Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia.

Previous studies have shown that endogenous brain levels of kynurenic acid (KYNA), a glutamate receptor antagonist, are elevated in patients with schizophrenia. Here we analyse KYNA in the cerebrospinal fluid (CSF) from a large cohort, including male healthy controls (n=49) and male patients with schizophrenia (n=90). We found that male patients with schizophrenia had significantly higher levels of CSF KYNA compared to healthy male controls (1.45 nM+/-0.10 vs. 1.06 nM+/-0.06 in the control group). Furthermore, when the patients with schizophrenia were divided into subgroups we found that CSF KYNA levels were significantly elevated in drug-naïve, first episode patients (1.53 nM+/-0.19, n=37) and in patients undergoing treatment with antipsychotic drugs (1.53 nM+/-0.17, n=34) compared to healthy male controls. No elevated CSF KYNA levels were detected in drug-free patients with schizophrenia, i.e. patients previously undergoing antipsychotic medications but drug-free at time of sampling (1.16 nM+/-0.10, n=19). Present results confirm that CSF KYNA concentration is elevated in patients with schizophrenia and are consistent with the hypothesis that KYNA contributes to the pathophysiology of the disease.

Immunoreactive beta-casomorphin-8 in cerebrospinal fluid from pregnant and lactating women: correlation with plasma levels.

We measured plasma and cerebrospinal fluid (CSF) beta-casomorphin-8, a product of beta-casein hydrolysis which has opioid activity, by RIA in women during late pregnancy and lactation and in nonpregnant nonpuerperal women. Before RIA, the samples were acidified and extracted by reverse phase silica gel chromatography, which removed most of the beta-casein. Lactating women had a significantly higher mean plasma beta-casomorphin-8 concentration (2.66 nmol/L; n = 8) than women in late pregnancy (0.82 nmol/L; n = 8) and nonpregnant women (0.32 nmol/L; n = 5). The CSF beta-casomorphin-8 concentration also was significantly higher in lactating women (mean, 0.35 nmol/L; n = 8) than during late pregnancy (0.22 nmol/L; n = 8) or in nonpregnant women (0.15 nmol/L; n = 5). A positive correlation was found between plasma and CSF beta-casomorphin-8 levels in the entire study group. The milk beta-casomorphin-8 concentration, measured in five puerperal women, averaged 19.8 nmol/L. Thus, there is a decreasing concentration gradient between milk and plasma and between plasma and CSF. Chromatographic analysis revealed mol wt heterogeneity of the RIA-active material. In CSF at least three different components were detected, two of mol wt around 900-2,000 and one of approximately 12,000. One of the low mol wt components coeluted in several chromatographic systems with synthetic beta-casomorphin-8 (mol wt, 900). Such a component was not found in milk or plasma, in which the major activity was due to larger sized peptides. The major peaks in milk were around 1,500-2,000 and 12,000 mol wt, corresponding to the larger peaks in CSF. The results suggest that fragments of the milk protein beta-casein may cross the breast parenchyma-blood barrier into plasma and subsequently penetrate the blood-brain barrier to reach the central nervous system. Thus, mammary tissue may assume endocrine function during galactopoiesis, and beta-casein could be considered a prohormone.

Reduced beta-casein levels in milk samples from patients with postpartum psychosis.

Defatted breast milk from women with postpartum psychosis and from healthy lactating women was analyzed by high-resolution gel permeation chromatography as well as by sodium dodecyl sulfate (SDS) and urea polyacrylamide gel electrophoresis. The gel permeation procedure allowed quantitative analysis of milk proteins (including beta-casein) with minute amounts of defatted milk (10-15 microliter). By electrophoresis, further characterization of the protein pattern, including the beta-casein fraction, was obtained. Milk samples from five control and seven psychotic subjects were analyzed. The concentration of the beta-casein-containing peak was significantly lower in milk samples from the psychotic group by both chromatography and electrophoresis. These lower levels of beta-casein may result from a higher rate of enzymatic degradation generating i.a. peptides with opioid activity, as shown earlier in plasma and CSF of women with postpartum psychosis.

Relationship between abnormal brainstem auditory-evoked potentials and subnormal CSF levels of HVA and 5-HIAA in first-episode schizophrenic patients.

