Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial.

INTRODUCTION: Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma. METHODS: ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure. CONCLUSIONS: ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

NR3C1 and NR3C2 Genes Increase the Risk of Suicide Attempt in Psychiatric Disorder Patients with History of Childhood Trauma.

Background: Hypothalamic-pituitary-adrenal axis gene variants and childhood trauma (CT) are considered risk factors for suicide attempt (SA). The aim of the present study was analyzed gene x environment (GxE) interaction of NR3C1, NR3C2, and CT, and NR3C1 and NR3C2 gene expression in the development of SA with CT. Participants and Methods: A total of 516 psychiatric Mexican patients from Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. Among them, 274 had SA at least once and 242 had not SA. Genetic variants of NR3C1 and NR3C2 were genotyped in all the patients, of which were obtained the CT information from medical records. Additionally, the gene expression of NR3C1 and NR3C2 was also analyzed for a subsample of 96 patients, obtaining the TC information from Childhood Trauma Questionnaire (CTQ). Results: The analysis showed a GxE interaction of NR3C1, NR3C2, and CT (OR=2.8, 95% CI [1.9-3.9], p<0.0001). Interactions were also observed with neglect (OR=2.1, 95% CI [1.4-3.1], p<0.0001), emotional abuse (OR=2.1, 95% CI [1.5-3], p<0.0001), and sexual abuse (OR=2.4, 95% CI [1.4-2.9], p<0.0001) in the prediction of SA. The analysis of gene expression identified an overexpression of NR3C1 in SA patients with high scores for physical and sexual abuse (p<0.0001; p<0.0006, respectively) and emotional neglect (p=0.014). An underexpression was observed of NR3C2, associated with high scores of trauma subtypes (p<0.0001) except physical neglect. Additionally, we observed an overexpression of NR3C1 gene in patients with SA carriers of A allele of rs6191 (p=0.0015). Also, overexpression of NR3C1 gene in carriers of G allele of rs6198 and underexpression of NR3C2 gene in carriers of G allele of rs5522 (p<0.0001). Conclusion: Our findings suggest that genetic variants of NR3C1 and NR3C2 differentially affect expression levels, increasing the susceptibility to SA in psychiatric patients with a history of CT.

Looking for factors affecting functioning in euthymic patients with bipolar I disorder: the importance of cognitive complaints and BDNF's Val66Met polymorphism.

INTRODUCTION: Functioning in Bipolar Disorder (BD) is affected in a substantial proportion of patients. The impact of demographic, clinical, cognitive, and genetic factors on functioning has been shown individually; however, as a complex phenomenon, a global approach to identify the most relevant as well as possible interactions is needed. METHODS: 102 patients with type I BD in euthymia were invited for evaluation of demographic, clinical, and cognitive characteristics as well as genotype for Val66Met polymorphism of BDNF gene to determine those associated with poor functioning according to the FAST scale cut-off score. Clinical evaluation included assessment of residual affective symptoms and anxiety. Cognitive evaluation included the COBRA scale, verbal memory, and executive functions testing. RESULTS: Residual depressive symptoms, anxiety, cognitive complaints and being a Met carrier were more frequent in the poor functioning group and were entered in a logistic regression model. Being a Met carrier (OR=4.46, CI=1.19-16.67) and cognitive complaints (OR=1.29, CI= 1.13-1.46) were the most important predictors of poor functioning in type I BD. LIMITATIONS: Cross-sectional study, with select population limiting generalizability of findings. CONCLUSIONS: A better understanding of underlying factors affecting cognition, including the possible involvement of BDNF Val66Met polymorphism, its systematic evaluation and a continued search for targeted treatment, along with recognition and attention of residual affective and anxious symptoms might improve psychosocial outcomes such as functioning in this population.

Prefrontal cortical thickness and clinical characteristics of long-term treatment response to valproate in bipolar disorder.

Valproate compositions are frequently used to treat bipolar disorder (BD); however, 87% of patients do not report full response in the long-term. There is scarce information about the clinical features and brain structural characteristics of long-term treatment response (LTTR) to this medication. In this study, we aim to evaluate the clinical characteristics and prefrontal cortical thickness (CT) of LTTR to valproate in BD. We evaluated 30 BD outpatients on valproate treatment, and 20 controls with a 3T T1-weighted 3D brain scan and Alda's scale for LTTR. An analysis of covariance was used to evaluate CT measures and a logistic regression was conducted to predict the full response (FR) using clinical features and CT measures. Patients with an insufficient response (IR) reported thinner right frontal eye fields, anterior and dorsolateral prefrontal cortexes compared with controls. FR patients presented thicker right dorsolateral prefrontal cortex than IR and no differences with controls. Patients with mixed features presented increased odds of achieving FR, while CT measures reported non-significant results. This is the first study to report mixed features as a clinical predictor of valproate LTTR. Our findings also suggest better preservation of the right prefrontal cortex of subjects with FR to valproate.

