Common Factors in Pediatric Psychiatry: A Review of Essential and Adjunctive Mechanisms of Treatment Outcome.

OBJECTIVE: The purpose of this article is to review the literature on hypothesized behavioral correlates of pharmacotherapy treatment response. A particular focus is placed on what have been referred to as "common factors" across mental health treatments, including medication adherence, therapeutic alliance, motivation for behavior change, and expectancies for positive treatment outcomes. These understudied factors may provide unique explanations for mechanisms of symptom change, patient risk as a result of protocol deviation, and attenuated treatment outcomes. METHOD: A literature search was conducted to evaluate the relationship between treatment processes in pediatric psychiatry and medication adherence, therapeutic alliance, motivation for behavior change, and expectancies for positive treatment outcomes. RESULTS: Substantial variability and room for improvement was identified for each common factor. Behavioral protocols have already been developed to address many aspects of common factors in pediatric psychiatric treatment, but are not yet a part of many practice parameters. CONCLUSION: Interventions to improve common factors can be used immediately in tandem with psychopharmacological interventions to provide increased symptom relief and reduce patient risk. Furthermore, incorporating instruction in common factors interventions can positively affect training of future providers and enhance understanding of the mechanisms of effect of medications. An increased focus on common factors, with a particular emphasis on quantifying the magnitude and mechanisms of their effects on psychopharmacological interventions stand to benefit child patients, their families, treatment providers, training facilities, and pharmaceutical manufacturers.

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.

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 Florida's 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.

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

PURPOSE: 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. METHODS: Children were identified who initiated an index episode of antipsychotic treatment before their sixth birthday in Florida's fee for service Medicaid program. With the use of claims data, the medication utilization of these children was tracked during the year before and the 4 years following the start of their index episodes (pre-index and four post-index periods). Generalized estimating equations were used to identify variables associated with the risk of additional days of antipsychotic exposure. RESULTS: Five hundred twenty-eight children were included in the cohort. The mean total number of days of exposure was 821.9 (± 431.9), representing 56.3% of all days during the four post-index periods. The mean days of exposure to combinations of antipsychotics and other classes of psychotherapeutic medications were 623.8 ± 447.6 days. Children with primary diagnoses of pervasive developmental disorders and affective disorders were at greater risk of additional days of exposure than children with attention deficit/hyperactivity disorder. Exposure tended to be greater among children with indicators of clinical complexity including the presence of secondary diagnoses and the use of other classes of psychotherapeutic medications in addition to antipsychotics. CONCLUSIONS: Exposure to antipsychotic mediations was extensive. Although these children may have had complex and severe problems, additional research is urgently needed on the benefits and risks of long-term antipsychotic exposure among very young children.

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.

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.

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.

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.

Metabolic monitoring in veterans with schizophrenia-related disorders and treated with second-generation antipsychotics: findings from a Veterans Affairs-based population.

OBJECTIVES: To describe the proportions of veterans living with schizophrenia-related disorders monitored for dyslipidemia and hyperglycemia and to investigate whether the likelihood of metabolic dysregulation monitoring was influenced by veterans' sociodemographic characteristics, preswitch pharmacologic treatment, and monitoring before the switch from one second-generation antipsychotic (SGA) to another. DESIGN: Retrospective, observational, descriptive study. SETTING: Veterans Affairs (VA) Healthcare System between October 1, 2001, and December 31, 2003. PATIENTS: 1,826 veterans with schizophrenia-related disorders. INTERVENTION: Veterans who were dispensed two or more prescriptions for one of five SGAs (i.e., clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) on the VA Healthcare System formulary were identified. Of these veterans, a subset that was switched from one SGA to another was identified. From this subset, veterans were identified who were on the first SGA continuously for at least 90 days before the index date and the new SGA for 180 or more days after. Finally, among these veterans, ICD-9 codes were used to identify veterans with a schizophrenia or schizoaffective disorder diagnosis (ICD-9 code 295.xx or 296). MAIN OUTCOME MEASURES: Proportions of veterans with lipid (i.e., low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides) and blood glucose (i.e., fasting blood glucose [FBG], glycosylated hemoglobin [A1C]) laboratory results. RESULTS: Nearly 39% of the veterans had at least one of three lipid fractions monitored 6 months or less before their SGA switch and 59% during the 12 months after. The corresponding proportions of veterans monitored were 57% and 80% for FBG and 19% and 31% for A1C. Pharmacologic agent for metabolic dysregulation, monitoring during the 6 months before the switch, and age 50 years or older were significant predictors of monitoring after the SGA switch for all three laboratory parameters. CONCLUSION: These findings serve as a benchmark for lipid and blood glucose monitoring among patients who switch SGA therapy. Veterans' metabolic dysregulation was more likely to be monitored after SGA switch for those receiving pharmacologic treatment for metabolic dysregulation, monitored before the switch, and aged 50 years or older. Implementation of monitoring guidelines in daily practice is emphasized to ensure that individuals living with schizophrenia-related disorders and taking SGAs achieve optimal physical health.

Identical neural risk factors predict cognitive deficit in dyslexia and schizophrenia.

In previous work, the authors found that an anatomical risk index created from the combination of 7 neuroanatomical measures predicted reading and oral language skills in individuals with learning disabilities. Individuals with small auditory brain structures and reduced asymmetry had more deficits than those with large structures and exaggerated asymmetry. In the present study, the same anatomical index predicted reading and other cognitive abilities in 45 individuals with chronic schizophrenia. The anatomical risk index was significantly associated with broad cognitive ability (Pearson r = .53, p < .0001), reading comprehension (r = .58, p < .0001), and a measure of nonverbal reasoning (r = .39, p < .01), but not with age, parental socioeconomic status, symptom measures, alcohol use, or processing speed. These findings support the prediction that reduced size and asymmetry in temporal lobe auditory cortex and cerebellum may not be specific risk factors for schizophrenia but for cognitive deficits that characterize a broad spectrum of developmental disorders.

