Neurophysiological differences between patients clinically at high risk for schizophrenia and neurotypical controls – first steps in development of a biomarker

Background: Schizophrenia is a severe, disabling and prevalent mental disorder without cure and with a variable, incomplete pharmacotherapeutic response. Prior to onset in adolescence or young adulthood a prodromal period of abnormal symptoms lasting weeks to years has been identified and operationalized as clinically high risk (CHR) for schizophrenia. However, only a minority of subjects prospectively identified with CHR convert to schizophrenia, thereby limiting enthusiasm for early intervention(s). This study utilized objective resting electroencephalogram (EEG) quantification to determine whether CHR constitutes a cohesive entity and an evoked potential to assess CHR cortical auditory processing. Methods: This study constitutes an EEG-based quantitative neurophysiological comparison between two unmedicated subject groups: 35 neurotypical controls (CON) and 22 CHR patients. After artifact management, principal component analysis (PCA) identified EEG spectral and spectral coherence factors described by associated loading patterns. Discriminant function analysis (DFA) determined factors’ discrimination success between subjects in the CON and CHR groups. Loading patterns on DFA-selected factors described CHR-specific spectral and coherence differences when compared to controls. The frequency modulated auditory evoked response (FMAER) explored functional CON–CHR differences within the superior temporal gyri. Results: Variable reduction by PCA identified 40 coherence-based factors explaining 77.8 % of the total variance and 40 spectral factors explaining 95.9 % of the variance. DFA demonstrated significant CON–CHR group difference (P <0.00001) and successful jackknifed subject classification (CON, 85.7 %; CHR, 86.4 % correct). The population distribution plotted along the canonical discriminant variable was clearly bimodal. Coherence factors delineated loading patterns of altered connectivity primarily involving the bilateral posterior temporal electrodes. However, FMAER analysis showed no CON–CHR group differences. Conclusions: CHR subjects form a cohesive group, significantly separable from CON subjects by EEG-derived indices. Symptoms of CHR may relate to altered connectivity with the posterior temporal regions but not to primary auditory processing abnormalities within these regions

The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders

Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs—valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine—in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective

Transcranial Magnetic Stimulation Provides Means to Assess Cortical Plasticity and Excitability in Humans with Fragile X Syndrome and Autism Spectrum Disorder

Fragile X Syndrome (FXS) is the most common heritable cause of intellectual disability. In vitro electrophysiologic data from mouse models of FXS suggest that loss of fragile X mental retardation protein affects intracortical excitability and synaptic plasticity. Specifically, the cortex appears hyperexcitable, and use-dependent long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are abnormal. Though animal models provide important information, FXS and other neurodevelopmental disorders are human diseases and as such translational research to evaluate cortical excitability and plasticity must be applied in the human. Transcranial magnetic stimulation paradigms have recently been developed to non-invasively investigate cortical excitability using paired pulse stimulation, as well as LTP- and LTD-like synaptic plasticity in response to theta burst stimulation (TBS) in vivo in the human. TBS applied on consecutive days can be used to measure metaplasticity (the ability of the synapse to undergo a second plastic change following a recent induction of plasticity). The current study investigated intracortical inhibition, plasticity and metaplasticity in full mutation females with FXS, participants with autism spectrum disorders (ASD), and neurotypical controls. Results suggest that intracortical inhibition is normal in participants with FXS, while plasticity and metaplasticity appear abnormal. ASD participants showed abnormalities in plasticity and metaplasticity, as well as heterogeneity in intracortical inhibition. Our findings highlight the utility of non-invasive neurophysiological measures to translate insights from animal models to humans with neurodevelopmental disorders, and thus provide direct confirmation of cortical dysfunction in patients with FXS and ASD

