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1.
Nature ; 604(7906): 509-516, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35396579

RESUMO

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.


Assuntos
Mutação , Transtornos do Neurodesenvolvimento , Esquizofrenia , Estudos de Casos e Controles , Exoma , Predisposição Genética para Doença/genética , Humanos , Transtornos do Neurodesenvolvimento/genética , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética
2.
Am J Med Genet B Neuropsychiatr Genet ; 171(4): 495-505, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26183902

RESUMO

Advanced paternal age (APA) is a risk factor for schizophrenia (Sz) and bipolar disorder (BP). Putative mechanisms include heritable genetic factors, de novo mutations, and epigenetic mechanisms. Few studies have explored phenotypic features associated with APA. The Genomic Psychiatry Cohort established a clinically characterized repository of genomic samples from subjects with a Sz-BP diagnosis or unaffected controls, 12,975 with parental age information. We estimated relative risk ratios for Sz, schizoaffective depressed and bipolar types (SA-D, SA-B), and BP with and without history of psychotic features (PF) relative to the control group, comparing each paternal age group to the reference group 20-24 years. All tests were two-sided with adjustment for multiple comparisons. Subjects with fathers age 45+ had significantly higher risk for all diagnoses except for BP w/o PF. APA also bore no significant relation to family psychiatric history. In conclusion, we replicated APA as a risk factor for Sz. To our knowledge, this is the first published report of APA in a BP sample stratified by psychosis history, extending this association only in BP w/PF. This suggests that phenotypic expression of the APA effect in Sz-BP spectrum is psychosis, per se, rather than other aspects of these complex disorders. The lack of a significant relationship between paternal age and familial disease patterns suggests that underlying mechanisms of the paternal age effect may involve a complex interaction of heritable and non-heritable factors. The authors discuss implications and testable hypotheses, starting with a focus on genetic mechanisms and endophenotypic expressions of dopaminergic function. © 2015 Wiley Periodicals, Inc.


Assuntos
Transtorno Bipolar/genética , Herança Paterna/genética , Transtornos Psicóticos/genética , Esquizofrenia/genética , Adulto , Fatores Etários , Transtorno Bipolar/metabolismo , Transtorno Bipolar/psicologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Idade Paterna , Transtornos Psicóticos/metabolismo , Transtornos Psicóticos/psicologia , Fatores de Risco , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Adulto Jovem
3.
Am J Med Genet B Neuropsychiatr Genet ; 171(4): 513-20, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26224136

RESUMO

A schizophrenia phenotype for paternal and maternal age effects on illness risk could benefit etiological research. As odor sensitivity is associated with variability in symptoms and cognition in schizophrenia, we examined if it was related to parental ages in patients and healthy controls. We tested Leukocyte Telomere Length (LTL) as an explanatory factor, as LTL is associated with paternal age and schizophrenia risk. Seventy-five DSM-IV patients and 46 controls were assessed for detection of PEA, WAIS-III for cognition, and LTL, assessed by qPCR. In healthy controls, but not schizophrenia patients, decreasing sensitivity was monotonically related to advancing parental ages, particularly in sons. The relationships between parental aging and odor sensitivity differed significantly for patients and controls (Fisher's R to Z: χ(2) = 6.95, P = 0.009). The groups also differed in the association of odor sensitivity with cognition; lesser sensitivity robustly predicted cognitive impairments in patients (<0.001), but these were unassociated in controls. LTL was unrelated to odor sensitivity and did not explain the association of lesser sensitivity with cognitive deficits.Parental aging predicted less sensitive detection in healthy subjects but not in schizophrenia patients. In patients, decreased odor sensitivity strongly predicted cognitive deficits, whereas more sensitive acuity was associated with older parents. These data support separate risk pathways for schizophrenia. A parental age-related pathway may produce psychosis without impairing cognition and odor sensitivity. Diminished odor sensitivity may furthermore be useful as a biomarker for research and treatment studies in schizophrenia. © 2015 Wiley Periodicals, Inc.


