Gregory L. Hanna

Demographic and Clinical Features of Obsessive-Compulsive Disorder in Children and Adolescents

OBJECTIVE To describe the demography, symptomatology, and comorbidity of 31 clinically referred children and adolescents with obsessive-compulsive disorder. METHOD The patients were assessed in an outpatient clinic for lifetime psychopathology with the Diagnostic Interview for Children and Adolescents. The child and adolescent version of the Yale-Brown Obsessive Compulsive Scale (CY-BOCS) was used to group obsessive-compulsive symptoms and rate symptom severity. Demographic, medical, developmental, academic, and behavioral information was recorded by the parents in the Yale Childrens Inventory and the Child Behavior Checklist. RESULTS The male-female ratio was approximately 3:2. Most patients had had multiple obsessions and compulsions that had changed over time. The CY-BOCS correlated highly with another measure of obsessive-compulsive behavior, but not with any of the Child Behavior Checklist scales. Symptom severity was influenced by an interaction between gender and age at onset of the illness. More than 80% of the subjects had other lifetime psychiatric diagnoses. CONCLUSIONS The results provide further evidence that obsessive-compulsive disorder is a chronic, severe illness in children and adolescents that is often associated with other forms of psychopathology. The data support the concurrent and discriminant validity of the CY-BOCS.

Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder.

The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (l) and short (s) variants of the HTT promoter have different transcriptional efficiencies. HTT promoter genotype and blood 5-HT concentration were examined in 70 subjects from 20 families ascertained through children and adolescents with a DSM-III-R diagnosis of OCD. The HTT promoter variant had a significant effect on blood 5-HT content. Subjects with the l/l and l/s genotypes had significantly higher blood 5-HT levels than did those with the s/s genotype. There was a significant interaction between HTT promoter genotype and seasonal variation in blood 5-HT content, with significant seasonal differences in 5-HT occurring only in the subjects with thel/l genotype. Further studies of the regulation of HTT gene expression are indicated.

A family study of obsessive-compulsive disorder with pediatric probands

Obsessive‐compulsive disorder (OCD) is a heterogeneous disorder of unknown etiology. We examined the lifetime history of obsessions, compulsions, and OCD in the first‐ and second‐degree relatives of 35 pediatric probands with OCD and 17 controls with no psychiatric diagnosis. All available first‐degree relatives were directly interviewed blind to proband status with two semi‐structured interviews. Parents were also interviewed to systematically assess the family psychiatric history of first‐ and second‐degree relatives. Best‐estimate lifetime diagnoses were made using all available sources of information. Data were analyzed with logistic regression by the generalized estimating equation method and with robust Cox regression models. The lifetime prevalence of definite OCD was significantly higher in case than control first‐degree relatives (22.5% vs. 2.6%, P < 0.05). Compared to controls, case first‐degree relatives also had significantly higher lifetime rates of obsessions and compulsions (both P < 0.05). There was no significant difference between case and control second‐degree relatives in lifetime rates of OCD. First‐degree relatives of case probands with ordering compulsions had a significantly higher lifetime rate of definite and subthreshold OCD than relatives of case probands without ordering compulsions (45.4% vs. 18.8%, P < 0.05). The lifetime prevalence of definite OCD was significantly higher in case first‐degree relatives with a history of tics than in case first‐degree relatives without a tic history (57.1% vs. 20.9%, P < 0.01). The results provide further evidence that early‐onset OCD is highly familial and suggest that two clinical variables are associated with its familial aggregation.

