Membrane polyunsaturated fatty acids and CSF cytokines in patients with schizophrenia.

Findings to date provide evidence that altered membrane structure and function are present in patients with either first-episode or chronic schizophrenia, suggesting defects in phospholipid metabolism and cell signaling in schizophrenia. The purpose of this investigation is to test whether decreased membrane polyunsaturated fatty acids (PUFAs) were associated with an increased secretion of proinflammatory cytokines. Thus, we measured interleukin 6 (IL-6) and interleukin 10 (IL-10) in cerebrospinal fluid (CSF) of patients with chronic schizophrenia as well as PUFAs of red blood cell (RBC) membranes from the same individuals. A significant and inverse correlation was found between CSF IL-6 (not IL-10) and RBC membrane PUFAs levels in both haloperidol-treated and medication-free patients with schizophrenia. Specifically, such an association was found in the n-6 (18:2, 20:4, and 22:4) and, to a lesser extent, the n-3 fatty acids. Taken together, the present findings suggest that decreased membrane PUFAs may be related to an immune disturbance in schizophrenia, possibly resulting from an increased phospholipase A2 activity mediated through the proinflammatory cytokines.

Characterization of human cleaved N-CAM and association with schizophrenia.

The neural cell adhesion molecule (N-CAM) is a cell recognition molecule involved in cellular migration, synaptic plasticity, and CNS development. A 105- to 115-kDa isoform of N-CAM (cleaved N-CAM or cN-CAM) is increased in schizophrenia in hippocampus, prefrontal cortex, and CSF. We purified and partially characterized cN-CAM, a putative novel isoform, and confirmed that the first 9 amino acids were identical to exon 1 of N-CAM, without the signal sequence. Analysis of trypsin-digested cN-CAM fragments by matrix-assisted laser desorption ionization on a time-of-flight mass spectrometer (MALDI-TOF) yielded peptides that could be identified as being derived from the first 548 amino acid residues of the expected N-CAM amino acid sequence. Immunological identification with four specific N-CAM antisera directed toward cytoplasmic, secreted, variable alternative spliced exon, or GPI epitopes failed to indicate other known splice variants. Neuraminidase treatment of cN-CAM produced a minor alteration resulting in a faster migrating immunoreactive band, indicating partial glycosylation of cN-CAM. Membranous particles from cytosolic brain extract containing cN-CAM were obtained by ultracentrifugation; however, CSF contained few such particles. cN-CAM and synaptophysin were colocalized on these particles. Both cN-CAM and N-CAM 180 were present in synaptosomal preparations of human brain. Following incubation of synaptosomes or brain tissue without protease inhibitors, N-CAM 180 was degraded and cN-CAM was increased. A cN-CAM-like band was present in human fetal neuronal cultures, but not in fetal astrocyte cultures. Thus, cN-CAM represents a protease- and neuraminidase-susceptible fragment possibly derived by proteolytic cleavage of N-CAM 180. An enlargement in ventricular volume in a group of adult patients with schizophrenia over a 2-year interval was found to be correlated with CSF cN-CAM levels as measured at the time of the initial MRI scan (r = 0.53, P = 0.01). cN-CAM is associated with ventricular enlargement; thus, the release of N-CAM fragments may be part of the pathogenic mechanism of schizophrenia in vulnerable brain regions such as the hippocampus and prefrontal cortex. Alternatively, the increases in cN-CAM in schizophrenia may be a reflection of a more general abnormality in the regulation of proteolysis or of extracellular matrix stability.

Neuroleptic effects on autonomic activity in schizophrenia: between-group and within-subject paradigms and comparisons with controls.

Effects of fluphenazine on electrodermal activity (EDA) and heart rate (HR) were studied in patients with schizophrenia and normal control subjects during rest periods, presentation of innocuous tones, and a reaction time (RT) task. Two types of analyses were used: (1) between-group analyses-patients taking placebo were compared with patients taking fluphenazine and with control subjects using only data from the first test session; and (2) within-subject analyses-the same patients were tested when taking fluphenazine and when taking placebo. Results showed higher resting EDA and HR and smaller increments to task performance in placebo patients than in control subjects. Fluphenazine attenuated EDA levels but not the tonic response. Fluphenazine attenuated the HR response but did not affect HR level. Placebo patients were electrodermally hyporesponsive to the RT stimuli but not to simple tones. Fluphenazine markedly attenuated responsivity to simple tones but it attenuated responsivity less for RT stimuli. Testing medicated patients may thus produce misleading results with respect to many, but not all, purported autonomic markers of diagnosis in schizophrenia studies.

