Michael A. Bengtson

D-cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder

Obsessive–compulsive disorder is a common, chronic, and oftentimes disabling disorder. The only established first-line treatments for obsessive–compulsive disorder are exposure and response prevention therapy and the serotonin reuptake inhibitors. Many patients do not experience complete symptom resolution with either modality and require augmentation approaches. Recent animal and clinical data suggest that D-cycloserine, a partial agonist that acts at the strychnine-insensitive glycine-recognition site of the N-methyl-D-aspartate receptor complex, may enhance extinction learning that occurs in exposure-based psychotherapies. Given this, this study examined if D-cycloserine (250 mg) enhances the overall efficacy and rate of change of exposure and response prevention therapy for adult obsessive–compulsive disorder. Participants were 24 adults meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for obsessive–compulsive disorder. The study design was a randomized, double-blinded, placebo-controlled augmentation trial examining exposure and response prevention therapy+D-cycloserine versus exposure and response prevention therapy+placebo. All patients received 12 weekly sessions of exposure and response prevention treatment. The first session involved building a ritual hierarchy and providing psychoeducation about obsessive–compulsive disorder. The second session involved a practice exposure. Sessions 3–12 involved exposure and response prevention exercises. D-cycloserine or placebo (250 mg) was taken 4 h before every session. No significant group differences were found across outcome variables. The rate of improvement did not differ between groups. The present results fail to support the use of D-cycloserine with exposure and response prevention therapy for adult obsessive–compulsive disorder. As this study is the first to explore this question and a number of methodological issues must be considered when interpreting the findings, the conclusions that may be drawn from our results are limited.

A Preliminary Study of D-Cycloserine Augmentation of Cognitive-Behavioral Therapy in Pediatric Obsessive-Compulsive Disorder

BACKGROUND Research on the neural circuitry underlying fear extinction has led to the examination of D-cycloserine (DCS), a partial agonist at the N-methyl-D-aspartate receptor in the amygdala, as a method to enhance exposure therapy outcome. Preliminary results have supported the use of DCS to augment exposure therapy in adult anxiety disorders; however, no data have been reported in any childhood anxiety disorder. Thus, we sought to preliminarily examine whether weight-adjusted DCS doses (25 or 50 mg) enhanced the overall efficacy of cognitive-behavioral therapy (CBT) for pediatric obsessive-compulsive disorder (OCD). METHOD Participants were 30 youth (aged 8-17) with a primary diagnosis of OCD. The study design was a randomized, double-blinded, placebo-controlled augmentation trial examining CBT + DCS versus CBT + Placebo (15 youth per group). All patients received seven exposure and response prevention sessions paired with DCS or placebo taken 1 hour before sessions. RESULTS Although not significantly different, compared with the CBT + Placebo group, youth in the CBT + DCS arm showed small-to-moderate treatment effects (d = .31-.47 on primary outcomes). No adverse events were recorded. CONCLUSIONS These results complement findings in adult OCD and non-OCD anxiety disorders and provide initial support for a more extensive study of DCS augmentation of CBT among youth with OCD.

Case series on the use of aripiprazole for Tourette syndrome

Characterized by multiple motor and phonic tics, Tourette syndrome (TS) is also associated with a constellation of comorbid disorders, including obsessive–compulsive symptoms that occur in 40–60% of patients. The pathophysiology of tics has been linked by many studies to specific cortical and basal ganglia changes and hypothesized to relate to dysregulation of dopamine responsive/dependent circuits (Jordan et al., 2004). Aripiprazole, a recently released atypical antipsychotic noted for its partial D2 agonist activity along with a low propensity for extrapyramidal effects, has been shown to be efficacious in reducing symptoms of schizophrenia in adults. The value of aripiprazole for treating neuropsychiatric disorders in children has not previously been reported. We present results of a retrospective chart review of six youth with TS and comorbid obsessive–compulsive disorder (OCD) who were treated for 12 wk with aripiprazole.

Open label aripiprazole in the treatment of youth with tic disorders.

