n-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2-3-dimethoxybenzamide and Schizophrenia

OBJECTIVE/INTRODUCTION: Lurasidone is an atypical antipsychotic medication approved for the treatment of schizophrenia over a dose range of 40-160 mg/day. This study examined D2 receptor occupancy and its association with clinical improvement and side effects in patients with schizophrenia or schizoaffective disorder following repeated doses of 80, 120, or 160 mg/day of lurasidone.. Twenty-five patients with The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnoses of schizophrenia or schizoaffective disorder were washed out of their antipsychotic medications (5 half-lives) and randomly assigned to 80, 120, or 160 mg/day of lurasidone. Subjects were imaged with 18F-fallypride at baseline and at steady-state lurasidone treatment to determine D2 receptor occupancy.. Blood lurasidone concentration (plus major metabolite), but not dose, significantly correlated with D2 receptor occupancy. D2 receptor occupancy in several subcortical structures is associated with positive but not negative symptom improvement or the presence of movement symptoms.. Blood concentrations greater than 70 ng/mL may be required to achieve a 65% occupancy level in subcortical areas. Intersubject blood concentrations at fixed dose were highly variable and may account for the lack of dose correlations.. Positron emission tomography (PET) occupancy data suggest that greater than 65% occupancy can be achieved across the dose range of 80-160 mg/day and that some patients require higher doses to achieve antipsychotic efficacy; this finding supports prior randomized clinical trial results.

Topics: Adult; Algorithms; Antipsychotic Agents; Benzamides; Brain; Dose-Response Relationship, Drug; Female; Humans; Isoindoles; Lurasidone Hydrochloride; Male; Middle Aged; Positron-Emission Tomography; Psychiatric Status Rating Scales; Psychotic Disorders; Pyrrolidines; Receptors, Dopamine D2; Schizophrenia; Statistics as Topic; Thiazoles; Young Adult

Combining measurements of the monoamine metabolites in the cerebrospinal fluid (CSF) and neuroimaging can increase efficiency of drug discovery for treatment of brain disorders. To address this question, we examined five drug-naïve patients suffering from schizophrenic disorder. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS): at baseline and then at weekly intervals. Plasma and CSF levels of quetiapine and norquetiapine as well CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were obtained at baseline and again after at least a 4 week medication trail with 600 mg/day quetiapine. CSF monoamine metabolites levels were compared with dopamine D(2) receptor occupancy (DA-D(2)) using [(18)F]fallypride and positron emission tomography (PET). Quetiapine produced preferential occupancy of parietal cortex vs. putamenal DA-D(2), 41.4% (p<0.05, corrected for multiple comparisons). DA-D(2) receptor occupancies in the occipital and parietal cortex were correlated with CSF quetiapine and norquetiapine levels (p<0.01 and p<0.05, respectively). CSF monoamine metabolites were significantly increased after treatment and correlated with regional receptor occupancies in the putamen [DOPAC: (p<0.01) and HVA: (p<0.05)], caudate nucleus [HVA: (p<0.01)], thalamus [MHPG: (p<0.05)] and in the temporal cortex [HVA: (p<0.05) and 5-HIAA: (p<0.05)]. This suggests that CSF monoamine metabolites levels reflect the effects of quetiapine treatment on neurotransmitters in vivo and indicates that monitoring plasma and CSF quetiapine and norquetiapine levels may be of clinical relevance.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adult; Antipsychotic Agents; Benzamides; Biogenic Monoamines; Brain Mapping; Dibenzothiazepines; Fluorine Radioisotopes; Homovanillic Acid; Humans; Magnetic Resonance Imaging; Male; Methoxyhydroxyphenylglycol; Middle Aged; Pilot Projects; Positron-Emission Tomography; Protein Binding; Pyrrolidines; Quetiapine Fumarate; Receptors, Dopamine D2; Schizophrenia; Tritium; Young Adult

To elucidate the "atypicality" of ziprasidone, its striatal and extrastriatal D2/D3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. [F]fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel [C]raclopride-PET study, striatal D2/D3-receptor occupancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol. Ziprasidone plasma concentrations correlated significantly with D2/D3-receptor occupancies in all volumes of interests. Occupancy in extrastriatal regions was approximately 10% higher than in striatal regions. Half maximal effective concentration values were consistently higher in striatal than in extrastriatal regions (temporal cortex: 39 ng/mL; putamen: 64 ng/mL), irrespective of the time between last dosing and scan. Single ziprasidone doses resulted in higher occupancies exceeding the 95% prediction limits of the occupancy versus plasma concentrations for chronic dosing. Ziprasidone shares moderate preferential extrastriatal D2/D3-receptor binding with some other atypicals. D2/D3-receptor occupancy is rapidly attuning to the daily course of ziprasidone plasma levels, suggesting relatively high intraday variations of D2/D3-receptor binding. The discrepancies between single-dose and steady-state results are important for the future design of dose-finding PET occupancy studies of novel antipsychotics. Single-dose studies may not be totally relied on for final dose selection.