Assuntos
Pais , Esquizofrenia/fisiopatologia , Adulto , Estudos de Casos e Controles , Transtornos Cognitivos/psicologia , Feminino , Humanos , Leucócitos/fisiologia , Masculino , Idade Materna , Odorantes , Percepção Olfatória/fisiologia , Idade Paterna , Transtornos Psicóticos/genética , Transtornos Psicóticos/metabolismo , Fatores de Risco , Esquizofrenia/genética , Esquizofrenia/metabolismo , Olfato/fisiologia , Telômero/genética
4.
Am J Med Genet B Neuropsychiatr Genet ; 162B(4): 306-12, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23650244

RESUMO

The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants.


Assuntos
Genoma Humano , Transtornos Mentais/genética , Adulto , Estudos de Coortes , Confidencialidade , Feminino , Seguimentos , Humanos , Masculino , Transtornos Mentais/diagnóstico , Inquéritos e Questionários
5.
J Steroid Biochem Mol Biol ; 231: 106329, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37182752

RESUMO

Many controversies exist regarding vitamin D3 supplementation. These include not only diseases that are responsive to vitamin D supplementation, but also the long-term safety of prolonged daily oral vitamin D3 intake above 4000-10,000 International Units (IU). In particular, supplementation levels that do not result in adverse events, and the upper limits of safe serum 25-hydroxyvitamin D (25OHD) concentrations. Adverse reactions reported to occur with excessive vitamin D intake include hypercalcemia, renal failure, calcium crystal formation, undetectable parathyroid hormone concentrations, and hypercalciuria, all of which are reported to be reversible. To address the long-term safety of vitamin D supplementation, we previously reported data from patients in our hospital who have been voluntarily supplemented with vitamin D3 ranging from 5,000 to 10,000 IU/day since July 2011 as a standard of care for the prevention and treatment of vitamin D deficiency. Historically 90% of patients have agreed to daily supplementation, with most taking 10,000 IU/day. These data indicate no evidence for hypercalcemia, renal failure, calcium crystal formation, nephrolithiasis. or undetectable parathyroid hormone concentrations in patients taking 5000 or 10,000 IU/day for extended periods of time. As another measure for potential vitamin D toxicity, we retrospectively assessed 24-hour urine calcium excretion in 14 individuals on long-term daily oral vitamin D intake ranging from 5000 to 50,000 IU/day to further assess the safety of supplementation using these doses. This included patients taking either 5000 (4), 10,000 (9), or 50,000 (1) IU/day. Time on supplementation ranged from 10 to 102 months. A patient taking 400 IU/day and getting frequent sun exposure was also included. All fifteen 24-hour urine calcium measurements were normal. The current findings complement our experience with over 7000 patients in the past 13 years, indicating that prolonged daily oral intake of vitamin D3 ranging from 5000 to 10,000 IU/day is safe.


Assuntos
Hipercalcemia , Insuficiência Renal , Deficiência de Vitamina D , Humanos , Adulto , Cálcio , Estudos Retrospectivos , Vitamina D , Vitaminas , Colecalciferol , Suplementos Nutricionais , Hormônio Paratireóideo , Cálcio da Dieta , Insuficiência Renal/induzido quimicamente , Insuficiência Renal/tratamento farmacológico
6.
Psychiatry Res Neuroimaging ; 320: 111428, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34954446

RESUMO

Diminished prefrontal function, dopaminergic abnormalities in the striatum and thalamus, reductions in white matter integrity and frontotemporal gray matter deficits are the most replicated findings in schizophrenia. We used four imaging modalities (18F-fluorodeoxyglucose and 18F-fallypride PET, diffusion tensor imaging, structural MRI) in 19 healthy and 25 schizophrenia subjects to assess the relationship between functional (dopamine D2/D3 receptor binding potential, glucose metabolic rate) and structural (fractional anisotropy, MRI) correlates of schizophrenia and their additive diagnostic prediction potential. Multivariate ANOVA was used to compare structural and functional image sets for identification of schizophrenia. Integration of data from all four modalities yielded better predictive power than less inclusive combinations, specifically in the thalamus, left dorsolateral prefrontal and temporal regions. Among the modalities, fractional anisotropy showed highest discrimination in white matter whereas 18F-fallypride binding showed highest discrimination in gray matter. Structural and functional modalities displayed comparable discriminative power but different topography, with higher sensitivity of structural modalities in the left prefrontal region. Combination of functional and structural imaging modalities with inclusion of both gray and white matter appears most effective in diagnostic discrimination. The highest sensitivity of 18F-fallypride PET to gray matter changes in schizophrenia supports the primacy of dopaminergic abnormalities in its pathophysiology.


