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.

Posttraumatic stress disorder: the missed diagnosis.

Posttraumatic stress disorder (PTSD) is frequently underdiagnosed in maltreated samples. Protective services information is critical for obtaining complete trauma histories and determining whether to survey PTSD symptoms in maltreated children. In the current study, without protective services information to supplement parent and child report, diagnosing PTSD was missed in a significant proportion of the cases. Collaboration between mental health professionals and protective service workers is critical in determining psychiatric diagnoses and treatment needs of children involved with the child welfare system.

Dissociative disorders and suicidality in psychiatric outpatients.

Although it is common for patients with dissociative disorders to report a history of suicide attempts, there is very little data systematically comparing suicidality in patients with dissociative disorders versus patients without these disorders. The subjects in our study were 231 patients consecutively admitted to an inner-city, hospital-based outpatient psychiatric clinic. Eighty-two of these patients completed structured interviews for dissociative disorders, borderline personality disorder, and trauma history (dissociative disorders interview schedule) and for posttraumatic stress disorder and substance abuse (Structured Clinical Interview for DSM-IV). Patients receiving a dissociative disorder diagnosis were compared with nondissociative patients on measures of self-harm and suicidality. Presence of a dissociative disorder was strongly associated with all measures of self-harm and suicidality. When we focused on patients with a history of multiple suicide attempts, significant associations were found between several diagnoses (dissociative disorder; borderline personality disorder; posttraumatic stress disorder; alcohol abuse/dependence) and multiple suicide attempter status. When these diagnoses were entered in a logistic regression, a highly significant association remained for dissociative diagnosis and multiple suicide attempter status (odds ratio, 15.09; 95% confidence interval, 2.67-85.32; p = 0.002). Dissociative disorders are commonly overlooked in studies of suicidality, but in this population they were the strongest predictor of multiple suicide attempter status.

Genetic and environmental predictors of early alcohol use.

BACKGROUND: The goal of the current investigation was to examine genetic and environmental predictors of early alcohol use, a potent predictor of later alcohol dependence. METHODS: This study represents an add-on project to an investigation examining the efficacy of an intervention for maltreated children entering out-of-home care. Predictors of early alcohol use include the following: maltreatment, family loading for alcohol or substance-use disorders, and serotonin transporter genotype (5-HTTLPR; locus SLC6A4). Participants included 127 subjects: 76 maltreated children and 51 demographically matched community controls. RESULTS: At follow-up, 29% of the maltreated children reported alcohol use, a rate more than seven times the rate observed in controls. Maltreated children also drank alcohol, on average, more than 2 years earlier than controls (11.2 vs. 13.5 years). Early alcohol use was predicted by maltreatment, 5-HTTLPR, and a gene by environment interaction, with increased risk for early alcohol use associated with the s-allele. Psychopathology at baseline, severity of maltreatment, and poor mother-child relations also predicted early alcohol use. CONCLUSIONS: Maltreated children are at high risk for psychiatric, alcohol, and substance abuse problems. Examination of genetic and environmental risk and protective factors can help identify those who are most vulnerable and help guide prevention and intervention efforts.

Prevalence of dissociative disorders in psychiatric outpatients.

OBJECTIVE: The purpose of the study was to assess the prevalence of DSM-IV dissociative disorders in an inner-city outpatient psychiatric population. METHOD: Subjects were 231 consecutive admissions (84 men and 147 women, mean age=37 years) to an inner-city, hospital-based outpatient psychiatric clinic. The subjects completed self-report measures of dissociation (Dissociative Experiences Scale) and trauma history (Traumatic Experiences Questionnaire). Eighty-two patients (35%) completed a structured interview for dissociative disorders (Dissociative Disorders Interview Schedule). RESULTS: The 82 patients who were interviewed did not differ significantly on any demographic measure or on the self-report measures of trauma and dissociation from the 149 patients who were not interviewed. Twenty-four (29%) of the 82 interviewed patients received a diagnosis of a dissociative disorder. Dissociative identity disorder was diagnosed in five (6%) patients. Compared to the patients without a dissociative disorder diagnosis, patients with a dissociative disorder were significantly more likely to report childhood physical abuse (71% versus 27%) and childhood sexual abuse (74% versus 29%), but the two groups did not differ significantly on any demographic measure, including gender. Chart review revealed that only four (5%) patients in whom a dissociative disorder was identified during the study had previously received a dissociative disorder diagnosis. CONCLUSIONS: Dissociative disorders were highly prevalent in this clinical population and typically had not been previously diagnosed clinically. The high prevalence of dissociative disorders found in this study may be related to methodological factors (all patients were offered an interview rather than only those who had scored high on a screening self-report measure) and epidemiological factors (extremely high prevalence rates for childhood physical and sexual abuse were present in the overall study population).

