Brain Serotonin Transporter Availability Research Articles

P.1.j.040 - Social cognition in autism spectrum disorder is associated with brain serotonin transporter availability

P.1.j.040 - Social cognition in autism spectrum disorder is associated with brain serotonin transporter availability

Suicidal ideation modulates the reduction in serotonin transporter availability in male military conscripts with major depression: A 4-[18F]-ADAM PET study

Objectives. Suicide is an important issue in the military service, since it can influence military morale and create dangerous situations for other personnel. The serotonin transporter (SERT) has been suggested to be involved in the pathophysiology of depression and suicidal behaviours. The aims of this study were to examine whether the brain SERT availability differs between military conscripts with depression and control subjects, and whether suicidal ideation is correlated with SERT availability. Methods.We used N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio)benzylamine (4-[18F]-ADAM) as a radioligand for positron emission tomography (PET) imaging. All participants completed the Hamilton Depression Rating Scale and Beck Scale for Suicide Ideation (BSS) prior to PET imaging. Results. The effect of major depression and BSS scores had an interaction on SERT availability. After adjusting for the BSS score, subjects with depression had lower SERT availability than control subjects (F1,17 = 23.85, P < 0.001). A positive correlation between SERT availability and BSS scores was observed in the depression group (F1,8 = 30.67, P = 0.001). The status of depression and intensity of suicidal ideation exert opposite effects on SERT availability. Conclusions. The extent of suicidal ideation may moderate the reduction effect in SERT binding observed in major depression in male military conscripts.

Association of Brain Serotonin Transporter Availability and Brain-Derived Neurotrophic Factor in Models of Serotonin Transporter Genotypes in Healthy Subjects

The S-allele of functional polymorphisms of the serotonin transporter (SERT) gene has been demonstrated to have lower transcriptional activity compared with the L-allele, which shows low expression of SERT in the brain. However, this finding cannot be consistently replicated in vivo. The aim of this study was to determine the availability of SERT based on SERT genotype. We also examined the relationship between brain-derived neurotrophic factor (BDNF) and the availability of SERT. Sixty-two healthy subjects were recruited. Each subject underwent single-photon emission computed tomography with I-ADAM (I-labeled 2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine) for imaging SERT in the brain. The specific uptake ratio was measured, and venous blood was drawn when the subject underwent single-photon emission computed tomography to evaluate BDNF levels and SERT genotype. All subjects expressed SERT genotypes that were consistent with a biallelic model, and 26 subjects had SERT genotypes that were consistent with a triallelic model. No differences in specific uptake ratio were detected in the midbrain, putamen, caudate, and thalamus based on the SERT genotype using the biallelic and triallelic models. Interestingly, The Pearson correlation coefficient revealed a positive correlation between BDNF and SERT availability. In particular, this relationship was observed in homozygous S-allele expression and a genotype with low functional expression (SaSa/SaLg) in the biallelic and triallelic models of SERT genotypes, respectively. This finding might explain why the SS genotype of SERT did not increase the risk of major depressive disorder in Asian populations and implicate an important role of BDNF in the patients, who has the SS genotype of the SERT gene.

Gender differences in brain serotonin transporter availability in panic disorder

The role of the serotonin (5-HT) system in the neurobiology and treatment of panic disorder (PD) remains unproven. Previously we detected lower brain 5-HT transporter (SERT) availability in PD, but the findings were preliminary and mainly limited to female patients. The aim of this study was to assess non-displaceable brain SERT binding potential (BP (ND)) in male and female patients with PD. The SERT BP (ND) was measured in groups of patients with PD (five males and six females) and matched healthy control subjects (12 males and 12 females) using positron emission tomography (PET) and [¹¹C]MADAM tracer. SERT BP (ND) were significantly higher in 13 of 20 studied brain regions, including several cortical and raphe areas, but lower in the hippocampus in males with PD as compared with healthy males. No significant differences in SERT BP (ND) were observed between female patients and controls. The results suggest gender-dependent regional differences in brain SERT availability and converge with previous PET findings of reduced 5-HT(1A) receptor binding in similar brain areas in PD. Distinctive functioning of the 5-HT system in males and females may underlie certain gender-dependent differences in expressions of PD.