BACKGROUND Primarily safe and efficacious treatments for chronic tic disorders are needed. Also needed are such treatments that target co-morbid conditions. Aripiprazole, a dopaminergic/serotonergic agent with partial agonist properties at the D2 dopamine receptor and 5-hydrdoxytryptamine 1A (5-HT(1A)) receptor and antagonist properties at the 5-HT(2A) receptor, holds promise in both regards. OBJECTIVE This was an open-label, flexible-dose study to evaluate the safety of aripiprazole in children and adolescents with a primary diagnosis of a chronic tic disorder with/without co-morbid disorder(s). METHOD Sixteen children (15 males) aged 8-17 years participated in the 6-week trial. Ratings for tic, obsessive compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and side effects were administered weekly. Baseline and exit laboratory measures, electrocardiograms (ECGs), weight, and height were obtained. RESULTS The average daily aripiprazole dose was 3.3 mg (range 1.25-7.5 mg). Significant pre-and posttreatment differences were ascertained for the Yale Global Tic Severity Scale motor (p < or = 0.0001), phonic (p < or = 0.0001), and total tic (p < or = 0.0001) scores. Results of other rating scales suggested significant improvements in co-morbid disorders as well, including OCD, ADHD, and depressive disorders. Although aripiprazole was well tolerated, increases in weight were found. CONCLUSION In this preliminary open-label trial, aripiprazole was a well-tolerated treatment for tics and co-morbid OCD and ADHD symptoms. Improvements in co-morbid conditions may be secondary to tic reduction or to specific to aripiprazole therapy; however, further study is warranted.

Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-α: implications for autism

Abnormalities in T‐lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein α (sAPP‐α) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well‐established role of sAPP‐α in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP‐α could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP‐α and characterized elements of T‐cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP‐α‐overexpressing (TgsAPP‐α) mice displayed increased proportions of CD8+ T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active‐caspase‐3/total‐caspase‐3 and Bax/Bcl‐2 ratios were decreased. Greater levels of IFN‐γ, IL‐2, and IL‐4 were observed after ex vivo challenge of TgsAPP‐α mouse splenocytes with T‐cell mitogen. Finally, after immunization, splenocytes from TgsAPP‐α mice displayed decreased levels IFN‐γ, IL‐2, and IL‐4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP‐α in some patients with autism, sAPP‐α could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T‐cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T‐cell recall stimulation.—Bailey, A. R., Hou, H., Obregon, D. F., Tian, J., Zhu, Y., Zou, Q., Nikolic, W. V., Bengtson, M., Mori, T., Murphy, T., Tan, J. Aberrant T‐lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein‐α: implications for autism. FASEB J. 26, 1040‐1051 (2012). www.fasebj.org

Exposure to antipsychotic medications over a 4-year period among children who initiated antipsychotic treatment before their sixth birthday†

This study aims the following: (i) to describe the exposure to antipsychotic medications over a 4‐year period experienced by a cohort of children who initiated antipsychotic treatment before their sixth birthday; and (ii) to identify variables associated with the risk of antipsychotic exposure.

Impact of the Florida Medicaid Prior-Authorization Program on Use of Antipsychotics by Children Under Age Six

OBJECTIVE This study assessed the impact of a prior-authorization process on the use of antipsychotic medications by children under six years old in Floridas fee-for-service Medicaid program. METHODS Child psychiatrists reviewed requests for antipsychotic treatment (N=1,424) using forms and criteria created by a panel of Florida-based experts. Data on the characteristics of the children and clinicians involved were organized into 11 consecutive quarters beginning in July 2008. Multivariate generalized estimating equations were used to examine the association between each study variable and changes in the odds of submission of a new request over time. RESULTS Prior-authorization requests declined from 124 in the first quarter to 81 in the last quarter. Compared with applications from child psychiatrists, the odds of applications being submitted by adult psychiatrists, neurologists, and pediatricians increased over time. CONCLUSIONS Although applications declined, the diminished role of child psychiatry specialists raises questions about the impact of the program on the quality of care provided.

