Gabriella Oxenstierna

Concentrations of monoamine metabolites in the cerebrospinal fluid of twins and unrelated individuals—A genetic study

The concentrations of the major monoamine metabolites, homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF), of platelet monoamine oxidase (MAO) and of dopamine beta-hydroxylase (DBH)-activity in serum and CSF were determined in pairs of healthy mono- and dizygotic twins, brothers and unrelated individuals. Intraclass correlations were calculated for each category of pairs. Of the monoamine metabolites, only MOPEG was found to be under any major genetic influence. Genetic heritability for MOPEG was 0.74 with no evidence of cultural heritability or environment common to twins. For HVA and 5-HIAA, a familial influence was found, where the cultural heritability was higher than the genetic. As in previous studies of MAO in blood platelets and of DBH activity in serum, there was strong evidence for a genetic component. The genetic heritability for MAO was 0.78. For DBH in serum the genetic component was 0.98, and for DBH in CSF, 0.83. The demonstration of a familial influence on 5-HIAA and HVA in CSF requires a more detailed analysis of the character of such environmental and genetic influences, using more direct techniques.

Clinical Evaluation of Sulpiride in Schizophrenic Patients ‐ A Double‐blind Comparison with Chlorpromazine

Abstract To evaluate the clinical potential of sulpiride for the treatment of schizophrenic patients, a double‐blind study was performed comparing fixed doses of sulpiride (800 mg daily) and chlorpromazine (400 mg daily). Twentyfive schizophrenic (RDC) patients participated in each treatment group. Antipsychotic effects were evaluated by CPRS and NOSIE ratings before and after 1, 2, 4 and 8 weeks of treatment. Interrater reliabilities for CPRS items and subscales were satisfactory.

Time Course for Effects of Sulpiride and Chlorpromazine on Monoamine Metabolite and Prolactin Levels in Cerebrospinal Fluid from Schizophrenic Patients

Abstract Schizophrenic patients were treated with the dopamine (DA)‐2 receptor blocking drug sulpiride (800 mg daily) or the non‐selective DA receptor blocking compound chlorpromazine (400 mg daily). Samples of lumbar cerebrospinal fluid (CSF) and blood were drawn before and after 1, 2, 4 and 8 weeks of treatment. Concentrations of the monoamine metabolites HVA, MOPEG and 5‐HIAA in CSF and of prolactin (PRL) in CSF and serum were determined.

Relationships Between Drug Concentrations in Serum and CSF, Clinical Effects and Monoaminergic Variables in Schizophrenic Patients Treated with Sulpiride or Chlorpromazine

Abstract Schizophrenic patients were treated with fixed doses of sulpiride (800 mg) or chlorpromazine (400 mg) during eight weeks using a double‐blind design. In order to examine relationships between pharmacokinetic, clinical and biochemical parameters in relation to treatment the following variables were recorded before and 1, 2, 4 and 8 weeks after treatment. Concentrations of sulpiride, CPZ, 7‐OH‐CPZ, nor1‐CPZ were determined in serum and CSF using liquid chromatography and mass fragmentography. Clinical variables were psychotic morbidity and side effects as evaluated by CPRS, NOSIE and side effect ratings. Monoaminergic variables were concentrations of the major cerebral monoamine metabolites, HVA, 5‐HIAA and MOPEG in the cerebrospinal fluid as measured by mass fragmentography. Prolactin levels in serum and CSF were measured by radioimmunoassay.

5‐Hydroxytryptophol in Human Cerebrospinal Fluid: Conjugation, Concentration Gradient, Relationship to 5‐Hydroxyindoleacetic Acid, and Influence of Hereditary Factors

Abstract: The serotonin metabolite 5‐hydroxyiryptophol was studied in human cerebrospinal fluid. A minor fraction (∼13%) was found in conjugated form from which it was liberated by treatment with sulphatase containing 3‐ glucuronidase activity. A concentration gradient of 5‐hydroxytryptophol concentration was shown on lumbar tapping and the concentration in ventricular CSF was about 2.5 times higher than that in lumbar CSF. 5‐Hydroxytryptophol and 5‐hydroxyindoleacetic acid concentrations were significantly correlated in healthy, psychotic, and depressed subjects, but not in alcoholics. 5‐Hydroxytryptophol concentrations in CSF of psychotic and depressed subjects were not different from those of healthy controls (4.22 pmol/ml ± 0.15, SEM). In healthy subjects, hereditary factors seemed to have little influence on the CSF level of 5‐hydroxytryptophol.

Characteristics of cerebrospinal fluid neuropeptides relevant to clinical research.

Studies of human cerebrospinal fluid (CSF) peptides were conducted in an attempt to broaden the utility of CSF peptide determinations in psychiatric research. Healthy volunteers had two lumbar punctures, at least 3 weeks apart, to assess reproducibility within subjects. CSF levels of eight peptides were reliably reproducible, indicating that longitudinal studies of these CSF neuropeptides are feasible. Levels of 10 peptides were determined in four sequential 8 ml aliquots of CSF. CSF rostrocaudal gradients were not found for any of these 10 peptides. Neuropeptide Y (NPY), growth hormone releasing factor (GHRF), and corticotropin releasing factor (CRF) were measured in CSF from twins and brothers. CSF NPY levels were heritable, while CRF and GHRF levels were influenced more by environment. CSF levels of CRF, beta-lipotropin, vasoactive intestinal peptide, adrenocorticotropic hormone, and somatostatin were highly correlated with one another, suggesting that a common factor is responsible for a significant proportion of the observed variance in their CSF levels. These results suggest that CSF peptide measurements may have a broad range of applicability to clinical psychiatric research.

