Search for cytomegalovirus in the postmortem brains of schizophrenic patients using the polymerase chain reaction.

Cytomegalovirus infection has a number of features that suggest a possible association between congenital infection and schizophrenia. Previous studies have investigated anticytomegalovirus antibody titers or attempted directly to identify viral antigens in body fluids or brain tissue from schizophrenic subjects but have been limited by the sensitivity of the available methods. The highly sensitive polymerase chain reaction, a newly developed technique for gene amplification, was used to search for cytomegalovirus in the DNA extracted from postmortem temporal cortex samples of eight schizophrenic subjects, eight nonschizophrenic suicide victims, and eight normal controls. Cytomegalovirus-specific DNA amplification was not detected in any of the samples. The implications of this finding for the viral hypothesis of schizophrenia are discussed.

Lack of evidence for a role of T-cell-associated retroviruses as an etiology of schizophrenia.

The evidence that schizophrenia may involve infection by a virus (or viruses) has been indirect. The recent discovery, however, of the human retroviruses--human T-cell lymphoma-leukemia virus-I, and II (HTLV-I, -II) and human immunodeficiency virus (HIV)--now also known to affect the central nervous system (CNS), together with the development of new techniques in retrovirology, have made it possible to investigate more directly the role of this class of viruses as an etiology of schizophrenia. In our first effort to screen for the presence of a T-cell lymphotropic virus in schizophrenia, short-term tissue cultures of peripheral lymphocytes from 17 chronic schizophrenic patients and 10 normal controls were established. The cells were cultured in the presence of T-cell growth factor (TCGF, IL-2), and the culture supernatants were tested for the presence of the retroviral enzyme reverse transcriptase. No T-cell-associated reverse transcriptase activity was detected in cultures from patients or normal controls. Therefore, the data do not provide evidence for a role for T-cell lymphotropic retroviruses as an etiology of schizophrenia.

Abnormal cerebrospinal fluid protein indices in schizophrenia.

Determinations of albumin and immunoglobulin G (IgG) were performed in paired cerebrospinal fluid (CSF) and serum samples from 24 subjects with schizophrenia. These determinations allowed calculation of two indices, one that is an indicator of integrity of the blood-brain barrier and the other a measure of selective IgG production within the central nervous system (CNS). In comparison with previously determined reference values, 7 of 24 (29%) subjects showed increased blood-brain barrier permeability, and 8 of 24 (33%) demonstrated elevated endogenous CNS IgG production. One of these eight also demonstrated oligoclonal banding on high-resolution protein electrophoresis of the CSF.

Defect symptoms and abnormal involuntary movement in schizophrenia.

Tardive dyskinesia (TD), a possible marker of the defect state of schizophrenia, was studied along with defect symptoms in 55 neuroleptic-treated chronic schizophrenic patients. Our cross-sectional data failed to replicate earlier findings of increased defect symptoms in TD patients (n = 14), except for more severe paucity of speech content when compared with non-TD patients (n = 41). Methodological issues that may account for some of the current and previously reported findings are discussed.

Tardive dyskinesia: neuropsychological, computerized tomographic, and psychiatric symptom findings.

Prior studies have suggested that schizophrenic patients with tardive dyskinesia (TD) have an unusual incidence of cognitive impairment, structural brain abnormalities, and negative symptoms. Twenty-seven schizophrenic patients with TD and an equal number of age-, gender-, and education-matched schizophrenic controls were studied. Each patient received neuropsychological testing, psychiatric symptom ratings, and most had cerebral computed tomography (CT) scans. Patients with TD significantly differed from controls on only 1 of 23, cognitive measures, and the overall group performance profiles were highly similar. No differences were observed on symptom ratings. Patients with TD had significantly smaller ventricular-brain ratios (VBRs) than controls. These data fail to support an association of TD with global measures of "organicity." Abnormal movements may result from specific dysfunction within the more purely motor circuits of the basal ganglia without compromising other neural systems involved in cognitive processing.

Increased serum soluble interleukin-2 receptors in Caucasian and Korean schizophrenic patients.

Recent studies have identified immunologic abnormalities in some schizophrenic subjects. This experiment replicates previous findings that serum soluble interleukin-2 receptors (SIL-2Rs) are elevated in schizophrenic patients, and is the first study to describe this phenomenon in non-Caucasian patients. Despite differences between Korean and Caucasian schizophrenic patients in absolute serum SIL-2R levels, both groups were significantly elevated when compared with their respective ethnic control groups (477 +/- 171 U/ml versus 354 +/- 172 U/ml and 763 +/- 347 U/ml versus 567 +/- 231 U/ml, respectively). Neither age, gender, medication status, nor duration of illness correlated with SIL-2R levels. These findings are further evidence that immune activation is present, regardless of ethnic origin, in some schizophrenic patients.

Polydipsia and hyponatremia in psychiatric patients.

