Faculty Bibliography

We used traditional volumetric regional analysis and a finer anterior-posterior (AP) profile volumetric analysis to examine the cerebral ventricular system in an all-male, demographically matched sample of schizophrenia patients (n = 73) and normal controls (n = 29) using 2.8-mm-thin coronal T1-weighted magnetic resonance images from a 1.5 tesla scanner. Traditional regional analysis was performed on various regions using absolute volumes after adjusting for intracranial volume (ICV) and age. The fine AP profile analysis was done by intrasubject 'stacking' of contiguous coronal cross-sectional volumes (adjusted for ICV and age) across the AP plane, intersubject AP alignment of all slices relative to the mammillary bodies, and plotting of slice volumes along the AP plane with 95 percent t-test-based confidence intervals. Schizophrenia subjects had mild to moderate multifocal ventricular enlargement (overall effect size d = 0.48), which was especially prominent in the right posterior temporal horn and, more generally, in the central to posterior portions of the lateral and third ventricles. Schizophrenia subjects also had milder enlargement in the left frontal horn, but no significant differences were found in the anterior temporal horns and the right frontal horn. Post hoc analyses of demographic, clinical, and neuropsychological variables did not account for much variance in the ventriculomegaly observed in the schizophrenia group. The lack of a single locus in the observed ventricular enlargement, the nonsignificant results from schizophrenia subtypes based on regional distributions, and the strong positive correlations among the ventricular regions for the schizophrenia group suggest that the ventriculomegaly seen in this chronic population reflects a single brainwide disease process leading to a multifocal or patchy loss of integrity in brain structure

BACKGROUND: Several short-term, controlled trials have documented the efficacy of vitamin E in treating tardive dyskinesia. However, the persistent nature of the disease prompted us to perform a multicenter, longer-term trial of vitamin E. METHODS: The study was a prospective, randomized, 9-site trial of up to 2 years of treatment with d-vitamin E (1600 IU/d) vs matching placebo. One hundred fifty-eight subjects with tardive dyskinesia who were receiving neuroleptic medications were enrolled. The blinded assessments performed were clinical (Abnormal Involuntary Movements Scale, Barnes Akathisia Scale, and Modified Simpson-Angus [for Extrapyramidal Symptoms] Scale) and electromechanical assessments of movement disorders, psychiatric status (Brief Psychiatric Rating Scale), and functioning (Global Assessment of Functioning). There were no significant differences in baseline demographic characteristics or in study assessments between the group that received vitamin E and the group that received placebo. RESULTS: Vitamin E was well tolerated and subject compliance with medication was good and similar between treatment groups. One hundred seven subjects (70% of those receiving vitamin E and 66% of subjects receiving placebo) completed at least 1 year of treatment. There were no significant effects of vitamin E on total scores or subscale scores for the AIMS, electromechanical measures of dyskinesia, or scores from the other 4 scales. CONCLUSION: This long-term, randomized trial of vitamin E vs placebo found no evidence for efficacy of vitamin E in the treatment of tardive dyskinesia

OBJECTIVE: Intersubject averaging of structural magnetic resonance (MR) images has been infrequently used as a means to study group differences in cerebral structure throughout the brain. In the present study, the authors used linear intersubject averaging of structural MR images to evaluate the validity and utility of this technique and to extend previous research, conducted using a different approach to image averaging, in which reduction in thalamic size and abnormalities in perithalamic white matter tracts in the brains of schizophrenic patients were reported by Andreasen et al. METHOD: A 1.5-T MR scanner was used to obtain high-resolution, whole brain T1-weighted structural MR images for an age-matched sample of 25 schizophrenic patients and 25 normal control subjects. A 'bounding box' procedure was used to create a single 'averaged' brain for the schizophrenic group and for the control group. Differences in signal intensity between the two average brains were examined on a pixel-wise basis through use of one-tailed effect size maps. RESULTS: Effect size maps revealed widespread patchy signal intensity differences between the two groups in both cortical and periventricular areas, including major white matter tracts. The signal intensity differences were consistent with cortical thinning/sulcal widening and ventricular enlargement. No differences were found within thalamus or in immediately surrounding white matter. Effect size maps for differences (schizophrenic minus normal subjects) had only small values. CONCLUSIONS: These results are consistent with diffuse structural brain abnormalities of both gray and white matter in schizophrenic populations such as the one in this study