Remoxipride — a new potential antipsychotic compound

The tolerability and pharmacokinetics of remoxipride were studied in 18 healthy normal male volunteers. Increasing oral doses of 0.5–100 mg were given to eight male volunteers in one study (study I). In addition, an intravenous (IV) infusion of 20 mg remoxipride and a 20 mg oral dose were given in an open crossover study to ten males (study II). Remoxipride was well tolerated with respect to cardiovascular effects, clinical chemistry, body temperature and adverse effects in all subjects. Following IV administration, remoxipride plasma concentrations declined exponentially in five subjects and biexponentially in the remaining five. The mean apparent volume of distribution was 0.5 1/kg (SD=0.10) and the mean half-life 4.1 h (range 2.6–6.6). The recovery of unchanged remoxipride in urine was 10–36%, and the mean renal clearance was 32 ml/min (SD=13). Remoxipride was a low clearance drug with a total plasma clearance of about 120 ml/min (SD=41). The mean oral bioavailability was 96%. There was a linear relationship between the peak plasma concentration as well as the area under the concentration versus time curve and the administered dose. A transient increase in plasma prolactin concentrations occurred but there were no effects on plasma growth hormone levels.

Neuropsychological test performance, brain morphological measures and CSF monoamine metabolites in schizophrenic patients

ABSTRACT Twenty‐three drug‐free patients with an acute schizophrenic psychosis were studied by clinical rating scales, neuropsychological tests, computed tomography (CT) of the brain and analysis of monoamine metabolites in the cerebrospinal fluid (CSF). The psychological tests used were the Swedish version of the Wechsler‐Bellevue Intelligence scale (WBI) and the Block Design test. The patients’ performance in the Block Design test was negatively correlated to the width of the third and lateral ventricles. Test profiles indicative of schizophrenic cognitive impairment and left hemisphere dysfunction correlated significantly with a wide third ventricle, but not with the size of the lateral ventricles. Patients with a test profile indicative of left hemisphere dysfunction also had wider Sylvian fissures than the remaining patients. Neuropsychological test scores did not correlate with the CSF levels of the monoamine metabolites HVA, MHPG and 5‐HIAA. Positive psychotic and autistic symptoms did not correlate with psychological test results, monoamine metabolites or with CT measures. The association between neuropsychological impairment and enlargement of the brain ventricles is in line with previous findings indicating that a subgroup of schizophrenic patients may be identified by neuropsychological and morphological methods.

Radionuclide cisternography and computed tomography in 30 healthy volunteers

SummaryRadiological assessments of patients with symptoms of impaired cerebrospinal fluid (CSF) circulation are usually based on observations of anatomical and functional alterations using computed tomography (CT) and radionuclide cisternography (RC). In order to define criteria of normality for these two techniques, 30 healthy volunteers have been studied. In the studies of CSF flow the radiopharmaceutical 99mTc-DTPA was used and single photon emission computed tomography (SPECT) was performed as a complement to planar scintigraphy. In 16 of the 30 volunteers the pattern of CSF flow was normal according to conventional criteria. In these subjects the radioactivity was symmetrically located over the parietal cortex 24 h after the injection and no intraventricular activity could be recorded. In 11 (41%) of the subjects, radioactivity could be observed in the lateral ventricles 6 h after injection. One of these subjects had a reflux of radioactivity into the lateral ventricles. The intraventricular radioactivity persisted for at least 24 h. This subject also had signs of obstruction of CSF flow over the convexities. Asymmetric distribution of radioactivity within the CSF spaces was observed in the images obtained after 6 but not 24 h in two cases. One of those also demonstrated transient intraventricular radioactivity. The results of the computed tomography were interpreted to be normal in 19 (63%) of the 30 volunteers. One subject had an asymmetric ventricular system. The CT scans of six subjects (20%) differed considerably from the others as they displayed wide cortical or vermian sulci at the borderline of normal variations. The case with the pathological RC belonged to the group of subjects who had wide sulci. He also had a wide third ventricle. No subject had dilated lateral ventricles on CT. It is concluded that transient but not persistent (up to 24 h) intraventricular reflux should be interpreted as a normal finding in radionuclide cisternography. The probable mechanism for this reflux is discussed.

A twin study of amino acid concentrations in cerebrospinal fluid

The concentrations of amino acids in the cerebrospinal fluid (CSF) were measured in pairs of healthy mono- and dizygotic twins. Intraclass correlations were calculated. Genetic and cultural heritabilities were estimated using a path analytical model. CSF levels of glycine, tyrosine and arginine were shown to be influenced by genetic factors. Genetic variation was also shown for serine, alpha-aminobutyrate and leucine. The results were compared with results from a genetic analysis of the amino acids in serum.