S. Evelyn Stewart

Impact of comorbidity on treatment response to paroxetine in pediatric obsessive-compulsive disorder: is the use of exclusion criteria empirically supported in randomized clinical trials?

OBJECTIVE To examine the influence of psychiatric comorbidity on response and relapse rates in children and adolescents treated with paroxetine for obsessive-compulsive disorder (OCD). METHODS Patients responding following 16 weeks of treatment (phase I) were randomized to continued paroxetine or to placebo for 16 additional weeks (phase II). OCD response (phase I) and relapse (phase II) criteria were based on the Clinical Global Impression-Improvement Scale and the Childrens Yale-Brown Obsessive Compulsive Scale. The presence of OCD and other psychiatric disorders was ascertained using the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version interview. RESULTS At entry, 193 of 335 (57.6%) patients had at least one psychiatric disorder in addition to OCD, and 102 of 335 (30.4%) had multiple other disorders. Although the response rate to paroxetine in the overall population was high (71%), the response rates in patients with comorbid attention deficit hyperactivity disorder, tic disorder, or oppositional defiant disorder (56%, 53%, and 39%, respectively) were significantly less than in patients with OCD only (75%) (intent-to-treat population, last observation carried forward analysis, p < 0.05). Psychiatric comorbidity was associated with a greater rate of relapse in the total patient population (46% for one or more comorbid disorders [p = 0.04] and 56% for two or more comorbid disorders [p < 0.05] vs. 32% for no comorbidity). CONCLUSIONS The results of these post hoc analyses show that comorbid illness adversely impacted response to pharmacotherapy with paroxetine in pediatric OCD and significantly increased risk of relapse following withdrawal from treatment. Continued paroxetine treatment reduced the relapse rates in all groups compared with placebo, including those with comorbid illness. Because pediatric OCD is frequently comorbid with other psychiatric disorders, results of randomized, controlled pediatric OCD trials that use multiple exclusion criteria may not generalize to more naturalistic OCD samples.

Association of the SLC1A1 glutamate transporter gene and obsessive‐compulsive disorder

Context: Obsessive‐Compulsive Disorder (OCD) is a debilitating illness with putative glutamatergic abnormalities. Two separate proximal haplotypes in the glutamate transporter gene, SLC1A1, were recently reported to be associated with OCD among males, but replication is required. Objectives: This study examines SLC1A1 as a candidate gene for OCD and explores gender influences. It was hypothesized that a significant association between SLC1A1 and OCD would be replicated in an independent sample of males but not females. Design: Family‐based association candidate gene study. Setting: Participants were recruited from tertiary care OCD specialty clinics. Participants: OCD probands and their first degree relatives. Main outcomes measures: Association of OCD with genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes. Results: Association between OCD and the three‐marker haplotype rs12682807/ rs2072657/ rs301430, with overtransmission of A/T/T, was observed in both genders combined (global P = 0.0015) and in males (global P = 0.0031). Single‐marker associations with OCD in the region (rs3780412 and rs2228622) demonstrated modest significance (permuted P = 0.045). Conclusions: This study identifies a significant association between the SLC1A1 glutamate transporter gene and OCD in a haplotype overlapping with that recently reported.

Principal Components Analysis of Obsessive-Compulsive Disorder Symptoms in Children and Adolescents

