Bengt Fyrö

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.

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.

The effect of lithium treatment on manic symptoms and levels of monoamine metabolites in cerebrospinal fluid of manic depressive patients

Clinical effects, levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in cerebrospinal fluid (CSF) and lithium levels in serum were examined in 13 manic depressive patients acutely admitted because of a manic or hypomanic episode. Patients were examined before and 12 days after the beginning of lithium treatment. Manic scores were significantly reduced during treatment. The levels of 5-HIAA as well as HVA increased significantly during treatment. The HVA to 5-HIAA ratio was significantly reduced, indicating a more pronounced change in 5-HIAA than in HVA. The 5-HIAA and HVA levels before as well as after 12 days of treatment were significantly correlated. No significant correlation was found between manic scores and monoamine metabolites in CSF or between lithium level in serum and reduction of manic scores or elevation of monoamine metabolites in CSF in the relative small number of patients studied.

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.

Antral Gastrin Activity in Duodenal and Gastric Ulcers

Summary Gastrin has been extracted from the antral mucosa of patients operated upon; 10 for duodenal ulcer, 11 for gastric ulcer, 2 for pyloric ulcer, and 1 for gastric carcinoma. The secretory activity of the gastrin preparations has been determined on unanesthetized gastric fistula cats. A satisfactory reproducibility of the extraction procedure and of the assay technique has been demonstrated. Gastrin activity per gram of antral mucosa amounted in the duodenal ulcer patients to more than 3 times the antral gastrin activity of the gastric ulcer patients, and the difference was highly significant. In the 2 patients with pyloric ulcer, antral gastrin activity corresponded to the average antral activity of the duodenal ulcer patients, and in the 1 patient with gastric carcinoma activity was less than the average antral activity of the gastric ulcer patients. The antral gastrin activity of 4 nonulcer human autopsy specimens varied greatly and gave no reliable information concerning the gastrin activity in antra from normal stomachs. The role of antral gastrin in ulcer genesis cannot be elucidated until the antral gastrin activity of normal stomachs has been established. The difference in gastrin activity between antra from duodenal and gastric ulcer patients suggests different genesis for these ulcers.

TIME COURSE FOR THE EFFECT OF LITHIUM ON THYROID FUNCTION IN MEN WOMEN

Some patients undergoing lithium treatment for manic-depressive disease develop thyroid enlargement (Fieve & Platman (1968) , Gonzales & Lauter (1968), Schou et al. (1968) ). Sedvall et al. (1968, 1969) found a significant reduction of protein bound iodine (PBI) in serum and an increase in the uptake of 1x11 into the thyroid gland in a small group of manic-depressive patients during the first weeks of lithium treatment. These findings were later verified in a preliminary study by Cooper & Simpson (1969). Rogers & Whybrow (1971) found a decrease in PBI concomitant with lithium treatment for an average of 15 months. Other authors have reported single cases of hypothyroidism in manic-depressive patients after lithium treatment for eight weeks to two years (Shopsin et aZ. (1969), O’Connell (1971), Candy (1972)). In the present study, which includes both manic-depressive patients and healthy volunteers, a distinct time course was found for the effect of lithium on thyroid function.

Mass fragmentographic analysis of clomipramine and its mono-demethylated metabolite in human plasma.

A mass fragmentographic method for the quantification of clomipramine (CIM) and monodemethyl-clomipramine (DCIM) in human plasma was developed. The deuterium labelled analogues of the compounds were used as internal standards. The sensitivity of the method allows the determination of CIM and DCIM in plasma after oral doses with a standard deviation less than 7% at concentrations of 25 ng/ml. The method was applied to the analysis of drug concentrations in plasma of clomipramine treated healthy volunteers and depressed patients. After acute treatment the level of DCIM in plasma was low as compared to chronical treatment.