Plasma 3-methoxy-4-hydroxyphenylglycol changes associated with clinical state and schizophrenic subtype.

In a study of 14 drug-free schizophrenic patients and 22 healthy control subjects, the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) level appeared to be altered by changes in clinical state. Repeated sampling in schizophrenic patients showed that plasma MHPG values were elevated in high-psychosis phases in comparison with metabolite levels at times of lower psychosis. There was a nonsignificant trend toward higher MHPG levels in paranoid schizophrenic patients in comparison with patients who had undifferentiated schizophrenia. Paranoid schizophrenic patients had significantly elevated plasma MHPG levels in comparison with previously studied healthy controls. These findings suggested that alterations in the plasma MHPG level may reflect psychosis-related changes in norepinephrine function in schizophrenia.

Preliminary evidence of reduced combined output of dopamine and its metabolites in chronic schizophrenia.

The mean combined total body excretion of dopamine (DA) and its metabolites, measured by summing the molar excretion of DA and its metabolites in 24-hour urine samples (Sum DA), was reduced in 20 patients with schizophrenia who had not been receiving medication for at least two weeks. These patients were relatively resistant to treatment, as they were unable to live independently outside institutional settings despite conventional neuroleptic therapy. In contrast, sum norepinephrine (Sum NE), measured by summing the molar excretion of NE and its metabolites, was not reduced. These results are highlighted by expressing the data in terms of the ratio of Sum DA/Sum NE. Patients with schizophrenia had a significantly lower ratio. Treatment with haloperidol normalized the low ratio. Urinary excretion of 5-hydroxyindoleacetic acid was normal in the schizophrenic patients. These results suggest that chronic schizophrenia is more likely to be associated with a low rather than a high state of DA activity.

Telemetered EEG-EOG during psychotic behaviors of schizophrenia.

In an effort to establish correlations between abnormal behaviors characteristic of schizophrenia and simultaneous cerebral electrical activity, EEGs and electro-oculograms (EOGs) were continuously recorded for 2 to 24 hours by radiotelemetry from 40 patients with schizophrenia and 12 normal control subjects. Trained observers recorded specific behavior patterns permitting visual and computer analysis of EEG during hallucinations, stereotypy, catatonia, psychomotor blocking, and other characteristic manifestations of schizophrenia. Electroencephalographic abnormalities consisting of focal slow or spike activity over either temporal region were found in nearly half of the patients so recorded. In contrast to the EEG during ictal episodes of epilepsy, the abnormal wave forms of schizophrenic patients seldom coincided with episodes of blocking, stereotypy, or other abnormal behaviors. Increased extraocular activity or blinking were recorded in a majority of patients, but were not consistently associated with the abnormal behavior or perceptual events.

Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect.

BACKGROUND: Although intellectual and neurocognitive deficits accompany schizophrenia, there are inconsistencies in the literature concerning issues of intellectual decline, premorbid deficits, a modal deficit pattern, and preserved abilities. METHODS: A battery of neuropsychological tests was administered once to 117 consecutively admitted patients with chronic schizophrenia and a group of 27 healthy control subjects to examine patterns of premorbid and current intellect (measured by means of reading scores and IQ, respectively) and the attendant cognitive profiles in schizophrenia using classification methods based on clinically derived (IQ levels) and atheoretical (cluster) techniques. RESULTS: Sixty patients (51%) with schizophrenia who displayed a general intellectual decline of 10 points or greater from estimated premorbid levels also exhibited deficits of executive function, memory, and attention. Twenty-eight patients (23%) with consistently low estimated premorbid intellect and current intellectual levels who displayed no evidence of IQ decline exhibited language and visual processing deficits in addition to deficits present in the intellectually declining group. The remaining 29 patients (25%) who displayed average estimated premorbid intellectual levels did not show IQ decline and exhibited a cognitive profile similar to normal, with the exception of executive function and attention impairment. Atheoretical analyses support the findings from clinically derived subgroups. CONCLUSIONS: These results suggest that IQ decline, although modal in schizophrenia, is not universally characteristic and that executive function and attention deficits may be core features of schizophrenia, independent of IQ variations.

Cerebral ventricular enlargement in chronic schizophrenia. An association with poor response to treatment.

