Llewellyn B. Bigelow

Relative risk for cognitive impairments in siblings of patients with schizophrenia

BACKGROUNDnPatients 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.nnnMETHODSnOne 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.nnnRESULTSnAs 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.nnnCONCLUSIONnUnselected 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.

A Histological Study of the Corpus Callosum in Chronic Schizophrenia

As a followup to a post-mortem study of the brains of schizophrenic and control subjects where the corpus callosum was found to be significantly thicker anteriorly in early onset compared to late onset schizophrenia, histological sections of 18 schizophrenic, 7 manic-depressive, and 11 medical/surgical control subjects were prepared using a stain for glia and a stain for callosal fibers. A quantitative study of the concentration of glial cells and interhemispheric callosal fibers revealed no difference between groups. A neuropathologist unaware of the tissue origin rated the histological sections for gliosis. There was significantly more severe gliosis in the callosi of the late onset schizophrenics compared to early onset schizophrenics as well as the control group. These preliminary findings suggesting callosal pathology are discussed, and the need for further studies is stressed.

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.

Violent Behavior in Schizophrenic Inpatients

We undertook a retrospective survey of assaultive behavior in 140 psychiatric inpatient research volunteers who had not previously responded well to neuroleptic treatment. Fortyone of 97 patients with schizophrenia became assaultive during their hospitalization, whereas only four of 43 patients with other diagnoses became assaultive (p < .0001). Most assaults were not a significant threat to the attacked person, but a small number were highly dangerous. Assaultive patients were significantly younger, and a greater proportion had a previous history of violence, compared with nonassaultive patients. A previous history of violent behavior was linked to more previous hospitalizations, indicating that such behavior might be associated with a poor prognosis.

Increased urine volume in chronic schizophrenic patients

Polydipsia and polyuria have a long association with schizophrenia. To assess the prevalence of polydipsia and polyuria in schizophrenia, urine volume was examined in medication-free chronic schizophrenic patients, normal controls, and nonschizophrenic patients. Mean urine volume was significantly higher in the schizophrenic patients (2319 +/- SD 2052 ml/24 hours) than in the other two groups (1054 +/- SD 471 ml/24 hours for nonschizophrenic patients and 1265 +/- SD 613 ml/24 hours for normals). Seven of 35 patients with schizophrenia but 0/7 nonschizophrenics had urine volumes greater than any normal control. Polyuria was associated with a good premorbid history and a positive neuroleptic response. Among polyuric patients, those with hyponatremia may represent a different, distinct subgroup. Neuroleptic treatment was associated with a further, significant increase in urine volume. Hence, polydipsia and polyuria appear to be relatively common in schizophrenia.

Lateralization of visual hallucinations in chronic schizophrenia

Visual hallucinations occur in approximately 30% of acutely hospitalized chronic patients with schizophrenia (Small et al. 1966). Two lines of evidence suggest that the visual field distribution of visual hallucinations in schizophrenia may be of interest. First, visual hallucinations are more frequently perceived in the visual hemifield contralateral to the side of the headache in migraine (Haas 1982) and contralateral to the seizure focus in epilepsy having an occipital (Lishman 1978) or parietal (Lance 1976) lobe focus. Second, stimulation of the visual association cortex produces contralateral visual field hallucinations in neurosurgical patients (Penfield and Perot 1963). We now report a study of the spatial location of visual hallucinations in patients with chronic schizophrenia.

Effect of valproic acid on behavior and plasma amino acid concentrations in chronic schizophrenic patients

Valproic acid (VPA), or 2-propylpentanoic acid, has an anticonvulsant effect and is used clinically in the treatment of petit mal seizures (Simon and Penry 1975). Although VPA increases brain gamma-aminobutyric acid (GABA) concentrations, the anticonvulsant effect appears to be more closely associated with a reduction in brain concentrations of aspartic acid (Chapman et al. 1982, 1983; Schechter et al. 1978). Based on the inhibitory action of GABA on brain dopamine systems (Waszczak and Waiters 1979), there has recently been considerable interest in the experimental treatment of schizophrenia with GABA agonists or agents that increase brain GABA concentrations. The results of these experiments have generally been equivocal (cf. Garbutt and van Kammen 1983). VPA in particular has been administered to schizophrenic patients in three previous studies. In two of these, patients improved during VPA treatment (Linnoila et al. 1976: Nagao et al. 1979). The third study reported that patients worsened

Pineal influence on exploratory behavior of the female rat

Abstract Female rats, pinealectomized at age 2–3 days and tested in an open field starting at age 80 days, showed more exploratory activity than either sham-operated or unoperated littermate controls. Treatment with an aqueous pineal extract had the opposite effect, lowering the activity of pinealectomized and control animals, while neither melatonin nor saline had a significant effect on this behavioral variable.

The assessment and clinical implications of haloperidol acute-dose, steady-state, and withdrawal pharmacokinetics.

In order to evaluate comprehensively haloperidol pharmacokinetics under fixed-dose treatment conditions, psychiatric patients were studied after treatment with an acute dose, during maintenance therapy, and after withdrawal from haloperidol following steady-state conditions. After single doses, haloperidol appeared rapidly in serum, achieving peak concentration at a mean of 4.5 hours. The range of observed elimination half-life was broad, between 8.5 and 66.6 hours, with a mean of 19.5 hours. Under conditions of chronic dosing, serial measurements of steady-state serum concentration revealed intrapatient coefficients of variation between 2 and 72%. The mean for all patients was 26.4%. Body clearance decreased nonsignificantly, and elimination half-life increased significantly after chronic dosing compared with kinetic parameters determined after a single dose. The concentration of haloperidol in serum obtained at 8 hours after a single dose correlated most strongly (r = 0.73; p < 0.0001) with steady-state concentration resulting from chronic dosing. A value of 4 ng/ml or lower determined 8 hours after a single oral dose of 0.2 mg/kg identified patients who did not accumulate haloperidol during chronic dosing of 0.4 mg/kg per day above a presumed therapeutic range for haloperidol of 5 to 15 ng/ml. The implications of these data for the clinical use of haloperidol are discussed.