Rev Psychiatr Neurosci 2007;32(2)
© 2007 Canadian Medical Association
This paper focuses on serotonin transporter 5-HTT imaging to investigate major depressive disorder (MDD) and antidepressant occu-
pancy. Such investigations have only recently been possible as a result of major advances in ligand development. The state of the art
method is [11C] DASB PET or [11C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) positron emission tomography.
[11C]DASB is a breakthrough for brain imaging 5-HTT. Compared with previous radioligands, [11C]DASB offers both high selectivity and
a favourable ratio of specific binding relative to free and nonspecific binding. These characteristics contribute to valid, reliable quantita-
tion of the 5-HTT binding potential (BP). The 5-HTT BP can be viewed as an index of 5-HTT density in a medication free state, or
unblocked 5-HTT density in a medication-treated state.During major depressive episodes with no other axis I comorbidity, either no dif-
ference in regional 5-HTT BP or a trend toward elevated 5-HTT BP is typically found. During major depressive episodes (of MDD) with
more severe symptoms of pessimism (dysfunctional attitudes), regional 5-HTT BP is elevated. In subjects with major depressive
episodes and comorbid axis I psychiatric illnesses, decreased regional 5-HTT BP is often reported. With selective serotonin reuptake in-
hibitor (SSRI) treatment at doses that distinguish from placebo in the treatment of major depressive episodes, 5-HTT occupancy is ap-
proximately 80%, and there is a strong relation between plasma level and occupancy that is not predictable based on affinity alone.
Implications of 5-HTT imaging findings for understanding major depressive disorder and antidepressant treatment will be discussed.
Cet article porte sur l'utilisation de l’imagerie de la 5-HTT, transporteur de la sérotonine, pour étudier le trouble dépressif majeur (TDM)
et l’occupation des récepteurs d’antidépresseurs. Une telle étude n’a que récemment été rendue possible par les grands progrès dans le
domaine des ligands. La méthode de pointe dans ce domaine est la tomographie par émission de positons avec le [11C]DASB ou [11C]-
3-amino-4-(2-diméthylaminométhyl-phénylsulfanyl)-benzonitrile). Le [11C]DASB représente une percée pour l’imagerie cérébrale de la 5-
HTT. Comparativement aux radioligands du passé, il se caractérise tant par une haute sélectivité que par un rapport favorable entre
liaison spécifique et libre liaison non spécifique. Ce sont ces caractéristiques qui contribuent à une quantification valable et sûre du po-
tentiel de fixation (PF) de la 5-HTT. On peut voir dans ce potentiel de fixation un indice de la densité de la 5-HTT dans un état de non-
médication ou de sa densité sans blocage dans un état de médication. Dans les épisodes dépressifs majeurs sans autre comorbidité
axe I, il n’y a habituellement aucune différence de PF régional ou on constate ordinairement une tendance à l’élévation de ce potentiel.
Dans les épisodes dépressifs majeurs (de TDM) avec des symptômes aggravés de pessimisme (attitudes dysfonctionnelles), le potentiel
de fixation régional de la 5-HTT. Chez les sujets en proie à de tels épisodes dépressifs avec troubles psychiatriques de comorbidité axe
I, on signale souvent une diminution du potentiel régional. Dans le traitement d’épisodes dépressifs majeurs à l’inhibiteur spécifique du
recaptage de la sérotonine (ISRS) à des doses distinctes du placebo, l’occupation des récepteurs de la 5-HTT est d’environ 80 %; on
note une étroite relation entre la concentration plasmatique et l’occupation qui ne saurait être prévue uniquement par l’affinité. Il sera
question des conséquences de ces données d’imagerie de la 5-HTT sur le plan de la compréhension du trouble dépressif majeur et de
son traitement aux antidépresseurs.
Imaging the serotonin transporter during major
depressive disorder and antidepressant treatment
Jeffrey H. Meyer, MD
Neurochemical Imaging Program in Mood Disorders, PET Centre, Centre for Addiction and Mental Health, Toronto, Ont.