Differential relationships of childhood abuse and neglect subtypes to PTSD symptom clusters among adolescent inpatients.

This article investigates whether childhood abuse and neglect subtypes (i.e., physical, sexual, and emotional abuse, and physical and emotional neglect) differentially predict the severity of individual posttraumatic stress disorder (PTSD) symptom clusters and overall posttraumatic stress. Eighty-nine patients admitted to the short-term adolescent treatment unit of a psychiatric hospital completed a battery of psychological assessments. Findings of multiple regression analyses showed that emotional and sexual abuse rather than physical abuse, emotional neglect, or physical neglect is related to individual symptom cluster severity and overall posttraumatic stress. Results suggested that a greater level of specificity is necessary when assessing child abuse and posttraumatic stress because each level provides more specific information about how to intervene to reduce the risk of negative outcomes.

Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children.

BACKGROUND: Child abuse and genotype interact to contribute to risk for depression in children. This study examined gene-by-gene and gene-by-environment interactions. METHODS: The study included 196 children: 109 maltreated and 87 nonmaltreated comparison subjects. Measures of psychiatric symptomatology and social supports were obtained using standard research instruments, and serotonin transporter (5-HTTLPR) (locus SLC6A4) and brain-derived neurotrophic factor (BDNF) (variant val66met) genotypes were obtained from saliva-derived DNA specimens. Population structure was controlled by means of ancestral proportion scores computed based on genotypes of ancestry informative markers in the entire sample. RESULTS: There was a significant three-way interaction between BDNF genotype, 5-HTTLPR, and maltreatment history in predicting depression. Children with the met allele of the BDNF gene and two short alleles of 5-HTTLPR had the highest depression scores, but the vulnerability associated with these two genotypes was only evident in the maltreated children. A significant four-way interaction also emerged, with social supports found to further moderate risk for depression. CONCLUSIONS: To the best of our knowledge, this is the first investigation to demonstrate a gene-by-gene interaction conveying vulnerability to depression. The current data also show a protective effect of social supports in ameliorating genetic and environmental risk for psychopathology.

Baseline and modulated acoustic startle responses in adolescent girls with posttraumatic stress disorder.

OBJECTIVE: To assess baseline and modulated acoustic startle responses in adolescent girls with posttraumatic stress disorder (PTSD). METHOD: Twenty-eight adolescent girls with PTSD and 23 healthy control girls were recruited for participation in the study. Acoustic stimuli were bursts of white noise of 104 dB presented biaurally through headphones. Baseline startle responses as well as prepulse inhibition, a 1,000-Hz prestimulation tone presented 120 milliseconds before the startle stimulus for 30 milliseconds, and prepulse facilitation, a 1000-Hz prestimulation tone presented continuously for 2, 000 milliseconds before the startle stimulus, were compared in these two groups of girls. RESULTS: At baseline and under neutral testing conditions, the magnitude of the startle response (eye blink) did not differ significantly between girls with PTSD and healthy control girls. There were no significant differences in the degree of prepulse inhibition or facilitation between the two groups of girls. CONCLUSIONS: Unlike combat veterans with PTSD, adolescent girls with PTSD who report exaggerated startle may not have exaggerated baseline acoustic startle responses in the laboratory. Further research should explore whether girls with PTSD demonstrate altered startle responses under stress and/or evidence of other types of psychophysiological abnormalities.

Smaller head of the hippocampus in Gulf War-related posttraumatic stress disorder.

