Andrea E. Spencer

Autistic Traits in Children With and Without ADHD

OBJECTIVE: To assess the implications of autistic traits (ATs) in youth with attention-deficit/hyperactivity disorder (ADHD) without a diagnosis of autism. METHODS: Participants were youth with (n = 242) and without (n = 227) ADHD and controls without ADHD in whom a diagnosis of autism was exclusionary. Assessment included measures of psychiatric, psychosocial, educational, and cognitive functioning. ATs were operationalized by using the withdrawn + social + thought problems T scores from the Child Behavior Checklist. RESULTS: A positive AT profile was significantly overrepresented among ADHD children versus controls (18% vs 0.87%; P < .001). ADHD children with the AT profile were significantly more impaired than control subjects in psychopathology, interpersonal, school, family, and cognitive domains. CONCLUSIONS: A substantial minority of ADHD children manifests ATs, and those exhibiting ATs have greater severity of illness and dysfunction.

Mild traumatic brain injury and ADHD: a systematic review of the literature and meta-analysis.

Objective: This study investigated the association between mild traumatic brain injury (mTBI) and ADHD, which increases risk of injuries and accidents. Method: We conducted a systematic review and meta-analysis of studies that examined the relationship between mTBI and ADHD. Results: Five studies, comprising 3,023 mTBI patients and 9,716 controls, fit our a priori inclusion and exclusion criteria. A meta-analysis found a significant association between ADHD and mTBI, which was significant when limited to studies that reported on ADHD subsequent to mTBI and when the direction of the association was not specified, but not for studies that reported mTBI subsequent to ADHD. Heterogeneity of effect size and publication biases were not evident. Conclusion: The literature documents a significant association between mTBI and ADHD. Further clarification of the relationship and direction of effect between mTBI and ADHD and treatment implications could have large clinical, scientific, and public health implications.

Examining the association between posttraumatic stress disorder and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis.

OBJECTIVE To conduct a systematic review and meta-analysis examining the relationship between attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD). DATA SOURCES We reviewed literature through PubMed and PsycINFO without a specified date range, utilizing the search (posttraumatic stress disorder OR PTSD) AND (ADHD OR attention deficit hyperactivity disorder OR ADD OR attention deficit disorder OR hyperkinetic syndrome OR minimal brain dysfunction). References from relevant articles were reviewed. STUDY SELECTION We identified 402 articles; 28 met criteria. We included original human research in English that operationalized diagnoses of ADHD and PTSD, evaluated the relationship between the disorders, and included controls. We excluded articles that failed to differentiate ADHD or PTSD from nonspecific or subsyndromal deficits or failed to compare their relationship. DATA EXTRACTION We extracted sample size, age, diagnostic methods, design, referral status, control type, and number of subjects with and without ADHD and PTSD alone and combined. We computed meta-analyses for 22 studies examining ADHD in PTSD and PTSD in ADHD using a random effects model and meta-analytic regression. We assessed for heterogeneity and publication bias and adjusted for intrastudy clustering. RESULTS The relative risk (RR) for PTSD in ADHD was 2.9 (P < .0005); in samples using healthy controls, the RR was 3.7 (P = .001); and in samples using traumatized controls, the RR was 1.6 (P = .003). The RR for ADHD in PTSD was 1.7 (P < .0005); in samples using traumatized controls, the RR was 2.1 (P < .0005). The association was not significant in samples using psychiatric controls. CONCLUSIONS Results indicate a bidirectional association between ADHD and PTSD, suggesting clinical implications and highlighting the need for neurobiological research that examines the mechanisms underlying this connection.

Glutamatergic dysregulation in pediatric psychiatric disorders: a systematic review of the magnetic resonance spectroscopy literature.

