Compromised myelin integrity during psychosis with repair during remission in drug-responding schizophrenia.

Functional connection among the information-processing (grey-matter) centres within the CNS are necessary for the coordinated processing of perception, affect, thought and behaviour. Myelinated neuronal bundles provide the links among such processing centres. Magnetic resonance diffusion tensor imaging (DTI) can assess the physical integrity of myelin. Using DTI, the authors assessed diffusivity (Dm) within whole brain in 14 controls and within 13 acutely psychotic, drug-free schizophrenics both before and after 28 d of antipsychotic drug treatment. Drug-responder schizophrenicss (D-RS) (n=8) were differentiated from poor responders (PR) (n=5) according to previously defined criteria. Differences of Dm at both baseline and following treatment were assessed using Dm distributional analyses and Statistical Parametric Software (SPM2). Impaired physical integrity of myelin, demonstrated by an increase (overall p<0.05) of Dm, was found in the D-RS patients, with multiple regions demonstrating p<0.0005 patient-control differences. The pathological increase in Dm was reduced (p<0.03) following treatment-associated reduction of psychotic symptoms by 84%. Dm of PR patients did not differ from controls at baseline or following subacute treatment. While the pathophysiology(ies) underlying psychosis in poorly responsive (PR) schizophrenics does not appear to be related to a disordered myelin, the findings are consistent with a partially reversible disorder of myelin integrity, and may underlie a dys-synchrony of information processing in a major subgroup of drug-responsive patients with schizophrenia. An antipsychotic drug-induced cascade may partially restore myelin integrity and functional connectivity concomitant with antipsychotic effects in such D-RS patients.

Evolution of antipsychotic intervention in the schizophrenic psychosis.

The accidental discovery (in the 1950s) and subsequent development of antipsychotic drugs have revolutionized the care of many patients with the schizophrenic psychoses. The first-generation antipsychotics, though effective for hallucinations, delusions, as well as a treatment of the disorder in two-thirds of patients with schizophrenia, burdened many patients with extrapyramidal effects (EPS), including dystonias, akathisia, and pseudo-Parkinsonian morbidity. Moreover, they had little or no effect on the most disabling, core symptoms associated with withdrawal of interests and interpersonal relationships. The second-generation antipsychotics, which began to appear in the late 1980s with the introduction of clozapine, had strikingly less morbidity, contributing little or no EPS and providing at least modest promise of reduction of negative symptoms and enhancement of some aspects of cognition. However, some second-generation antipsychotics have induced considerable weight gain, and appear to lower the threshold for the development of the metabolic syndrome, which increases cardio-vascular morbidity. The actual mechanism(s) of action of the antipsychotic drugs is still in dispute. Direct and indirect effects on dopamine transmission have been supported by much of the evidence. Direct blockade of dopamine hyperactivity and partial restoration deficient dopamine has been the standard explanation of their effects. However, dysfunctional intracellular signal transduction and dysfunction of myelin are emerging as competing pathologies upon which antipsychotics act. It is likely that the next generation of antipsychotics will act more directly and more specifically on such underlying neuropathology.

Volume increases in striatum associated with positive symptom reduction in schizophrenia: a preliminary observation.

Eleven drug-free patients with a DSM-IV diagnosis of schizophrenia who were in a period of psychotic exacerbation were treated with antipsychotics for 4 weeks. To evaluate treatment-associated changes in the basal ganglia and in psychotic symptomatology, the patients were studied with magnetic resonance imaging and with the Scale for the Assessment of Positive Symptoms. Serial assessments of striatal volumes and psychotic symptoms were performed at baseline and at 4 weeks of treatment; dual assessments of striatal volumes were also performed in 11 untreated normal controls. Patients and controls did not differ in striatal volumes at baseline, but the patients demonstrated a significant posttreatment increase in striatal tissues (caudate-putamen). An increase in left striatum was not associated with drug treatment itself, but with a reduction of positive symptoms.

Cerebral cortical gray expansion associated with two second-generation antipsychotics.

BACKGROUND: Second-generation antipsychotics (SGAs) differ from first-generation antipsychotics (FGAs) with respect to induction of less extrapyramidal morbidity, partially reducing negative symptoms, and causing modest improvement in neurocognitive functioning in patients with schizophrenia. SGAs demonstrate 5-HT2a antagonism. Differential effects of SGAs and FGAs on cortical gray volumes are explored herein. METHODS: Cerebral cortical gray was examined volumetrically in 19 patients with schizophrenia before and following 28 days of treatment with two SGAs (risperidone and ziprasidone; n = 13) or a FGA (haloperidol; n = 6). Seven (untreated) control subjects were also assessed at a similar interval. RESULTS: During treatment with the SGAs risperidone and ziprasidone, cerebral cortical gray of 13 patients with schizophrenia expanded 20.6 +/- 11.4 cc (p < .0005). Six patients receiving the FGA haloperidol, as well as 7 control subjects, showed no change in cortical gray volumes (p = .983 and p = .932, respectively) at the time of reassessment. CONCLUSIONS: Volumetric increase of cerebral cortical gray occurred early in the course of treatment with the SGAs ziprasidone and risperidone, but not with the FGA haloperidol. Such cortical gray expansion may be relevant to the reported enhanced neurocognition and quality of life associated with SGA treatment.

