T.J. Crow

CEREBRAL VENTRICULAR SIZE AND COGNITIVE IMPAIRMENT IN CHRONIC SCHIZOPHRENIA

By comparison with age-matched controls in employment, 17 institutionalised schizophrenic patients were shown by computerised axial tomography of the brain to have increased cerebral ventricular size. Within the group of schizophrenic patients increased ventricular size was highly significantly related to indices of cognitive impairment.

Childhood antecedents of schizophrenia and affective illness: social adjustment at ages 7 and 11.

Abstract Objective: To investigate the social adjustment in childhood of people who as adults have psychiatric disorders. Design - Subjects in a prospectively followed up cohort (the national child development study) who had been admitted as adults to psychiatric hospitals were compared with the rest of the cohort on ratings of social behaviour made by teachers at the ages of 7 and 11 years. Subjects: 40 adult patients with schizophrenic illnesses, 35 with affective psychoses, and 79 with neurotic illness who had been admitted for psychiatric reasons by the age of 28. 1914 randomly selected members of the cohort who had never been admitted for psychiatric treatment. Main outcome measures: Overall scores and scores for overreaction (externalising behaviour) and underreaction (internalising behaviour) with the Bristol social adjustment guide at ages 7 and 11. Results: At the age of 7 children who developed schizophrenia were rated by their teachers as manifesting more social maladjustment than controls (overall score 4.3 (SD 2.4) v 3.1 (2.0); P <0.01). This was more apparent in the boys (5 (2.6)) than the girls underreactive behaviour. At both ages prepsychotic (affective) children differed little from normal controls. By the age of 11 preneurotic children, particularly the girls, had an increased rating of maladjustment (including overreactions and underreactions). Conclusion: Abnormalities of social adjustment are detectable in childhood in some people who develop psychotic illness. Sex and the rate of development of different components of the capacity for social interaction are important determinants of the risk of psychosis and other psychiatric disorders in adulthood.

Neurotransmitter receptors and monoamine metabolites in the brains of patients with Alzheimer-type dementia and depression, and suicides

In patients with Alzheimer-type dementia, in addition to the well-known losses of cholinergic neurones, there is evidence of degeneration of the noradrenergic and serotonergic innervation of the cerebral cortex. While noradrenergic and cholinergic receptors are preserved there is a loss of serotonin S1 and S2 receptors, particularly in the temporal lobe. The loss of serotonin S2 receptors may occur at an early stage of the disease and, in temporal and frontal cortex, is correlated with the loss of somatostatin immunoreactivity. In patients dying in hospital with depression, and in individuals committing suicide, there are no consistent changes in monoamine metabolites. Noradrenergic, serotonergic, and other neurotransmitter receptors were found to be unchanged, although there was a moderate decrease in imipramine binding in a small group (n = 6) of subjects with a history of depression, who had committed suicide.

Schizophrenia and the brain: a prospective clinico-neuropathological study

The neuropathological results from a prospective, systematically assessed, series of 56 schizophrenic patients and 56 age- and sex-matched normal controls have been presented. When compared with the normal controls, the brains of the schizophrenic subjects showed a significant reduction in brain weight and brain length with a concomitant increase in ventricular size. (All findings relate to measurements made after formalin fixation). In addition, the brains of the schizophrenic patients contained significantly more non-specific focal pathology and fibrillary gliosis than the controls. After exclusion of cases with moderate and severe Alzheimer-type change, cerebro-vascular disease and all forms of focal pathology, the structural brain changes (i.e. decrease in brain weight and brain length) continued to distinguish the schizophrenia group from the controls. Furthermore, an analysis of the clinical data showed that the structural brain changes were correlated in the schizophrenic patients with a measurement of pre-morbid function. The findings and their possible aetiological implications have been discussed.

A combined analysis of D22S278 marker alleles in affected sib-pairs: Support for a susceptibility locus for schizophrenia at chromosome 22q12

Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets (Vallada et al., Am J Med Genet 60:139-146, 1995; Polymeropoulos et al., Neuropsychiatr Genet 54:93-99, 1994; Lasseter et al., Am J Med Genet, 60:172-173, 1995. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not share (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that may be a susceptibility locus for schizophrenia at 22q12.

Lateral ventricular size in schizophrenia: relationship to the disease process and its clinical manifestations.