Reductions in hippocampal volume and impairment in short-term verbal memory have been reported in Vietnam combat veterans with posttraumatic stress disorder (PTSD) and in women with abuse-related PTSD. The present investigation evaluated hippocampal volume and memory in Gulf War veterans. This research is timely given the ongoing war in Iraq and the anticipated high rates of PTSD among returning combat soldiers. Fourteen veterans with PTSD related to traumatic experiences during the Gulf War (1990-1991), 23 deployed veterans without PTSD, 22 non-deployed reservists and 29 healthy civilians were studied. Volumes of the hippocampus, temporal lobe, and whole brain were measured on coronal MRI scans, and hippocampal mediated memory function was evaluated. The head of the hippocampus was the only subregion that was significantly smaller in Gulf War veterans with PTSD than in healthy civilians. Deployed veterans with PTSD, deployed veterans without PTSD, and non-deployed reservists had significantly smaller whole hippocampal volume and lower scores on immediate and delayed verbal and visual retrieval compared with healthy civilians.

A comparison of adolescent inpatients with and without a history of violence perpetration: impulsivity, PTSD, and violence risk.

How childhood maltreatment and violence victimization contributes to subsequent violent behavior remains an understudied area. We examined 130 psychiatrically hospitalized adolescents and compared those with a history of perpetrating violence to those without a history of violence perpetration. Perpetrators of physical violence were significantly more likely to have been a victim and/or witness to family and community violence and also reported significantly higher levels of a broad range of psychopathology than nonperpetrators. Correlational analyses with the study group of violence perpetrators revealed that higher levels of impulsivity, dissociation, and PTSD were significantly associated with higher levels of violence. Furthermore, multiple regression analysis showed that symptoms of impulsivity and PTSD contributed significantly to the prediction of violence risk. Our findings demonstrate that violence exposure and childhood maltreatment are indeed common negative life events among adolescent inpatients, and that symptoms of PTSD may predispose traumatized youth toward impulsive violent behavior.

Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine.

RATIONALE: Sensitization to the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists is robust in animals. However, the applicability of this model to humans is unclear because it currently rests on highly confounded retrospective studies of individuals who experienced protracted psychoses following repeated binges with NMDA receptor antagonists. OBJECTIVES: The purpose of the current study was to determine whether there was evidence of sensitization to the behavioral effects of ketamine in healthy human subjects with repeated exposure to this drug. METHODS: Data were studied from 295 healthy human subjects who participated in one or more of 11 separate studies that involved ketamine administration over 14 years. Positive and negative symptoms (Brief Psychiatric Rating Scale: BPRS), perceptual alterations (Clinician-Administered Dissociative States Scale: CADSS), and "high" and "anxiety" states (Visual Analog Scale: VAS) that were measured in all studies were included as outcome measures. RESULTS: After including the number of previous exposures, number of previous studies, and time since first exposure as variables, repeated exposure to ketamine did not result in increased behavioral responses, suggestive of behavioral sensitization. CONCLUSIONS: The current data do not provide evidence that repeated exposure to ketamine, albeit limited, is associated with sensitization to the behavioral effects of ketamine.

Social supports and serotonin transporter gene moderate depression in maltreated children.

In this study, measures of the quality and availability of social supports were found to moderate risk for depression associated with a history of maltreatment and the presence of the short (s) allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR). The present investigation (i) replicates research in adults showing that 5-HTTLPR variation moderates the development of depression after stress, (ii) extends the finding to children, and (iii) demonstrates the ability of social supports to further moderate risk for depression. Maltreated children with the s/s genotype and no positive supports had the highest depression ratings, scores that were twice as high as the non-maltreated comparison children with the same genotype. However, the presence of positive supports reduced risk associated with maltreatment and the s/s genotype, such that maltreated children with this profile had only minimal increases in their depression scores. These findings are consistent with emerging preclinical and clinical data suggesting that the negative sequelae associated with early stress are not inevitable. Risk for negative outcomes may be modified by both genetic and environmental factors, with the quality and availability of social supports among the most important environmental factors in promoting resiliency in maltreated children, even in the presence of a genotype expected to confer vulnerability for psychiatric disorder.