Oxidative damage and schizophrenia: an overview of the evidence and its therapeutic implications.

Free radicals are highly reactive chemical species generated during normal metabolic processes. which in excess can lead to membrane damage. Elaborate antioxidant defence systems exist to protect against oxidative stress. There is accumulating evidence of altered antioxidant capacity in schizophrenia. Membrane dysfunction can be secondary to free radical-mediated pathology, and may contribute to specific aspects of schizophrenic symptomatology and complications of its treatment. Specifically, free radical-mediated abnormalities may contribute to the development of a number of clinically significant consequences, including prominent negative symptoms, tardive dyskinesia, neurological 'soft' signs and parkinsonian symptoms. Our previous results showing altered membrane dynamics and antioxidant enzyme activities in schizophrenia, and findings from other investigators, are consistent with the notion of free radical-mediated neurotoxicity in schizophrenia. These findings provide a theoretical basis from which the development of novel therapeutic strategies such as fatty acid and antioxidant supplementation can occur in the future.

Confirmation of a two-factor model of premorbid adjustment in males with schizophrenia.

Because schizophrenia is considered to be a neurodevelopmental disorder, premorbid adjustment is of particular interest. Premorbid adjustment is probably not a unitary construct but rather is expressed across a number of developmental domains. The current investigation examined the validity of a two-factor model that differentiated premorbid adjustment across social and academic domains and evaluated relationships between these premorbid adjustment domains and other variables of interest. Participants with schizophrenia (n = 141) underwent evaluation of premorbid adjustment (using the Premorbid Adjustment Scale), intellectual functioning, and psychiatric symptoms. Using confirmatory factor analysis, a two-factor model of premorbid adjustment was identified that included an academic domain and a social domain. The social domain was associated with symptom variables, while the academic domain was associated with measures of intelligence. Results provide evidence for at least two domains of premorbid adjustment in schizophrenia. Distinguishing between these two premorbid domains may be theoretically important because of potential differences in incidence rates and deterioration courses; some individuals with schizophrenia may exhibit adequate academic adjustment but poor social adjustment, while others may exhibit the opposite pattern.

A 39-year followup of the Genain quadruplets.

The Genains, a unique group of monozygotic female quadruplets, all developed a schizophrenic disorder by age 24. They have been studied since the 1950s, because of the rarity of this occurrence (estimated to be one in 1.5 billion) and because their illnesses varied in severity. The identical inheritance would tend to rule out genetic differences as the cause of the neuropsychological differences; however, we cannot disentangle the effects of early brain injury and harsh punitive treatment as factors accounting for the differences in the severity of their disorders. We conducted neuropsychological examinations of the Genains at age 66, compared their test profiles, and contrasted certain test scores at 66 with those at ages 27 and 51. Test results indicate generally stable (or even improved) performance over time and support the notion that cognitive decline is not a degenerative process in schizophrenia. The Genains remind us of the exquisite interaction among variables that must be understood before additional, satisfactory progress can be made in preventing the development and predicting the course of schizophrenia.

Factor structure of neurologic examination abnormalities in unmedicated schizophrenia.

The heterogeneity and uncertain significance of neurologic exam abnormalities in schizophrenia prompted us to evaluate their factor structure. We administered a modified version of the Neurological Evaluation Scale (NES) to 103 unmedicated patients with schizophrenia. Data were distilled by combining right- and left-side scores, and by eliminating superfluous, rarely abnormal and unreliable items from the analysis. Exploratory principal components analysis yielded four factors: repetitive motor tasks (fist-ring, fist-edge-palm, alternating fist-palm, dysdiadochokinesis); cognitive-perceptual tasks (memory, audiovisual integration, right-left orientation, face-hand test, rhythm tapping reproduction); balancing tasks (Romberg, tandem gait); and the palmomental reflex. Evaluation of the relationship between these factors and clinical and demographic variables revealed a robust correlation between the cognitive-perceptual factor and full-scale IQ score. This analysis is a step toward developing empirical subscales of a modified NES, which may provide insights into the nature of neurologic impairment in schizophrenia and may prove clinically useful.

Neurologic examination abnormalities in schizophrenia with and without a history of alcoholism.

