flb-457 and Schizophrenia

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Benztropine; Dopamine Antagonists; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Muscarinic Antagonists; Neostriatum; Positron-Emission Tomography; Prolactin; Prospective Studies; Psychiatric Status Rating Scales; Psychomotor Agitation; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenic Psychology

Although the kinetic profile of antipsychotics at dopamine D2 receptor sites has been suggested to be important for antipsychotic action and dosing schedule, the kinetic profiles of the respective antipsychotic drugs in the brain have not yet been clearly defined. We aimed to estimate the time-course of dopamine D2 receptor occupancy from plasma pharmacokinetics and the apparent in-vivo affinity parameter (ED50; concentration required to induce 50% occupancy). Dopamine D2 receptor occupancies and plasma concentrations of risperidone were measured in five patients with schizophrenia using positron emission tomography with [11C]FLB 457. Measured dopamine D2 occupancies were compared with those estimated from plasma kinetics and in-vivo ED50. The time-course of dopamine D2 receptor occupancy was simulated with altered plasma kinetics or apparent in-vivo affinity parameters of the drug. Mean half-life of dopamine D2 receptor occupancy of risperidone was 80.2 h while that of the plasma concentration was 17.8 h. Dopamine D2 receptor occupancy estimated from plasma pharmacokinetics and in-vivo ED50 was within 1 S.D. of the mean measured occupancy. When the ED50 value was changed to one-tenth and 10-fold, the simulated half-life of receptor occupancy changed to 117.6 h and 27.3 h respectively. Using plasma pharmacokinetics and in-vivo ED50, the time-course of receptor occupancy could be calculated. Simulation of drug kinetics at receptors would provide useful information for the evaluation of antipsychotics.

Topics: Adult; Algorithms; Antipsychotic Agents; Brain; Brain Chemistry; Computer Simulation; Dopamine Antagonists; Half-Life; Humans; Male; Middle Aged; Pyrrolidines; Radioligand Assay; Radiopharmaceuticals; Receptors, Dopamine D2; Risperidone; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Connectivity between brain networks may adapt flexibly to cognitive demand, a process that could underlie adaptive behaviors and cognitive deficits, such as those observed in neuropsychiatric conditions like schizophrenia. Dopamine signaling is critical for working memory but its influence on internetwork connectivity is relatively unknown. We addressed these questions in healthy humans using functional magnetic resonance imaging (during ann-back working-memory task) and positron emission tomography using the radiotracer [(11)C]FLB457 before and after amphetamine to measure the capacity for dopamine release in extrastriatal brain regions. Brain networks were defined by spatial independent component analysis (ICA) and working-memory-load-dependent connectivity between task-relevant pairs of networks was determined via a modified psychophysiological interaction analysis. For most pairs of task-relevant networks, connectivity significantly changed as a function of working-memory load. Moreover, load-dependent changes in connectivity between left and right frontoparietal networks (Δ connectivity lFPN-rFPN) predicted interindividual differences in task performance more accurately than other fMRI and PET imaging measures. Δ Connectivity lFPN-rFPN was not related to cortical dopamine release capacity. A second study in unmedicated patients with schizophrenia showed no abnormalities in load-dependent connectivity but showed a weaker relationship between Δ connectivity lFPN-rFPN and working memory performance in patients compared with matched healthy individuals. Poor working memory performance in patients was, in contrast, related to deficient cortical dopamine release. Our findings indicate that interactions between brain networks dynamically adapt to fluctuating environmental demands. These dynamic adaptations underlie successful working memory performance in healthy individuals and are not well predicted by amphetamine-induced dopamine release capacity.. It is unclear how communication between brain networks responds to changing environmental demands during complex cognitive processes. Also, unknown in regard to these network dynamics is the role of neuromodulators, such as dopamine, and whether their dysregulation could underlie cognitive deficits in neuropsychiatric illness. We found that connectivity between brain networks changes with working-memory load and greater increases predict better working memory performance; however, it was not related to capacity for dopamine release in the cortex. Patients with schizophrenia did show dynamic internetwork connectivity; however, this was more weakly associated with successful performance in patients compared with healthy individuals. Our findings indicate that dynamic interactions between brain networks may support the type of flexible adaptations essential to goal-directed behavior.

