Remission in schizophrenia: the relationship to baseline symptoms and changes in symptom domains during a one-year study.

The concepts of partial recovery and remission have become increasingly important for the evaluation of the effectiveness of schizophrenia therapeutics. The relationship of baseline symptoms and changes in symptoms to remission of psychosis was evaluated. Fifty-six outpatients with residual schizophrenia completed a double-blind trial of olanzapine versus haloperidol and were then enrolled into a one-year open-label trial of olanzapine. Out of these 56 subjects, 13 (23%) met remission criteria at the beginning of the open-label treatment and were excluded. During the one-year study, 7/43 (16%) subjects met remission criteria. These subjects had significantly lower baseline ratings for tardive dyskinesia (TD) than subjects who did not achieve remission (1.8 +/- 1.5 vs. 4.2 +/- 4.6, P = 0.03). As expected, remitted subjects had significantly greater improvements in Brief Psychiatric Rating Scale total scores, positive subscale scores and scale for the Assessment of Negative Symptoms total scores. Remitted subjects also experienced a significantly greater improvement in depressive symptoms (P = 0.001), activation (P = 0.005), and Clinical Global Impressions scores (P < 0.001), as well as greater improvements in extrapyramidal symptoms (P = 0.007) and TD (P < 0.001). These results suggest that the relationship of depressive symptoms and improved side effects to the construct of remission in schizophrenia may deserve special attention. Future studies should aim to relate remission criteria to functional outcomes, cognition, and other important symptom domains.

A separate disease within the syndrome of schizophrenia.

If schizophrenia is a clinical syndrome rather than a single disease, the identification of specific diseases within the syndrome would facilitate the advance of knowledge and the development of more specific treatments. We propose that deficit psychopathology (ie, enduring, idiopathic negative symptoms) defines a group of patients with a disease different from schizophrenia without deficit features, as the deficit and nondeficit groups differ in their signs and symptoms, course, biological correlates, treatment response, and etiologic factors. These differences cannot be attributed to more severe positive psychotic symptoms or a greater duration of illness in the deficit group. The alternative interpretation that patients with deficit schizophrenia are at the severe end of a single disease continuum is not supported by risk factor and biological features data, but there is a need for independent replication of these findings. We suggest a series of studies designed to falsify one of these hypotheses, ie, multiple diseases vs a single disease.

Neuropsychological impairments in deficit vs nondeficit forms of schizophrenia.

BACKGROUND: Previous studies have suggested that functional impairments of the frontal and parietal lobes are related to the deficit symptoms of schizophrenia. The purpose of the current study was to examine whether neuropsychological measures of frontal and parietal lobe function differentiated deficit from nondeficit patients. Neuropsychological measures of temporal lobe function were used as contrast measures. METHODS: The performance of 18 deficit and 21 nondeficit schizophrenic patients was examined on neuropsychological measures of executive, visuospatial, and memory functions, selected on the basis of their association with lesions of either the frontal, parietal, or temporal lobes. The results from the schizophrenic subgroups were compared with the results on the same measures obtained from 30 normal controls. RESULTS: Deficit patients performed more poorly than nondeficit patients on two frontal lobe measures, the Stroop Color-Word Interference and Trails Making B tests, and one parietal lobe measure, the Mooney Faces Closure Test. There were no differences in performance on the temporal lobe measures between the two groups. Both groups performed more poorly on the tests than the normal controls. CONCLUSIONS: The results suggest that deficit patients may have greater performance impairments on neuropsychological measures associated with frontal and parietal neuropsychological abnormalities.

Strong inference, theory testing, and the neuroanatomy of schizophrenia.

Failure to address the putative etiologic and pathophysiologic heterogeneity of the schizophrenia syndrome and problems in definitive assessment of human brain function have impaired progress in schizophrenia research. New approaches to psychopathology and converging evidence from antemortem and postmortem study can now result in more decisive study of the neuroanatomy and neuropathology of schizophrenia.

Catching up on schizophrenia. The Fifth International Congress on Schizophrenia Research, Warm Springs, Va, April 8-12, 1995.

