Bayesian hierarchical modeling of receptor occupancy in PET trials.

Receptor occupancy (RO) PET is a non-invasive way to determine drug on target. Given the complexity of procedures, long acquisition times, and high cost, ligand displacement imaging trials often have a limited size and produce sparse RO results over the time course of the blocking drug. To take the best advantage of the available data, we propose a Bayesian hierarchical model to analyze RO as a function of the displacing drug. The model has three components: the first estimates RO using brain regional time-radioactivity concentrations, the second shapes the pharmacokinetic profile of the blocking drug, and the last relates PK to RO. Compared to standard 2-steps RO estimation methods, our Bayesian approach quantifies the variability of the individual RO measures. The model has also useful prediction capabilities: to quantify brain RO for dosage regimens of the drug that were not tested in the experiment. This permits the optimal dose selection of neuroscience drugs at a limited cost. We illustrate the method in the prediction of RO after multiple dosing from a single-dose trial.

In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram.

BACKGROUND: Escitalopram is a dual serotonin reuptake inhibitor (SSRI) approved for the treatment of depression and anxiety disorders. It is the S-enantiomer of citalopram, and is responsible for the serotonin reuptake activity, and thus for its pharmacological effects. Previous studies pointed out that clinically efficacious doses of other SSRIs produce an occupancy of the serotonin reuptake transporter (SERT) of about 80% or more. The novel radioligand [123I]ADAM and single photon emission computer tomography (SPECT) were used to measure midbrain SERT occupancies for different doses of escitalopram and citalopram. METHODS: Twenty-five healthy subjects received a single dose of escitalopram [5 mg (n=5), 10 mg (n=5), and 20 mg (n=5)] or citalopram [(10 mg (n=5) and 20 mg (n=5)]. Midbrain SERT binding was measured with [(123)I]ADAM and SPECT on two study days, once without study drug and once 6 h after single dose administration of the study drug. The ratio of midbrain-cerebellum/cerebellum was the outcome measure (V3") for specific binding to SERT in midbrain. Subsequently, SERT occupancy levels were calculated using the untreated baseline level for each subject. An Emax model was used to describe the relationship between S-citalopram concentrations and SERT occupancy values. Additionally, four subjects received placebo to determine test-retest variability. RESULTS: Single doses of 5, 10, or 20 mg escitalopram led to a mean SERT occupancy of 60+/-6, 64+/-6, and 75+/-5%, respectively. SERT occupancies for subjects treated with single doses of 10 and 20 mg citalopram were 65+/-10 and 70+/-6%, respectively. A statistically significant difference was found between SERT occupancies after application of 10 and 20 mg escitalopram, but not for 10 and 20 mg citalopram. There was no statistically significant difference between the SERT occupancies of either 10 mg citalopram or 10 mg escitalopram, or between 20 mg citalopram and 20 mg escitalopram. Emax was slightly higher after administration of citalopram (84%) than escitalopram (79%). In the test-retest study, a mean SERT "occupancy" of 4% was found after administration of placebo, the intraclass correlation coefficient was 0.92, and the repeatability coefficient was 0.25. CONCLUSION: SPECT and [123I]ADAM were used to investigate SERT occupancies after single doses of escitalopram or citalopram. The test-retest study revealed good reproducibility of SERT quantification. Similar SERT occupancies were found after administration of equal doses (in respect to mg) of escitalopram and citalopram, giving indirect evidence for a fractional blockade of SERT by the inactive R-citalopram.

[Early recognition and intervention for schizophrenia]. / Früherkennung und Frühintervention der Schizophrenie.

Studies dealing with the prodromal stage of schizophrenia point to the possibility of early detection and early intervention. Major socioeconomic and social consequences are associated with this disorder. The duration of untreated psychosis seems to play an important role in the course of the disease; i.e. a prolonged duration until adequate treatment is obtained correlates to poorer prognosis. Social, cognitive, affective, and structural brain variations appear in the early prodromal stage. Recent early intervention studies show the possibility of reducing transition rates by preventive treatment of patients at a higher risk of psychosis and already manifesting impaired function. In this review, prodromal signs and possibilities for early detection and intervention in schizophrenia are presented.

[Neuroimaging in substance abuse disorders]. / Neuroimaging bei Substanzabhängigkeit.

The use of neuroimaging techniques in research on substance abuse disorders has advanced our understanding of the underlying pathophysiological and neuropsychological mechanisms. While initial structural imaging techniques were applied to investigate substance abuse-related cerebral atrophy, the functional techniques of SPECT, PET, and later fMRT and MRS provide a much broader range of possible research in this field. Besides their use in characterizing the pharmacology of abused substances and their relations to the pathophysiology of substance abuse disorders, they have also played an essential role in examining the neuropsychiatric underpinnings of the illness and their manifestation in changes of cerebral metabolism. Here, the influence of these techniques on the developing picture of substance abuse disorders is discussed by examining areas of particular scientific interest and reviewing exemplary findings.