Auditory brainstem-evoked responses (ABRs) were recorded and the CSF concentration of the amine metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were measured in 39 drug-free schizophrenic patients. Twenty-four of the patients were first admissions and had never received antipsychotic medication. The ABRs were judged according to our normative data and the CSF concentrations of the amine metabolites were compared with those of 47 healthy volunteers. Clear-cut abnormal ABRs, identified as a lack of one or more peaks or abnormal peak latencies, were found in 15 patients. In controls and patients with normal ABRs, there was a significant positive correlation between the cerebrospinal fluid (CSF) levels of HVA and 5-HIAA; no such correlation was found in patients with abnormal ABRs. Schizophrenics with abnormal ABRs had significantly lower levels of HVA, but not 5-HIAA, in the CSF when compared with controls. Schizophrenic patients with normal ABRs (n = 24) did not differ from the controls with regard to the amine metabolites in CSF. A comparison of the CSF levels of HVA and 5-HIAA yielded no significant difference between patients with normal and those with abnormal ABRs. In contrast, when only first-episode, never-treated schizophrenics were considered, patients with abnormal ABRs (n = 10) had significantly lower levels of both HVA and 5-HIAA when compared with those having normal ABRs (n = 14). The results indicate an association between brainstem dysfunction and reduced central nervous dopaminergic and possibly also serotoninergic activity in schizophrenia.

Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET.

BACKGROUND: The aim of the present study was to investigate dopamine synthesis in the brain of drug-free schizophrenic patients, not only in the striatum but also in extrastriatal areas like the prefrontal cortex, brain areas that for a long time has been in focus of interest in the pathophysiology of schizophrenia. METHODS: PET was performed in 12 drug-free (10 drug-naive) psychotic schizophrenic patients and 10 healthy volunteers matched for age and gender using 11C-labelled L-DOPA as the tracer. The time-radioactivity curve from occipital cortex (located within Brodman area 17 and 18) was used as input function to calculate L-DOPA influx rate, Ki images, that were matched to a common brain atlas. A significant overall increase of the Ki values was found in the schizophrenic group as compared with healthy controls. RESULTS: In particular, significantly higher Ki were found in the schizophrenic patients compared to the controls in the caudate nucleus, putamen and in parts of medial prefrontal cortex (Brod 24). The Ki value reflect an increased utilization of L-DOPA, presumably due to increased activity of the amino acid decarboxylate enzyme. CONCLUSIONS: The results indicate that the synthesis of dopamine is elevated within the striatum and parts of medial prefrontal cortex in schizophrenia.

Season of birth and electrodermal unresponsiveness in male schizophrenics.

The present study was designed to examine differences in the electrodermal activity of schizophrenics born in the season of excessive risk (January-April), and those born in the season of nonexcessive risk (May-December). Thirty-two male schizophrenics were presented with a series of orienting tones (1000 Hz, 80dB, 2 sec duration) while electrodermal activity was monitored. They were subdivided according to season of birth and compared in three electrodermal variables, and also in some background and clinical parameters. We found that schizophrenics born in the season of excessive risk were characterized by significantly lower electrodermal activity and more negative symptoms than those born in the season of nonexcessive risk.

CSF and plasma beta-casomorphin-like opioid peptides in postpartum psychosis.

The authors measured opioid receptor-active components in the CSF of 11 women with postpartum psychosis, 11 healthy lactating women, and 16 healthy women who were not lactating. Activity that eluted with 0.2 M acetic acid 0.7-0.9 times the total volume of the column (fraction II activity) was significantly higher in the CSF of both healthy and psychotic women in the puerperium than in that of the lactating women. Very high levels of fraction II activity were seen in four psychotic patients. Material from these patients was further characterized by electrophoresis and high-performance liquid chromatography: The material migrated as bovine beta-casomorphin. Receptor-active material with the same characteristics was also found in the plasma of these four patients. The authors conclude that certain cases of postpartum psychosis are associated with the occurrence in plasma and CSF of unique opioid peptides probably related to bovine beta-casomorphin.

Clinical and biological markers for outcome in schizophrenia: a review of a longitudinal follow-up study in Uppsala schizophrenia research project.