BACKGROUND Obsessive-compulsive disorder (OCD) has a broadly diverse clinical expression that may reflect etiologic heterogeneity. Several adult studies have identified consistent symptom dimensions of OCD. The purpose of this study was to conduct an exploratory principal components analysis of obsessive-compulsive (OC) symptoms in children and adolescents with OCD to identify improved phenotypes for future studies. METHODS This study examined lifetime occurrence of OC symptoms included in the 13 symptom categories of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Childrens Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Principal components analysis with promax rotation was performed on 231 children and adolescents with OCD and compared with results of similar adult studies. RESULTS A four-factor solution emerged explaining 59.8% of symptom variance characterized by 1) symmetry/ordering/repeating/checking; 2) contamination/cleaning/aggressive/somatic; 3) hoarding; and 4) sexual/religious symptoms. All factors included core symptoms that have been consistently observed in adult studies of OCD. CONCLUSIONS In children and adolescents, OCD is a multidimensional disorder. Symptom dimensions are predominantly congruent with those described in similar studies of adults with OCD, suggesting fairly consistent covariation of OCD symptoms through the developmental course. Future work is required to understand changes in specific symptom dimensions observed across the life span.

A Single-Blinded Case-Control Study of Memantine in Severe Obsessive-Compulsive Disorder

Background: Obsessive-compulsive disorder (OCD) is a common debilitating psychiatric illness that typically improves but does not remit with first-line medication and behavioral treatments. Serotonergic agents including selective serotonin reuptake inhibitors and clomipramine have provided the mainstay of OCD medication management for decades. Combined dopamine/serotonergic agents such as atypical antipsychotics are presently the only OCD-augmenting strategies proven effective via randomized controlled trials. Despite increasing evidence for a pathogenic role of glutamate in OCD, no controlled trials of glutamatergic augmenting agents have been reported. Methods: An intent-to-treat sample included 44 subjects receiving standard treatment at the McLean/Massachusetts General Hospital Intensive Residential Treatment (IRT) program, 22 of whom also received memantine augmentation. Admission, monthly and discharge measures of OCD, depression, and psychosocial functioning were collected by raters blinded to augmentation status. Matched controls were selected based on sex, initial OCD severity, psychosocial functioning, and timing of admission. The Clinical Global Improvement Scale captured global clinical change. Results: Mean (SD) Yale-Brown Obsessive Compulsive Scale score decreases were 7.2 (6.4) among the cases and 4.6 (5.9) among the matched controls, reflecting mean clinical improvement among the cases (27.0% decrease) but not the controls (16.5% decrease). Mean (SD) depression severity score decreases were 5.8 (9.5) among the cases and 4.7 (9.9) among the controls. Initial intrusive obsessions were significantly more severe among marked responders compared with limited response or nonresponse cases (4.4 vs 2.9; t = 2.15; P = 0.048). Conclusions: This study provides preliminary supportive evidence for the effectiveness of memantine as a glutamatergic augmenting agent in severe OCD. Future randomized double-blind placebo-controlled trials are warranted.

Symptom Dimensions in OCD: Item-Level Factor Analysis and Heritability Estimates

To reduce the phenotypic heterogeneity of obsessive-compulsive disorder (OCD) for genetic, clinical and translational studies, numerous factor analyses of the Yale-Brown Obsessive Compulsive Scale checklist (YBOCS-CL) have been conducted. Results of these analyses have been inconsistent, likely as a consequence of small sample sizes and variable methodologies. Furthermore, data concerning the heritability of the factors are limited. Item and category-level factor analyses of YBOCS-CL items from 1224 OCD subjects were followed by heritability analyses in 52 OCD-affected multigenerational families. Item-level analyses indicated that a five factor model: (1) taboo, (2) contamination/cleaning, (3) doubts, (4) superstitions/rituals, and (5) symmetry/hoarding provided the best fit, followed by a one-factor solution. All 5 factors as well as the one-factor solution were found to be heritable. Bivariate analyses indicated that the taboo and doubts factor, and the contamination and symmetry/hoarding factor share genetic influences. Contamination and symmetry/hoarding show shared genetic variance with symptom severity. Nearly all factors showed shared environmental variance with each other and with symptom severity. These results support the utility of both OCD diagnosis and symptom dimensions in genetic research and clinical contexts. Both shared and unique genetic influences underlie susceptibility to OCD and its symptom dimensions.

Four-factor structure of obsessive-compulsive disorder symptoms in children, adolescents, and adults.