Assuntos
Fluordesoxiglucose F18 , Esquizofrenia , Benzamidas , Imagem de Tensor de Difusão , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Esquizofrenia/diagnóstico
7.
Brain Lang ; 223: 105046, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34763166

RESUMO

Reading impairments are prominent trait-like features of cognitive deficits in schizophrenia, predictive of overall cognitive functioning and presumably linked to dopaminergic abnormalities. To evaluate this, we used 18F-fallypride PET in 19 healthy and 21 antipsychotic-naïve schizophrenia subjects and correlated dopamine receptor binding potentials in relevant AFNI-derived regions and voxelwise with group performance on WRAT4 single-word reading subtest. Healthy subjects' scores were positively and linearly associated with D2/D3 receptor availability in the rectus, orbital and superior frontal gyri, fusiform and middle temporal gyri, as well as middle occipital gyrus and precuneus, all predominantly in the left hemisphere and previously implicated in reading, hence suggesting that higher dopamine receptor density is cognitively advantageous. This relationship was weakened in schizophrenia subjects and in contrast to healthy participants followed an inverted U-shaped curve both in the cortex and dorsal striatum, indicating restricted optimal range of dopamine D2/D3 receptor availability for cognitive performance in schizophrenia.


Assuntos
Esquizofrenia , Cognição , Dopamina , Humanos , Tomografia por Emissão de Pósitrons , Leitura , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo
8.
Law Hum Behav ; 34(5): 402-17, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19771499

RESUMO

This study asked whether latent class modeling methods and multiple ratings of the same cases might permit quantification of the accuracy of forensic assessments. Five evaluators examined 156 redacted court reports concerning criminal defendants who had undergone hospitalization for evaluation or restoration of their adjudicative competence. Evaluators rated each defendant's Dusky-defined competence to stand trial on a five-point scale as well as each defendant's understanding of, appreciation of, and reasoning about criminal proceedings. Having multiple ratings per defendant made it possible to estimate accuracy parameters using maximum likelihood and Bayesian approaches, despite the absence of any "gold standard" for the defendants' true competence status. Evaluators appeared to be very accurate, though this finding should be viewed with caution.


Assuntos
Erros de Diagnóstico/prevenção & controle , Psiquiatria Legal/normas , Competência Mental/psicologia , Adulto , Teorema de Bayes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Estados Unidos
9.
Brain Imaging Behav ; 14(3): 736-752, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30523488

RESUMO

Dopaminergic dysfunction and changes in white matter integrity are among the most replicated findings in schizophrenia. A modulating role of dopamine in myelin formation has been proposed in animal models and healthy human brain, but has not yet been systematically explored in schizophrenia. We used diffusion tensor imaging and 18F-fallypride positron emission tomography in 19 healthy and 25 schizophrenia subjects to assess the relationship between gray matter dopamine D2/D3 receptor density and white matter fractional anisotropy in each diagnostic group. AFNI regions of interest were acquired for 42 cortical Brodmann areas and subcortical gray matter structures as well as stereotaxically placed in representative white matter areas implicated in schizophrenia neuroimaging literature. Welch's t-test with permutation-based p value adjustment was used to compare means of z-transformed correlations between fractional anisotropy and 18F-fallypride binding potentials in hypothesis-driven regions of interest in the diagnostic groups. Healthy subjects displayed an extensive pattern of predominantly negative correlations between 18F-fallypride binding across a range of cortical and subcortical gray matter regions and fractional anisotropy in rostral white matter regions (internal capsule, frontal lobe, anterior corpus callosum). These patterns were disrupted in subjects with schizophrenia, who displayed significantly weaker overall correlations as well as comparatively scant numbers of significant correlations with the internal capsule and frontal (but not temporal) white matter, especially for dopamine receptor density in thalamic nuclei. Dopamine D2/D3 receptor density and white matter integrity appear to be interrelated, and their decreases in schizophrenia may stem from hyperdopaminergia with dysregulation of dopaminergic impact on axonal myelination.