During a 10-year period, 120 drugfree DSM-III-R schizophrenic patients were consecutively and unselectively admitted to a ward for young psychotic patients and subjected to a battery of examinations including symptomatology, cerebrospinal fluid (CSF)-biochemistry, computed tomography (CT)-scan, neurophysiologic and psychophysiologic (Electrodermal activity, EDA) parameters before antipsychotic treatment was initiated. After discharge, the patients were longitudinally followed with ratings of outcome (Strauss-Carpenters outcome scale) at years 1, 3, and 5 after index admission. The aim of the study was to find possible early markers for outcome in schizophrenia. At 5 years, 30% of the patients had a good outcome (total score > 13) and 15% a poor outcome (total score < 8). Poor premorbid adjustment and low level of education as well as negative schizophrenic symptomatology at index admission were associated with a poor outcome 5 years later. Positive symptomatology and a family history of schizophrenia did not predict outcome. Patients with a poor outcome (total score < 8) had a significantly more deviant CSF HVA/5-HIAA quotient than those with a very good outcome (total score > 15) as compared with healthy controls. Further, the CSF-peptides neuropeptide Y, dynorphin A, and CRF were predictable for outcome at the 5-year follow-up evaluation. Male schizophrenics who were "nonresponders" on the EDA test showed an almost 100% poor outcome, which was not found in females. In summary, several clinical and biological variables seem to have a predictable value for outcome in schizophrenia and, early identification of them might be a challenge for our future treatment strategies.

A retrospective study on the long-term efficacy of clozapine in 96 schizophrenic and schizoaffective patients during a 13-year period.

The effect of long-term treatment with clozapine in schizophrenia and schizoaffective disorder was evaluated in a retrospective study comprising 96 patients treated with the drug during the period 1974-1986 at the Psychiatric Research Center in Uppsala. All patients had previously been treated with different kinds of antipsychotic drugs but with insufficient clinical effect or distressing extrapyramidal side effects. When clozapine treatment was initiated, the mean duration of the illness was 8 years and 9 months. In 36% of the patients clozapine treatment was discontinued, the main reasons being lack of efficacy, poor compliance or temporary withdrawal from the market in 1975. Clinical evaluation of the effect revealed that 85% of the patients could be discharged from the hospital within a year and that 43% of the patients were significantly and 38% moderately improved compared to previous treatments. Of those patients who were still on clozapine 2 years after the treatment was initiated, 39% had employment compared to only 3% before clozapine. In ten patients a transient decrement in white blood cells (WBC) was noted but normalized during ongoing treatment. One patient developed leukopenia and one agranulocytosis, none with fatal outcome. Common side effects were sedation, hypersalivation, weight gain and obstipation. In one patient clozapine treatment was stopped because of grand mal seizures. No extrapyramidal side effects were observed or reported during clozapine treatment. It is concluded that clozapine offers particular advantages for many "therapy-resistant" schizophrenic patients when compared to classical neuroleptics.

Determination of clozapine and its N-demethylated metabolite in plasma by use of gas chromatography-mass spectrometry with single ion detection.

A gas chromatographic-mass spectrometric method with single ion detection has been developed for determination of clozapine and its N-demethylated metabolite norclozapine in plasma. Propylnorclozapine was used as internal standard and the mass spectrometer was adjusted to record the ion m/z 373 for the compounds analyzed. The precision of the method was found to be high, with a relative standard deviation of 6% or less for replicated samples. The limit of determination was 1.0 ng/ml for clozapine and 5.0 ng/ml norclozapine. A significant correlation was obtained between the daily oral dose of clozapine within the dose interval 100-800 mg/day and the plasma level of clozapine in 22 chronic schizophrenic patients. The plasma levels of clozapine and norclozapine were also significantly correlated. The quotient norclozapine/clozapine showed great interindividual variation and was not correlated to the daily dose of clozapine. The method is rapid and sensitive to allow evaluation of the pharmacokinetic properties of clozapine in the treatment of schizophrenic patients.

Supersensitivity psychosis in schizophrenic patients after sudden clozapine withdrawal.

In two patients with chronic schizophrenia, who were on clozapine medication for more than 6 months, a sudden withdrawal of the drug resulted in a very pronounced deterioration of the psychosis within 24-48 h. The most prominent symptoms were auditory hallucinations and persecutory ideas and one patient tried to commit suicide. These observations are interpreted as supersensitivity psychoses induced by the very effective clozapine treatment.

Striatal and frontal cortex binding of 11-C-labelled clozapine visualized by positron emission tomography (PET) in drug-free schizophrenics and healthy volunteers.

