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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.

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.

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.

Background: The purposes of the present study were to attempt to replicate a previous finding of increased cerebrospinal fluid (CSF) neuronal cell adhesion molecule (N-CAM) in schizophrenia, and to assess whether the increases could be related to medication, clinical state effects, or brain structural measures., Methods: CSF N-CAM was measured by the Western blot technique in 45 DSM-III-R diagnosed male schizophrenic patients both on and off haloperidol treatment and in 20 healthy male control subjects., Results: CSF N-CAM was significantly increased in schizophrenic patients, with no overlap in the ranges, when compared to controls. There were no significant effects of medication or exacerbation on CSF N-CAM. No associations with measures of brain structure were found., Conclusions: Because N-CAM levels were not shown to be different on and off treatment or in exacerbated versus nonexacerbated patients, the higher levels seen in schizophrenic patients may be inherent to the disorder and possibly related to neurodevelopment.

Neuropsychological measures of recent and remote memory as well as general attention were administered to two groups of DSM-III-R schizophrenic patients in a within-subject repeated measures design across a 3-week interval. One group of patients (n = 12) was maintained on haloperidol for both test sessions, whereas a second group (n = 9) was tested first on haloperidol and again 3-weeks drug free. Patients received no adjunctive anticholinergic medication during the study. No differences were observed between the patient groups in level of psychotic symptomatology or general attention across the two test sessions. Patients withdrawn from haloperidol showed significant decreases in recent verbal memory function, while at the same time demonstrating significant increases in remote verbal memory. We speculate that the observed pattern of results is consistent with medial temporal lobe dysfunction particularly prominent in the left hemisphere as patients become drug free, and provides support for the existence of state-dependent cognitive changes in schizophrenia.

Language comprehension, measured by the Luria-Nebraska Relational Concepts Factor Scale, was evaluated twice in 15 male DSM-III-R schizophrenic patients during a controlled double-blind haloperidol maintenance (without anticholinergics) and placebo replacement protocol. Fifteen male normal controls were tested once. Patients and controls were matched on age and education. Language comprehension was significantly reduced in patients under both pharmacologic conditions, as compared with controls. Patients' comprehension accuracy did not differ significantly between neuroleptic-treatment and placebo replacement conditions. Patients' comprehension accuracy was independent of positive symptoms, anxiety-depression, measures of clinical course, and CSF and plasma monoamines. Comprehension accuracy was also not associated with patients' educational level or WAIS-R measures of their intellectual and short-term memory functioning. Patients' comprehension performance was significantly associated only with the negative symptom anhedonia-asociality during haloperidol maintenance. Thus, language comprehension in schizophrenic patients was independent of changes in pharmacologic treatment and the positive symptoms of psychosis. Results suggest language comprehension may represent a stable or trait characteristic in schizophrenia.

Diazepam-binding inhibitor (DBI) is a 9-kD neuropeptide that interacts with the benzodiazepine (BZD) binding sites of the neuronal gamma-aminobutyric acid type A (GABAA) receptor and with the glial mitochondrial BZD receptor (MBR). We explored the involvement of CSF DBI-LI in schizophrenia, based on the potential role of GABA in the negative symptoms associated with schizophrenia, the relationship of its receptors with dopamine and norepinephrine release, and the proposed therapeutic efficacy of BZDs in schizophrenia. Clinical data, CSF DBI-LI and CSF monoamine measures were obtained in 65 drug-free male chronic (DSM-IIIR) schizophrenic patients, 53 of whom were also tested prior to haloperidol withdrawal. Following haloperidol withdrawal, CSF DBI-LI increased significantly. Drug-free CSF DBI-LI did not correlate with CSF monoamines. CSF DBI-LI was significantly higher in paranoid compared to chronic undifferentiated schizophrenic patients. The data suggest that DBI may have a symptom modulatory rather than an etiological role in schizophrenia.

EEG sleep studies in schizophrenic patients are influenced by alterations in clinical state and medication status. The current study defines longitudinal alterations in electroencephalographic (EEG) sleep for 10 healthy men who were schizophrenic patients who remained relatively clinically stable during a double-blind neuroleptic withdrawal study. Clinical assessments and EEG sleep studies were performed at baseline on haloperidol, and then at 2-week and 6-week drug-free periods. Sleep continuity and rapid eye movement (REM) sleep measures declined not only between the haloperidol baseline and 2-week drug-free conditions, but continued to decline from 2-week to 6-weeks neuroleptic-free. Alterations in EEG sleep from the 2-week to 6-week haloperidol-free assessments did not correlate with changes in clinical symptoms suggesting effects related to drug-withdrawal or subclinical state changes. These results show that despite relative clinical stability over time, the EEG sleep of schizophrenic patients continues to change following withdrawal of a neuroleptic and is dependent on the duration of the drug-free interval.