BACKGROUND: Several studies have found that alpha-tocopherol (vitamin E) can effectively treat tardive dyskinesia (TD). A limitation of these trials is their short treatment durations (maximum of 12 weeks), which do not allow us to address the effects of long-term treatment. METHODS: To participate, patients had to have TD and be on stable oral medications. The study enrolled 40 patients who received up to 36 weeks of treatment with d-vitamin E (1600 IU per day) or placebo. RESULTS: Using the Abnormal Involuntary Movements Scale (AIMS) score (sum of items #1-7) to measure TD severity, the study found a significant difference (3 points) in mean AIMS scores, in favor of vitamin E, starting at 10 weeks of treatment and continuing through the full 36 weeks. We used linear mixed-effects regression to quantify the impact of several covariates, and found that treatment assignment. TD duration, and chlorpromazine equivalents had significant effects on decreasing the AIMS score. CONCLUSIONS: The study's finding that vitamin E is effective in treating TD agrees with results from prior studies and provides evidence that the effect may extend to treatment of up to 36 weeks. These findings are in direct contrast to those of VA Cooperative Study #394, a much larger, long-term, multi-site study, conducted by many of the same investigators, in which Vitamin E was not superior to placebo

Nine VA Medical Centers are participating in a 2-year double-blind placebo controlled study of antioxidant treatment for tardive dyskinesia (TD) conducted by the Department of Veteran Affairs Cooperative Studies Program. One of the principal outcome measures of this study is the score derived from the instrumental assessment of upper extremity dyskinesia. Dyskinetic hand movements are quantified by assessing the variability associated with steady-state isometric force generated by the patient. In the present report, we describe the training procedures and results of a multi-center reliability assessment of this procedure. Data from nine study centers comprising 45 individual patients with six trials each (three from left hand and three from right hand) were reanalyzed by an independent investigator and the results were subjected to reliability assessment. For the statistic of interest (average coefficient of variation over trials 2 and 3 for each hand, then take the larger of these two values), we found very high intraclass correlation coefficients for reliability over all patients across sites (ICC = 0.995). We also calculated the reliability of the measures across trials within patient for each combination of hand (right, left, dominant), rater group (site, control), and trials set (all three, trials 2 and 3). For a given hand and trial set, the reliability of the site raters was similar to that of the control. This study demonstrates that instrumental measures for the assessment of dyskinesia are reliable and can be implemented in multi-center studies with minimal training

This article describes a standardized method for establishing and maintaining desired levels of interrater reliability (IRR) in multicenter trials. The procedure involves six steps: distribution of procedural guides, distribution of an introduction tape, initial distribution of patient interviews to rate, training at the study kickoff meeting, ongoing IRR monitoring, and group training throughout the study. This method is being used in a national Veterans Affairs Cooperative Study (CS #394), involving nine sites to examine the treatment effects of vitamin E on tardive dyskinesia. The six-step standardized process allowed for early detection of areas of concern in assessment administration. When comparing intraclass correlation coefficients (ICCs) at different points in the initial training, the Barnes Akathisia Scale and Anchored Brief Psychiatric Rating Scale reliability improved from 0.68 to 0.74 and from 0.54 to 0.87, respectively. After analyzing the ratings collected prior to the start of CS #394, data were collected to conduct the first check on Abnormal Involuntary Movement Scale (AIMS) IRR during enrollment; the estimated ICC for the AIMS had decreased from 0.87 to 0.60. Raters were instructed to re-assess the subjects from the first videotape on the AIMS and received additional training. The re-rating indicated very good reliability, 0.84, IRR was measured once for the Global Assessment of Functioning Scale resulting in an ICC of 0.90. The companion article (Part II: Edson et al. 1997, page 59 of this issue) describes the statistical procedures used to measure IRR

The primary goal of Veterans Affairs (VA) Cooperative Study (CS) #394 is to determine if vitamin E is a safe and efficacious treatment for tardive dyskinesia (TD). The study uses various instruments to assess subjects for movement disorders (Abnormal Involuntary Movement Scale [AIMS], and Barnes Akathisia Scale [BAS]), psychopathology (Anchored Brief Psychiatric Rating Scale [BPRS]), and level of functioning (Global Assessment of Functioning scale [GAF]). Since the study involves nine sites, each with its own set of raters, it is important to establish and maintain high interrater reliability (IRR) on these instruments throughout the study and to identify raters who differ significantly from the others. To make this determination, personnel at each site assessed subjects from standardized videotapes on the AIMS, BAS, and Anchored BPRS, and rated written vignettes on the GAF. We fit these data to a two-way additive model to identify nonstandardized raters (i.e., those whose average ratings were significantly lower or higher than the others, or those whose scores, after adjusting for subject and rater effects, were highly variable). The proportion of nonstandardized raters ranged from 7 percent (Anchored BPRS) to 33 percent (AIMS). The estimated intraclass correlation coefficients (ICCs) indicated moderate reliability for the AIMS, BAS, and Anchored BPRS (0.73 to 0.75) and excellent agreement for the GAF (0.90). The companion article (Part I: Tracy et al. 1997, page 53 of this issue) describes the procedures used to train the raters for this study