Topics: Adult; Dopamine; Female; Frontal Lobe; Humans; Individuality; Magnetic Resonance Imaging; Male; Memory, Short-Term; Nerve Net; Parietal Lobe; Positron-Emission Tomography; Psychomotor Performance; Pyrrolidines; Radiopharmaceuticals; Salicylamides; Schizophrenia; Schizophrenic Psychology

Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cortex (PFC) in schizophrenia. Despite the prevalence of the concept of prefrontal cortical hypodopaminergia in schizophrenia, in vivo imaging of dopamine release in the PFC has not been possible until now, when the validity of using the positron emission tomographic D2/3 radiotracer carbon 11-labeled FLB457 in combination with the amphetamine paradigm was clearly established.. To (1) test amphetamine-induced dopamine release in the dorsolateral PFC (DLPFC) in drug-free or drug-naive patients with schizophrenia (SCZ) and healthy control (HC) individuals matched for age, sex, race/ethnicity, and familial socioeconomic status;(2) test blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging activation during a working memory task in the same participants; and (3) examine the relationship between positron emission tomographic and functional magnetic resonance imaging outcome measures.. Positron emission tomographic imaging with carbon 11-labeled FLB457 before and following 0.5 mg/kg of amphetamine by mouth. Blood oxygenation level-dependent functional magnetic resonance imaging during the self-ordered working memory task. Twenty patients with schizophrenia recruited from the inpatient and outpatient research facilities at New York State Psychiatric Institute and 21 healthy control individuals participated, and data were acquired between June 16, 2011, and February 25, 2014.. The percentage change in binding potential (∆BPND) in the DLPFC following amphetamine, BOLD activation during the self-ordered working memory task compared with the control task, and the correlation between these 2 outcome measures.. We observed significant differences in the effect of amphetamine on DLPFC BPND (mean [SD], ∆BPND in HC: -7.5% [11%]; SCZ: +1.8% [11%]; P = .01); a generalized blunting in dopamine release in SCZ involving most extrastriatal regions and the midbrain; and a significant association between ∆BPND and BOLD activation in the DLPFC in the overall sample including patients with SCZ and HC individuals.. To our knowledge, these results provide the first in vivo evidence for a deficit in the capacity for dopamine release in the DLPFC in SCZ and suggest a more widespread deficit extending to many cortical and extrastriatal regions including the midbrain. This contrasts with the well-replicated excess in dopamine release in the associative striatum in SCZ and suggests a differential regulation of striatal dopamine release in associative striatum vs extrastriatal regions. Furthermore, dopamine release in the DLPFC relates to working memory-related activation of this region, suggesting that blunted release may affect frontal cortical function.

Topics: Adult; Amphetamine; Carbon Radioisotopes; Case-Control Studies; Dopamine; Dopamine Antagonists; Female; Functional Neuroimaging; Humans; Magnetic Resonance Imaging; Male; Memory, Short-Term; Mesencephalon; Positron-Emission Tomography; Prefrontal Cortex; Pyrrolidines; Salicylamides; Schizophrenia; Schizophrenic Psychology; Young Adult

Blonanserin is a novel antipsychotic with high affinities for dopamine D(2) and 5-HT(2A) receptors, and it was recently approved for the treatment of schizophrenia in Japan and Korea. Although double-blind clinical trials have demonstrated that blonanserin has equal efficacy to risperidone, and with a better profile especially with respect to prolactin elevation, its profile of in vivo receptor binding has not been investigated in patients with schizophrenia. Using positron emission tomography (PET), we measured striatal and extrastriatal dopamine D(2) receptor occupancy by blonanserin in 15 patients with schizophrenia treated with fixed doses of blonanserin (ie, 8, 16, and 24 mg/d) for at least 4 weeks before PET scans, and in 15 healthy volunteers. Two PET scans, 1 with [(11)C]raclopride for the striatum and 1 with [(11)C]FLB 457 for the temporal cortex and pituitary, were performed on the same day. Striatal dopamine D(2) receptor occupancy by blonanserin was 60.8% (3.0%) [mean (SD)] at 8 mg, 73.4% (4.9%) at 16 mg, and 79.7% (2.3%) at 24 mg. The brain/plasma concentration ratio calculated from D(2) receptor occupancy in the temporal cortex and pituitary was 3.38, indicating good blood-brain barrier permeability. This was the first study to show clinical daily dose amounts of blonanserin occupying dopamine D(2) receptors in patients with schizophrenia. The clinical implications obtained in this study were the optimal therapeutic dose range of 12.9 to 22.1 mg/d of blonanserin required for 70% to 80% dopamine D(2) receptor occupancy in the striatum, and the good blood-brain barrier permeability that suggested a relatively lower risk of hyperprolactinemia.