During an asymptomatic phase platelet MAO activity was examined in 28 unipolar patients, 8 of whom previously had developed mania during clomipramine treatment for depression. The platelet MAO activity was not lower in these switchers than in 20 unipolar patients who did not become manic during a similar clomipramine treatment. High but nonsignificant correlations were found among platelet MAO activity and age of onset of mania, duration of clomipramine treatment before the switch, and the duration of manic behavior. These clinical variables correlated significantly amongst themselves. The high and normal platelet MAO activities of these patients neither support nor rule out a Bipolar I diagnosis. This study supports the pharmacologic basic of the induction of mania during clomipramine treatment.

Alterations in neutrophil subpopulations during human hemodialysis or following injection of C5a des arg into rabbits were studied. Whereas baseline peripheral blood neutrophils contained approximately 80% of cells that formed rosettes with IgG-sensitized erythrocytes, neutrophils harvested at the granulocyte nadir (20 min after initiating hemodialysis or the injection of C5a des arg) were markedly depleted of this population. This was seen in a change in ratio of rosette-forming neutrophils (RFN) to non-rosette-forming neutrophils (non-RFN) from 4:1 at 0 time to 1:2 at 20 min. Since non-RFN are less active in assays of adherence and chemotaxis, these alterations in circulating neutrophil populations were reflected in abnormal functional capacity of neutrophils harvested at 20 min. To study the mechanism of RFN depletion, we investigated the ability of C5a des arg to aggregate various human neutrophil suspensions. Unfractionated neutrophils and RFN demonstrated prompt in vitro aggregation in response to C5a des arg, whereas this activated complement fragment induced little aggregation in a population enriched for non-RFN. These results may explain the alterations in neutrophil adherence, chemotaxis, phagocytosis, and bactericidal activity, which have been reported to accompany clinical disorders characterized by in vivo complement activation (i.e., hemodialysis or gram-negative sepsis).

The excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG), the urinary metabolite which may best reflect brain norepinephrine, was measured in eight depressed patients on a longitudinal basis during the administration of placebo, d- and 1-amphetamine (30 mg/day), lithium carbonate (0.9 - 2.1 g/day), and d- and 1-amphetamine together with lithium. d-Amphetamine significantly decreased MHPG excretion. No significant change in MHPG was observed during administration of 1-amphetamine or when d- or 1-amphetamine was given together with lithium carbonate. Six patients responded with behavioral activation and euphoria to d-amphetamine, and these patients tended to have lower base line MHPG values in comparison to the nonresponders. Reductions in MHPG excretion during amphetamine administration were greatest in the patients with minimal behavioral responses to the drug, while some of the patients demonstrating more marked stimulant effects had elevated levels of MHPG during the amphetamine administration period. Variable changes, including elevated levels of MHPG in the responders, might represent the contribution of amphetamine-related changes in clinical state, including increased physical activity and (in two of the responding patients) the development of hypomania.

The authors evaluated whether the dysphoric effects reported by normals given lithium in several recent studies might also be found in depressed patients if detailed self-ratings were used in a double-blind study design. Nine depressed patients were studied at the end of lithium and placebo treatment trials. No overall adverse effects of lithium were found for the entire group, but individuals showed significant inverse correlations between pretreatment dysphoria and depression and the development of these symptoms with lithium, i.e., the less dysphoric and depressed patients (the more "normal" individuals) did report more adverse symptoms while the patients with higher initial symptom scores rated themselves as improved.

Thirty-two male DSM-III diagnosed schizophrenic patients received a lumbar puncture (LP) during chronic haloperidol treatment that was followed by replacement with placebo for up to 6 weeks. Fourteen patients relapsed on placebo within 6 weeks. Patients received a second LP at the time of relapse or at the end of 6 weeks if they had not relapsed. Bunney-Hamburg Global Psychosis Ratings of the day and the hours of sleep of the night before the LP were obtained, as were the Brief Psychiatric Ratings Scale (BPRS) ratings during the week of the LPs. CSF norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5 HIAA) concentrations were measured with high-pressure liquid chromatography (HPLC). Patients who relapsed had significantly higher CSF NE levels on and off haloperidol than patients who did not relapse. CSF MHPG was higher in the relapsers in the drug-free condition only, but CSF HVA and 5-HIAA were not significantly different in either condition. In the drug-free relapsed patients, CSF NE correlated significantly with the psychosis ratings of the day and hours of sleep the night prior to the LP. Our data indicate that elevated CSF NE levels during neuroleptic treatment may predict behavioral decompensation after discontinuing the medication.