Dopamine depletion results in increased neostriatal D(2), but not D(1), receptor binding in humans.

The effect of endogenous dopamine (DA) on neostriatal DA D(1) and D(2) receptor binding potentials (D(1)RBP and D(2)RBP, respectively) in vivo was evaluated with positron emission tomography (PET) and the radiotracers [(11)C]SCH23390 and [(11)C]raclopride, respectively, by comparing the D(1)RBP and D(2)RBP before and after acute DA depletion. DA depletion was achieved by per-oral administration of 4500 mg alpha-methyl-para-tyrosine (AMPT) given in the 25 h prior to [(11)C]SCH23390 PET and of 5250 mg AMPT given in the 29 h prior to [(11)C]raclopride PET. Six healthy subjects completed the protocol. The AMPT treatment decreased plasma levels of the DA metabolite homovanillic acid by 61 +/- 16% (4500 mg; average +/- standard deviation) and 62 +/- 17% (5250 mg), and levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenethyleneglycol by 58 +/- 7% (4500 mg) and 66 +/- 5% (5250 mg). This AMPT treatment increased D(2)RBP significantly from 3.18 +/- 0.34 to 3.59 +/- 0.30 but no significant change was observed in D(1)RBP (1.64 +/- 0.24 pre AMPT vs 1.70 +/- 0.17 post AMPT). Thus, while DA depletion "uncovers" D(2)receptors, it does not do so for D(1) receptors. The implications of this finding for measuring endogenous DA and its effects on in vivo receptor binding in humans are discussed.

Choosing the right dose of antipsychotics in schizophrenia: lessons from neuroimaging studies.

Despite vast clinical experience with antipsychotics, there is no broad consensus on the doses of these substances that should be administered. Currently, most antipsychotics are administered empirically according to clinical dose-finding studies, in which arbitrarily selected doses were tested to find the "most efficient" dose range in a patient population, with no regard for the molecular effects of the tested drug. Brain imaging studies using nuclear medical techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), can now provide a rationale for doses, directly derived from the central effects of the drugs on neurotransmitter receptors measured in vivo. PET results indicate that occupancy of at least 65% of dopamine D(2) receptors is needed for clinical response to antipsychotics, and that occupancy rates exceeding 72 and 78% are associated with a high risk for elevation of prolactin levels and motor adverse effects, respectively. For example, clinical studies with haloperidol do not point to an advantage of dosages exceeding 5 mg/day. The relevance of D(2) receptor occupancy for drug administration is also borne out by studies relating the effects of antipsychotics to their D(2) receptor occupancy in relevant animal models. Taken together, neuroimaging and clinical studies, as well as animal models, provide a rationale for the use of relatively low doses of typical antipsychotics and equivalent doses of novel antipsychotics. The lower risk of adverse effects with appropriate doses of antipsychotics may further enhance compliance and outcome. This seems to be particularly important in individuals experiencing a first episode of schizophrenia, as they appear to be especially responsive to pharmacotherapy and quite sensitive to adverse effects.

In vivo (123)I IBZM SPECT imaging of striatal dopamine 2 receptor occupancy in schizophrenic patients.

RATIONALE: Single photon emission computed tomography (SPECT) using (123)I iodobenzamide (IBZM) as tracer substance has been shown to be a useful tool to visualize dopamine 2 (D2) receptor occupancy. OBJECTIVES: We investigated the striatal D2 receptor occupancy of zotepine which is referred to the class of atypical antipsychotic drugs. METHODS: (123)I IBZM and SPECT were used to visualize striatal dopamine 2 (D2) receptor occupancy in zotepine-treated schizophrenic patients. Two groups of schizophrenic patients receiving either 150 mg/day zotepine (n=6) or 300 mg/day (n=6) underwent examination. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to untreated healthy controls (n=8) reported earlier. RESULTS: Zotepine led to a mean overall striatal D2 receptor occupancy of 73%. Patients with 150 mg daily showed a significantly lower occupancy (65.8%, SD=6.2) than patients with 300 mg/day (77.8%, SD=10.7; P<0.05). No clinically relevant extrapyramidal side effects occurred during treatment with zotepine. CONCLUSIONS: There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.

Quetiapine: efficacy and tolerability in schizophrenia.

