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Original Article |

Differential Effects of 5-HTTLPR Genotypes on the Behavioral and Neural Responses to Tryptophan Depletion in Patients With Major Depression and Controls FREE

Alexander Neumeister, MD; Xian-Zhang Hu, MD; David A. Luckenbaugh, MA; Markus Schwarz, MD; Allison C. Nugent, PhD; Omer Bonne, MD; Peter Herscovitch, MD; David Goldman, MD; Wayne C. Drevets, MD; Dennis S. Charney, MD
[+] Author Affiliations

Author Affiliations: Department of Psychiatry, Yale University School of Medicine, West Haven, Conn (Dr Neumeister); Mood and Anxiety Disorders Program, Sections on Experimental Therapeutics and Pathophysiology (Drs Neumeister and Charney) and Neuroimaging in Mood and Anxiety Disorders (Drs Nugent, Bonne, and Drevets and Mr Luckenbaugh), National Institute of Mental Health, Bethesda, Md; Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Bethesda (Drs Hu and Goldman); Department of Neurochemistry, University Hospital of Psychiatry, Munich, Germany (Dr Schwarz); PET Department, Clinical Center, National Institutes of Health, Bethesda (Dr Herscovitch); and Department of Psychiatry, Mount Sinai School of Medicine, New York, NY (Dr Charney).


Arch Gen Psychiatry. 2006;63(9):978-986. doi:10.1001/archpsyc.63.9.978.
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Context  Tryptophan depletion (TD) is a model used to study the contribution of reduced serotonin transmission to the pathogenesis of major depressive disorder (MDD). Recent studies have not sufficiently addressed the relative contribution of a functional-length triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, to the behavioral and neural responses to TD in individuals with remitted MDD (rMDD) and controls.

Objective  To determine the role of 5-HTTLPR on the behavioral and neural responses to TD in medication-free patients with rMDD and individually matched controls.

Design  Participants were stratified according to diagnosis and 5-HTTLPR genotypes and underwent TD on one test day and sham depletion on the other test day in a prospective, double-blind, randomized order.

Setting  Outpatient clinic.

Participants  Twenty-seven medication-free patients with rMDD (18 women and 9 men) and 26 controls (17 women and 9 men).

Interventions  Tryptophan depletion was induced by administration of capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing lactose. Fludeoxyglucose F 18 positron emission tomography was performed 6 hours after TD. Magnetic resonance images were obtained for each participant.

Main Outcome Measures  Quantitative positron emission tomography of regional cerebral metabolic rates for glucose and measures of depression using the Hamilton Depression Rating Scale.

Results  Behavioral responses to TD are affected by 5-HTTLPR in patients with rMDD and controls. A direct effect of 5-HTTLPR on the regulation of regional cerebral metabolic rates for glucose was identified in patients with rMDD for the amygdala, hippocampus, and subgenual anterior cingulate cortex.

Conclusions  Variations in 5-HTTLPR modulate the sensitivity of patients with rMDD and controls to the behavioral effects of TD. In patients with rMDD, variations in triallelic 5-HTTLPR have a direct effect on regulation of regional cerebral metabolic rates for glucose in a corticolimbic circuit that has been implicated in rMDD.

Figures in this Article

Major depressive disorder (MDD) is increasingly understood as a disorder involving brain neurotransmitter imbalances and neuroanatomic disruptions in the context of genetic and environmental factors.1 To understand the etiology of MDD, it is important to characterize the interaction between brain transmitter systems and their genetic regulation and how this interaction affects behavior and neural circuits that are believed to be involved in the pathogenesis of MDD.

Brain serotonin systems have been a focus of considerable research efforts to explain the pathogenesis of MDD. We and others have used tryptophan depletion (TD) to test the hypothesis of decreased serotonin function in MDD (for a review see Neumeister2). It has demonstrated in unmedicated patients with remitted MDD (rMDD) but not in controls that TD causes a transient return of depressive symptoms. Also, TD is associated with increased regional cerebral metabolic rates for glucose (rCMRGlu) in the orbitofrontal cortex, anterior cingulate cortex, and ventral striatum.3 Abnormal cerebral blood flow and rCMRGlu in these and other areas, including the amygdala and hippocampus, have also been described in medicated patients with rMDD during TD4,5 and in patients with MDD during spontaneous episodes of MDD.6 Although there is growing consensus that this corticostriatolimbic circuit is involved in rMDD, not all regions are reported in all studies, and there is considerable variability in the direction of cerebral blood flow and rCMRGlu changes.

On the basis of the evidence that serotonin plays an important role in the pathogenesis of rMDD, an obvious next step of investigation is to determine whether serotonin-related genes account for the robust differential neural and behavioral responses to TD in patients with rMDD and controls. One major focus of research has been the serotonin transporter (for a review see Owens and Nemeroff7) responsible for the reuptake of released serotonin from the synaptic cleft into nerve terminals,8 and it is the target of antidepressant drug therapy.911 A relatively common polymorphism, a 44–base pair (bp) deletion/insertion in the transcriptional control region approximately 1 kPa upstream of the transcription initiation site, designated 5-HTTLPR,12 has been studied intensively, and originally 2 variants, long (L) and short (S) allelic variants, were described. Recently, functional variants were identified in the L allele and designated as LA and LG.13 The LG and S alleles have comparable levels of serotonin transporter expression, and both are lower than that of the LA allele. This finding suggests that 5-HTTLPR is truly a triallelic functional polymorphism. This may explain some of the conflicting results in the literature about the functional significance of the biallelic polymorphism related to serotonin transporter expression1418 or its role in the pathogenesis of MDD.1921

In a previous study,22 an association between the biallelic 5-HTTLPR and the behavioral response to TD was reported. To date, the relative contribution of the triallelic 5-HTTLPR polymorphism to the behavioral responses to TD and to the regulation of rCMRGlu in the corticolimbic circuit that has been implicated in rMDD has not been studied. For the present study, we recruited unmedicated patients with rMDD to avoid the confounding effects of acute illness and current or recent antidepressant drug treatment. The present study sought to extend previous research by aiming to substantiate previous studies on the behavioral and neural effects of TD in patients with rMDD and controls and to examine the role of the triallelic 5-HTTLPR polymorphism to moderate the effects on TD in patients with rMDD and controls.

