The Impact of BDNF Polymorphisms on Suicidality in Treatment-Resistant Major Depressive Disorder: A European Multicenter Study.

Background: Numerous studies have reported associations between the brain-derived neurotrophic factor (BDNF) gene and psychiatric disorders, including suicidal behavior, although with conflicting results. Methods: A total of 250 major depressive disorder patients were collected in the context of a European multicenter resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and Hamilton Rating Scale for Depression, and treatment response using the HAM-D. Genotyping was performed for the functional Val66Met polymorphism (rs6265) and 7 additional tagging single nucleotide polymorphisms within the BDNF gene. Results: Neither BDNF single markers nor haplotypes were found to be associated with suicide risk and lifetime history of suicide attempts. Gender-specific analyses revealed nonsignificant single marker (rs908867) and haplotypic association with suicide risk in males after multiple testing correction. Analyzing treatment response phenotypes, the functional Val66Met polymorphism as well as rs10501087 showed significant genotypic and haplotypic association with suicide risk in remitters (n=34, 13.6%). Conclusions: Considering the sample size, the present findings need to be replicated in larger samples to confirm or refute a role of BDNF in the investigated suicidal behavior phenotypes.

Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010.

BACKGROUND: Antidepressants (ADs) are known to have the potential to cause various cardiovascular adverse drug reactions (ADRs). The tricyclic antidepressants (TCAs) were first revealed to be a possible source of cardiovascular ADRs. In recent years, newer classes of ADs were also suggested to have a higher risk of cardiovascular adverse effects. In particular, the selective serotonin reuptake inhibitors (SSRIs) were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia. This descriptive study is based on the continuous pharmacovigilance program of German-speaking countries (Austria, Germany, and Switzerland), the Arzneimittelsicherheit in der Psychiatrie (AMSP), which assesses severe ADRs occurring in clinical routine situations. METHODS: Of 169,278 psychiatric inpatients treated with ADs between 1993 and 2010, 198 cases of cardiovascular ADRs (0.12%) were analyzed. RESULTS: Our study showed that the incidence rates of cardiovascular ADRs were highest during treatment with monoamine oxidase inhibitors (0.27%), TCAs (0.15%), and serotonin noradrenaline reuptake inhibitors (0.14%); the risk of occurring during treatment with SSRIs (0.08%) was significantly lower. The noradrenergic and specific serotonergic AD mirtazapine (0.07%) had a significantly lower risk of cardiovascular ADRs than all other ADs. Severe hypotension was the most frequent ADR, followed by hypertension, arrhythmia, and in some rare cases heart failure. CONCLUSIONS: Despite certain limitations due to the AMSP study design, our observations on cardiovascular ADRs can contribute to a better knowledge of the cardiovascular risk profiles of antidepressants in the clinical routine setting. However, prospective studies are needed to verify our findings.

Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas.

Recent mathematical models suggest restored serotonergic burst-firing to underlie the antidepressant effect of selective serotonin reuptake inhibitors (SSRI), resulting from down-regulated serotonin transporters (SERT) in terminal regions. This mechanism possibly depends on the interregional balance between SERTs in the raphe nuclei and in terminal regions before treatment. To evaluate these hypotheses on a systems level in humans in vivo, we investigated SERT availability and occupancy longitudinally in patients with major depressive disorder using positron emission tomography (PET) and the radioligand [11C]DASB. Measurements were performed before and after a single oral dose, as well as after three weeks (mean 24.73±3.3 days) of continuous oral treatment with either escitalopram (10 mg/day) or citalopram (20 mg/day). Data were analyzed using voxel-wise linear regression and ANOVA to evaluate SERT binding, occupancy and binding ratios (SERT binding of the entire brain compared to SERT binding in the dorsal and median raphe nuclei) in relation to treatment outcome. Regression analysis revealed that treatment response was predicted by pre-treatment SERT binding ratios, i.e., SERT binding in key regions of depression including bilateral habenula, amygdala-hippocampus complex and subgenual cingulate cortex in relation to SERT binding in the median but not dorsal raphe nucleus (p<0.05 FDR-corrected). Similar results were observed in the direct comparison of responders and non-responders. Our data provide a first proof-of-concept for recent modeling studies and further underlie the importance of the habenula and subgenual cingulate cortex in the etiology of and recovery from major depression. These findings may indicate a promising molecular predictor of treatment response and stimulate new treatment approaches based on regional differences in SERT binding.

