S. Charles Schulz

Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices

BACKGROUND A limited number of reports have demonstrated abnormalities involving the glutamate and gamma amino butyric acid systems in blood and platelets of subjects with autism. To further investigate these studies, brain levels of rate limiting enzyme, glutamic acid decarboxylase, which is responsible for normal conversion of glutamate to gamma amino butyric acid in the brain, were investigated. METHODS Postmortem cerebellar and parietal cortices of age (mean +/- SD for controls 23 +/- 4.2, autistic 25.2 +/- 5.2 cerebellum; controls 23.5 +/- 4.8, autistic 21.6 +/- 3.8 parietal cortex), gender and postmortem interval-matched autistic and control subjects (n = 8 control, n = 5 autism, cerebellum; n = 4 control, n = 5 autism, parietal cortex) were subjected to SDS-PAGE and western blotting. Brain levels of glutamic acid decarboxylase proteins of 65 and 67 kDa and beta-actin were determined. RESULTS Glutamic acid decarboxylase protein of 65 kDa was reduced by 48% and 50% in parietal and cerebellar (p <.02) areas of autistic brains versus controls respectively. By the same token, glutamic acid decarboxylase protein of 67 kDa was reduced by 61% and 51% in parietal (p <.03) and cerebellar areas of autistic brains versus controls respectively. Brain levels of beta-actin were essentially similar in both groups. CONCLUSIONS The observed reductions in glutamic acid decarboxylase 65 and 67 kDa levels may account for reported increases of glutamate in blood and platelets of autistic subjects. Glutamic acid decarboxylase deficiency may be due to or associated with abnormalities in levels of glutamate/gamma amino butyric acid, or transporter/receptor density in autistic brain.

The expert consensus guideline series

Abstract Over the past decade, many new epilepsy treatments have been approved in the United States, promising better quality of life for many with epilepsy. However, clinicians must now choose among a growing number of treatment options and possible combinations. Randomized clinical trials (RCTs) form the basis for evidence-based decision making about best treatment options, but they rarely compare active therapies, making decisions difficult. When medical literature is lacking, expert opinion is helpful, but may contain potential biases. The expert consensus method is a new approach for statistically analyzing pooled opinion to minimize biases inherent in other systems of summarizing expert opinion. We used this method to analyze expert opinion on treatment of three epilepsy syndromes (idiopathic generalized epilepsy, symptomatic localization-related epilepsy, and symptomatic generalized epilepsy) and status epilepticus. For all three syndromes, the experts recommended the same general treatment strategy. As a first step, they recommend monotherapy. If this fails, a second monotherapy should be tried. Following this, the experts are split between additional trials of monotherapy and a combination of two therapies. If this fails, most agree the next step should be additional trials of two therapies, with less agreement as to the next best step after this. One exception to these recommendations is that the experts recommend an evaluation for epilepsy surgery after the third failed step for symptomatic localization-related epilepsies. The results of the expert survey were used to develop user-friendly treatment guidelines concerning overall treatment strategies and choice of specific medications for different syndromes and for status epilepticus.

Comparing the mental health needs of female and male incarcerated juvenile delinquents

The present study was undertaken to survey the prevalence of mental disorder in juvenile justice facilities and to compare the mental health needs for females and males. Girls displayed significantly more mental health needs than boys. The estimated prevalence of mental disorder for boys was 27%, compared with 84% for girls. The difference is highly significant and is discussed in terms of service system issues in juvenile justice that affect males and females differently.

Higher brain blood flow at amygdala and lower frontal cortex blood flow in PTSD patients with comorbid cocaine and alcohol abuse compared with normals.

Posttraumatic stress disorder (PTSD) patients with histories of cocaine and alcohol abuse (CA-PTSD) were compared with normal volunteers. Positron emission tomography (PET) scans with 15O-butanol were used to compare regional cerebral blood flow (rCBF) between the groups during rest and during an auditory continuous performance task (ACPT). CA-PTSD patients had significantly higher rCBF in right amygdala and left parahippocampal gyrus than normals during the ACPT. Normals had higher rCBF at frontal cortex during the resting scan and during the ACPT. The role of the amygdala in attention and fear conditioning suggests that increased amygdala rCBF may be related to clinical features of PTSD. Cocaine use may be associated with increased amygdala rCBF in PTSD patients. Amygdala and frontal cortex attention system components may be reciprocally related and their relative contributions to processing of neutral stimuli perturbed in CA-PTSD.

