Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry.

OBJECTIVES: To determine whether epigenetic markers predict dimensional ratings of depression in maltreated children. METHOD: A genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 healthy nontraumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible. RESULTS: Methylation in 3 genes emerged as genome-wide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (ID3); Glutamate Receptor, Ionotropic N-methyl-D-aspartate (NMDA) 1 (GRIN1); and Tubulin Polymerization Promoting Protein (TPPP) (p < 5.0 × 10(-7), all analyses). These genes are all biologically relevant with ID3 involved in the stress response, GRIN1 involved in neural plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different ß values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5). CONCLUSIONS: This study suggests that epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. The study adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. Although epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed.

Child abuse and epigenetic mechanisms of disease risk.

BACKGROUND: Child abuse is highly prevalent and associated with increased risk for a range of health problems, including cancer, cardiovascular disease, diabetes, psychiatric disorders, and other health problems. Little is currently known about the mechanism by which early adversity confers risk for health problems later in life. PURPOSE: To determine if there are epigenetic differences associated with child maltreatment that may help explain association between adverse childhood experiences and later health problems. METHODS: As part of a study examining genetic and environmental factors associated with depression, saliva DNA specimens were collected on 96 maltreated children removed from their parents due to abuse or neglect and 96 demographically matched control children between 2003 and 2010. In 2011, the Illumina 450K BeadChip was used on stored DNA specimens and analyzed to examine whole-genome methylation differences between maltreated and control children. RESULTS: After controlling for multiple comparisons, maltreated and control children had significantly different methylation values at 2868 CpG sites (p<5.0 × 10(-7), all sites; average methylation difference per site=17%; range=1%-62%). The gene set contained numerous markers of diseases and biological processes related to the health problems associated with early childhood adversity. CONCLUSIONS: Although replication is required, this study suggests that epigenetic mechanisms may be associated with risk for health problems later in life in maltreated children. This study lays the groundwork for future studies examining health and methylation measures to further characterize the role of epigenetic mechanisms in conferring risk for medical problems in individuals with histories of early adversity.

Safe return to homeland of an illegal immigrant with psychosis.

The disposition of illegal immigrants who lack social support and wish to return to their homeland is a frequent and difficult challenge for many mental health facilities in the United States. This case involved an undocumented Mexican patient with severe psychosis who was safely transferred to his hometown according to his and his family's wishes through the use of specific services provided by the Mexican Consulate. We hope that publication of this case will make the medical community more aware of the availability of these underused services, which can make a major difference in the prognosis of some undocumented patients who would otherwise be left without resources or appropriate care.

MAOA genotype, maltreatment, and aggressive behavior: the changing impact of genotype at varying levels of trauma.

BACKGROUND: Childhood adversity has been shown to interact with monoamine oxidase-A (MAOA) genotype to confer risk for antisocial behavior. Studies examining this gene-by-environment (G x E) association, however, have produced mixed results. METHODS: Relevant research is reviewed, and results of a study with 114 children (73 maltreated and 41 control subjects) are presented. The maltreated children represent the extreme on a continuum of adversity and were assessed at a time of extreme stress-shortly after removal from their parents' care due to abuse. Measures of aggressive behavior were obtained using standard research instruments, and monoamine oxidase-A MAOA genotypes were obtained from saliva-derived DNA specimens. Population structure was controlled for using ancestral proportion scores computed on the basis of genotypes of ancestry informative markers. RESULTS: Many prior investigations appear to have had reduced power to detect the predicted G x E interaction because of low base rates of maltreatment and antisocial behavior in their samples and failure to use optimal procedures to control for population structure in ethnically diverse cohorts. In this investigation, a significant interaction was detected between exposure to moderate trauma and the "low-activity" MAOA genotype in conferring risk for aggression. Children with exposure to extreme levels of trauma, however, had high aggression scores regardless of genotype. CONCLUSIONS: Our study suggests that problems in aggressive behavior in maltreated children are moderated by MAOA genotype, but only up to moderate levels of trauma exposure. Extreme levels of trauma appear to overshadow the effect of MAOA genotype, especially in children assessed at time of acute crisis.

Catatonia: a review.

BACKGROUND: To write an up-to-date review paper on catatonia using published literature. METHODS: This review involved a search using the terms "catatonia," "stupor," "catatonic schizophrenia" and "catalepsy" in the Cochrane Database of Systematic Reviews, the Medline database and EMBASE and PsychINFO. Additional use was made of these databases in searching for randomized controlled trials, meta-analyses, cohort studies, case-control studies, case series, case reports and reviews. RESULTS: Available evidence indicates that catatonia is a common neuropsychiatric syndrome characterized by the presence of various motor signs and symptoms. The underlying pathophysiologic-mechanisms points to a heterogeneous group of etiologies. Current classifications are based on the type of presentation and the duration of symptoms; agitated versus retarded and acute versus chronic. Available data supports the efficacy of benzodiazepines and electroconvulsive therapy (ECT) in the treatment of this condition, but the treatment response is limited by the chronicity of symptoms. CONCLUSIONS: Catatonia is a common disorder that occurs in a wide variety of psychiatric, neurological and medical conditions. At the current time, there is sufficient evidence to consider it as a specific nosologic syndrome with different subtypes and treatment responses.

Frontotemporal dementias: a review.

Dementia is a clinical state characterized by loss of function in multiple cognitive domains. It is a costly disease in terms of both personal suffering and economic loss. Frontotemporal dementia (FTD) is the term now preferred over Picks disease to describe the spectrum of non-Alzheimers dementias characterized by focal atrophy of the frontal and anterior temporal regions of the brain. The prevalence of FTD is considerable, though specific figures vary among different studies. It occurs usually in an age range of 35-75 and it is more common in individuals with a positive family history of dementia. The risk factors associated with this disorder include head injury and family history of FTD. Although there is some controversy regarding the further syndromatic subdivision of the different types of FTD, the three major clinical presentations of FTD include: 1) a frontal or behavioral variant (FvFTD), 2) a temporal, aphasic variant, also called Semantic dementia (SD), and 3) a progressive aphasia (PA). These different variants differ in their clinical presentation, cognitive deficits, and affected brain regions. Patients with FTD should have a neuropsychiatric assessment, neuropsychological testing and neuroimaging studies to confirm and clarify the diagnosis. Treatment for this entity consists of behavioral and pharmacological approaches. Medications such as serotonin reuptake inhibitors, antipsychotics, mood stabilizer and other novel treatments have been used in FTD with different rates of success. Further research should be directed at understanding and developing new diagnostic and therapeutic modalities to improve the patients' prognosis and quality of life.

The catatonic dilemma expanded.

Catatonia is a common syndrome that was first described in the literature by Karl Kahlbaum in 1874. The literature is still developing and remains unclear on many issues, especially classification, diagnosis, and pathophysiology. Clinicians caring for psychiatric patients with catatonic syndromes continue to face many dilemmas in diagnosis and treatment. We discuss many of the common problems encountered in the care of a catatonic patient, and discuss each problem with a review of the literature. Focus is on practical aspects of classification, epidemiology, differential diagnosis, treatment, medical comorbidity, cognition, emotion, prognosis, and areas for future research in catatonic syndromes.