Serotonin-1A receptor binding is positively associated with gray matter volume -- a multimodal neuroimaging study combining PET and structural MRI.

Animal models revealed that the serotonin-1A (5-HT(1A)) receptor modulates gray matter structure. However, there is a lack of evidence showing the relationship between 5-HT(1A) receptor concentration and gray matter in the human brain in vivo. Here, to demonstrate an association between the 5-HT(1A) receptor binding potential, an index for receptor concentration, and the local gray matter volume (GMV), an index for gray matter structure, we measured 35 healthy subjects with both positron emission tomography (PET) and structural magnetic resonance imaging (MRI). We found that regional heteroreceptor binding was positively associated with GMV in distinctive brain regions such as the hippocampi and the temporal cortices in both hemispheres (R(2) values ranged from 0.308 to 0.503, p<0.05 cluster-level FDR-corrected). Furthermore, autoreceptor binding in the midbrain raphe region was positively associated with GMV in forebrain projection sites (R(2)=0.656, p=0.001). We also observed a broad range between 5-HT(1A) receptor binding and GMV. Given the congruence of altered 5-HT(1A) receptor concentrations and GMV reduction in depression or Alzheimer's disease as reported by numerous studies, these results might provide new insights towards understanding the mechanisms behind GMV alterations observed in these brain disorders.

Light-dependent alteration of serotonin-1A receptor binding in cortical and subcortical limbic regions in the human brain.

OBJECTIVE: Climate, in particular sunshine, influences mood and energy levels, creating a positive upswing of mood on bright, sunny days and negative downswing in cold, dark winter seasons. Higher serotonin transporter availability in healthy human subjects in times of lesser light exposure and lower serotonin levels have been shown in winter. METHODS: We examined the light-dependent variations in serotonin-1A receptor binding in limbic regions in 36 drug-naive healthy human subjects. Receptor binding was quantified using positron emission tomography and the radioligand [carbonyl-¹¹C]WAY-100635. Binding potential values were related to the amount of individual exposure to sunlight (daily duration of sunshine) and global radiation (total light intensity). RESULTS: We found a 20-30% lower serotonin-1A receptor binding in the group exposed to a lower amount of global light radiation. Partial correlation analysis revealed significant positive correlations between the regional postsynaptic serotonin-1A receptor binding and global radiation accumulated over a period of 5 days. CONCLUSIONS: Seasonal factors, such as daily amount of sunshine and global radiation, influence serotonin-1A receptor binding in limbic brain regions of healthy human subjects. Combined with recently demonstrated seasonal fluctuations in the serotonin transporter availability, our results underline the importance of seasonal factors in the regulation of the serotonergic transmission.

Progesterone level predicts serotonin-1a receptor binding in the male human brain.

BACKGROUND: Progesterone (P) is thought to influence mood and affective states. Alterations of the inhibitory serotonin-1A (5-HT(1A)) receptor distribution are associated with depression and anxiety. This study evaluates the influence of plasma P levels on the 5-HT(1A) receptor binding in healthy male subjects. METHODS: Molecular neuroimaging of the 5-HT(1A) receptor distribution using positron emission tomography and hormone assays for total plasma P and cortisol were done in a sample of 18 healthy men. RESULTS: Plasma P levels explained up to 65% of the variability in 5-HT(1A) receptor binding in limbic regions including the amygdala, orbitofrontal cortex and retrosplenial cortex. When controlling for cortisol in the model, there was an expected decline in explained variances of 5-HT(1A) binding attributed to P. CONCLUSIONS: The results of this study provide further support for the effect of P on 5-HT(1A) receptor expression and raise the possibility that P mediates the vulnerability to mood disorders by affecting the serotonergic system.