A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder

OBJECTIVE: The goal of this study was to assess the effectiveness and tolerability of olanzapine in the treatment of acute mania in children and adolescents. METHODS: This was an 8-week, open-label, prospective study of olanzapine monotherapy (dose range 2.5-20 mg/day) involving 23 bipolar youths (manic, mixed, or hypomanic; 5-14 years old). Weekly assessments were made using the Young Mania Rating Scale (YMRS), Clinical Global Impressions Severity Scale (CGI-S), Brief Psychiatric Rating Scale, and Children\u27s Depression Rating Scale. Adverse events were assessed through self-reports, vital sign and weight monitoring, laboratory analytes, and extrapyramidal symptom rating scales (Barnes Akathisia Scale, Simpson-Angus Scale, and Abnormal Involuntary Movement Scale). RESULTS: Twenty-two of the 23 youths (96%) completed the study. Olanzapine treatment was associated with significant improvement in mean YMRS score (-19.0 +/- 9.2, p \u3c 0.001). Using predefined criteria for improvement of \u3e or = 30% decline in the YMRS and a CGI-S Mania score of \u3c or = 3 at endpoint, the overall response rate was 61%. Overall, olanzapine was well tolerated, and extrapyramidal symptom measures were not significantly different from baseline. Body weight increased significantly over the study (5.0 +/- 2.3 kg, p \u3c 0.001). CONCLUSIONS: Open-label olanzapine treatment was efficacious and well tolerated in the treatment of acute mania in youths with bipolar disorder. Future placebo-controlled, double-blind studies are warranted

The Experience Journal: A Computer-Based Intervention For Families Facing Congenital Heart Disease

This study tested the feasibility and safety of a computer-based application designed to facilitate the healthy coping of children and their families who must contend with significant congenital heart disease (CHD). The application, called the Experience Journal (EJ), is a psychoeducational intervention based upon a narrative model involving the sharing of personal stories about an illness. Testing was conducted in two phases. In Phase 1, 9 parents of children with CHD and 1 adult with CHD were asked to use the EJ. After utilization, semistructured interviews assessed EJ usability and safety. In Phase 2, 40 mothers of children with CHD used the EJ during a hospitalization. Assessment of feasibility and safety was measured through the use of semistructured interviews prior to EJ utilization and 2-4 weeks after hospital discharge. Results revealed that the EJ was safe and useful for decreasing social isolation, increasing understanding of familial feelings about cardiac illness, and fost..

Young children with psychotic symptoms and risk for suicidal thoughts and behaviors: a research note

Abstract Objective Suicidal thoughts and behaviors (STBs) are prevalent among youth with psychotic disorders (PD) relative to the general population. Recent research now suggests that STBs may present during the prodromal phase of the disease, or the clinical high risk (CHR) state. While this knowledge is important for the development of suicide prevention strategies in adolescent and adult populations, it remains unclear whether risk for suicide extends to children with or at risk for psychosis. The current study is an extension of previous work assessing STBs in youth across the psychosis continuum. We examine STBs in 37 CHR and PD children ages 7–13 years old, and further explore the prodromal symptom correlates of STB severity among CHR children. Results CHR and PD children endorsed STBs with a frequency and severity similar to what is observed in older CHR and PD populations. A number of children had never previously vocalized their suicidal plans or intent. Among CHR children, Social Anhedonia and Odd Behavior or Appearance were significantly correlated with STB severity. These findings underscore the importance of screening for STBs even in young children presenting with psychotic symptoms

The Use of Antiepileptic Drugs (AEDs) for the Treatment of Pediatric Aggression and Mood Disorders

Aggressive symptomatology presents across multiple psychiatric, developmental, neurological and behavioral disorders, complicating the diagnosis and treatment of the underlying pathology. Anti-Epileptic Drugs (AEDs) have become an appealing alternative in the treatment of aggression, mood lability and impulsivity in adult and pediatric populations, although few controlled trials have explored their efficacy in treating pediatric populations. This review of the literature synthesizes the available data on ten AEDs – valproate, carbamazepine, oxcarbazepine, phenytoin, lamotrigine, topiramate, levetiracetam, zonisamide, gabapentin and tiagabine – in an attempt to assess evidence for the efficacy of AEDs in the treatment of aggression in pediatric populations. Our review revealed modest evidence that some of the AEDs produced improvement in pediatric aggression, but controlled trials in pediatric bipolar disorder have not been promising. Valproate is the best supported AED for aggression and should be considered as a first line of treatment. When monotherapy is insufficient, combining an AED with either lithium or an atypical anti-psychotic can result in better efficacy. Additionally, our review indicates that medications with predominately GABA-ergic mechanisms of action are not effective in treating aggression, and medications which decrease glutaminergic transmission tended to have more cognitive adverse effects. Agents with multiple mechanisms of action may be more effective