Currently, genome editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR/Cas9), are predominantly used to model genetic diseases. This genome editing system can correct point or frameshift mutations in risk genes. Here, we analyze and discuss the advantages of genome editing, its current applications, and the feasibility of the CRISPR/Cas9 system in research on psychiatric disorders. These disorders produce cognitive and behavioral alterations and their etiology is associated with polygenetic and environmental factors. CRISPR/Cas9 may reveal the biological mechanisms of psychiatric disorders at a basic research level, translating a suitable clinical approach for use in the diagnosis and treatment of psychiatric disorders. Genetic diagnosis and treatment for these disorders have not yet been fully established in psychiatry due to the limited understanding of their heterogeneity and polygenicity. We discuss the challenges and ethical issues in using CRISPR/Cas9 as a tool for diagnosis or gene therapy.

Objective: Individuals with schizophrenia and substance use disorders have a poor prognosis and increased psychiatric symptoms. The present study aimed to explore the association of 106 genes in individuals with schizophrenia and comorbid substance use through a next-generation sequencing (NGS) analysis and different in silico algorithms. Methods: We included 105 individuals diagnosed with schizophrenia and a family history of schizophrenia, of whom 49 (46.67%) presented comorbid substance use. Using NGS, we sequenced 106 genes previously associated with schizophrenia. Logistic regression models were used to assess differences in allele frequencies, and a generalized gene-set analysis was performed at the gene level. Functional annotations were performed using different algorithms and databases. Results: We identified a total of 3,109 variants, of which 25 were associated with schizophrenia and comorbid substance use and were located in regulatory and coding regions. We found low-frequency variants in COMT p.Ala72Ser, independently of p.Val158Met, that were associated with substance use. The endocannabinoid functional variant FAAH p.Pro129Thr was also associated with substance use. Conclusions: Genetic variants of genes related to dopaminergic and cannabinoid neurotransmitter systems were associated with comorbid substance use in schizophrenia. Nevertheless, more studies with larger sample sizes are needed to confirm our findings.

SUMMARY Objective : To explore the perceived parental rearing behavior in adolescents diagnosed with an eating disorder, and to identify eventual differences with altered eating and self-injurious behaviors. Material and methods : A total of 45 adolescents diagnosed with some eating disorder (11 diagnosed with anorexia nervosa, 23 with bulimia nervosa and 11 with binge eating disorder), recruited from the outpatient and hospitalization areas of the Juan N Navarro Children's Psychiatric Hospital, were included. Results : It was found that the greater the memories of favoritism (r = 0.41, p-value = 0.005) or rejection (r = 0.36, p-value = 0.016) by the father, the higher the scores on the Eating Attitude Scale. Differences were also found in the mother's warmth dimension, between the adolescents who presented self-injuries (mean = 39.6, de = 11.3) and those who did not present them (mean = 47.4, de = 8.8) (t = -2.6, value p = 0.015). Conclusions : Adolescents with a diagnosis of eating disorders presented differences in their perception of parental rearing, a factor that may decisively influence the manifestation of other psychopathological behaviors.

RESUMEN Objetivo : Explorar las percepciones de crianza parental en adolescentes diagnosticados con algún trastorno de la conducta alimentaria, e identificar posibles diferencias con alteraciones de la conducta alimentaria y conductas autolesivas. Material y métodos : Un total de 45 adolescentes con algún tipo de trastorno de la conducta alimentaria (TCA) (11 diagnosticados con anorexia nervosa, 23 con bulimia nervosa y 11 con trastorno “por atracón”), pacientes en áreas de consulta externa y hospitalización del Hospital Psiquiátrico Infantil Juan N. Navarro fueron sistemáticamente estudiados. Resultados : Se encontró que cuánto mayores las percepciones de favoritismo (r = 0,41, valor p = 0,005) o rechazo (r = 0,36, valor p = 0,016) del padre, mayores fueron también los puntajes en la Escala de Actitudes Alimentarias. Se encontraron asimismo diferencias en la dimensión de calidez de la madre, entre los adolescentes que presentaron autolesiones (media = 39,6, d.e = 11,3) comparados con aquéllos que no las presentaron (media = 47,4, d.e = 8.8) (t = -2,6, valor p = 0,015). Conclusiones : Los adolescentes con diagnóstico de TCA presentaron diferencias en la percepción de crianza parental, factor que puede influenciar decisivamente la manifestación de otras conductas psicopatológicas.