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.

Weight and blood pressure changes after switching second-generation antipsychotics in a population of veterans with schizophrenia-related disorders.

OBJECTIVES: To describe (1) the association between systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes and weight change and (2) weight, SBP, and DBP changes attributable to the medication following a switch from one second-generation antipsychotic (SGA) to another. DESIGN: Retrospective, naturalistic, nonequivalent control group study. SETTING: United States between April 1, 2002, and September 30, 2002. PATIENTS: 1,425 U.S. Veterans Healthcare System enrollees with diagnoses of schizophrenia or schizoaffective disorders. INTERVENTION: Analysis of data from the Veterans Integrated System Technology Architecture. MAIN OUTCOME MEASURES: Veterans' weight, SBP, and DBP. RESULTS: Weight change and change in SBP (r = 0.19) and DBP (r = 0.15) were significant (P < 0.001), even after adjusting for obesity status (body mass index <30 or > or = 30 kg/m2). Veterans who were switched from olanzapine to another SGA lost weight (P < 0.001), whereas those switched from another SGA to olanzapine gained weight (P < 0.05). Weight change remained significant after controlling for preswitch obesity status (P < 0.001). Blood pressure was not associated with switch type after adjusting for preswitch obesity status. CONCLUSION: Monitoring and aggressively treating weight change is an evidence-based and relatively inexpensive strategy that primary care practitioners and psychiatrists can use in working in tandem toward reducing the already greater cardiovascular risk of patients with schizophrenia.

Effect on lipid profiles of switching from olanzapine to another second-generation antipsychotic agent in veterans with schizophrenia.

OBJECTIVE: To compare (1) mean low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride differences after switching from olanzapine to quetiapine, risperidone, or ziprasidone and (2) the mean lipid change between switch patterns. DESIGN: Retrospective, naturalistic, nonequivalent control group design. SETTING: United States between April 1, 2002, and September 30, 2002. PATIENTS: 1,826 U.S. Veterans Healthcare System enrollees with diagnoses of schizophrenia or schizoaffective disorders and receiving a second-generation antipsychotic (SGA) medication. INTERVENTIONS: Analysis of data from the Veterans Information Systems and Technology Architecture. MAIN OUTCOME MEASURES: Differences in LDL-C, HDL-C, and triglycerides and mean differences between switch patterns. Predictors were the type of switch (e.g., olanzapine to quetiapine) and switch patterns (e.g., olanzapine to quetiapine versus olanzapine to risperidone). Data were analyzed using Pearson's X2 and multivariate analysis of covariance with planned comparisons. RESULTS: After adjusting for age, gender, and race/ethnicity, LDL-C decreased significantly among patients switched from olanzapine to ziprasidone (-16.9 mg/dL, P <0.01) and olanzapine to quetiapine (-7.6 mg/dL, P = 0.04) and trended upward in patients switched from olanzapine to risperidone (+6.6 mg/dL, P = 0.12). Triglyceride levels decreased among those switched from olanzapine to ziprasidone (-62.9 mg/dL, P <0.01) and olanzapine to risperidone (-48.5 mg/dL, P <0.01) but not among veterans switched from olanzapine to quetiapine (+7.8 mg/dL, P = 0.54). HDL-C levels did not change significantly when veterans were switched from olanzapine to quetiapine, risperidone, or ziprasidone. CONCLUSION: Switching SGAs can increase or decrease cardiovascular risk depending on the clinician's follow-on SGA choice. LDL-C and triglyceride levels decreased significantly among veterans switched from olanzapine to ziprasidone. Switching to quetiapine was associated with a reduction in LDL-C, while switching to risperidone resulted in lower triglyceride levels. Clinicians should use these results when building a patient care plan that includes switching of SGAs.

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.

Weight change after an atypical antipsychotic switch.

BACKGROUND: Atypical antipsychotics successfully treat schizophrenia and other conditions, with a lower incidence of extrapyramidal side effects than other agents used in treatment of these disorders. However, some atypical antipsychotics are associated with weight gain. OBJECTIVE: To quantify the impact on weight and identify atypical antipsychotics causing the least amount of weight gain among patients switched from risperidone to olanzapine and olanzapine to risperidone. METHODS: Patients included in the study (n = 86) were > or =18 years and had received > or =2 prescriptions for risperidone or olanzapine for > or =60 days, switched to the other atypical antipsychotic, and were dispensed > or =2 prescriptions for at least 60 days after the index date. Age, weight, and body mass index (BMI) were retrospectively abstracted from automated databases containing patient-specific prescription and vital sign information. RESULTS: At the time of their switch, the average patient age was 53.2 years (range 25-83). The average weight change in patients switched to olanzapine (n = 47) was +2.3 kg (p = 0.01) and the BMI change was +0.8 kg/m(2) (p = 0.02). The average percent body weight change was +2.8% and the BMI change was +3.0%. The average weight change after patients switched to risperidone (n = 39) was -0.45 kg (p = 0.69) and BMI change was -0.2 kg/m2 (p = 0.64). The average percentage weight change was -0.4% and BMI change was -0.5%. CONCLUSIONS: Practitioners' concern regarding weight changes after switching atypical antipsychotics seems warranted and patients should be provided consistent, ongoing weight monitoring. Further investigations should examine whether weight changes associated with atypical antipsychotic treatment further jeopardize this already at-risk population for severe comorbid conditions such as hypertension, coronary artery disease, and type 2 diabetes.