Reduced resting-state functional connectivity between amygdala and orbitofrontal cortex in social anxiety disorder.

Social anxiety disorder patients suffer from excessive anxious responses in social interaction leading to avoidance behavior and social impairment. Although the amygdala has a central role in perception and processing of threatening cues, little is known about the involved networks and corresponding dysfunctions in social anxiety. Therefore, this study aims to investigate the functional connectivity network of the amygdala in patients with social anxiety disorder and to identify regions that might influence amygdalar reactivity via modulatory pathways. Ten patients with anxiety disorders (social and/or panic) and 27 healthy controls underwent a facial emotion processing task as well as 6-min functional MRI at resting state. Individual voxel-wise functional connectivity maps were calculated using the amygdala as seed region. Group comparisons were done by random-effects analysis in SPM. Patients exhibited an amygdala hyperactivation during the emotional task and decreased functional coupling of the left amygdala with the medial orbitofrontal cortex and the posterior cingulate cortex/precuneus. The strength of this functional connectivity showed a negative association with the severity of state anxiety. In addition, an exploratory analysis revealed further reduced functional connectivity and a marked functional separation between the medial orbitofrontal and anterior cingulate cortices in the patient group. Our results suggest alterations within the amygdalar functional connectivity network in social anxiety disorder. Combined with the amygdalar hyperactivation our findings corroborate the proposed dysfunction of the fronto-amygdalar inhibition in anxiety disorders and indicate a modulatory influence of the anterior and posterior cingulate cortices on threat perception and processing.

Escitalopram enhances the association of serotonin-1A autoreceptors to heteroreceptors in anxiety disorders.

Selective serotonin reuptake inhibitors (SSRIs) represent one of the most common treatment options in major depression and anxiety disorders. By blocking the serotonin transporter, SSRIs modulate serotonergic neurotransmission as well as the function of autoreceptors and heteroreceptors. However, treatment-induced changes on a network level primarily remain unknown. Thus, we evaluated the association between serotonin-1A (5-HT1A) autoreceptors and heteroreceptors before and after SSRIs. Twenty-one patients with anxiety disorders underwent positron emission tomography using [carbonyl-11C]WAY-100635 before and after 12 weeks of escitalopram treatment; 15 of them completed the study protocol. Additionally, 36 drug-naive healthy controls were measured once. The 5-HT1A receptor binding potential (BPND) was quantified for the dorsal raphe nucleus (DRN) using a region-of-interest approach and for the entire brain by calculating parametric maps. Voxel-wise linear regression was applied between DRN autoreceptor and whole-brain heteroreceptor 5-HT1A BPND. Consistent with previous observations, healthy subjects showed widespread positive correlations of 5-HT1A BPND between autoreceptors and heteroreceptors. Comparing patients before versus after escitalopram treatment revealed enhanced associations of autoreceptor-to-heteroreceptor 5-HT1A BPND within the amygdala and hippocampus (R2=0.21-0.28 vs 0.49-0.81; p<0.05-0.001). In contrast, no significant SSRI-induced changes were found for correlations of heteroreceptor-to-heteroreceptor 5-HT1A BPND between several limbic regions. This interregional approach suggests a treatment-induced reinforcement of the association of 5-HT1A binding between autoreceptors and heteroreceptors specifically in areas involved in anxiety disorders. These findings provide complementary information about treatment effects on a network level and confirm the central role of the DRN as a prime regulatory area.

Cortisol plasma levels in social anxiety disorder patients correlate with serotonin-1A receptor binding in limbic brain regions.