Abstract Objective: To evaluate the progression by means of nuclear magnetic resonance of the lesion in the schizophrenia model of lesion of the ventral hippocampal nucleus (LVNH). Method: Magnetic resonance imaging (MRI) were performed in male Wistar rats, from 8 days postnatal to 139 days, in animals with LNHV and without lesion (sham). The MRI were carried out on a Variant 7 T equipment. The data were analyzed with the Amira software, for a voxel-based morphometric analysis. Results: We observed the presence of hypersignals with a significant enhancement in the structures analyzed in the group with LVNH, and greater volume in the lateral ventricles, presenting a larger size of the lesion on day PD96 and significantly reducing on day PD139. Conclusions: We found a cell rearrangement during the progression of the lesion, which could be the effect of the activation of immune cells.

Resumen Objetivo: Evaluar mediante resonancia magnética (RM) la progresión de la lesión en el modelo de esquizofrenia de lesión del núcleo del hipocampo ventral (LNHV). Método: Se realizaron RM en ratas Wistar macho, desde los 8 días posnatales hasta los 139 días, en animales con LNHV y sin lesión (sham). Las RM se realizaron con un equipo Variant de 7 T. Los datos se analizaron con el software Amira para un análisis de morfometría basada en vóxels. Resultados: Observamos hiperseñales con un realce significativo en las estructuras analizadas en el grupo con LNHV, y mayor volumen en los ventrículos laterales, presentando un mayor tamaño de la lesión el día PD96 y significativamente reducido en el día PD139. Conclusiones: Encontramos un reacomodo celular durante la progresión de la lesión, lo cual podría ser efecto de la activación de las células inmunitarias.

Abstract Background: Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes. Objective: The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides. Methods: Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database. Results: We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the non-suicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre- and post-natal developmental periods, according to BrainSpan database. Conclusions: The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms. (REV INVEST CLIN. 2020;72(5):283-92)

Abstract Introduction It has been hypothesized that pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) etiology results from an abnormal immune response to streptococcal infection. There is evidence that the serotonergic system is involved in both obsessive-compulsive disorder (OCD) physiopathology and immunological processes. In the 5’ promoter region of 5-HTT, gene encoding for the serotonin transporter we can find the 5-HTTLPR polymorphism that has been associated with OCD. Being PANDAS a disorder with OCD symptoms and likely immune abnormalities, 5-HTT polymorphisms may be particularly relevant for this disorder. Objective This study aimed to test the association between the 5-HT genotypes and the presence of serum antibodies in patients with PANDAS. Method We compared the genotype frequencies and serum anti-streptococcal, anti-neural, and anti-enolase antibodies titers between 56 patients with PANDAS and 20 healthy controls from Mexico and Cuba. Results Antibody titers were higher (anti-enolase, anti-streptococcal) in PANDAS patients compared to healthy controls. No differences in anti-neural antibody levels between both groups were detected. The anti-enolase and anti-neural antibody titer increased according to the polymorphism of the PANDAS patients as follows: LL >SL >SS. Discussion and conclusion This is the first study evaluating the association between the 5-HTTLPR genotypes and antibody titers in PANDAS patients. Associations between polymorphisms in serotonergic genes and immune response could provide valuable information about the interaction between both systems. Our results suggest an association between the S allele and elevated antibody levels in PANDAS patients.