Correspondence to: Dr. Jeffrey Meyer, Neurochemical Imaging Program in Mood Disorders, PET Centre, Centre for Addiction and
Mental Health, 250 College St., Toronto ON M5T 1R8; fax 416 979-4656; firstname.lastname@example.org
J Psychiatry Neurosci 2007;32(2):86-102.
Medical subject headings: serotonin; serotonin transporter; depression; antidepressant; PET; positron emission tomography
2005 CCNP Young Investigator Award Paper
Submitted Aug. 30, 2006; Revised Oct. 20, 2006; Accepted Oct. 22, 2006
Imaging the serotonin transporter
J Psychiatry Neurosci 2007;32(2)
What properties of the serotonin transporter are
important for major depressive disorder?
The serotonin transporter 5-hydroxy-tryptamine (5-HTT) is a
630 amino acid long receptor with 12 transmembrane do-
mains.1,2The human 5-HTT gene is localized on chromosome
17, centred at 17q11.2.3Most 5-HTT are located at outer cell
membranes, either perisynaptically or along axons.4In the
human brain, the density of 5-HTT varies by region: Superior
and inferior raphe nuclei > hypothalamus > thalamus (de-
pending on the nucleus) ∼ amygdala > putamen > caudate ~
hippocampus > insular cortex > prefrontal cortex > white
matter > cerebellar cortex (except vermis).5–7
The serotonin transporter is coupled to sodium, chlorine
and potassium transport.3However, the physiological role of
interest of 5-HTT in major depressive disorder (MDD) and
antidepressant treatment is its influence on extracellular sero-
tonin levels. It is clear that many antidepressant drugs that
bind to the serotonin transporter raise extracellular serotonin,
and 5-HTT knockout mice have elevated extracellular sero-
tonin, confirming the role of the serotonin transporter in
modulating extracellular serotonin levels in vivo.8–14
Methods of imaging serotonin transporter in vivo
The following is a critical comparison of all 5-HTT imaging
methods that have been applied in humans, with an emphasis
on data relevant to humans (See Table 1). Previous compar-
isons have largely emphasized comparisons in baboons.15Al-
though this information is valuable during radiotracer devel-
opment,16it does not fully correspond to radioligand
performance during human brain imaging because 5-HTT
density can vary between animal species,7and the brain phar-
macokinetics of 5-HTT radiotracers can differ between ba-
boons and humans.15,17–21
These methods are used to derive the binding potential
(BP). There are different versions of the BP but the one that is
typically used is defined as follows: BP = f2× Bmax/Kd. f2is a
fraction of free and nonspecific radiotracer that interacts with
the specific binding compartment. Bmaxis receptor density
and Kdis the dissociation constant. BP tends to be viewed as
an index of Bmaxand, in the medication treated condition, it
tends to be viewed as an index of receptor density not
blocked by medication.
In the medication-treated state, a related measure is the 5-
HTT occupancy, which can be defined as 5-HTT occupancy =
(5-HTT BP1- 5-HTT BP2)/ 5-HTT BP1× 100%. 5-HTT BP1is the
BP found in the untreated state and 5-HTT BP2is the BP
found in the treated state.