Dysregulation of the hypothalamic-pituitary-adrenocortical axis with deficient glucocorticoid feedback and alterations in the serotonergic system have been identified as biological correlates of mood disorders. Close examination of the interaction between these systems may offer insights into the pathophysiology of anxiety disorders and depression to understand how stress and these disorders are related. In this study, we investigated the relationship between plasma levels of cortisol and the dominant inhibitory serotonergic receptor, serotonin-1A (5-HT1A). Using positron emission tomography (PET) and the radioligand [carbonyl-11C]WAY-100635, we quantified the 5-HT1A receptor binding. Data from 12 male patients with social phobia and 18 matched control subjects were analysed. Seven brain regions were investigated: the anterior and posterior cingulate cortices, hippocampus, amygdala, medial orbitofrontal and retrosplenial cortices, and dorsal raphe nucleus. Partial correlation analysis, controlled for age and radiochemical variables, was performed to demonstrate the association between cortisol plasma levels and 5-HT1A receptor binding. Cortisol plasma levels were significantly lower in patients with social phobia compared to healthy controls. Moreover, we found strong negative correlations between cortisol plasma levels and 5-HT1A binding in the amygdala (r=-0.93, p=0.0004), hippocampus (r=-0.80, p=0.009), and retrosplenial cortex (r=-0.48, p=0.04) in patients with social phobia. Within the former two regions, these associations were significantly higher in patients than in healthy controls. This PET study confirms a negative association between plasma cortisol levels and the 5-HT1A receptor distribution consistent with studies in rodents and non-human primates. Dysregulation of the cortisol level might increase the vulnerability for mood disorders by altering limbic 5-HT1A receptors.

Hypothalamic serotonin-1A receptor binding measured by PET predicts the plasma level of dehydroepiandrosterone sulfate in healthy women.

Serotonin modulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis particularly via the serotonin-1A receptor (5-HT(1A)). Therefore, the rationale of this positron emission tomography (PET) study was to investigate the influence of the 5-HT(1A) receptor distribution in the human brain on plasma levels of dehydroepiandrosterone sulfate (DHEAS) and cortisol in vivo. Eighteen healthy female were measured with PET and the selective 5-HT(1A) receptor radioligand [carbonyl-(11)C]WAY-100635. Nine a priori defined brain regions (hypothalamus, orbitofrontal cortex, amygdala, hippocampus, anterior and posterior cingulate cortices, dorsal raphe nucleus, retrosplenial cortex, and insula) and the cerebellum (reference region) were delineated on coregistered MR images. DHEAS and cortisol plasma levels were collected by blood sampling in the morning of the PET day. Linear regression analysis of DHEAS plasma level as dependent variable and hypothalamic 5-HT(1A) receptor binding potential (BP) as independent variable showed a highly significant association (r=.691, p=.002). The hypothalamic 5-HT(1A) BP predicted 47.7% of the variability in DHEAS plasma levels. Regressions were borderline significant (p<.01, Bonferroni corrected threshold <.0056) between 5-HT(1A) BP in the anterior cingulate and orbitofrontal cortices and free cortisol levels. No significant associations between DHEAS or cortisol and the 5-HT(1A) receptor BP in other investigated brain regions were found. In conclusion, the serotonergic system may influence the DHEAS plasma level by modulating CRH and ACTH release via hypothalamic 5-HT(1A) receptors as reported for cortisol before. As disturbances of the HPA axis as well as changes of the 5-HT(1A) receptor distribution have been reported in affective disorders, future studies should focus on these interactions.

Favourable results in treatment-resistant schizophrenic patients under combination of aripiprazole with clozapine.

Clozapine is still the gold standard in treatment-resistant schizophrenia. However, a substantial amount of patients do not fully recover on clozapine monotherapy. Though there is still a lack of randomised controlled studies of combination strategies in treatment-resistant schizophrenia, they are widely used. Aripiprazole is a relatively new therapeutic option due to its partial D2 agonism. Both clozapine and aripiprazole, though having a generally favourable side-effect profile, may lead to insufficient response and might provoke side effects in monotherapy. We report the case of four patients in whom we observed a distinct clinical improvement with respect to positive and negative symptoms without major side effects under a combination of clozapine and aripiprazole. The combination of clozapine action and aripiprazole-mediated D(2) receptor regulation could be responsible for the described favourable effects and for the increase of D(2) receptor blockade after adding aripiprazole to clozapine observed in one patient. A combination of clozapine and aripiprazole may be an effective therapeutic strategy for some schizophrenic patients, leading to a good response with respect to positive and negative symptoms without the occurrence of major side effects.

