Birgitta Wode-Helgodt

Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: An association study

Polymorphisms in the brain-derived neurotrophic factor (BDNF) gene have been suggested to be associated with schizophrenia. In a replication attempt, Swedish patients with schizophrenia (n=187) and control subjects (n=275) were assessed for four BDNF gene polymorphisms. There were no significantly different allele, genotype or haplotype frequencies between cases or controls. Neither were there any differences when schizophrenic patients were sub-divided with regard to a number of different clinical variables, although a small group of psychotic patients with prominent affective features displayed higher frequencies of the less common alleles of the Val66Met and 11757 G/C polymorphisms compared to controls. The present Swedish results do not verify previous associations between putative functional BDNF gene polymorphisms and schizophrenia. However, when combined with previous studies meta-analyses indicated that the BDNF 270 T-allele and the Val66Met homozygous state were associated with the disorder. Thus, the BDNF gene may confer susceptibility to schizophrenia. Additional studies are warranted to shed further light on this possibility.

Effect of chlorpromazine treatment on monoamine metabolite levels in cerebrospinal fluid of psychotic patients

Levels of HVA, MOPEG and 5‐HIAA in cerebrospinal fluid (CSF) from psychotic men and women with a schizophrenic symptomatology were measured by mass fragmentography. Measurements were made before, 2 and 4 weeks after treatment with chlorpromazine (CPZ) which was given randomly in doses of 200, 400 or 600 mg per day.

Clinical effects and drug concentrations in plasma and cerebrospinal fluid in psychotic patients treated with fixed doses of chlorpromazine.

The clinical effects of chlorpromazine (CPZ) administered in accordance with a double‐blind design in one of three doses (200, 400 or 600 mg) were examined in 44 psychotic patients. The relationships between the effects and the CPZ concentrations in plasma and cerebrospinal fluid (CSF) were analyzed. The antipsychotic and side effects were rated according to the CPRS and the Simpson and Angus scale. CPZ concentrations were measured by a mass fragmentographic method. Treatment with CPZ resulted in a significant reduction of morbidity scores, without any clear dose relation. The final outcome was more favourable in women than in men. Extrapyramidal side effects but not somnolence were positively dose related.

Mass fragmentometric determination of homovanillic acid in lumbar cerebro-spinal fluid of schizophrenic patients during treatment with antipsychotic drugs

DOPAMINE is stored in specific neurons of the central nervous system,l where it in all probability plays a role as a, transmitter substance. Dopamine is formed from dietary tyrosine and it is metabolized to homovanillic acid @WA), which appears to be the major metabolite leaving the central nervous system (Fig. 1). From experiments in animals there is evidence that antipsychotic drugs markedly accelerate brain dopamine synthesis. Thus, following administration of chlorpromazine and haloperidol, levels of the dopamine metabolites, 3-methoxy-tyramine and HVA, are markedly elevated.2*3 The effects of drugs ‘on brain dopamine metabolism can also be studied using 14C-tyrosine as a tool. In a series of papers we have demonstrated that antipsychotic drugs belonging to the phenothiazine, thioxanthene, butyrophenone and dibenzoazepine series, all markedly accelerate synthesis as well as turnover of dopamine formed from 14C-tyrosine in the brain of rats and mice.4-6 It is evident from Table 1 that all the compounds tested, with the exception of promethazine which is a non-neuroleptic phenothiazine analogue, accelerate 14C-dopamine synthesis in brain of mice. Effects on 14C-noradrenaline are less consistent. Since such an acceleration of brain dopamine metabolism is not produced by other groups of psychoactive drugs as sedatives, antidepressants, central stimulants or hallucinogens,’ it appears likely that the acceleration of brain dopamine synthesis induced by neuroleptics is related to their antipsychotic efficacy.6,s The relatively specific effect of chlorpromazine and related neuroleptic drugs on schizophrenic behaviour,g and the demonstration of their marked effects on brain dopamine metabolism, suggested a role for dopamine in the pathophysiology of schizophrenia.10-12 Since the doses of neuroleptics required to accelerate brain dopamine synthesis in animals are comparable to those used for treatment of schizophrenia in patients, one would also expect brain dopamine synthesis in the human brain to be markedly increased during treatment with neuroleptic drugs. This would also be expected if the antipsychotic efficacy of neuroleptics is related to an acceleration of brain dopamine synthesis. The evidence for the effects of neuroleptics on human brain dopamine metabolism is highly ambiguous .13 This may be due partly to the previous use of fluorimetric methods

Effect of chlorpromazine treatment on prolactin levels in cerebrospinal fluid and plasma of psychotic patients

In psychotic patients, levels of prolactin in cerebrospinal fluid (CSF) and plasma were determined by radioimmunoassay before and after 2 and 4 weeks of treatment with chlorpromazine (CPZ). CPZ was given in one of three randomly selected fixed doses: 200, 400 or 600 mg per day.