single photon emission tomography (SPECT) was once the only
technique developed for measuring the 5-HTT binding poten-
tial in humans.37,38,44This radiotracer has almost equal affinity for
the dopamine transporter, compared with the serotonin trans-
porter.22,23Because dopamine transporter density is high in the
substantia nigra,45one cannot determine whether any changes
in specific binding in the midbrain in an experimental para-
digm are due to 5-HTT binding in superior raphe nuclei or
dopamine transporter binding in substantia nigra. That there
are specific binding sites that are not 5-HTT is consistent with
the low 5-HTT occupancy estimates for selective serotonin re-
uptake inhibitors found with this method,30,31compared with 5-
HTT occupancy estimates with selective 5-HTT binding radio-
tracers.34,35To the best of my knowledge, there are no reliability
estimates of binding potential found in the midbrain with this
method. Typically, this radiotracer is used for measuring
dopamine transporter BP in the striatum in humans.44
The PET radiotracer [11C](+)McN5652 (trans-1,2,3,5,6,10-β-
line) shows greater selectivity for the serotonin transporter,
compared with other monoamine transporters. It is estimated
that this radiotracer has 1 or 2 orders of magnitude greater
affinity for the serotonin transporter over the norepinephrine
transporter and at least 2 orders of magnitude greater affinity
for the serotonin transporter over the dopamine trans-
porter.24,25[11C](+)McN5652 has a low ratio of specific binding
relative to free and nonspecific binding, which combined with
modest reversibility, makes valid and reliable quantitation
Table 1: Comparison of radioligands for imaging of 5-HTT in humans
SelectivityNonselective, near 1:1 affinity
for 5-HTT to DAT
Likely selective 10:1 to 100:1
affinity for 5-HTT over
In most, but not all,
Not adequate to adequate,
depending on region‡
Highly selective 1000:1
affinity for 5-HTT over NET or
Highly selective 1000:1
affinity for 5-HTT over NET or
Displaceability of specific
Adequate in midbrain, good
to very good in other
Adequate to very good‡
Adequate in midbrain
Specific binding to free
and nonspecific binding
Reliability of 5-HTT BP†
5-HTT BP measurability in
Not adequate in most
regions, adequate in
Measurable in thalamus,
measurable in cortex
Not adequate in most
regions; adequate in
Most regions reasonable
Measurable in midbrain;
unclear for other regions
Very good to excellent
†For humans (radiotracer performance differs across species.)
‡Depending on brain region.
11C]DASB is also highly selective for 5-HTT over several other targets tested in vitro.
difficult in regions other than the thalamus, and impossible in
the human cortex.18,19,32,39Applications of this radiotracer in ill-
ness and in treatment have mostly focused on the thalamus,
using the cerebellum as a reference region with noninvasive
models.33,39,46However, some investigators use arterial sam-
pling to measure 5-HTT BP in other subcortical brain regions
to obtain a total distribution volume (an index of total radio-
tracer binding) and use the cerebellar cortex region to obtain
an index of free and nonspecific binding.32
The radiotracer [11C] 3-amino-4-(2-dimethylaminomethyl-
phenylsulfanyl)-benzonitrile (DASB) was a major advance
because of its selectivity, reversibility, greater specific bind-
ing relative to free and nonspecific binding and reliabil-
ity.20,21,26,27,34,35,40,43,47This radiotracer was found to be 3 orders of
magnitude more selective for the 5-HTT than for the
monoamine transporters and was highly selective for the 5-
HTT, compared with several other screened targets.26,27More-
over, 92% to 95% of the specific binding to 5-HTT is displace-
able by 5-HTT binding medications in animal models.26,27In
humans, [11C]DASB has good brain uptake20,40; its ratio of spe-
cific binding relative to free and nonspecific binding is good
and the latter has low between–subject variability.20,21Multi-
ple brain regions may be assessed with noninvasive
methods,20,21,26,27,34,35,40,43,47and the reliability of regional 5-HTT
BP measures is good.34,35,43,48The 5-HTT BP measures are low
in the cortex, but with standardized region of interest meth-
ods, good reliability of 5-HTT BP in the human cortex may be
obtained.34,35,43,48In summary, [11C]DASB PET imaging is the
state of the art method in quantifying 5-HTT in humans.