OBJECTIVE As the major excitatory neurotransmitter in the brain, glutamate plays a critical role in normal brain function; thus, its dysregulation could lead to psychopathology in youth. A growing body of literature has investigated the role of glutamate in the pathophysiology of childhood psychiatric disorders through magnetic resonance spectroscopy (MRS). The aim of this study was to review the existing literature to gauge the specificity of such findings. DATA SOURCES PubMed was searched for all scientific, peer-reviewed articles published in English that included MRS measurements of glutamatergic metabolites in pediatric psychiatric populations through August 14, 2013. STUDY SELECTION 50 articles were included in this review. These studies included measurements of glutamate or related metabolites with MRS in children with psychiatric disorders. DATA EXTRACTION All relevant data (eg, population; number, sex, and age of subjects; method of comparison; treatment history; MRS Tesla; brain regions of interest; glutamatergic findings; other findings; and comorbidities) were extracted from the included articles. The direction and significance of glutamate dysregulation and brain region(s) examined were used to compare the studies. RESULTS Most consistently, increases in glutamatergic metabolites were found in the anterior cingulate cortex (ACC) and other regions in youth with attention-deficit/hyperactivity disorder (ADHD). Limited data suggested increases in glutamatergic metabolites in youth with autism spectrum disorders, emotional dysregulation, and high risk for schizophrenia and decreases in youth with major depression, bipolar disorder, and obsessive-compulsive disorder. There was limited but consistent evidence for normalization of glutamatergic levels with treatment, particularly in bipolar disorder and ADHD. CONCLUSIONS A relatively small number of studies have examined the role of glutamatergic dysregulation in pediatric psychiatric disorders. Some consistencies can be found, but interpretation of the data is limited by differences in methodology, including age of subjects, severity of current symptoms, treatment, and scanning parameters.

A Systematic Evaluation of the QTc Interval and Antidepressants in Youth: An Electronic Health Record Study.

Objective: The US Food and Drug Administration announced that citalopram was associated with dose-related prolongation of the QTc interval in adults. This study aimed to assess how antidepressants affect QTc intervals in children. The authors hypothesized that some antidepressants would show an association with QTc prolongation. Methods: An electronic medical record review was conducted of children aged 5 to 18 years in the Partners Healthcare system with at least 1 prescription of an antidepressant or methadone between February 1990 and August 2011. The authors extracted lifetime diagnoses and QTc interval of patients who had received an electrocardiogram 14 to 90 days after antidepressant or methadone prescription (N = 297). The mean QTc per medication was calculated as compared with the mean of all QTc measurements across medications. The number of patients taking medications who had QTc values in normal, borderline, abnormal, or high were also calculated. Results: Mean QTc values for all medications were in the normal range. The highest mean QTc was in patients on escitalopram (436 milliseconds). The mean QTc for sertraline (416 milliseconds) was significantly lower than all other drugs measured (t(331) = −2.21, p < .05). After controlling for confounding effects, none of the differences in mean QTc compared with other study drugs reached statistical significance. The greatest percentages of abnormal and high QTc values were found among patients taking paroxetine (18.8%), followed by escitalopram (15.4%). None of the children had documented ventricular arrhythmia. Conclusion: The results suggest that most antidepressants are not associated with prolonged QTc at doses typically prescribed for children.

Abnormal fear circuitry in Attention Deficit Hyperactivity Disorder: A controlled magnetic resonance imaging study

We examined whether non-traumatized subjects with Attention Deficit Hyperactivity Disorder (ADHD) have dysfunctional activation in brain structures mediating fear extinction, possibly explaining the statistical association between ADHD and other disorders characterized by aberrant fear processing such as PTSD. Medication naïve, non-traumatized young adult subjects with (N=27) and without (N=20) ADHD underwent a 2-day fear conditioning and extinction protocol in a 3T functional magnetic resonance imaging (fMRI) scanner. Skin conductance response (SCR) was recorded as a measure of conditioned response. Compared to healthy controls, ADHD subjects had significantly greater insular cortex activation during early extinction, lesser dorsal anterior cingulate cortex (dACC) activation during late extinction, lesser ventromedial prefrontal cortex (vmPFC) activation during late extinction learning and extinction recall, and greater hippocampal activation during extinction recall. Hippocampal and vmPFC deficits were similar to those documented in PTSD subjects compared to traumatized controls without PTSD. Non-traumatized, medication naive adults with ADHD had abnormalities in fear circuits during extinction learning and extinction recall, and some findings were consistent with those previously documented in subjects with PTSD compared to traumatized controls without PTSD. These findings could explain the significant association between ADHD and PTSD as well as impaired emotion regulation in ADHD.

