Aberrant amino acid transport in fibroblasts from patients with bipolar disorder.

Aberrant tyrosine transport is a repeated finding in fibroblasts from schizophrenic patients. The transport aberration could lead to disturbances in the dopaminergic and noradrenergic neurotransmitter systems. Tyrosine and tryptophan are the precursors of the neurotransmitters dopamine and serotonin. Disturbed dopaminergic, noradrenergic and serotoninergic systems are implicated as causes of bipolar disorder. Hence, the aim of this study was to explore whether patients with bipolar disorder have an aberrant transport of tyrosine and/or tryptophan. Fibroblast cell lines from patients with bipolar type-1 disorder (n=10) and healthy controls (n=10) were included in this study. All patients fulfilled the DSM-IV diagnostic criteria. The transport of amino acids across the cell membranes was measured by the cluster tray method. The kinetic parameters, maximal transport velocity (V(max)) and affinity constant (K(m)) were determined. A significantly lower V(max) for tyrosine (p=0.027) was found in patients with bipolar type-1 disorder in comparison to healthy controls. No significant differences in K(m) for tyrosine and in the kinetic parameters of tryptophan between patients with bipolar type-1 disorder and healthy controls were observed. The decreased tyrosine transport (low V(max)) found in this study may indicate less access of dopamine in the brain, resulting in disturbed dopaminergic and/or noradrenergic neurotransmission, that secondarily could lead to disturbances in other central neurotransmitter systems, such as the serotoninergic system. However, as sample size was small in this study and an age difference between patients and controls existed, the present findings should be considered as pilot data. Further studies with larger sample number are needed to elucidate the transport aberration and the significance of these findings.

Aberrant tyrosine transport across the cell membrane in patients with schizophrenia.

BACKGROUND: There is evidence that patients with schizophrenia exhibit abnormalities, not only in the brain but also in peripheral organs. An abnormal cell membrane composition has been suggested to be a common denominator, supported by findings of alterations in membrane phospholipid levels. In a previous study, the transport of amino acids across the plasma membrane was investigated with fibroblasts from patients with schizophrenia and controls. An isolated decrease in the maximal transport capacity (V(max)) of tyrosine was observed in the cells from patients. In this context, tyrosine transport across the fibroblast membrane was investigated in patients with schizophrenia and healthy control subjects. METHODS: Skin fibroblasts were obtained from 36 patients with schizophrenia (15 first episode and 21 chronic) and 10 healthy controls. Tyrosine transport across the cell membrane was studied in cultivated fibroblasts. The V(max) and the affinity of the tyrosine binding sites (K(m)) were determined. RESULTS: Significantly lower V(max) (F(1,41) = 12.80; P =.001; effect size = 1.36) and K(m) (F(1,41) = 24.85; P<.001; effect size = 1.00) were observed in fibroblasts from the patients. The findings were present in both neuroleptic-naive patients with their first episode and patients with chronic schizophrenia. CONCLUSIONS: The lower V(max) and K(m) are compatible with a cell membrane disturbance and support the view of schizophrenia as a systemic disorder. The decreased V(max) and K(m) observed in cells from schizophrenic patients probably reflect a genetic trait, as the changes were transmitted through several cell generations of cultured fibroblast.

Muscle biopsy, macro EMG, and clinical characteristics in patients with schizophrenia.

BACKGROUND: In a previous study of motor unit properties in patients with schizophrenia, muscle fiber histologic and electrophysiologic abnormalities were observed. The present study was designed to compare patients with schizophrenia with healthy control subjects with regard to muscle fiber histology and motor unit function. A second objective was to relate these variables to clinical characteristics. METHODS: Twelve patients with first-episode schizophrenia and fifteen patients with chronic schizophrenia (DSM-III-R) and 27 matched control subjects were included in the study. Muscle biopsies were performed either in m. tibialis anterior or m. vastus lateralis. Electromyographic recordings (macro EMG) were made from the m. tibialis anterior motor units. Psychiatric ratings included the PANSS and extrapyramidal side effects. RESULTS: Seven of the muscle biopsy specimens from the patients and one from the control subjects were classified as abnormal (p =.049). The most frequent abnormality was atrophic muscle fibers. Eight patients and no control subjects exhibited pathological macro EMG (p =.032). The findings were present in chronic as well as in first-episode patients with schizophrenia. CONCLUSIONS: In approximately 50% of the patients, neuromuscular abnormalities were found either in the muscle biopsy or the macro EMG investigations. The results indicate that either a common pathologic process or different pathological processes are at hand in the neuromuscular system in patients with schizophrenia. The findings are compatible with a disturbed cell membrane function.

