Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.

Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

Cortical correlates of neuromotor development in healthy children.

OBJECTIVE: To examine the relationship between acquisition of fine motor skills in childhood and development of the motor cortex. METHODS: We measured finger tapping speed and mirror movements in 43 healthy right-handed subjects (6-26 years of age). While recording surface electromyographic activity from right and left first dorsal interosseus, we delivered focal transcranial magnetic stimulation (TMS) over the hand areas of each motor cortex. We measured motor evoked potential (MEP) threshold, and ipsilateral (iSP) and contralateral (CSP) silent periods. RESULTS: As children got older, finger speeds got faster, MEP threshold decreased, iSP duration increased and latency decreased. Finger tapping speed got faster as motor thresholds and iSP latency decreased, but was unrelated to CSP duration. In all subjects right hemisphere MEP thresholds were higher than those on the left and duration of right hemisphere CSP was longer than that on the left. Children under 10 years of age had higher left hand mirror movement scores, and fewer left hemisphere iSPs which were of longer duration. CONCLUSIONS: Maturation of finger tapping skills is closely related to developmental changes in the motor threshold and iSP latency. Studies are warranted to explore the relationship between these measures and other neuromotor skills in children with motor disorders. SIGNIFICANCE: TMS can provide important insights into certain functional aspects of neurodevelopment in children.

Height, weight and body mass index (BMI) in psychiatrically ill US Armed Forces personnel.

BACKGROUND: In both psychiatrically ill and psychiatrically healthy adults, the connection between health and individuals' height and weight has long been examined. Specifically, research on the idea that individuals with certain body types were prone to particular psychiatric diseases has been explored sporadically for centuries. The hypothesis that psychiatrically ill individuals were shorter and weighed less than psychiatrically healthy counterparts would correspond with the neurodevelopmental model of psychiatric disease. METHOD: To evaluate possible links between psychiatric illness and physique, the height, weight and BMI of 7514 patients and 85,940 controls were compared. All subjects were part of the National Collaborative Study of Early Psychosis and Suicide (NCSEPS). Patients were US military active duty personnel hospitalized for either bipolar disorder, major depressive disorder, or schizophrenia and controls were psychiatrically-healthy US military active duty personnel matched for date of entry into the service. RESULTS: No consistent differences in height, weight or BMI were found between patients and controls, or between patient groups. Some weak ANOVA differences were found between age at the time of entering active duty and weight, as well as BMI, but not height. CONCLUSIONS: Unlike most previous studies that have looked at the links between height and psychiatric illness, this study of the NCSEPS cohort found that, at entry into the US Armed Forces, there were no consistent decreases in height for patients with bipolar disorder, major depressive disorder or schizophrenia compared with a large control group. Furthermore, there were no consistent differences for weight or BMI.

Molecular abnormalities in the major psychiatric illnesses: Classification and Regression Tree (CRT) analysis of post-mortem prefrontal markers.

Post-mortem specimens from the Stanley Foundation Neuropathology Consortium, which contains matched samples from patients with schizophrenia, bipolar disorder, non-psychotic depression and normal controls (n = 15 per group), have been distributed to many research groups around the world. This paper provides a summary of abnormal markers found in prefrontal cortical areas from this collection between 1997 and 2001. With parametric analyses of variance of 102 separate data sets, 14 markers were abnormal in at least one disease. The markers pertained to a variety of neural systems and processes including neuronal plasticity, neurotransmission, signal transduction, inhibitory interneuron function and glial cells. The data sets were also examined using the non-parametric Classification and Regression Tree (CRT) technique for the four diagnostic groups and in pair-wise combinations. In contrast to the results obtained with analyses of variance, the CRT method identified a smaller set of nine markers that contributed maximally to the diagnostic classifications. Three of the nine markers observed with CRT overlapped with the ANOVA results. Six of the nine markers observed with the CRT technique pertained to aspects of glutamatergic, GABA-ergic, and dopaminergic neurotransmission.