Can pediatric bipolar-I disorder be diagnosed in the context of posttraumatic stress disorder? A familial risk analysis

Despite ongoing concerns that traumatized children with severe symptoms of emotional dysregulation may be inappropriately receiving a diagnosis of pediatric bipolar-I (BP-I) disorder, this issue has not been adequately examined in the literature. Because both pediatric BP-I disorder and posttraumatic stress disorder (PTSD) are familial disorders, if children with both BP-I and PTSD were to be truly affected with BP-I disorder, their relatives would be at high risk for BP-I disorder. To this end, we compared patterns of familial aggregation of BP-I disorder in BP-I children with and without PTSD with age and sex matched controls. Participants were 236 youths with BP-I disorder and 136 controls of both sexes along with their siblings. Participants completed a large battery of measures designed to assess psychiatric disorders, psychosocial, educational, and cognitive parameters. Familial risk analysis revealed that relatives of BP-I probands with and without PTSD had similar elevated rates of BP-I disorder that significantly differed from those of relatives of controls. Pediatric BP-I disorder is similarly highly familial in probands with and without PTSD indicating that their co-occurrence is not due to diagnostic error.

Screening for Attention-Deficit/Hyperactivity Disorder and Comorbidities in a Diverse, Urban Primary Care Setting

We tested the accuracy of 2 parent-report tools, the Pediatric Symptom Checklist (PSC-35) and Child Behavior Checklist (CBCL), to identify attention-deficit/hyperactivity disorder (ADHD) and distinguish complex (highly comorbid) cases in an urban, largely Latino pediatric practice. Spanish- and English-speaking parents of children aged 6 to 10 years completed a PSC-35 and CBCL at well visits. Those with CBCL Attention Problems Subscale (CBCL-APS) T scores ≥60 plus controls completed the diagnostic MINI-KID (Miniature International Neuropsychiatric Interview) for Children. Receiver operating characteristic (ROC) curves quantified accuracy of both scales to distinguish ADHD from non-ADHD, and complex from simple ADHD. Two hundred and nine children were screened, and 41 completed diagnostic interviews. Both the CBCL-APS and PSC Attention Scale (PSC-AS) accurately identified ADHD; the CBCL-APS performed best (AUROCCBCL_APS = 0.837; AUROCPSC_AS = 0.728). The PSC Total and Internalizing Scores and the number of CBCL subscale elevations accurately distinguished complex from simple ADHD; the PSC Internalizing Score performed best (AUROCPSC_TOTAL = 0.700; AUROCPSC_INT = 0.817; AUROCCBCL_SUBS = 0.762).

A Pilot Study: Cardiac Parameters in Children Receiving New-generation Antidepressants.

Objective Because of concerns about potential associations between high doses of citalopram and QTc prolongation in adults, this study examined whether such associations are operant in children. We hypothesized that therapeutic doses of nontricyclic antidepressant medications (non-TCAs) prescribed to children would be cardiovascularly safe. Study Design The sample consisted of 49 psychiatrically referred children and adolescents 6 to 17 years old of both sexes treated with a non-TCA (citalopram, escitalopram, fluoxetine, paroxetine, sertraline, bupropion, duloxetine, venlafaxine, mirtazapine). To standardize the doses of different antidepressants, we converted doses of individual medicines into “citalopram equivalent doses” (CEDs) based on dosing recommendation for individual antidepressants. Correlation analysis was carried out to compare the continuous and weight-based CED to variables of interest. A QTc grouping was defined as normal, borderline, or abnormal, and CED was compared across QTc groupings using linear regression. An antidepressant dosage group was defined as low or high dose, and a t test compared variables of interest across dosage groups. Results No significant associations were found between total or weight-corrected CEDs of any antidepressant examined and QTc or any other electrocardiogram or blood pressure parameters. In patients taking citalopram or escitalopram, a significant correlation was found between PR interval and total daily dose, which disappeared when weight-based doses were used or when corrected by age. Conclusions Although limited by a relatively small sample size, these results suggest that therapeutic doses of non-TCA antidepressants when used in children do not seem to be associated with prolonged QTc interval or other adverse cardiovascular effects.