PARTICIPANTS

Participants were entered into the study after full explanation of the purpose and procedures of the study and after written consent had been obtained as approved by the National Institute of Mental Health institutional review board. The study used a double-blind, randomized, placebo-controlled design, and at least 6 days between each test day was established to avoid carryover effects. Participants first underwent history, physical examination, and DNA extraction from blood samples to determine the triallelic 5-HTTLPR polymorphism, and then they were called back for the TD brain imaging studies after the comparison groups were constructed (Table 1). The triallelic classification was then reclassified into a biallelic model by level of transporter expression as follows: LG/S, LG/LG, and S/S were classified as S/S; LA/S and LA/LG as L/S; and LA/LA as L/L.13

Table Graphic Jump LocationTable 1. Clinical and Demographic Characteristics of 27 Unmedicated Patients With rMDD and 26 Control Subjects

Twenty-seven medication-free patients with rMDD (6 were African American, 1 was Asian, 2 were Hispanic, and 18 were white) who met DSM-IV, nonpatient version,23 criteria for MDD in full remission and had experienced at least 2 past major depressive episodes on the basis of the Structured Clinical Interview for DSM-IV and 26 controls (6 were African American and 20 were white) were included in the study (Table 1). Duration of the depressive illness and number of episodes were estimated from the Past History of MDD addendum to the Structured Clinical Interview for DSM-IV. Remission was defined as at least 3 months during which the individual did not take an antidepressant agent and had 24-item Hamilton Depression Rating Scale (HDRS) scores in the nondepressed range (<8).24 Information about family history of mental illness (Axis I diagnoses) was obtained from the study participants for all first-degree relatives using the Family Interview for Genetic Studies.25 Controls had no personal or family (first-degree relatives) history of psychiatric disorders. No use of medication was allowed during the study. Treatment of the most recent episode of MDD included administration of selective serotonin reuptake inhibitors (n = 13), tricyclic antidepressants (n = 1), dual reuptake inhibitors (n = 6), or a combination of these (n = 7). Participants were free of medical illness on the basis of history and results of physical examination, electrocardiography, and laboratory tests, including liver and kidney function tests, hematologic profile, thyroid function tests, urinalysis, and toxicology. Pregnant and nursing women were excluded. Premenopausal women were studied during the follicular phase of the menstrual cycle. The menstrual phase was determined using plasma estradiol and progesterone concentrations, time since onset of last menses, and home urine ovulation kits to detect the midcycle luteinizing hormone surge (Clear Plan Easy; Whitehall Laboratories, Madison, NJ) to identify the time of ovulation in the index menstrual cycle.

2-STAGE 5′ NUCLEASE GENOTYPING OF 5-HTTLPR, INCLUDING S, LA, AND LG ALLELES

Oligonucleotide primers and dye-labeled probes were designed to optimize allele discrimination using a software program (Primer Express; Applied Biosystems Inc, Foster City, Calif). Genotyping was accomplished in 2 stages: stage 1 discriminated S vs L alleles and stage 2 discriminated LA vs LG alleles. We used 4 fluorogenic probes, 2 for each stage,26 labeled at the 5′ end with either FAM or VIC (Applied Biosystems Inc). The L amplicon was 182 bp and the S amplicon was 138 bp. For stage 1, the allele-discriminating probe was capable of hybridizing only once to the 43-bp L insertion, and an internal control probe hybridized to a sequence located in the same amplicon but specific to a divergent repeat found only once in the amplicon and not involved in the insertion/deletion. In stage 1, the S/S, S/L, and L/L genotypes are discriminated. For stage 2, probes were designed that were specific for the LA and LG alleles. After combining the 2 stages, 6 genotypes—S/S, S/LG, S/LA, LG/LG, LG/LA, and LA/LAwere detected. Although the SG allele (G substitution on the S allele background) rarely occurs, we did not detect it by sequencing 106 samples and also not in a second independent set of 148 samples.27 Therefore, we did not genotype the SG allele or other rare 5-HTTLPR alleles27 whose functional significance is, like that of SG, unknown.

Polymerase chain reaction was performed in a 25-μL volume: 25 to 50 ng of DNA, 120 nmol of allele-discriminating probe, 60 nmol of internal control probe, polymerase chain reaction primers (200 nmol of each), dimethylsulfoxide (4% by volume), and 1× MasterMix (Applied Biosystems Inc). Amplification conditions were 2 minutes at 50°C, 10 minutes at 95°C, and then 40 cycles at 96°C for 15 seconds and at 62.5°C for 90 seconds. Genotypes were generated using sequence detection system software (PRISM 7700; Applied Biosystems Inc). On each plate, previously sequenced standards were introduced: stage 1 standards were S/S, L/S, and L/L, and stage 2 standards were LA/LA, LA/LG, and LG/LG. Certain samples were analyzed using real-time amplification curves, which are helpful when DNA concentrations are not optimal; otherwise, allele-specific signals were measured after DNA amplification.

TD AND MOOD RATINGS

Tryptophan depletion was induced by the administration of 70 white capsules containing l-isoleucine (4.2 g), l-leucine (6.6 g), l-lysine (4.8 g), l-methionine (1.5 g), l-phenylalanine (6.6 g), l-threonine (3.0 g), and l-valine (4.8 g) at 7 am. During sham depletion (SD), controls received 70 white capsules containing a total of 31.5 g of lactose at 7 am. Patients were restricted from eating on day 1 of the study until completion of the positron emission tomography (PET) study at approximately 4 pm, at which time they returned to unrestricted food intake. Study raters were masked to the participant's diagnosis, genotype, and depletion condition.

The effects of TD and SD were evaluated using measures of depression and measures of plasma total and free tryptophan concentrations. Baseline clinical ratings were obtained at 7 am and then 7 and 24 hours later using a modified version of the HDRS. The items assessing insomnia, weight change, and diurnal variation were removed because they could not be meaningfully assessed on the days of the study.

ASSESSMENTS OF PLASMA TOTAL AND FREE TRYPTOPHAN CONCENTRATIONS

Plasma total and free tryptophan levels were measured on each study day at baseline and then 5, 7, and 24 hours after intake of the capsules. Collected blood samples were immediately centrifuged and stored at −80°C. Before analysis, plasma was deproteinized for total tryptophan measurement or filtered for free tryptophan measurement before it was subjected to isocratic reversed-phase high-performance liquid chromatography with fluorimetric detection (Waters Corp; Milford, Mass) (excitation and emission wavelengths, 300 and 350 nm) as described previously.3

IMAGE ACQUISITION AND ANALYSIS

Magnetic resonance images were obtained for each participant using a commercially available scanner (3.0T Signa; General Electric Medical Systems, Waukesha, Wis) and a 3-dimensional magnetization-prepared rapid-acquisition gradient-echo sequence (echo time, 2.98 milliseconds; repetition time, 7.5 milliseconds; inversion time, 725 milliseconds; and voxel size, 0.9 × 0.9 × 1.2 mm) to provide an anatomical framework for analysis, partial volume correction of the PET images, and morphologic characterization so that individuals with anatomical abnormalities could be excluded.