Assuntos
Esquizofrenia , Animais , Anisotropia , Benzamidas , Encéfalo/diagnóstico por imagem , Imagem de Tensor de Difusão , Dopamina , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Esquizofrenia/diagnóstico por imagem
10.
World J Biol Psychiatry ; 21(5): 368-382, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31552783

RESUMO

Objectives: Overlapping decreases in extrastriatal dopamine D2/D3-receptor availability and glucose metabolism have been reported in subjects with schizophrenia. It remains unknown whether these findings are physiologically related or coincidental.Methods: To ascertain this, we used two consecutive 18F-fluorodeoxyglucose and 18F-fallypride positron emission tomography scans in 19 healthy and 25 unmedicated schizophrenia subjects. Matrices of correlations between 18F-fluorodeoxyglucose uptake and 18F-fallypride binding in voxels at the same xyz location and AFNI-generated regions of interest were evaluated in both diagnostic groups.Results:18F-fluorodeoxyglucose uptake and 18F-fallypride binding potential were predominantly positively correlated across the striatal and extrastriatal grey matter in both healthy and schizophrenia subjects. In comparison to healthy subjects, significantly weaker correlations in subjects with schizophrenia were confirmed in the right cingulate gyrus and thalamus, including the mediodorsal, lateral dorsal, anterior, and midline nuclei. Schizophrenia subjects showed decreased D2/D3-receptor availability in the hypothalamus, mamillary bodies, thalamus and several thalamic nuclei, and increased glucose uptake in three lobules of the cerebellar vermis.Conclusions: Dopaminergic system may be involved in modulation of grey matter metabolism and neurometabolic coupling in both healthy human brain and psychopathology. Hyperdopaminergic state in untreated schizophrenia may at least partly account for the corresponding decreases in grey matter metabolism.


Assuntos
Fluordesoxiglucose F18 , Esquizofrenia , Benzamidas , Dopamina , Radioisótopos de Flúor , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Humanos , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/diagnóstico por imagem
11.
Psychiatry Res Neuroimaging ; 299: 111060, 2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32135405

RESUMO

Decreased fractional anisotropy and increased glucose utilization in the white matter have been reported in schizophrenia. These findings may be indicative of an inverse relationship between these measures of white matter integrity and metabolism. We used 18F-fluorodeoxyglucose positron emission tomography and diffusion-tensor imaging in 19 healthy and 25 schizophrenia subjects to assess and compare coterritorial correlation patterns between glucose utilization and fractional anisotropy on a voxel-by-voxel basis and across a range of automatically placed representative white matter regions of interest. We found a pattern of predominantly negative correlations between white matter metabolism and fractional anisotropy in both healthy and schizophrenia subjects. The overall strength of the relationship was attenuated in subjects with schizophrenia, who displayed significantly fewer and weaker correlations in all regions assessed with the exception of the corpus callosum. This attenuation was most prominent in the left prefrontal white matter and this region also best predicted the diagnosis of schizophrenia. There exists an inverse relationship between the measures of white matter integrity and metabolism, which may therefore be physiologically linked. In subjects with schizophrenia, hypermetabolism in the white matter may be a function of lower white matter integrity, with lower efficiency and increased energetic cost of task-related computations.


Assuntos
Imagem de Tensor de Difusão , Glucose/metabolismo , Esquizofrenia/fisiopatologia , Substância Branca/fisiopatologia , Anisotropia , Corpo Caloso/fisiopatologia , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Adulto Jovem
12.
Schizophr Bull ; 35(2): 383-402, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19011234

RESUMO

Psychiatric comorbidities are common among patients with schizophrenia. Substance abuse comorbidity predominates. Anxiety and depressive symptoms are also very common throughout the course of illness, with an estimated prevalence of 15% for panic disorder, 29% for posttraumatic stress disorder, and 23% for obsessive-compulsive disorder. It is estimated that comorbid depression occurs in 50% of patients, and perhaps (conservatively) 47% of patients also have a lifetime diagnosis of comorbid substance abuse. This article chronicles these associations, examining whether these comorbidities are "more than chance" and might represent (distinct) phenotypes of schizophrenia. Among the anxiety disorders, the evidence at present is most abundant for an association with obsessive-compulsive disorder. Additional studies in newly diagnosed antipsychotic-naive patients and their first-degree relatives and searches for genetic and environmental risk factors are needed to replicate preliminary findings and further investigate these associations.


