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1.
Am J Psychiatry ; : appiajp201919060583, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32046535

RESUMO

OBJECTIVE: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group. METHODS: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female). RESULTS: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. CONCLUSIONS: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31900526

RESUMO

Functional magnetic resonance imaging (fMRI) has been widely used to gain a greater understanding of brain circuitry abnormalities in CNS disorders. fMRI has also been used to examine pharmacological modulation of brain circuity and is increasingly being used in early clinical drug development as functional pharmacodynamic index of target engagement, and to provide early indication of clinical efficacy. In this short review, we summarize data from experimental medicine and early clinical development studies of a mu-opioid receptor antagonist, GSK1521498 developed for disorders of compulsive consumption including binge eating in obesity. We demonstrate how fMRI can be used to answer important questions of early clinical drug development relating to; (1) target engagement, (2) dose response relationships, (3) differential efficacy and (4) prediction of behavioural and clinically relevant outcomes. We also highlight important methodological factors that need to be considered when conducting fMRI studies in drug development given the challenges faced with small sample sizes in Phase 1 and early proof of mechanism studies. While these data highlight the value of fMRI as a biomarker in drug development, its use for making Go/No-go decisions is still faced with challenges given the variability of responses, interpretation of brain activation changes and the limited data linking drug induced changes in brain activity to clinical or behavioural outcome. These challenges need to be addressed to fulfil the promise of fMRI as a tool in clinical drug development.

3.
Drug Discov Today ; 24(12): 2307-2314, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31499186

RESUMO

Cholinergic dysfunction is involved in a range of neurological and psychiatric disorders, including schizophrenia, dementia and Lewy body disease (LBD), leading to widespread use of cholinergic therapies. However, such drugs have focused on increasing the availability of acetylcholine (ACh) generally, with relatively little work done on the muscarinic system and specific muscarinic receptor subtypes. In this review, we provide an overview of the major cholinergic pathways and cholinergic muscarinic receptors in the human brain and evidence for their dysfunction in several neurological and psychiatric disorders. We discuss how the selectivity of cholinergic system dysfunction suggests that targeted cholinergic therapeutics to the muscarinic receptor subtypes will be vital in treating several disorders associated with cognitive dysfunction and behavioural and psychological symptoms.

4.
Mol Psychiatry ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358905

RESUMO

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.

5.
Psychiatry Res Neuroimaging ; 290: 5-13, 2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31252222

RESUMO

An increasing number of studies implicate the muscarinic cholinergic system in cognitive dysfunction associated with psychosis. This study examined the effect of muscarinic M1 receptor modulation on anterior cingulate cortex (ACC) and striatal choline concentrations and the relation with cognitive performance, as well as functional connectivity of cognitive networks. Thirty medication-free subjects with a psychosis spectrum disorder and 30 gender, age and IQ-matched healthy control subjects underwent 1H-proton magnetic resonance spectroscopy (1H-MRS) twice, once after placebo and once after a single dose of biperiden (M1 receptor antagonist, 4 mg). A subset of 19 psychotic subjects and 28 controls underwent resting-state functional magnetic resonance imaging (rs-fMRI) as well. No significant differences were found in ACC and striatal choline levels, nor in functional connectivity, between the two groups after placebo. Moreover, M1 antagonism did not significantly affect choline levels or functional connectivity. No correlations were found between choline levels and cognition as well as psychotic symptoms. Our findings do not support an association between the cholinergic system and cognition and psychotic symptoms. However, the lack of group differences in choline concentrations and functional connectivity, both after biperiden and placebo, may indicate that there were no severe cholinergic abnormalities present in our sample.

6.
Mol Psychiatry ; 2018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29895892

RESUMO

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

7.
Neuroimage Clin ; 18: 713-719, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29560312

RESUMO

Background: It is still unclear which underlying mechanisms are involved in cognitive deficits of psychotic disorders. Pro-cognitive effects of muscarinic M1 receptor agonists suggest alterations in M1 receptor functioning may modulate these symptoms. Post mortem studies in patients with schizophrenia have shown significantly reduced M1 receptor expression rates in the dorsolateral prefrontal cortex (DLPFC) compared to controls. To date no in-vivo examinations of M1 receptor binding in relation to cognitive impairments have been done. As cognitive deficits have similar course and prognostic relevance across psychotic disorders, the current study assessed M1 receptor binding in the DLPFC and hippocampus in relation to cognitive functioning. Methods: Muscarinic M1 receptor binding potential (BPND) was measured using 123I-IDEX, single photon emission computed tomography (SPECT) in 30 medication-free subjects diagnosed with a psychotic disorder. A computerized neuropsychological test battery was used to assess cognition, and the positive and negative syndrome scale (PANSS) to assess severity of psychotic symptoms. Results: Assessment of cognitive domains showed that lower M1 BPND in the DLPFC was related to overall lower performance in verbal learning and memory. In addition, lower M1 BPND in the DLPFC was related to greater negative symptom severity. Lastly, lower M1 BPND in the hippocampus was related to worse delayed recognition of verbal memory. Conclusion: This is the first study to show that variation in M1 receptors in the DLPFC is related to cognitive and negative symptom outcome in psychotic disorders. The M1 receptor may be an important biomarker in biological stratification of patients with psychotic disorders.