Tyrosine transport is regulated differently in patients with schizophrenia.

Previous PET studies of tyrosine transport have suggested that the transport of tyrosine from blood to brain compartment is not dependent on its plasma concentration in patients with schizophrenia. In order to examine this relationship, the transport constant (K1) of tyrosine was determined in five patients with schizophrenia and five normals. L-[1-11C]Tyrosine was injected i.v. and arterial blood samples were taken during PET scanning. The tyrosine transport was assessed during baseline conditions and after oral administration of L-tyrosine at a dose (175 mg/kg) that significantly elevated the plasma levels. K1 was determined from tracer kinetic modelling. The transport rate dropped in the normals after tyrosine loading, which is consistent with the prevailing notion that the brain transport system for neutral amino acids works close to saturation, whereas it was virtually unchanged in the schizophrenics. The results demonstrated that tyrosine transport was not saturated in the patients with schizophrenia and thus could lead to elevated brain concentrations of tyrosine.

Neurological signs and psychomotor performance in patients with schizophrenia, their relatives and healthy controls.

Schizophrenic patients (DSM-III-R) were consecutively recruited and 39 were included. Twenty-one were first-episode and 18 were chronic schizophrenic patients. Thirty of the patients were on neuroleptic medication. Thirty-three parents were included, of whom nine were classified as 'family history positive' and 22 as 'family history negative' of a disposition to psychosis. Fifty-five healthy controls volunteered. The subjects were investigated according to a protocol divided into neurological signs and psychomotor performance (finger-tapping rate, Purdue pegboard test, pronation-supination test, gait and hand-grasp strength). Seventy-eight percent of the patients and 7% of the controls were classified as globally aberrant in signs. The patients and their parents, classified as 'family history positive', exhibited a similar laterality pattern in a finger-tapping test improving performance with the preferred hand, significantly different from the performance of the 'family history negative' parents and normal subjects. Duration of illness, neuroleptic medication and negative symptoms were not related to the occurrence of neurological signs and psychomotor performance. These findings indicate that neurological aberrations are present at the onset of illness and that hereditary factors are associated with motor laterality.

Tyrosine transport as an indicator of cell membrane dysfunction in schizophrenia.

In a series of studies tyrosine transport was investigated in patients with schizophrenia. Plasma amino acids competing with tyrosine for transport with the L-system were found to be elevated, and correlated negatively with homovanillic acid levels in the cerebrospinal fluid of the patients. The results were interpreted as a decrease in the transport of tyrosine to the brain leading to a reduced dopamine turnover. In in vitro studies with fibroblasts the transport capacity of tyrosine was found to be decreased (a lower Vmax value) in the patients. No changes in transport mechanism for the other neutral amino acids were found. The finding of a lower transport capacity in patients was replicated in a new sample in whom tyrosine transport also was determined in vivo with positron emission tomography. The in vivo studies demonstrated a decrease in the influx of tyrosine across the blood-brain barrier. Altogether the results were interpreted in support of the view of schizophrenia as a systemic disorder with a primary disturbance in cell membrane function.

Tyrosine transport in schizophrenia.

Tyrosine transport was examined in cultured skin fibroblasts from patients with schizophrenia (DSM-III-R) and normal subjects. The transport capacity (Vmax) was lower in the patients. The results confirm previous findings of decreased tyrosine transport in schizophrenia. In cells incubated with psychotropic drugs at different concentrations, tyrosine transport was not differentially influenced across patients and normal subjects. Dopaminergic and beta-adrenergic receptor mechanisms did not seem to influence tyrosine uptake. There seems to be a primary disturbance of tyrosine transport in schizophrenia which indicates a generalized cell membrane dysfunction.

A controlled Nordic multicentre study of zuclopenthixol acetate in oil solution, haloperidol and zuclopenthixol in the treatment of acute psychosis.