OBJECTIVE To determine whether the four-factor category-based obsessive-compulsive disorder (OCD) symptom structure from a previous confirmatory factor analysis (CFA) may be appropriately used in child, adolescent, and adult groups. Symptom dimensions are increasingly used as quantitative traits in genetic, neuroimaging, and treatment studies of OCD across all ages. Identification of a category-based OCD symptom dimension structure that is validated for use across child, adolescent, and adult age groups is necessary to guide ongoing translational research. METHOD Four OCD samples comprising 356 individuals were divided into child, adolescent, and adult groups. The fit of the only CFA-defined four-factor model was compared across these independent age group samples. Multiple-group CFA using maximum likelihood estimation assessed adequacy of fit comparing unconstrained and measurement weight-constrained models. The fit of previous exploratory factor analysis-defined three- and five-factor models on adults was also examined using CFA. RESULTS A four-factor solution provided adequate but imperfect fit across age groups, with comparable indices to the only previous OCD CFA: factor 1 (aggressive/sexual/religious/somatic/checking); factor 2 (symmetry/ordering/counting/repeating); factor 3 (contamination/cleaning), and factor 4 (hoarding). Models in which factor loadings were constrained and unconstrained across the three age groups yielded comparable model fit. Factors were highly correlated and were not mutually exclusive. The four-factor solution provided an improved fit to both three- and five-factor solutions using CFA across the three age groups. CONCLUSIONS A four-factor, CFA-defined, category-based model of OCD symptom dimensions is adequate for use in children, adolescents, and adult age groups. The factor structure of this multiple age group sample has limitations and is imperfect, but current findings support the comparability of the defined latent OCD dimensions across age groups. Further work is needed to optimize a comprehensive symptom dimension model reflecting clinical heterogeneity for use in emergent translational studies.

Predictors of Family Accommodation in Obsessive-Compulsive Disorder

BACKGROUND Obsessive-compulsive disorder (OCD) is a serious, disabling illness. Family members are frequently involved by attempting to stop rituals or by performing rituals for their relative. Factors associated with family accommodation of OCD have been largely overlooked in the literature. This study aims to identify the frequency and clinical predictors of OCD family accommodation behaviors. METHODS Participants include those with a first admission to the McLean/Massachusetts General Hospital OCD Institute (N = 110). The Family Accommodation Scale was completed independently by family members. Univariate relationships between factors and family accommodation were assessed via graphs, parametric and non-parametric testing. Multiple regression analyses modeled relationships between family accommodation and predictor variables. RESULTS Family accommodation was reported in 96.9% of cases, and predominantly occurred at least daily (59.1% of cases). Most common behaviors included providing reassurance and waiting for ritual completion. Two of 13 potential predictors were significantly correlated with family accommodation both in univariate regression analysis and in the final regression model (F = 10.15; p < 0.0001; R-square = 0.17; adjusted R-Square = 0.15). These include OCD severity (p = 0.0007) and the cleaning/contamination symptom dimension (p = 0.03). CONCLUSIONS Family accommodation is ubiquitous in OCD. Psychoeducation regarding potential deleterious effects of accommodation must not be overlooked in management of this illness.

Suicidal Children and Adolescents With First Emergency Room Presentations: Predictors of Six-Month Outcome

OBJECTIVE To examine risk of future documented suicide attempts and emergency room (ER) returns among children and adolescents with first suicidal ER presentations. METHOD A total of 548 consecutive ER presentations of suicidal 5- to 19-year-olds to a Canadian center over a 1-year period (1997-1998) were reviewed. Relative risk analyses were performed on 224 first-time patients (mean age 14.6+/-2.1) to determine the strength of associations between predictors and outcomes (ER return and suicide attempts). RESULTS At 6-month follow-up, 32.6% (n = 73) had returned to the ER, 24.1% (n = 54) had a documented suicide attempt, and 14.3% (n = 32) required psychiatric hospitalization. Predictors for both ER return and future documented suicide attempts included 15- to 19-year age range, past foster/group home placement, past mental health care, a suicide plan, reported mood symptoms, sobriety at ER visit, and general substance use. Child welfare guardianship and abuse history were also predictors of ER returns. CONCLUSIONS Clinicians should be aware of these risk factors when assessing and managing suicidal youths with first ER presentations.

