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.

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.

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.

CSF levels of HVA and 5-HIAA in drug-free schizophrenic patients and healthy controls: a prospective study focused on their predictive value for outcome in schizophrenia.

The CSF levels of HVA and 5-HIAA were determined in 90 drug-free DSM-III-R schizophrenic patients and 47 healthy control subjects, and their predictive value for 5-year outcome was evaluated. CSF was collected by lumbar puncture at index admission, and in 37 of the patients a second sample was drawn after approx. 7 weeks of neuroleptic treatment. Outcome was rated prospectively 5 years after index admission by means of the Strauss-Carpenter outcome scale. Schizophrenic patients had significantly lower levels of HVA in the CSF than the control group, but no difference was found for 5-HIAA. The CSF-amine metabolite levels were not correlated with age at admission, age at first symptoms or duration of the disorder. Neither HVA nor 5-HIAA correlated with the total outcome scores at a 1- and 5-year follow-up evaluation. First-admitted previously untreated patients with the poorest 5-year outcome had significantly lower HVA/5-HIAA quotients than those with a good outcome. Furthermore, patients still having a low HVA/5-HIAA quotient after treatment with neuroleptics had a poorer 5-year outcome than patients with an increased quotient. The data indicate that both HVA and 5-HIAA in the CSF, and especially their sensitivity to neuroleptic treatment, have a predictive value for the prognosis in schizophrenia.

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%.

Prenatal and neonatal risk factors for schizophrenia.

BACKGROUND: The present study examines the effects of independent, single pre- and perinatal risk factors and rates of obstetric complications upon the subsequent development of schizophrenia. METHOD: This study was based on prospectively recorded birth records of 107 cases (82 with schizophrenic disorders and 25 with other psychotic reactions) and 214 controls, individually matched by gender and time and place of birth. Variables univariately associated with significantly elevated risk were entered in a logistic regression model. RESULTS: A high non-optimality summary score (> or = 7 complications of 34 possible) was a significant risk estimate for the total index group (OR 4.58, 95% CI 1.74-12.03) and the 82 schizophrenic patients (OR 3.67, CI 1.30-10.36). Patients with 2-6 complications also had an increased, although lower, risk (OR 1.67, CI 1.02-2.75). A disproportionate birth weight for body length (OR 3.57, CI 1.77-7.19) and a small head circumference (OR 3.93, CI 1.32-11.71) were the strongest independent risk factors. CONCLUSIONS: A contribution of obstetric complications to the risk of schizophrenia was confirmed. Only aberrations in physical size remained as individual independent risk factors.

Symptoms at index admission as predictor for 1-5 year outcome in schizophrenia.

A total of 107 drug-free schizophrenic patients (76 males and 31 females) were consecutively admitted to an emergency ward and rated for psychotic symptoms by means of 32 items from the Comprehensive Psychopathological Rating Scale (CPRS). They were followed prospectively with ratings of social functioning by use of Strauss-Carpenter's outcome scale at 1, 3 and 5 years after index admission with the aim of determining possible early symptoms that are predictors of social outcome. In total, 59 of the patients were first admissions and had never been treated. At index admission, no difference was found in total CPRS scores between first-admission patients and chronic readmitted patients, or between male and female subjects. When subscales for positive symptoms (flights of ideas, feeling controlled, disrupted thoughts, auditory hallucinations, ideas of persecution) and negative symptoms (indecision, withdrawal, reduced speech, lack of appropriate emotions, slowness of movements) from the CPRS were applied, no relationship between the two subscales and outcome scores was found. However, in patients with a duration of the disorder of less than 24 months before index admission, high scores on both negative and positive subscales were significantly correlated with a poor 5-year outcome. No correlation was found in the group with a duration of illness of more than 24 months before index admission. It is concluded that symptoms at index admission have a predictive value for outcome in schizophrenic patients. Negative symptoms measured by use of a subscale of the CPRS have a predictive value for outcome up to 5 years after index admission, but high scores on both positive and negative symptoms are more strongly associated with a poor outcome. The duration of the symptoms before admission, as well as the kind of neuroleptic treatment given (clozapine vs. classical neuroleptics), seem to be important factors for prediction of outcome. Our data support the view that early negative symptoms in particular have a predictive value for the prognosis in schizophrenia for up to 5 years.

Schizophrenia and antipsychotic somatic treatment.

Schizophrenia typically affects individuals in early life and leads to long-term suffering at high cost to both the individual and the community. Structural, functional, and biochemical factors may play a role in the pathogenesis and perhaps the course, of schizophrenia. Although early research into the treatment of schizophrenia was not fruitful, the results of recent research, particularly the use of narcoleptics combined with new clinical appreciation of psychosocial factors in chronic psychotic disorders, give reason for hope and optimism.

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 prospective 1-5 year outcome study in first-admitted and readmitted schizophrenic patients; relationship to heredity, premorbid adjustment, duration of disease and education level at index admission and neuroleptic treatment.

