Lars Bjerkenstedt

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.

Amino acids in plasma and CSF and monoamine metabolites in CSF: interrelationship in healthy subjects.

Abstract: Plasma and cerebrospinal fluid (CSF) concentrations of amino acids were measured in 65 healthy volunteers (50 men and 15 women). The CSF levels of the monoamine metabolites homovanillic acid (HVA), 3‐methoxy‐4‐hydroxyphenylethylene glycol (MOPEG), and 5‐hydroxyindoleacetic acid (5‐HIAA) were also determined. Sex differences were observed in both plasma and CSF amino acid levels as well as in the relationship between these concentrations. No significant correlations were observed between the CSF levels of HVA and 5‐HIAA, and the concentrations of their precursor amino acids in either plasma or CSF. The MOPEG level in CSF correlated positively with the plasma concentrations of several amino acids.

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.

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. MOPEG 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.

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.

Effects of melperone and thiothixene on prolactin levels in cerebrospinal fluid and plasma of psychotic women

SummaryLevels of prolactin (PRL) were determined by radioimmunoassay in cerebrospinal fluid (CSF) and plasma from psychotic women before and during treatment with melperone 100 mg×3 (n=29) or thiothixene 10 mg×3 (n=34). Small amounts of PRL were found in the CSF of most patients before treatment. The level of PRL in CSF was about 20% of that in the plasma. Both drugs elevated PRL levels in CSF and plasma significantly. Thiothixene was more potent and also more long acting than melperone in this regard. For neither drug was there any marked tolerance to the effects within a 4 week period. The highest PRL level in CSF, 26 ng/ml, was found in a thiothixene treated patient.Positive correlations were found between the contents of PRL in CSF and plasma before treatment. During thiothixene treatment there were also significant positive correlations between PRL levels in CSF and plasma. During melperone treatment this correlation was probably significant only after treatment for 4 weeks. Neither drug affected the levels of total protein in CSF. The results indicate that with the doses used thiothixene causes a more marked and long lasting blockade of central dopamine receptors controlling prolactin release. The study also demonstrated the versatility of using prolactin analyses of CSF and plasma as tools for quantitation of biochemical effects of neuroleptic drugs on the human central nervous system.

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.

A double-blind comparison of melperone and thiothixene in psychotic women using a new rating scale, the CPRS.

SummaryEighty-one women with psychosis of schizophrenic and paranoid type were assigned to a double-blind study comparing the clinical effects of melperone (l00 mg × 3) and thiothixene (10 mg × 3). The antipsychotic effect was evaluated by clinical rating according to the CPRS and the NOSIE-30 scales before and after 2 and 4 weeks of drug treatment. A satisfactory interrater reliability was obtained for the CPRS. Significant correlation was also found between the CPRS and NOSIE ratings.Treatment with both drugs was associated with significant reductions in morbidity as estimated by several measures of therapeutic effect from the CPRS, by the NOSIE scale and by global ratings. There were no marked differences at any rating time point between the drugs in this regard. There were more extrapyramidal side effects in the thiothixene group than in the melperone-treated patients.The results encourage the use and further evaluation of melperone in the treatment of psychotic patients.

Monoamine metabolite levels in cerebrospinal fluid of psychotic women treated with melperone or thiothixene

SummaryPsychotic women with schizophrenic symptoms were treated with melperone 100 mg×3 (n=29) or thiothixene 10 mg×3 (n=34) using a double-blind procedure. Before and during treatment, levels of HVA, MOPEG, and 5-HIAA, the major metabolites of DA, NE, and 5-HT, were determined in lumbar cerebrospinal fluid by a mass fragmentographic technique. Both treatments resulted in an elevation of the HVA levels after 2 weeks, thiothixene having a more marked effect. The effect of thiothixene but not of melperone persisted after 4 weeks. Thiothixene did not influence the MOPEG level, but melperone reduced it after 4 weeks of treatment. The 5-HIAA levels were not significantly altered by the drugs. The HVA/MOPEG and the HVA/5-HIAA ratios were highly significantly elevated by both drugs after 2 as well as 4 weeks. Thiothixene induced a significantly greater change of these ratios than melperone. The results supply evidence that thiothixene accelerates central dopamine metabolism in man, presumably by blocking DA receptors. Melperone appears to act similarly, but has an effect which is weaker and/or of shorter duration. During long-term treatment with melperone the receptors develop tolerance to it. The acceleration in DA metabolism declines and the effect of melperone switches instead to central NA metabolism. The results indicate that both drugs cause long-term changes in the activity ratios of central monoamine systems. It is suggested that such changes in several systems rather than single biochemical events may be related to the antipsychotic effects of neuroleptic drugs. This study also demonstrated the versatility of using monoamine metabolite analysis of the CSF as a tool for the quantification of biochemical effects of neuroleptic drugs on the human CNS.

Aberrant amino acid transport in fibroblasts from children with autism

Autism is a developmental, cognitive disorder clinically characterized by impaired social interaction, communication and restricted behaviours. The present study was designed to explore whether an abnormality in transport of tyrosine and/or alanine is present in children with autism. Skin biopsies were obtained from 11 children with autism (9 boys and 2 girls) fulfilling the DSM-IV diagnostic criteria for autistic disorder and 11 healthy male control children. Transport of amino acids tyrosine and alanine across the cell membrane of cultured fibroblasts was studied by the cluster tray method. The maximal transport capacity, V(max) and the affinity constant of the amino acid binding sites, K(m), were determined. Significantly increased V(max) for alanine (p=0.014) and increased K(m) for tyrosine (p=0.007) were found in children with autism. The increased transport capacity of alanine across the cell membrane and decreased affinity for transport sites of tyrosine indicates the involvement of two major amino acid transport systems (L- and A-system) in children with autism. This may influence the transport of several other amino acids across the blood-brain-barrier. The significance of the findings has to be further explored.