Assuntos
Transtornos Cognitivos/epidemiologia , Transtornos Mentais/epidemiologia , Esquizofrenia/epidemiologia , Transtornos Cognitivos/fisiopatologia , Comorbidade , Transtorno Depressivo/epidemiologia , Humanos , Transtorno Obsessivo-Compulsivo/epidemiologia , Transtorno de Pânico/epidemiologia , Prevalência , Escalas de Graduação Psiquiátrica , Fatores de Risco , Esquizofrenia/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Terminologia como Assunto
13.
J Steroid Biochem Mol Biol ; 189: 228-239, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611908

RESUMO

Vitamin D3 is a secosteroid hormone produced in the skin in amounts estimated up to 25,000 international units (IUs) a day by the action of UVB radiation on 7-dehydrocholesterol. Vitamin D deficiency is common due to both lack of adequate sun exposure to the skin, and because vitamin D is present in very few food sources. Deficiency is strongly linked to increased risk for a multitude of diseases, several of which have historically been shown to improve dramatically with either adequate UVB exposure to the skin, or to oral or topical supplementation with vitamin D. These diseases include asthma, psoriasis, rheumatoid arthritis, rickets and tuberculosis. All patients in our hospital have been routinely screened on admission for vitamin D deficiency since July 2011, and offered supplementation to either correct or prevent deficiency. During this time, we have admitted over 4700 patients, the vast majority of whom agreed to supplementation with either 5000 or 10,000 IUs/day. Due to disease concerns, a few agreed to larger amounts, ranging from 20,000 to 50,000 IUs/day. There have been no cases of vitamin D3 induced hypercalcemia or any adverse events attributable to vitamin D3 supplementation in any patient. Three patients with psoriasis showed marked clinical improvement in their skin using 20,000 to 50,000 IUs/day. Analysis of 777 recently tested patients (new and long-term) not on D3 revealed 28.7% with 25-hydroxyvitaminD3 (25OHD3) blood levels < 20 ng/ml, 64.1% < 30 ng/ml, a mean 25OHD3 level of 27.1 ng/ml, with a range from 4.9 to 74.8 ng/ml. Analysis of 418 inpatients on D3 long enough to develop 25OHD3 blood levels > 74.4 ng/ml showed a mean 25OHD3 level of 118.9 ng/ml, with a range from 74.4 to 384.8 ng/ml. The average serum calcium level in these 2 groups was 9.5 (no D3) vs 9.6 (D3), with ranges of 8.4 to 10.7 (no D3) vs 8.6 to 10.7 mg/dl (D3), after excluding patients with other causes of hypercalcemia. The average intact parathyroid hormone levels were 24.2 pg/ml (D3) vs. 30.2 pg/ml (no D3). In summary, long-term supplementation with vitamin D3 in doses ranging from 5000 to 50,000 IUs/day appears to be safe.


Assuntos
Colecalciferol/administração & dosagem , Vitaminas/administração & dosagem , Adulto , Idoso , Colecalciferol/efeitos adversos , Colecalciferol/sangue , Colecalciferol/uso terapêutico , Feminino , Hospitalização , Humanos , Hipercalcemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/prevenção & controle , Vitaminas/efeitos adversos , Vitaminas/sangue , Vitaminas/uso terapêutico , Adulto Jovem
14.
Biol Psychiatry ; 86(2): 110-119, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-30686506

RESUMO

BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.


Assuntos
Transtorno Bipolar/genética , Variações do Número de Cópias de DNA/genética , Transtornos Psicóticos/genética , Transtorno Bipolar/psicologia , Estudos de Casos e Controles , Estudos de Coortes , Duplicação Gênica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Transtornos Psicóticos/psicologia , Esquizofrenia/genética
15.
J Steroid Biochem Mol Biol ; 177: 21-29, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28756294