Efficacy and Tolerability of Second-Generation Antipsychotics in Children and Adolescents With Schizophrenia

Early-onset schizophrenia-spectrum (EOSS) disorders (onset of psychotic symptoms before 18 years of age) represent a severe variant associated with significant chronic functional impairment and poor response to antipsychotic treatment. All drugs with proven antipsychotic effects block dopamine D2 receptors to some degree. The ongoing development of the dopamine and other neurotransmitter receptor systems during childhood and adolescence may affect clinical response and susceptibility to side effects in youth. A literature search was conducted of clinical trials of antipsychotics in children and adolescents with EOSS disorders between 1980 and 2007 from the Medline database, reference lists, and conference proceedings. Trials were limited to double-blind studies of duration of 4 or more weeks that included 15 or more patients. Ten clinical trials were identified. Antipsychotic medications were consistently found to reduce the severity of psychotic symptoms in children and adolescents when compared with placebo. The superiority of clozapine has been now demonstrated relative to haloperidol, standard-dose olanzapine, and “high-dose” olanzapine for EOSS disorders. However, limited comparative data are available regarding whether there are differences among the remaining second-generation antipsychotics (SGAs) in clinical effectiveness. The available data from short-term studies suggest that youth might be more sensitive than adults to developing antipsychotic-related adverse side effects (eg, extrapyramidal side effects, sedation, prolactin elevation, weight gain). In addition, preliminary data suggest that SGA use can lead to the development of diabetes in some youth, a disease which itself carries with it significant morbidity and mortality. Such a substantial risk points to the urgent need to develop therapeutic strategies to prevent and/or mitigate weight gain and diabetes early in the course of treatment in this population.

A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls

The purpose of this study was to compare thalamic size in adolescent patients with either schizophrenia or bipolar disorder and healthy controls. T2-weighted axial magnetic resonance images were used to manually define the area of the thalamus for 20 schizophrenia patients, 15 bipolar patients and 16 normal control subjects, all of whom were adolescents. Two orthogonal planned contrasts were tested: Contrast 1, patients with schizophrenia vs. patients with bipolar disorder; and Contrast 2, both patient groups taken as a single group compared to controls. Contrast 1 was not statistically significant for right or left thalamic area. Contrast 2 was statistically significant and indicated reductions in thalamic area in the patients as compared to controls. The same pattern of results emerged after adjustment for total brain volume. Our results indicate that thalamic abnormalities reported in adult schizophrenic and bipolar patients are also observed in adolescent patients. Our findings also add to the evidence implicating the thalamus in the pathophysiology of schizophrenia and bipolar disorder.

Olanzapine versus Placebo in Adolescents with Schizophrenia; a 6-Week, Randomized Double-Blind, Placebo-Controlled Trial.

OBJECTIVE To assess olanzapines efficacy and tolerability in adolescents with schizophrenia. METHOD One hundred seven inpatient and outpatient adolescents (olanzapine, n = 72, mean age 16.1 years; placebo, n = 35, mean age 16.3 years) with schizophrenia participated in this randomized (2:1), international, multisite, industry-sponsored trial. All patients met DSM-IV-TR criteria for schizophrenia, and they were treated for up to 6 weeks with flexible doses of olanzapine (2.5-20.0 mg/day) or placebo. Last-observation-carried-forward mean changes from baseline to endpoint on the anchored version of the Brief Psychiatric Rating Scale for Children, Clinical Global Impression Scale-Severity of Illness, and Positive and Negative Syndrome Scale (PANSS) were assessed. RESULTS More olanzapine-treated versus placebo-treated patients completed the trial (68.1% versus 42.9%, p =.020). Compared with placebo-treated patients, olanzapine-treated adolescents had significantly greater improvement in Brief Psychiatric Rating Scale for Children total (p =.003), Clinical Global Impressions Scale-Severity of Illness (p =.004), PANSS total (p =.005), and PANSS positive scores (p =.002). Olanzapine-treated patients gained significantly more baseline-to-endpoint weight (4.3 kg versus 0.1 kg, p <.001). Significantly more olanzapine-treated versus placebo-treated patients gained 7% or greater of their body weight at any time during treatment (45.8% versus 14.7%, p =.002). Prolactin and triglyceride mean baseline-to-endpoint changes were significantly higher in olanzapine-treated versus placebo-treated adolescents. The incidence of treatment-emergent significant changes in fasting glucose, cholesterol, or triglycerides did not differ between the groups at endpoint, but significantly more olanzapine-treated patients had high triglycerides at any time during treatment. CONCLUSIONS Olanzapine-treated adolescents with schizophrenia experienced significant symptom improvement. Significant increases in weight, triglycerides, uric acid, most liver function tests, and prolactin were observed during olanzapine treatment.Clinical trial registration information-Olanzapine Versus Placebo in the Treatment of Adolescents With Schizophrenia. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00051298.