Because the biochemical and behavioral effects of TD peak 5 to 7 hours after administration of the amino acid mixture, fludeoxyglucose F 18 was infused approximately 6 hours after administration of the capsules containing either lactose or amino acids. The rCMRGlu was measured noninvasively by combining left ventricular chamber time activity curve data with venous blood samples to give the input function needed to calculate the metabolic rate. The left ventricular input function was obtained from dynamic PET of the heart, with venous blood samples obtained concurrently during imaging after injection of 4.5 mCi (166500 Bq) of fludeoxyglucose F 18. Image data from the heart were acquired using a GE Advance PET scanner (General Electric Medical Systems) in 2-dimensional mode for 35 minutes (10 × 30-second frames and 10 × 3-minute frames). This was followed by a 10-minute emission and an 8-minute transmission brain scan 45 minutes after tracer injection. Cardiac sections were reconstructed, and 5 left ventricular sections were identified for region of interest (ROI) placement. The 0- to 5-minute frames were averaged to allow location of the left ventricular blood pool, and the 25- to 35-minute frames allowed identification of myocardial fludeoxyglucose F 18 uptake. Circular ROIs 2 cm in diameter over the left ventricular chamber were positioned on each of the difference images (left ventricular image blood pool minus myocardial fludeoxyglucose F 18 uptake) such that spillover from the myocardium was minimized. An average left ventricular time activity curve was obtained from the time activity curves derived from the ROI in each of the 5 sections. The time activity curve was extended in time to include the period of brain imaging by using venous blood sample values. The average of the venous blood samples obtained at approximately 25, 30, 35, and 50 minutes and the average of the left ventricular concentration during the 25- to 35-minute period were divided. This ratio was then used to scale the 50-minute venous sample concentration, which was then appended to the left ventricular curve, completing the input function used to generate parametric images of rCMRGlu.28

The effects of TD on rCMRGlu were assessed using magnetic resonance imaging–based ROI analysis and image-processing software (MEDx; Medical Numerics Inc, Sterling, Va). Whole-brain fludeoxyglucose F 18 uptake was measured using a magnetic resonance imaging–based template. No significant main effects or interactions were found for whole-brain CMRGlu. The ROI selection was theory and data driven. The ideal model would have included all regions shown in the accumulated literature, but the model was intentionally limited to regions that are known to share extensive, reciprocal anatomical connections with each other; that consistently have been shown in previous studies to be involved in the pathogenesis of MDD; and that have been identified in previous TD studies in patients with rMDD taking29,30 and not taking3 antidepressant drugs to be involved in the neural response to TD. The ROIs included the amygdala, hippocampus, orbitofrontal cortex, subgenual anterior cingulate, pregenual anterior cingulate, and ventral striatum. These regions were placed on each patient's registered magnetic resonance image. A binary mask of the gray matter was then used to ensure that only gray matter pixels were included in the analysis. Regions were then transferred to the coregistered PET images, and the rCMRGlu was obtained for each ROI.

STATISTICAL ANALYSIS

A full-factorial repeated-measures multivariate analysis of variance was used to examine the whole-brain CMRGlu and rCMRGlu for 6 ROIs (amygdala, hippocampus, subgenual and pregenual anterior cingulate cortices, orbitofrontal cortex, and ventral striatum). The model included group (rMDD vs control), sex, and genotype (L/L, L/S, and S/S) as between-subject factors and treatment (TD vs SD) and brain side (left vs right) as within-subject factors. Multivariate tests were followed by separate analyses of variance for each ROI using the same factors as the multivariate analysis of variance.

Behavioral measures were examined by means of repeated-measures analysis of variance, where group and genotype were between-subject factors and treatment and time (baseline, 7 hours, and 24 hours) were within-subjects factors. The measures included HDRS total and subitem scores.

The Shapiro-Wilks test was used to evaluate the normality of the distribution of each outcome variable, and the Mauchly test was used to examine sphericity. When problems with sphericity arose, the Greenhouse-Geisser adjustment was used. Significant interactions were followed by Bonferroni-corrected simple effects tests. Significance was interpreted at P<.05, 2-tailed, and corrected P values are reported. Data are reported as mean ± SEM.

BIOCHEMICAL EFFECTS

As predicted, TD lowered the plasma levels of total tryptophan (treatment × time interaction: F2.23,96.07 = 195.15; P<.001) and free tryptophan (F2.71,124.81 = 75.02; P<.001), with peak effects 5 hours after intake of the amino acid composition. The experimental and control samples did not differ significantly with respect to total and free tryptophan levels at any time. Genotype did not affect the outcome, and total and free tryptophan levels were reduced by 76%, 75%, and 82%, and 76%, 75%, and 80% in the L/L, L/S, and S/S groups, respectively.

BEHAVIORAL RESULTS

At baseline, no significant between-group (rMDD vs control and across the 3 genotypes) differences in HDRS total scores were found. Tryptophan depletion, but not SD, induced profound behavioral effects that differed significantly between groups. Patients with rMDD showed greater mood changes than controls 7 hours after ingestion of the amino acids (treatment × group × time: F1.2,56.6 = 26.85; P<.001).

There was an association between 5-HTTLPR genotypes and depressive response to TD in the rMDD and control samples (treatment × group × genotype: F2,47 = 3.48; P = .04). This association was accounted for by a nearly significant treatment × group × genotype × time interaction (F2.4,56.6 = 2.95; P = .05). Among patients with rMDD, TD induced significant increases in HDRS total scores at 7 hours for all the genotype groups (Figure 1A). Compared with baseline, increases in depression scores were more prominent in carriers of the L/L (t7 = 9.17) and L/S (t11 = 9.42) genotypes than in S/S carriers (t6 = 4.46) (P<.001 for all). Among controls, TD induced an increase in HDRS total scores from baseline to 7 hours after ingestion of the amino acid mixture in S/S (t6 = 2.14; P = .11) and L/S (t11 = 4.15; P<.001) carriers (Figure 1B). In contrast, L/L carriers remained unaffected by TD.

Place holder to copy figure label and caption
Figure 1.