It is axiomatic that the diversity and ingenuity of strategies in the study of schizophrenia bear testimony to the complexity of this disorder. Accordingly, the opportunity for investigators of diverse interests to share their latest findings and be informed of developments in key areas of science is critical to advance our understanding of schizophrenia. Nearly 700 investigators from around the world gathered at Warm Springs, Va, to present their data at the Fifth International Congress on Schizophrenia Research (April 8-12, 1995). This 5-day conference, held every other year alternating with the European Winter Workshop on Schizophrenia, is co-organized by S. Charles Schulz, MD, Case Western Reserve University, Cleveland, Ohio, and Carol Tamminga, MD, Maryland Psychiatric Research Center, University of Maryland at Baltimore. Drs Schulz and Tamminga first held the Congress in 1987 in Clearwater, Fla, with 170 investigators presenting. The Congress has flourished since then and is now the largest research meeting devoted solely to schizophrenia. The Congress organizers, the program coordinator (Jeffrey Lieberman, MD, Hillside Hospital, Glen Oaks, NY), and the Congress coordinator (Susan Nusbaum, Maryland Psychiatric Research Center) are congratulated on the success of this event and its contribution to fostering initiatives and collaborations within schizophrenia research.

Effects of metabolic perturbation on plasma homovanillic acid in schizophrenia. Relationship to prefrontal cortex volume.

OBJECTIVE: Several recent hypotheses suggest that deficits in normal prefrontal cortical inhibition of subcortical dopamine activity result in dysregulated dopamine function and may contribute to the pathophysiology of schizophrenia. These effects seem to be more consistently demonstrable during stressful perturbation of the dopamine system, as opposed to during the resting state. We have developed a novel paradigm involving infusion of the glucose analog, 2-deoxyglucose (2DG), to examine the effects of perturbation on the dopamine metabolite, plasma homovanillic acid (HVA), in schizophrenics and healthy controls. DESIGN: Pharmacologic doses of 2DG (50 mg/kg) and placebo were infused in a double-blind manner. 2-Deoxyglucose-induced effects on plasma HVA were related to magnetic resonance imaging-derived prefrontal cortex volumes. SUBJECTS: Schizophrenic outpatients (N = 18) and healthy volunteers (N = 11) participated in the study. RESULTS: Schizophrenic patients, as compared with controls, had significantly greater 2DG-induced plasma HVA elevations. These effects were observed in subgroups of neuroleptic-free and neuroleptic-treated patients. Other neuroendocrine (plasma cortisol), physiologic (heart rate, diastolic blood pressure, temperature) and behavioral (self-ratings of stress, fatigue) variables were significantly effected by 2DG but did not differeniate schizophrenics and controls suggesting that the effects on plasma HVA may be relatively specific. Magnetic resonance imaging-derived volumes of the prefrontal cortex were significantly and inversely correlated to 2DG-related peak changes in plasma HVA levels in the schizophrenics. CONCLUSION: These data support the hypothesis that schizophrenia is associated with abnormal regulation of dopamine and that this deficit may be related to reduced frontal cortical inhibitory influences.

Brain morphology and schizophrenia. A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures.

We used magnetic resonance imaging to examine the morphologic characteristics of the amygdala/hippocampus, prefrontal cortex, and caudate nucleus in 29 healthy volunteers matched for age, gender, and head of household socioeconomic status and 44 patients with chronic schizophrenia. Total volumes of these structures were determined from 3-mm contiguous coronal sections. Schizophrenic patients, compared with healthy controls, had significantly smaller right and left amygdala/hippocampal complex volumes, smaller right and left prefrontal volumes, and larger left caudate volumes. A secondary analysis revealed reductions in the right and left amygdala and the left hippocampus. In addition, prefrontal white matter, but not gray matter, was reduced in the schizophrenic patients. Moreover, the right white matter volume in schizophrenic patients was significantly related to right amygdala/hippocampal volume (r = .39), data that provide preliminary support for a hypothesis of abnormal limbic-cortical connection in schizophrenia. We studied the implications of these data for the pathophysiology of schizophrenia.

Carbamazepine maintenance treatment in outpatient schizophrenics.

A double-blind crossover trial was used to evaluate carbamazepine as the sole maintenance treatment of chronic, nonmanic schizophrenic outpatients whose conditions had been stabilized with the use of neuroleptics prior to study. Criteria of treatment effectiveness included the number of patients relapsing and time to relapse over a 95-day neuroleptic-free period during which either carbamazepine or placebo was administered. Relapse was determined by the concordance of psychiatric ratings and independent clinical judgements indicating significant worsening. Results for 27 patients (13 receiving carbamazepine and 14 receiving placebo) involved in the first phase of this treatment comparison were nondifferentiating. Corroborating descriptive findings in the second phase were available for 14 of these patients. There was no evidence supporting the existence of a treatment-relevant subgroup defined by episodic dyscontrol phenomena.

The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance.