Zuclopenthixol acetate--a new injectable formulation with a duration of action of 2-3 days--was compared with conventional intramuscular and oral formulations of haloperidol and zuclopenthixol in the initial treatment of acutely disturbed, psychotic patients. The patients were stratified into 3 diagnostic categories: acute psychoses (48 patients), mania (22 patients), and exacerbation of chronic psychoses (73 patients). The patients were rated on the Brief Psychiatric Rating Scale (BPRS), the Bech-Rafaelsen Mania Rating Scale (BRMAS) (only manic patients) and globally on the Clinical Global Impression (CGI). The study was an open, randomized multicentre trial with a 6-day treatment period. The zuclopenthixol acetate patients received 1-4 doses, the haloperidol patients 1-26 and the zuclopenthixol patients 1-22 doses. The assessments on the CGI showed that all 3 treatments caused a clear reduction of the severity of illness scores in all 3 diagnostic categories, with no differences between treatments. The ratings of the acute and chronic psychotic patients on the BPRS also showed significant reductions in scores with no differences between treatments. All 3 treatments caused a rapid remission of symptoms on the BRMAS. Haloperidol induced hypokinesia in significantly more patients than zuclopenthixol acetate after 24 h. Later there were no significant differences between treatments. Zuclopenthixol acetate fulfils many desires for an amended neuroleptic formulation for the initial treatment of acutely disturbed psychotic patients.

The transport of tyrosine into the human brain as determined with L-[1-11C]tyrosine and PET.

An alteration of dopaminergic transmission in the brain has been proposed for schizophrenia. To explore this, the rate constant for the intransport of L-tyrosine across the blood-brain barrier in healthy controls and in patients with schizophrenia (DSM-III-R) was determined with PET and L-[1-11C] tyrosine as the tracer. Kinetics for tyrosine transport were determined according to a two-compartment model using radioactivity data of arterial blood and brain tissue sampled between 1 and 3.5 min after a bolus injection of L-[1-11C] tyrosine. Radioactivity was measured every second in the blood and in 10-sec intervals in the brain tissue. In the normal controls the brain intransport rate constant for tyrosine was 0.052 ml/g/min with an influx rate of 2.97 nmol/g/min. The patients had a similar intransport rate constant (0.045 ml/g/min) but a lower influx rate of tyrosine 1.95 nmol/g/min (p less than 0.05). The patients' tyrosine concentrations in the blood were lower. For data sampled between 5 and 25 min, the net accumulation rate of tyrosine into the brain was 0.015 ml/g/min in the controls which did not differ to the patients' rate. However, the net utilization of tyrosine was lower in the patients (0.672 nmol/g/min) than in the controls (0.883 nmol/g/min) despite similar tissue concentrations of tyrosine.

A clinical comparison of melperone and placebo in schizophrenic women on a milieu therapeutic ward.

Twenty schizophrenic women participated in a double-blind comparison of melperone (300 mg daily) and placebo lasting 4 weeks. All the patients received milieu treatment. Two patients in the melperone and four in the placebo group were removed from the study due to unsatisfactory therapeutic response. In the melperone group, there were significant reductions in psychotic morbidity. In the placebo group, there were occasional significant reductions of psychotic morbidity during but not at the end of treatment. The melperone-treated patients exhibited significantly lower morbidity scores than the placebo group after treatment for two and four weeks. The melperone group demonstrated significantly more adverse reactions than placebo-treated patients at the end of the study. The results support the view that melperone exerts an antipsychotic effect. The study is consistent with the opinion that milieu therapy should be combined with neuroleptics to achieve an optimal result in the treatment of an acute phase of schizophrenia.

Melperone in the treatment of schizophrenia.

Eighty-one women with psychosis of schizophrenic or paranoid type participated in a double-blind comparison of melperone (300 mg daily) and thiothixene (30 mg daily). The purpose of the study was to analyse clinical and biochemical effects of the drugs. Both treatments were associated with significant reductions in psychotic morbidity. No significant difference in the clinical ratings was found between the drugs. However, there were more extrapyramidal side effects in the thiothixene as compared to the melperone group. Biochemically, the dopaminergic variables HVA in CSF and prolactin in plasma and CSF showed significantly greater elevations in the thiothixene group.

Decreased tyrosine transport in fibroblasts from schizophrenic patients.