Topics: Adult; Antipsychotic Agents; Basal Ganglia; Benzamides; Binding, Competitive; Carbon Radioisotopes; Dopamine Antagonists; Dose-Response Relationship, Drug; Female; Fluorine Radioisotopes; Humans; Male; Piperazines; Positron-Emission Tomography; Pyrrolidines; Raclopride; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Thiazoles; Time Factors; Young Adult

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

Topics: Adult; Antipsychotic Agents; Benzamides; Benzodiazepines; Brain Chemistry; Corpus Striatum; Dopamine Antagonists; Female; Haloperidol; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Olanzapine; Positron-Emission Tomography; Pyrimidinones; Pyrrolidines; Radiopharmaceuticals; Receptor, Serotonin, 5-HT2A; Receptors, Dopamine D3; Schizophrenia; Serotonin Antagonists

Topics: Adult; Benzamides; Brain; Executive Function; Female; Fluorine Radioisotopes; Humans; Male; Neuropsychological Tests; Positron-Emission Tomography; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3; Rest; Schizophrenia; Schizophrenic Psychology

The purpose of this study was to investigate the relationship between specific symptom severity and D

Topics: Adult; Antipsychotic Agents; Benzamides; Cerebral Cortex; Dopamine D2 Receptor Antagonists; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Positron-Emission Tomography; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Young Adult

A considerable body of research links cognitive function to dopaminergic transmission in the prefrontal cortex, but less is known about cognition in relation to striatal dopamine D. We investigated this association by obtaining PET recordings with the high-affinity D. The patients' performance in cognitive tests was significantly impaired in almost all domains. Irrespective of medication history, the mean [. The association between better cognitive performance and greater BP

Topics: Adolescent; Adult; Benzamides; Brain Mapping; Cognition; Corpus Striatum; Dopamine D2 Receptor Antagonists; Female; Humans; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Young Adult

In addition to probing regional differences in receptor availability, molecular positron emission tomography (PET) is proving useful for investigating perturbations in neurotransmitter networks using interregional correlation analyses. In a multi-modal imaging study, we examined interregional correlations of dopamine D

Topics: Adult; Antipsychotic Agents; Benzamides; Connectome; Corpus Striatum; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Pyrrolidines; Radiopharmaceuticals; Schizophrenia

Previous studies demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents have been suggested as a useful model of schizophrenia. This study was aimed to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [18F]fallypride as a radioligand to estimate the release in a rat model of schizophrenia. Six rats were scanned by positron emission tomography (PET) twice before and after methylphenidate challenge to evaluate dopamine release. After the scans, these rats were sensitized by using repeated methamphetamine (MAP) administration. Then, they were re-scanned twice again before and after methylphenidate challenge to evaluate whether MAP-sensitized rats show greater sensitivity to methylphenidate. We revealed a main effect of MAP-pretreatment and that of metylphenidate challenge. We found that % change of distribution volume ratio after repeated administration of MAP was greater than that before sensitization. These results suggest that methylphenidate-induced striatal dopamine release increased after sensitization to MAP. PET scan using [18F]fallypride at methylphenidate-challenge may provide a biological marker for schizophrenia and be useful to diagnose schizophrenia.

Topics: Animals; Benzamides; Biomarkers; Central Nervous System Stimulants; Corpus Striatum; Disease Models, Animal; Dopamine; Humans; Male; Methamphetamine; Methylphenidate; Positron-Emission Tomography; Rats; Receptors, Dopamine D2; Schizophrenia

Previous studies have demonstrated that patients with schizophrenia show greater sensitivity to psychostimulants than healthy subjects. Sensitization to psychostimulants and resultant alteration of dopaminergic neurotransmission in rodents has been suggested as a useful model of schizophrenia. This study sought to examine the use of methylphenidate as a psychostimulant to induce dopamine release and that of [(18)F]fallypride as a radioligand to quantify the release in a primate model of schizophrenia. Four common marmosets were scanned by positron emission tomography twice, before and after methylphenidate challenge, to evaluate dopamine release. Four other marmosets were sensitized by repeated methamphetamine (MAP) administration. Then, they were scanned twice, before and after methylphenidate challenge, to evaluate whether MAP-sensitization induced greater sensitivity to methylphenidate. We revealed a main effect of the methylphenidate challenge but not the MAP pretreatment on the striatal binding potential. These results suggest that methylphenidate-induced striatal dopamine release in the common marmoset could be evaluated by [(18)F]fallypride.