Area-specific modulation of neural activation comparing escitalopram and citalopram revealed by pharmaco-fMRI: a randomized cross-over study.

Area-specific and stimulation-dependent changes of human brain activation by selective serotonin reuptake inhibitors (SSRI) are an important issue for improved understanding of treatment mechanisms, given the frequent prescription of these drugs in depression and anxiety disorders. The aim of this neuroimaging study was to investigate differences in BOLD-signal caused by administration of the SSRIs escitalopram and citalopram using pharmacological functional magnetic resonance imaging (pharmaco-fMRI). Eighteen healthy subjects participated in a placebo-controlled, randomized, double-blind study in cross-over repeated measures design. Each volunteer performed facial emotional discrimination and a sensorimotor control paradigm during three scanning sessions. Citalopram (20 mg/d), escitalopram (10 mg/d) and placebo were administered for 10 days each with a drug-free period of at least 21 days. Significant pharmacological effects on BOLD-signal were found in the amygdala, medial frontal gyrus, parahippocampal, fusiform and middle temporal gyri. Post-hoc t-tests revealed decreased BOLD-signal in the right amygdala and left parahippocampal gyrus in both pharmacological conditions, compared to placebo. Escitalopram, compared to citalopram, induced a decrease of BOLD-signal in the medial frontal gyrus and an increase in the right fusiform and left parahippocampal gyri. Drug effects were concentrated in brain regions with dense serotonergic projections. Both escitalopram and citalopram attenuated BOLD-signal in the amygdala and parahippocampal cortex to emotionally significant stimuli compared to control stimuli. We believe that reduced reactivity in the medial frontal gyrus found for escitalopram compared to citalopram administration might explain the response differences between study drugs as demonstrated in previous clinical trials.

Social anxiety disorder: epidemiology, biology and treatment.

Social anxiety disorder (SAD) is considered to be one of the most common anxiety disorders. Despite its high prevalence, the disorder is still considerably underdiagnosed and undertreated. SAD shows a typically early onset in childhood or early adolescence and generally becomes chronic. The disease places a massive burden on patients lives, affecting not only their social interactions but also their educational and professional activities, thereby constituting a severe disability. Although substantial progress in the study of the etiology of SAD has been made, no commonly accepted model has emerged yet. Data from genetic and neuroimaging studies point towards a contribution of several neurotransmitter systems (i.e. norepinephrine, dopamine and serotonin) to the pathophysiology of this disorder. Functional magnetic resonance imaging studies have repeatedly emphasized the central role of the amygdalae and insula in the neural circuitry of the disorder. Selective serotonin reuptake inhibitors (SSRI) are commonly accepted as first line therapy, however other substance classes like serotonin norepineprine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOI), benzodiazepines and several other agents have also proved effective. There is still a substantial lack of data on therapeutic options in cases of non-responsive SAD as well as on add-on therapy. A combined treatment-approach including psychotherapy (e.g. cognitive behavioural therapy) may prove useful.

Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram.

Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, high-affinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.

Aggression is related to frontal serotonin-1A receptor distribution as revealed by PET in healthy subjects.