The role of glutamate signaling in the pathogenesis and treatment of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a common and often debilitating neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions) and excessive anxiety. While the neurobiology and etiology of OCD has not been fully elucidated, there is growing evidence that disrupted neurotransmission of glutamate within corticalstriatal-thalamocortical (CSTC) circuitry plays a role in OCD pathogenesis. This review summarizes the findings from neuroimaging, animal model, candidate gene and treatment studies in the context of glutamate signaling dysfunction in OCD. First, studies using magnetic resonance spectroscopy are reviewed demonstrating altered glutamate concentrations in the caudate and anterior cingulate cortex of patients with OCD. Second, knockout mouse models, particularly the DLGAP3 and Sltrk5 knockout mouse models, display remarkably similar phenotypes of compulsive grooming behavior associated with glutamate signaling dysfunction. Third, candidate gene studies have identified associations between variants in glutamate system genes and OCD, particularly for SLC1A1 which has been shown to be associated with OCD in five independent studies. This converging evidence for a role of glutamate in OCD has led to the development of novel treatment strategies involving glutamatergic compounds, particularly riluzole and memantine. We conclude the review by outlining a glutamate hypothesis for OCD, which we hope will inform further research into etiology and treatment for this severe neuropsychiatric condition.

Prepulse inhibition of startle and the neurobiology of primary nocturnal enuresis

BACKGROUND Children with primary nocturnal enuresis (PNE) wet the bed during all stages of sleep and irrespective of state of arousal, suggesting that during sleep, when voluntary, i.e., cortical control, is not available, the signal from the distended bladder is not registered in the subcortical centers inhibiting micturition. Deficient prepulse inhibition (PPI) of startle has been reported in PNE. This study evaluates the association of this PPI deficit in PNE with comorbidity with attention-deficit hyperactivity disorder (ADHD) and with intelligence. METHODS Prepulse modulation of startle was studied in 96 boys with PNE and 105 nonenuretic boys using intervals of 60, 120, and 4000 msec between the onset of a 75-dB 1000-Hz tone and a 104-dB noise burst. Thirty-one percent of the enuretic and 36% of the nonenuretic boys were diagnosed with ADHD. RESULTS After adjustment for presence or absence of ADHD, lower or higher IQ, age, and unmodulated startle amplitude, there was a significant association between PNE and deficient PPI of startle following the 120-msec prepulse interval. Those enuretic boys who also were ADHD or had higher performance IQs (> or = 110) showed the greatest PPI deficit. CONCLUSIONS A common deficiency of inhibitory signal processing in the brain stem may underlie both deficient PPI and the inability to inhibit micturition in PNE. Strong familiarity for PNE, ADHD, and intelligence suggests a possible genetic mediation of these effects.

Altered function and connectivity of the medial frontal cortex in pediatric obsessive compulsive disorder

BACKGROUND Exaggerated concern for correct performance has been linked to hyperactivity of the medial frontal cortex (MFC) in adult obsessive-compulsive disorder (OCD), but the role of the MFC during the early course of illness remains poorly understood. We tested whether hyperactive MFC-based performance monitoring function relates to altered MFC connectivity within task control and default mode networks in pediatric patients. METHODS Eighteen pairs of OCD and matched healthy youth underwent functional magnetic resonance imaging during performance monitoring and at rest. Task-related hyperactivations in the posterior and ventral MFC were used as seeds for connectivity analyses during task and resting state. RESULTS In posterior MFC, patients showed greater activation of dorsal anterior cingulate cortex (dACC) than control subjects, with greater activation predicting worse performance. In ventral MFC, control subjects exhibited deactivation, whereas patients activated this region. Compared with control subjects, patients showed increased dACC-ventral MFC connectivity during task and decreased dACC-right anterior operculum and ventral MFC-posterior cingulate connectivity during rest. CONCLUSIONS Excessive activation and increased interactions of posterior and ventral MFC during performance monitoring may combine with reduced resting state connectivity of these regions within networks for task control and default mode to reflect early markers of OCD. Alteration of reciprocal interactions between these networks could potentiate the intrusion of ventral MFC-based affectively laden, self-referential thoughts, while disrupting posterior MFC-based performance-monitoring function in young patients.

