Andrés Martin

An fMRI Study of the Effects of Psychostimulants on Default-Mode Processing During Stroop Task Performance in Youths With ADHD

OBJECTIVE The authors examined the effect of psychostimulants on brain activity in children and adolescents with ADHD performing the Stroop Color and Word Test. METHOD The authors acquired 52 functional MRI scans in 16 youths with ADHD who were known responders to stimulant medication and 20 healthy comparison youths. Participants with ADHD were scanned on and off medication in a counterbalanced design, and comparison subjects were scanned once without medication. RESULTS Stimulant medication significantly improved suppression of default-mode activity in the ventral anterior cingulate cortex in the ADHD group. When off medication, youths with ADHD were unable to suppress default-mode activity to the same degree as comparison subjects, whereas when on medication, they suppressed this activity to comparison group levels. Greater activation of the lateral prefrontal cortex when off medication predicted a greater reduction in ADHD symptoms when on medication. Granger causality analyses demonstrated that activity in the lateral prefrontal and ventral anterior cingulate cortices mutually influenced one another but that the influence of the ventral anterior cingulate cortex on the lateral prefrontal cortex was significantly reduced in youths with ADHD off medication relative to comparison subjects and increased significantly to normal levels when ADHD youths were on medication. CONCLUSIONS Psychostimulants in youths with ADHD improved suppression of default-mode activity in the ventral anterior cingulate and posterior cingulate cortices, components of a circuit in which activity has been shown to correlate with the degree of mind-wandering during attentional tasks. Stimulants seem to improve symptoms in youths with ADHD by normalizing activity within this circuit and improving its functional interactions with the lateral prefrontal cortex.

Age, Rapid-Cycling, and Pharmacotherapy Effects on Ventral Prefrontal Cortex in Bipolar Disorder: A Cross-Sectional Study

BACKGROUND Neuroimaging data suggest that deficits in ventral prefrontal cortex (VPFC) function in bipolar disorder (BD) progress during adolescence and young adulthood. However, the developmental trajectory of VPFC morphological abnormalities in BD is unknown. This study investigated potential age-dependent volume abnormalities in VPFC in BD. METHODS Thirty-seven individuals diagnosed with BD I (14 adolescents, 10 young adults and 13 older adults) and 56 healthy comparison subjects (HC) participated in imaging. Gray and white matter volumes of VPFC were measured using high-resolution structural magnetic resonance imaging (MRI). We used a mixed model, repeated measures analysis to examine VPFC volumes across age groups while co-varying for total brain volume. Potential effects of illness features including rapid-cycling and medication were explored. RESULTS VPFC volumes declined with age (p < .001). The diagnosis-by-age group interaction was significant (p = .01). Relative to HC subjects, VPFC gray and white matter volumes were significantly smaller in BD patients only in young adulthood (p = .04). In participants with BD, VPFC volumes were significantly smaller in participants with rapid-cycling than participants without rapid-cycling (p = .02). Conversely, current use of medication was associated with larger VPFC gray matter volumes (p = .005), independent of age. CONCLUSIONS These preliminary findings suggest the presence of a more rapid initial decline in VPFC volumes with age in adolescents and young adults with BD than HC. These findings also suggest that the rapid-cycling subtype of BD is associated with larger VPFC volume deficits than the non-rapid-cycling subtype, and that pharmacotherapy may have trophic or protective effects on VPFC volumes in BD patients.

Higher-functioning pervasive developmental disorders : Rates and patterns of Psychotropic drug use

OBJECTIVE To explore the frequency, characteristics, and associated target symptoms of psychotropic drug use among subjects with higher-functioning pervasive developmental disorders (HFPDDs). METHOD A total of 109 children, adolescents, and adults (mean age = 13.9 years, SD = 6.9) consecutively seeking enrollment into the Yale Child Study Centers Project on Social Learning Disabilities were included in the study. Individuals in whom Aspergers disorder, autism, or pervasive developmental disorder-not otherwise specified had been previously diagnosed and who had a documented Full Scale IQ > or = 70 completed surveys on demographic, clinical, and medication history information. To naturalistically evaluate medication use patterns in this population, each drug class was analyzed with respect to demographic and clinical variables. RESULTS In all, 55% of subjects were taking psychotropics, with 29.3% taking 2 or more medications simultaneously. Antidepressants were the most commonly used agents (32.1%), followed by stimulants (20.2%) and neuroleptics (16.5%). The clinical presentation of subjects taking psychotropic agents was heterogeneous, and most consistently included anxiety-related target symptoms (in 65% of medicated individuals). CONCLUSIONS Psychotropic medication use appears to be common among subjects with HFPDDs, yet not generally based on the results of empirical research. Clinical heterogeneity among treated subjects suggests that psychiatric comorbidity may be overlooked in this population.