Adverse events during a placebo phase for inpatients with chronic schizophrenia.

BACKGROUND: This report builds on a previous analysis examining the long-term effects of a placebo period on a group of inpatients with chronic schizophrenia. In the present analysis, outcome was evaluated through the use of the Psychiatric Adverse Events Rating Scale. METHODS: This retrospective analysis examined adverse events for 55 patients with chronic schizophrenia who were placed in a double-blind placebo study on the inpatient units of the National Institute of Mental Health Neuropsychiatric Research Hospital. The number and severity of adverse events experienced by these patients during baseline, placebo, and discharge periods were analyzed. RESULTS: The frequency and severity of adverse events for this group of patients were modest. Most patients did not experience a statistically significant increase in adverse events during their placebo phase; however, a subgroup of patients who were hospitalized for less than 2 months after antipsychotic medications were restored did experience a statistical elevation in adverse events, and that frequency remained statistically elevated at discharge. CONCLUSIONS: The results confirm the findings from our previous analysis. Regardless of whether outcome is measured by a behavioral rating scale or by an adverse event scale, given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline.

Multivariate analysis of prefrontal cortical data from the Stanley Foundation Neuropathology Consortium.

Prefrontal cortical tissue from the Stanley Foundation Neuropathology Consortium, which contains samples from patients with schizophrenia, bipolar disorder, non-psychotic depression, and normal controls (n = 15 per group), was studied in a blinded fashion in 14 different laboratories between 1997 and 2000. The results of 69 separate data sets were analyzed with univariate and multivariate techniques. A total of 17 abnormal markers were identified that pertained to a variety of neural systems and processes, including neuronal plasticity, neurotransmission, signal transduction, inhibitory interneuron function, and glial cells. Schizophrenia was associated with the largest number of abnormalities, many of which were also present in bipolar disorder. Major depression was associated with relatively few abnormalities. The majority of abnormal findings represented a decline in function and could not be easily explained by exposure to psychotropic or illicit drugs. It is argued that the abnormal findings are not simply due to stochastic processes but represent viable markers for independent replication and further study as candidate genes or targets for new treatments.

New graphical method to measure silent periods evoked by transcranial magnetic stimulation.

OBJECTIVES: Manual methods of measuring duration of cortical silent periods (CSP) evoked by transcranial magnetic stimulation (TMS) depend upon subjective visual estimation of onset and offset. Because of this, the measurements are susceptible to poor rater reliability. We describe a graphical method to measure silent periods with greater precision. The statistical process underlying this new method is simple and particularly suited to signal detection in serially dependent data. METHODS: TMS-evoked silent periods were recorded in 13 healthy subjects. Two investigators subjectively measured silent period duration on each subject to estimate rater reliability. Using the graphical method, the mean and 99.76% variation limits of pre-stimulus electromyogram (EMG) activity were computed. Each averaged trial was displayed and CSP onset and offset detected when post-stimulus EMG activity moved outside the 99.76% limits. RESULTS: Maximum variation in silent period duration was 21.8 ms between the two investigators' subjective measurements. Silent period duration measured with the graphical method closely approximated measurements obtained using the manual method. It was possible to automate the procedure. CONCLUSIONS: This graphical method allowed precise measurement of CSP duration, independent of subjective estimations of onset or offset points. Further studies are necessary to determine if this method can provide a framework for other physiologic measures.

Schizophrenia and season of birth in a tropical region: relationship to rainfall.

Winter birth has been shown to increase the risk of schizophrenia in adult life. It has been hypothesized that this effect is due to seasonal variation in infectious diseases, including influenza, as exposure to influenza during mid gestation also increases the risk of schizophrenia. However, in many areas there is little variation in temperature during the year, although rainfall may vary greatly. We tested the hypothesis that, in a tropical region with wet and dry seasons, schizophrenia births would be related to rainfall. The data came from the city of Mossoro in north-eastern Brazil. In this area there is no meaningful variation in temperature, but there is a rainy season with little precipitation during the rest of the year. In this region, the prevalence of influenza parallels that of rainfall. There was a significant relationship between rainfall and the number of schizophrenia births three months later. In contrast, there was no significant relationship between rainfall and general population births three months later. The relationship of birth to rainfall, rather than winter birth, may be associated with risk of schizophrenia in tropical regions; exposure to influenza during gestation may be the basis for such a relationship.