[123I] ADAM (2-((2-((dimethylamino)methyl)-phenyl) thio)-
5-iodophenylamine) SPECT is a fourth brain imaging method
that has recently been applied to investigate 5-HTT BP in hu-
mans. It has a clear advantage of selectivity over [123I] β-CIT
SPECT, since most of the specific binding in most brain re-
gions is displaceable in animal models, and it is selective for
the 5-HTT over several other binding sites, including other
monoamine transporters.28,29[123I] ADAM has been modelled
in baboons but not yet in humans.49The specific binding rela-
tive to free and nonspecific binding in humans is not
optimal,41likely limiting the use of this method to assessing
midbrain 5-HTT BP. However, reliability in the midbrain for
5-HTT BP measurement is good.41
[11C]MADAM (11C-N,N-Dimethyl-2-(2-amino-4 methyl-
phenylthio)benzylamine) is a recently developed PET radio-
tracer that shows excellent selectivity over other monoamine
transporters in vitro and good displacability in animal mod-
els.50,51Time activity curves presented show good reversibility
potentially similar to [11C]DASB but appear to have some-
what greater variability, particularly for the raphe.20,52,53Initial
reports of reliability are also promising, although the scatter
in repeated-measurement (standard deviation of percent dif-
ference in repeated-measure) appears greater than what has
been reported for [11C]DASB.34,35,43,48,52,54
What is the optimal method of applying
[11C]DASB PET for research protocols?
For selecting regions of interest, my group recommends auto-
mated region of interest approaches with visual validation,
such as those involving subroutines from linear transforma-
tions and/or nonlinear deformations applied in the spatial
normalization procedure from statistical parametric map-
ping.55,56Reliability of 5-HTT BP measurement is typically
excellent when such applications are applied.35,43,54,57For sub-
cortical regions, manual drawing upon coregistered MRI also
has excellent reliability.34
For a reference region, my group recommends selecting
the posterior half of the cerebellar cortex, excluding vermis,
excluding white matter and keeping at least one full width
half the maximum from the venous sinuses and from occipi-
tal cortex. At a distance of one full width half maximum,
spillover from the occipital cortex (which possesses specific
binding) or venous sinuses is negligible. White matter is ex-
cluded because [11C]DASB has different kinetics in this tis-
sue, compared with grey matter. The vermis is excluded
because it has [11C]DASB kinetics compatible with significant
specific binding. We routinely use these methods.34,35,43,58,59
For selecting models for region of interest methods, we en-
dorse reference tissue approaches.20,21,34,35,43,58,59By applying a lin-
ear regression between 5-HTT density and total distribution
volume, we estimate that the reference tissue of posterior cere-
bellar cortex is composed of 93% free and nonspecific binding
and 7% specific binding.6Knowing that the true BP = distribu-
tion volume of specific binding in region of interest divided by
the distribution volume of free and nonspecific binding in the
cerebellar cortex, the effect of specific binding in the cerebellar
cortex is quite subtle. Disease influences of even 50% magni-
tude on the specific binding in reference tissue translate to
3.5% changes in the distribution volume estimate of free and
nonspecific binding, which ultimately results in a 3.5% bias for
between–group comparisons. For occupancy studies, the na-
ture of the occupancy equation is such that the bias from a 7%
underestimate during untreated conditions is translated into a
lesser bias in the overall occupancy measure (less than 2%). For
example, if the striatal 5-HTT BP has a true value of 1 in the
untreated condition and 0.2 in the SSRI-treated condition, the
true 5-HTT occupancy is ([1–0.2]/1) = 0.8 or 80% (5-HTT occu-
pancy = (5-HTT BP1–5-HTT BP2)/ 5-HTT BP1× 100%). Taking
into account the slight specific binding of reference tissue, the
measured striatal 5-HTT BP, respectively, would be 0.93 in the
untreated condition and 0.197 in the SSRI-treated condition
(most of the 7% specific binding in reference tissue is blocked
during treatment), leading to a measured 5-HTT occupancy of
([0.93–0.1972]/0.93) = 0.79 or 79%.