Effects of Short- and Long-Term Risperidone Treatment on Prolactin Levels in Children with Autism

BACKGROUND The effects of short- and long-term risperidone treatment on serum prolactin were assessed in children and adolescents with autism. METHODS Patients with autism (N = 101, 5-17 years of age) were randomized to an 8-week trial of risperidone or placebo and 63 then took part in a 4-month open-label follow-up phase. Serum samples were obtained at Baseline and Week-8 (N = 78), and at 6-month (N = 43) and 22-month (N = 30) follow-up. Serum prolactin was determined by immunoradiometric assay; dopamine type-2 receptor (DRD2) polymorphisms were genotyped. RESULTS Baseline prolactin levels were similar in the risperidone (N = 42) and placebo (N = 36) groups (9.3 +/- 7.5 and 9.3 +/- 7.6 ng/ml, respectively). After 8 weeks of risperidone, prolactin increased to 39.0 +/- 19.2 ng/ml, compared with 10.1 +/- 8.8 ng/ml for placebo (p < .0001). Prolactin levels were also significantly increased at 6 months (32.4 +/- 17.8 ng/ml; N = 43, p < .0001) and at 22 months (N = 30, 25.3 +/- 15.6 ng/ml, p < .0001). Prolactin levels were not associated with adverse effects and DRD2 alleles (Taq1A, -141C Ins/Del, C957T) did not significantly influence baseline levels or risperidone-induced increases in prolactin. CONCLUSIONS Risperidone treatment was associated with two- to four-fold mean increases in serum prolactin in children with autism. Although risperidone-induced increases tended to diminish with time, further research on the consequences of long-term prolactin elevations in children and adolescents is needed.

Validity of the Autism Diagnostic Interview-Revised

The factor structure, internal consistency, and convergent validity of the Autism Diagnostic Interview-Revised (ADI-R) algorithm items were examined in a sample of 226 youngsters with pervasive developmental disabilities. Exploratory factor analyses indicated a three-factor solution closely resembling the original algorithm and explaining 38% of the variance, with one significant discrepancy: Unlike the algorithm, all nonverbal communication items were associated with the Social factor. Internal consistencies of domain scores ranged from .54 to .84. Correlations between ADI-R domain and total scores and instruments assessing adaptive behavior, psychopathology, and autism were examined. They indicated some similarities between constructs, but also that the ADI-R measures autism in a unique fashion.

Effects of development on olanzapine-associated adverse events.

OBJECTIVE Atypical antipsychotic medications are increasingly prescribed for child and adolescent patients. Relatively little information on adverse events (AEs), specifically in children or adolescents taking atypical antipsychotics, is available. METHOD The Food and Drug Administration spontaneous AE reporting postmarketing surveillance database was queried for olanzapine until March 31, 2000. Patient exposure estimates as of the same date were provided by the manufacturer. AE complaints and exposure estimates were divided by age: children (birth-9 years), adolescents (10-19), and adults (20+). AE complaint risks per 10,000 patients exposed were calculated along with risk ratios across age groups and their 95% confidence intervals. RESULTS Extrapyramidal syndrome complaint risks were similar across development, and tardive dyskinesia complaint risks were comparable in adolescents and adults. Overrepresented AE complaints in children included sedation, weight gain, liver function abnormalities, and tardive dyskinesia. Overrepresented AE complaints in adolescents included sedation, weight gain, liver function abnormalities, and prolactin increase. CONCLUSIONS Extrapyramidal syndromes may be no more common in children and adolescents with olanzapine than in adults. The frequency of some other AEs may differ across development. Caution is warranted because of the likelihood of reporting bias. Similar analyses should be conducted with other atypical antipsychotics.

Assessment in Multisite Randomized Clinical Trials of Patients with Autistic Disorder: The Autism RUPP Network

Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders.

