Higher serotonin transporter occupancy after multiple dose administration of escitalopram compared to citalopram: an [123I]ADAM SPECT study.

OBJECTIVES: Previous studies have investigated the occupancy of the serotonin reuptake transporter (SERT) after clinical doses of citalopram and other selective serotonin reuptake inhibitors. In the present study, the occupancies of SERT after multiple doses of escitalopram and citalopram were compared using the radioligand [(123)I]ADAM and single photon emission computed tomography (SPECT). METHODS: Fifteen healthy subjects received escitalopram 10 mg/day (n = 6) or citalopram 20 mg/day (n = 9) for a total of 10 days. SERT occupancies in midbrain were determined with SPECT and [(123)I]ADAM at three different time points: at baseline (no medication) and at 6 and 54 h after last drug intake. RESULTS: At 6 h after the last dose, mean SERT occupancies were 81.5 +/- 5.4% (mean+/-SD) for escitalopram and 64.0 +/- 12.7% for citalopram (p < 0.01). At 54 h after the last dose, mean SERT occupancies were 63.3 +/- 12.1% for escitalopram and 49.0 +/- 11.7% for citalopram (p < 0.05). The plasma concentrations of the S-enantiomer were of the same magnitude in both substances. For both drugs, the elimination rate of the S-enantiomer in plasma was markedly higher than the occupancy decline rate in the midbrain. CONCLUSION: The significantly higher occupancy of SERT after multiple doses of escitalopram compared to citalopram indicates an increased inhibition of SERT by escitalopram. The results can also be explained by an attenuating effect of R-citalopram on the occupancy of S-citalopram at the SERT.

Striatal D(2) receptor occupancy in bipolar patients treated with olanzapine.

We explored the relationship between striatal dopamine-2 (D(2)) receptor occupancy and extra-pyramidal symptoms (EPS) in bipolar patients receiving olanzapine. Seventeen patients with a DSM-IV diagnosis of bipolar disorder were treated with 5-45 mg/day olanzapine for at least 14 days. After that period, D(2) receptor occupancy was determined using Iodobenzamide (IBZM) and SPECT. EPS were assessed by the Simpson-Angus Scale (SAS) and Barnes-Akathisia Scale (BAS). We found a dose-dependent increase in occupancy: 5 mg led to 28-50%, 10 mg to 40-68%, 15 mg to 69%, 20 mg to 57-66%, 30 mg to 66% and 45 mg to 80% D(2) receptor occupancy; and a significant correlation between plasma levels and occupancy (R(2)=.55, P=.001). Similar to schizophrenic patients, bipolar patients did not exhibit EPS at D(2) occupancy levels of 28 to 80%. Although we did not find an increased vulnerability for acute EPS in bipolar patients receiving olanzapine at clinical relevant doses, this needs to be replicated with larger sample sizes.

Reduced serotonin-1A receptor binding in social anxiety disorder.

BACKGROUND: Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). METHODS: Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. RESULTS: We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). CONCLUSIONS: The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.

Binding kinetics of 123I[ADAM] in healthy controls: a selective SERT radioligand.

[123I]ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) is a promising radioligand for in-vivo quantification of serotonin transporters (SERT) using single photon emission computed tomography (SPECT) in man. We performed tracer kinetic analysis in various brain regions to determine the optimum equilibrium time for SERT quantification with [123I]ADAM and SPECT. Radiosyntheses of [123I]ADAM were performed at MAP Medical Technologies Oy, Tikkakoski, Finland. Thirty healthy male volunteers (21-41 yr) received between 104 and 163 MBq [123I]ADAM intravenously as a bolus. Consecutively, multiple SPECT scans were performed between 14 and 420 min post-injection (p.i.) using a Siemens Multispect 3 camera. Reconstruction was performed applying filtered back projection with a Butterworth filter (cut-off 0.7, order 7) in 128x128 matrices. Regions of interest (ROI) were drawn manually on the individual T1-weighted magnetic resonance image (MRI) comprising midbrain/hypothalamus for specific binding to SERT, and the cerebellum as reference region. After re-orientation to the MRI, the ROI template was applied to SPECT studies. We generated time-activity curves for the ROI and calculated the ratio countstarget/countscerebellum minus 1 (=V3'') as a measure for specific SERT binding. Counts were corrected for applied activity, acquisition time and body-weight. Peak uptakes were observed between 14 and 50 min after bolus injection. Counts per voxel were highest in the midbrain/hypothalamus, 798 (max. 872, min. 728), whereas 462 counts per voxel (max. 599, min. 412) were measured in the cerebellum at a mean time of 31 min p.i. Stable values for V3'' reached 205-320 min p.i. Mean peak V3'' value was 1.43 (95% CI 171-230) for the midbrain/hypothalamus at 205 min p.i. [123I]ADAM is a useful ligand for in-vivo quantification of human SERT by means of SPECT, with a comparatively better signal-to-noise ratio compared to beta-CIT. Our data suggest that the acquisition time for the SPECT scan is optimally, under pseudo-equilibrium conditions, between 205-320 min post-bolus injection of the tracer.

T cell cytokine profile during primary Epstein-Barr virus infection (infectious mononucleosis).

Cytokine profiles of CD4+ and CD8+ T-cell subsets were evaluated in 8 patients with infectious mononucleosis (IM). Intracellular detection of cytokines using flow cytometry revealed an expansion of IFN-gamma-expressing CD4+ T cells, and particularly CD8+ T cells, while IL-2 expressing cells were less frequently encountered when compared to healthy controls. Single TNF-alpha-expressing CD4+ and CD8+ T cells were likewise reduced and shifted towards IFN-gamma/TNF-alpha co-production. The predominant pro-inflammatory type 1-biased immune response during IM was emphasized by low frequencies of IL-10 expression in both T cell subsets, although some patients displayed elevated serum levels. Six months later, a decreased, but still elevated IFN-gamma expression within the CD8+ T cell subset, and an increased percentage of IL-2-expressing CD4+ and CD8+ T cells, reaching values shown for controls, were noted. Type 2-associated cytokines such as IL-4 and IL-13, as well as IL-6 and TNF-alpha were not significantly different when compared to controls at study entry and at follow-up. The striking expansion of IFN-gamma-producing CD8+ T cells with rather low expression of IL-10, appears to be a key factor for clinically overt disease, but is nevertheless compatible with successful control of the viral infection.