An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD.

We recently found increased adrenal cortisol responses to adrenocorticotropic hormone (ACTH)1-24 and increased pituitary ACTH and adrenal cortisol responses to corticotropin-releasing factor in premenopausal women with chronic post-traumatic stress disorder (PTSD) compared to healthy nontraumatized subjects. This pattern of hypothalamic-pituitary-adrenal axis (HPA) hyper-reactivity has been previously seen in healthy individuals treated with the antiglucocorticoid mifepristone. We therefore investigated whether endogenous plasma levels of antiglucocorticoids such as dehydroepiandrosteroine (DHEA) and progesterone were increased in premenopausal women with PTSD at baseline or in response to adrenal activation by ACTH1-24. The study revealed that DHEA responses to 250 microg ACTH1-24 were increased in 13 PTSD subjects compared to 13 healthy nontraumatized subjects, while DHEA levels were generally increased in the PTSD subjects compared to seven healthy traumatized subjects. Cortisol responses to ACTH1-24 were also higher in the women with PTSD, while progesterone levels and responses were not different among the three groups. In addition, among the PTSD subjects, the peak change in DHEA in response to ACTH1-24 was negatively correlated with the total Clinician Administered PTSD Scale score, while the peak DHEA to cortisol ratio was inversely associated with negative mood symptoms measured by the Profile of Mood States scale. This work suggests that an increased capacity for DHEA release in response to extreme adrenal activation may influence the pattern of HPA axis adaptation to extreme stress, as well as mitigate the severity of PTSD and negative mood symptoms in premenopausal women with PTSD.

Posttraumatic stress disorder and substance use in inner-city adolescent girls.

The purpose of this study is to examine rates of nicotine, marijuana, and alcohol use as well as patterns of problematic substance use and posttraumatic stress disorder (PTSD) symptoms in inner-city adolescent girls. One hundred four adolescents who obtained medical care at a hospital-based adolescent clinic were systematically surveyed for trauma exposure, posttraumatic stress symptoms, and substance use. A subset (N = 54, 52%) of girls completed a semistructured psychiatric diagnostic interview (K-SADS-PL) to ascertain timing of PTSD symptoms relative to substance use. Compared with traumatized girls without PTSD, girls with full and partial PTSD were significantly more likely to use nicotine, marijuana, and/or alcohol on a regular basis. Fifteen girls met criteria for both PTSD and a substance-use disorder. For 80% of these girls, the age of onset of PTSD was either before or concurrent with the onset of their substance-use disorder. Inner-city adolescent girls with PTSD exhibit problematic substance use and may be at high risk of developing a comorbid substance-use disorder.

Salivary cortisol responses to dexamethasone in adolescents with posttraumatic stress disorder.

OBJECTIVE: Previous studies of adults with posttraumatic stress disorder (PTSD) have found various abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis, including enhanced suppression of cortisol following low-dose dexamethasone. The purpose of the present study was to investigate salivary cortisol responses to low-dose dexamethasone in adolescents with PTSD. METHOD: Forty-eight adolescents (20 with current PTSD, 9 trauma controls without PTSD, and 19 healthy nontraumatized controls) were enrolled in the study. On day 1, baseline saliva samples were obtained at 8 a.m. and 0.5 mg of dexamethasone was administered at 11 p.m. Cortisol and dexamethasone levels were assessed at 8 a.m. the following day. RESULTS: Adolescents with current PTSD showed no difference in the suppression of salivary cortisol in response to low-dose (0.5 mg) dexamethasone compared to trauma controls without PTSD and nontraumatized controls. More severely affected PTSD subjects with co-occurring major depression showed higher pre- and post-dexamethasone salivary cortisol levels compared to controls. CONCLUSIONS: The present study did not find evidence for enhanced suppression of salivary cortisol at 8 a.m. following low-dose dexamethasone in multiply traumatized adolescents with PTSD. This result differs from findings in adults with PTSD. Further investigations of hypothalamic-pituitary-adrenal axis abnormalities in traumatized children and adolescents are needed.