Resumen Introducción Se ha hipotetizado que el trastorno pediátrico neuropsiquiátrico autoinmune asociado a estreptococo (PANDAS) es resultado de una respuesta inmune anormal a una infección estreptocócica. Existe evidencia de que el sistema serotoninérgico está involucrado tanto en la fisiopatología del trastorno obsesivo compulsivo (TOC) como en procesos inmunológicos. En la región promotora de 5-HTT, gen que codifica el transportador de serotonina, podemos encontrar el polimorfismo 5-HTTLPR que se ha asociado con el TOC. Siendo PANDAS un trastorno con síntomas de TOC y probables anormalidades inmunes, los polimorfismos de 5-HTT pueden ser relevantes en este trastorno. Objetivo Evaluar la asociación entre los genotipos de 5-HT y la presencia de anticuerpos séricos en pacientes con PANDAS. Método Comparamos la frecuencia de genotipos de 5-HT y los títulos de anticuerpos anti-estreptococo, antineurales y antienolasa en suero de 56 pacientes con PANDAS y 20 controles sanos de México y Cuba. Resultados Los títulos de anticuerpos antienolasa y antiestreptococo fueron mayores en pacientes con PANDAS en comparación con los controles. El título de anticuerpos antienolasa y antineural aumentó de acuerdo con el polimorfismo de los pacientes con PANDAS de la siguiente manera: LL >SL >SS. Discusión y conclusión Éste es el primer estudio que evalúa la asociación entre los genotipos de 5-HTTLPR y anticuerpos en pacientes con PANDAS. Las asociaciones entre polimorfismos de genes serotoninérgicos y la respuesta inmune podrían proporcionar información sobre la interacción entre ambos sistemas. Nuestros resultados sugieren una asociación entre el alelo S y niveles altos de anticuerpos en pacientes con PANDAS.

Abstract Introduction Risk factors for autism spectrum disorders (ASD) have been identified, as is the case of advanced parental age. Advanced parental age as an ASD risk factor has been studied in Scandinavian populations; there are no reports for Mexican children. Objective The present work aim is to analyze if advanced parental age is a risk factor for ASD in a Mexican children sample. Method Mexican children (N = 1 068) participated in a case-control study, 162 had an ASD diagnosis. Multivariate logistic regression adjusted by cofounders was performed to explore the effect of paternal age on ASD risk. Results Advanced paternal age in Mexican children increases the risk for ASD, and also, a difference of 10 years between parental ages have a higher risk. Discussion and conclusion The effect of advanced paternal age in Mexican children was lower than those reported previously for other populations. Advanced paternal age and difference between parental ages could be a risk factor for ASD in Mexican population. Nevertheless, the analysis of larger sample sizes is required.

Resumen Introducción Se han identificado algunos factores de riesgo para el trastorno del espectro autista (TEA) como es el caso de la edad parental avanzada. La edad parental avanzada es un factor de riesgo que ha sido muy explorado en poblaciones escandinavas; sin embargo, no existen reportes en niños de ascendencia mexicana. Objetivo El presente trabajo tiene el objetivo de analizar si la edad parental avanzada es un factor de riesgo para TEA en una muestra de niños mexicanos. Método Un total de 1 068 niños de la Ciudad de México se incluyeron en un estudio de casos-controles, de los cuáles 162 contaban con diagnóstico de TEA. Regresiones logísticas multivariable, ajustadas por confusores, se realizaron para explorar el efecto de la edad parental avanzada en el riesgo para TEA. Resultados La edad paterna avanzada en niños mexicanos aumentó el riesgo para TEA; también, una diferencia de edad de 10 años entre los padres presenta un mayor riesgo. Discusión y conclusión El efecto de la edad paterna avanzada en los niños mexicanos fue mucho más bajo que aquella reportada para otras poblaciones. La edad paterna avanzada y la diferencia entre la edad parental puede ser un factor de riesgo para TEA en población mexicana. Sin embargo, se requieren análisis en poblaciones con mayor tamaño de muestra.

Background Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). Methods We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. Results We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. Conclusions Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.

Abstract Background Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer’s type (DAT) or SCZ. Methods We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes. Results We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment. Discussion As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies.

Abstract: Introduction: The study of autistic spectrum disorders (ASD) at the genetic level is extremely important to understand their origin. In Mexico, there are few works addressed from this perspective. Objective: We investigated the role of the Brain Derived Neurotrophic Factor (BDNF) gene variant rs6265 G/A for single nucleotide polymorphism analysis in Mexican children with ASD using a case-control association design. Method: We made a pilot study by case-control analysis adjusting by gender, age, and ancestry. Results: Our study found no association between the BDNF rs6265 gene polymorphism and ASD [p = .419, OR = 1.597 (.514, 4.967)] Discussion and conclusion: Worldwide, the results of case-control association studies with the rs6265 of BDNF are controversial and do not always replicate. This may be due to the ethnicity of our population and additional factors not studied in the present work. Our study suggests that the SNP rs6265 is not contributing for ASD susceptibility in Mexican population.