Quetiapine, in common with clozapine, has a greater affinity for 5-HT(2) receptors than D(2) receptors and preclinical studies have consistently predicted efficacy against schizophrenia, with a low potential for causing extrapyramidal symptoms (EPS). In clinical trials, the efficacy of quetiapine was consistently superior to placebo and it was effective against both positive and negative symptoms. Quetiapine was also at least as effective as chlorpromazine or haloperidol in improving the symptoms of acute schizophrenia and moreover was associated with higher response rates. The consistent, placebo-level incidence of EPS associated with quetiapine in clinical trials was not seen with haloperidol. Thus, the combination of efficacy comparable to other antipsychotic agents, with an acceptable side effect and tolerability profile, provides support for the use of quetiapine as a first-line antipsychotic agent in the long-term treatment of schizophrenia.

Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers.

OBJECTIVE: The authors investigated the relationship between anxiety--a facet of the Revised NEO Personality Inventory dimension of neuroticism--and serotonin 5-HT(1A) receptor binding potential. METHOD: Positron emission tomography with [(11)C]WAY-100635 was used to estimate regional 5-HT(1A) binding potential in 19 healthy volunteers who completed the Revised NEO Personality Inventory. Correlation coefficients were calculated to determine the degree of association between 5-HT(1A) binding potential and personality inventory measures. RESULTS: There was a significant negative correlation between 5-HT(1A) binding potential and anxiety in four regions: the dorsolateral prefrontal cortex, anterior cingulate cortex, parietal cortex, and occipital cortex. CONCLUSIONS: The inverse relationship between 5-HT(1A) receptor binding potential and anxiety is consistent with 1) animal models that have shown higher anxiety in mice lacking 5-HT(1A) receptors and 2) clinical trial data that have demonstrated antianxiety properties of partial 5-HT(1A) agonists.

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.

Inverse relation between stimulus intensity and seizure duration: implications for ECT procedure.

A retrospective analysis of the effects of electroconvulsive therapy (ECT) was performed for two groups of 11 patients matched according to age (mean age, 52 years), sex, and diagnosis. Group 1 received ECT according to the age-dose protocol; group 2 was treated according to the titration method. A higher dose relative to the seizure threshold appeared to shorten the seizure duration. At the first treatment, the correlation between stimulus intensity and seizure duration was negative. In the titration group, the initial mean charge of 91 mC resulted in a seizure duration of 51 s, whereas in the age-dose group the seizure duration of 31 s was significantly shorter despite a higher mean charge of 312 mC. Seizure duration decreased during the ECT course in the group treated first at low dose (titrated) and then at 2.5 times the initial threshold. High stimulus intensity represented adequate treatment, although it produced short seizures. Thus, seizure duration proved to be an unreliable guideline for effective treatment. Furthermore, focus on seizure duration led to frequent high-dose restimulation in the elderly. The titration method obviates inadequate or excessive charges because the seizure threshold must first be determined.

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-HT(1A) BP with age (set level <.001). ROI analysis revealed significant age-related 5-HT(1A) 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-HT(1A) 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.

[123I] beta-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]-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I] beta-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] beta-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] beta-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.

A voxel-by-voxel analysis of [18F]setoperone PET data shows no substantial serotonin 5-HT(2A) receptor changes in schizophrenia.

Several postmortem studies have reported regionally localized decreases in serotonin(2A) receptors (5-HT(2A)R) in schizophrenia. This was not confirmed by two recent [18F]setoperone positron emission tomography (PET) studies. In these two studies relatively large regions of interest (ROIs) were used; hence, 5-HT(2A)R changes may have been missed in some brain areas. Therefore, data from one study were analyzed on a voxel-by-voxel basis using Statistical Parametric Mapping (SPM). We also used this method to examine the relationship between 5-HT(2A)R binding potential (BP) and five PANSS-derived factors: negative, positive, activation, dysphoric and autistic preoccupation. Thirteen schizophrenic patients (10 antipsychotic-naïve, 3 antipsychotic-free; 11 M, 2 F; age 31+/-7 years) and 35 age-matched control subjects (15 M, 20 F; age 30+/-7 years) were scanned. The 5-HT(2A)R BP was determined for each voxel using the pseudoequilibrium ratio method on PET data obtained between 65 and 90 min after [18F]setoperone bolus injection. The resulting parametric 5-HT(2A)R BP images were spatially normalized using a ligand specific template. Analyses of covariance were done using SPM99 with age as covariate. In tests for the effect of schizophrenia and for partial correlations between 5-HT(2A)R BP and the five factors, corrected P values <0.05 at cluster or voxel level were considered significant. No significant differences were detected between patients and control subjects, and no significant correlations were observed between 5-HT(2A)R BP and any of the five factors. Thus, in agreement with the previous ROI studies, voxel-by-voxel analysis confirmed the lack of substantial 5-HT(2A)R BP differences between schizophrenic patients and control subjects.

Efficacy, cardiac safety and tolerability of sertindole: a drug surveillance.

