Michael H. Bloch

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.

The Effect of Antidepressant Medication Treatment on Serum Levels of Inflammatory Cytokines: A Meta-Analysis

Serum levels of inflammatory cytokines, for example, tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), and IL-1 beta (IL-1β), are elevated in subjects with major depressive disorder (MDD). The reason why this occurs is unclear. Elevated levels of inflammatory cytokines could be a result of brain dysfunction in MDD. It is also possible that inflammatory cytokines contribute to depressive symptoms in MDD. If the first assumption is correct, one would expect levels to normalize with resolution of the depressive episode after treatment. Several studies have measured changes in cytokine levels during antidepressant treatment; however, the results vary. The purpose of this study was to pool all available data on changes in serum levels of TNFα, IL-6, and IL-1β during antidepressant treatment to determine whether these levels change. Studies were included if they used an approved pharmacological treatment for depression, patients had a diagnosis of MDD, and serum levels of TNFα, IL-6, and/or IL-1β were measured before and after treatment. Twenty-two studies fulfilled these criteria. Meta-analysis of these studies showed that, overall, while pharmacological antidepressant treatment reduced depressive symptoms, it did not reduce serum levels of TNFα. On the other hand, antidepressant treatment did reduce levels of IL-1β and possibly those of IL-6. Stratified subgroup analysis by class of antidepressant indicated that serotonin reuptake inhibitors may reduce levels of IL-6 and TNFα. Other antidepressants, while efficacious for depressive symptoms, did not appear to reduce cytokine levels. These results argue against the notion that resolution of a depressive episode is associated with normalization of levels of circulating inflammatory cytokines; however, the results are consistent with the possibility that inflammatory cytokines contribute to depressive symptoms and that antidepressants block the effects of inflammatory cytokines on the brain.

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.

Caudate volumes in childhood predict symptom severity in adults with Tourette syndrome

Background: Most children with Tourette syndrome (TS) experience a marked decline in the severity of tic symptoms during adolescence. Currently no clinical measures can predict whose tic symptoms will persist into adulthood. Previous cross-sectional imaging studies have identified reduced caudate nucleus volumes in subjects with TS. Objective: To evaluate whether caudate nucleus volumes in childhood can predict the severity of tic or obsessive–compulsive symptoms at follow-up in early adulthood. Methods: In a prospective longitudinal study, clinical status and basal ganglia volumes of 43 children with TS were measured on high-resolution magnetic resonance images before age 14 years. Follow-up clinical assessments were conducted after age 16 years, an average of 7.5 years later. Linear regression and Tobit regression analyses were used to assess the association of basal ganglia volumes measured in childhood with the severity of tic and obsessive–compulsive disorder (OCD) symptoms at the time of childhood MRI and at follow-up in early adulthood. Results: Volumes of the caudate nucleus correlated significantly and inversely with the severity of tic and OCD symptoms in early adulthood. Caudate volumes did not correlate with the severity of symptoms at the time of the MRI scan. Conclusions: Caudate volumes in children with Tourette syndrome predict the severity of tic and obsessive–compulsive symptoms in early adulthood. This study provides compelling evidence that morphologic disturbances of the caudate nucleus within cortico-striatal-thalamo-cortical circuits are central to the persistence of both tics and obsessive–compulsive symptoms into adulthood.

Clinical course of Tourette syndrome

OBJECTIVE Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by multiple motor and vocal tics lasting at least a year in duration. Children with TS often experience comorbid conditions such as obsessive-compulsive disorder (OCD) and attention-deficit disorder. The goal of this article was to review the long-term clinical course of tics and comorbid conditions in children with TS. METHOD We conducted a traditional literature search to locate relevant articles regarding long-term outcome and prognosis in TS and tic disorders. RESULTS Tics typically have an onset between the ages of 4 and 6 years and reach their worst-ever severity between the ages of 10 and 12 years. On average, tic severity declines during adolescence. By early adulthood, roughly three-quarters of children with TS will have greatly diminished tic symptoms and over one-third will be tic free. Comorbid conditions, such as OCD and other anxiety and depressive disorders, are more common during the adolescence and early adulthood of individuals with TS than in the general population. CONCLUSION Although tics are the sine qua non of TS, they are often not the most enduring or impairing symptoms in children with TS. Measures used to enhance self-esteem, such as encouraging strong friendships and the exploration of interests, are crucial to ensuring positive adulthood outcome in TS.

