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.

Flexible system for the diagnosis of schizophrenia: report from the WHO International Pilot Study of Schizophrenia.

Behavioral data on a large patient group were collected by investigators from nine countries in the International Pilot Study of Schizophrenia, sponsored by the World Health Organization. The data on half the group were analyzed to derive a system of 12 signs and symptoms for the identification of schizophrenia, as this disorder is diagnosed in many centers throughout the world. The findings were replicated with the other half of the patient group. The criteria constitute an operational method for identifying patients who would be commonly considered schizophrenic in many centers.

Monoamine neurotransmitter interactions and the prediction of antidepressant response.

Clinical studies of monoamine neurotransmitter function in depression have concentrated on individual monoamines without focusing on interactions between monoamine systems. Virtually all modern studies have found significant correlations between monoamine metabolite concentrations in cerebrospinal fluid (CSF). These correlations should in part reflect interactions between central monoamine systems. In the present analysis, CSF had been obtained from depressed patients before (n = 40) and after (n = 36) antidepressant treatment. The patients were grouped based on their response to treatment. Absolute concentrations of CSF monoamine metabolites (homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol) did not differ between the two groups before or after treatment. However, when correlations between metabolites were compared, nonresponders to treatment differed considerably from responders. In responders, as in previously described normal populations, all three metabolites correlated with one another before and after treatment, and treatment-induced changes in metabolite concentrations also correlated with one another. In contrast, metabolites in nonresponders did not correlate with one another before treatment, nor did treatment-induced changes correlate with one another in this group. Furthermore, correlations between treatment-induced changes in metabolites differed significantly between responders and nonresponders, and there was a trend for pretreatment correlations to differ as well. The lack of correlation between monoamine metabolites in nonresponders suggests that interactions between monoamine systems may be disrupted in these individuals. Using CSF metabolite correlations to study neurotransmitter interactions may have clinical relevance and yields information not available from examining neurotransmitters in isolation.

Another view of schizophrenia subtypes. A report from the international pilot study of schizophrenia.

Schizophrenia subtypes are defined predominantly my manifest symptoms and behavior. This report, based on sign and symptom data from the International Pilot Study of Schizophrenia, addresses three questions: (1) Are traditional subtype diagnoses applied similarly across cultures? (2) Are the various traditional subtypes symptomatically distinguishable from one another? (3) Can cluster analytic techniques define a more distinctive set of schizophrenic subgroups? Present State Examination data were reduced to 27 psychopathologic signs and symptoms. Profile analysis of variance results indicate that each subtype appears similar, regardless of center of origin. However, this is based on a lack of distinguishing features between different subtypes. On the other hand, when a cluster analytic technique was used, it showed one large and three small subgroups, each readilty distinguishable from the others. These subgroups, labeled "usual," "flagrant," "insightful," and "hypochondriacal," are described clinically. If replicated or validated, such subgroups may prove meaningful in future considerations of subdivisions of the schizophrenia syndrome.

Epidemiological findings of seasonal changes in mood and behavior. A telephone survey of Montgomery County, Maryland.

Patterns of seasonal changes in mood and behavior in Montgomery County, Maryland, were evaluated in randomly selected household samples by lay interviewers using a telephone version of the Seasonal Pattern Assessment Questionnaire. The method for selecting the sample unit was random-digit dialing. We found that 92% of the survey subjects noticed seasonal changes of mood and behavior to varying degrees. For 27% of the sample seasonal changes were a problem and 4.3% to 10% of subjects, depending on the case-finding definition, rated a degree of seasonal impairment equivalent to that of patients with seasonal affective disorder. The seasonal pattern of "feeling worst" exhibited a bimodal distribution with a greater winter and a substantially lower summer peak (ratio, 4.5:1). Younger women who have a problem with seasonal changes and who feel worse on short days tended to exhibit the highest seasonality scores. It is apparent from our study that seasonal affective disorder represents the extreme end of the spectrum of seasonality that affects a large percentage of the general population. The influence of environmental factors on mood disorders and mood changes in the general population might provide valuable insight into pathogenesis, treatment, and prevention of affective illness.

Monoamine neurotransmitter interactions in drug-free and neuroleptic-treated schizophrenics.