OBJECTIVE: The current investigation examines the impact of a past history of alcoholism on neurologic examination abnormalities in schizophrenia (SZ). BACKGROUND: Individuals with SZ have a high rate of comorbid alcohol use disorders (AUDs), but relatively little is known about the potential adverse consequences of alcoholism for neuropsychological and neurologic functioning in SZ. Recent evidence suggests consistent but subtle neurocognitive differences between groups, with more prominent differences in neurologic examination abnormalities. METHOD: Thirty-three male patients with SZ or SZ/AUDs were evaluated using a modified Neurologic Evaluation Scale (NES) and ratings for positive and negative symptoms. RESULTS: The SZ/AUD group exhibited a greater impairment in the Cognitive-Perceptual factor of the Neurologic Evaluation Scale. Greater impairment in the tandem-Romberg factor or in motor items was not found, nor were groups different based on positive or negative symptoms. CONCLUSIONS: A history of alcoholism in SZ is associated with greater overall neurologic impairment, particularly in the area of cognitive-perceptual dysfunction, an area often found to be impaired in patients with schizophrenia without alcoholism.

Influence of haloperidol on the relationship of frontal lobe function to psychomotor poverty and disorganization syndromes.

The aim of the study was to examine effects of haloperidol on the relationships between neuropsychological measures of frontal lobe functioning and the schizophrenia syndromes of psychomotor poverty and disorganization. Twenty-one participants with schizophrenia were initially evaluated when clinically stable and chronically treated with haloperidol, and 19 were evaluated again after a 3-week haloperidol-free period. Participants were evaluated with the Trail Making Test, the Wisconsin Card Sorting Test, the Purdue Pegboard, and psychiatric rating scales at each evaluation. There were significant correlations between schizophrenia syndromes and the tests sensitive to frontal lobe function when participants were medicated but not when drug-free. No significant changes in symptom severity or motor function occurred from the medication to the medication-free evaluation. The results indicate that haloperidol mediates the relationship between tests sensitive to frontal lobe function and the schizophrenia syndromes of psychomotor poverty and disorganization. This mediation effect was not attributable to changes in overall symptom severity or motor function.

Abnormal age-related changes of plasma antioxidant proteins in schizophrenia.

Albumin and bilirubin are metal-binding proteins, shown to possess free radical scavenging properties, and may thus be selective antioxidants. In the present study we examined whether individual plasma antioxidants such as albumin and bilirubin, which significantly contribute to total antioxidant status (TAS), are reduced in patients with schizophrenia. We prospectively studied plasma antioxidant proteins, i.e. albumin and bilirubin, in male veteran schizophrenic patients using a within-subject, repeated measures, on-off-on haloperidol treatment design, as well as age- and sex-matched healthy volunteers. Male patients with schizophrenia either during haloperidol treatment (n=46) or in a drug-free condition (n=35) had significantly lower levels of both plasma albumin and bilirubin compared with age- and sex-matched healthy volunteers (n=31). Such reductions of plasma antioxidant proteins in schizophrenic patients appear to be age-related changes, in contrast to those observed in healthy volunteers. On the other hand, levels of plasma albumin and bilirubin were not significantly affected by haloperidol treatment, haloperidol withdrawal, or length of drug-free period. Moreover, plasma TAS was not influenced significantly by cigarette smoking, even though it may selectively decrease plasma bilirubin but not albumin levels. The present findings, taken together with our previous results of reduced plasma TAS and uric acid, as well as an increased Red blood cell superoxide dismutase, lend further support to the hypothesis that a defect in the antioxidant defense system exists in schizophrenia that may lead to oxidative damage.

Relations between cognitive and symptom profile heterogeneity in schizophrenia.

Although numerous studies have consistently revealed cognitive heterogeneity in schizophrenia, the relationships between such heterogeneity and clinical phenomenology are not clear. Clusters derived from cognitive heterogeneity studies may or may not be associated with symptom profile or severity of illness. The purpose of this study was to examine the relationship between cognitive heterogeneity and demographic and clinical phenomenological measures. We examined cognitive heterogeneity in schizophrenia by empirically deriving clusters of patients based upon WAIS-R subtest scores and then analyzed the way in which these clusters related to demographic and symptom variables and to DSM-III-R diagnostic subtypes. Four cognitive clusters were identified that were consistent with previous research. These clusters were differentiated on the basis of educational level and occupational status but not on the basis of symptom profile, severity, or DSM-III-R subtypes. Results suggest that cognitive measures are independent of severity of the disorder and phenomenological symptom presentation in these subgroups of schizophrenic patients.

Human plasma glutathione peroxidase and symptom severity in schizophrenia.