Subjective reactions of children to single-pulse transcranial magnetic stimulation.

Single-pulse transcranial magnetic stimulation is a useful tool to investigate cortical function in childhood neuropsychiatric disorders. Magnetic stimulation is associated with a shock-like sensation that is considered painless in adults. Little is known about how children perceive the procedure. We used a self-report questionnaire to assess children's subjective experience with transcranial magnetic stimulation. Normal children and children with attention-deficit hyperactivity disorder (ADHD) underwent transcranial magnetic stimulation in a study of cortical function in ADHD. Subjects were asked to rate transcranial magnetic stimulation on a 1 to 10 scale (most disagreeable = 1, most enjoyable = 10) and to rank it among common childhood events. Thirty-eight subjects completed transcranial magnetic stimulation; 34 said that they would repeat it. The overall rating for transcranial magnetic stimulation was 6.13, and transcranial magnetic stimulation was ranked fourth highest among the common childhood events. These results suggest that although a few children find transcranial magnetic stimulation uncomfortable, most consider transcranial magnetic stimulation painless. Further studies are necessary to confirm these findings.

Decisional capacity for informed consent in schizophrenia research.

BACKGROUND: The adequacy of subjects' informed consent to research is the focus of an important public and professional debate. The potential impairment of decisional capacity in persons with schizophrenia is central to the discussions. This study ascertains the decisional capacity for informed consent in schizophrenic research subjects, to determine if reduced capacity relates to specific aspects of psychopathologic features and to test the hypothesis that reduced capacity can be remediated with an educational informed consent process. METHODS: Decisional capacity was assessed for 30 research subjects with schizophrenia and 24 nonill (normal) comparison subjects. Measures of psychopathologic features and cognition were obtained for the subjects with schizophrenia. Subjects who performed poorly on the decisional capacity measure received an educational intervention designed to improve their ability to provide informed consent and were then retested. RESULTS: The patient group did not perform as well as the controls on initial decisional capacity assessment. Poor performance was modestly related to the extent of symptoms but robustly related to cognitive impairments. Following the educational intervention, the performance of subjects with schizophrenia was equal to that of the nonill comparison group. CONCLUSIONS: Many persons with schizophrenia may be challenged by the cognitive demands of an informed consent process for research participation. In many cases, their reduced capacity can be compensated by a more intensive educational intervention as part of the informed consent process.

Penny-wise and pound-foolish: the impact of measurement error on sample size requirements in clinical trials.

BACKGROUND: Clinical research studies must compensate for measurement error by increasing the number of subjects that are studied, thereby increasing the financial costs of research and exposing greater numbers of subjects to study risks. In this article, we model the relationship between reliability and sample-size requirements and consider the potential tangible cost savings resulting from the decreased number of subjects needed when reliability of raters is improved or multiple ratings are used. METHODS: Standard methods are used to model reliability based on the intraclass correlation coefficient (R) and to perform power calculations. The impact of multiple raters on reliability for a given baseline level of reliability is modeled according to the Spearman Brown formula. RESULTS: Our models demonstrate that meaningful reductions in sample size requirements are gained from improvements in reliability. For example, improving reliability from R = .7 to R = .9 will decreases sample size requirements by 22%. Reliability is improved by training and by the use of the mean of multiple ratings. For example, if the reliability of a single rating is 0.7, the reliability of the mean of two ratings will be 0.8. CONCLUSIONS: The costs to improve reliability either through rater training efforts or use of the mean of multiple ratings is cost effective because of the consequent reduction in number of subjects needed. Efforts to improve reliability and thus reduce subject requirements in a study also may lead to fewer patients bearing the burden of research participation and to a shortening of the duration of studies.