Resumen: Introducción: El estudio de los trastornos del espectro autista a nivel genético es de suma importancia para entender su origen. En México existen pocos trabajos abordados desde esta perspectiva. Objetivo: Investigamos el papel de la variante del gen rs6265 G/A del factor neurotrófico derivado del cerebro (BDNF) para el análisis del polimorfismo de un solo nucleótido en niños mexicanos con TEA por medio de un diseño de asociación de casos y controles. Método: Realizamos un estudio piloto mediante un análisis de casos y controles ajustando por género, edad y ancestría. Resultados: Nuestro estudio no encontró asociación entre el polimorfismo del gen BDNF rs6265 y TEA [p = .419, OR = 1.597 (.514, 4.967)]. Discusión y conclusión: A nivel mundial, los resultados de estudios de asociación caso-control con el rs6265 de BDNF son controvertidos y no siempre se replican. Esto puede deberse a la etnicidad de nuestra población y a otros factores no estudiados en el presente trabajo. El estudio sugiere que el SNP rs6265 no contribuye a la susceptibilidad al TEA en población mexicana.

Resumen Los trastornos de la conducta alimentaria son un problema de salud pública. La etiología de la enfermedad es desconocida, pero se sugiere que tiene una base psiquiátrica, química y biológica. El objetivo de esta revisión es presentar evidencias de cómo la investigación genómica ha contribuido en el estudio de los trastornos de la conducta alimentaria y muestra la intensa investigación dirigida a conocer los genes que pudieran estar participando en la etiológica de los trastornos de la conducta alimentaria.

Abstract Eating behavior disorders are a public health issue. The etiology of these types of disorders is unknown, and they may have psychiatric, chemical and biological origins. The aim of this review is to present evidence that shows the contribution of genomic research in the study of eating behavior disorders. It also shows the considerable research that has been undertaken to identify the genes that may participate in the etiology of eating behavior disorders.

Summary: The potential for violence in a number of persons with mental illnesses stimulates public fear and prevents general acceptance of persons with psychiatric disabilities. Schizophrenia has been the diagnosis most often associated with violence as it has been taken as a paradigm of insanity, incompetence and dangerousness. Clinicians’ efforts to prevent violence through conventional external patient treatment are impede by several situational variables and patients become trapped in a costly cycle of repeated institutional admissions (revolving door phenomenon) in the most restrictive settings, going through involuntary in-patient treatment. The major hypothesis proposed in this review is that violence in schizophrenia can become a part of a self-perpetuating cycle, in which the combination of non-adherence to treatment and an inadequate management of illness from families and caregivers leads to violent behavior and deteriorated social relationships, finally resulting in institutional recidivism. As some of the initial symptoms of the illness, such as irritability and agitation may not be detected by the patient and his/her family, these symptoms eventually can easily escalate into open hostility, and the accompanying behavior is frequently violent. Disturbed moods secondary to psychotic symptoms, such as fear and anger apparently can also activate violent psychotic action. Accordingly, the path from the characteristics of the illness to violence leads to them through psychotic symptoms and lack of insight, and results in symptom-consistent violence. When psychotic symptoms and violent behavior cannot be managed by caregivers, patients are brought to the attention of psychiatric services and frequently admitted to patient service. During admission for a psychotic episode, there are more violent incidents than later on in the disease. As patients respond to medication and hospital environment, violent incidents and psychotic symptoms decrease in frequency and severity. After hospital discharge, patients may assume greater autonomy and control over several aspects of their daily lives. Nevertheless, this process may be hampered by familial reactions to the burden of living with a family member with schizophrenia. This burden can also be exacerbated because many patients have a history of violent behavior and families may experience negative attitudes towards them. In line with this, there is evidence of significant differences between the professionals’ perception about symptoms and illness, and that of the patient and his/her family. Sometimes, these different conceptions may reflect a lack of awareness regarding illness and treatment that may lead to discontinue medication. Medication suspension can lead to an eventual relapse which most obvious sign is the emergence of positive psychotic symptoms. Nevertheless if a patient has a past history of violent behavior, it is very likely that these behaviors will appear during relapse and it may be necessary to consider hospitalization. Although treatment with antipsychotics may be useful when violence is secondary to psychotic symptoms, violence might be indirectly reduced through clinical programs aimed at increasing insight into illness and treatment. A psychoeducational strategy may improve antipsychotic treatment compliance by helping the patients to work through their ambivalence regarding antipsychotic medication. For families, a psychoeducation strategy can lead to a change in attitudes toward the disorder, as well as to promote problem-solving skills for violence. The model presented here suggests that violence in schizophrenia is conditioned by several factors such as psychotic symptoms, medication non-compliance and lack of social support. The prevention of violent behavior in schizophrenia should include attention to other areas, such as the quality of the social environment surrounding the patient. For the “revolving door” patients, violence may be a key factor that complicates treatment. Health professionals have the responsibility to work in partnership with patients and their families for the prevention of violence.