Topics: Adult; Antipsychotic Agents; Blood-Brain Barrier; Brain; Case-Control Studies; Corpus Striatum; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Piperazines; Piperidines; Positron-Emission Tomography; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Tissue Distribution; Young Adult

Olanzapine is described as a multi-acting receptor-targeted antipsychotic agent. Although regional differences of dopamine D(2) receptor occupancy, i.e., limbic selectivity, were reported for olanzapine, contradictory results were also reported. We measured dopamine D(2) receptor occupancy of olanzapine in extrastriatal regions in patients with schizophrenia using positron-emission tomography with [(11)C]FLB457 and the plasma concentrations of olanzapine. Ten patients with schizophrenia taking 5-20 mg/day of olanzapine participated. Dopamine D(2) receptor occupancy in the temporal cortex ranged from 61.1 to 85.8%, and plasma concentration was from 12.7 to 115.4 ng/ml. The ED(50) value was 3.4 mg/day for dose and 10.5 ng/ml for plasma concentration. The ED(50) values obtained in this study were quite similar to those previously reported in the striatum. In conclusion, although the subjects and methods were different from previous striatal occupancy studies, these results suggest that limbic occupancy by olanzapine may not be so different from that in the striatum.

Topics: Adult; Benzodiazepines; Carbon Isotopes; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine Antagonists; Dose-Response Relationship, Drug; Humans; Middle Aged; Olanzapine; Positron-Emission Tomography; Protein Binding; Psychiatric Status Rating Scales; Pyrrolidines; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Young Adult

Hyperprolactinemia is a common side effect of antipsychotic drugs used in the treatment of schizophrenia. However, the magnitude of hyperprolactinemia differs among antipsychotics, and there is no reliable mechanism-related marker for the risk of hyperprolactinemia that would allow us to characterize antipsychotics.. In this study, 11 healthy male subjects taking different doses of sulpiride and 24 male patients with DSM-IV-diagnosed schizophrenia taking different antipsychotic drugs (risperidone, olanzapine, haloperidol, and sulpiride) participated. Positron emission tomography scanning using [¹¹C]FLB 457 was performed on all subjects. The dopamine D₂receptor occupancy of antipsychotics in the pituitary and temporal cortex was calculated. Correlations between plasma concentration of prolactin and dopamine D₂receptor occupancies were evaluated. The ratio of drug concentration of cerebral receptor site to that of pituitary receptor site (brain/plasma concentration ratio; B/P ratio) was calculated from the receptor occupancies in the 2 regions. Data were collected between November 2001 and September 2007.. Significant positive correlation was observed between the plasma concentration of prolactin and dopamine D₂receptor occupancy in the pituitary by all 4 antipsychotics (P = .001). Dopamine D₂receptor occupancies of sulpiride were markedly different between the pituitary and temporal cortex, and the B/P ratio for sulpiride (0.34) was significantly lower than for olanzapine (P = .007) and risperidone (P = .015). Olanzapine had a relatively high B/P ratio (2.70), followed by haloperidol (2.40) and risperidone (1.61).. Dopamine D₂receptor occupancy in the pituitary is a good indicator of hyperprolactinemia. B/P ratio, indicating the penetrating capability across the blood-brain barrier, seems to be a good characteristic biomarker of each antipsychotic drug for the risk of hyperprolactinemia at therapeutic dose.

Topics: Adult; Antipsychotic Agents; Benzodiazepines; Carbon Radioisotopes; Cerebellar Cortex; Cerebral Cortex; Computer Graphics; Dopamine Antagonists; Dose-Response Relationship, Drug; Haloperidol; Humans; Hyperprolactinemia; Male; Mathematical Computing; Middle Aged; Olanzapine; Pituitary Gland; Positron-Emission Tomography; Prolactin; Pyrrolidines; Receptors, Dopamine D2; Risperidone; Salicylamides; Schizophrenia; Statistics as Topic; Sulpiride; Temporal Lobe; Young Adult