A dose-outcome analysis of risperidone.

BACKGROUND: Although the establishment of appropriate dosage ranges for antipsychotics has important ramifications for both short-term treatment and long-term therapeutic outcomes, difficulties in dosing persist. Evidence exists that initial dosing recommendations for the titration of risperidone to 6 mg/day in 3 days are excessive. This study examines dosage trends of risperidone and further examines the relationship between dose and outcome by determination of discharge rates among individuals receiving varying doses of the drug. METHOD: Records of individuals receiving risperidone in Maryland state psychiatric facilities from March 1994 through February 1997 (N = 1056) were examined. Discharge rates and time to discharge were measured by Kaplan-Meier survival curve analysis. RESULTS: As risperidone use has risen each year since its introduction, mean doses in both inpatients and discharged patients have steadily declined. Additionally, risperidone doses for discharged patients were significantly lower than those for patients remaining in the hospital. Furthermore, patients receiving 2 and 4 mg/day were significantly more likely to be discharged than those receiving 6 mg/day (log-rank chi2 = 13.54, df = 2, p = .0011). This difference was seen in patients with similar diagnoses, ages, and racial status. CONCLUSION: Patients treated with doses less than the 6-mg/day initial dosing recommendations have better outcomes in terms of discharge. This finding should encourage clinicians to utilize adequate trials of risperidone aimed at stabilizing patients on doses in the 2- to 4-mg/day range before proceeding to higher doses.

Repeatable battery for the assessment of neuropsychological status as a screening test in schizophrenia, II: convergent/discriminant validity and diagnostic group comparisons.

OBJECTIVE: In a companion article in this issue of the Journal, the authors presented data suggesting that the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is sensitive to the types of impairments observed in schizophrenia, correlates highly with standard measures of intelligence and memory, and is related to employment status in a group of patients with schizophrenia drawn from a tertiary care research center. The objectives of the current study were 1) to determine if evidence of the convergent validity of the RBANS could be replicated in a diagnostically heterogeneous sample drawn from a public mental health system, 2) to examine the relationship of the RBANS to a broad neuropsychological battery, and 3) to compare the performance of patients with schizophrenia and patients with bipolar disorder on a neuropsychological battery and the RBANS. METHOD: The RBANS and a standard neuropsychological battery, including the WAIS-III and Wechsler Memory Scale, 3rd ed. (WMS-III), were given to 150 patients drawn from a larger study of vocational rehabilitation. RESULTS: Correlations of RBANS total scores with WAIS-III and WMS-III variables were highly similar across study groups. The RBANS correlated highly with a composite z score derived from 22 standard measures of IQ, memory, language, motor, attention, and executive function. Principal component analyses of the neuropsychological battery resulted in a six-factor solution: the RBANS correlated most highly with a general ability factor and had limited correlations with measures of motor performance, vigilance, and executive function. Patients with schizophrenia demonstrated greater deficits on the neuropsychological battery and the RBANS than patients with bipolar disorder. CONCLUSIONS: These data suggest that the RBANS is a useful screening instrument for assessing the severity of cognitive impairment in psychiatric populations.

The long-term effects of placebo in patients with chronic schizophrenia.

BACKGROUND: It has been hypothesized that placebo periods may increase long-term morbidity for patients with schizophrenia. In this study, the long-term effect of a placebo period was evaluated in a group of relatively treatment-refractory patients with chronic schizophrenia. METHODS: This retrospective study examined behavioral rating scores for 127 patients with chronic schizophrenia who were placed in a double-blind placebo study on the inpatient units of the National Institute of Mental Health Neuropsychiatric Research Hospital. Patients were rated daily with the Psychiatric Symptom Assessment Scale (PSAS), an extended and anchored version of the Brief Psychiatric Rating Scale (BPRS). At the end of the placebo phase, most patients were placed on haloperidol. Pre-placebo baseline PSAS ratings were compared with, first, discharge ratings and second, post-placebo ratings. To determine expected variability in the course of illness, patients in the placebo group were compared with patients hospitalized during the same time period, but who did not enter the placebo study. RESULTS: By discharge, ratings for placebo patients had returned to baseline. Post-placebo ratings were quite variable. Although many of the placebo patients had returned to baseline by day 3 of the post-placebo phase, others had not returned to baseline by post-placebo day 42. PSAS Total Scores for patients who left the study early were no different at baseline, placebo, or through post-placebo day 35 compared with patients who completed the study. CONCLUSIONS: The results indicate that given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline, but that the speed with which they attain that recovery is highly variable.