Increased Cardiovascular Risk with Second-Generation Antipsychotic Agent Switches

OBJECTIVE To model the risk of long-term, adverse cardiovascular events after switching from one second-generation antipsychotic medication (SGA) to another in patients with schizophrenia or schizoaffective disorder. DATA SOURCES PubMed from 1985 to 2004 using the search terms atypical antipsychotics, obesity, weight, diabetes mellitus, dyslipidemia, hypercholesterolemia, lipids, second generation antipsychotics, antipsychotic agents, schizophrenia, metabolic syndrome, cardiovascular disease, and cardiovascular risk factors. STUDY SELECTION By the authors. DATA EXTRACTION By the authors. DATA SYNTHESIS The selection of an SGA for an individual patient should be primarily based upon its therapeutic effectiveness. However, when two medications are clinically equivalent with respect to treatment outcomes, other important consequences of the medication choice should be considered. Depending upon the type of SGA switch, the risk of an adverse cardiovascular event may be lower, as when olanzapine is switched to risperidone, or may increase by as much as 33%, as when risperidone is switched to olanzapine or clozapine. CONCLUSION Cardiovascular risk likely differs depending upon SGA choice, but limited data make it difficult to predict the metabolic changes associated with switching. Prospective controlled studies are needed to describe the cardiovascular consequences of switching among the antipsychotic agents so that evidence-based strategies can be developed for selection of the optimal SGA.

Glucose dysregulation among veterans living with schizophrenia-related disorders after switching second-generation antipsychotics

OBJECTIVES To compare (1) blood glucose and glycosylated hemoglobin (A1C) laboratory results and (2) longitudinal trends in blood glucose levels among veterans switched from one second-generation antipsychotic (SGA) to another. DESIGN Retrospective, naturalistic, nonequivalent control group. SETTING United States between April 1, 2003, and September 30, 2003. PATIENTS 1,776 U.S. Veterans Health System beneficiaries living with schizophrenia-related disorders switching (1) from olanzapine to another SGA, (2) to olanzapine from another SGA, and (3) among nonolanzapine SGAs. INTERVENTION Data were retrieved from the laboratory results (LAR) database for a maximum of 180 days before and 365 days after the index date. MAIN OUTCOME MEASURES Mean blood glucose, A1C, and change in blood glucose. RESULTS Blood glucose (36.0 mg/dL, paired t test109 = -4.87, P < 0.001) and A1C (1.0%, paired t143 = -4.84, P < 0.001) declined among veterans switched from olanzapine who were taking a blood glucose-lowering agent before the switch but was unchanged for those who were not. Adjusting for age, gender, and race, addition of the switch-type variables improved prediction of blood glucose change (F-ratio = 3.76, P = 0.03). Linear mixed-effects models confirmed that blood glucose levels declined for veterans switched from olanzapine with glucose dysregulation before the switch (Est(beta2 - beta1) = -34.5 mg/dL, t424 = -5.05, P < 0.001). CONCLUSION Blood glucose and A1C were significantly improved among veterans switched from olanzapine with evidence of glucose dysregulation before the switch. They were stable among those without evidence of preexisting glucose dysregulation. Therapeutic switches from one SGA to another should be monitored as a risk factor for changes in glucose regulation.

Potential Autoepitope within the Extracellular Region of Contactin-Associated Protein-like 2 in Mice.

Aims Implicated in autoimmune encephalitis, neuromyotonia and genetic forms of autism, here we report that contactin-associated protein-like 2 (CNTNAP2) contains a potential autoepitope within the extracellular region. Methodology CNTNAP2 sequence-similar regions (CSSRs) from human pathogens were identified. Sera from autistic and control children were obtained and analyzed for the presence of antibodies able to bind CSSRs. One such candidate CSSR was evaluated for evidence of autoimmune responses to CNTNAP2 in a mouse model of acute infection. Results Autistic and control children sera contained antibodies able to discrete regions of CNTNAP2. In a murine model of acute infection, a CSSR derived from the N-terminal extracellular region of CNTNAP2 resulted in anti-CNTNAP2 antibody production, proinflammatory cytokine elevation, cerebellar and cortical white matter T-cell infiltration as well as motor dysfunction. Conclusion Taken together, these data suggest that CNTNAP2 contains a potential autoepitope within the extracellular region.