OBJECTIVES: Various studies indicate that serotonin regulates impulsivity and the inhibitory control of aggression. Aggression is also known to be modified by sex hormones, which exert influence on serotonergic neurotransmission. The present study aimed to elucidate potential interactions between human aggression, the inhibitory serotonergic 5-HT(1A) receptor, and sex hormones. EXPERIMENTAL DESIGN: Thirty-three healthy volunteers (16 women, aged 26.24 +/- 5.5 yr) completed a validated questionnaire incorporating five dimensions of aggression. Subsequently, all subjects underwent positron emission tomography with the radioligand [carbonyl-(11)C]WAY-100635 to quantify 5-HT(1A) binding potentials (BP(ND)s) in the prefrontal cortex, limbic areas, and midbrain. Also, plasma levels of testosterone, 17beta-estradiol and sex hormone-binding globulin (SHBG) were measured. Relations between aggression scores, regional 5-HT(1A) BP(ND)s, and hormone levels were analyzed using correlations, multivariate analyses of variance, and linear regressions. PRINCIPAL OBSERVATIONS: Statistical analyses revealed higher 5-HT(1A) receptor BP(ND)s in subjects exhibiting higher aggression scores in prefrontal (all P < 0.041) and anterior cingulate cortices (P = 0.016). More aggressive subjects were also characterized by lower SHBG levels (P = 0.015). Moreover, higher SHBG levels were associated with lower 5-HT(1A) BP(ND)s in frontal (P = 0.048) and cingulate cortices (all P < 0.013) and in the amygdala (P = 0.03). CONCLUSIONS: The present study provides first-time evidence for a specific interrelation between the 5-HT(1A) receptor distribution, sex hormones, and aggression in humans. Our findings point to a reduced down-stream control due to higher amounts or activities of frontal 5-HT(1A) receptors in more aggressive subjects, which is presumably modulated by sex hormones.

The serotonin-1A receptor distribution in healthy men and women measured by PET and [carbonyl-11C]WAY-100635.

PURPOSE: The higher prevalence rates of depression and anxiety disorders in women compared to men have been associated with sexual dimorphisms in the serotonergic system. The present positron emission tomography (PET) study investigated the influence of sex on the major inhibitory serotonergic receptor subtype, the serotonin-1A (5-HT(1A)) receptor. METHODS: Sixteen healthy women and 16 healthy men were measured using PET and the highly specific radioligand [carbonyl-(11)C]WAY-100635. Effects of age or gonadal hormones were excluded by restricting the inclusion criteria to young adults and by controlling for menstrual cycle phase. The 5-HT(1A) receptor BP(ND) was quantified using (1) the 'gold standard' manual delineation approach with ten regions of interest (ROIs) and (2) a newly developed delineation method using a PET template normalized to the Montreal Neurologic Institute space with 45 ROIs based on automated anatomical labeling. RESULTS: The 5-HT(1A) receptor BP(ND) was found equally distributed in men and women applying both the manual delineation method and the automated delineation approach. Women had lower mean BP(ND) values in every region investigated, with a borderline significant sex difference in the hypothalamus (p = 0.012, uncorrected). There was a high intersubject variability of the 5-HT(1A) receptor BP(ND) within both sexes compared to the small mean differences between men and women. CONCLUSIONS: To conclude, when measured in the follicular phase, women do not differ from men in the 5-HT(1A) receptor binding. To explain the higher prevalence of affective disorders in women, further studies are needed to evaluate the relationship between hormonal status and the 5-HT(1A) receptor expression.

Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers.

Atypical antipsychotics have been linked to a higher risk for glucose intolerance, and consequentially the development of type 2 diabetes mellitus (DM2). We have therefore set out to investigate the acute effects of oral administration of olanzapine and ziprasidone on whole body insulin sensitivity in healthy subjects. Using the standardized hyperinsulinemic euglycemic clamp technique we compared whole body insulin sensitivity of 29 healthy male volunteers after oral intake of either olanzapine 10 mg/day (n = 14) or ziprasidone 80 mg/day (n = 15) for 10 days. A significant decrease (p<0.001) in whole body insulin sensitivity from 5.7 ml/h/kg ( = mean, SM = 0.4 ml/h/kg) at baseline to 4.7 ml/h/kg ( = mean, SM = 0.3 ml/h/kg) after oral intake of olanzapine (10 mg/day) for 10 days was observed. The ziprasidone (80 mg/day) group did not show any significant difference (5.2+/-0.3 ml/h/kg baseline vs 5.1+/-0.3 ml/h/kg) after 10 days of oral intake. Our main finding demonstrates that oral administration of olanzapine but not ziprasidone leads to a decrease in whole body insulin sensitivity in response to a hyperinsulinemic euglycemic challenge. Our finding is suggestive that not all atypical antipsychotics cause acute direct effects on glucose disposal and that accurate determination of side effect profile should be performed when choosing an atypical antipsychotic.

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.

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.