Prediction of neuropsychological performance by neurological signs in schizophrenia.

OBJECTIVE: The major purposes of this study were 1) to examine whether neurological signs predict cognitive performance in both schizophrenic patients and healthy subjects and 2) to determine the ability of neurological signs and neuropsychological tests to discriminate schizophrenic patients from healthy subjects. METHOD: Eighty-five patients with a DSM-III-R diagnosis of schizophrenia and 36 normal comparison subjects were included in the study. All subjects were administered a comprehensive neuropsychological test battery, and neurological signs were assessed with the Neurological Evaluation Scale. Stepwise regression analyses were used to predict neuropsychological test performance from the subscale scores on the Neurological Evaluation Scale. Forward stepwise linear discriminant function analyses were used to examine the discriminative ability of neurological subscale scores, neuropsychological test scores, and the two combined. RESULTS: Scores on the Neurological Evaluation Scale predicted the neuropsychological test performance of both patients and comparison subjects. The sensory integration subscale score was the most frequent predictor of neuropsychological test performance. In contrast, the "others" subscale, which includes frontal release signs, abnormalities in eye movements, and short-term memory, was the most highly discriminating subscale, correctly classifying 78.5% of the total study group. The best predictors from the neuropsychological battery (category fluency and Trail Making Test, part A, time test) correctly classified 81.8%. When both sets of variables were used, the Neurological Evaluation Scale "others" subscale entered the discriminant function first. CONCLUSIONS: Neurological signs are reliably related to measures of neuropsychological performance and also reliably discriminate between patients and healthy subjects. However, some neurological signs may be more sensitive to the presence of schizophrenia, while others may be more predictive of neuropsychological performance.

Rehospitalization rates of patients recently discharged on a regimen of risperidone or clozapine.

OBJECTIVE: The purpose of this study was to examine rehospitalization rates of people receiving risperidone or clozapine who had been discharged from state psychiatric hospitals in Maryland. METHOD: Rehospitalization status was monitored for all patients discharged from state psychiatric facilities on a regimen of either risperidone or clozapine between March 14, 1994, and Dec. 31, 1995. Patients were followed up with respect to readmission until Dec. 31, 1996. Time to readmission was measured by the product-limit (Kaplan-Meier) formula. Risk factors associated with rehospitalization were examined. RESULTS: One hundred sixty patients were discharged on risperidone, 75 having the diagnosis of schizophrenia. The patients with schizophrenia were more likely to be readmitted than the 85 patients with other mental disorders. Recidivism rates for schizophrenic patients discharged on risperidone versus those discharged on clozapine were not significantly different over the 24-month study period. However, no patient who received clozapine and remained discharged for more than 10 months (N = 49) was readmitted, while the readmission rate for risperidone-treated patients appeared to be steady up to 24 months. At 24 months 87% of the clozapine-treated patients and 66% of the risperidone-treated patients remained in the community. No clinical or demographic variables were found to predict rehospitalization. CONCLUSIONS: This study demonstrates that the rehospitalization rates of patients taking the second-generation antipsychotics risperidone and clozapine are lower than those in previously published reports of conventional antipsychotic treatment.

Nerve and tendon gliding exercises and the conservative management of carpal tunnel syndrome.

