Johannes Tauscher

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.

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

Abstract Background: Numerous findings indicate alterations in brain serotonin systems in seasonal affective disorder (SAD). [ 123 I]-2-β-carbomethoxy-3-β-(4-iodophenyl)-tropane ([ 123 I]-β-CIT) labels serotonin transporters (5-HTTs) in the midbrain. We performed a [ 123 I]-β-CIT single photon emission computer tomography (SPECT) study under the hypothesis of lower [ 123 I]-β-CIT binding reflecting reduced central 5-HTT availability in depressed SAD patients. Methods: Depressed SAD patients and healthy control subjects were investigated using [ 123 I]-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 [ 123 I]-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.

Significant dissociation of brain and plasma kinetics with antipsychotics.

Current dosing regimens of psychotropic drugs are based on plasma kinetic considerations, although it is unclear whether plasma levels faithfully reflect brain kinetics of drugs.1,2 To examine this, we compared the kinetics of plasma levels of two widely used antipsychotics, olanzapine and risperidone, vs the time course of their effects in the brain. We used positron emission tomography (PET) and [11C]-labeled ligands to quantify striatal and extra-striatal dopamine-2 (D2), and cortical serotonin-2A (5-HT2A) receptor occupancy in healthy subjects after a single dose, and in patients chronically treated for psychosis. We found a significant dissociation of brain and plasma kinetics. Mean plasma elimination half-lives of single doses of olanzapine and risperidone were 24.2 and 10.3 h, respectively, whereas it took on average 75.2 h with olanzapine, and 66.6 h with risperidone to decline to 50% of their peak striatal D2 receptor occupancy. We found similar discrepancies between the time course of plasma levels and extra-striatal D2 as well as 5-HT2A receptor occupancy. Our results question the current reliance on plasma kinetics as the main basis for dosing regimens of antipsychotics. Studies of brain kinetics may provide a sounder basis for determining dosing schedules of psychotropic medications.

The Role of Imaging in Proof of Concept for CNS Drug Discovery and Development

Neuroimaging, particularly that of neuroreceptor radioisotope and functional magnetic resonance imaging (fMRI), has played a fundamental role in neuropharmacology and neurophysiology. Because of the unique and pioneering role, especially of the radiolabeling of central nervous system (CNS) drugs for receptor and neurotransmitter system imaging, there is an increasingly major role to aid in CNS drug development. One component is providing evidence for proof of concept of the target for which candidate drugs are being tested for receptor occupancy mechanism of action and ultimately rational drug dosing. There is also a role for other areas of neuroimaging, including fMRI and magnetic resonance spectroscopy in other magnetic resonance-based techniques that, together with radioisotope imaging, represent ‘CNS molecular imaging.’ The role of these approaches and a review of the recent advances in such neuroimaging for proof-of-concept studies is the subject for this paper. Moreover, hypothetical examples and possible algorithms for early discovery/phase I development using neuroimaging provide specific working approaches. In summary, this article reviews the vital biomarker approach of neuroimaging in proof of concept studies.

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism

BACKGROUND A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.

Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET

Positron emission tomography (PET) and [11C]WAY-100635 were used to examine the effect of age on serotonin-1A (5-HT1A) receptor binding potential (BP) in 19 healthy subjects. Regions of interest (ROI) were drawn on the co-registered magnetic resonance imaging (MRI) in orbitofrontal (OFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), lateral (LTC), and mediotemporal (MTC), parietal, occipital and cerebellar cortex, and the raphe nuclei. BP values were calculated using a simplified reference tissue method. In addition, a voxelwise analysis was performed using SPM99. Voxelwise analysis revealed a significant global decrease of 5-HT1A BP with age (set level < .001). ROI analysis revealed significant age-related 5-HT1A BP decreases in DLPFC (r = −0.56), ACC (r = −0.44), OFC (r = −0.42), LTC (r = −0.40), parietal (r = −0.65), and occipital cortex (r = −0.43), but not in MTC or raphe nuclei. Overall, cortical 5-HT1A BP declined by approximately 10% per decade, except for the MTC, where we did not find a significant age effect. Hence, careful age matching may be recommended for future studies using PET and [11C]WAY-100635 to examine 5-HT1A receptors.

