Stability of neurological signs with clozapine treatment.
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Adult↗
Biomedical subjects
R W Buchanan
Publications and source records attributed to R W Buchanan.
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.
Adult↗
The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy.
Clozapine is an atypical neuroleptic medication with superior efficacy to conventional antipsychotic agents for patients with chronic, symptomatic schizophrenia. Neurochemical characteristics that distinguish clozapine from other neuroleptics and contribute to its differential efficacy are not known. We assessed the effects of clozapine on plasma levels of norepinephrine (NE) in a double-blind, parallel groups comparison of clozapine (n = 11) and haloperidol (n = 15) in chronic schizophrenic outpatients who had been previously treated with fluphenazine. Simultaneous measurements were obtained for plasma levels of the catecholamine precursor dopa, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), the NE metabolite 3,4-dihydroxyphenylglycol (DHPG), adrenocorticotropin (ACTH), cortisol, and hemodynamic parameters. Clozapine produced marked increases (471%) in plasma NE levels, whereas haloperidol had no significant effects on plasma NE levels. Clozapine also increased dopa and tended to increase DOPAC levels, without effects on DHPG, ACTH, or cortisol levels and without consistent changes in blood pressure. Across patients, the magnitude of clozapine-induced increments in plasma NE levels was positively related to improvement in positive symptoms and global symptomatology and was unrelated to the occurrence of extrapyramidal symptoms. The results suggest that clozapine differs importantly from other neuroleptics in increasing plasma NE levels, with the peripheral noradrenergic stimulation related to its superior efficacy profile. The unchanged DHPG levels and absence of hypertension suggest a more complex mechanism of action of clozapine than heightened NE release alone.
3,4-Dihydroxyphenylacetic Acid↗
Depressive symptoms and the deficit syndrome of schizophrenia.
One of the most influential ideas in schizophrenia research is that schizophrenia may be a syndrome with significant pathophysiological heterogeneity, rather than a single disease. Among patients with schizophrenia, presence or absence of the deficit syndrome has been suggested as a method for defining relatively homogeneous groups. The criteria for the deficit syndrome require the presence of negative symptoms that are judged primary to the illness, rather than to factors, such as depressive mood, that may resemble the negative symptoms of schizophrenia. To test one aspect of the validity of the primary/secondary judgment, we tested the relationship of depressive symptoms to the deficit/nondeficit categorization. Using independent clinician ratings, the depressive mood of deficit and nondeficit patients was compared at the time the categorization was made, and at an average follow-up of 2 1/2 years. Using patients' self ratings, deficit and nondeficit patients were compared at an average follow-up of 1 1/2 years. Deficit patients had significantly less severe depressive symptoms by clinicians' ratings both cross-sectionally and at follow-up, and less severe self-rated symptoms at follow-up. These differences were not due to confounding by age, race, sex, socioeconomic status, or chronicity. These results support the validity of the deficit/nondeficit categorization.
Adult↗
Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia.
OBJECTIVE: Clozapine is an atypical neuroleptic with superior efficacy in severely ill, treatment-resistant inpatients with schizophrenia. To determine if clozapine's differential efficacy generalizes to less ill, outpatients populations, the authors examined the effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. METHOD: Outpatients with schizophrenia who had histories of partial response to conventional neuroleptics and who had not responded to a prospective 6-week trial of fluphenazine participated in a 10-week, double-blind, parallel-groups comparison of clozapine and haloperidol. Thirteen men and six women were given clozapine, and 15 men and five women were given haloperidol. Clinical response rates were determined and effects on primary versus secondary negative symptoms were addressed. Doses of clozapine and haloperidol at the end of the 10-week trial were 410.5 mg/day (SD = 45.8) and 24.8 mg/day (SD = 5.5), respectively. RESULTS: Clozapine was superior to haloperidol for treating positive symptoms. In addition, eight of the patients given clozapine and only one of the patients given haloperidol fulfilled clinical responder criteria. Clozapine was also superior to haloperidol for treating negative symptoms, although these effects were relatively minor. Negative symptoms were significantly affected in the subgroup of patients with nondeficit schizophrenia but not in the subgroup with deficit schizophrenia. Overall, clozapine was well tolerated. CONCLUSIONS: Clozapine has superior efficacy for treating positive symptoms in partially responsive outpatients with chronic schizophrenia, suggesting that it has utility for a broad spectrum of patients with schizophrenia beyond the most severely ill.
Adult↗
Basal ganglia pathology in schizophrenia and tardive dyskinesia: an MRI quantitative study.
Magnetic resonance imaging was used to measure the volumes of the caudate, putamen, and globus pallidus of 25 schizophrenic patients (17 men and eight women) and 26 age- and sex-matched comparison subjects (18 men and eight women). Schizophrenic patients had significantly larger right and left globus pallidus and right putamen volumes than comparison subjects. There were no significant differences between schizophrenic patients with and without persistent tardive dyskinesia in the volume of any of the three structures.
Adult↗
Domains of psychopathology: an approach to the reduction of heterogeneity in schizophrenia.