In a prospective outcome study, 120 DSM-III-R schizophrenic patients were followed for up to 5 years after index admission, when a comprehensive clinical and demographical examination was undertaken with the aim to find early prognostic factors for outcome. They were 86 males (72%) and 34 females (28%), and 66 (55%) were first-admitted and never before treated at index admission from a geographically defined area. Outcome was evaluated 1, 3 and 5 years after index admission by use of a Strauss-Carpenter outcome scale. At year five, 101 patients could be evaluated. Seven (7%) patients had committed suicide during the 5 years' follow-up period. 30% of the patients was considered to have a good, 14% a poor and 56% an intermediate outcome. It was found that 58% had not been in hospital during the last year, 27% were employed on the open market, 25% met friends regularly and 38% had no or only mild symptoms at the five years' follow-up evaluation. Females had a significantly better outcome than males. High education level and absence of premorbid deviant behaviour at index admission predicted a good outcome whereas problems in school (with friends and/or teachers) reported by relatives predicted poor outcome. No relationship was found between outcome and age at onset of the disorder and no gender difference in age at onset of the disorder. Patients with a family history of schizophrenia improved more between year one and five as compared with those without a family history, but heredity in itself was not an important factor for outcome. At 5 years after index admission, 40% of patients were on classical neuroleptics and 33% on clozapine whereas 19% were without medication. Of the total sample of 101 patients, 10% were drug-free and had a very good outcome at the 5 years' evaluation. The data indicate that there is a substantial subgroup of schizophrenic patients with a good prognosis and they can be characterized by female sex (even in a group without gender difference in age at onset), absence of premorbid deviant behaviour and a high education level at index admission.

A subscale for negative symptoms from the Comprehensive Psychopathological Rating Scale (CPRS): a comparison with the Schedule for Assessment of Negative Symptoms (SANS).

The Comprehensive Psychopathological Rating Scale (CPRS) was used to determine symptomatology in 145 schizophrenic patients. In 40 of these patients the Schedule for Assessment of Negative Symptoms (SANS) was also applied in order to determine which items in the CPRS represent negative schizophrenic symptoms. Of the patients, 115 were drug-free and 30 were treated with major tranquilizers at the time of the rating. A principal component analysis with oblique solution and Varimax rotation grouped the items from CPRS into ten factors. These factors were subsequently correlated to the total scores of the SANS. When a factor showed a positive correlation with the SANS, the individual items within the factor were examined for correlation to both the subscales and the total SANS scores. Of the 33 items, 5 used in the CPRS showed a positive correlation with the SANS and were therefore considered to represent negative symptomatology in schizophrenia. These items were withdrawal, reduced speech, lack of appropriate emotions, slowness of movements and indecision. The items were grouped as a negative symptom subscale in the CPRS.

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.

Long-term clinical and social outcome studies in schizophrenia in relation to the cognitive and emotional side effects of antipsychotic drugs.

Evaluation of neuroleptics should include not only the effects on symptoms but also social functioning and the quality of life. Akathisia, cognitive and emotional impairment (cognitive and emotional parkinsonism) are probably the most important reasons for lack of compliance with classical neuroleptics. Atypical neuroleptics such as clozapine and remoxipride offer an advantage because of little impairment of cognitive and emotional functioning. In 122 schizophrenic and schizoaffective therapy-resistant patients treated with clozapine for up to 17 years, the treatment was stopped in only 8 cases (7%) because of lack of compliance. In patients treated for more than 2 years, 40% were employed and functioned well socially. It is concluded that, in many schizophrenic patients, atypical neuroleptics should be preferred in long-term maintenance treatment because of a low incidence of extrapyramidal syndromes as well as cognitive and emotional parkinsonism. An "awakening" is often seen when changing from a classical neuroleptic to an atypical one.

Electrodermal orienting response and central nervous system dopamine and serotonin activity in schizophrenia.

The present study was designed to examine the relationship between electrodermal activity and the levels of the dopamine metabolite homovanillic acid (HVA) and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid. Lumbar cerebrospinal fluid from 36 unmedicated and six medicated schizophrenic patients and 23 controls was analyzed by gas chromatograph-mass spectrometer. The schizophrenic patients and a group of 14 normal controls were presented with a series of orienting tones (1000 Hz, 80 db, 2-second duration) while electrodermal activity was monitored. For the patients, this occurred during an acute episode of schizophrenia. The results suggest an inverse relation between electrodermal activity and the CSF-level of HVA. Although the picture is not entirely consistent, electrodermal nonresponders appear to have normal HVA levels, while electrodermal responders have decreased levels compared with normal controls. There is also a relation between electrodermal activity and 5-HIAA, but this association is not as clear-cut as the one between electrodermal activity and HVA.

Symptomatology and electrodermal activity as predictors of neuroleptic response in young male schizophrenic inpatients.

This study examined whether the response to treatment with neuroleptic medication in 21 schizophrenic patients could be predicted from symptomatology, electrodermal activity, and premorbid adjustment. Positive symptoms and high levels of electrodermal activity were associated with a good response to conventional neuroleptic drugs. However, multivariate analysis indicated that symptomatology was the only independent predictor of treatment response.

Electrodermal orienting response, maternal age, and season of birth in schizophrenia.

Consistent with earlier research, male schizophrenic patients born during the season of excess risk for schizophrenia (January-April) showed significantly lower electrodermal responsivity than controls born during the season of excess risk, and patients and controls born during the season not associated with increased risk (May-December). No support for maternal age as an explanation for the season-of-birth effect was found.