A mass fragmentographic method for the determination of chlorpromazine and two of its active metabolites in human plasma and CSF

A mass fragmentographic method for the quantitation of chlorpromazine (CPZ), monodemethyl-chlorpromazine (nor1-CPZ), and 7-hydroxychlorpromazine (7-OH-CPZ) in plasma, cerebrospinal fluid, and tissues has been developed. The deuterated analogues of the compounds are used as internal standards. The high specificity was ascertained by multiple ion determination. The experimental error is below 10%. The sensitivity allows determination of sub ng quantities of CPZ per ml cerebrospinal fluid. The method has been applied to the analysis of drug concentrations in plasma and cerebrospinal fluid (CSF) of chlorpromazine-treated patients. The amount of CPZ in CSF was about 3% of the plasma level. The CPZ levels in plasma and CSF were significantly correlated.

The effect of chlorpromazine on homovanillic acid levels in cerebrospinal fluid of schizophrenic patients.

A mass fragmentometric method was used for determination of homovanillic acid levels in cerebrospinal fluid of acutely admitted schizophrenic patients. Spinal puncture was performed before and 12 days following the beginning of chlorpromazine treatment (200–600 mg/day). The level of homovanillic acid in cerebrospinal fluid before treatment was significantly higher in women than in men. Chlorpromazine treatment resulted on the average in a more than 2-fold elevation of the homovanillic acid level in cerebrospinal fluid. There were marked individual differences in the effect. The results are compatible with the view that therapeutic doses of chlorpromazine accelerate brain dopamine synthesis in man.A close analysis of the relation between effects of chlorpromazine on brain dopamine synthesis and psychotic and motor behaviour in schizophrenic patients seems required.

Central Biochemical Correlates to Antipsychotic Drug Action in Man

The present paper summarizes work carried out at the Karolinska Institute, Stockholm, Sweden, over the last few years. The studies deal with the possibility of finding chemical parameters useful for the selection of drugs and their dosage to treat psychotic patients.

RELATIONSHIPS BETWEEN ABERRANT MONOAMINE METABOLITE CONCENTRATION IN CEREBROSPINAL FLUID AND FAMILY DISPOSITION FOR PSYCHIATRIC DISORDERS IN HEALTHY AND SCHIZOPHRENIC SUBJECTS

Concentrations of 5-HIAA, HVA and MOPEG were determined by massfragmentography in lumbar CSF from healthy volunteers and schizophrenic patients. In both groups of subjects highly significant relationships were found between family history for psychiatric disorder and deviant concentrations of 5-HIAA and HVA in CSF. In the healthy volunteers subjects with schizophrenia in the family had significantly higher 5-HIAA concentrations as compared to subjects with depressive disorders in the family. Aberrant 5-HIAA in CSF was not related to the tryptophan concentration in the CSF. There were no relationships between CSF concentrations of tryptophan and total protein or demographic variables and family occurrance of psychiatric disorders in either group of subjects. The results are compatible with the hypothesis that genetic factors determine the development of monoaminergic mechanisms in the central nervous system. Studies in twins were performed in order to determine the relative importance of genetic and environmental factors for the variation in monoamine metabolite concentrations in the CSF. The results obtained in both patients and healthy volunteers support the view that groups of schizophrenic and manic depressive patients may be heterogenous with regard to the development of monoaminergic mechanisms in the CNS. Increased concentration of 5-HIAA appears to be related to increased family vulnerability for schizophrenic reactions whereas low concentrations of this metabolite is related to severe depressive reactions.

MASS FRAGMENTOMETRIC DETERMINATION OF HOMOVANILLIC ACID IN LUMBAR CEREBROSPINAL FLUID OF SCHIZOPHRENIC PATIENTS DURING TREATMENT WITH ANTIPSYCHOTIC DRUGS

Publisher Summary This chapter discusses mass fragmentometric determination of homovanillic acid (HVA) in lumbar cerebrospinal fluid (CSF) of schizophrenic patients during treatment with antipsychotic drugs. Dopamine is stored in specific neurons of the central nervous system, where it in all probability plays a role as a transmitter substance. Dopamine is formed from dietarytyrosine and it is metabolized to HVA, which appears to be the major metabolite leaving the central nervous system. From experiments in animals, there is evidence that antipsychotic drugs markedly accelerate brain dopamine synthesis. Thus, following administration of chlorpromazine and haloperidol, levels of the dopamine metabolites, 3-methoxy-tyramine and HVA, are markedly elevated. The mass fragmentometric technique involves the use of dideuterium labeled HVA as an internal standard.