Amino acid transport was studied in vitro in cultured fibroblasts from schizophrenic patients and controls. An isolated decrease in the transport capacity (Vmax) for tyrosine was observed in cells from the patients. The Km for tyrosine transport was unaffected. The kinetic parameters for phenylalanine, tryptophan, leucine and glycine transport did not differ between patients and controls. Competitive inhibition among the amino acids transported by the L-system and its exchange properties were normal in cells from the patients. No differences in intracellular levels of amino acids between patients and controls were observed. The decreased tyrosine transport in the cells from schizophrenic patients appears not to be related to any known amino acid transport system and may reflect a more general defect in plasma membrane function in schizophrenia.

Muscle biopsy findings, conduction velocity and refractory period of single motor nerve fibres in schizophrenia.

Eight untreated and eight neuroleptic treated male schizophrenic patients were studied. Light and electron microscopical analysis of muscle biopsies from the anterior tibial muscle showed a spectrum of pathological changes without significant quantitative or qualitative differences between the two groups. The changes included atrophic fibres, central nuclei, "moth-eaten fibres", "ring fibres", fibre splitting and subsarcolemmal and intermyofibrillar glycogen droplets. Electrophysiological investigation of single motor unit properties showed impaired peripheral impulse propagation in both patient groups while the conduction velocity and the refractory period of single motor nerve fibres were within the same range as in healthy subjects. In conclusion there are neuromuscular abnormalities in schizophrenic patients which cannot be attributed to medication or drug abuse.

Zuclopenthixol acetate in Viscoleo--a new drug formulation. An open Nordic multicentre study of zuclopenthixol acetate in Viscoleo in patients with acute psychoses including mania and exacerbation of chronic psychoses.

Eighty-three acutely disturbed, psychotic patients were included in an open multicentre study. The aim of the study was to evaluate the clinical effect of zuclopenthixol acetate in Viscoleo (CPT-A). Each patient received from one to four intramuscular injections of CPT-A during the 6-day study period. The duration of action after one injection was between 2 and 3 days and doses from 50 mg to 150 mg were sufficient for most patients. Treatment with CPT-A caused a pronounced and rapid reduction of the psychotic symptoms. At the end of the 6-day test period the mean total score on BPRS in acute non-manic and exacerbated chronic patients was reduced by more than 50 per cent. In acute manic patients the mean total score on BRMS was reduced by 57 per cent already 1 day after injection. Rapidly after the injection of CPT-A a useful short-acting sedation can be expected, but the risk for oversedation even after a second injection is low. The frequency of unwanted effects, including extrapyramidal reactions, was low and the severity of symptoms was most often mild. With a rapid onset of action, a duration of effect of 2 to 3 days, and few and mild side effects, CPT-A offers advantages over the neuroleptic preparations conventionally used in the initial treatment of acutely disturbed, psychotic patients.

Plasma amino acids in relation to cerebrospinal fluid monoamine metabolites in schizophrenic patients and healthy controls.

Compared to healthy controls, unmedicated schizophrenic patients had significantly higher plasma concentrations of taurine, methionine, valine, isoleucine, leucine, phenylalanine, and lysine. Except for taurine, these amino acids share the L-transport system for neutral amino acids. In the patients, homovanillic (HVA) acid levels in CSF were decreased and the plasma levels of the amino acids competing with tyrosine and tryptophan for transport into the brain, were all negatively correlated to the CSF concentrations of HVA and 5-HIAA. These findings could be explained by a change in the affinity of the L-system or by a decrease in its overall capacity in schizophrenia. Raised plasma levels of the competing amino acids may limit the brain uptake of tyrosine, leading to a diminished dopamine turnover, and resulting in a compensatory development of supersensitive dopamine receptors.

Relationship between clinical effects, serum drug concentration and serotonin uptake inhibition in depressed patients treated with citalopram. A double-blind comparison of three dose levels.

Three dose levels (5, 25, and 50 mg once daily) of the selective serotonin uptake inhibitor citalopram were compared in a four-week, double-blind trial in depressed patients. Serum levels of citalopram and desmethylcitalopram, and the inhibitory effect of serum on serotonin uptake by fresh platelets, were assessed once weekly during the trial. The serum concentrations of citalopram were highly correlated with inhibition of serotonin uptake. Less of the metabolite was found, it being detected only in the higher dose groups. Steady state levels of citalopram, attained after 1 week, were linearly related to dose. The relationship between improvement (percentage reduction in total score on the Montgomery-Asberg Depression Rating Scale) and serum level of citalopram indicated a lower limit of effect in endogenous depression at about 100 nM, corresponding to an average dose of 15 mg. Marked improvement was seen in ten patients with steady state levels in the range 70 to 335 nM. The ten nonendogenously depressed patients had steady state levels from 15 to 620 nM; complete remission was seen in the three with the lowest levels (15-25 nM). No significant correlation was found between serum drug level and the few reported side effects.