Behavioral effects of tryptophan depletion and sham depletion in unmedicated patients with remitted major depressive disorder (rMDD) (A) and control subjects (B). Most prominent behavioral effects were found approximately 7 hours after administration of the amino acids in patients with rMDD in the L/L and L/S subgroups. Behavioral effects were generally less prominent in controls and more prominent in the S/S and L/S subgroups. LG/S, LG/LG, and S/S were classified as S/S, and LA/LA was classified as L/L. HDRS indicates Hamilton Depression Rating Scale (modified, 24-item version); L, long allelic variant; S, short allelic variant. Error bars represent SEM.

Graphic Jump Location

The individual item analysis on the HDRS revealed that lowering of serotonin function induced sadness and anxiety (treatment × time × group interaction: F1.22,57.15 = 12.27; P<.001 and F1.29,60.49 = 5.79; P = .01, respectively) in patients with rMDD, irrespective of genotype. No sadness was evoked in control subjects during TD. An additional effect of the 5-HTTLPR genotype, however, was found for the anxiety response to TD (treatment × group × genotype interaction: F2,47 = 6.01; P = .005). Among patients with rMDD, anxiety increased in all 3 genotype groups during TD (S/S: t6 = 8.27, P = .02; L/S: t11 = 6.72, P<.001; and L/L: t7 = 5.85, P<.001). In contrast, controls showed increased anxiety scores only in the S/S (t6 = 2.32; P = .05) and L/S (t11 = 3.36; P = .005) subgroups but not in the L/L subgroup (t6 = 0.70; P = .91).

Behavioral effects of TD were transient, and all the patients who experienced depressive or anxiety symptoms during TD reported feeling back to baseline at the follow-up interview 24 hours after TD. There were no sex effects on any of the behavioral outcome measures.

EFFECTS OF TD ON rCMRGlu

Relative to SD, TD was associated with higher rCMRGlu in patients with rMDD compared with controls in the orbitofrontal cortex (F1,47 = 6.89; P = .01), the subgenual anterior cingulate (F1,47 = 4.93; P = .03), and the pregenual anterior cingulate (F1,47 = 3.98; P = .05). No significant differences were found in the other a priori–selected ROIs of the circuit.

In patients with rMDD, the triallelic 5-HTTLPR polymorphism exerted significant effects on the rCMRGlu responses to TD (Figure 2A). The treatment × group × genotype interaction was significant for the hippocampus (F2,47 = 3.79; P = .03) and subgenual anterior cingulate (F2,47 = 3.25; P = .048) and showed a trend for the amygdala (F2,47 = 2.68; P = .08). A significant effect of brain side was found for the amygdala (F1,47 = 15.21; P<.001). During TD, relative to SD, patients with rMDD who were L/S carriers showed decreased rCMRGlu in the left amygdala (t11 = 3.57; P<.001) but not in the right amygdala and in the hippocampus (t11 = 1.99; P = .05). Patients with rMDD who carried the L/L genotype showed increased rCMRGlu during TD relative to SD in the left amygdala (t7 = 3.40; P = .001) but not the right amygdala, the hippocampus (t7 = 2.52; P = .02), and the subgenual anterior cingulate cortex (t7 = 2.55; P = .01). Patients with rMDD who carried the S/S genotype showed decreased rCMRGlu during TD vs SD in the hippocampus (t6 = 2.05; P = .046).

Place holder to copy figure label and caption
Figure 2.

Effects of the triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, genotype on regional cerebral metabolic rates for glucose (rCMRGlu) in unmedicated patients with remitted major depressive disorder (rMDD) (A) and control subjects (B) during tryptophan depletion (TD) and sham depletion. The rCMRGlu data are presented as TD − sham depletion mean values. AC indicates anterior cingulate; L, long allelic variant; S, short allelic variant; *, P<.001; and †, P<.05. Error bars represent SEM. LG/S, LG/LG, and S/S were classified as S/S; LA/S and LA/LG as L/S; and LA/LA as L/L.

Graphic Jump Location

In patients with rMDD, genotype did not affect the rCMRGlu response to depletion condition in the pregenual anterior cingulate cortex, the orbitofrontal cortex, or the ventral striatum. Tryptophan depletion did not induce any significant changes in rCMRGlu relative to SD in the controls for any genotype group (Figure 2B). Sex did not affect the outcome.

The results of the present study agree with those of previous studies3,3032 showing that TD induces a transient return of depressive symptoms in patients with rMDD. Moreover, TD induces abnormal regulation of rCMRGlu in patients with rMDD but not in controls in areas of a corticolimbic circuit, suggesting a trait abnormality that is characteristic of MDD.3 In addition, we show differential effects of the triallelic 5-HTTLPR polymorphism on the behavioral and neural responses to TD in controls and patients with rMDD. We found that patients with rMDD who carry at least 1 copy of the LA allele show a transient return of depressive symptoms during TD. In contrast, control subjects who carry at least 1 copy of the S or the LG allele, both of which are associated with lower serotonin transporter expression than LA,13 show an increase in depression ratings during TD. Patients with rMDD showed a return of depression and anxiety symptoms, whereas in controls, we observed increased anxiety but no sadness during TD. Control subjects were capable of maintaining their mood in a nondepressed range and maintained brain activity in a way that did not significantly vary from baseline measures.

The present results provide novel evidence that the triallelic 5-HTTLPR polymorphism directly affects the regulation of rCMRGlu in the amygdala, hippocampus, and subgenual anterior cingulate in rMDD, whereas no such effect was found in controls. Patients with L/L rMDD showed increased rCMRGlu during TD in the left amygdala, hippocampus, and subgenual anterior cingulate cortex. This suggests a common final pathway of TD-induced amygdaloid-hippocampal complex and subgenual anterior cingulate cortex hyperreactivity in L/L patients in a circuit that plays an important role in MDD. Patients with L/S rMDD who did not differ from L/L carriers in their phenotypic response to TD showed decreased rCMRGlu in the left amygdala and hippocampus. This suggests that carriers of this genotype may represent a distinct and not necessarily intermediate group between S/S and L/L carriers with rMDD.

These partially unpredicted study results raise the question about the underlying biology that explains the robust differential effects of 5-HTTLPR genotypes on behavioral and neural responses to TD in patients with rMDD and controls. Given the central role of the serotonin transporter for regulation of the extracellular concentrations of serotonin,33 as well as evidence that the triallelic 5-HTTLPR polymorphism is functional in people,26 one can expect profound changes in serotonin homeostasis in carriers of different 5-HTTLPR genotypes. In addition, because serotonin dysfunction is an important pathophysiologic factor in MDD, it is reasonable to consider other regulatory components of serotonin transmission besides the serotonin transporter in a model to explain what is going on at the synaptic level. This provides an opportunity to generate models of interactions of multiple interactive components, including the serotonin transporter and presynaptic serotonin type 1A and serotonin type 1B receptors,34 all of which affect the regulation of synaptic availability of serotonin.