Resumen: La esquizofrenia ha sido el principal diagnóstico psiquiátrico asociado con la violencia. La prevención de la violencia a través del tratamiento ambulatorio se ha visto obstaculizada por diversas variables situacionales y muchos pacientes llegan a verse inmersos en un ciclo de continuas admisiones hospitalarias (fenómeno de la puerta revolvente). La hipótesis central de la presente revisión es que la violencia en la esquizofrenia puede formar parte de un ciclo recurrente de hospitalizaciones psiquiátricas, en el que, combinados la falta de adhesión al tratamiento y el manejo inadecuado de la enfermedad por parte de los familiares, dan por resultado la manifestación del comportamiento violento. Diversas investigaciones han mostrado que tanto los síntomas psicóticos, como las alteraciones del ánimo secundarias a su presencia y la falta de una conciencia de enfermedad, son las principales características de la esquizofrenia, asociadas con la manifestación de la violencia en dicho padecimiento. Cuando los familiares no pueden manejar los síntomas psicóticos y el comportamiento violento del paciente, se busca la atención en un servicio especializado de psiquiatría, y con frecuencia, el paciente tiene que ser hospitalizado. La manifestación de conductas violentas ha sido considerada como una de las principales causas de hospitalización psiquiátrica. Diversas investigaciones han documentado que los actos violentos se presentan con mayor frecuencia durante la admisión hospitalaria por un episodio psicótico que en otros momentos durante el curso del padecimiento. Asimismo, la hospitalización psiquiátrica pos sí misma reduce la frecuencia e intensidad de la violencia, debido probablemente al tratamiento con antipsicóticos y al entorno restrictivo de las instalaciones. Tras la alta hospitalaria, los pacientes viven un proceso de transición mediante el cual van asumiendo mayor autonomía y control sobre diversos aspectos de su vida cotidiana. Sin embargo, este proceso se puede ver obstaculizado por las reacciones familiares secundarias al desgaste físico y emocional de vivir con un familiar con esquizofrenia. Asimismo, este desgaste puede verse exacerbado debido al antecedente de violencia en muchos de estos pacientes. Se ha descrito que la percepción que tienen los pacientes y sus familiares con respecto a los síntomas de la enfermedad difiere significativamente de la de los especialistas de la salud mental. A veces, estas diferencias se asocian con falta de discernimiento y conciencia sobre la enfermedad y con la necesidad de tratamiento médico, lo que a su vez puede llevar a la suspensión del mismo. La suspensión del tratamiento farmacológico induce a una eventual recaída cuyos signos más evidentes son los síntomas psicóticos. No obstante, si un paciente tiene antecedentes de comportamiento violento, es muy probable que este comportamiento surja durante la recaída y que sea necesario considerar nuevamente la hospitalización. En estos pacientes, en quienes la violencia tiene un importante papel en las hospitalizaciones recurrentes, es necesario considerar el establecimiento de programas clínicos, que incluyan la psicoeducación, dirigidos a incrementar la conciencia del paciente y de los familiares, sobre la enfermedad y la necesidad del tratamiento farmacológico. El modelo presentado en esta revisión sugiere que la violencia en la esquizofrenia es una condición generada por diversos factores tales como los síntomas psicóticos, la falta de adherencia al tratamiento y el inadecuado apoyo social. La prevención de la conducta violenta en la esquizofrenia no sólo debe fundamentarse en el uso de antipsicóticos, ya que existen otras áreas en las que intervienen las características propias del individuo y su entorno social. Los profesionales de la salud mental tienen la responsabilidad de trabajar en conjunto con los pacientes y sus familiares para prevenir la manifestación de conductas violentas. Es necesario realizar futuros estudios dirigidos a evaluar la forma en la que los servicios de salud mental pueden ser más efectivos en la reducción y prevención de la violencia en la esquizofrenia.