For [11C]DASB PET, arterial methods offer no advantage
for identifying subcompartments of free and nonspecific
binding, because [11C]DASB kinetics fit a single tissue com-
partment model in all regions.21,60Arterial methods do permit
measurement of total distribution volume in the cerebellum,
but this value is assumed to represent free and nonspecific
binding, so as to quantitate binding potential measures in
other regions. Thus, when arterial sampling is done, a very
similar set of assumptions as compared with reference tissue
models are applied.
Among the reference tissue methods, the noninvasive lo-
gan,61simplified reference tissue model 2 and multilinear
Rev Psychiatr Neurosci 2007;32(2)
Imaging the serotonin transporter
J Psychiatry Neurosci 2007;32(2)
120. Simons AD, Garfield SL, Murphy GE. The process of change in
cognitive therapy and pharmacotherapy for depression. Changes
in mood and cognition. Arch Gen Psychiatry 1984;41:45-51.
121. Cane DB, Olinger LJ, Gotlib IH, et al. Factor structure of the dys-
functional attitude scale in a student population. J Clin Psychol
122. Oliver JM, Baumgart EP. The dysfunctional attitude scale: psycho-
metric properties and relation to depression in an unselected adult
population. Cognit Ther Res 1985;9:161-7.
123. Weissman A. The Dysfunctional Attitude Scale: A validation
study. Dissertation Abstracts International 1979; 40:1389B-1390B.
124. Bouvard M, Charles S, Guerin J, et al. [Study of Beck’s hopelessness
scale. Validation and factor analysis]. Encephale 1992;18:237-40.
125. Cannon B, Mulroy R, Otto MW, et al. Dysfunctional attitudes and
poor problem solving skills predict hopelessness in major depres-
sion. J Affect Disord 1999;55:45-9.
126. DeRubeis RJ, Evans MD, Hollon SD, et al. How does cognitive
therapy work? Cognitive change and symptom change in cogni-
tive therapy and pharmacotherapy for depression. J Consult Clin
127. Norman WH, Miller W, Dow MG. Characteristics of depressed pa-
tients with elevated levels of dysfunctional cognitions. Cognit Ther
128. Beck AT, Steer RA, Kovacs M, et al. Hopelessness and eventual
suicide: A 10-year prospective study of patients hospitalized with
suicidal ideation. Am J Psychiatry 1985;142:559-63.
129. Beck AT, Brown G, Steer RA. Prediction of eventual suicide in psy-
chiatric inpatients by clinical ratings of hopelessness. J Consult Clin
130. Bhagwagar Z, Hinz R, Taylor M, et al. Increased 5-HT2A Receptor
Binding in Euthymic Medication Free Patients Recovered from De-
pression: A Positron Emission Tomography Study With [11C]
MDL 100,907. Am J Psychiatry 2006; 163:1580-7.
131. Boldrinin M, Underwood MD, Martini A, et al. Brainstem raphe
nucleus changes in suicide victims. Psychiatr Danub 2006; 18
132. Compan V, Segu L, Buhot MC, et al. Differential effects of sero-
tonin (5-HT) lesions and synthesis blockade on neuropeptide-Y
immunoreactivity and 5-HT1A, 5-HT1B/1D and 5-HT2A/2C re-
ceptor binding sites in the rat cerebral cortex. Brain Res 1998;795:
133. McCann UD, Szabo Z, Seckin E, et al. Quantitative PET studies of
the serotonin transporter in MDMA users and controls using
[11C]McN5652 and [11C]DASB. Neuropsychopharmacology 2005;30:
134. Bernheimer H, Birkmayer W, Hornykiewicz O. [Distribution of 5-
hydroxytryptamine (serotonin) in the human brain and its behav-
ior in patients with Parkinson’s syndrome.] Klin Wochenschr
135. Kish SJ. What is the evidence that Ecstasy (MDMA) can cause
Parkinson’s disease? Mov Disord 2003;18:1219-23.
136. Linnet K, Koed K, Wiborg O, et al. Serotonin depletion decreases sero-
tonin transporter mRNA levels in rat brain. Brain Res 1995;697:251-3.