We propose that in healthy S/S carriers, compensatory changes that occur in response to elevated synaptic concentrations of serotonin35 lead to decreased postsynaptic serotonin type 1A receptors8,36,37 that may mediate the anxiety responses during TD, similar to the consequences of reduced serotonin type 1A receptor expression in MDD (Figure 3A).38 Reduction in presynaptic serotonin type 1A receptors37,39 permits firing of serotonin neurons40 despite high synaptic serotonin concentrations,34 which may prevent development of the more pronounced symptoms seen in patients with rMDD during TD. Further adjustment of serotonin release is mediated by serotonin type 1B receptors, which adjust the release amount according to the level of synaptic serotonin.41 Although unknown, we speculate that the serotonin type 1B receptor–mediated process of regulation of the amount of released serotonin into the synaptic cleft is normal and responsive to the amount of extracellular serotonin in healthy people. In contrast, L/L carriers have lower synaptic serotonin concentrations but elevated postsynaptic serotonin receptor expression relative to healthy S/S carriers (Figure 3B). This, and an increased serotonin type 1A autoreceptor–mediated inhibitory threshold, makes neuronal firing more likely and allows the system to quickly adjust to a state of short-term disrupted serotonin transmission. Low synaptic serotonin concentrations permit serotonin type 1B receptor–mediated enhanced serotonin release during TD. This maintains optimal functioning of critical circuits necessary for normal affective functioning and prevents symptom provocation. Important differences between depressed patients and controls that may account for the profound between-group differences in behavioral and neural responses to TD are the widespread reduction in postsynaptic serotonin type 1A receptors42,43 and reductions in serotonin transporter expression44 reported in patients with MDD. No association, however, was found between the triallelic 5-HTTLPR polymorphism and serotonin transporter expression in patients with rMDD and controls.45 The serotonin type 1B receptor has also been implicated in the pathogenesis of MDD,46 which may result in loss of responsiveness to extracellular serotonin concentrations so that levels of serotonin released remain constant.41,47,48 We propose that patients with rMDD who carry the L/L genotype have lower postsynaptic serotonin type 1A receptors but increased presynaptic serotonin type 1A receptors, resulting in a decreased threshold that makes firing less likely (Figure 3C). Also, impaired serotonin type 1B receptor–mediated serotonin release makes these individuals more vulnerable to a transient state of serotonin deficiency during TD. We had predicted that S/S rMDD carriers with lower postsynaptic serotonin type 1A receptors and possibly also serotonin type 1B receptors but higher synaptic serotonin availability were particularly vulnerable to the effects of TD (Figure 3D). Instead, these individuals were capable of maintaining normal function of the corticolimbic circuit during TD, as suggested by the absence of changes in brain activity compared with SD, and did not show robust depressive symptom recurrence during TD. Animal data suggest that reduction of serotonin types 1A and 1B receptors during critical periods of brain development may cause permanent changes in the formation of selected neural connections and in serotonin neuronal numbers.49 Neurobiological systems other than serotonin systems may be more critical in these patients in the pathogenesis of MDD.

Place holder to copy figure label and caption
Figure 3.

Dynamic model that explains interactions among regulatory components of the serotonin system involved in serotonin transmission in S/S controls (A), L/L controls (B), patients with L/L who had remitted major depressive disorder (C), and patients with S/S who had remitted major depressive disorder (D). Parameters represent synaptic serotonin clearance rates via the serotonin transporter, serotonin release levels regulated by serotonin type 1B terminal autoreceptors, and inhibitory thresholds as an indication of serotonin type 1A autoreceptor sensitivity, which is regulated by extracellular serotonin concentrations. The function and expression of the individual components of the model are believed to be affected by the triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, genotype, which affects serotonin system function and ultimately leads to differential sensitivity of an individual to the effects of tryptophan depletion. LG/S, LG/LG, and S/S were classified as S/S and LA/LA was classified as L/L. L indicates long allelic variant; S, short allelic variant.

Graphic Jump Location

A limitation of this study is that only 1 gene single-nucleotide polymorphism was assessed. Major depressive disorder is considered a polygenic disorder, and the relative contributions of the many genes that have been implicated in the pathogenesis of MDD are unknown. We designed this study to determine the effects of 5-HTTLPR variants on the behavioral and neural responses to TD in patients with rMDD and controls. Nevertheless, we cannot exclude the possibility that other potentially functional variants of 5-HTTLPR40,49,50 or gene-gene interactions may have affected the results. Animal models using behavioral phenotyping of mutant mice on multiple genetic backgrounds and simulated dynamic models of epistatic interactions among regulatory components of transmitter systems may guide in the design of future studies aimed at selecting candidate genes in humans that will allow us to characterize genetically driven variations in brain function and behavior in mood disorders and to identify vulnerable people before illness onset.51

Correspondence: Alexander Neumeister, MD, Molecular Imaging Program of the Clinical Neuroscience Division, Yale University School of Medicine, 950 Campbell Ave, Bldg 1, Room 9-174, MSC 151E, West Haven, CT 06516 (alexander.neumeister@yale.edu).

Submitted for Publication: September 15, 2005; final revision received January 20, 2006; accepted January 26, 2006.

Financial Disclosure: Dr Charney is currently a consultant to Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Neuroscience Education Institute, Organon International Inc, Otsuka America Pharmaceutical Inc, Quintiles Inc, and Sepracor Inc.

Acknowledgment: We thank Marilla Geraci, RN, and Tracy Waldeck, PhD, for obtaining behavioral ratings on all the study participants and the National Institute of Mental Health 4 West nursing staff for their support of this study.