The binding of 11C-labelled clozapine in the brain was studied in three drug-free schizophrenic patients and in three healthy volunteers. High radioactivities were found in the striatum and in the frontal cortex. The rate constant k3, which is proportional to receptor association rate and the number of receptors, was lower in the frontal cortex compared to the striatum. No obvious difference between the two brain areas was seen for the dissociation rate constant from the receptors (k4). Two schizophrenic patients were reexamined after pretreatment with haloperidol, one after 6 weeks of treatment with a low oral dose, the other one after an IV injection 1 h before 11C-clozapine was given. After haloperidol pretreatment, the binding of 11C-clozapine in striatum and frontal cortex was reduced, more pronounced in the striatum, indicating competition for D-2 dopamine binding sites. Our finding indicates that clozapine has an affinity for a receptor population in the frontal cortex that is predominantly not of the dopamine-D2 type. This feature might be of importance for the unique clinical profile of the drug.

Reduced CSF neurotensin concentration in drug-free schizophrenic patients.

The concentration of the tridecapeptide neurotensin was measured in CSF from 76 drug-free schizophrenic patients and 45 healthy controls. A highly significant difference was found between the two groups with lower concentration of neurotensin-like immunoreactivity in schizophrenic patients. Normalization of the lower concentrations was obtained in the same patients during ongoing neuroleptic treatment. The neurotensin concentrations in CSF was unrelated to sex, age, duration of the disorder or to previous neuroleptic treatment. Neurotensin levels did not differ between patients with or without a family history. A significant correlation was found between low neurotensin concentrations and decreased motor activity. No significant relationship was seen between the increment in CSF concentrations of neurotensin and clinical improvement during neuroleptic treatment. No significant correlation between CSF concentrations of neurotensin and HVA or 5-HIAA, major metabolites of dopamine and serotonin, respectively, could be demonstrated. However, in a limited number of the schizophrenic patients in this population, a significant correlation was seen between neurotensin and the noradrenaline metabolite MOPEG. The data support the hypothesis that certain schizophrenic patients may have a compromised CNS neurotensin system which might increase vulnerability for this disorder.

Enhancement of signal quality in esophageal recordings of diaphragm EMG.

The crural diaphragm electromyogram (EMGdi) is recorded from a sheet of muscle, the fiber direction of which is mostly perpendicular to an esophageal bipolar electrode. The region from which the action potentials are elicited, the electrically active region of the diaphragm (EAR(di)) and the center of this region (EAR(di ctr)) may vary during voluntary contractions in terms of their position with respect to an esophageal electrode. Depending on the bipolar electrode's position with respect to the EAR(di ctr), the EMGdi is filtered to different degrees. The objectives of the present study were to reduce these filtering effects on the EMGdi by developing an analysis algorithm referred to as the "double-subtraction technique." The results showed that changes in the position of the EAR(di ctr) by +/- 5 mm with respect to the electrode pairs located 10 mm caudal and 10 mm cephalad provided a systematic variation in the EMG power spectrum center-frequency values by +/- 10%. The double-subtraction technique reduced the influence of movement of the EAR(di ctr) relative to the electrode array on EMG power spectrum center frequency and root mean square values, increased the signal-to-noise ratio by 2 dB, and increased the number of EMG samples that were accepted by the signal quality indexes by 50%.

Neuropeptide Y and peptide YY as possible cerebrospinal fluid markers for major depression and schizophrenia, respectively.

Neuropeptide Y (NPY)-like and peptide YY (PYY)-like immunoreactivities were measured in cerebrospinal fluid (CSF) from patients with major depressive disorder or schizophrenia and from healthy volunteers without physical or mental illness. NPY-like material was significantly lower (P less than 0.001) in CSF of patients with depressive disorders than in schizophrenic patients or healthy controls. Treatment with the antidepressant, amiflamine, a selective MAO-A inhibitor, did not alter CSF peptide concentrations. In drug-free schizophrenic patients, normal NPY but reduced PYY concentrations in CSF were observed. Treatment with neuroleptics did not affect the levels of NPY or PYY in the CSF. The finding of reduced CSF concentrations of NPY in patients with major depression and of reduced PYY concentrations in schizophrenia may reflect disturbed synthesis, turnover or degradation of the peptides. These findings suggest that the reduced concentrations of NPY or PYY in the CSF may be used as trait markers of the respective illnesses.

Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia.

Kynurenic acid is an endogenous glutamate antagonist with a preferential action at the glycine-site of the N-methyl D-aspartate-receptor. Mounting evidence indicate that the compound is significantly involved in basal neurophysiological processes in the brain. In the present investigation, cerebrospinal fluid (CSF) level of kynurenic acid was analyzed in 28 male schizophrenic patients and 17 male healthy controls by means of high pressure liquid chromatography and fluorescence detection. Schizophrenic patients showed elevated CSF levels of kynurenic acid (1.67+/-0.27 nM) compared to the control group (0.97+/-0.07 nM). Furthermore, CSF levels of kynurenic acid in schizophrenic patients were also found to correlate with age. The present finding is indicative of a contribution of kynurenic acid in the pathogenesis of schizophrenia.

Delta-sleep inducing peptide in cerebrospinal fluid from schizophrenics, depressives and healthy volunteers.

CSF levels of DSIP was measured in healthy volunteers and in hospitalized patients with schizophrenia or major depressive disorders. Both patient groups had significantly lower CSF levels of DSIP than the healthy volunteers. There was a tendency for lower CSF levels of DSIP in female compared to male schizophrenics. Neuroleptic treatment did not significantly affect those levels. The levels of DSIP in CSF tended to be inversely correlated to the sleep disturbancy scores in the depressed patients.

Electrodermal activity as a predictor of social functioning in female schizophrenics.

Twenty-nine female schizophrenics and 20 female controls were presented with a series of moderately intense tones in a standard orienting habituation paradigm while skin conductance was monitored. Premorbid adjustment and symptoms were also rated, and the schizophrenics were observed 2 years later. The total schizophrenic group was divided into a good-outcome group and a poor-outcome group. Good social functioning outcome required both self-supporting ability in the job market and at least a minimal social life. The poor-outcome group had a significantly higher skin-conductance level and frequency of spontaneous skin-conductance fluctuations than the control group, whereas the few patients with good outcome did not differ from controls. These results are contrary to previous findings with a group of schizophrenic men in which poor social functioning was associated with low electrodermal activity. This discrepancy is discussed in terms of sex differences in schizophrenic disorder.

Electrodermal nonresponding, premorbid adjustment, and symptomatology as predictors of long-term social functioning in schizophrenics.

The hypothesis that electrodermal nonresponsiveness to orienting stimuli delineates a core group of "Kraepelinian" type schizophrenics was tested by following up social functioning outcome over a 2-year period in 37 schizophrenics. Good social functioning outcome required both some self-supporting ability in the job market and a minimal social life. The prior assessments included monitoring of electrodermal responses to a series of moderately intense tones, ratings of reported and observed symptoms during an interview, and ratings of premorbid adjustment on the basis of an interview with a close relative. Electrodermal nonresponding, poor premorbid adjustment, and negative symptomatology predicted poor social functioning during the second follow-up year, but the relationship to nonresponding pertained exclusively to a group of 15 first-episode patients. Discriminant analysis showed that electrodermal nonresponding and symptoms were the only independent predictors of outcome.

Low HVA and normal 5HIAA CSF levels in drug-free schizophrenic patients compared to healthy volunteers: correlations to symptomatology and family history.

Cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were determined in 40 drug-free schizophrenic patients and 21 healthy volunteers by a mass fragmentographic method. Twenty-one of the schizophrenic patients were first admissions who had never received neuroleptics. Significantly, lower levels of HVA but not 5HIAA were found in the patient group, and no difference was found between chronic, previously neuroleptic-treated and never-medicated patients. HVA levels correlated positively with social interest and total positive scores on the Nurses Observation Scale for Inpatient Evaluation (NOSIE-30) and negatively with lassitude and slowness of movements on the Comprehensive Psychopathological Rating Scale (CPRS). Low levels of 5HIAA were correlated to the CPRS items delusions and apparent sadness. There were slightly higher CSF levels of 5HIAA in patients with a family history of schizophrenia, but no such difference was seen for HVA. In both schizophrenic and control subjects CSF levels of HVA and 5HIAA showed a strong intraindividual correlation. The results indicate decreased central nervous system dopaminergic turnover in schizophrenia which seems to be associated with "negative" symptomatology.