Assuntos
Cognição/fisiologia , Hipocampo/diagnóstico por imagem , Transtornos Psicóticos/diagnóstico por imagem , Receptor Muscarínico M1/metabolismo , Adulto , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Testes Neuropsicológicos , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/psicologia , Tomografia Computadorizada de Emissão de Fóton Único , Adulto Jovem
8.
Psychiatry Res Neuroimaging ; 272: 65-70, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29174435

RESUMO

Striatal dopamine (DA) dysfunction has been consistently reported in psychotic disorders. Differences and similarities in the pathogenesis between populations at clinical and genetic risk for developing psychosis are yet to be established. Here we explored markers of dopamine (DA) function in subjects meeting clinically ultra-high risk criteria for psychosis (UHR) and in subjects with 22q11.2 deletion syndrome (22q11DS), a genetic condition associated with significant risk for developing psychotic disorders. Single Photon Emission Computed Tomography (SPECT) with 123I-labelled iodobenzamide ([123I]IBZM) was used to measure striatal DA D2/3 receptor binding potential (D2R BPND). Also, peripheral DAergic markers were assessed in serum and urine (plasma prolactin (pPRL), plasma homovanillic acid (pHVA) and urine DA(uDA)). No significant difference in striatal D2R BPND was found between UHR and 22q11DS subjects. Compared to UHR subjects, pPRL and pHVA were lower and uDA levels were higher in the 22q11DS subjects. However, after correcting for age and gender, only pPRL as significantly lower in the 22q11DS patients. These results may suggest that there are differences in DAergic markers between subjects with UHR and with 22q11DS that may reflect differences in the pathways to psychosis. However, bigger samples are needed to replicate these findings.


Assuntos
Corpo Estriado/metabolismo , Síndrome de DiGeorge/metabolismo , Dopamina/urina , Transtornos Psicóticos/metabolismo , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Casos e Controles , Síndrome de DiGeorge/diagnóstico por imagem , Síndrome de DiGeorge/psicologia , Feminino , Ácido Homovanílico/sangue , Humanos , Masculino , Prolactina/sangue , Transtornos Psicóticos/diagnóstico por imagem , Transtornos Psicóticos/genética , Fatores de Risco , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto Jovem
9.
Eur Neuropsychopharmacol ; 27(9): 854-864, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28689687

RESUMO

The acetylcholine muscarinic M1 receptor has been implicated in both psychosis and cognition. Post-mortem research has shown reduced muscarinic M1 receptor density in 25% of chronic patients with schizophrenia. It is unknown whether reduced M1 receptor density is related to cognitive symptoms of psychosis. We investigated the role of the M1 receptor in separate cognitive domains in subjects with a psychotic disorder using a muscarinic M1 antagonist as an acute pharmacological challenge. 33 young subjects with a psychotic disorder and 30 gender, age and IQ matched healthy controls were enrolled. All participants completed a comprehensive cognitive test battery twice: once after placebo and once after oral administration of 4mg. biperiden (M1 antagonist). The order of drug administration was counterbalanced. Biperiden significantly negatively influenced both verbal (p< 0.001 and p=0.032) and visual learning and memory (p=0.028) in both groups. A medication x group interaction effect was found for reasoning and problem solving (p=0.005). No main or interaction effects were found for other cognitive domains. These results provide further in-vivo evidence that the M1 receptor is involved in cognitive functioning, particularly verbal and visual memory processes. Lack of differential effects of biperiden between psychotic subjects and healthy controls may suggest that decreased M1 receptor density is only present in chronic, older schizophrenia patients. However, it remains possible that differential effects of biperiden would be present in more severe cognitive impaired subjects with psychosis after several doses of biperiden instead of a single administration.