Charney  DSManji  HK Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE 2004;2004re5
PubMed
Neumeister  A Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull 2003;3799- 115
PubMed
Neumeister  ANugent  ACWaldeck  TGeraci  MSchwarz  MBonne  OBain  EELuckenbaugh  DAHerscovitch  PCharney  DSDrevets  WC Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry 2004;61765- 773
PubMed Link to Article
Smith  KAMorris  JSFriston  KJCowen  PJDolan  RJ Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion. Br J Psychiatry 1999;174525- 529
PubMed Link to Article
Bremner  JDInnis  RBNg  CKStaib  LHSalomon  RMBronen  RADuncan  JSouthwick  SMKrystal  JHRich  DZubal  GDey  HSoufer  RCharney  DS Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry 1997;54246- 254
PubMed Link to Article
Drevets  WC Neuroimaging studies of mood disorders. Biol Psychiatry 2000;48813- 829
PubMed Link to Article
Owens  MJNemeroff  CB Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994;40288- 295
PubMed
Gainetdinov  RRCaron  MG Monoamine transporters: from genes to behavior. Annu Rev Pharmacol Toxicol 2003;43261- 284
PubMed Link to Article
Tauscher  JPirker  Wde Zwaan  MAsenbaum  SBrucke  TKasper  S In vivo visualization of serotonin transporters in the human brain during fluoxetine treatment. Eur Neuropsychopharmacol 1999;9177- 179
PubMed Link to Article
Pirker  WAsenbaum  SKasper  SWalter  HAngelberger  PKoch  GPozzera  ADeecke  LPodreka  IBrucke  T β-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo. J Neural Transm Gen Sect 1995;100247- 256
PubMed Link to Article
Meyer  JHWilson  AAGinovart  NGoulding  VHussey  DHood  KHoule  S Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study. Am J Psychiatry 2001;1581843- 1849
PubMed Link to Article
Heils  ATeufel  APetri  SStober  GRiederer  PBengel  DLesch  KP Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;662621- 2624
PubMed Link to Article
Hu  XZhu  GLipsky  RGoldman  D HTTLPR allele expression is codominant, correlating with gene effects on fMRI and SPECT imaging, intermediate phenotypes, and behavior [abstract]. Biol Psychiatry 2004;55 ((suppl 1)) 191S
van Dyck  CHMalison  RTStaley  JKJacobsen  LKSeibyl  JPLaruelle  MBaldwin  RMInnis  RBGelernter  J Central serotonin transporter availability measured with [123I]β-CIT SPECT in relation to serotonin transporter genotype. Am J Psychiatry 2004;161525- 531
PubMed Link to Article
Shioe  KIchimiya  TSuhara  TTakano  ASudo  YYasuno  FHirano  MShinohara  MKagami  MOkubo  YNankai  MKanba  S No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse 2003;48184- 188
PubMed Link to Article
Willeit  MStastny  JPirker  WPraschak-Rieder  NNeumeister  AAsenbaum  STauscher  JFuchs  KSieghart  WHornik  KAschauer  HNBrucke  TKasper  S No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism. Biol Psychiatry 2001;508- 12
PubMed Link to Article
Mann  JJHuang  YYUnderwood  MDKassir  SAOppenheim  SKelly  TMDwork  AJArango  V A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 2000;57729- 738
PubMed Link to Article
Heinz  AJones  DWMazzanti  CGoldman  DRagan  PHommer  DLinnoila  MWeinberger  DR A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 2000;47643- 649
PubMed Link to Article
Collier  DAStober  GLi  THeils  ACatalano  MDi Bella  DArranz  MJMurray  RMVallada  HPBengel  DMuller  CRRoberts  GWSmeraldi  EKirov  GSham  PLesch  KP A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996;1453- 460
PubMed
Caspi  ASugden  KMoffitt  TETaylor  ACraig  IWHarrington  HMcClay  JMill  JMartin  JBraithwaite  APoulton  R Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301386- 389
PubMed Link to Article
Minov  CBaghai  TCSchule  CZwanzger  PSchwarz  MJZill  PRupprecht  RBondy  B Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neurosci Lett 2001;303119- 122
PubMed Link to Article
Moreno  FARowe  DCKaiser  BChase  DMichaels  TGelernter  JDelgado  PL Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion. Mol Psychiatry 2002;7213- 216
PubMed Link to Article
First  MBGibbon  MSpitzer  RLWilliams  JB Structured Clinical Interview for DSM-IV Axis I Disorders.  New York Biometrics Department, New York State Psychiatric Institute1996;
Frank  EPrien  RFJarrett  RBKeller  MBKupfer  DJLavori  PWRush  AJWeissman  MM Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991;48851- 855
PubMed Link to Article
Maxwell  ME Manual for the Family Interview for Genetic Studies (FIGS).  Bethesda, Md Clinical Neurogenetics Branch, National Institute of Mental Health1992;
Hu  XOroszi  GChun  JSmith  TLGoldman  DSchuckit  MA An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 2005;298- 16
PubMed Link to Article
Nakamura  MUeno  SSano  ATanabe  H The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 2000;532- 38
PubMed Link to Article
Moore  DFAltarescu  GBarker  WCPatronas  NJHerscovitch  PSchiffmann  R White matter lesions in Fabry disease occur in “prior” selectively hypometabolic and hyperperfused brain regions. Brain Res Bull 2003;62231- 240
PubMed Link to Article
Bremner  JDInnis  RBSalomon  RMStaib  LHNg  CKMiller  HLBronen  RAKrystal  JHDuncan  JRich  DPrice  LHMalison  RDey  HSoufer  RCharney  DS Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion–induced depressive relapse. Arch Gen Psychiatry 1997;54364- 374
PubMed Link to Article
Smith  KAFairburn  CGCowen  PJ Relapse of depression after rapid depletion of tryptophan. Lancet 1997;349915- 919
PubMed Link to Article
Delgado  PLCharney  DSPrice  LHAghajanian  GKLandis  HHeninger  GR Serotonin function and the mechanism of antidepressant action: reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990;47411- 418
PubMed Link to Article
Moreno  FAGelenberg  AJHeninger  GRPotter  RLMcKnight  KMAllen  JPhillips  APDelgado  PL Tryptophan depletion and depressive vulnerability. Biol Psychiatry 1999;46498- 505
PubMed Link to Article
Iversen  LL Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol 1971;41571- 591
PubMed Link to Article