OBJECTIVE: To study recent suggestions by a number of investigators that interactions between monoamine neurotransmitter systems play an important role in schizophrenia. It has not been clear how hypotheses about interactions might be tested in clinical data. One means for indexing interactions between monoamine neurotransmitter systems may be to compare correlations between cerebrospinal fluid (CSF) monoamine metabolite (homovanillic acid [HVA], 5-hydroxyindoleacetic acid [5-HIAA], and 3-methoxy-4-hydroxyphenylglycol [MHPG]) or ratios of these metabolites (HVA/5-HIAA and HVA/MHPG). DESIGN: We compared these putative measures of monoamine neurotransmitter interaction in 50 drug-free patients with schizophrenia (hospitalized on an inpatient ward of a tertiary care hospital) and 33 normal controls and examined the effects of neuroleptic antipsychotic treatment on these measures in 41 patients (22 of whom had antecedent drug-free CSF data). RESULTS: Drug-free patients with schizophrenia had significantly smaller correlations between CSF monoamine metabolites than normal controls. Longer drug-free time was associated with even smaller correlations between metabolites, suggesting that the difference between controls and patients was not due to acute drug withdrawal. After treatment with neuroleptic antipsychotics there were significant increases in the HVA/5-HIAA and HVA/MHPG ratios, as well as increases in correlations between monoamine metabolites. After treatment, there were no significant differences in metabolite correlations between patients and controls. Metabolite ratios and correlations did not predict subsequent treatment response, but preliminary analyses demonstrated negative relationships between HVA/5-HIAA and HVA/MHPG ratios and Brief Psychiatric Rating Scale rating at that time. CONCLUSIONS: The present findings are consistent with and support hypotheses suggesting that interactions between monoamine systems are altered in schizophrenia and that antipsychotic treatment may affect the functional balance between different monoamine neurotransmitters (although one should keep in mind factors other than interactions between monoamine systems that affect metabolite correlations and ratios.

Cognitive-behavioral and pharmacological treatments of social phobia. A controlled study.

Sixty-five patients with social phobia were treated in a study that compared a cognitive-behavioral group treatment program with pharmacotherapy with alprazolam, phenelzine sulfate, or pill-placebo plus instructions for self-directed exposure to phobic stimuli. Statistically significant repeated-measures effects were shown on all measures, indicating that the treatments studied were associated with substantial improvements in patients with severe and chronic social phobia. Patients who were treated with phenelzine were rated by clinicians as more improved on a measure of work and social disability than patients who were treated with alprazolam or placebo (patients in the cognitive-behavior therapy group were not rated on this measure). Subjects showed positive cognitive changes from before to after treatment, and there were no differences between treatment groups on the cognitive measure. We discuss the implications of these findings within the context of demographic and clinical predictors of response.

A 2-year prospective follow-up study of children and adolescents with disruptive behavior disorders. Prediction by cerebrospinal fluid 5-hydroxyindoleacetic acid, homovanillic acid, and autonomic measures?

A 2-year prospective follow-up study of 100% (N = 29) of a sample of children and adolescents with disruptive behavior disorders found that the baseline lumbar cerebrospinal fluid monoamine metabolite concentration and autonomic nervous system activity predicted some subsequent outcomes. The 5-hydroxyindoleacetic acid concentration significantly predicted severity of physical aggression during follow-up. The skin conductance level significantly predicted institutionalization. Correlations were in predicted directions with lower cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and autonomic activity correlated with poor outcome. Moreover, in multivariate analyses, which included nonlaboratory measures as predictors, cerebrospinal fluid and autonomic measures still contributed significantly to the prediction. However, hypothesized predictions of cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations for suicide attempts and of low autonomic nervous system activity for arrests were not supported thus far. Patients are still at risk; consequently, these results must be considered preliminary. Nonetheless, the results suggest that further investigation of relationships between biological factors and outcome of children with disruptive behavior disorders is warranted.

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.

A 2- to 7-year follow-up study of 54 obsessive-compulsive children and adolescents.

OBJECTIVE: Due to the generally poor prognosis previously reported for patients with obsessive-compulsive disorder (OCD), this report systematically assessed the outcome of patients who had had access to new psychopharmacologic treatments to determine whether there had been any long-term gains and if there were any predictors of outcome. DESIGN: Prospective follow-up study of a cohort of consecutive pediatric patients with OCD who had participated in controlled treatment (clomipramine hydrochloride) trials and then received a variety of interim treatments. PATIENTS: Fifty-four children and adolescents were reevaluated 2 to 7 years (mean, 3.4 +/- 1.0 years) after initial clomipramine treatment. Information for 48 (89%) of the patients was from direct interview and for the remaining six (11%) from at least two sources. RESULTS: On follow-up, 23 of the subjects (43%) still met diagnostic criteria for OCD, and only three (6%) could be considered in true remission. Thirty-eight subjects (70%) were taking psychoactive medication at the time of follow-up. Although OCD symptoms continued, the group as a whole was significantly improved at follow-up, with only 10 subjects (19%) rated as unchanged or worse. A worse OCD outcome score at follow-up was predicted in a stepwise multiple regression by (1) more severe OCD symptoms score after 5 weeks of clomipramine therapy, (2) lifetime history of a tic disorder, and (3) presence of parental Axis I psychiatric diagnosis (R2 = .31, P < .01). CONCLUSIONS: With new treatments available, most patients with pediatric OCD can expect significant longterm improvements but not complete remission. This study supports previous reports of the chronicity and intractability of the disorder, as there still remained a significant subgroup of subjects who exhibited continued morbidity despite multiple interventions.

Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders.

We investigated the validity and reliability of diagnoses made by eight neuropathologists who used the preliminary NINDS neuropathologic diagnostic criteria for progressive supranuclear palsy (PSP) and related disorders. The specific disorders were typical, atypical, and combined PSP, postencephalitic parkinsonism, corticobasal ganglionic degeneration, and Pick's disease. These disorders were chosen because of the difficulties in their neuropathologic differentiation. We assessed validity by measuring sensitivity and positive predictive value. Reliability was evaluated by measuring pairwise and group agreement. From a total of 62 histologic cases, each neuropathologist independently classified 16 to 19 cases for the pairwise analysis and 5 to 6 cases for the group analysis. The neuropathologists were unaware of the study design, unfamiliar with the assigned cases, and initially had no clinical information about the cases. Our results showed that with routine sampling and staining methods, neuropathologic examination alone was not fully adequate for differentiating the disorders. The main difficulties were discriminating the subtypes of PSP and separating postencephalitic parkinsonism from PSP. Corticobasal ganglionic degeneration and Pick's disease were less difficult to distinguish from PSP. The addition of minimal clinical information contributed to the accuracy of the diagnosis. On the basis of results obtained, we propose clinicopathologic diagnostic criteria to improve on the NINDS criteria.

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.

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.

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.

Eye tracking disorder in schizophrenia is characterized by specific ocular motor defects and is associated with the deficit syndrome.

The objective was to determine the relationships between eye tracking disorder (ETD) in schizophrenia, specific ocular motor measures, and the deficit syndrome. Twenty-five normal comparison subjects and 53 schizophrenic patients had eye movements tested with infrared oculography using a sinusoidal target. Patients were assessed with the Schedule for the Deficit Syndrome. For the patients, the distribution of position root mean square error (a global measure of pursuit) was best fit by a mixture of two normal distributions. This information was used to divide the patients into two subgroups, those with and those without ETD. ETD was almost completely accounted for by several specific ocular motor measures and was significantly associated with the deficit syndrome. The finding that ETD was almost completely accounted for by specific measures bridges a gap of interpretation in this field. ETD and the deficit syndrome of schizophrenia may share a common pathophysiology of cerebral cortical-subcortical circuits.

Statistical basis for exploring schizophrenia.

The authors illustrate the use of multivariate statistics as a tool for exploring diagnostic factors in schizophrenia in two areas: the derivation and replication of the 12-point flexible diagnostic system and the definition of schizophrenic subtypes. They suggest an interactive approach between clinician and statistician to ensure the optimal combination of clinical judgment and systematic data analysis. Statistical concepts are presented with a minimum of statistical terminology.

Beyond diagnosis: the phenomenology of schizophrenia.

The authors believe that sharp distinctions of schizophrenia based on cross-sectional signs and symptoms provide the basis for precise and reliable diagnoses, but they do not believe that diagnoses derived from a narrow descriptive base are generously informative on the broad range of human functioning vulnerable to impairment in the course of schizophrenic illness. They comment on the 12-point flexible diagnostic system, illustrating the strengths and weaknesses of well-defined but narrow models for diagnosis, and on the results of testing the predictive validity of several diagnostic approaches. Finally, they contrast the phenomenologic approaches to schizophrenic illness with modern-day descriptive psychiatry, noting implications for clinical practice.

New directions in diagnosis: the longitudinal processes of schizophrenia.

Kraepelin's description of "dementia praecox" was a synthesizing influence in a field that had for too long been fragmented in its thinking about severe psychiatric disorders. Now, once again, the field is attempting to deal with some of the complexities involved in psychopathology and its evolution, complexities that have been reemphasized by newer descriptive research methods. To account for patients deviations from stereotyped diagnostic and prognostic concepts, multiple aspects of course of disorder have been defined and principles of multiaxial diagnosis supported. These principles can provide a basic structure for practice and research using a biopsychosocial orientation within the context of a system model.

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.

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.