Angeli Landeros-Weisenberger

A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder

As many as half of obsessive-compulsive disorder (OCD) patients treated with an adequate trial of serotonin reuptake inhibitors (SRIs) fail to fully respond to treatment and continue to exhibit significant symptoms. Many studies have assessed the effectiveness of antipsychotic augmentation in SRI-refractory OCD. In this systematic review, we evaluate the efficacy of antipsychotic augmentation in treatment-refractory OCD. The electronic databases of PubMed, PsychINFO (1967–2005), Embase (1974–2000) and the Cochrane Central Register of Controlled Trials (CENTRAL, as of 2005, Issue 3) were searched for relevant double-blind trials using keywords ‘antipsychotic agents’ or ‘neuroleptics’ and ‘obsessive-compulsive disorder’. Search results and analysis were limited to double-blind, randomized control trials involving the adult population. The proportion of subjects designated as treatment responders was defined by a greater than 35% reduction in Yale Brown Obsessive-Compulsive Scale (Y-BOCS) rating during the course of augmentation therapy. Nine studies involving 278 participants were included in the analysis. The meta-analysis of these studies demonstrated a significant absolute risk difference (ARD) in favor of antipsychotic augmentation of 0.22 (95% confidence interval (CI): 0.13, 0.31). The subgroup of OCD patients with comorbid tics have a particularly beneficial response to this intervention, ARD=0.43 (95% CI: 0.19, 0.68). There was also evidence suggesting OCD patients should be treated with at least 3 months of maximal-tolerated therapy of an SRI before initiating antipsychotic augmentation owing to the high rate of treatment response to continued SRI monotherapy (25.6%). Antipsychotic augmentation in SRI-refractory OCD is indicated in patients who have been treated for at least 3 months of maximal-tolerated therapy of an SRI. Unfortunately, only one-third of treatment-refractory OCD patients show a meaningful treatment response to antipsychotic augmentation. There is sufficient evidence in the published literature, demonstrating the efficacy of haloperidol and risperidone, and evidence regarding the efficacy of quetiapine and olanzapine is inconclusive. Patients with comorbid tics are likely to have a differential benefit to antipsychotic augmentation.

Meta-Analysis of the Symptom Structure of Obsessive-Compulsive Disorder

OBJECTIVE OCD is a clinically heterogeneous condition. This heterogeneity has the potential to reduce power in genetic, neuroimaging, and clinical trials. Despite a mounting number of studies, there remains debate regarding the exact factor structure of OCD symptoms. The authors conducted a meta-analysis to determine the factor structure of the Yale-Brown Obsessive Compulsive Scale Symptom Checklist. METHOD Studies were included if they involved subjects with OCD and included an exploratory factor analysis of the 13 Yale-Brown Obsessive Compulsive Scale Symptom Checklist categories or the items therein. A varimax-rotation was conducted in SAS 9.1 using the PROC FACTOR CORR to extract factors from sample-size weighted co-occurrence matrices. Stratified meta-analysis was conducted to determine the factor structure of OCD in studies involving children and adults separately. RESULTS Twenty-one studies involving 5,124 participants were included. The four factors generated were 1) symmetry: symmetry obsessions and repeating, ordering, and counting compulsions; 2) forbidden thoughts: aggression, sexual, religious, and somatic obsessions and checking compulsions, 3) cleaning: cleaning and contamination, and 4) hoarding: hoarding obsessions and compulsions. Factor analysis of studies including adults yielded an identical factor structure compared to the overall meta-analysis. Factor analysis of child-only studies differed in that checking loaded highest on the symmetry factor and somatic obsessions, on the cleaning factor. CONCLUSIONS A four-factor structure explained a large proportion of the heterogeneity in the clinical symptoms of OCD. Further item-level factor analyses are needed to determine the appropriate placement of miscellaneous somatic and checking OCD symptoms.

Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders.

OBJECTIVE The Food and Drug Administration currently requires the package inserts of most psychostimulant medications to list the presence of a tic disorder as a contraindication to their use. Approximately half of children with Tourettes syndrome experience comorbid attention-deficit/hyperactivity disorder (ADHD). We sought to determine the relative efficacy of different medications in treating ADHD and tic symptoms in children with both Tourettes syndrome and ADHD. METHOD We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of medications in the treatment of ADHD in the children with comorbid tics. We used a random effects meta-analysis with standardized mean difference as our primary outcome to estimate the effect size of pharmaceutical agents in the treatment of ADHD symptoms and tics. RESULTS Our meta-analysis included nine studies involving 477 subjects. We assessed the efficacy of six medications-dextroamphetamine, methylphenidate, alpha-2 agonists (clonidine and guanfacine), desipramine, atomoxetine, and deprenyl. Methylphenidate, alpha-2 agonists, desipramine, and atomoxetine demonstrated efficacy in improving ADHD symptoms in children with comorbid tics. Alpha-2 agonists and atomoxetine significantly improved comorbid tic symptoms. Although there was evidence that supratherapeutic doses of dextroamphetamine worsens tics, there was no evidence that methylphenidate worsened tic severity in the short term. CONCLUSIONS Methylphenidate seems to offer the greatest and most immediate improvement of ADHD symptoms and does not seem to worsen tic symptoms. Alpha-2 agonists offer the best combined improvement in both tic and ADHD symptoms. Atomoxetine and desipramine offer additional evidence-based treatments of ADHD in children with comorbid tics. Supratherapeutic doses of dextroamphetamine should be avoided.

Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder

We sought to determine differences in efficacy and tolerability between different doses of selective serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder (OCD) using meta-analysis. We identified 9 studies involving 2268 subjects that were randomized, double-blind placebo-controlled clinical trials that compared multiple, fixed-doses of selective serotonin reuptake inhibitors (SSRIs) to each other and to placebo in the treatment of adults with OCD. Change in Y-BOCS score, proportion of treatment responders, and dropouts (all-cause and due to side-effects) were determined for each included study. Weighted mean difference was used to examine mean change in Y-BOCS score. Pooled absolute risk difference was used to examine dichotomous outcomes. Meta-analysis was performed using a fixed effects model in RevMan 4.2.8. We found that compared with either low or medium doses, higher doses of SSRIs were associated with improved treatment efficacy, using either Y-BOCS score or proportion of treatment responders as an outcome. Dose of SSRIs was not associated with the number of all-cause dropouts. Higher doses of SSRIs were associated with significantly higher proportion of dropouts due to side-effects. These results suggests that higher doses of SSRIs are associated with greater efficacy in the treatment of OCD. This SSRI efficacy pattern stands in contrast to other psychiatric disorders like Major Depressive Disorder. This greater treatment efficacy is somewhat counterbalanced by the greater side-effect burden with higher doses of SSRIs. At present, there are insufficient data to generalize these findings to children or adolescents with OCD.

Association of the Serotonin Transporter Polymorphism and Obsessive-Compulsive Disorder: Systematic Review

We investigated the association between the long (l) and short (s) alleles of the serotonin transporter polymorphism (5‐HTTLPR) in the promoter region of the SLC6A4 gene and obsessive‐compulsive disorder (OCD) using meta‐analysis to combine all published data from case–control and family based association studies (2,283 cases). In stratified meta‐analysis we investigated whether age of sample (child and adult), ethnicity (Caucasian and Asian) and study design (case–control and family‐based association studies) moderated any association. In the overall meta‐analysis we found no evidence of association between genetic variation at the 5‐HTTLPR locus and OCD. We did find significant heterogeneity between studies. In the stratified meta‐analyses, we demonstrated a significant association between the l‐allele and OCD in family‐based association studies and in studies involving children and Caucasians. Our meta‐analysis suggests the possibility that the l‐allele may be associated with OCD in specific OCD subgroups such as childhood‐onset OCD and in Caucasians. Further meta‐analyses based on individual patient data would be helpful in determining whether age of OCD onset, gender and the presence of comorbid illness (e.g., tics) moderates the relationship between 5‐HTTLPR and OCD.

Predictors of Early Adult Outcomes in Pediatric-Onset Obsessive-Compulsive Disorder

OBJECTIVE: The aim of this study was to determine the childhood clinical predictors of early adult outcomes in pediatric-onset obsessive-compulsive disorder (OCD) and to assess whether dimensional subtypes of OCD and the presence of comorbid tic symptoms influence long-term outcomes. METHODS: We conducted a longitudinal cohort study in which 45 of 62 eligible children with OCD were reassessed an average of 9 years later, in early adulthood. Main outcome measures included expert-rated, obsessive-compulsive (OC) symptom severity and time to remission of OC symptoms. Baseline clinical characteristics were evaluated in terms of their influence on OCD severity in adulthood and time to remission of OC symptoms. RESULTS: Forty-four percent of subjects were determined to have subclinical OC symptoms at the follow-up evaluation. The absence of a comorbid tic disorder and the presence of prominent hoarding symptoms were associated with the persistence of OCD symptoms. Female gender, earlier age at childhood assessment, later age of OCD onset, more-severe childhood OCD symptoms, and comorbid oppositional defiant disorder also were associated with persistence of OCD symptoms into adulthood. CONCLUSIONS: These results confirm that a significant proportion of treated children with OCD experience remission by adulthood. The presence of comorbid tics heralds a positive outcome, whereas primary hoarding symptoms are associated with persistent OCD.

Effects of Ketamine in Treatment-Refractory Obsessive-Compulsive Disorder

BACKGROUND Treatments for obsessive-compulsive disorder (OCD) usually lead to incomplete symptom relief and take a long-time to reach full effect. Convergent evidence suggests that glutamate abnormalities contribute to the pathogenesis of OCD. Ketamine is a potent noncompetitive antagonist of the N-methyl-D-aspartate glutamate receptor. Trials have reported rapid antidepressant effects after low-dose ketamine infusion. METHODS We conducted an open-label trial of ketamine (.5 mg/kg IV over 40 min) in 10 subjects with treatment-refractory OCD. Response was defined as >35% improvement in OCD symptoms and >50% improvement in depression symptoms from baseline at any time between 1 and 3 days after infusion. RESULTS None of 10 subjects experienced a response in OCD symptoms in the first 3 days after ketamine. Four of seven patients with comorbid depression experienced an antidepressant response to ketamine in the first 3 days after infusion. Both OCD and depression symptoms demonstrated a statistically significant improvement in the first 3 days after infusion compared with baseline, but the OCD response was <12%. The percentage reduction in depressive symptoms in the first 3 days after ketamine infusion was significantly greater than the reduction in OCD symptoms. CONCLUSIONS Ketamine effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated.