Paliperidone ER is a novel antipsychotic drug in an extended-release (ER) formulation. As with all antipsychotics, careful dose setting is necessary to avoid side effects.. In this study, we measured striatal and extrastriatal dopamine D2 receptor occupancy during paliperidone ER treatment in patients with schizophrenia using positron emission tomography (PET) to compare regional occupancy and to estimate the optimal dose.. Thirteen male patients with schizophrenia participated in this 6-week multiple-dose study. Six of them took 3 mg of paliperidone ER per day, four took 9 mg, and three took 15 mg. Two to 6 weeks after first drug intake, two PET scans, one with [11C]raclopride and one with [11C]FLB 457, were performed in each patient on the same day. The relationship between the dose or plasma concentration of paliperidone and dopamine D2 receptor occupancy was calculated.. The dopamine D2 receptor occupancies in the striatum measured with [11C]raclopride and the temporal cortex measured with [11C]FLB 457 were 54.2-85.5% and 34.5-87.3%, respectively. ED50 values of the striatum and temporal cortex were 2.38 and 2.84 mg/day, respectively. There was no significant difference in dopamine D2 receptor occupancy between the striatum and the temporal cortex.. The data from this study suggest that paliperidone ER at 6-9 mg provides an estimated level of dopamine D2 receptor occupancy between 70-80% and that the magnitude of dopamine D2 receptor occupancy is similar between the striatum and temporal cortex.

Topics: Adult; Antipsychotic Agents; Brain Chemistry; Data Interpretation, Statistical; Delayed-Action Preparations; Dopamine Antagonists; Dose-Response Relationship, Drug; Humans; Isoxazoles; Male; Neostriatum; Paliperidone Palmitate; Positron-Emission Tomography; Psychiatric Status Rating Scales; Pyrimidines; Pyrrolidines; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Salicylamides; Schizophrenia

Most antipsychotics were thought to induce antipsychotic action at an excess of 70% striatal dopamine D2 receptor occupancy, while the clinical dose of clozapine was reported to show less than 60% occupancy. High-dose clozapine could occupy as high as 80% of striatal dopamine D2 receptor in monkey PET studies. Although the time course of dopamine D2 receptor occupancy is an important property of antipsychotics, that by clozapine has not been investigated in a clinical setting. We measured the time course of extrastriatal dopamine D2 receptor occupancy with different doses of clozapine and evaluated whether the measured occupancies fitted the binding theory. Three consecutive PET scans with [11C]FLB 457 were performed for two patients with schizophrenia, chronically taking 600 mg/day and 200 mg/day of clozapine, respectively. Series of occupancies were also measured in combination with fluvoxamine or paroxetine in one patient. Dopamine D2 receptor occupancies were also simulated using individual clozapine plasma data and previously determined in vivo ED50 value. The occupancy of one patient with high plasma concentration (1207 ng/ml at peak time) was around 75% at peak and around 60% after 26 h. Another patient with medium plasma concentration (649 ng/ml at peak time) showed less than 50% occupancy at peak, decreasing to 15% after 25 h. The measured occupancy values fitted well with the simulated occupancy values. At high plasma concentration, clozapine can induce high extrastriatal dopamine D2 receptor occupancy in the human brain, and this finding fitted well with the theoretical estimation.

Topics: Adult; Antipsychotic Agents; Carbon Isotopes; Chromatography, High Pressure Liquid; Clozapine; Computer Simulation; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Electrochemistry; Fluvoxamine; Humans; Male; Paroxetine; Positron-Emission Tomography; Pyrrolidines; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Time Factors

Several structural and functional brain imaging studies have pointed to a disturbance of thalamic subnuclei in patients with schizophrenia. The dopamine hypothesis of schizophrenia has, however, not been thoroughly examined in terms of this complex structure, which has connections with most brain regions of central interest in schizophrenia research. The aim of the present study was to examine dopamine D(2) receptor binding in subregions of the thalamus in patients with schizophrenia.. The authors used positron emission tomography and the radioligand [(11)C]FLB457 to examine dopamine D(2) receptor binding in thalamic subregions of 10 drug-naive patients with schizophrenia. Binding potential was calculated by the reference tissue method and used as an index for dopamine D(2) receptor binding. Comparisons were made with 19 healthy subjects. Subregions of interest were defined on individual magnetic resonance images using a percentage-based operational approach. Clinical symptoms were rated by using the Brief Psychiatric Rating Scale (BPRS).. The [(11)C]FLB457 binding potential was lower in the central medial and posterior subregions of the thalamus in patients with schizophrenia. At a functional level, there was a significant negative correlation between binding potential and BPRS positive symptom scores.. The subregions with low D(2) receptor binding comprise primarily the dorsomedial nucleus and pulvinar, two important components in circuitries previously suggested in the pathophysiology of schizophrenia. Aberrant dopaminergic neurotransmission in thalamic subregions might be a mechanism underlying positive symptoms in schizophrenia.