Stoltenberg  SF Epistasis among presynaptic serotonergic system components. Behav Genet 2005;35199- 209
PubMed Link to Article
Torres  GEGainetdinov  RRCaron  MG Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 2003;413- 25
PubMed Link to Article
Fabre  VBeaufour  CEvrard  ARioux  AHanoun  NLesch  KPMurphy  DLLanfumey  LHamon  MMartres  MP Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci 2000;122299- 2310
PubMed Link to Article
David  SPMurthy  NVRabiner  EAMunafo  MRJohnstone  ECJacob  RWalton  RTGrasby  PM A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 2005;252586- 2590
PubMed Link to Article
Sullivan  GMOquendo  MASimpson  NVan Heertum  RLMann  JJParsey  RV Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety. Biol Psychiatry 2005;58947- 954
PubMed Link to Article
Li  QWichems  CHeils  ALesch  KPMurphy  DL Reduction in the density and expression, but not G-protein coupling, of serotonin receptors (5-HT1A) in 5-HT transporter knock-out mice: gender and brain region differences. J Neurosci 2000;207888- 7895
PubMed
Gobbi  GMurphy  DLLesch  KBlier  P Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J Pharmacol Exp Ther 2001;296987- 995
PubMed
Knobelman  DAHen  RLucki  I Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse. J Pharmacol Exp Ther 2001;2981083- 1091
PubMed
Drevets  WCFrank  EPrice  JCKupfer  DJHolt  DGreer  PJHuang  YGautier  CMathis  C PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;461375- 1387
PubMed Link to Article
Sargent  PAKjaer  KHBench  CJRabiner  EAMessa  CMeyer  JGunn  RNGrasby  PMCowen  PJ Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000;57174- 180
PubMed Link to Article
Parsey  RVHastings  RSOquendo  MAHuang  YYSimpson  NArcement  JHuang  YOgden  RTVan Heertum  RLArango  VMann  JJ Lower serotonin transporter binding potential in the human brain during major depressive episodes. Am J Psychiatry 2006;16352- 58
PubMed Link to Article
Parsey  RVHastings  RSOquendo  MAHu  XGoldman  DHuang  YYSimpson  NArcement  JHuang  YOgden  RTVan Heertum  RLArango  VMann  JJ Effect of a triallelic functional polymorphism of the serotonin-transporter–linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 2006;16348- 51
PubMed Link to Article
Sari  Y Serotonin1B receptors: from protein to physiological function and behavior. Neurosci Biobehav Rev 2004;28565- 582
PubMed Link to Article
Evrard  ALaporte  AMChastanet  MHen  RHamon  MAdrien  J 5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice. Eur J Neurosci 1999;113823- 3831
PubMed Link to Article
de Groote  LOlivier  BWestenberg  HG Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT(1B) autoreceptors: a microdialysis study in knockout mice. Psychopharmacology (Berl) 2002;162419- 424
PubMed Link to Article
Rumajogee  PVerge  DHanoun  NBrisorgueil  MJHen  RLesch  KPHamon  MMiquel  MC Adaption of the serotoninergic neuronal phenotype in the absence of 5-HT autoreceptors or the 5-HT transporter: involvement of BDNF and cAMP. Eur J Neurosci 2004;19937- 944
PubMed Link to Article
Lira  AZhou  MCastanon  NAnsorge  MSGordon  JAFrancis  JHBradley-Moore  MLira  JUnderwood  MDArango  VKung  HFHofer  MAHen  RGingrich  JA Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol Psychiatry 2003;54960- 971
PubMed Link to Article
Cryan  JFHolmes  A Model organisms: the ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 2005;4775- 790
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Behavioral effects of tryptophan depletion and sham depletion in unmedicated patients with remitted major depressive disorder (rMDD) (A) and control subjects (B). Most prominent behavioral effects were found approximately 7 hours after administration of the amino acids in patients with rMDD in the L/L and L/S subgroups. Behavioral effects were generally less prominent in controls and more prominent in the S/S and L/S subgroups. LG/S, LG/LG, and S/S were classified as S/S, and LA/LA was classified as L/L. HDRS indicates Hamilton Depression Rating Scale (modified, 24-item version); L, long allelic variant; S, short allelic variant. Error bars represent SEM.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Effects of the triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, genotype on regional cerebral metabolic rates for glucose (rCMRGlu) in unmedicated patients with remitted major depressive disorder (rMDD) (A) and control subjects (B) during tryptophan depletion (TD) and sham depletion. The rCMRGlu data are presented as TD − sham depletion mean values. AC indicates anterior cingulate; L, long allelic variant; S, short allelic variant; *, P<.001; and †, P<.05. Error bars represent SEM. LG/S, LG/LG, and S/S were classified as S/S; LA/S and LA/LG as L/S; and LA/LA as L/L.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Dynamic model that explains interactions among regulatory components of the serotonin system involved in serotonin transmission in S/S controls (A), L/L controls (B), patients with L/L who had remitted major depressive disorder (C), and patients with S/S who had remitted major depressive disorder (D). Parameters represent synaptic serotonin clearance rates via the serotonin transporter, serotonin release levels regulated by serotonin type 1B terminal autoreceptors, and inhibitory thresholds as an indication of serotonin type 1A autoreceptor sensitivity, which is regulated by extracellular serotonin concentrations. The function and expression of the individual components of the model are believed to be affected by the triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, genotype, which affects serotonin system function and ultimately leads to differential sensitivity of an individual to the effects of tryptophan depletion. LG/S, LG/LG, and S/S were classified as S/S and LA/LA was classified as L/L. L indicates long allelic variant; S, short allelic variant.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Clinical and Demographic Characteristics of 27 Unmedicated Patients With rMDD and 26 Control Subjects