Assuntos
Biperideno/uso terapêutico , Cognição/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Nootrópicos/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Administração Oral , Adulto , Cognição/fisiologia , Estudos Cross-Over , Feminino , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Testes Neuropsicológicos , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/psicologia , Receptor Muscarínico M1/antagonistas & inibidores , Receptor Muscarínico M1/metabolismo , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Método Simples-Cego , Pensamento/efeitos dos fármacos , Pensamento/fisiologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia
10.
PLoS One ; 11(11): e0159928, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27828960

RESUMO

INTRODUCTION: Subjects with 22q11.2 deletion syndrome (22q11DS) and subjects with ultra-high risk for psychosis (UHR) share a risk of approximately 30% to develop a psychotic disorder. Studying these groups helps identify biological markers of pathophysiological processes involved in the development of psychosis. Total cortical surface area (cSA), total cortical grey matter volume (cGMV), cortical thickness (CT), and local gyrification index (LGI) of the cortical structure have a distinct neurodevelopmental origin making them important target markers to study in relation to the development of psychosis. MATERIALS AND METHODS: Structural T1-weighted high resolution images were acquired using a 3 Tesla Intera MRI system in 18 UHR subjects, 18 22q11DS subjects, and 24 matched healthy control (HC) subjects. Total cSA, total cGMV, mean CT, and regional vertex-wise differences in CT and LGI were assessed using FreeSurfer software. The Positive and Negative Syndrome Scale was used to assess psychotic symptom severity in UHR and 22q11DS subjects at time of scanning. RESULTS: 22q11DS subjects had lower total cSA and total cGMV compared to UHR and HC subjects. The 22q11DS subjects showed bilateral lower LGI in the i) prefrontal cortex, ii) precuneus, iii) precentral gyrus and iv) cuneus compared to UHR subjects. Additionally, lower LGI was found in the left i) fusiform gyrus and right i) pars opercularis, ii) superior, and iii) inferior temporal gyrus in 22q11DS subjects compared to HC. In comparison to 22q11DS subjects, the UHR subjects had lower CT of the insula. For both risk groups, positive symptom severity was negatively correlated to rostral middle frontal gyrus CT. CONCLUSION: A shared negative correlation between positive symptom severity and rostral middle frontal gyrus CT in UHR and 22q11DS may be related to their increased vulnerability to develop a psychotic disorder. 22q11DS subjects were characterised by widespread lower degree of cortical gyrification linked to early and postnatal neurodevelopmental pathology. No implications for early neurodevelopmental pathology were found for the UHR subjects, although they did have distinctively lower insula CT which may have arisen from defective pruning processes during adolescence. Implications of these findings in relation to development of psychotic disorders are in need of further investigation in longitudinal studies.


Assuntos
Córtex Cerebral/patologia , Síndrome de DiGeorge/patologia , Lobo Frontal/patologia , Substância Cinzenta/patologia , Transtornos Psicóticos/patologia , Adulto , Mapeamento Encefálico , Córtex Cerebral/diagnóstico por imagem , Síndrome de DiGeorge/diagnóstico por imagem , Feminino , Lobo Frontal/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Humanos , Modelos Lineares , Imagem por Ressonância Magnética , Masculino , Transtornos Psicóticos/diagnóstico por imagem , Medição de Risco , Fatores de Risco , Tomografia Computadorizada por Raios X , Adulto Jovem
11.
J Nucl Med ; 56(2): 317-22, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25593117

RESUMO

UNLABELLED: The muscarinic M1 receptor (M1R) is highly involved in cognition, and selective M1 agonists have procognitive properties. Loss of M1R has been found in postmortem brain tissue for several neuropsychiatric disorders and may be related to symptoms of cognitive dysfunction. (123)I-iododexetimide is used for imaging muscarinic acetylcholine receptors (mAchRs). Considering its high brain uptake and intense binding in M1R-rich brain areas, (123)I-iododexetimide may be an attractive radiopharmaceutical to image M1R. To date, the binding affinity and selectivity of (123)I-iododexetimide for the mAchR subtypes has not been characterized, nor has its brain distribution been studied intensively. Therefore, this study aimed to address these topics. METHODS: The in vitro affinity and selectivity of (127)I-iododexetimide (cold-labeled iododexetimide), as well as its functional antagonist properties (guanosine 5'-[γ-(35)S-thio]triphosphate [GTPγ(35)S] assay), were assessed on recombinant human M1R-M5R. Distributions of (127)I-iododexetimide and (123)I-iododexetimide in the brain were evaluated using liquid chromatography-mass spectrometry and storage phosphor imaging, respectively, ex vivo in rats, wild-type mice, and M1-M5 knock-out (KO) mice. Inhibition of (127)I-iododexetimide and (123)I-iododexetimide binding in M1R-rich brain areas by the M1R/M4R agonist xanomeline, or the antipsychotics olanzapine (M1R antagonist) and haloperidol (low M1R affinity), was assessed in rats ex vivo. RESULTS: In vitro, (127)I-iododexetimide displayed high affinity for M1R (pM range), with modest selectivity over other mAchRs. In biodistribution studies on rats, ex vivo (127)I-iododexetimide binding was much higher in M1R-rich brain areas, such as the cortex and striatum, than in cerebellum (devoid of M1Rs). In M1 KO mice, but not M2-M5 KO mice, (127)I-iododexetimide binding was strongly reduced in the frontal cortex compared with wild-type mice. Finally, acute administration of both an M1R/M4R agonist xanomeline and the M1R antagonist olanzapine was able to inhibit (123)I-iododexetimide ex vivo, and (123)I-iododexetimide binding in M1-rich brain areas in rats, whereas administration of haloperidol had no effect. CONCLUSION: The current results suggest that (123)I-iododexetimide preferentially binds to M1R in vivo and can be displaced by M1R ligands. (123)I-iododexetimide may therefore be a useful imaging tool as a way to further evaluate M1R changes in neuropsychiatric disorders, as a potential stratifying biomarker, or as a clinical target engagement biomarker to assess M1R.