Response to neuroleptic drug treatment in ten chronic schizophrenic patients with enlarged cerebral ventricles was compared with ten similar patients with normal ventricles. The groups were closely matched for age, age at onset of illness, years of illness and hospitalization, drug dosage, and plasma neuroleptic concentration as measured by radioreceptor assay. Response was significantly worse in the patients with enlarged ventricles. This finding supports the notion that ventricular enlargement is clinically relevant in patients with chronic schizophrenia and that patients with this abnormality may have a biologically different illness than similar patients without it.

Plasma prolactin concentrations and psychopathology in chronic schizophrenia.

Plasma prolactin concentrations in 17 drug-free chronic schizophrenic patients correlated inversely with ratings of their psychopathology. An inverse relationship between psychotic symptoms and plasma prolactin concentrations was particularly clear in patients with normal cerebral ventricular size as determined by computed tomography. The psychosis-prolactin relationship did not hold for schizophrenic patients with large ventricular size. These data suggest that the degree of psychosis is related to dopaminergic activity insofar as this is reflected by plasma prolactin concentrations, especially in schizophrenic patients with normal ventricular size. These findings lend further support to the hypothesis that ventricular size is a meaningful factor in subtyping chronic schizophrenic patients.

Inhibition of dopamine synthesis in chronic schizophrenia. Clinical ineffectiveness of metyrosine.

According to the dopamine (DA) hypothesis of schizophrenia, there is a functional excess of dopaminergic activity within unspecified areas of the brain in schizophrenic patients. As a clinical test of this hypothesis, we administered metyrosine for three weeks to symptomatic chronic male schizophrenic patients who were maintained on suboptimal doses of neuroleptic agents. Metyrosine inhibits tyrosine hydroxylase, the rate-limiting enzymatic step in the synthesis of DA. No clinical improvement was observed, using the National Institute of Mental Health Inpatient Behavioral Rating Scale or the Brief Psychiatric Rating Scale. Central inhibition of DA synthesis by metyrosine was suggested, however, by (1) the development of extrapyramidal side effects and (2) a significant increase in plasma prolactin concentrations. Plasma chlorpromazine concentrations remained unchanged during metyrosine treatment. There was, nevertheless, a significant improvement on the scores of the Wechsler Adult Intelligence Scale Comprehension subtest, which measures judgment and common sense. This finding suggests that DA may be involved in the regulation of subtle psychological processes. The results are discussed in light of the DA hypothesis of schizophrenia and previous reports suggesting that metyrosine potentiates the antipsychotic effect of neuroleptics in schizophrenia.

Neuropsychological assessment of monozygotic twins discordant for schizophrenia.

A comparison of monozygotic twins discordant for schizophrenia controls for genetic variance and reduces variance due to environmental circumstances, thus serving to highlight differences due to phenotypic-related variables. In this study, we assessed 16 such twin pairs on a wide range of neuropsychological tests. The affected twins tended to perform worse than their unaffected counterparts on most of the tests. Deficits were especially severe on tests of vigilance, memory, and concept formation, suggesting that dysfunction is greatest in the frontotemporal cortex. While manifest symptoms were not highly associated with neuropsychological scores, global level of functioning was. To address the issue of genetic liability, we also compared the sample of discordant unaffected twins with a sample of seven pairs of normal monozygotic twins. No significant differences between the groups were found for any neuropsychological test. In fact, the results suggest that neuropsychological dysfunction is a consistent feature of schizophrenia and that it is related primarily to the clinical disease process and not to genetic or nonspecific environmental factors.

Clinical effects of L-5-hydroxytryptophan administration in chronic schizophrenic patients.

L-5-Hydroxytryptophan (L-5HTP) and the peripheral decarboxylase inhibitor carbidopa were administered to chronic schizophrenic patients in three separate experiments using a double-blind placebo-controlled crossover design. The three experiments were: (i) L-5HTP administration to 15 patients who had been withdrawn from all neuroleptic medication; (ii) L-5HTP administration to seven patients maintained on haloperidol; (iii) L-5HTP administration to nine patients maintained on chlorpromazine. Although the groups were diagnostically homogeneous, individual responses were highly variable. Considering each group as a whole, the only significant changes in rated psychosis consisted of an increase in the first group consequent to coming off neuroleptic medication and an increase in psychosis scores associated with adding L-5HTP to chlorpromazine. Neuroleptics apparently sensitize the central nervous system to the effects of L-5HTP loading. Acute exacerbations of psychosis induced by L-5HTP can be reversed by neuroleptics. Our experience does not give encouragement to the hypothesis that schizophrenic illnesses arise consequent to a deficit of serotonergic function that can be treated by giving a serotonin precursor in pharmacological quantities.