Changes in Thalamus–Hypothalamus Serotonin Transporter Availability during Clomipramine Administration in Patients with Obsessive–Compulsive Disorder

To the authors' knowledge there is as of yet no study demonstrating in vivo alterations in human serotonin transporters (SERT) during clomipramine treatment in patients with obsessive-compulsive disorder. The only study in which SERT binding has been investigated in obsessive-compulsive disorder (OCD) patients before and after treatment is a small pilot study by Stengler-Wenzke et al (2006), who treated five OCD patients with citalopram. In the study at hand, we measured transporter availability in the thalamus-hypothalamus with [(123)I] beta-CIT single photon emission computed tomography (SPECT) in 24 patients with DSM-IV OCD. All patients displayed prominent behavioral checking compulsions (OC-checkers). At baseline and upon medication after 12 weeks of treatment with clomipramine (150 mg daily) 24 non-depressed OC-checkers underwent a SPECT measurement of brain SERT availability using [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane. For quantification of brain serotonin transporter availability, a ratio of specific to non-displaceable [(123)I] beta-CIT brain binding was used (BP(ND)=(thalamus and hypothalamus-cerebellum)/cerebellum). The SERT availability was compared between baseline and after treatment and correlated with severity of OC symptomatology and treatment response as assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). After treatment with clomipramine patients showed a 48% reduced brain serotonin transporter availability in the thalamus-hypothalamus, as compared with values at baseline (0.72+/-0.12 vs 1.39+/-0.18, p<0.001). Correlations between brain SERT availability and OC symptomatology (Y-BOCS scores) revealed significantly negative associations both at baseline and after treatment (r=-0.46; p<0.05 and r=-0.53; p<0.01 respectively). These data suggest that the SERT availability values could be considered a biological indicator of disease severity. Moreover, in search of predictors we found that higher pretreatment SERT availability significantly predicted better treatment response 12 weeks later (B=14.145+/-4.514; t=3.133; p=0.005). These results provide further support for an important role of alterations in serotonergic neurons in the pathophysiology of OCD.

123I] ADAM and SPECT in patients with borderline personality disorder and healthy control subjects

Background: Impulsive behaviour, a key feature in borderline personality disorder (BPD), is associated with an impairment of the central serotonergic system. We hypothesized that the serotonin transporter availability is altered in patients with BPD and that there is an association between scores of impulsive aggression and serotonin transporter availability. Methods: In a group of eight female patients with BPD and nine healthy female controls, single photon emission computed tomography (SPECT) was conducted by using the serotonin specific radioligand [123I] ADAM. Using an occipital reference region, brain serotonin transporter availability was measured and ratios of specific to nonspecific [123I] ADAM binding for the brainstem and hypothalamus were calculated. Impulsiveness, anger and depressive symptoms were assessed using the Barratt Impulsiveness Scale, the State-Trait Anger Expression Inventory and the Beck Depression Inventory. Results: Mean specific-to-nonspecific ratios showed a 27% higher brainstem and a 29% higher hypothalamus [123I] ADAM binding in BPD patients compared to healthy controls. Significant correlations were found between ADAM binding and age, impulsiveness, and anger, but not depression. Conclusion: Our results are consistent with previous data suggesting a serotonergic dysfunction in the pathophysiology of BPD. Scores of impulsiveness and anger seemed to be associated with serotonin transporter availability in patients and in healthy controls.

123I]-β-CIT SPECT Imaging Shows Reduced Thalamus–Hypothalamus Serotonin Transporter Availability in 24 Drug-Free Obsessive-Compulsive Checkers

Numerous findings indicate alterations in brain serotonin systems in obsessive-compulsive disorder (OCD). We investigated the in vivo availability of thalamus-hypothalamus serotonin transporters (SERT) in patients with DSM-IV OCD who displayed prominent behavioral checking compulsions (OC-checkers). Four hours after injection of [(123)I]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT), single photon emission computed tomography (SPECT) scans were performed in 24 medication-free non-depressed OC-checkers and 24 age- and gender-matched healthy controls. For quantification of brain serotonin transporter availability, a ratio of specific to non-displaceable [(123)I]-beta-CIT brain binding was used (V''(3)=(thalamus and hypothalamus-cerebellum)/cerebellum). Drug-free non-depressed OC-checkers showed an 18% reduced brain serotonin transporter availability in the thalamus and hypothalamus, as compared with healthy control subjects (1.38+/-0.19 vs 1.69+/-0.21; p<0.001). There was a strong negative correlation between severity of OC symptomatology (Y-BOCS scores) and SERT availability (r=-0.80; p<0.001). Moreover, we found a significant positive correlation between illness duration and serotonin transporter availability (r=0.43; p<0.05). This first report of significantly reduced [(123)I]-beta-CIT binding in the thalamus-hypothalamus region in OC-checkers suggests reduced brain serotonin transporter availability, which is more pronounced with increased severity of OC symptomatology and short duration of illness. The results provide direct evidence for an involvement of the serotonergic system in the pathophysiology of OCD.