Many psychiatric patients have polydipsia and polyuria without identifiable underlying medical causes. Hyponatremia develops in some polydipsic patients and can progress to water intoxication with such symptoms as confusion, lethargy, psychosis, and seizures or death. This syndrome is sometimes called "compulsive water drinking," "psychogenic polydipsia," and "self-induced water intoxication." Although the underlying pathophysiology of the syndrome is unclear, several factors have been implicated in producing polydipsia and symptomatic hyponatremia. These include a possible hypothalamic defect, the syndrome of inappropriate secretion of ADH (SIADH), and neuroleptic medication. Evaluation of psychiatric patients with polydipsia includes a search for other medical causes of polydipsia, polyuria, hyponatremia, and SIADH. Treatment modalities currently available include fluid restriction and medications.

Treatment of schizophrenia with a vasopressin analogue.

Ten patients with chronic schizophrenia completed a 3-month double-blind, placebo-controlled trial with a vasopressin analogue. Modest improvement occurred, but several patients also experienced significant fluid and electrolyte imbalance.

MRI changes during water loading in patients with polydipsia and intermittent hyponatremia.

OBJECTIVE: Patients with polydipsia and intermittent hyponatremia have greater ventricle-brain ratios (VBRs) than matched patients without polydipsia and intermittent hyponatremia and normal subjects. Unlike previous studies, this study controlled for the impact of water loading when examining the volume of intracranial structures. METHOD: Under controlled conditions, eight male schizophrenic patients with polydipsia and intermittent hyponatremia were first assigned to either normal fluid intake or oral water loading and then the alternative condition the following day. Magnetic resonance imaging (MRI) volumetric measurements were made with the use of a standardized protocol. RESULTS: During water loading, total VBR and lateral ventricle volume significantly decreased by 13.1% and 12.6%, respectively. A strong association between change in serum sodium concentration and change in VBR was noted across conditions. CONCLUSIONS: These findings indicate that 1) water loading does not account for the diminished brain volume observed in patients with polydipsia and intermittent hyponatremia in previous studies, and 2) hyponatremia can significantly alter brain morphology on MRI.

Electrophysiological interactions between haloperidol and reduced haloperidol, and dopamine, norepinephrine and phencyclidine in rat brain.

Haloperidol and its metabolite, reduced haloperidol, were compared as antagonists of catecholaminergic neurotransmission in central nervous system of the rat. Agonists and antagonists were applied from multibarrelled micropipettes, which were also used to record extracellularly the effects of these substances on neuronal discharge. Haloperidol antagonized dopaminergic inhibition of caudate neurons and inhibition of cerebellar Purkinje neurons induced by noradrenaline, whereas reduced haloperidol was an ineffective antagonist. Phencyclidine, which is an indirect dopaminergic agonist in the caudate, caused inhibition of the discharges of caudate neurons resembling that induced by dopamine itself. These indirect effects of phencyclidine were also antagonized by haloperidol but not by reduced haloperidol. The data suggest that the metabolite, reduced haloperidol, is not an effective neuroleptic drug in the central nervous system.

Effect of chronic caffeine administration on monoamine and monoamine metabolite concentrations in rat brain.

Caffeine was chronically administered in four doses (0, 10, 25, and 50 mg/kg/day) to rats via twice-daily intraperitoneal injections for 30 days. Concentrations of brain tissue monoamines, dopamine (DA), norepinephrine (NE), and serotonin (5HT), and monoamine metabolites, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5HIAA), were determined. At the 10 mg/kg/day dose, no significant changes were found compared with controls. At 25 mg/kg/day and 50 mg/kg/day significant changes were observed within each monoamine system. In striatum, DA and 5HT were increased, while DOPAC was decreased. In frontal cortex, NE was increased. In cerebellum, 5HT and MHPG were increased.

Polydipsia and chronic hyponatremia in schizophrenic inpatients.

The occasional presence of polydipsia in psychiatric patients, at times progressing to hyponatremia with severe medical complications, has been previously noted. The clinical history and laboratory data from eight chronically hyponatremic psychiatric inpatients were examined. Common characteristics were a diagnosis of chronic undifferentiated schizophrenia, an early age of onset of their illness, extended hospitalizations with minimal response to neuroleptic medications, heavy tobacco use, and a relatively high frequency of tardive dyskinesia and brain scan abnormalities. Water loading in three patients showed responses consistent with inappropriate secretion of antidiuretic hormone. Potential pathophysiologic mechanisms and treatment considerations are discussed.

Effects of chronic nicotine and haloperidol administration on muscarinic receptor-mediated phosphoinositide turnover in rat brain slices.

Muscarinic receptor-mediated phosphoinositide (PI) turnover in rat brain slices was assessed after chronic administration of nicotine (12 mg/kg/day) or haloperidol decanoate (1.5 mg/kg/day), either alone or in combination, for 6 weeks. Nicotine alone did not significantly alter carbachol-induced inositol monophosphate (IP1) accumulation in the frontal cortex, but did result in a significant increase in the hippocampus, and in a decrease in the striatum. Haloperidol alone attenuated carbachol-stimulated IP1 accumulation in all three brain regions. Chronic treatment with combined nicotine and haloperidol resulted in no significant change in carbachol-sensitive IP1 accumulation in either the frontal cortex or hippocampus but did result in a decrease in the striatum. The results suggest significant cross-talk between cholinergic and dopaminergic systems in affecting PI metabolism.