Structural Differences in Adult Orbital and Ventromedial Prefrontal Cortex Predicted by Infant Temperament at 4 Months of Age

CONTEXT The term temperament refers to a biologically based predilection for a distinctive pattern of emotions, cognitions, and behaviors first observed in infancy or early childhood. High-reactive infants are characterized at age 4 months by vigorous motor activity and crying in response to unfamiliar visual, auditory, and olfactory stimuli, whereas low-reactive infants show low motor activity and low vocal distress to the same stimuli. High-reactive infants are biased to become behaviorally inhibited in the second year of life, defined by timidity with unfamiliar people, objects, and situations. In contrast, low-reactive infants are biased to develop into uninhibited children who spontaneously approach novel situations. OBJECTIVE To examine whether differences in the structure of the ventromedial or orbitofrontal cerebral cortex at age 18 years are associated with high or low reactivity at 4 months of age. DESIGN Structural magnetic resonance imaging in a cohort of 18-year-olds enrolled in a longitudinal study. Temperament was determined at 4 months of age by direct observation in the laboratory. SETTING Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital. PARTICIPANTS Seventy-six subjects who were high-reactive or low-reactive infants at 4 months of age. MAIN OUTCOME MEASURE Cortical thickness. RESULTS Adults with a low-reactive infant temperament, compared with those categorized as high reactive, showed greater thickness in the left orbitofrontal cortex. Subjects categorized as high reactive in infancy, compared with those previously categorized as low reactive, showed greater thickness in the right ventromedial prefrontal cortex. CONCLUSIONS To our knowledge, this is the first demonstration that temperamental differences measured at 4 months of age have implications for the architecture of human cerebral cortex lasting into adulthood. Understanding the developmental mechanisms that shape these differences may offer new ways to understand mood and anxiety disorders as well as the formation of adult personality.

Cognitive Inflexibility and Frontal-Cortical Activation in Pediatric Obsessive-Compulsive Disorder

OBJECTIVE Deficits in cognitive flexibility and response inhibition have been linked to perturbations in cortico-striatal-thalamic circuitry in adult obsessive-compulsive disorder (OCD). Although similar cognitive deficits have been identified in pediatric OCD, few neuroimaging studies have been conducted to examine its neural correlates in the developing brain. In this study, we tested hypotheses regarding group differences in the behavioral and neural correlates of cognitive flexibility in a pediatric OCD and a healthy comparison (HC) sample. METHOD In this functional magnetic resonance imaging (fMRI) study, a pediatric sample of 10- to 17-year-old subjects, 15 with OCD and 20 HC, completed a set-shifting task. The task, requiring an extradimensional shift to identify a target, examines cognitive flexibility. Within each block, the dimension (color or shape) that identified the target either alternated (i.e., mixed) or remained unchanged (i.e., repeated). RESULTS Compared with the HC group, the OCD group tended to be slower to respond to trials within mixed blocks. Compared with the HC group, the OCD group exhibited less left inferior frontal gyrus/BA47 activation in the set-shifting contrast (i.e., HC > OCD, mixed versus repeated); only the HC group exhibited significant activation in this region. The correlation between set shifting-induced right caudate activation and shift cost (i.e., reaction time differential in response to mixed versus repeated trials) was significantly different between HC and OCD groups, in that we found a positive correlation in HC and a negative correlation in OCD. CONCLUSIONS In pediatric OCD, less fronto-striatal activation may explain previously identified deficits in shifting cognitive sets.