The manifest clinical heterogeneity of schizophrenia, combined with the failure, to date, to demonstrate the existence of a unitary disease process, has led to the conceptualization of schizophrenia as a pathophysiologically heterogeneous disorder. Various approaches have been developed to define homogeneous subgroups of schizophrenic patients. An alternative approach to the use of multiple criteria for defining putative disease entities is the use of specific sign and symptom complexes, or domains of psychopathology, for reducing heterogeneity. There is now considerable evidence supporting the separation of schizophrenic symptoms into three domains: hallucinations and delusions, thought disorder, and deficit symptoms. The conceptual evolution and validating evidence for this approach are reviewed, and an illustration of how the domains of psychopathology are applied in schizophrenia research is presented.
Brain↗
Clozapine attenuates meta-chlorophenylpiperazine (mCPP)-induced plasma cortisol increases in schizophrenia.
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Adult↗
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.
Adult↗
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.
Brain↗
Case identification and stability of the deficit syndrome of schizophrenia.
In certain situations, such as large epidemiological studies, it may be necessary to use proxy case-identification tools instead of "gold-standard" assessments. The deficit syndrome of schizophrenia requires a clinical assessment that may not be feasible in some study populations. Measures for the discrimination of deficit and nondeficit patients, based on the Brief Psychiatric Rating Scale (BPRS), were assessed in a group of 100 outpatients with chronic schizophrenia. A rationally based case-identification tool was validated, and its case-identification properties were found to be stable over time; consequently, this proxy measure may be of use in other data sets. The stability of the relationship between this BPRS measure and the deficit/nondeficit categorization supports the view that it is a valid categorization.
Adult↗
Relations between attentional deficits and clinical symptoms in schizophrenic outpatients.
Information-processing impairments have been suggested to be at the core of the cognitive deficits observed in schizophrenia and may represent preclinical markers of genetic vulnerability to the illness. Of particular importance in information-processing research have been measures such as the Continuous Performance Test (CPT) and the Partial Report Span of Apprehension (SPAN) that place high momentary loads on processing resources. The relationships between the two cognitive measures and between the two measures and clinical symptoms were examined in 50 patients with either DSM-III-R schizophrenia or schizoaffective disorder. The information-processing measures were modestly correlated with each other and with an estimate of verbal, but not nonverbal IQ. The SPAN was correlated with negative symptoms and the CPT with formal thought disorder. These results provide some evidence of convergent validity but also suggest that constructs other than high momentary processing load are implicated in their sensitivity to schizophrenia.
Adult↗
Structural abnormalities in deficit and nondeficit schizophrenia.
OBJECTIVE: Previous studies have suggested the involvement of the frontal and parietal cortices and thalamus in a neural circuit underlying the production of primary enduring negative or deficit symptoms of schizophrenia. The purpose of this study was to examine whether structural changes in the proposed circuit are associated with the production of deficit symptoms. METHOD: Magnetic resonance imaging was used to measure the volume of selected circuit brain regions (i.e., the prefrontal region and caudate) and noncircuit brain regions (i.e., the amygdala/hippocampus complex) in 17 deficit and 24 nondeficit schizophrenic outpatients and 30 normal comparison subjects. RESULTS: Right and left total prefrontal volumes discriminated deficit from nondeficit patients, with prefrontal volumes being smaller in nondeficit patients. There were no differences between the two schizophrenic subgroups in left caudate or right and left amygdala/hippocampus complex volumes. The right caudate was larger in deficit patients, but the difference between the two schizophrenic subgroups was not significant. There were no differences between deficit and normal subjects on any prefrontal region measure. Nondeficit patients had smaller total right and left prefrontal volumes than normal subjects. Both schizophrenic subgroups had larger left caudate volumes and smaller right and left amygdala/hippocampus complex volumes than the normal subjects. There was a trend for deficit patients to have larger right caudate volumes. CONCLUSIONS: These results suggest that structural changes in the prefrontal region are not responsible for deficit symptoms. The caudate, particularly the right caudate, may be associated with the production of these symptoms.
Frontal Lobe↗
Clozapine treatment of outpatients with schizophrenia: outcome and long-term response patterns.
OBJECTIVE: The purpose of the study was to examine the effects of clozapine in treating moderately ill schizophrenic outpatients and to determine the length of medication trial needed to identify responders and nonresponders. METHODS: Rates of clinical responses, relapses and hospitalizations, and levels of symptomatology and functioning were assessed for 30 chronic schizophrenic outpatients who received clozapine for one year. For some patients, data on relapse and hospitalization during treatment were compared with data from the year before treatment. RESULTS: Eighteen of the 30 patients met criteria for sustained response; 17 of the responders were identified within the first four months of treatment. Patients experienced significantly fewer relapses and hospitalizations during treatment than in the previous year. Improvement in positive symptoms, general symptomatology, and levels of functioning reached a plateau during the first six months of treatment and remained at that level during the second six months. Negative symptoms and quality of life showed nonsignificant improvements at 12 months. CONCLUSIONS: Results support the use of clozapine in treating chronic, residually symptomatic schizophrenic outpatients. A four-month clozapine trial may be adequate to detect clinical responders in this population.
Adult↗
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.
Administration, Oral↗
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.
Administration, Oral↗
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.
Adult↗