Reverse transcriptase activity in 5-azacytidine-treated lymphocyte cultures of patients with schizophrenia.

We investigated the involvement of human lymphotropic retroviruses in the etiology of schizophrenia. Short-term cultures of peripheral lymphocytes of 11 chronic schizophrenic patients and six controls were established and treated with 2.5 and 5 microM 5-azacytidine. No reverse transcriptase activity could be detected in any of the 5-azacytidine-treated cultures indicating that 5-azacytidine did not activate a putative retrovirus in lymphocytes of patients with schizophrenia. Therefore, our findings do not support a role of lymphotropic retroviruses as an etiology in schizophrenia.

Schizophrenia, just the facts. What do we know, how well do we know it?

The basic facts of schizophrenia are subjectively reviewed in terms of their reproducibility and significance for understanding the disorder. Some of the facts that are either less well known or of greater importance for future investigation are discussed in more detail. The purpose of establishing what we know about schizophrenia is to develop firm ground for generating hypotheses. One attempt to synthesize these facts is outlined.

CSF IL-1 and IL-2 in medicated schizophrenic patients and normal volunteers.

It is clear that cytokines exert a variety of modulatory actions on the central nervous system. As part of our work exploring the relationship between immune activation and psychosis, we measured cerebrospinal fluid (CSF) IL-1 alpha and IL-2 levels in 60 medicated schizophrenic patients and in 21 normal volunteers using a competitive enzyme immunoassay. The two groups did not differ significantly in their mean cytokine levels: 1.01 (0.149) ng/ml (patients) vs. 1.28 (0.150) ng/ml (controls) for IL-1 alpha and 0.970 (0.038) ng/ml (patients) vs. 1.25 (0.086) ng/ml (controls) for IL-2. There was a significant positive correlation between CSF IL-1 alpha and IL-2 levels for all subjects (r = 0.50, n = 44, p = 0.0001).

The continued search for evidence of retroviral infection in schizophrenic patients.

Retroviral infection has been proposed as an etiologic factor in schizophrenia. In an effort to unmask a latent retrovirus, short term cultures of peripheral lymphocytes from 15 schizophrenic subjects and nine normal controls were exposed to ionizing radiation and co-cultured with indicator cells. Reverse transcriptase activity, a marker of retroviral infection, could not be detected in any of the cultures. Our findings are further evidence against a role for retroviral infection in the etiology of schizophrenia.

Effects of water loading in schizophrenic patients with polydipsia-hyponatremia: an MRI pilot study.

We conducted an MRI pilot study of three schizophrenic patients with the syndrome of polydipsia-hyponatremia. Paired MRI scans were obtained at baseline and in the water-loaded state to study the acute effects of water loading and accompanying changes in serum sodium and osmolality on brain structures. We report the pilot data on the observed individual MRI changes of reduced volume of the lateral ventricles in all three patients, and the third ventricles in two patients, in the water-loaded state. These changes were not statistically significant possibly because of small sample size.

Cerebrospinal fluid oxytocin concentration in schizophrenic patients does not differ from control subjects and is not changed by neuroleptic medication.

Cerebrospinal fluid (CSF) oxytocin concentrations in 20 neuroleptic-treated schizophrenic patients, 31 neuroleptic-withdrawn schizophrenic patients, and 15 normal control subjects were compared. Neither within-subject comparisons of CSF oxytocin concentration measurements made during neuroleptic treatment and withdrawal (n = 11), nor comparison of the combined neuroleptic-withdrawn and neuroleptic-treated patient group (n = 40) with control subjects (n = 15) differed significantly, suggesting that CSF oxytocin concentration is not altered in schizophrenia.

Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms.

Levels of the histamine metabolites, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), and metabolites of other aminergic transmitters and of norepinephrine were measured in cerebrospinal fluid of 36 inpatients with chronic schizophrenia and eight controls. The mean t-MH level from controls was nearly identical to the levels seen previously in healthy volunteers. Compared with controls, the mean level of t-MH in the schizophrenic patients was 2.6-fold higher (p = 0.006); 21 of the patients had levels exceeding the range of controls. There was no significant difference (p > 0.05) in levels of other analytes, although the levels of t-MH correlated significantly with those of t-MIAA, homovanillic acid, 3,4-dihydroxyphenylacetic acid, norepinephrine, 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid. The difference in levels of t-MH were not attributable to medication, since those taking (n = 10) or withdrawn from (n = 26) neuroleptic drugs had nearly the same mean levels of t-MH; each group had higher levels than controls (ANOVA: p < 0.05). Patients with or without tardive dyskinesia showed no significant differences in means of any analyte. Only levels of t-MH among those with schizophrenia correlated with positive symptom scores on the Psychiatric Symptom Assessment Scale (rs = 0.45, p < 0.02). The elevated levels of t-MH in cerebrospinal fluid, which represent histamine that was released and metabolized, suggest increased central histaminergic activity in patients with chronic schizophrenia.