137. Xiao Q, Pawlyk A, Tejani-Butt SM. Reserpine modulates serotonin
transporter mRNA levels in the rat brain. Life Sci 1999;64:63-8.
138. Yu A, Yang J, Pawlyk AC, et al. Acute depletion of serotonin
down-regulates serotonin transporter mRNA in raphe neurons.
Brain Res 1995;688:209-12.
139. Benmansour S, Cecchi M, Morilak D, et al. Effects of Chronic Anti-
depressant Treatments on Serotonin Transporter Function, Density
and mRNA level. J Neurosci 1999;19:10494-501.
140. Dewar KM, Grondin L, Carli M, et al. [3H]paroxetine binding and
serotonin content of rat cortical areas, hippocampus, neostriatum,
ventral mesencephalic tegmentum, and midbrain raphe nuclei re-
gion following p-chlorophenylalanine and p-chloroamphetamine
treatment. J Neurochem 1992;58:250-7.
141. Graham D, Tahraoui L, Langer SZ. Effect of chronic treatment
with selective monoamine oxidase inhibitors and specific 5-hy-
droxytryptamine uptake inhibitors on [3H]paroxetine binding to
cerebral cortical membranes of the rat. Neuropharmacology 1987;26:
142. Gordon I, Weizman R, Rehavi M. Modulatory effect of agents ac-
tive in the presynaptic dopaminergic system on the striatal
dopamine transporter. Eur J Pharmacol 1996;298:27-30.
143. Han S, Rowell PP, Carr LA. D2 autoreceptors are not involved in
the down-regulation of the striatal dopamine transporter caused
by alpha-methyl-p-tyrosine. Res Commun Mol Pathol Pharmacol
144. Ikawa K, Watanabe A, Kaneno S, et al. Modulation of [3H]mazin-
dol binding sites in rat striatum by dopaminergic agents. Eur J
145. Kilbourn MR, Sherman PS, Pisani T. Repeated reserpine adminis-
tration reduces in vivo [18F]GBR 13119 binding to the dopamine
uptake site. Eur J Pharmacol 1992;216:109-12.
146. Blier P, De Montigny C. Electrophysiological investigations on the
effect of repeated zimelidine administration on serotonergic neu-
rotransmission in the rat. J Neurosci 1983;3:1270-8.
147. Laruelle M. Imaging synaptic neurotransmission with in vivo
binding competition techniques: a critical review. J Cereb Blood
Flow Metab 2000;20:423-51.
148. Ginovart N, Wilson AA, Meyer JH, et al. [11C]-DASB, a tool for in
vivo measurement of SSRI-induced occupancy of the serotonin
transporter: PET characterization and evaluation in cats. Synapse
149. Lundquist P, Wilking H, Hoglund AU, et al. Potential of [11C]DASB
for measuring endogenous serotonin with PET: binding studies.
Nucl Med Biol 2005;32:129-36.
150. Celada P, Artigas F. Monoamine oxidase inhibitors increase pref-
erentially extracellular 5-hydroxytryptamine in the midbrain
raphe nuclei. A brain microdialysis study in the awake rat. Naunyn
Schmiedebergs Arch Pharmacol 1993;347:583-90.
151. Malyszko J, Urano T, Serizawa K, et al. Serotonergic measures in blood
and brain and their correlations in rats treated with tranylcypromine,
a monoamine oxidase inhibitor. Jpn J Physiol 1993;43:613-26.
152. Ferrer A, Artigas F. Effects of single and chronic treatment with
tranylcypromine on extracellular serotonin in rat brain. Eur J Phar-
153. Talbot PS, Frankle WG, Hwang DR, et al. Effects of reduced en-
dogenous 5-HT on the in vivo binding of the serotonin transporter
radioligand 11C-DASB in healthy humans. Synapse 2005;55:164-75.
154. Bligh-Glover W, Kolli TN, Shapiro-Kulnane L, et al. The serotonin
transporter in the midbrain of suicide victims with major depres-
sion. Biol Psychiatry 2000;47:1015-24.
