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1.
Artigo em Inglês | MEDLINE | ID: mdl-38296154

RESUMO

Current treatment for schizophrenia (SZ) ameliorates the positive symptoms, but is inefficient in treating the negative and cognitive symptoms. The SZ glutamatergic dysfunction hypothesis has opened new avenues in the development of novel drugs targeting the glutamate storm, an inducer of progressive neuropathological changes. Positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2), such as JNJ-46356479 (JNJ), reduce the presynaptic release of glutamate, which has previously been demonstrated to attenuate glutamate- and dopamine-induced apoptosis in human neuroblastoma cell cultures. We hypothesised that JNJ treatment would modify the brain levels of apoptotic proteins in a mouse model of ketamine (KET)-induced schizophrenia. We analysed the levels of proapoptotic (caspase-3 and Bax) and antiapoptotic (Bcl-2) proteins by western blot in the prefrontal cortex and hippocampus of JNJ-treated mice. JNJ attenuated apoptosis in the brain by partially restoring the levels of the antiapoptotic Bcl-2 protein, which is significantly reduced in animals exposed to KET. Additionally, a significant inverse correlation was observed between proapoptotic protein levels and behavioural deficits in the mice. Our findings suggest that JNJ may attenuate brain apoptosis in vivo, as previously described in cell cultures, providing a link between neuropathological deficits and SZ symptomatology.


Assuntos
Ketamina , Receptores de Glutamato Metabotrópico , Esquizofrenia , Humanos , Camundongos , Animais , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Encéfalo/metabolismo , Ketamina/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Glutamatos/metabolismo
2.
Psychiatry Res ; 332: 115722, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38198858

RESUMO

Genome-wide association studies (GWAS) have revealed the polygenic nature of treatment-resistant schizophrenia TRS. Gene expression imputation allowed the translation of GWAS results into regulatory mechanisms and the construction of gene expression (GReX) risk scores (GReX-RS).  In the present study we computed GReX-RS from the largest GWAS of TRS to assess its association with clinical features. We perform transcriptome imputation in the largest GWAS of TRS to find GReX associated with TRS using brain tissues. Then, for each tissue, we constructed a GReX-RS of the identified genes in a sample of 254 genotyped first episode of psychosis (FEP) patients to test its association with clinical phenotypes, including clinical symptomatology, global functioning and cognitive performance. Our analysis provides evidence that the polygenic basis of TRS includes genetic variants that modulate the expression of certain genes in certain brain areas (substantia nigra, hippocampus, amygdala and frontal cortex), which at the same time are related to clinical features in FEP patients, mainly persistence of negative symptoms and cognitive alterations in sustained attention, which have also been suggested as clinical predictors of TRS. Our results provide a clinical explanation of the polygenic architecture of TRS and give more insight into the biological mechanisms underlying TRS.


Assuntos
Transtornos Psicóticos , Esquizofrenia , Humanos , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Esquizofrenia Resistente ao Tratamento , Estudo de Associação Genômica Ampla , Transtornos Psicóticos/psicologia , Estratificação de Risco Genético , Expressão Gênica
3.
Eur Neuropsychopharmacol ; 81: 28-37, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38310718

RESUMO

Schizophrenia and bipolar disorder exhibit substantial clinical overlap, particularly in individuals at familial high risk, who frequently present sub-threshold symptoms before the onset of illness. Severe mental disorders are highly polygenic traits, but their impact on the stages preceding the manifestation of mental disorders remains relatively unexplored. Our study aimed to examine the influence of polygenic risk scores (PRS) on sub-clinical outcomes over a 2-year period in youth at familial high risk for schizophrenia and bipolar disorder and controls. The sample included 222 children and adolescents, comprising offspring of parents with schizophrenia (n = 38), bipolar disorder (n = 80), and community controls (n = 104). We calculated PRS for psychiatric disorders, neuroticism and cognition using the PRS-CS method. Linear mixed-effects models were employed to investigate the association between PRS and cognition, symptom severity and functioning. Mediation analyses were conducted to explore whether clinical features acted as intermediaries in the impact of PRS on functioning outcomes. SZoff exhibited elevated PRS for schizophrenia. In the entire sample, PRS for depression, neuroticism, and cognitive traits showed associations with sub-clinical features. The effect of PRS for neuroticism and general intelligence on functioning outcomes were mediated by cognition and symptoms severity, respectively. This study delves into the interplay among genetics, the emergence of sub-clinical symptoms and functioning outcomes, providing novel evidence on mechanisms underpinning the continuum from sub-threshold features to the onset of mental disorders. The findings underscore the interplay of genetics, cognition, and clinical features, providing insights for personalized early interventions.