Whole blood serotonin and disruptive behaviors in juvenile obsessive-compulsive disorder

OBJECTIVE The study was conducted with children and adolescents with obsessive-compulsive disorder (OCD) to assess the relationship of whole blood serotonin (5-HT) content to a concurrent diagnosis of a disruptive behavior disorder (DBD) and to severity ratings of aggressive behavior. METHOD Eighteen children and adolescents who met DSM-III-R criteria for OCD were evaluated with a structured interview, clinician rating scales, and the Child Behavior Checklist (CBCL). Blood 5-HT concentration was assayed with a fluorometric procedure. Relationships among categorical diagnoses, dimensional ratings, and blood 5-HT content were analyzed with bivariate and multivariate techniques. RESULTS OCD subjects with a DBD (n = 6) had significantly higher scores than those without a DBD (n = 12) on the Total Problem scale, the Externalizing Problem scale, and several of the behavioral syndrome scales of the CBCL. Blood 5-HT concentrations were significantly lower in those with a DBD than in those without a DBD, and blood 5-HT concentrations had significant negative correlations with the Total score, the Externalizing score, and the Aggressive Behavior score of the CBCL. CONCLUSIONS The results provide further evidence of a significant relationship between aggressive behavior and serotonergic functioning.

Developmental Alterations of Frontal-Striatal-Thalamic Connectivity in Obsessive-Compulsive Disorder

OBJECTIVE Pediatric obsessive-compulsive disorder is characterized by abnormalities of frontal-striatal-thalamic circuitry that appear near illness onset and persist over its course. Distinct frontal-striatal-thalamic loops through cortical centers for cognitive control (anterior cingulate cortex) and emotion processing (ventral medial frontal cortex) follow unique maturational trajectories, and altered connectivity within distinct loops may be differentially associated with OCD at specific stages of development. METHOD Altered development of striatal and thalamic connectivity to medial frontal cortex was tested in 60 OCD patients compared with 61 healthy control subjects at child, adolescent, and adult stages of development, using resting-state functional connectivity MRI. RESULTS OCD in the youngest patients was associated with reduced connectivity of dorsal striatum and medial dorsal thalamus to rostral and dorsal anterior cingulate cortex, respectively. Increased connectivity of dorsal striatum to ventral medial frontal cortex was observed in patients at all developmental stages. In child patients, reduced connectivity between dorsal striatum and rostral anterior cingulate cortex correlated with OCD severity. CONCLUSIONS Frontal-striatal-thalamic loops involved in cognitive control are hypoconnected in young patients near illness onset, whereas loops implicated in emotion processing are hyperconnected throughout the illness.

Association studies of serotonin system candidate genes in early-onset obsessive-compulsive disorder.

BACKGROUND Family-based evidence for association at serotonin system genes SLC6A4, HTR1B, HTR2A, and brain-derived neurotrophic factor (BDNF) has been previously reported in obsessive-compulsive disorder (OCD). Early-onset OCD is a more familial form of the disorder. METHODS We used the transmission-disequilibrium test of association at common polymorphisms in each of these genes in 54 parent-child trios ascertained through probands with early-onset OCD. RESULTS No evidence for association was detected at any of the polymorphisms in the entire set of subjects. Nominally significant association was found at the HTR2A rs6311 polymorphism in subjects with tic disorder and OCD (p = .05), replicating a previous finding in Tourette syndrome and OCD. Nominally significant association was also found for the SLC6A4 HT transporter gene-linked polymorphic region (5-HTTLPR) polymorphism for female subjects (p = .03). Neither association would remain significant after statistical correction for multiple testing. Despite no individual study reporting replication, a pooled analysis of five replication studies of the SLC6A4 5-HTTLPR polymorphism supports association (p = .02). CONCLUSIONS Low power across individual association studies in OCD may lead to a false acceptance of the null hypothesis. Accumulation of evidence from multiple studies will be necessary to evaluate the potential role for these genes in contributing to susceptibility to OCD.

Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive-compulsive disorder

In this preliminary study, 16 psychotropic-naïve pediatric patients with obsessive-compulsive disorder (OCD) were studied using magnetic resonance spectroscopy (MRS) and genotyped for six candidate polymorphisms in two glutamate system genes. A significant association was identified between the rs1019385 polymorphism of the glutamate receptor, ionotropic, N-methyl-d-aspartate 2B (GRIN2B) and decreased anterior cingulate cortex (ACC) glutamatergic concentration (Glx) but not with occipital Glx. These results suggest that GRIN2B may be associated with Glx in the ACC, a region consistently implicated in OCD.