While developments continue in the surgical management of carpal tunnel syndrome, little emphasis has been placed on the evaluation of a comprehensive non-surgical treatment. In this study, 197 patients (240 hands) presenting for treatment of carpal tunnel syndrome were divided into two groups. Patients in both groups were treated by standard conservative methods, and those in one group were also treated with a program of nerve and tendon gliding exercises. Of those who did not perform the nerve and tendon gliding exercises, 71.2% underwent surgery compared with only 43.0% of patients who did perform them. Patients in the experimental group who did not undergo surgery were interviewed at an average follow-up time of 23 months (range, 14-38 months). Of these 53 patients, 47 (89%) responded to this detailed interview. Of the 47 who responded, 70.2% reported good or excellent results, 19.2% remained symptomatic, and 10.6% were non-compliant. Thus, a significant number of patients who would otherwise have undergone surgery for failure of traditional conservative treatment were spared the surgical morbidity of a carpal tunnel release (p = 0.0001).

The relationship between smooth pursuit eye movements and tardive dyskinesia in schizophrenia.

OBJECTIVE: To examine the relationship between smooth pursuit eye movements and tardive dyskinesia (TD) in schizophrenia. METHODS: Forty schizophrenic patients with TD and 25 non-TD patients had smooth pursuit eye movements tested with infrared oculography. In addition to the diagnosis of TD (present or absent), each patient had ratings of severity of TD. RESULTS: There was no significant or strong association between TD and poor smooth pursuit eye movements. CONCLUSION: The results stand in contrast to those of several previous studies, which were based on limited methodology. However, this study was not able to exclude definitively the possibility that TD is associated with poor smooth pursuit, perhaps with a small to moderate effect. Furthermore, these conclusions are limited to simple eye tracking protocols in which distractions are minimized. The question of whether or not TD is associated with poor smooth pursuit in schizophrenia needs to be resurrected.

Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study.

BACKGROUND: Whether Parkinson disease (PD) and dementia with Lewy bodies (DLB) represent 2 distinct nosologic entities or are diverse phenotypes of Lewy body disease is subject to debate. OBJECTIVES: To determine the accuracy of the diagnoses of Lewy body disease, PD, and DLB by validating the clinical diagnoses of 6 neurologists with the neuropathologic findings and to identify early predictors of the diagnoses. METHODS: Six raters who were unaware of the neuropathologic diagnoses analyzed 105 clinical vignettes corresponding to 29 cases of Lewy body disease (post hoc analysis of 15 patients with PD and 14 with DLB) and 76 patients without PD or DLB whose cases were confirmed through autopsy findings. MAIN OUTCOME MEASURES: Sensitivity and positive predictive value (PPV) were chosen as validity measures and the K statistic as a reliability measure. RESULTS: Interrater reliability for the diagnoses of Lewy body disease and PD was moderate for the first visit and substantial for the last, whereas agreement for diagnosis of DLB was fair for the first visit and slight for the last. Median sensitivity for diagnosis of Lewy body disease was 56.9% for the first visit and 67.2% for the last; median PPV was 60.0% and 77.4%, respectively. Median sensitivity for the diagnosis of PD was 73.3% for the first visit and 80.0% for the last; median PPV was 45.9% and 64.1%, respectively. Median sensitivity for the diagnosis of DLB was 17.8% for the first visit and 28.6% for the last; median PPV was 75.0% for the first visit and 55.8% for the last. The raters' results were similar to those of the primary neurologists. Several features differentiated PD from DLB, predicted each disorder, and could be used as clinical pointers. CONCLUSIONS: The low PPV with relatively high sensitivity for the diagnosis of PD suggests overdiagnosis. Conversely, the extremely low sensitivity for the diagnosis of DLB suggests underdiagnosis. Although the case mix included in the study may not reflect the frequency of these disorders in practice, limiting the clinical applicability of the validity measures, the raters' results were similar to those of the primary neurologists who were not exposed to such limitations. Overall, our study confirms features suggested to predict these disorders, except for the early presence of postural imbalance, which is not indicative of either disorder.