Michael H. Joseph

Brain tryptophan metabolism in schizophrenia: A post mortem study of metabolites on the serotonin and kynurenine pathways in schizophrenic and control subjects

Serotonin (5HT), its chief metabolite 5-hydroxyindoleacetic acid (5 HIAA), its precursor tryptophan, and kynurenine, another metabolite of tryptophan, have been measured in post mortem human brain samples. Concentrations of these metabolites were not found to be significantly different in putamen, hippocampus or temporal cortex from 23 normal subjects compared with 15 subjects in whom a diagnosis of schizophrenia could be restrospectively confirmed. The results have been analysed with respect to cause of death, medication and post mortem changes. Post mortem increases in tryptophan and kynurenine were observed. Some interrelationships between the variables measured within and between the different areas studied are discussed. It is concluded that there is no evidence for a generalised deficit of 5HT in the brain in schizophrenia, nor for gross changes in turnover along the serotonin or kynurenine pathways of tryptophan metabolism in brain.

Determination of 3-methoxy-4-hydroxyphenylglycol conjugates in urine. Application to the study of central noradrenaline metabolism in unmedicated chronic schizophrenic patients

On the basis of post-mortem studies it has been proposed that the central deficit in schizophrenia may be in noradrenergic transmission. It has also been proposed that there is a substantial central contribution to the excretion of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) and more particularly of its sulphate conjugate in man. There is thought to be a lesser central contribution to the excretion of the other major noradrenaline metabolites, vanillylmandelic acid (VMA) and the glucuronide conjugate of MHPG.A strong negative correlation was found between severity of illness in a group of 18 unmedicated chronic schizophrenic patients and their 24-h excretion of MHPG-sulphate but not of MHPG-glucuronide or VMA. However there was no significant difference in the mean excretion of MHPG conjugates or of VMA between the schizophrenic group and an institutional control group.This supports the idea of a relation between MHPG-sulphate excretion and central noradrenergic activity, but suggests that reduced brain noradrenaline turnover is neither necessary nor sufficient for schizophrenia to occur. One possible explanation is that reduced turnover pre-disposes towards a more severe illness in schizophrenics.

Platelet serotonin concentration and monoamine oxidase activity in unmedicated chronic schizophrenic and in schizoaffective patients.

Elevated blood serotonin, perhaps secondary to reduced platelet MAO, has been reported in a group of chronic schizophrenic patients. We have failed to find elevated platelet serotonin, or any relationship between platelet serotonin and MAO either in a group of unmedicated chronic schizophrenic patients or in a group of schizoaffective patients. Possible reasons for these discrepancies are discussed.

The determination of 5-hydroxytryptophan and its metabolites in plasma following administration to man

The estimation of 5-hydroxytryptophan and its metabolites 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in plasma is described. The method is based on solvent extraction and the use of a liquid cation exchange reagent to separate 5-hydroxytryptamine and 5-hydroxytryptophan. The 5-hydroxyindoles are determined fluorimetrically following derivatisation with o-phthalaldehyde in strong acid. Data on the specificity and linearity of the method are presented. The time course of plasma 5-hydroxyindoles after oral administration of 5-hydroxytryptophan is studied in two subjects as an example of the application of the method and of its possible role in monitoring the plasma levels in therapy or in provocative tests.

Arousal related to excretion of noradrenaline metabolites and clinical aspects of unmedicated chronic schizophrenic patients

Abstract 1. 1. The interrelationship between the following psychophysiological, biochemical and clinical measures have been investigated in a group of unmedicated chronic schizophrenics; skin conductance level and orienting responses to tones; heart rate; excretion of vanillylmandelic acid (VMA), sulphate and total methoxyhydroxyphenylglycol (MHPG); clinical ratings of symptom severity. 2. 2. More severely ill subjects showed evidence of overarousal and had higher skin conductance levels and heart rates, and less habituation of skin conductance orienting responses to tones than the less severely ill. These measures were not related to ratings of anxiety. 3. 3. Physiological measures of peripheral autonomic function (skin conductance level and heart rate) were unexpectedly inversely related to VMA excretion, a noradrenaline metabolite putatively of peripheral origin, and to MHPG excretion. 4. 4. The central processes of habituation and symptom severity were more closely related to excretion of MHPG than VMA. This offers support for the suggestion that this noradrenaline metabolite more closely reflects brain noradrenaline turnover than VMA. The inverse relationship between MHPG excretion and measures of arousal suggests that brain noradrenergic transmission is not directly related to arousal levels in schizophrenia. 5. 5. Studies of these variables in control subjects will determine whether these findings are specific to schizophrenia.

3-Methoxy-4-hydroxyphenylglycol excretion in acutely schizophrenic patients during a controlled clinical trial of the isomers of flupenthixol.

Urinary MHPG excretion in patients with acute schizophrenia was studied before and during a trial of the isomers of flupenthixol and placebo. Pretrial MHPG excretion was not related to severity of illness before the trial or to other pretrial clinical variables. In male subjects higher pretrial MHPG excretion was associated with a better outcome 1 year post-trial. However in females no relationship between MHPG excretion and outcome was established. During the trial there was a reduction in MHPG excretion in patients treated with β-flupenthixol but no decrease in the group treated with α-flupenthixol or chlorpromazine. In patients on placebo there was a reduction in MHPG excretion in those who dit well clinically, but not in those who did poorly. Thus low MHPG excretion may be a predictor of poor outcome in schizophrenia, but MHPG excretion also changes both as a function of clinical state and of neuroleptic drug administration.

MHPG excretion in endogenous depression: Relationship to clinical state and the effects of ECT

In a group of 70 patients with endogenous depression entering a controlled trial of real versus sham ECT, urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) excretion was significantly reduced by comparison with previously studied groups of control subjects, of acute and chronic schizophrenic patients and of anxious patients. However, urinary MHPG was unrelated to severity of depression, or to the presence of delusions, retardation or agitation. MHPG excretion did not predict clinical outcome, or the response to ECT. Urinary MHPG content at trial entry was unrelated to past tricyclic antidepressant or benzodiazepine medication, although an influence of the latter on the findings cannot be excluded, since all patients received benzodiazepine (nitrazepam) night sedation during the trial.During the 4-week trial MHPG excretion remained low and did not increase in relation to change in clinical state, although there was a small but significant increase in patients who received real ECT. The findings confirm that urinary MHPG excretion is reduced in depression, but establish that such reductions are not state dependent. Since the increase in MHPG excretion with ECT is not related to changes in clinical state, the former presumably does not reflect the mechanism of action of ECT.