Thirteen schizophrenic patients underwent a d-amphetamine infusion while being treated with pimozide, an antipsychotic agent and a relatively specific dopamine (DA) blocker. Six patients who showed an acute increase in psychosis with d-amphetamine relapsed within 3 months after pimozide withdrawal. Of the seven patients who did not change in psychosis with d-amphetamine, six did not relapse after pimozide discontinuation (Fisher's exact test, p less than 0.005). Retrospectively, the psychosis-inducing effects of d-amphetamine were found to be predictive of psychotic exacerbation following subsequent pimozide withdrawal. Pimozide failed to block the psychotogenic effects of d-amphetamine in six patients indicating that other mechanisms besides DA may play a role in psychotic decompensation. The d-amphetamine infusion paradigm should be studied further to determine its clinical value for identifying which schizophrenic patients are at risk for relapse after discontinuation of neuroleptic treatment.

The accuracy of smooth pursuit eye movements (SPEMs) was evaluated electrooculographically in 14 medication-free schizophrenics. Concentrations of monoamine metabolites and gamma-amino-butyric acid (GABA) were measured in their cerebrospinal fluid (CSF). Ventricular-brain ratios (VBR) were determined by computed axial tomography (CT scan). Premorbid adjustment was evaluated by the Phillips Scale. The SPEMs of eight of the patients were reevaluated after 2 weeks of treatment with either prazosin or pimozide. No consistent significant correlations were found between SPEM accuracy and CSF metabolite concentrations, VBR, or premorbid adjustment. SPEM accuracy was not correlated with number of days off medication and was significantly correlated when measured before and during medication.

Probenecid is used to block the transport of acid monoamine metabolites from cerebrospinal fluid (CSF), on the assumption that the resultant rise in CSF concentrations of the metabolites will reflect presynaptic "turnover" of the parent monoamine. However, CSF levels of probenecid correlate with CSF levels of the metabolite, suggesting that the blockade is incomplete at the probenecid levels obtained in human studies. This article reviews the literature on CSF probenecid-metabolite correlations and presents data demonstrating variations in the correlations across diagnostic groups. These cross-diagnostic variations may be due to group differences in membrane transport characteristics and and confound attempts to "correct for" CSF probenecid concentrations in studies of monoamine turnover.

The activity of dopamine-beta-hydroxylase (DBH) in cerebrospinal fluid (CSF) from 59 psychiatric patients has been analyzed by a highly sensitive radio-enzymatic assay. There was no sex difference in DBH, but there was a significant positive correlation with age. Probenecid administration had no effect on CSF DBH. DBH in CSF correlated positively (r = 0.60) with the plasma enzyme. Among patients hospitalized for major depressive disorder, unipolar or bipolar, schizo-affective disorder, schizophrenia, alcoholism, or personality disorders there were no significant between-group differences. Among the patients with bipolar affective disorder, DBH activity from manic patients was significantly lower than that from depressed or euthymic patients. The results are discussed with reference to the theory that the amount of DBH in CSF may serve as an indicator of central noradrenergic activity.

Recently, increased brain and spinal fluid (CSF) norepinephrine (NE), and a decreased cAMP response to prostaglandin E1 (PgE1) stimulation of platelet NE sensitive adenylcyclase were observed in some schizophrenic patients. Low CSF dopamine-beta-hydroxylase (DBH) activity was related to brain atrophy, whereas high plasma DBH was associated with tardive dyskinesia. Increased NE (in brain and CSF) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels and decreased plasma DBH activity in the brain were associated with a diagnosis of paranoid schizophrenia. Impaired NE transmission in schizophrenia may relate to disturbances in the autonomic nervous system, deficits in attention and information processing and to an impaired ability to deal with stress. Although pharmacological studies have suggested a major role for dopamine (DA) in schizophrenic psychosis, this review indicates the need for further exploration of the NE system. Future studies should address the relationship with DA, the autonomic nervous system (ANS), cerebral blood flow, brain metabolism, stress response, negative and prodromal symptoms.

In a study of electrolytes in lumbar cerebrospinal fluid (csf) from psychiatric patients, the authors found a positive correlation between calcium concentration and symptom severity in hospitalized depressed patients. CSF calcium levels tended to decrease as patients improved. In four rapidly cycling patients, CSF calcium was higher during depression than during mania. Mean CSF calcium for the depressed patients as a group was not significantly different from neurological controls or other psychiatric patients. Symptom remission from acute psychosis in schizophrenic patients was accompanied by a significant increase in CSF calcium concentration. These findings are discussed in relationship to calcium-induced alterations in neuronal and physiological excitability.