Previous studies have suggested that clozapine may improve neuropsychological test performance. The current study was designed to examine the comparative efficacy and the long-term effect of clozapine (versus haloperidol), on neuropsychological test performance. Neuropsychological measures of executive/attention, visuospatial, and memory function were administered to schizophrenic patients at baseline, at the end of a 10-week double-blind study, and after 1 year of open clozapine treatment. Symptoms and function ratings were obtained at the same time points. The 10-week double-blind study revealed significant group-by-time interactions for two measures: Categorical Fluency and WAIS-R Block Design. At the end of 1 year of open treatment there were significant improvements in Verbal Fluency, Mooney Faces Closure, and WAIS-R Block Design performance, and trend improvements in Stroop Color-Word Interference, Category Fluency, and WMS-R Logical Memory performance. Improvements in neuropsychological performance were unrelated to symptom changes. Change in selected neuropsychological measures were significantly correlated with improvement in quality of life. The results suggest that long-term clozapine treatment may have beneficial effects on a broad range of cognitive functions.

Deficit psychopathology and a paradigm shift in schizophrenia research.

Despite recognition that schizophrenia must have syndrome status in the absence of proof of a single etiopathophysiologic process, a century of work has been based on designs that conceptualize schizophrenia as a single disease entity. Reducing heterogeneity at several levels of functioning is desirable. In this article we summarize progress using deficit syndrome psychopathology to address heterogeneity. The deficit syndrome has proven to be reliable, with construct validity, as well as predictive validity with biological, treatment, and course variables. We propose a shift in schizophrenia research away from the syndrome level toward study designs that identify more homogeneous entities. Doing so will increase the statistical power of study designs by reducing false positive cases.

Effect of neuroleptic withdrawal on plasma prolactin: a possible marker of receptor adaptation.

Stable schizophrenic and schizoaffective outpatients underwent abrupt withdrawal from a fixed dose of neuroleptic. Prolactin concentrations were determined preceding and following drug withdrawal. Basal prolactin concentrations were significantly lower 3, 4, or 5 days following drug withdrawal than on subsequent days. This rebound effect may be related to dopaminergic receptor changes in the tuberoinfundibular system that are induced by chronic neuroleptic administration.

Plasma prolactin as a predictor of relapse in drug-free schizophrenic outpatients.

A low plasma prolactin concentration has been reported to be associated with an increased risk of subsequent relapse in patients with schizophrenia. Prolactin concentration was measured in samples from stable schizophrenic men who were outpatients just prior to neuroleptic withdrawal. No relationship between prolactin concentration and time to subsequent relapse was found. Prolactin concentration may predict time to relapse only in populations characterized by specific demographic features or medication history.

Clinical predictors of relapse following neuroleptic withdrawal.

The validity of previously hypothesized predictors of elapse following neuroleptic discontinuation was examined. One hundred sixty-two outpatients, with either Research Diagnostic Criteria schizophrenia or schizoaffective disorder, were discontinued from neuroleptic medication for a 28-day period or until judged to be relapsed. Pre-discontinuation neuroleptic dosage level, the severity of psychotic symptoms, and the presence of dyskinetic movements prior to neuroleptic discontinuation were the predictor variables. Of the 162 patients, 62.7% did not relapse during the study period. There were no differences in the survival rates between the patients withdrawn from oral versus depot neuroleptics. Neuroleptic dosage, but not severity of psychotic symptoms or dyskinetic movements, predicted relapse. These results support the hypothesis that pre-withdrawal neuroleptic dosage level predicts relapse, but fail to validate either severity of psychotic symptoms or presence of dyskinetic movements as predictors of relapse.

Effects of contextual processing on visual conditional associative learning in schizophrenia.

BACKGROUND: We adapted visual conditional associative learning paradigms to assess the contextual processing deficit model of schizophrenic cognitive impairment proposed by J.D. Cohen and D. Servan-Schreiber in 1992. In this task subjects learn the associations between four sets of stimuli through the use of feedback. We administered two experimental conditional associative learning conditions: in one, the eight stimuli used to make four pairs were all different; in the other, the pairs were made from different combinations of four identical stimuli, requiring the use of contextual information to mediate correct performance. Two additional associative learning tasks were administered where subjects generated the stimulus pairings or observed the experimenter form the pairs, eliminating the need to learn from feedback. METHODS: We tested 37 patients with schizophrenia and 20 healthy control subjects in each conditional associative learning task condition. RESULTS: Patients demonstrated significant impairments on all four conditional associative learning tasks. The demand to process contextual information did not differentially impact patient performance. Patients were better able to learn associations if they generated or observed the pairings rather than utilized feedback to guide learning. CONCLUSIONS: Patients with schizophrenia demonstrate pronounced deficits in the ability to utilize feedback to guide learning. We found no evidence of an additional deficit in processing of contextual information.