155. Klimek V, Roberson G, Stockmeier CA, et al. Serotonin transporter
and MAO-B levels in monoamine nuclei of the human brainstem
are normal in major depression. J Psychiatr Res 2003;37:387-97.
156. Perry EK, Marshall EF, Blessed G, et al. Decreased imipramine
Rev Psychiatr Neurosci 2007;32(2)
binding in the brains of patients with depressive illness. Br J Psy-
157. Crow TJ, Cross AJ, Cooper SJ, et al. Neurotransmitter receptors
and monoamine metabolites in the brains of patients with
Alzheimer-type dementia and depression, and suicides. Neu-
158. Mann JJ, Huang YY, Underwood MD, et al. A serotonin trans-
porter gene promoter polymorphism (5-HTTLPR) and prefrontal
cortical binding in major depression and suicide. Arch Gen Psychia-
159. Austin MC, Whitehead RE, Edgar CL, et al. Localized decrease in
serotonin transporter-immunoreactive axons in the prefrontal cor-
tex of depressed subjects committing suicide. Neuroscience 2002;
160. Hrdina PD, Foy B, Hepner A, et al. Antidepressant binding sites in
brain: autoradiographic comparison of [3H]paroxetine and
[3H]imipramine localization and relationship to serotonin trans-
porter. J Pharmacol Exp Ther 1990;252:410-8.
161. Lawrence KM, De Paermentier F, Cheetham SC, et al. Brain 5-HT
uptake sites, labelled with [3H]paroxetine, in antidepressant-free
depressed suicides. Brain Res 1990;526:17-22.
162. Little KY, McLauglin DP, Ranc J, et al. Serotonin transporter bind-
ing sites and mRNA levels in depressed persons committing sui-
cide. Biol Psychiatry 1997;41:1156-64.
163. Arango V, Underwood MD, Boldrini M, et al. Serotonin 1A recep-
tors, serotonin transporter binding and serotonin transporter
mRNA expression in the brainstem of depressed suicide victims.
164. Hendricksen M, Thomas AJ, Ferrier IN, et al. Neuropathological
study of the dorsal raphe nuclei in late-life depression and
Alzheimer’s disease with and without depression. Am J Psychiatry
165. Leake A, Fairbairn AF, McKeith IG, et al. Studies on the serotonin
uptake binding site in major depressive disorder and control post-
mortem brain: neurochemical and clinical correlates. Psychiatry Res
166. Malison RT, Price LH, Berman R, et al. Reduced brain serotonin
transporter availability in major depression as measured by [123I]-2
beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single pho-
ton emission computed tomography. Biol Psychiatry 1998;44:1090-8.
167. Newberg AB, Amsterdam JD, Wintering N, et al. 123I-ADAM bind-
ing to serotonin transporters in patients with major depression and
healthy controls: a preliminary study. J Nucl Med 2005;46:973-7.
168. Parsey RV, Hastings RS, Oquendo MA, et al. Lower serotonin
transporter binding potential in the human brain during major de-
pressive episodes. Am J Psychiatry 2006;163:52-8.
169. Herold N, Uebelhack K, Franke L, et al. Imaging of serotonin
transporters and its blockade by citalopram in patients with major
depression using a novel SPECT ligand [(123)I]-ADAM. J Neural
170. Meyer JH, Houle S, Sagrati S, et al. Brain serotonin transporter
binding potential measured with [11C]DASB positron emission to-
mography: effects of major depressive episodes and severity of
dysfunctional attitudes. Arch Gen Psychiatry 2004;61(12):1271-9.
171. Lesch KP, Bengel D, Heils A, et al. Association of anxiety-related
traits with a polymorphism in the serotonin transporter gene regu-
latory region. Science 1996;274:1527-31.