References

Charney  DSManji  HK Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE 2004;2004re5
PubMed
Neumeister  A Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull 2003;3799- 115
PubMed
Neumeister  ANugent  ACWaldeck  TGeraci  MSchwarz  MBonne  OBain  EELuckenbaugh  DAHerscovitch  PCharney  DSDrevets  WC Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry 2004;61765- 773
PubMed Link to Article
Smith  KAMorris  JSFriston  KJCowen  PJDolan  RJ Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion. Br J Psychiatry 1999;174525- 529
PubMed Link to Article
Bremner  JDInnis  RBNg  CKStaib  LHSalomon  RMBronen  RADuncan  JSouthwick  SMKrystal  JHRich  DZubal  GDey  HSoufer  RCharney  DS Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry 1997;54246- 254
PubMed Link to Article
Drevets  WC Neuroimaging studies of mood disorders. Biol Psychiatry 2000;48813- 829
PubMed Link to Article
Owens  MJNemeroff  CB Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. Clin Chem 1994;40288- 295
PubMed
Gainetdinov  RRCaron  MG Monoamine transporters: from genes to behavior. Annu Rev Pharmacol Toxicol 2003;43261- 284
PubMed Link to Article
Tauscher  JPirker  Wde Zwaan  MAsenbaum  SBrucke  TKasper  S In vivo visualization of serotonin transporters in the human brain during fluoxetine treatment. Eur Neuropsychopharmacol 1999;9177- 179
PubMed Link to Article
Pirker  WAsenbaum  SKasper  SWalter  HAngelberger  PKoch  GPozzera  ADeecke  LPodreka  IBrucke  T β-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo. J Neural Transm Gen Sect 1995;100247- 256
PubMed Link to Article
Meyer  JHWilson  AAGinovart  NGoulding  VHussey  DHood  KHoule  S Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study. Am J Psychiatry 2001;1581843- 1849
PubMed Link to Article
Heils  ATeufel  APetri  SStober  GRiederer  PBengel  DLesch  KP Allelic variation of human serotonin transporter gene expression. J Neurochem 1996;662621- 2624
PubMed Link to Article
Hu  XZhu  GLipsky  RGoldman  D HTTLPR allele expression is codominant, correlating with gene effects on fMRI and SPECT imaging, intermediate phenotypes, and behavior [abstract]. Biol Psychiatry 2004;55 ((suppl 1)) 191S
van Dyck  CHMalison  RTStaley  JKJacobsen  LKSeibyl  JPLaruelle  MBaldwin  RMInnis  RBGelernter  J Central serotonin transporter availability measured with [123I]β-CIT SPECT in relation to serotonin transporter genotype. Am J Psychiatry 2004;161525- 531
PubMed Link to Article
Shioe  KIchimiya  TSuhara  TTakano  ASudo  YYasuno  FHirano  MShinohara  MKagami  MOkubo  YNankai  MKanba  S No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse 2003;48184- 188
PubMed Link to Article
Willeit  MStastny  JPirker  WPraschak-Rieder  NNeumeister  AAsenbaum  STauscher  JFuchs  KSieghart  WHornik  KAschauer  HNBrucke  TKasper  S No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism. Biol Psychiatry 2001;508- 12
PubMed Link to Article
Mann  JJHuang  YYUnderwood  MDKassir  SAOppenheim  SKelly  TMDwork  AJArango  V A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefrontal cortical binding in major depression and suicide. Arch Gen Psychiatry 2000;57729- 738
PubMed Link to Article
Heinz  AJones  DWMazzanti  CGoldman  DRagan  PHommer  DLinnoila  MWeinberger  DR A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 2000;47643- 649
PubMed Link to Article
Collier  DAStober  GLi  THeils  ACatalano  MDi Bella  DArranz  MJMurray  RMVallada  HPBengel  DMuller  CRRoberts  GWSmeraldi  EKirov  GSham  PLesch  KP A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996;1453- 460
PubMed
Caspi  ASugden  KMoffitt  TETaylor  ACraig  IWHarrington  HMcClay  JMill  JMartin  JBraithwaite  APoulton  R Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003;301386- 389
PubMed Link to Article
Minov  CBaghai  TCSchule  CZwanzger  PSchwarz  MJZill  PRupprecht  RBondy  B Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression. Neurosci Lett 2001;303119- 122
PubMed Link to Article
Moreno  FARowe  DCKaiser  BChase  DMichaels  TGelernter  JDelgado  PL Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion. Mol Psychiatry 2002;7213- 216
PubMed Link to Article
First  MBGibbon  MSpitzer  RLWilliams  JB Structured Clinical Interview for DSM-IV Axis I Disorders.  New York Biometrics Department, New York State Psychiatric Institute1996;
Frank  EPrien  RFJarrett  RBKeller  MBKupfer  DJLavori  PWRush  AJWeissman  MM Conceptualization and rationale for consensus definitions of terms in major depressive disorder: remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991;48851- 855
PubMed Link to Article
Maxwell  ME Manual for the Family Interview for Genetic Studies (FIGS).  Bethesda, Md Clinical Neurogenetics Branch, National Institute of Mental Health1992;
Hu  XOroszi  GChun  JSmith  TLGoldman  DSchuckit  MA An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk. Alcohol Clin Exp Res 2005;298- 16
PubMed Link to Article
Nakamura  MUeno  SSano  ATanabe  H The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants. Mol Psychiatry 2000;532- 38
PubMed Link to Article
Moore  DFAltarescu  GBarker  WCPatronas  NJHerscovitch  PSchiffmann  R White matter lesions in Fabry disease occur in “prior” selectively hypometabolic and hyperperfused brain regions. Brain Res Bull 2003;62231- 240
PubMed Link to Article
Bremner  JDInnis  RBSalomon  RMStaib  LHNg  CKMiller  HLBronen  RAKrystal  JHDuncan  JRich  DPrice  LHMalison  RDey  HSoufer  RCharney  DS Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion–induced depressive relapse. Arch Gen Psychiatry 1997;54364- 374
PubMed Link to Article
Smith  KAFairburn  CGCowen  PJ Relapse of depression after rapid depletion of tryptophan. Lancet 1997;349915- 919
PubMed Link to Article
Delgado  PLCharney  DSPrice  LHAghajanian  GKLandis  HHeninger  GR Serotonin function and the mechanism of antidepressant action: reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990;47411- 418
PubMed Link to Article
Moreno  FAGelenberg  AJHeninger  GRPotter  RLMcKnight  KMAllen  JPhillips  APDelgado  PL Tryptophan depletion and depressive vulnerability. Biol Psychiatry 1999;46498- 505
PubMed Link to Article
Iversen  LL Role of transmitter uptake mechanisms in synaptic neurotransmission. Br J Pharmacol 1971;41571- 591
PubMed Link to Article
Stoltenberg  SF Epistasis among presynaptic serotonergic system components. Behav Genet 2005;35199- 209
PubMed Link to Article
Torres  GEGainetdinov  RRCaron  MG Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 2003;413- 25
PubMed Link to Article
Fabre  VBeaufour  CEvrard  ARioux  AHanoun  NLesch  KPMurphy  DLLanfumey  LHamon  MMartres  MP Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci 2000;122299- 2310
PubMed Link to Article
David  SPMurthy  NVRabiner  EAMunafo  MRJohnstone  ECJacob  RWalton  RTGrasby  PM A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans. J Neurosci 2005;252586- 2590
PubMed Link to Article
Sullivan  GMOquendo  MASimpson  NVan Heertum  RLMann  JJParsey  RV Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety. Biol Psychiatry 2005;58947- 954
PubMed Link to Article
Li  QWichems  CHeils  ALesch  KPMurphy  DL Reduction in the density and expression, but not G-protein coupling, of serotonin receptors (5-HT1A) in 5-HT transporter knock-out mice: gender and brain region differences. J Neurosci 2000;207888- 7895
PubMed
Gobbi  GMurphy  DLLesch  KBlier  P Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J Pharmacol Exp Ther 2001;296987- 995
PubMed
Knobelman  DAHen  RLucki  I Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse. J Pharmacol Exp Ther 2001;2981083- 1091
PubMed
Drevets  WCFrank  EPrice  JCKupfer  DJHolt  DGreer  PJHuang  YGautier  CMathis  C PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;461375- 1387
PubMed Link to Article
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