Subtle signs of prenatal maldevelopment of the hand ectoderm in schizophrenia: a preliminary monozygotic twin study.

Genes that predispose to psychosis may act by making individuals more vulnerable to the disruptive effects of various prenatal insults. Fetal organogenesis is mostly completed in the first prenatal trimester. The second trimester is a critical period of massive neuronal migration from the periventricular germinal matrix to the cortex. A peripheral appendage developing simultaneously with this neural migration to the cortex is the distal upper limb. The ectodermal cells of the fetal upper limb migrate to form the hand skin during the fourth and fifth months of gestation (first two-thirds of the second prenatal trimester). Discrepancies in hand morphology between two identical (monozygotic [MZ]) co-twins may be temporal markers, that is, the "fossilized" evidence of various ischemic and other nongenetic insults that may have affected one fetus more than his MZ co-twin during that early part of the second trimester. In twins, prenatal insults (e.g., ischemia) frequently do not affect both co-twins to the same extent, so we examined seven putative markers of prenatal injury to the hand in 24 MZ twin pairs discordant for schizophrenia or delusional disorder. Compared with well co-twins, the affected co-twins had significantly higher total scores of fourth- and fifth-month dysmorphological hand anomalies.

Quantitative autoradiography of dopamine-D1 receptors, D2 receptors, and dopamine uptake sites in postmortem striatal specimens from schizophrenic patients.

A number of previously published homogenate receptor binding studies have postulated that dopaminergic dysfunction in schizophrenia may be related to abnormalities in dopamine receptors. In this study, postmortem striatal specimens from patients with schizophrenia, normal controls, and psychiatric controls that had received neuroleptics were studied with quantitative autoradiography for dopamine receptors. Autoradiography with single concentrations of [3H]-SCH 23390 for D1 receptors, [3H]-raclopride for D2 receptors, and [3H]-CFT for dopamine uptake sites failed to define significant differences between the study groups. [3H]-CFT bound in a patchy distribution in the striatum that is believed to correspond to striosomal and matrix striatal compartments. There were no differences between groups when [3H]-CFT binding density was examined in the striosomal and matrix compartments. There were also no differences between groups in the percentage of striatal area occupied by striosomal or matrix compartments as defined by [3H]-CFT binding. We conclude that abnormalities of these dopamine receptor subtypes are probably not primary features of the schizophrenic syndrome in the brain collection examined. Previous reports of elevated D2 receptor binding in schizophrenia may have been related to drug treatment effects. Alternatively, the relatively high affinity of ligands used in previous studies for D4 receptors may explain the discrepancy in our findings. Unchanged [3H]-CFT binding in the schizophrenic group also suggests that the density of mesostriatal neuronal terminals is not altered in schizophrenia.

Evaluation of superior vermal Purkinje cell placement in mental illness.

BACKGROUND: A number of neuroimaging and neuropathological studies have reported abnormalities in the cerebellar vermis in schizophrenia and bipolar disorder. In an effort to further understand vermal abnormalities in mental illness, we have analyzed ectopic placement of Purkinje-like cells. METHODS: The superior cerebellar vermis was evaluated in 39 cases of severe mental illness [schizophrenia (n = 12), bipolar disease (n = 12), and depression (n = 15)]. We also examined 9 subjects with polysubstance abuse and 15 normal controls. All normally placed Purkinje cells and displaced Purkinje-like cells (i.e., in the internal granule layer and intrafoliar white matter) were counted in the same foliar field. The ratio of displaced Purkinje-like cells to total Purkinje cells and Purkinje cell density were calculated. RESULTS: No significant difference in the ratio of displaced to normally placed Purkinje cells or in Purkinje cell density between groups of subjects was found. CONCLUSIONS: Our study does not support a hypothesis of abnormalities of Purkinje cell migration or other events related to their displacement as a basis for the vermal abnormalities reported previously in schizophrenia and bipolar disorder.

Tardive dyskinesia: neuropsychological, computerized tomographic, and psychiatric symptom findings.