Assuntos
Dexetimida/análogos & derivados , Radioisótopos do Iodo , Receptores Muscarínicos/metabolismo , Animais , Ligação Competitiva , Biomarcadores , Cromatografia Líquida , Cognição , Dexetimida/química , Humanos , Ligantes , Masculino , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M1 , Proteínas Recombinantes/metabolismo , Espectrometria de Massas em Tandem , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único
12.
Front Psychiatry ; 4: 157, 2013 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-24363646

RESUMO

Schizophrenia is a disabling, chronic psychiatric disorder with a prevalence rate of 0.5-1% in the general population. Symptoms include positive (e.g., delusions, hallucinations), negative (e.g., blunted affect, social withdrawal), as well as cognitive symptoms (e.g., memory and attention problems). Although 75-85% of patients with schizophrenia report cognitive impairments, the underlying neuropharmacological mechanisms are not well understood and currently no effective treatment is available for these impairments. This has led to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, which established seven cognitive domains that are fundamentally impaired in schizophrenia. These domains include verbal learning and memory, visual learning and memory, working memory, attention and vigilance, processing speed, reasoning and problem solving, and social cognition. Recently, a growing number of studies have been conducted trying to identify the underlying neuropharmacological mechanisms of cognitive impairments in schizophrenia patients. Specific cognitive impairments seem to arise from different underlying neuropharmacological mechanisms. However, most review articles describe cognition in general and an overview of the mechanisms involved in these seven separate cognitive domains is currently lacking. Therefore, we reviewed the underlying neuropharmacological mechanisms focusing on the domains as established by the MATRICS initiative which are considered most crucial in schizophrenia.

13.
Eur Neuropsychopharmacol ; 23(11): 1577-86, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23978392

RESUMO

BACKGROUND: The brain reward circuitry innervated by dopamine is critically disturbed in schizophrenia. This study aims to investigate the role of dopamine-related brain activity during prediction of monetary reward and loss in first episode schizophrenia patients. METHODS: We measured blood-oxygen-level dependent (BOLD) activity in 10 patients with schizophrenia (SCH) and 12 healthy controls during dopamine depletion with α-methylparatyrosine (AMPT) and during a placebo condition (PLA). RESULTS: AMPT reduced the activation of striatal and cortical brain regions in SCH. In SCH vs. controls reduced activation was found in the AMPT condition in several regions during anticipation of reward and loss, including areas of the striatum and frontal cortex. In SCH vs. controls reduced activation of the superior temporal gyrus and posterior cingulate was observed in PLA during anticipation of rewarding stimuli. PLA patients had reduced activation in the ventral striatum, frontal and cingulate cortex in anticipation of loss. The findings of reduced dopamine-related brain activity during AMPT were verified by reduced levels of dopamine in urine, homovanillic-acid in plasma and increased prolactin levels. CONCLUSIONS: Our results indicate that dopamine depletion affects functioning of the cortico-striatal reward circuitry in SCH. The findings also suggest that neuronal functions associated with dopamine neurotransmission and attribution of salience to reward predicting stimuli are altered in schizophrenia.


Assuntos
Encéfalo/fisiopatologia , Dopamina/deficiência , Dopamina/metabolismo , Recompensa , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , alfa-Metiltirosina/farmacologia , Adulto , Antecipação Psicológica/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Mapeamento Encefálico , Dopamina/urina , Método Duplo-Cego , Ácido Homovanílico/sangue , Humanos , Imagem por Ressonância Magnética , Masculino , Placebos , Prolactina/sangue , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
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