Thiobarbituric acid reactive substances in the cerebrospinal fluid in schizophrenia.

Increased levels of lipid peroxidation products (thiobarbituric acid reactive substances [TBARS]) are reported in plasma/serum from patients with schizophrenia. CSF TBARS levels were assessed in 10 neuroleptic-free patients with schizophrenia and in 9 normal controls. Controlling for duration of storage, CSF TBARS content was significantly lower in patients with schizophrenia vs. controls (p<0.002). No significant correlations were found between CSF TBARS and patients' age, gender, or duration of illness. The likely source of reported elevated plasma/serum TBARS in schizophrenia is therefore in the periphery. Degeneration of central neuronal membranes in schizophrenia is not supported by the present study.

Magnetic resonance imaging study of brain asymmetries in dyslexic patients.

Research studies suggest that the left hemisphere is involved in the pathophysiology of dyslexia. Thus far, the exact location and nature of the purported lesion(s) remain a matter of contention. The present study describes the distribution of structural abnormalities as related to brain symmetry in the brains of dyslexic individuals. High-resolution three-dimensional magnetic resonance images (MRIs) were analyzed in 16 dyslexic men and 14 controls matched for sex, age, educational level, and handedness. A computerized image analysis system was used to assess the volumetric deformations required to match each brain with its left-right mirror image. The results showed significant abnormalities in five left hemisphere structures involving the extrapyramidal and limbic systems: amygdala, hippocampus proper, parahippocampal gyrus, putamen, and globus pallidus. The left hemisphere is thought to play a major role in the temporal analysis of information. This stream of temporal analysis is of importance in motor movements. Reading might have evolved as an exaptation to motor movements requiring the sequential analysis of information.

State-related changes in cerebral white matter may underlie psychosis exacerbation.

Previous reports have described accelerated loss of cerebral white matter in schizophrenia. Others have reported changes of ventricle volumes in schizophrenic patients, with greatest increases following remission of psychotic symptoms. In this study changes in cerebral white matter volumes and psychotic symptoms were measured in 16 recently decompensated schizophrenic patients from neuroleptic-free baseline to 4 weeks later during treatment with antipsychotics. Serial white matter assessments were also performed in eight controls at similar intervals. Thirteen of 16 patients showed reduction of psychotic symptoms (reduction of SAPS scores by 24.4+/-12.6) during treatment. Three patients failed to respond (increase of SAPS scores by 15.7+/-13.8). Serial volumetric studies of cerebral white matter during the 4-week period showed a decrease of white matter volume in the responders by 8.2+/-8.2 cm(3) (P=0.003). Patients who failed to respond showed a non-significant increase in white matter during the same period by 11.4+/-11.7 cm(3). Absolute and percentage changes change in white matter volumes during the 4-week period were positively correlated with changes in SAPS scores (both P<0.01). Cerebral white matter, composed of myelin-containing oligodendrocytes, is highly sensitive to excitotoxicity. Swelling of myelin and of white matter, associated interference with the speed of neurotransmission through myelinated axons, and dyssynchrony of information processing by subcortical and cortical networks may be associated with psychosis exacerbation. Partial remission of symptoms may mark temporary reduction of an active, toxic process that interferes with information processing.

State-related thalamic changes during antipsychotic treatment in schizophrenia: preliminary observations.

Thalamic volumes and psychotic symptoms were assessed during psychotic exacerbation and during antipsychotic drug treatment. Reduction of psychotic symptoms (SAPS) during four weeks of treatment was highly correlated with volumetric expansion as measured by magnetic resonance imaging in both left and right thalamus [r(s)=0.75 and r(s)=0.82, respectively (both P<0.04)].

Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype.

Evidence of immune activation has occasionally, but not consistently, been reported in schizophrenia. Investigations of cytokine abnormalities in serum, and occasionally in CSF, have yielded inconsistent results, which have been difficult to resolve. In such studies, schizophrenia has been assumed to consist of a single process rather than a group of disorders. This study assesses differences in the pro-inflammatory cytokine, interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) in two previously delineated subtypes of schizophrenics ("delayed-responders"(DR) (n=23) and "poor-responders" (PR) (n=8)) during periods of neuroleptic-free psychotic exacerbation, and in a comparison group of normal controls (n=14). The two response subtypes were separated by subsequent treatment response (greater/less than 60% reduction of SAPS scores from baseline during 6 months of systematic treatment). The IL-6 assay, a sandwich enzyme-linked immunosorbent assay, was sensitive and reliable to detect IL-6 levels in the CSF of all subjects. CSF IL-6 was found to be significantly higher in the DR than the PR (P=0.017) and the controls (P=0.013). In addition to supporting the concept of heterogeneity in schizophrenia, this study also provides evidence that a central immune process may be occurring centrally in one subtype of schizophrenia.

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.