Prior studies have suggested that schizophrenic patients with tardive dyskinesia (TD) have an unusual incidence of cognitive impairment, structural brain abnormalities, and negative symptoms. Twenty-seven schizophrenic patients with TD and an equal number of age-, gender-, and education-matched schizophrenic controls were studied. Each patient received neuropsychological testing, psychiatric symptom ratings, and most had cerebral computed tomography (CT) scans. Patients with TD significantly differed from controls on only 1 of 23, cognitive measures, and the overall group performance profiles were highly similar. No differences were observed on symptom ratings. Patients with TD had significantly smaller ventricular-brain ratios (VBRs) than controls. These data fail to support an association of TD with global measures of "organicity." Abnormal movements may result from specific dysfunction within the more purely motor circuits of the basal ganglia without compromising other neural systems involved in cognitive processing.

Relative risk for cognitive impairments in siblings of patients with schizophrenia.

BACKGROUND: Patients with schizophrenia have impairments in several domains of cognition, including working memory/executive function, verbal memory, language, oculomotor scanning/psychomotor speed, and general intelligence. Impairments have also been found in unaffected siblings, suggesting they could be heritable. To assess the suitability of cognitive dysfunction for use in genetic studies, we estimated relative risk (lambda) in a large cohort of siblings. METHODS: One hundred forty-seven patients with schizophrenia, 193 of their siblings, and 47 control subjects were studied using a neuropsychological test battery, which included intelligence quotient (IQ), Wide Range Achievement Test, Wisconsin Card Sort, Wechsler Memory Scale (revised), California Verbal List Test, Trails A and B, and Letter and Category Fluency. Relative risk was estimated using a cutoff score of 1 SD below the control mean. RESULTS: As expected, patients performed markedly worse than control subjects on all tests except the Wide Range Achievement Test. Siblings had impaired performance on the Wisconsin Card Sort and Trails B, with trends for reduction (p = .01-.05) on the California Verbal List Test and Letter Fluency. Relative risk to siblings was elevated on the Trails B (lambda = 4.0) and California Verbal List Test (lambda = 2.8). Trends (p = .01-.05) for increased lambda were also seen for Wisconsin Card Sort, Letter Fluency, Wechsler Memory Scale and decline in IQ (lambda = 1.74-2.4). Correlations between tests of different cognitive functions were weak, indicating they measure relatively independent processes. CONCLUSION: Unselected siblings of patients with schizophrenia have impairments in several cognitive domains. Relative risk scores were in the moderate range, suggesting a significant genetic component. Impairments on one test only weakly predicted impairments on other tests. Thus, cognitive phenotypes identify distinct, familial traits associated with schizophrenia. Using this dimensional approach to subdividing schizophrenia may reduce the clinical and genetic heterogeneity of schizophrenia and improve the power of genetic studies.

Synergism of combined lithium-neuroleptic therapy: a double-blind, placebo-controlled case study.

The authors describe a longitudinal, placebo-controlled study of the response to drug treatment of a 62-year-old schizoaffective patient hospitalized for 40 years. While neither lithium nor a neuroleptic drug alone was effective, both drugs administered simultaneously led to the gradual extinction of a pronounced behavioral cycle and the disappearance of manifest psychosis. The authors suggest a synergistic interaction between the two drugs and stress the need for sustained trials of the combination in patients with similar behavioral cycles.

Relative risk of attention deficits in siblings of patients with schizophrenia.

OBJECTIVE: Impaired attention has frequently been observed in studies of unaffected siblings of patients with schizophrenia. To assess the suitability of impaired attention for use as an intermediate phenotype in genetic studies, the authors estimated the relative risk of impaired attention in a large group of siblings. METHOD: The authors used the Continuous Performance Test, 1-9 version, with and without a distraction condition, to study 147 patients with schizophrenia, 193 of their siblings, and 47 normal comparison subjects. Relative risk (l) was estimated by using cutoff scores that were one, two, and three standard deviations below the mean sensitivity index value (d cent) of the normal comparison group in both Continuous Performance Test conditions. RESULTS: Patients but not their siblings performed worse than the normal comparison subjects in both conditions. Fifty percent of the patients, 24% of their siblings, and 18% of the normal comparison subjects scored one standard deviation below the mean score of the comparison group for the more difficult distraction version of the Continuous Performance Test. The patients with Continuous Performance Test scores one standard deviation below the mean score of the comparison group had a total of 97 siblings. Compared with the comparison group, this subgroup of siblings had significantly lower Continuous Performance Test scores. Relative risk was also significantly higher for the siblings of patients whose scores were one standard deviation (l=2. 1) and two standard deviations (l=3.3) below the mean of comparison subjects. Attempts to assess ascertainment bias suggest that this may be an underestimate. CONCLUSIONS: Poor performance on the Continuous Performance Test appears to be familial and, possibly, genetic. Relative risk estimates were in the moderate range. Given the ease of administering the Continuous Performance Test, the use of impaired attention as an intermediate phenotype could increase the power of genetic studies of schizophrenia.

Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia.

OBJECTIVE: The authors sought to determine if an acute dose of dextroamphetamine might have positive effects on affect and cognition in schizophrenic patients maintained on a regimen of haloperidol and, if so, what variables might predict such improvements. METHOD: Twenty-one patients with chronic schizophrenia who were hospitalized on a research ward received a single oral dose of dextroamphetamine (0.25 mg/kg) in a double-blind, placebo-controlled, crossover study. All patients were receiving 0.4 mg/kg per day of haloperidol. Cognitive tests, motor tests, global ratings, mood ratings, and videotape ratings were used to determine the effect of the coadministration of these drugs. Ventricle-brain ratios derived from CT scans were used to predict response to the coadministration of these drugs. RESULTS: Amphetamine improved performance on a measure of concept formation on the Wisconsin Card Sorting Test but did not result in changes in performance on tests of memory or attention. As a group, the patients were more active and performed psychomotor tests more quickly while receiving amphetamine. Six patients were judged by clinical raters to have improved in terms of affect, cooperation, and engagement with the environment. Improvement was associated with enlarged cerebral ventricles and increases in blink rate from the placebo to the active drug condition. No patient unequivocally worsened. CONCLUSIONS: These results may be consistent with the theory that coadministration of amphetamine and haloperidol produces relatively selective enhancement of cortical dopaminergic activity. However, because of the acute nature of the trial and the specialized research environment in which it was conducted, the authors do not advocate amphetamine as a routine clinical treatment of schizophrenia.

Treatment of schizophrenia with a vasopressin analogue.

Ten patients with chronic schizophrenia completed a 3-month double-blind, placebo-controlled trial with a vasopressin analogue. Modest improvement occurred, but several patients also experienced significant fluid and electrolyte imbalance.

Second-trimester markers of fetal size in schizophrenia: a study of monozygotic twins.

OBJECTIVE: Since the second prenatal trimester is the critical period of massive neural cell migration to the cortex, and fingertip dermal cells migrate to form ridges during this same period, the authors sought to determine whether there are differences in fingertip ridge count in pairs of monozygotic twins discordant for schizophrenia, possibly indicating that a prenatal anatomical insult affected the twins differently. METHOD: The fingertip dermal ridges of 30 pairs of monozygotic twins (23 pairs in which the twins were discordant for schizophrenia and seven pairs in which both twins were normal) were counted by two persons trained in anthropometric research. Intrapair differences in the counts were then measured, and the differences among the pairs of normal twins were compared with the differences among the pairs discordant for schizophrenia. RESULTS: The twins discordant for schizophrenia had significantly greater absolute intrapair differences in total finger ridge count and significantly greater percent intrapair differences than the normal twins; i.e., their fingerprints were significantly less "twin-like." CONCLUSIONS: The study suggests that various second-trimester prenatal disturbances in the epigenesis of one twin in a pair discordant for schizophrenia may be related to the fact that only one of the twins expresses his or her genetic predisposition toward schizophrenia. This is consistent with a "two-strike" etiology of schizophrenia: a genetic diathesis plus a second-trimester environmental stressor.

Cerebellar pathology in schizophrenia: a controlled postmortem study.

In a morphometric study of the anterior cerebellar vermis of 47 brains in the Yakovlev collection, the area of the vermis of 5 of 12 brains of schizophrenic patients was smaller than that of any of 11 brains of control subjects without psychiatric or neurologic disease and 9 of 10 brains of control subjects with other psychiatric diagnoses (p less than .02). This finding confirms computerized tomography scan observations in live patients and supports the idea that some schizophrenic patients have structural abnormalities of the cerebellar vermis.