Using computed tomography, lateral ventricular size was studied in a sample of 112 institutionalized chronic schizophrenic patients (selected from 510 cases to investigate the correlates of the defect state and intellectual decline and the effects of insulin, electroconvulsive and neuroleptic treatment), and compared with matched groups of non-institutionalized schizophrenics, patients with first schizophrenic episodes, institutionalized and non-institutionalized patients with primary affective disorder, and neurotic out-patients. Age was significantly correlated (P less than 0.0002) with lateral ventricular size, but the institutionalized schizophrenic patients had significantly larger (P less than 0.025) lateral ventricles than the neurotics when age was taken into account. Ventricular enlargement was unrelated to past physical treatment (neuroleptics, insulin coma and electroconvulsive therapy). Within the group of institutionalized schizophrenic patients few correlates of ventricular enlargement were identified; thus in this population increased ventricular size was not clearly associated with the features of the defect state (negative symptoms and intellectual impairment). However, there was a curvilinear (inverted-U) relationship between intellectual function and ventricular size. Increased ventricular size was significantly related to absence of hallucinations, impairment of social behaviour, inactivity and the presence of abnormal involuntary movements. The findings confirm that structural brain changes do occur in chronic schizophrenia, but illustrate some of the difficulties in elucidating the clinical significance of ventricular enlargement. Lateral ventricular size is strongly age-related and the distribution in chronic schizophrenia is skewed and not bimodal; the relationship to particular features of the disease is complex and likely to emerge only in studies with a large sample size.

Temporal lobe structure as determined by nuclear magnetic resonance in schizophrenia and bipolar affective disorder.

Temporal lobe structure has been assessed by magnetic resonance imaging in groups of patients with schizophrenia (n = 21) bipolar affective disorder (n = 20) and normal controls (n = 21). In the temporal lobe area a significant (p less than 0.05) diagnosis by side interaction was present, the area being less on the left than on the right side in patients with schizophrenia in contrast to findings in the two other groups. Lateral ventricular and temporal horn area did not distinguish the groups as a whole. However, there was a significant (p less than 0.05) relationship between lateral ventricular area and poor outcome, and in an analysis confined to males, patients with schizophrenia (n = 15) were found to have significantly (p less than 0.05) enlarged temporal horns.

3H-flupenthixol binding in post-mortem brains of schizophrenics: Evidence for a selective increase in dopamine D2 receptors

The binding of 3H-cis flupenthixol (3H-FPT) to dopamine receptors in membrane preparations from control subjects and schizophrenics was studied. Using a fixed concentration of 3H-FPT, no differences were observed between controls and all schizophrenics, although 3H-FPT binding was increased in schizophrenics who apparently were drug-free at the time of death. Scatchard analysis of 3H-FPT binding revealed that in drug-treated schizophrenics both the number of binding sites (BM) and the dissociation constant (KD) were increased, whilst in drug-free schizophrenics only the BM was increased. Using domperidone to differentiate 3H-FPT binding to D1 and D2 dopamine sites, it was found that only D2 sites were increased in drug-free schizophrenics. The results are discussed with reference to previous studies on dopamine receptors in schizophrenia, and the effects of neuroleptic treatment. It is suggested that a selective increase in D2 receptors may be associated with the disease process in schizophrenia.

Serotonergic mechanisms in brains of suicide victims

Serotonergic mechanisms have been investigated in postmortem brain samples from controls and suicide victims. The concentrations of 5-hydroxytryptamine (serotonin; 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in occipital cortex and hippocampus and the high-affinity binding of ligands to the 5-HT1, 5-HT2 and imipramine-binding sites was assessed in frontal cortex, occipital cortex and hippocampus. The only significant difference between the two groups was a modest increase in 5-HIAA levels in the hippocampus of suicide victims. There was no evidence to suggest that those suicide victims with a clinical history of depression represented a subgroup with altered metabolite levels or binding values. The storage conditions of the samples were not related to the metabolite levels or binding values. There was, however, a significant positive correlation between [3H]imipramine binding and age in some brain regions. The results do not provide any evidence of gross alterations in 5-HT mechanisms in suicide or depression.

The spectrum of structural brain changes in schizophrenia: age of onset as a predictor of cognitive and clinical impairments and their cerebral correlates

A range of cerebral structures was assessed in a series of 172 CT scans of groups of psychiatric patients (including 101 in-patients with chronic schizophrenia) and related to assessments of clinical state and psychological function. Ventricular indices were increased in patients with schizophrenia by comparison with patients with other psychiatric disorders: brain area, which is modestly positively correlated with ventricular indices, was significantly (P less than 0.01) reduced in patients with schizophrenia. Among in-patients with chronic schizophrenia, measures of increased ventricular size were significantly associated with impaired social behaviour and with movement disorder. Memory for famous names in the distant past (a test of remote memory) was the only psychological test which showed significant associations with indices of ventricular size; this suggests that ventricular enlargement and its psychological sequelae occur relatively early in the disease process. Dichotomization of the sample of schizophrenic patients around the mean age of onset revealed that a range of clinical and psychological functions are significantly more abnormal in those with an early age of onset than in those in whom the onset was later. Early onset cases also perform less well academically and occupationally before illness onset. Within the early onset group some significant correlations between cognitive function and brain area were seen. The findings suggest that: (i) some at least of the structural changes in schizophrenia arise at a time when the brain is still developing; and (ii) age of onset is an important determinant of social and intellectual impairment and is relevant to the relationship between brain structure and cognitive deficits.