172. Filipenko ML, Beilina AG, Alekseyenko OV, et al. Increase in ex-
pression of brain serotonin transporter and monoamine oxidase a
genes induced by repeated experience of social defeats in male
mice. Biochemistry (Mosc) 2002;67:451-5.
173. Little KY, McLaughlin DP, Zhang L, et al. Cocaine, ethanol, and
genotype effects on human midbrain serotonin transporter bind-
ing sites and mRNA levels. Am J Psychiatry 1998;155:207-13.
174. Heinz A, Jones DW, Mazzanti C, et al. A relationship between
serotonin transporter genotype and in vivo protein expression and
alcohol neurotoxicity. Biol Psychiatry 2000;47:643-9.
175. Willeit M, Stastny J, Pirker W, et al. No evidence for in vivo regulation
of midbrain serotonin transporter availability by serotonin trans-
porter promoter gene polymorphism. Biol Psychiatry 2001;50:8-12.
176. Shioe K, Ichimiya T, Suhara T, et al. No association between geno-
type of the promoter region of serotonin transporter gene and
serotonin transporter binding in human brain measured by PET.
177. Parsey RV, Hastings RS, Oquendo MA, et al. Effect of a triallelic
functional polymorphism of the serotonin-transporter-linked pro-
moter region on expression of serotonin transporter in the human
brain. Am J Psychiatry 2006;163:48-51.
178. Lim JE, Papp A, Pinsonneault J, et al. Allelic expression of serotonin
transporter (SERT) mRNA in human pons: lack of correlation with
the polymorphism SERTLPR. Mol Psychiatry 2006;11:649-62.
179. Kim DK, Lim SW, Lee S, et al. Serotonin transporter gene poly-
morphism and antidepressant response. Neuroreport 2000;11:215-9.
180. Zanardi R, Benedetti F, Di Bella D, et al. Efficacy of paroxetine in
depression is influenced by a functional polymorphism within the
promoter of the serotonin transporter gene. J Clin Psychopharmacol
181. Pollock BG, Ferrell RE, Mulsant BH, et al. Allelic variation in the
serotonin transporter promoter affects onset of paroxetine treat-
ment response in late-life depression. Neuropsychopharmacology
182. Kraft JB, Slager SL, McGrath PJ, et al. Sequence analysis of the
serotonin transporter and associations with antidepressant re-
sponse. Biol Psychiatry 2005;58:374-81.
183. Caspi A, Sugden K, Moffitt TE, et al. Influence of life stress on de-
pression: moderation by a polymorphism in the 5-HTT gene. Sci-
184. Faravelli C, Ambonetti A, Pallanti S, et al. Depressive relapses and in-
complete recovery from index episode. Am J Psychiatry1986;143:888-91.
185. Georgotas A, McCue RE, Cooper TB, et al. How effective and safe
is continuation therapy in elderly depressed patients? Factors af-
fecting relapse rate. Arch Gen Psychiatry 1988;45:929-32.
186. Paykel ES, Ramana R, Cooper Z, et al. Residual symptoms after
partial remission: an important outcome in depression. Psychol
187. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in resid-
ual depression by cognitive therapy: a controlled trial. Arch Gen
188. Cannon DM, Ichise M, Fromm SJ, et al. Serotonin transporter bind-
ing in bipolar disorder assessed using [11C]DASB and positron
emission tomography. Biol Psychiatry 2006;60:207-17.
189. Takano A, Suzuki K, Kosaka J, et al. A dose-finding study of du-
loxetine based on serotonin transporter occupancy. Psychopharma-
cology (Berl) 2006;185:395-9.
190. Parsey RV, Kent JM, Oquendo MA, et al. Acute occupancy of brain
serotonin transporter by sertraline as measured by [11C]DASB and
positron emission tomography. Biol Psychiatry 2006;59:821-8.
191. Fineberg NA, Gale TM. Evidence-based pharmacotherapy of obses-
sive-compulsive disorder. Int J Neuropsychopharmacol 2005;8:107-29.