Dimensional predictors of response to SRI pharmacotherapy in obsessive-compulsive disorder.

BACKGROUND Obsessive-compulsive disorder (OCD) is clinically heterogeneous. Previous studies have reported different patterns of treatment response to serotonin reuptake inhibitors (SRI) based on symptom dimension. Our objective was to replicate these results in OCD patients who participated in one of four randomized, placebo-controlled, clinical trials (RCT). METHODS A total of 165 adult OCD subjects participated in one or more eight-week RCT with clomipramine, fluvoxamine, or fluoxetine. All subjects were classified as having major or minor symptoms in four specific OC symptom dimensions that were derived in a previous factor analytic study involving many of these same patients. Ordinal logistic regression was used to test the association between OC symptom dimensions and SRI response. RESULTS We found a significant association between the symptom dimension involving sexual, religious and harm-related obsessions as well as checking compulsions (AGG/SR) and improved SRI response. This increased rate of SRI response was experienced primarily by individuals with harm-related obsessions. Over 60% of patients with AGG/SR OCD symptoms were rated as very much improved after SRI treatment. LIMITATIONS As some of the RCTs included were conducted prior to the development of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), improvement in OCD severity was assessed using the Clinical Global Improvement (CGI) Scale. Data from the double-blind and open-label continuation phases of these trials was collapsed together to increase statistical power. CONCLUSIONS Patients with OCD vary in their response to SRIs. The presence of AGG/SR symptoms is associated with an initial positive response to SRIs. These data add to the growing body of work linking central serotonin systems with aggressive behavior.

Streptococcal Upper Respiratory Tract Infections and Psychosocial Stress Predict Future Tic and Obsessive-Compulsive Symptom Severity in Children and Adolescents with Tourette Syndrome and Obsessive-Compulsive Disorder

BACKGROUND One goal of this prospective longitudinal study was to identify new group A beta-hemolytic streptococcal infections (GABHS) in children and adolescents with Tourette syndrome (TS) and/or obsessive-compulsive disorder (OCD) compared with healthy control subjects. We then examined the power of GABHS infections and measures of psychosocial stress to predict future tic, obsessive-compulsive (OC), and depressive symptom severity. METHODS Consecutive ratings of tic, OC, and depressive symptom severity were obtained for 45 cases and 41 matched control subjects over a 2-year period. Clinical raters were blinded to the results of laboratory tests. Laboratory personnel were blinded to case or control status and clinical ratings. Structural equation modeling for unbalanced repeated measures was used to assess the sequence of new GABHS infections and psychosocial stress and their impact on future symptom severity. RESULTS Increases in tic and OC symptom severity did not occur after every new GABHS infection. However, the structural equation model found that these newly diagnosed infections were predictive of modest increases in future tic and OC symptom severity but did not predict future depressive symptom severity. In addition, the inclusion of new infections in the model greatly enhanced, by a factor of three, the power of psychosocial stress in predicting future tic and OC symptom severity. CONCLUSIONS Our data suggest that a minority of children with TS and early-onset OCD were sensitive to antecedent GABHS infections. These infections also enhanced the predictive power of current psychosocial stress on future tic and OC symptom severity.

Autism spectrum and obsessive-compulsive disorders: OC behaviors, phenotypes and genetics.

Autism spectrum disorders (ASDs) are a phenotypically and etiologically heterogeneous set of disorders that include obsessive–compulsive behaviors (OCB) that partially overlap with symptoms associated with obsessive–compulsive disorder (OCD). The OCB seen in ASD vary depending on the individuals mental and chronological age as well as the etiology of their ASD. Although progress has been made in the measurement of the OCB associated with ASD, more work is needed including the potential identification of heritable endophenotypes. Likewise, important progress toward the understanding of genetic influences in ASD has been made by greater refinement of relevant phenotypes using a broad range of study designs, including twin and family‐genetic studies, parametric and nonparametric linkage analyses, as well as candidate gene studies and the study of rare genetic variants. These genetic analyses could lead to the refinement of the OCB phenotypes as larger samples are studied and specific associations are replicated. Like ASD, OCB are likely to prove to be multidimensional and polygenic. Some of the vulnerability genes may prove to be generalist genes influencing the phenotypic expression of both ASD and OCD while others will be specific to subcomponents of the ASD phenotype. In order to discover molecular and genetic mechanisms, collaborative approaches need to generate shared samples, resources, novel genomic technologies, as well as more refined phenotypes and innovative statistical approaches. There is a growing need to identify the range of molecular pathways involved in OCB related to ASD in order to develop novel treatment interventions.