Relation Between Amygdala Structure and Function in Adolescents With Bipolar Disorder

OBJECTIVE Previous study supports the presence of reduced volume and elevated response to emotional stimuli in amygdala in adolescents with bipolar disorder (BD). In the present study, structural and functional magnetic resonance imaging scans were obtained during the same neuroimaging session to examine amygdala structure-function relations in adolescents with BD. We hypothesized that amygdala volume would be inversely associated with amygdala response to emotional stimuli, such that BD participants with the smallest amygdala volumes would exhibit the highest amygdala response. METHOD Fifty-one adolescents (21 with BD I and 30 control adolescents, ages 10-18 years) underwent structural and functional magnetic resonance imaging scans. Amygdala volume (n = 49) and signal change (n = 44) during emotional face processing were compared between groups, and structure-function correlations were examined within the BD group (n = 16). RESULTS Adolescents with BD showed decreased amygdala volume (p =.009) and increased amygdala response to emotional faces (p =.043). There was no significant interaction between diagnosis and emotion type. A significant inverse association between amygdala volume and activation during emotional face processing was observed (r = -0.54, p =.029). CONCLUSIONS Decreased volume and increased response to emotional stimuli in the amygdala in adolescents with BD are consistent with previous reports. This study represents the first report, to our knowledge, of the two findings in the same adolescent BD sample and supports an amygdala structure-function relation characterized by an inverse association between volume and response to emotional stimuli. This preliminary finding requires replication and suggests a possible pathophysiological link between abnormalities in amygdala structure and response to emotional stimuli in BD.

Neuropsychiatric Disorders Associated with Streptococcal Infection: A Case-Control Study among Privately Insured Children.

OBJECTIVE To assess whether antecedent streptococcal infection(s) increase the risk of subsequent diagnosis of obsessive-compulsive disorder (OCD), Tourette syndrome (TS), other tic disorders, attention-deficit/hyperactivity disorder (ADHD), or major depressive disorder (MDD) in a national sample of privately insured children. METHOD Using health insurance claims data, we compared the prior years occurrence of streptococcal infection in children ages 4 to 13 years with OCD, TS, or tic disorder newly diagnosed between January 1998 and December 2004 to that of a cohort of matched controls. Conditional logistic regression models were used to determine the association of prior streptococcal sore throat or scarlet fever with a diagnosis of OCD, TS, or tic disorder. We repeated the analyses for two other infectious diseases (otitis media and sinusitis) and one noninfectious condition (migraine). We also investigated the potential specificity of this association by performing similar analyses focused on newly diagnosed ADHD and newly diagnosed MDD. RESULTS Subjects with newly diagnosed OCD, TS, or tic disorder were more likely than controls to have had a diagnosis of streptococcal infection in the previous year (odds ratio 1.54, 95% confidence interval 1.29-2.15). Prior streptococcal infection was also associated with incident diagnoses of ADHD (odds ratio 1.20, 95% confidence interval 1.06-1.35) and MDD (odds ratio 1.63, 95% confidence interval 1.12-2.30). CONCLUSIONS These findings provide epidemiologic evidence that some pediatric-onset neuropsychiatric disorders, including OCD, tic disorders, ADHD, and MDD, may be temporally related to prior streptococcal infections. Whether this is the result of a nonspecific stress response or secondary to an activation of the immune system remains to be determined.

Adolescents in transition : school and family characteristics in the development of violent behaviors entering high school.

Adolescents are vulnerable to becoming involved in problematic behaviors, disengaging academically, and dropping out of school. This study was designed to evaluate the protective role of self-perceived school attachment and family involvement on the development of these negative behaviors during adolescence. The Social and Health Assessment (SAHA) survey was conducted among 652 predominantly minority, inner-city adolescents during their transition from middle to high school in order to examine school attachment, perceived teacher support, parental control, and exposure to community violence as predictors of engagement in violent activities, development of aggressive beliefs, perception of school climate, and academic motivation one year later. Family and school factors appeared to be differentially associated with the negative outcomes. School attachment was associated with lower levels of violent delinquency and aggressive beliefs, as well as with academic motivation. Perceived teacher support was associated with positive perceptions of school climate and with academic motivation. Parental control was associated with lower levels of violent activity and with higher levels of academic motivation. Violence exposure was related to violent delinquency and negative perception of school climate. School attachment, teacher support, parental control, and violence exposure must all be incorporated into school reform efforts intended to break the inner city cycle of violence.