1, January 2006
a
Bars represent mean values.
tracer, f 1 is the free concentration of the radiotracer in
plasma, and f2 is the free concentration of the radiotracer
in the cerebrospinal fluid. Ideally we would measure BP,
but f1 is not measurable with [11C]McN 5652. Our findings
were similar when either of the outcome measures that can
be determined with [11C]McN 5652 was used, i.e., the principal region-by-diagnosis interaction was significant with
BP′ or V3′′ (p<0.05), and the interaction of region and prior
antidepressant medication status was significant with V3′′
(p<0.03). We believe the lower BP′ in major depressive disorder is not a consequence of f1, because our findings are
consistent with postmortem findings, where f1 is not a factor, and because changes in f1 would result in global differences, not regionally specific ones. Finally, postmortem
studies suggested that lower levels of serotonin transporter
in subjects with major depressive disorder are not due to
changes in receptor affinity (1/Kd) (14). It is unlikely that
the lower BP′ in major depressive disorder could be a consequence of higher synaptic levels of 5-HT, because of the
hypothesized serotonin abnormality in depression. Moreover, in postmortem studies that included a preincubation
period to promote catabolism and a washout of endogenous 5-HT before adding ligand in vitro, lower serotonin
transporter binding was found in major depressive disorder (40–42). These findings appear to rule out elevated intrasynaptic levels of 5-HT as an explanation. Therefore, our
finding of lower serotonin transporter BP′ in major depressive disorder is likely a result of lower serotonin transporter
Bmax, i.e., fewer serotonin transporters.
There are several possible explanations for the lower serotonin transporter Bmax in major depressive disorder.
http://ajp.psychiatryonline.org
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SEROTONIN TRANSPORTER AND DEPRESSION
TABLE 2. Characteristics of Subjects With Major Depressive Disorder Who Were Antidepressant Naive or Previously Treated
With Antidepressants
Antidepressant-Naive
Subjects
(N=12)
N
%
Item
Sex
Male
Female
Patient status
Inpatient
Outpatient
First-degree relative with major depressive disorder
Age (years)
24-item Hamilton Depression Rating Scale score
Beck Depression Inventory score
Global Assessment Scale score
Age at illness onset (years)
Number of major depressive episodes
Length of current major depressive episode (days)
Subjects With Recent
Antidepressant Use
(N=13)
N
%
p
χ2 (df=1)
0.57
4
8
33
67
3
10
23
77
3
9
6
25
75
50
11
2
7
85
15
54
0.86
Mean
SD
Mean
SD
t (df=23)
0.003
34.46
24.00
24.00
56.64
17.92
3.82
70.5
12.50
8.01
8.29
11.87
10.97
2.99
165.9
41.34
26.23
26.54
49.00
23.00
4.50
59.5
13.82
6.62
11.37
9.23
12.80
3.23
73.8
0.21
0.46
0.54
0.10
0.30
0.61
0.83
Lower levels of synaptic 5-HT could facilitate serotonin
transporter internalization (6); there could be fewer 5-HT
neurons or neuronal processes or decreased expression of
serotonin transporter per terminal; or a combination of
these factors could be operating. Lower levels of synaptic
5-HT in the raphe nuclei could be related to the presence
of the C(-1019)G polymorphism of the promoter region of
the 5-HT1A gene that has been shown to be overrepresented in patients with major depressive disorder (43).
The C(-1019) allele is part of a 26-base pair imperfect palindrome with less affinity for the nuclear deformed epidermal autoregulatory factor transcriptional repressor,
and this lower level of affinity could potentially result in a
higher level of expression of the 5-HT 1A protein in the
raphe nuclei. Because the raphe nuclei 5-HT1A receptors
are inhibitory, higher levels of 5-HT1A in the raphe nuclei
would result in lower levels of 5-HT release and possible
down-regulation of serotonin transporter. Alternatively,
lower levels of synaptic 5-HT could be related to having a
variant of the tryptophan hydroxylase-2 gene, which has
less catalytic activity and is present in 10% of subjects with
major depressive disorder (44, 45). Down-regulation of serotonin transporter should be accompanied by reduced
mRNA for serotonin transporter. Our previous autoradiography studies suggested that the number of neurons that
express serotonin transporter mRNA is reduced by 54% in
subjects with major depressive disorder who commit suicide (42), although the number of 5-HT-producing neurons did not appear to be decreased (46).
For the differences in serotonin transporter BP′ to be
limited to the midbrain and amygdala, the abnormality
may be confined to a subpopulation of serotonin-transporter-expressing 5-HT neurons within the dorsal raphe
nuclei. Less 5-HT input to the amygdala, as suggested by
the finding of lower serotonin transporter BP′, may result
in increased amygdala activity (47), as serotonin enhances
inhibition in the amygdala, presumably through activation of γ-aminobutyric-acid-ergic interneurons (48). Serotonergic projections to the amygdala are implicated in
anxiety disorders as well (49). Previous research has suggested an association between hyperactivity in the
amygdala and a greater likelihood that sensory or social
stimuli are perceived or remembered as emotionally
arousing or aversive (50); thus, hyperactivity in the
amygdala may contribute to the relationship between adverse childhood experiences and adult mood disorders.
We hypothesized that a lower level of serotonin transporter in all six regions of interest was necessary for the expression of major depressive disorder, but we found differences in serotonin transporter binding potential only in
the midbrain and amygdala. These findings can be interpreted in several ways. First, it is possible that the mid-
Received June 2, 2004; revisions received Jan. 11 and March 1,
2005; accepted April 13, 2005. From the Departments of Psychiatry
and Radiology, Columbia University College of Physicians and Surgeons, New York; the Departments of Neuroscience and Analytic Psychopharmacology, New York State Psychiatric Institute; and the Department of Biostatistics, Columbia University School of Public
Health, New York. Address correspondence and reprint requests to
56
http://ajp.psychiatryonline.org
brain and amygdala are the crucial structures in the
pathophysiology of depression, and serotonin transporter
abnormalities in these regions are sufficient to result in
major depressive disorder. Second, the abnormalities in
the other regions of interest may not be specific to serotonin transporter but perhaps may involve other measures
of serotonergic function. Third, the lower level of serotonin transporter BP′ in the midbrain and amygdala may be
secondary to as yet undetermined primary pathological
process(es). Finally, the PET ligand we used may not be
sensitive enough to detect serotonin transporter abnormalities in the other regions.
Am J Psychiatry 163:1, January 2006
PARSEY, HASTINGS, OQUENDO, ET AL.
Dr. Parsey, Department of Neuroscience, New York State Psychiatric
Institute, 1051 Riverside Dr., Box 42, New York, NY 10032;
[email protected] (e-mail).
This article is the second of two on serotonin transporters in the
human brain in this issue of the Journal. The first article immediately
precedes this one.
Supported by NIMH grants P30 MH-46745, MH-40695, MH-40210,
and MH-62185, the National Alliance for Research on Schizophrenia
and Depression, and the American Foundation for Suicide Prevention.
The authors thank the staff of the Brain Imaging Division, Kreitchman PET Center, and Sarina M. Rodrigues, Ph.D., for their assistance.
18.
19.
20.
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