RESUMO

Tuberculosis remains an epidemic throughout the world, with over 2 billion people, or more than one third of the world's population, infected with TB. In 2015, there were an estimated 10.4 million new cases of tuberculosis, and 1.8 million deaths, making TB one of the top ten causes of death worldwide. Approximately 95% of new TB cases occur in developing countries, where the costs of treatment force many patients and their families into poverty. The United Nations and the World Health Organization are working to end this global epidemic. Historically, cod liver oil in the 1840's, phototherapy in the 1890's, sunshine in the 1890's and 1930's, oral vitamin D in doses of 100,000-150,000 international units a day the 1940's, and injectable vitamin D in the 1940's were all shown to be able to safely treat tuberculosis. However, for reasons that are unclear, these treatments are no longer being used to treat tuberculosis. We will review several reports that documented the clinical efficacy of these seemingly disparate treatments in treating tuberculosis. Taken together, however, these reports show the consistent efficacy of vitamin D in treating tuberculosis infections, regardless of whether the vitamin D was produced in the skin from the effects of phototherapy or sunshine, taken orally as a pill or in cod-liver oil, or put into solution and injected directly into the body. We will discuss how vitamin D, through its action as a steroid hormone that regulates gene transcription in cells and tissues throughout the body, enables the body to eradicate TB by stimulating the formation of a natural antibiotic in white blood cells, the mechanism of which was discovered in 2006. We will speculate as to why vitamin D, cod liver oil, sunshine, and phototherapy are no longer being used to treat tuberculosis, in spite of their proven efficacy in safely treating this disease dating back to the early 1800's. In fact, in 1903 the Nobel Prize in Medicine or Physiology was awarded to a physician who was able to cure hundreds of cases of long-standing lupus vulgaris (cutaneous TB) with refracted light rays from an electric arc lamp. Vitamin D, cod liver oil, sunshine, and phototherapy have never been shown to lose their ability to safely eradicate tuberculosis infections, and deserve consideration to be re-examined as first-line treatments for tuberculosis. These treatments have the potential to help cost-effectively and safely end the global TB epidemic.


Assuntos
Óleo de Fígado de Bacalhau/uso terapêutico , Fototerapia , Tuberculose/terapia , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Animais , Humanos , Luz Solar
16.
Psychiatry Res ; 259: 251-253, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29091824

RESUMO

WHODAS-2.0 is a suggested replacement to the GAF in DSM-5. This study's purpose was to assess their comparative correlation in adults with schizophrenia spectrum disorder. 42 individuals with a diagnosis of schizophrenia or schizoaffective disorder were administered both tools and the PANSS. Pearson product moment correlations were computed and the different methods compared using bootstrap. There was no significant correlation between raw WHODAS-2.0 and GAF scores for all participants and a modest correlation between corrected WHODAS-2.0 and GAF scores for outpatients. The WHODAS-2.0 and GAF did not correlate when WHODAS-2.0 was self-rated, and only modestly correlated when clinician-rater corrected.


Assuntos
Avaliação da Deficiência , Escalas de Graduação Psiquiátrica/normas , Transtornos Psicóticos/diagnóstico , Esquizofrenia/diagnóstico , Adulto , Interpretação Estatística de Dados , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Organização Mundial da Saúde
17.
Schizophr Res ; 192: 442-456, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28576546

RESUMO

Converging evidence indicates that the prefrontal cortex is critically involved in executive control and that executive dysfunction is implicated in schizophrenia. Reduced dopamine D2/D3 receptor binding potential has been reported in schizophrenia, and the correlations with neuropsychological test scores have been positive and negative for different tasks. The aim of this study was to examine the relation between dopamine D2/D3 receptor levels with frontal and temporal neurocognitive performance in schizophrenia. Resting-state 18F-fallypride positron emission tomography was performed on 20 medication-naïve and 5 previously medicated for brief earlier periods patients with schizophrenia and 19 age- and sex-matched healthy volunteers. Striatal and extra-striatal dopamine D2/D3 receptor levels were quantified as binding potential using fallypride imaging. Magnetic resonance images in standard Talairach position and segmented into gray and white matter were co-registered to the fallypride images, and the AFNI stereotaxic atlas was applied. Two neuropsychological tasks known to activate frontal and temporal lobe function were chosen, specifically the Wisconsin Card Sorting Test (WCST) and the California Verbal Learning Test (CVLT). Images of the correlation coefficient between fallypride binding and WCST and CVLT performance showed a negative correlation in contrast to positive correlations in healthy volunteers. The results of this study demonstrate that lower fallypride binding potential in patients with schizophrenia may be associated with better performance. Our findings are consistent with previous studies that failed to find cognitive improvements with typical dopamine-blocking medications.