Omega-3 Fatty Acid Supplementation for the Treatment of Children With Attention-Deficit/Hyperactivity Disorder Symptomatology: Systematic Review and Meta-Analysis

OBJECTIVE Several studies have demonstrated differences in omega-3 fatty acid composition in plasma and in erythrocyte membranes in patients with attention-deficit/hyperactivity disorder (ADHD) compared with unaffected controls. Omega-3 fatty acids have anti-inflammatory properties and can alter central nervous system cell membrane fluidity and phospholipid composition. Cell membrane fluidity can alter serotonin and dopamine neurotransmission. The goal of this meta-analysis was to examine the efficacy of omega-3 fatty acid supplementation in children with ADHD. METHOD PubMed was searched for randomized placebo-controlled trials examining omega-3 fatty acid supplementation in children with ADHD symptomatology. The primary outcome measurement was standardized mean difference in rating scales of ADHD severity. Secondary analyses were conducted to determine the effects of dosing of different omega-3 fatty acids in supplements. RESULTS Ten trials involving 699 children were included in this meta-analysis. Omega-3 fatty acid supplementation demonstrated a small but significant effect in improving ADHD symptoms. Eicosapentaenoic acid dose within supplements was significantly correlated with supplement efficacy. No evidence of publication bias or heterogeneity between trials was found. CONCLUSION Omega-3 fatty acid supplementation, particularly with higher doses of eicosapentaenoic acid, was modestly effective in the treatment of ADHD. The relative efficacy of omega-3 fatty acid supplementation was modest compared with currently available pharmacotherapies for ADHD such as psychostimulants, atomoxetine, or α(2) agonists. However, given its relatively benign side-effect profile and evidence of modest efficacy, it may be reasonable to use omega-3 fatty supplementation to augment traditional pharmacologic interventions or for families who decline other psychopharmacologic options.

Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis.

We conducted a meta-analysis of randomized, placebo-controlled trials of omega-3 fatty acid (FA) treatment of major depressive disorder (MDD) in order to determine efficacy and to examine sources of heterogeneity between trials. PubMed (1965-May 2010) was searched for randomized, placebo-controlled trials of omega-3 FAs for MDD. Our primary outcome measure was standardized mean difference in a clinical measure of depression severity. In stratified meta-analysis, we examined the effects of trial duration, trial methodological quality, baseline depression severity, diagnostic indication, dose of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in omega-3 preparations, and whether omega-3 FA was given as monotherapy or augmentation. In 13 randomized, placebo-controlled trials examining the efficacy of omega-3 FAs involving 731 participants, meta-analysis demonstrated no significant benefit of omega-3 FA treatment compared with placebo (standard mean difference (SMD)=0.11, 95% confidence interval (CI): −0.04, 0.26). Meta-analysis demonstrated significant heterogeneity and publication bias. Nearly all evidence of omega-3 benefit was removed after adjusting for publication bias using the trim-and-fill method (SMD=0.01, 95% CI: −0.13, 0.15). Secondary analyses suggested a trend toward increased efficacy of omega-3 FAs in trials of lower methodological quality, trials of shorter duration, trials which utilized completers rather than intention-to-treat analysis, and trials in which study participants had greater baseline depression severity. Current published trials suggest a small, non-significant benefit of omega-3 FAs for major depression. Nearly all of the treatment efficacy observed in the published literature may be attributable to publication bias.

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.

GLUTAMATE ABNORMALITIES IN OBSESSIVE COMPULSIVE DISORDER: NEUROBIOLOGY, PATHOPHYSIOLOGY, AND TREATMENT

Obsessive compulsive disorder is prevalent, disabling, incompletely understood, and often resistant to current therapies. Established treatments consist of specialized cognitive-behavioral psychotherapy and pharmacotherapy with medications targeting serotonergic and dopaminergic neurotransmission. However, remission is rare, and more than a quarter of OCD sufferers receive little or no benefit from these approaches, even when they are optimally delivered. New insights into the disorder, and new treatment strategies, are urgently needed. Recent evidence suggests that the ubiquitous excitatory neurotransmitter glutamate is dysregulated in OCD, and that this dysregulation may contribute to the pathophysiology of the disorder. Here we review the current state of this evidence, including neuroimaging studies, genetics, neurochemical investigations, and insights from animal models. Finally, we review recent findings from small clinical trials of glutamate-modulating medications in treatment-refractory OCD. The precise role of glutamate dysregulation in OCD remains unclear, and we lack blinded, well-controlled studies demonstrating therapeutic benefit from glutamate-modulating agents. Nevertheless, the evidence supporting some important perturbation of glutamate in the disorder is increasingly strong. This new perspective on the pathophysiology of OCD, which complements the older focus on monoaminergic neurotransmission, constitutes an important focus of current research and a promising area for the ongoing development of new therapeutics.

NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia

Glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain’s global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate’s role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.