Topics: Animals; Benzamides; Brain; Callithrix; Central Nervous System Stimulants; Cerebellum; Corpus Striatum; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Fluorodeoxyglucose F18; Male; Methamphetamine; Methylphenidate; Positron-Emission Tomography; Prefrontal Cortex; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia

Quetiapine is next to clozapine an antipsychotic agent that exerts hardly any extrapyramidal side-effects at clinical efficacious doses. Some previous receptor occupancy studies reported preferential extrastriatal D2/3 receptor (D2/3R)-binding properties of second-generation antipsychotics and suggested this as possible reason for improved tolerability. This positron emission tomography (PET) investigation was designed to compare the occupancy of dopamine D2/3Rs by quetiapine in striatal and extrastriatal brain regions. Therefore, a cohort of 16 quetiapine-treated psychotic patients underwent an [18F]fallypride (FP) PET scan. Due to the high affinity of FP and its comparatively long half-life, striatal and extrastriatal binding potentials could be determined in one single scan. Receptor occupancy was calculated as percent reduction in binding potential relative to age-matched medication-free patients suffering from schizophrenia. Quetiapine occupied 44+/-18% in the temporal cortex and 26+/-17% in the putamen, a difference significant at the level of p=0.005 (Student's t test). Quetiapine showed a mean occupancy of 36+/-16% and in the thalamus. In the caudate nucleus there was an occupancy of 29+/-16% (p=0.0072). Individual occupancy levels did not exceed 59% in any of the striatal volumes of interest. The time-interval between scan and last drug ingestion did not influence the relationship between plasma concentration and central D2/3R occupancy. Taken together, quetiapine shows preferential extrastriatal binding at D2/3Rs; the extent of this difference is comparable to that previously described for clozapine. Both antipsychotics show very low affinity for D2/3Rs.

Topics: Adult; Antipsychotic Agents; Benzamides; Binding, Competitive; Corpus Striatum; Dibenzothiazepines; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Pyrrolidines; Quetiapine Fumarate; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Temporal Lobe; Visual Cortex; Young Adult

Molecular imaging of dopaminergic parameters has contributed to the dopamine hypothesis of schizophrenia, expanding our understanding of pathophysiology, clinical phenomenology and treatment. Our aim in this study was to compare (18)F-fallypride binding potential BP(ND) in a group of patients with schizophrenia-spectrum illness vs. controls, with a particular focus on the cortex and thalamus.. We acquired (18)F-fallypride positron emission tomography images on 33 patients with schizophrenia spectrum disorder (28 with schizophrenia; 5 with schizoaffective disorder) and 18 normal controls. Twenty-four patients were absolutely neuroleptic naïve and nine were previously medicated, although only four had a lifetime neuroleptic exposure of greater than two weeks. Parametric images of (18)F-fallypride BP(ND) were calculated to compare binding across subjects.. Decreased BP(ND) was observed in the medial dorsal nucleus of the thalamus, prefrontal cortex, lateral temporal lobe and primary auditory cortex. These findings were most marked in subjects who had never previously received medication.. The regions with decreased BP(ND) tend to match brain regions previously reported to show alterations in metabolic activity and blood flow and areas associated with the symptoms of schizophrenia.

Topics: Adolescent; Adult; Analysis of Variance; Benzamides; Brain; Brain Mapping; Case-Control Studies; Female; Fluorine Radioisotopes; Humans; Magnetic Resonance Imaging; Male; Positron-Emission Tomography; Protein Binding; Pyrrolidines; Schizophrenia; Statistics as Topic; Young Adult

Studies in schizophrenic patients have reported dopaminergic abnormalities in striatum, substantia nigra, thalamus, anterior cingulate, hippocampus, and cortex that have been related to positive symptoms and cognitive impairments.. [(18)F]fallypride positron emission tomography studies were performed in off-medication or never-medicated schizophrenic subjects (n = 11, 6 men, 5 women; mean age of 30.5 +/- 8.0 [SD] years; 4 drug-naive) and age-matched healthy subjects (n = 11, 5 men, 6 women, mean age of 31.6 +/- 9.2 [SD]) to examine dopamine D(2) receptor (DA D(2)r) levels in the caudate, putamen, ventral striatum, medial thalamus, posterior thalamus, substantia nigra, amygdala, temporal cortex, anterior cingulate, and hippocampus.. In schizophrenic subjects, increased DA D(2)r levels were seen in the substantia nigra bilaterally; decreased levels were seen in the left medial thalamus. Correlations of symptoms with ROI data demonstrated a significant correlation of disorganized thinking/nonparanoid delusions with the right temporal cortex ROI (r = .94, p = .0001), which remained significant after correction for multiple comparisons (p < .03). Correlations of symptoms with parametric images of DA D(2)r levels revealed no significant clusters of correlations with negative symptoms but significant clusters of positive correlations of total positive symptoms, delusions and bizarre behavior with the lateral and anterior temporal cortex, and hallucinations with the left ventral striatum.. The results of this study demonstrate abnormal DA D(2)r-mediated neurotransmission in the substantia nigra consistent with nigral dysfunction in schizophrenia and suggest that both temporal cortical and ventral striatal DA D(2)r mediate positive symptoms.