Topics: Adult; Brief Psychiatric Rating Scale; Carbon Radioisotopes; Humans; Magnetic Resonance Imaging; Male; Pyrrolidines; Radioligand Assay; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenic Psychology; Thalamic Nuclei; Thalamus; Tomography, Emission-Computed

The clinical efficacy of dopamine D2 receptor antagonism on the psychotic symptoms of schizophrenia has been widely demonstrated. However, most in vivo imaging studies have not been able to detect significant changes in striatal D2 receptors in schizophrenia. On the other hand, a number of studies have reported abnormalities in the cerebral cortex of schizophrenia. The aim of this study was to examine the extrastriatal D2 receptors of patients with schizophrenia.. Eleven drug-naive male patients with schizophrenia were examined with positron emission tomography using carbon 11-labeled FLB 457. Symptoms were assessed using the Brief Psychiatric Rating Scale. Eighteen healthy controls were used for comparison. Region-of-interest analysis was performed using the reference tissue method, and binding potential (BP) was used for the index of dopamine D2 receptor binding.. The BP value was significantly lower, by about 12.5%, in the anterior cingulate cortex in drug-naive patients with schizophrenia than in healthy controls. A significant negative correlation was observed between BP in the anterior cingulate cortex and the positive symptom score on Brief Psychiatric Rating Scale.. The lower BP values indicate fewer D2 receptors in the anterior cingulate cortex in patients with schizophrenia. Alterations in D2 receptor function in the extrastriatal region may underlie the positive symptoms of schizophrenia.

Topics: Adult; Brain Mapping; Dopamine Antagonists; Gyrus Cinguli; Humans; Male; Psychiatric Status Rating Scales; Pyrrolidines; Receptors, Dopamine D2; Reference Values; Salicylamides; Schizophrenia; Schizophrenic Psychology; Tomography, Emission-Computed

Topics: Artifacts; Brain Mapping; Dopamine Antagonists; Gyrus Cinguli; Humans; Pyrrolidines; Receptors, Dopamine D2; Reproducibility of Results; Salicylamides; Schizophrenia; Tomography, Emission-Computed

Amisulpride, a substituted benzamide with high affinity for dopamine D2 and D3 receptors only, has been reported to have therapeutic effects on both negative and positive schizophrenic symptoms, although at distinct dose ranges (50-300 mg/day vs. 400-1,200 mg/day). The purpose of this study was to investigate the binding of amisulpride to extrastriatal (i.e., thalamus and temporal cortex) and striatal D2 dopamine receptors with respect to plasma amisulpride determinations. Ten patients with schizophrenia treated with amisulpride over a wide range of doses (25-1,200 mg/day) were studied. Positron emission tomography images were acquired by using 76Br-FLB-457, a highly specific antagonist of the D2 and D3 dopamine receptors. Binding indexes (BI) in the regions studied were estimated with reference to values from six healthy subjects. A curvilinear relationship was demonstrated between plasma concentration of amisulpride and the BI in extrastriatal regions. The BI also varied as a function of plasma concentration in striatum. Furthermore, the data provide evidence for different binding profiles: low plasma concentrations (28-92 ng/mL) induced marked extrastriatal binding and low striatal binding, whereas higher plasma concentrations (>153 ng/mL) induced marked binding both in extrastriatal and striatal regions. Dose-dependent differential binding profiles of amisulpride to D2 receptors in extrastriatal and striatal regions were demonstrated, and two therapeutic ranges of plasma concentrations for negative and positive schizophrenic symptoms, respectively, are suggested.

Topics: Adult; Amisulpride; Antipsychotic Agents; Corpus Striatum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Middle Aged; Pyrrolidines; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Statistics, Nonparametric; Sulpiride; Temporal Lobe; Thalamus; Tomography, Emission-Computed

The authors' goal was to test the hypothesis of extrastriatal D(2) receptor selectivity as the mechanism of action of clozapine.. Positron emission tomography (PET) was used to examine extrastriatal as well as striatal dopamine D(2) receptor occupancy in four patients treated with clozapine and three patients treated with haloperidol. The reference radioligand [(11)C]raclopride was used for determination of D(2) receptor occupancy in the striatum. The radioligand [(11)C]FLB 457 was chosen for determination of D(2) receptor occupancy in the thalamus, the temporal cortex, and the frontal cortex.. In patients treated with haloperidol the D(2) receptor occupancy was high in all examined brain regions. In clozapine-treated patients the D(2) receptor occupancy was relatively low in both the striatum and the extrastriatal regions.. The results from the present study give no support for the hypothesis of regional selectivity as the mechanism of action for clozapine.

Topics: Adult; Antipsychotic Agents; Brain; Clozapine; Corpus Striatum; Female; Haloperidol; Humans; Male; Middle Aged; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenia, Paranoid; Tomography, Emission-Computed