Assuntos
Transtorno Bipolar , Esquizofrenia , Criança , Humanos , Adolescente , Estratificação de Risco Genético , Predisposição Genética para Doença/genética , Transtorno Bipolar/psicologia , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Cognição , Fatores de Risco
4.
Psychiatry Res ; 325: 115249, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37178502

RESUMO

Cannabis use is highly prevalent in first-episode psychosis (FEP) and plays a critical role in its onset and prognosis, but the genetic underpinnings promoting both conditions are poorly understood. Current treatment strategies for cannabis cessation in FEP are clearly inefficacious. Here, we aimed to characterize the association between cannabis-related polygenic risk scores (PRS) on cannabis use and clinical course after a FEP. A cohort of 249 FEP individuals were evaluated during 12 months. Symptom severity was measured with the Positive and Negative Severity Scale and cannabis use with the EuropASI scale. Individual PRS for lifetime cannabis initiation (PRSCI) and cannabis use disorder (PRSCUD) were constructed. Current cannabis use was associated with increased positive symptoms. Cannabis initiation at younger ages conditioned the 12-month symptom progression. FEP patients with higher cannabis PRSCUD reported increased baseline cannabis use. PRSCI was associated with the course of negative and general symptomatology over follow-up. Cannabis use and symptom progression after a FEP were modulated by cannabis PRS, suggesting that lifetime initiation and use disorders may have partially independent genetic factors. These exploratory results may be the first step to identify those FEP patients more vulnerable to cannabis use and worse outcomes to ultimately develop tailored treatments.


Assuntos
Cannabis , Transtornos Psicóticos , Humanos , Cannabis/efeitos adversos , Transtornos Psicóticos/genética , Transtornos Psicóticos/terapia , Fatores de Risco , Herança Multifatorial
5.
Eur Neuropsychopharmacol ; 75: 80-92, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37603902

RESUMO

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11-0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse.

6.
Schizophrenia (Heidelb) ; 8(1): 61, 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35869075

RESUMO

The main objective of the present study was to investigate the association between several epigenetic clocks, covering different aspects of aging, with schizophrenia relapse evaluated over a 3-year follow-up period in a cohort of ninety-one first-episode schizophrenia patients. Genome-wide DNA methylation was profiled and four epigenetic clocks, including epigenetic clocks of chronological age, mortality and telomere length were calculated. Patients that relapsed during the follow-up showed epigenetic acceleration of the telomere length clock (p = 0.030). Shorter telomere length was associated with cognitive performance (working memory, r = 0.31 p = 0.015; verbal fluency, r = 0.28 p = 0.028), but no direct effect of cognitive function or symptom severity on relapse was detected. The results of the present study suggest that epigenetic age acceleration could be involved in the clinical course of schizophrenia and could be a useful marker of relapse when measured in remission stages.

7.
Front Pharmacol ; 12: 729474, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34483940

RESUMO

Antipsychotics (APs) are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. This translational study aimed to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects. An integrative gene expression analysis was performed in four different mouse tissues (striatum, liver, pancreas and adipose) after risperidone or olanzapine treatment. The analytical approach combined the identification of the gene co-expression modules related to AP treatment, gene set enrichment analysis and protein-protein interaction network construction. We found several co-expression modules of genes involved in glucose and lipid homeostasis, hormone regulation and other processes related to metabolic impairment. Among these genes, EP300, which encodes an acetyltransferase involved in transcriptional regulation, was identified as the most important hub gene overlapping the networks of both APs. Then, we explored the genetically predicted EP300 expression levels in a cohort of 226 patients with first-episode psychosis who were being treated with APs to further assess the association of this gene with metabolic alterations. The EP300 expression levels were significantly associated with increases in body weight, body mass index, total cholesterol levels, low-density lipoprotein cholesterol levels and triglyceride concentrations after 6 months of AP treatment. Taken together, our analysis identified EP300 as a key gene in AP-induced metabolic abnormalities, indicating that the dysregulation of EP300 function could be important in the development of these side effects. However, more studies are needed to disentangle the role of this gene in the mechanism of action of APs.

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