Sertindole is a novel atypical antipsychotic, which has shown efficacy in the treatment of positive and negative symptoms of schizophrenia in phase II and III studies. Furthermore, these studies have demonstrated tolerability and a favourable side-effect profile. In contrast to classical antipsychotics, sertindole was not associated with extrapyramidal symptoms (EPS). We report drug surveillance data in 34 comorbid and comedicated sertindole treated patients suffering from different psychotic disorders. The drug surveillance consisted of two distinct phases: inpatient treatment and outpatient follow-up. Clinical global impression (severity and improvement of illness), psychotic symptoms, side-effects, and blood parameters have been carefully documented. With special respect to cardiac safety electrocardiograms (ECGs) have been recorded twice (during sertindole treatment and during treatment with an antipsychotic different from sertindole). Recommended ECG-parameters for assessment of the proarrhythmic risk of a drug have been calculated (QTc-, QTc2-interval; QT-, QTc-dispersion). The majority of patients (n = 29) have been treated previously with several typical and/or atypical antipsychotics. We observed a clinical response to sertindole treatment in 29 patients (85%). Both positive and negative symptoms improved with sertindole and no severe side-effects have been documented. EPS occurred at placebo level. A mean QTc-interval prolongation of 19.7 ms (4.7%) has been detected. None of the patients developed clinical or electrocardiographic evidence of cardiac dysrhythmia during sertindole treatment, or other clinical evidence of cardiac abnormalities. In summary, sertindole did show efficacy for positive and negative symptoms together with a favourable side-effect profile. No evidence for an increased proarrhythmic risk has been found.

[123I]-beta-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). [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane ([(123)I]-beta-CIT) labels serotonin transporters (5-HTTs) in the midbrain. We performed a [(123)I]-beta-CIT single photon emission computer tomography (SPECT) study under the hypothesis of lower [(123)I]-beta-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]-beta-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]-beta-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.

Imaging serotonin and dopamine transporters with 123I-beta-CIT SPECT: binding kinetics and effects of normal aging.

UNLABELLED: [123I]beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane (CIT) is a useful ligand for dopamine transporters (DATs) and serotonin transporters (5-HTTs). Previous SPECT studies have shown a state of sustained equilibrium in the striatum on day 2 after injection that allows quantification of striatal DATs using a simple ratio of specific-to-nondisplaceable binding. The aim of this study was to investigate the kinetics of [123I]beta-CIT uptake in the thalamus, hypothalamus, and midbrain, areas known to contain 5-HTTs in high densities. METHODS: SPECT with a triple-head camera was performed on 16 healthy volunteers (13 women, 3 men; mean age [+/-SD], 32 +/- 11 y) after intravenous bolus injection of 130 +/- 20 MBq (3.5 +/- 0.5 mCi) [123I]beta-CIT. Two individuals were scanned 1, 2, 4, 7, 10, 13, 16, and 24 h after injection, and the remaining 14 were scanned 4, 7, 10, 20, and 24 h after injection. Values from 19 previously examined healthy volunteers (8 women, 11 men; mean age, 52 +/- 20 y) were included in the analysis to study the age dependency of beta-CIT binding in striatal and 5-HTT-rich brain areas in a larger control sample. RESULTS: Peak uptake 4 h after injection, followed by stable uptake until 10 h and a slow decrease until 24 h, was observed in the thalamus-hypothalamus region. Activity in the midbrain-pons region peaked 2 h after injection. Because of a concomitant slow but steady decline of uptake in reference regions starting 4 h after injection, a higher stability of binding ratios for 5-HTT-rich brain areas was observed on day 2, suggesting that a state of transient equilibrium is reached between 20 and 24 h but that conditions are only close to transient equilibrium between 4 and 10 h after injection for 5-HTT-rich brain areas. In addition to an age-related decline of striatal [123I]beta-CIT binding of 6.6% per decade, a significant age-associated decrease of beta-CIT binding of 3-4% per decade was found in 5-HTT-rich brain areas. The decline of beta-CIT binding in these regions may be explained, at least in part, by a loss of monoamine transporters with age but may also be related to age-associated morphologic changes. CONCLUSION: [123I]beta-CIT appears to be a suitable ligand for imaging serotonin transporters with SPECT. However, careful age matching is warranted for [123I]beta-CIT SPECT studies of 5-HTT changes in patients with neuropsychiatric disorders.

In vivo visualization of serotonin transporters in the human brain during fluoxetine treatment.

Beta-CIT can be used as a tracer for SPECT to visualize serotonin transporters in the human brain. We present a case of bulimia nervosa and major depressive disorder, who had been treated with up to 60 mg/d fluoxetine for several weeks. Four hours after injection of the tracer more than 40% of serotonin transporters were blocked. To our knowledge, this is the first direct documentation of the pharmacodynamic action of fluoxetine in the human brain in vivo.

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

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.