Neuropsychiatric Genetics of Psychosis in the Mexican Population: A Genome-Wide Association Study Protocol for Schizophrenia, Schizoaffective, and Bipolar Disorder Patients and Controls.

No large-scale genome-wide association studies (GWASs) of psychosis have been conducted in Mexico or Latin America to date. Schizophrenia and bipolar disorder in particular have been found to be highly heritable and genetically influenced. However, understanding of the biological basis of psychosis in Latin American populations is limited as previous genomic studies have almost exclusively relied on participants of Northern European ancestry. With the goal of expanding knowledge on the genomic basis of psychotic disorders within the Mexican population, the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM), the Harvard T.H. Chan School of Public Health, and the Broad Institute's Stanley Center for Psychiatric Research launched the Neuropsychiatric Genetics Research of Psychosis in Mexican Populations (NeuroMex) project to collect and analyze case-control psychosis samples from 5 states across Mexico. This article describes the planned sample collection and GWAS protocol for the NeuroMex study. The 4-year study will span from April 2018 to 2022 and aims to recruit 9,208 participants: 4,604 cases and 4,604 controls. Study sites across Mexico were selected to ensure collected samples capture the genomic diversity within the Mexican population. Blood samples and phenotypic data will be collected during the participant interview process and will contribute to the development of a local biobank in Mexico. DNA extraction will be done locally and genetic analysis will take place at the Broad Institute in Cambridge, MA. We will collect extensive phenotypic information using several clinical scales. All study materials including phenotypic instruments utilized are openly available in Spanish and English. The described study represents a long-term collaboration of a number of institutions from across Mexico and the Boston area, including clinical psychiatrists, clinical researchers, computational biologists, and managers at the 3 collaborating institutions. The development of relevant data management, quality assurance, and analysis plans are the primary considerations in this protocol article. Extensive management and analysis processes were developed for both the phenotypic and genetic data collected. Capacity building, partnerships, and training between and among the collaborating institutions are intrinsic components to this study and its long-term success.

CACNA1C Risk Variant and Mood Stabilizers Effects in the Prefrontal Cortical Thickness of Mexican Patients with Bipolar Disorder.

PURPOSE: Bipolar disorder (BD) is a condition associated with structural alterations in the prefrontal cortex (PFC); some genetic variants and mood stabilizer medications like lithium or valproate are associated with these changes. CACNA1C is a gene involved in BD pathology and brain function; carriers of the A allele of rs1006737 are reported to have increased risk for BD and increased cortical thickness (CT) in the PFC compared to non-carriers. Lithium is also associated with increased CT in the PFC of BD subjects compared to the ones on valproate. The influence of these treatments and gene variants over the PFC structure of Mexican subjects has not been explored. Therefore, we evaluate the effects of mood stabilizers and risk A allele of CACNA1C rs1006737 on the prefrontal cortical thickness of Mexican BD patients treated with lithium or valproate. PATIENTS AND METHODS: A cross-sectional study of 40 BD type I euthymic adult outpatients (20 treated with lithium and 20 with valproate) who underwent a 3T T1-weighted 3D brain scan and genotyping for CACNA1C risk allele rs1006737 was conducted. We performed a cortical thickness analysis of the dorsolateral and orbitofrontal regions of the prefrontal cortex with BrainVoyager 20.6. The effects of treatment and gene variants were analyzed with a two-way multivariate analysis of covariance. RESULTS: There was no association of CACNA1C risk allele rs1006737 with CT measures of both PFCs nor significant interaction between the genetic variant and treatment. Mood stabilizers reported the main effect on the CT measures of the right PFC of our sample. Patients on treatment with lithium showed higher mean CT on the right orbitofrontal cortex. CONCLUSION: We did not find any association between the prefrontal CT and CACNA1C risk A allele rs1006737 in BD Mexican patients treated with lithium or valproate. Our results suggest that mood stabilizers had the main effect in the CT of the right PFC.