The effects of citalopram (Lu 10-171) on the serotonin (5-HT) uptake kinetics in platelets from endogenously depressed patients.

The uptake kinetics of serotonin (5-HT) in platelets from eight patients with endogenous depression was determined in platelet rich plasma (PRP). From the uptake data the Scatchard correlation coefficient (r[S] ), Sips' index of heterogeneity (alpha), Km and Vmax (Lineweaver-Burk) were calculated. The measurements were performed before and after two weeks treatment with Citalopram, 1-(3-dimethylaminopropyl)-1-(p-fluorophenyl)-5-phtalan carbonitrile (Lu 10-171), a selective 5-HT uptake inhibitor. After two weeks treatment with Citalopram (5, 25 or 50 mg/day) a lowered platelet count in whole blood and PRP was observed and none of the patients had a measurable 5-HT uptake for which kinetic parameters (Km and Vmax, Lineweaver-Burk) could be calculated. However, all the patients but one improved significantly in Global score.

Clinical and biochemical effects of citalopram, a selective 5-HT reuptake inhibitor--a dose-response study in depressed patients.

Citalopram is a bicyclic phtalane derivative. In animal experiments, citalopram has been demonstrated to possess a potent and highly selective inhibitory effect on serotonin reuptake. Several studies in man have indicated that citalopram given in daily doses of 40-60 mg has antidepressant properties and few side effects. The present double-blind study investigated the effects of three doses of citalopram (5 mg, 25 mg, and 50 mg) on depressive symptoms and various biochemical variables in 26 depressive patients. A significant reduction of the clinical ratings of depressive symptoms occurred at all dose levels. In endogenously depressed patients, a dose of 25 or 50 mg daily seemed to have the most pronounced antidepressive effect. The side effects were few and not related to dose level. A highly significant decrease in 5-HIAA in the CSF was found. MO-PEG in the CSF was also significantly decreased, while HVA in the CSF was increased. In addition, a significant decrease in the plasma concentrations of valine, leucine, tyrosine, and histidine was found. None of the biochemical effects was dose-dependent. The complex pattern of biochemical effects indicate that the amelioration of depressive symptoms might be related to effects of citalopram on central monoaminergic mechanisms and peripheral amino acid concentrations.

Scale construction of the Swedish CPRS version.

A sample of 161 schizophrenic and depressive patients were interviewed in a Stockholm hospital to find out whether the Comprehensive Psychopathological Rating Scale construction carried out by Maurer et al. [Int. Pharmacopsychiat. 17: 338-353, 1982] and valid for German-speaking areas could be reproduced with a Swedish-speaking sample. Only the superimposed 2-factor solution resembled, in its factor-structure, that of Maurer et al. (depressive and schizophrenic syndrome). The fact that a 'depressive' syndrome was found instead of a 'manic-depressive' syndrome, is to be attributed to the different sample compositions.

Evidence of disturbed CSF circulation and brain atrophy in cases of schizophrenic psychosis.

The cerebrospinal fluid (CSF) circulation was studied with isotope cisternography in 30 patients with a schizophrenic type of psychosis. All had previously received neuroleptic treatment. Disturbed CSF circulation was found in 10 cases. In four of these, persistent intraventricular radioactivity was observed as well as partly obstructed CSF spaces. In the other six cases a slow CSF circulation was noted as well as evidence of partly obstructed CSF spaces especially of the upper posterior frontal region. Signs of atrophy of the cortex and vermis were found on CT scan in 10 cases. In four of these subjects a local atrophy was noticed in the upper posterior frontal cortex and around the frontal part of the interhemispheric fissure. Seventeen of the patients (57 per cent) had pathological findings at isotope cisternography and/or at CT. Disturbed circulation did not correlate with CT-findings, age, duration of psychosis, alcohol abuse, drug consumption or family history for psychosis. CT evidence of brain atrophy was significantly related to nonfamilial type of psychosis.