BACKGROUND: Previous studies have shown impaired antioxidant defense system in schizophrenia, including alterations in glutathione peroxidase (GSH-Px) activity in erythrocytes. There exists a related enzyme, human plasma GSH-Px (hpGSH-Px), that has not been previously examined in schizophrenia. METHODS: An enzyme-linked immunoassay was used to determine hpGSH-Px levels in male schizophrenic patients (n = 39), using a within-subject, on-off haloperidol (HD) treatment design, compared with age- and gender-matched normal control subjects (n = 37). RESULTS: hpGSH-Px was not significantly different between normal control subjects and patients, consistent with our previous findings in erythrocyte GSH-Px. There were no significant treatment effects. hpGSH-Px was significantly and positively correlated with psychosis rating scores in patients both on and off HD treatment. CONCLUSIONS: Although not different from normal controls, hpGSH-Px levels in patients may reflect oxidative stress associated with greater psychosis severity. The present findings thus suggest that schizophrenic patients, without obvious increase of endogenous antioxidant enzymes (e.g., hpGSH-Px), may be at risk for oxidative damage.

Modulation of language processing in schizophrenia: effects of context and haloperidol on the event-related potential.

BACKGROUND: Disturbances in language associations were among the first clinical symptoms reported for individuals described as schizophrenic (Bleuler 1911/1950). Currently, associative language disturbance is a diagnostic feature of schizophrenia (American Psychiatric Association 1994); however, the mechanisms that produce this symptom remain unknown. In the present study, two candidate psychological functions were examined: sensitivity to semantic context and expectancy (attention). METHODS: Visual event-related potentials were recorded during a lexical decision task in which semantic relationship and expectancy (relatedness proportions) were varied. Semantic priming processes were compared between 34 male normal control subjects tested once and 37 male schizophrenic inpatients evaluated during their participation in a double-blind haloperidol maintenance therapy and placebo replacement protocol. RESULTS: Schizophrenic patients failed to discriminate between associated and unassociated words, as measured by the amplitude of the N400 component (i.e., absence of the N400 priming effect); however, the overall mean amplitude of N400 did not differ between patients and control subjects. In addition, patients and control subjects did not differ significantly in the amplitude of N400 elicited to associated words or to unassociated words. Finally, the effect of expectancy-based processing on the magnitude of the N400 priming effect did not differ between patients and control subjects. CONCLUSIONS: On the basis of these findings, a tentative hypothesis is suggested that schizophrenic patients are characterized by a pattern of indiscriminate or random spread of activation in their semantic network during the processing of single-word semantic contexts.

Plasma catecholamine metabolites as markers for psychosis and antipsychotic response in schizophrenia.

The objective of this study was to determine the association between the patterns of change in the dopaminergic metabolite plasma homovanillic acid (HVA), the noradrenergic metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), and psychosis following haloperidol withdrawal in schizophrenic patients. Weekly plasma measurements were obtained in 107 subjects with schizophrenia or schizoaffective disorder. Random regression was used to control for individual variance while modeling metabolite changes over time and relationships with psychosis. Changes in plasma MHPG were not significantly associated with relapse or psychosis, while increased plasma HVA was found to be associated with relapse. Psychosis was correlated negatively with plasma HVA levels. The current analysis, controlling for individual variance, indicates that there is evidence for pharmacological effects on plasma HVA, but not plasma MHPG. In addition, these metabolites do not appear to be direct markers of psychosis, but may be associated with a compensatory response by the system to return to the steady state.

Empirical validation of primary negative symptoms: independence from effects of medication and psychosis.

OBJECTIVE: Recent studies of negative symptoms in schizophrenia-specifically, those involving the deficit syndrome-have focused on uncovering the symptoms that are primary to the disease rather than secondary to the psychotic process. One of the foremost concerns in this effort is establishing whether the negative symptoms observed are the result of medication effects. METHOD: This study used negative symptom ratings obtained in a drug withdrawal paradigm to compare symptom profiles in the same schizophrenic patients when they were on and off antipsychotic drug treatment. The study group consisted of 93 physically healthy male patients with DSM-III-R-defined schizophrenia. Principal components analysis was performed on negative symptom data obtained separately during haloperidol treatment and again when the patients were drug free to determine whether there were meaningful factor scores that were consistent across medication conditions. Drug withdrawal effects on negative symptom factors were then tested for associations with secondary sources of variance including extrapyramidal side effects, anxiety/depression, and psychosis. RESULTS: Two factors, termed affective flattening and diminished motivation, exhibited similar loadings when the patients were both on and off medication. Changes in motivation were associated with changes in anxiety/depression and psychosis, while changes in affective flattening were associated with changes in extrapyramidal side effects. CONCLUSIONS: The documented secondary sources of negative symptoms are related to different and distinct aspects of negative symptoms; this finding will aid in the identification of primary negative symptoms.