Increased presence of white matter hyperintensities in adolescent patients with bipolar disorder

Several reports have noted an increase in white matter hyperintensities (WMH) on MRI scans of adult patients with bipolar disorder. We investigated whether this increase was also evident in a group of adolescent patients with bipolar disorder. The sample consisted of 15 bipolar patients, 19 patients with schizophrenia and 16 healthy comparison subjects. All subjects were adolescents. WMH were blindly rated on T2-weighted and PD-weighted MRI scans using our own scale with documented inter-rater reliability. WMH were present in 10 of 15 bipolar patients (67%), seven of 19 patients with schizophrenia (37%) and five of 16 comparison subjects (31%). The bipolar adolescent group had a statistically significant increased presence of WMH compared both with healthy comparison subjects and the schizophrenic group. The association between WMH and bipolar disorder appears to extend to the adolescent years.

Global White Matter Abnormalities in Schizophrenia: A Multisite Diffusion Tensor Imaging Study

BACKGROUND Emerging evidence implicates white matter (WM) abnormalities in the pathophysiology of schizophrenia. However, there is considerable heterogeneity in the presentation of WM abnormalities in the existing studies. The object of this study was to evaluate WM integrity in a large sample of patients with first-episode (FE) and chronic schizophrenia in comparison to matched control groups. Our goal was to assess whether WM findings occurred early in the illness or whether these abnormalities developed with the illness over time. METHODS Participants included 114 patients with schizophrenia (31 FE and 83 chronic patients) and 138 matched controls. High-resolution structural and diffusion tensor images were obtained on all participants. Measures of fractional anisotropy (FA) were calculated for the 4 cortical lobes and the cerebellum and brain stem. RESULTS FA was significant lower in patients vs controls in the whole brain and individually in the frontal, parietal, occipital, and temporal lobes. FA was not significantly different in the brain stem or cerebellum. FA differences were significant only in patients with chronic schizophrenia and not in the FE group. CONCLUSIONS We found global differences in the WM microstructure in patients with chronic but not FE schizophrenia. These findings suggest progressive alterations in WM microstructure.

An MRI study of adolescent patients with either schizophrenia or bipolar disorder as compared to healthy control subjects

BACKGROUND There are few imaging studies in adolescent patients with either schizophrenia or bipolar disorder. Such studies are of interest because adolescents may have a more severe illness and neurodevelopmental events may have a greater role in their pathophysiology. METHODS We compared 20 patients with schizophrenia and 15 patients with bipolar disorder (10 to 18 years) to 16 normal adolescents on magnetic resonance imaging (MRI) measures of intracranial volume and ventricular and sulcal enlargement. Two planned comparison contrasts were employed, one comparing the two patient groups to each other (contrast 1), and one comparing both patient groups combined to control subjects (contrast 2). RESULTS None of the contrast 1 comparisons (schizophrenia vs bipolar) were statistically significant. Contrast 2 comparisons (control subjects vs patients) were statistically significant for intracranial volume (reduced in patients) as well as frontal and temporal sulcal size (increased in patients). CONCLUSIONS The patient groups were not statistically significantly different from each other on any measure. The combined patient groups were different from control subjects on intracranial volume and frontal and temporal sulcal size. Also, there was evidence for ventricular enlargement, after removal of a control subject with an extreme value. These findings indicate that the same abnormalities noted in adult populations are present in adolescents.