Receptor and Transporter Imaging Studies in Schizophrenia, Depression, Bulimia and Tourette's Disorder—Implications for Psychopharmacology-

Summary: Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. To determine patterns of brain dysfunction and to uncover the mechanism of action of centrally active compounds we used single photon emission computerized tomography (SPECT) as well as positron emission tomography (PET) in patients diagnosed with schizophrenia, depression, bulimia and Tourettes disorder. Striatal D2 and 5-HTIA receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia. Patients were either drug-naive or drug free, or we studied the influence of specifically acting compounds on receptor/transporter occupancy. We could demonstrate that atypical antipsychotics have a dose-dependent (with the exception of clozapine and quetiapine) lower striatal D2 receptor occupancy rate compared with typical neuroleptics, paralleling the more favourable extrapyramidal side effects of atypical antipsychotics. However, no association between striatal D2 receptor occupancy rates and antipsychotic efficacy has been found. The measurement of S-HTIA receptors in drug-naïve schizophrenic patients using the in vivo PET methodology revealed an increase of cortical 5-HTIA receptor binding potential in schizophrenia. β-CIT as a ligand for measurement of 5-HT transporter densities (5-HTT) revealed lower rates in depression compared to age-and sex-matching healthy controls, a measurement that has also been obtained for bulimia. We also documented seasonal variations in brain serotonergic function by our finding of reduced brain 5-HTT availability in winter (compared to summer) in healthy controls. Furthermore, displaceable [124I]/β-CIT binding in the area corresponding to the left striatum (representing predominantly the density of dopamine transporters) was significantly reduced in SAD patients compared to healthy controls. In depression as well as in bulimia, selective serotonin reuptake inhibitors significantly decreased the β-CIT binding potential, however, no significant dose relationship has been obtained in depression. Genotyping depressed patients for the serotonin transporter promoter gene region (5-HTTLPR) did not provide evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects. In patients suffering from Tourettes disorder (TD) we were unable to detect differences of dopamine transporter densities between psychotropic drug-naïve TD patients and controls. Furthermore, no difference could be found between currently treated (with antipsychotics) and psychotropic drugnaive TD patients. Our data provide insight into the pathophysiology of neuropsychiatric disorders and may guide future psychopharmacological drug developments.

In vivo 123I IBZM SPECT imaging of striatal dopamine-2 receptor occupancy in schizophrenic patients treated with olanzapine in comparison to clozapine and haloperidol

Abstract We investigated the degree of striatal dopamine-2 (D2) receptor occupancy in six schizophrenic patients receiving clinically effective antipsychotic treatment with olanzapine 10–25 mg/day in comparison to patients treated with clozapine 300–600 mg/day (n = 6) or haloperidol 5–20 mg/day (n = 10). 123I Iodobenzamide (IBZM) and single photon emission computerized tomography (SPECT) were used for the visualization of striatal D2 receptors. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to that in untreated healthy controls (n = 8) reported earlier. Olanzapine led to a mean striatal D2 receptor occupancy rate of 75% (range 63–85). Haloperidol-treated patients showed dose-dependently (Pearson r = 0.64; P < 0.05) a significantly higher (P < 0.05) mean occupancy rate of 84% (range 67–94). During clozapine treatment, the mean D2 receptor occupancy of 33% (range < 20–49) was significantly lower than with olanzapine (P < 0.005). The higher striatal D2 receptor occupancy of haloperidol was correlated with the incidence and severity of extrapyramidal motor side-effects (EPS). No clinical relevant EPS occurred during treatment with olanzapine or clozapine. There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.