Assuntos
Encéfalo/metabolismo , Função Executiva , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/metabolismo , Psicologia do Esquizofrênico , Adulto , Benzamidas , Encéfalo/diagnóstico por imagem , Função Executiva/fisiologia , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Descanso , Esquizofrenia/diagnóstico por imagem
18.
Schizophr Res ; 85(1-3): 232-44, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16713185

RESUMO

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Benzamidas , Córtex Cerebral , Radioisótopos de Flúor , Pirrolidinas , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/efeitos dos fármacos , Receptores de Dopamina D3/metabolismo , Esquizofrenia , Tálamo , Adulto , Benzamidas/farmacocinética , Sítios de Ligação/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Feminino , Radioisótopos de Flúor/farmacocinética , Humanos , Masculino , Modelos Biológicos , Tomografia por Emissão de Pósitrons , Pirrolidinas/farmacocinética , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Tálamo/efeitos dos fármacos , Tálamo/metabolismo , Tálamo/fisiopatologia
19.
Am J Psychiatry ; 162(5): 931-8, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15863795

RESUMO

OBJECTIVE: Because neuroleptic treatment may cause long-lasting changes in brain structure and function, a group of patients with schizophrenia who had never been medicated was recruited to examine regional glucose metabolic rates in the frontal-striato-thalamic circuit. METHOD: Twelve never medicated patients with schizophrenia (seven men, five women; mean age=29 years) and 13 normal volunteers (eight men and five women; mean age=28.5 years) underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography, and coregistered anatomical magnetic resonance imaging scans were also obtained. During FDG uptake, subjects performed a spatial attention task previously shown to activate the pulvinar region of the thalamus. RESULTS: Diminished regional glucose metabolism was found in the medial dorsal nucleus, posterior thalamus, and prefrontal cortex of patients with schizophrenia relative to normal volunteers, extending earlier results from studies of medicated and previously medicated patients. CONCLUSIONS: The finding of lower relative metabolic rates in the frontothalamic circuits of patients with schizophrenia is consistent with extended circuit deficits involving interactions of frontal executive areas with thalamic sensory and association processes.


Assuntos
Glucose/metabolismo , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Córtex Pré-Frontal/metabolismo , Esquizofrenia/diagnóstico , Tálamo/metabolismo , Adulto , Atenção/fisiologia , Corpo Estriado/metabolismo , Feminino , Fluordesoxiglucose F18 , Percepção de Forma/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/metabolismo , Desempenho Psicomotor/fisiologia , Pulvinar/metabolismo , Esquizofrenia/metabolismo , Análise e Desempenho de Tarefas
20.
Innov Clin Neurosci ; 11(5-6): 10-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-25152841

RESUMO

OBJECTIVE: Poor insight is a cardinal symptom of schizophrenia that, while not universally and uniformly expressed in all patients, is among the most common of its manifestations. Available neurobiological and neurocognitive evidence linking the phenomenon to core pathophysiology of schizophrenia justifies extension of the anosognosia construct to schizophrenia-related insight deficits. Poor insight is a core attribute of schizophrenia, occurring in 57 to 98 percent of patients. Insight is an important outcome predictor, associated with treatment adherence, relapse frequency, symptom remission, psychosocial functioning, vocational attainment, and risk of violence toward self or others. Combined findings lend urgency to the importance of reducing psychotic relapse. This can only be achieved in the majority of patients with consistent medication adherence- something that is often exceedingly difficult in patients lacking belief in the fact of their illness. This article examines whether anosognosia, the unawareness of deficit or illness, should apply to our understanding of insight deficits in patients with schizophrenia. Although research in the field is limited at this time, there is hope that anosognosia as a symptom of schizophrenia will become a focus of further research and a critically important therapeutic target amenable to treatment. DESIGN: This article is a literature review and conceptualization. CONCLUSION: Limited research in the field gives cause for hope that anosognosia as a symptom of schizophrenia will become a critically important therapeutic target that is amendable to treatment.

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