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.

Significance and meaning of neurological signs in schizophrenia.

The authors review studies of abnormal signs on clinical neurological examination of schizophrenic patients. In spite of a number of methodologic limitations, the cumulative evidence strongly argues that there are more neurological signs in schizophrenic patients than in nonpsychiatric control subjects. Although less consistent, there is considerable evidence of more neurological signs in schizophrenic patients than in patients with affective disorders or with mixed, nonpsychotic disorders. The existing literature suggests several preliminary hypotheses with respect to neuroanatomical localization of neurological signs, subtyping of schizophrenia, and utility of studies of relatives at high risk and family history studies. Directions for future research in these areas are described.

Neurological signs and the heterogeneity of schizophrenia.

OBJECTIVE: More than 20 studies of schizophrenia have found a three-factor model of symptom complexes or syndromes consisting of hallucinations/delusions, disorganization of thought and behavior, and negative symptoms. Several lines of evidence suggest that these syndromes relate to neurobiological differences. We examined the relationship of these three syndromes to neurological signs. METHOD: The relationships among the subscales of the Neurological Evaluation Scale and hallucinations/delusions, disorganization, and the deficit syndrome were examined in 83 clinically stable outpatients with schizophrenia. Patients with the deficit syndrome have enduring, idiopathic (or primary) negative symptoms. RESULTS: Each of the three syndromes had a distinctive pattern of relationships to neurological signs. Disorganization was significantly related to the total score on the Neurological Evaluation Scale, to sensory integration, and to the sequencing of complex motor acts. The deficit syndrome was significantly related to sensory integration only. Neither hallucinations/delusions nor a continuous measure of negative symptoms derived from the Brief Psychiatric Rating Scale (that measured both primary and secondary negative symptoms, as well as enduring and transient symptoms) was related to any of the Neurological Evaluation Scale subscales or total score. Drug treatment was not related to neurological impairment. CONCLUSIONS: The results further support the neurobiological significance of the three clinical syndromes of schizophrenia. Ratings on a scale measuring negative symptoms appear to be less sensitive to neurobiological correlates than is the categorization of the presence or absence of the deficit syndrome.

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 I: sensitivity, reliability, and validity.

OBJECTIVE: Cognitive impairment is an important feature of schizophrenia and is correlated with functional outcome. However, psychiatry lacks a screening instrument that can reliably assess the types of cognitive impairment often seen in schizophrenia. The authors assessed the sensitivity, convergent validity, and reliability of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) as well as the relationship of the RBANS to symptoms and employment status. This newly published test takes 25 minutes to administer and was standardized on a U.S.-Census-matched adult population. The test provides a total score and five index scores, each with a mean value of 100 (SD = 15). METHOD: RBANS data were obtained from 129 patients with schizophrenia in the outpatient and inpatient programs of the Maryland Psychiatric Research Center. RBANS data were correlated with WAIS-III and Wechsler Memory Scale, 3rd ed. performance in 38 patients. Reliability data for alternate forms of the RBANS were obtained from 53 patients; symptom ratings were obtained from 48 patients; and employment status was examined in 77 patients. RESULTS: The patients with schizophrenia demonstrated marked impairment on the RBANS (their mean total score was 71.4). The patients' index scores suggested that they had relatively less impairment of language and visual functions than of memory and attention. The RBANS demonstrated high correlations with full-scale IQ and memory measures. The total score demonstrated good reliability. RBANS performance minimally correlated with Brief Psychiatric Rating Scale ratings but was strongly related to employment outcome. CONCLUSIONS: The RBANS appears to be a useful cognitive screening instrument in schizophrenia. The instrument may be a useful prognostic indicator and offers a means of assessing cognitive status.

Differential effect of clozapine on weight: a controlled study.

OBJECTIVE: This study examined whether clozapine induces more weight gain than haloperidol and whether weight gain is related to clinical improvement. METHOD: The weight and symptoms of 39 outpatients with schizophrenia who were randomly assigned to double-blind treatment with either clozapine or haloperidol were assessed. The weight and symptoms of 33 of the patients who chose to take clozapine during a 1-year follow-up after the study ended were also assessed. RESULTS: The patients treated with clozapine gained significantly more weight over baseline (7%) than the haloperidol-treated patients (1%). Weight gain was not significantly correlated with improvements in either positive or negative symptoms. Fifty-eight percent of the patients followed for 1 year gained at least 10% over their baseline weight. CONCLUSIONS: Weight gain is an important side effect of clozapine and is unrelated to the drug's differential antipsychotic efficacy.