Striatal dopamine-2 receptor occupancy as measured with [123I]iodobenzamide and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol

AbstractRationale. Extrapyramidal symptoms (EPS) are common with conventional antipsychotics. Clozapine and other novel antipsychotic substances with lower in vitro affinity for dopamine-2 (D2) receptors have a lower propensity to induce EPS. Objective. We investigated whether striatal D2 receptor occupancy predicted the occurrence of EPS with atypical antipsychotics and the typical neuroleptic haloperidol. Methods. [123I]Iodobenzamide (IBZM) and single photon emission tomography (SPECT) were used to quantify receptor occupancy in 71 patients treated with antipsychotics. EPS were rated according to the Simpson-Angus scale (SAS). EPS were deemed clinically relevant, if the SAS score was ≥5 and/or anticholinergic medication was required. Patients received atypical antipsychotic monotherapy for at least 14 days with amisulpride (n=2), clozapine (n=6), haloperidol (n=10), olanzapine (n=6), quetiapine (n=4), risperidone (n=14), sertindole (n=13), or zotepine (n=16). Results. The striatal D2 receptor occupancy ranged from <20% to almost saturation. The lowest occupancy was seen with quetiapine and clozapine, the highest with haloperidol. Twenty-two of 71 patients (29%) experienced clinically relevant EPS. These patients displayed significantly higher mean striatal D2 receptor occupancy (77%) than those without EPS (61%; P=0.002). We found a positive correlation between the percentage of striatal D2 receptor occupancy and the SAS score (r=0.28; P=0.02), despite 18 of these patients receiving anticholinergics, thus lowering their SAS score. Conclusions. Striatal D2 receptor occupancy as measured with [123I]IBZM and SPECT predicted the occurrence of EPS in patients treated with atypical antipsychotics and haloperidol. In vivo imaging of brain receptors with SPECT may provide a useful clinical tool to titrate doses individually and avoid motor side effects in patients treated with novel antipsychotics.

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

The cannabinoid CB1 receptor is one of the most abundant G protein-coupled receptors in the brain and is a promising target of therapeutic drug development. Success of drug development for neuropsychiatric indications is significantly enhanced with the ability to directly measure spatial and temporal binding of compounds to receptors in central compartments. We assessed the utility of a new positron emission tomography (PET) radioligand to image CB1 receptors in monkey brain. [11C]MePPEP ((3R,5R)-5-(3-methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one) has high CB1 affinity (Kb=0.574±0.207 nM) but also moderately high lipophilicity (measured LogD7.4=4.8). After intravenous injection of [11C]MePPEP, brain activity reached high levels of almost 600% standardized uptake value (SUV) within 10–20 min. The regional uptake was consistent with the distribution of CB1 receptors, with high radioactivity in striatum and cerebellum and low in thalamus and pons. Injection of pharmacological doses of CB1-selective agents confirmed that the tracer doses of [11C]MePPEP reversibly labeled CB1 receptors. Preblockade or displacement with two CB1 selective agents (ISPB; (4-(3-cyclopentyl-indole-1-sulfonyl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide) and rimonabant) showed that the majority (>89%) of brain uptake in regions with high receptor densities was specific and reversibly bound to CB1 receptors in the high binding regions. [11C]MePPEP was rapidly removed from arterial plasma. Regional brain uptake could be quantified as distribution volume relative to the concentration of parent radiotracer in plasma. The P-glycoprotein (P-gp) inhibitor DCPQ ((R)-4-[(1a,6,10b)-1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-[(5-quinolinyloxy)methyl]-1-piperazineethanol) did not significantly increase brain uptake of [11C]MePPEP, suggesting it is not a substrate for this efflux transporter at the blood–brain barrier. [11C]MePPEP is a radioligand with high brain uptake, high specific signal to CB1 receptors, and adequately fast washout from brain that allows quantification with 11C (half-life=20 min). These promising results in monkey justify studying this radioligand in human subjects.