Topics: Adult; Benzamides; Brain Chemistry; Cerebral Cortex; Data Interpretation, Statistical; Female; Humans; Image Processing, Computer-Assisted; Limbic System; Magnetic Resonance Imaging; Male; Middle Aged; Neostriatum; Positron-Emission Tomography; Pyrrolidines; Radiopharmaceuticals; Receptors, Dopamine D2; Schizophrenia; Substantia Nigra; Thalamus; Young Adult

Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia.. Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole.. Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142).. Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzamides; Binding Sites; Brain; Female; Fluorine Radioisotopes; Humans; Male; Middle Aged; Piperazines; Positron-Emission Tomography; Pyrrolidines; Quinolones; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia

Positron emission tomography (PET) and the high affinity D(2/3) radiotracer [(18)F]fallypride allow the assessment of D(2/3) receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D(2) agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6+/-5.5% at 2 mg/day to 96.8+/-5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D(2) occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Benzamides; Binding, Competitive; Brain; Brain Chemistry; Cerebral Cortex; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Piperazines; Pituitary Gland; Positron-Emission Tomography; Pyrrolidines; Quinolones; Receptors, Dopamine D2; Schizophrenia; Young Adult

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p<0.005). While the maximum attainable receptor occupancy Emax approached 100% both in the striatum and cortex, the plasma concentration at 50% of Emax (ED50) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D2/D3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.

Topics: Adult; Antipsychotic Agents; Benzamides; Binding, Competitive; Clozapine; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Pyrrolidines; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Temporal Lobe

Abnormalities in the dopaminergic system are implicated in schizophrenia. [F-18]fallypride is a highly selective, high affinity PET ligand well suited for measuring D2/D3 receptor availability in the extrastriatal regions of the brain including thalamus, prefrontal, cingulate, and temporal cortex, brain regions implicated in schizophrenia with other imaging modalities.. Resting [F-18]fallypride PET studies were acquired together with anatomical MRI for accurate coregistration and image analysis on 15 drug naïve schizophrenics (10 men, 5 women, mean age 28.5 years) and 15 matched controls (9 men, 6 women, mean age 27.4 years). Dopamine D2/D3 receptor levels were measured as binding potential (BP). The fallypride BP images of each subject were spatially normalized and subsequently smoothed for group comparison. Measures of significance between the schizophrenic and control groups were determined using statistical parametric mapping (SPM). The medial dorsal nucleus and pulvinar were also traced on coregistered MRI for detailed assessment of BP in these regions.. The thalamus of patients with schizophrenia had lower [F-18]fallypride BP than normal controls and this was the brain area with the greatest difference (range -8.5% to -27.2%). Left medial dorsal nucleus and left pulvinar showed the greatest decreases (-21.6% and -27.2% respectively). The patients with schizophrenia also demonstrated D2/D3 BP reduction in the amygdala region, cingulate gyrus, and the temporal cortices.. These findings suggest that drug naïve patients with schizophrenia have significant reductions in extrastratial D2/D3 receptor availability. The reductions were most prominent in regions of the thalamus, replicating other studies both with high affinity D2/D3 ligands and consistent with FDG-PET studies, further supporting the hypothesis of thalamic abnormalities in this patient population.

Topics: Adult; Benzamides; Binding Sites; Cerebral Cortex; Female; Fluorine Radioisotopes; Humans; Male; Models, Biological; Positron-Emission Tomography; Pyrrolidines; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Thalamus

Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D2r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D2r using PET with [18F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D2r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D2r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D2r, 59.8% (p=0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p=0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D2r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D2r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D2r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D2r, sparing occupancy of substantia nigra receptors, and non-DA D2r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.

Topics: Adolescent; Adult; Antipsychotic Agents; Benzamides; Brain; Clozapine; Data Interpretation, Statistical; Dibenzothiazepines; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neostriatum; Positron-Emission Tomography; Pyrrolidines; Quetiapine Fumarate; Radiopharmaceuticals; Receptors, Dopamine D2; Schizophrenia