Brain serotonin transporter availability predicts treatment response to selective serotonin reuptake inhibitors

Few studies have investigated the predictive value of central serotonin transporter (SERT) availability for treatment response to serotonin reuptake inhibitors (SSRIs). This study used brain imaging to examine the relationship between pretreatment brain SERT availability and transporter occupancy by SSRIs with treatment response in two independent depressed populations. Study 1: Twenty-three patients with major depression underwent a single photon emission computed tomography (SPECT) measurement of brain SERT availability using [123I]beta-CIT ([123I]methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate. The SERT availability was correlated with treatment response to fluoxetine (20 mg/day) assessed with weekly Hamilton Depression Rating Scale (HDRS) for 6 weeks. Study 2: The second group included 10 depressed patients who received 6 weeks of paroxetine treatment (20 mg/day) and serial SPECT scans (baseline, during, and after the treatment). In Study 1, higher pretreatment diencephalic SERT availability significantly predicted better treatment response 4 weeks later. Similar results were found in Study 2 and supported Study 1 findings. The data showed that greater occupancy of diencephalic transporters by paroxetine correlated with better treatment response. Higher pretreatment availability and greater occupancy of SERT in diencephalon may predict better treatment course in response to SSRIs.

Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder

BackgroundA central serotonergic dysfunction is considered to be involved in the pathophysiology of obsessive-compulsive disorder (OCD). The aim of this study was to investigate the serotonin transporter availability in patients with OCD as an in vivo marker of the central serotonergic system. MethodsNine unmedicated (7 drug-naive) patients with OCD and 10 healthy control subjects were included and received single photon emission computed tomography (SPECT) 20.75 ± 1.51 hours after injection of a mean 147.20 ± 6.74 MBq [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([123I]β-CIT). As a measure of brain serotonin transporter availability, a ratio of specific-to-nonspecific [123I]β-CIT binding for the midbrain-pons (V3″ = [midbrain/pons-occipital]/occipital) was used. ResultsMean specific-to-nonspecific ratios showed a 25% higher midbrain-pons [123I]β-CIT binding in the patients as compared with healthy controls (2.26 ± .37 vs. 1.81 ± .23, p < .01). The difference remained significant after adjustment for clinical variables and controlling for age and gender. Stratification of the patients according to onset of the disorder revealed significant differences between controls and patients with early (childhood, adolescence) but not late (adult) onset of OCD. ConclusionsThe study provides evidence of a serotonergic dysfunction in patients with OCD and suggests a serotonergic component in the pathophysiology of the disorder.

123I] β-CIT and single photon emission computed tomography reveal reduced brain serotonin transporter availability in bulimia nervosa

Background: Impaired serotonin transmission has been implicated in the pathophysiology of eating disorders. We investigated the in vivo availability of brain serotonin transporters and dopamine transporters in bulimia nervosa patients. Methods: Approximately 24 hours after injection of [ 123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([ 123I] β-CIT), single photon emission computed tomography scans were performed in 10 medication-free, female bulimic patients and 10 age-matched, healthy females. For quantification of brain serotonin transporter and dopamine transporter availability, a ratio of specific to nonspecific [ 123I] β-CIT brain binding was used (V 3″ = target region − cerebellum/cerebellum). Results: Drug-free bulimia nervosa patients showed a 17% reduced brain serotonin transporter availability in the hypothalamus and thalamus, as compared with healthy control subjects (2.4 ± 0.4 vs. 2.9 ± 0.4, p = .026), and a similar reduction in striatal dopamine transporter availability. There was a negative correlation of illness duration and serotonin transporter availability ( r = −.65; p = .042) and a strong positive correlation between hypothalamic/thalamic and striatal V 3″ ( r = .80, p < .001). Conclusions: This first report of reduced [ 123I] β-CIT binding in a relatively small group of patients with bulimia nervosa suggests a reduced hypothalamic and thalamic serotonin transporter availability in bulimia, which is more pronounced with longer duration of illness.