Construct validity of neuropsychological tests in schizophrenia.

Validity studies of neuropsychological tests have typically examined individuals with neurological disorders. The present study was designed to investigate the construct validity of neuropsychological measures in patients with schizophrenia. We used Wechsler Adult Intelligence Scale Revised (WAIS-R) factor scores that were generated from the population of interest as marker variables in the present analysis. The current study included 39 patients with schizophrenia who were evaluated with a battery of neuropsychological tests assessing attention, memory, and abstract reasoning abilities. Pearson correlations indicated significant relationships between (a) WAIS-R Verbal Comprehension factor and tests of sustained attention, verbal memory and remote memory; (b) WAIS-R Perceptual Organization factor and tests of visual memory and abstraction and problem solving; and (c) WAIS-R Freedom From Distractibility factor and neuropsychological measures of attention and concentration. These results provide support for the construct validity of the neuropsychological tests in patients with schizophrenia, and indicate that these tests evaluate essentially the same constructs in patients with schizophrenia as they do for patients with structural neurological disorders.

Effects of haloperidol on antioxidant defense system enzymes in schizophrenia.

Dysregulation of free radical metabolism as reflected by abnormal erythrocyte activities of three critical enzymes of the antioxidant defense system (AODS), i.e. superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), has been reported in schizophrenic patients. The present study examined the effects of haloperidol, a standard antipsychotic agent, on the AODS enzymes, using a within-subject, repeated-measures, on-off haloperidol treatment design. The mean drug free period was 40 days. At baseline, there were no significant differences for all three enzymes between patients and age and sex-matched normal volunteers. During the drug-free condition, SOD activity, but not GSH-Px and CAT activities, was significantly higher relative to normal control subjects. However, within-subjects both SOD and GSH-Px activities, but not CAT activity, were higher in the drug-free condition compared to the treatment condition. No significant correlation was observed between SOD activity and plasma haloperidol (or daily haloperidol dose) levels. Smoking status, as assessed by the cotinine level, was unrelated to enzyme activities. In addition, none of the major AODS enzymes showed significant differences between relapsed and clinically stable patients. These findings suggest that haloperidol may not have direct regulatory effect on AODS enzyme activities and that SOD and GSH-Px activities may change in response to other factors such as change in symptom severity.

Glutamatergic neurotransmission involves structural and clinical deficits of schizophrenia.

BACKGROUND: Phencyclidine and ketamine induce a syndrome closely resembling schizophrenia due to their blockade of N-methyl-D-aspartate (NMDA) receptor. These findings suggested that some aspects of schizophrenia are associated with decreased NMDA--glutamatergic function. We hypothesized that structural and symptomatic deficits in schizophrenia are related to glutamatergic neurotransmission. METHODS: We studied the relationships among cerebrospinal fluid (CSF) glutamatergic markers, clinical presentation of schizophrenia, and CT parameters of brain structure in drug-free schizophrenics. RESULTS: We found no significant differences between patients with schizophrenia and controls in CSF glutamatergic markers. When patients with schizophrenia were considered as a group, significant negative correlations between glutamatergic markers and brain structural measures as well as clinical measures were observed. Cluster analysis reveals a group of lower indices of glutamatergic neurotransmission, and more prominent thought disorder as well as ventricular enlargement, and a group with increased glutamate level. CONCLUSIONS: The findings support the hypothesis that altered glutamatergic neurotransmission plays a role in the brain structure and the clinical symptoms of schizophrenia.

Confirmatory factor analysis of the WAIS-R in patients with schizophrenia.

Although factor scores are commonly used to interpret the Weschsler Adult Intelligence Scale--Revised (WAIS-R), the WAIS-R factor structure has not been investigated in patients with schizophrenia. We used confirmatory factor analysis (CFA) to examine five latent construct models in 169 males with schizophrenia. The WAIS-R standardization sample (ages 35-44; n = 250) was used as a comparison group. For both groups, all model fit indexes used to determine model adequacy supported models composed of Verbal Comprehension (VC), Perceptual Organization (PO) and Freedom from Distractibility (FFD) factors. However, the Digit Symbol subtest loaded on both the PO and FFD factors for patients with schizophrenia but only on the FFD factor for the WAIS-R standardization sample. Patients with schizophrenia performed significantly worse on the FFD and PO factors compared to the VC factor, reflecting the well-characterized attention and problem solving deficits associated with schizophrenia. Also, patients with schizophrenia performed significantly worse than the WAIS-R sample on all factors. These results provide support for the validity of the WAIS-R factors in patients with schizophrenia.