360. Seasonal variation of central 5-HTT availability in healthy females

Seasonal fluctuations in central and peripheral serotonergic function have been postulated in previous studies. We studied eleven healthy drug-free women (five in summer, six in winter) to examine possible differences in brain serotonin transporter availability between summer and winter. To visualize binding to the serotonin transporter sites in the thalamus/hypothalamus and in the midbrain/pons area we employed the single photon emission computed tomography (SPECT) ligand [125I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([123I]-β-CIT). The cerebellum was served as reference region. Brain imaging studies were performed in one group between May and August, in the other group between November and December. We found significant differences in the specific-to-nondisplaceable [123I]-β-CIT binding in the region corresponding to the thalamus/hypothalamus between the summer group and the winter group (1.9 ± 0.3 vs. 1.4 ± 0.2, respectively; p < .01). No significant difference was detected in the region corresponding to mesencephalon/pons. The result of the present study suggests that brain serotonin transporter availability is reduced in healthy drug-free female subjects in winter, thus supporting hypotheses of circannual variations in brain serotonergic functioning. However, our findings have to be regarded as preliminary unless they are replicated in a larger sample of subjects, as well as, in both genders. It would be worthwhile to do within-subject comparisons during summer and winter in order to determine whether possible differences in brain serotonin transporter availability follow a seasonal rhythm within subjects.

123I]-β-CIT SPECT imaging shows reduced brain serotonin transporter availability in drug-free depressed patients with seasonal affective disorder

Background: Numerous findings indicate alterations in brain serotonin systems in seasonal affective disorder (SAD). [ 123I]-2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane ([ 123I]-β-CIT) labels serotonin transporters (5-HTTs) in the midbrain. We performed a [ 123I]-β-CIT single photon emission computer tomography (SPECT) study under the hypothesis of lower [ 123I]-β-CIT binding reflecting reduced central 5-HTT availability in depressed SAD patients. Methods: Depressed SAD patients and healthy control subjects were investigated using [ 123I]-β-CIT SPECT 4 hours and again 24 hours after tracer injection. Subjects had either never used psychotropic medication or had been drug-free for at least 6 months prior to the investigation. Specific-to-nondisplaceable partition coefficient (V 3′′) was calculated for the thalamus-hypothalamus and the midbrain-pons; the cerebellum served as a reference region. Results: Patients showed a reduction in V 3′′ in thalamus-hypothalamus (2.41 ± 0.3 vs. 2.84 ± 0.4; p = .026) 24 hours post tracer injection (p.i.). No difference between patients and control subjects was found in midbrain-pons (1.31 ± 0.2 vs. 1.42 ± 0.2; p = .39). No differences were detected in the SPECT acquisitions 4 hours p.i. Conclusions: Depressed SAD patients showed lower specific-to-nondisplaceable [ 123I]-β-CIT binding in the region of interest (ROI) thalamus-hypothalamus. The small size of the midbrain-pons ROI may have contributed to the failure to show a difference in this ROI as well. Similar to reduced midbrain 5-HTT availability in nonseasonal depression, depression in SAD seems to be associated with reduced 5-HTT availability to the thalamus-hypothalamus.

Seasonal variation of availability of serotonin transporter binding sites in healthy female subjects as measured by [ 123I]-2β-carbomethoxy-3β- (4-iodophenyl)tropane and single photon emission computed tomography

%Background: Previous studies have indicated annual variations in central and peripheral serotonergic activity. In the present study we studied five women in summer and six women in winter and evaluated possible differences in availability of brain serotonin transporters between summer and winter. Methods: We employed the single photon emission computed tomography ligand [ 123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([ 123I]β-CIT) to visualize binding to the serotonin transporter site in the human thalamus/hypothalamus midbrain area in vivo. Brain imaging studies were performed in one group between May and August and in the other between November and December. Results: We found significant differences in displaceable [ 123I]β-CIT binding in the region corresponding to thalamus/hypothalamus between the summer group and the winter group (1.9 ± 0.3 vs. 1.4 ± 0.2, respectively; p < .01). Conclusions: The results of the present study suggest reduced brain serotonin transporter availability in winter. This finding further substantiates evidence of seasonal variations in brain serotonergic function.

Reduced brain serotonin transporter availability in major depression as measured by [ 123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane and single photon emission computed tomography

Background: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [ 123I]β-CIT SPECT and platelet [ 3H]paroxetine binding. Methods: Drug-free depressed and healthy subjects were injected with 211 ± 22 MBq [ 123I]β-CIT and imaged 24 ± 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V 3″ = (brainstem-occipital)/occipital), a measure proportional to the binding potential (B max/K d), was used for all comparisons. Results: Results showed a statistically significant reduction in brainstem V 3″ values in depressed as compared to healthy subjects (3.1 ± .9 vs. 3.8 ± .8, p = .02). Platelet [ 3H]paroxetine binding was not altered (B max = 2389 ± 484 vs. 2415 ± 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [ 123I]β-CIT binding ( r = −0.14, p = .48). Conclusions: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.