Oxidative reactions and schizophrenia: a review-discussion.

Now that definitive direct evidence has been obtained that oxidized metabolites of catecholamines-aminochrome (derived from dopamine) and related compounds-occur in the human brain the question this paper explores is what is their function there, if any. They are precursors of neuromelanin and are formed inter alia by co-oxidation by prostaglandin H synthase during the synthesis of prostaglandin H from arachidonic acid. Their further metabolism by NAHPD-cytochrome P450 reductase forms the highly neurotoxic o-semiquinone together with free oxygen radicals. The defenses against these orthoquinones (o-quinones) and o-semiquinones (which include reduction, O-methylation, 5-cysteinylization, glutathione conjugation, conversion to the o-hydroquinone, and neuromelanin formation), and their possible status in schizophrenia, are reviewed. This system is closely linked with glutamate neurotoxicity because glutamate receptors activate PGH synthase and because dopamine toxicity is mediated by these o-quinones acting on NMDA receptors. Interactions between glutamate and dopamine neurotoxicity are explored, including a possible role for the redox properties of catecholamines. The hypothesis is presented that some of the demonstrated cellular damage in the schizophrenic brain may be mediated by catecholamine o-quinones. The significance of the evidence from previous studies carried out 40 years ago, that a closely related catecholamine o-quinone-adrenochrome-has psychotomimetic properties in humans and behavior disrupting properties in animals, is reviewed in the light of these recent findings.

Clinical correlations of one-carbon metabolism abnormalities.

1. Ninety psychiatric inpatients with a DSM III diagnosis of schizophrenia, mania, or major depression were studied. 2. Upon admission/transfer to the Clinical Studies Unit, and prior to discharge, measurements of symptom severity (BPRS, Ham-D, Young's Mania Scale) and blood samples were obtained. 3. Erythrocytes from these paired (admission and discharge) blood samples were assayed for methionine adenosyltransferase (MAT) activity and phosphatidylcholine (PC) content. 4. Comparisons were made between the changes in MAT Vmax, or % PC, and changes in symptom severity. 5. For the majority of the patients (79.3% of the schizophrenics; 84.6% of the depressives; and 93.8% of the manics), clinical improvement was associated with a "normalization" of enzyme activity. The association between changes in % PC and clinical response did not achieve significant correlation.

Abnormalities of one-carbon metabolism in psychiatric disorders: study of methionine adenosyltransferase kinetics and lipid composition of erythrocyte membranes.

Two independent lines of inquiry have implicated some disturbance of one-carbon cycle metabolism in affective disorders. Folic acid deficiency commonly leads to depression, and S-adenosylmethionine has been reported to have antidepressant properties. Methionine adenosyltransferase has been reported to be underactive in depression and schizophrenia and overactive in mania. This study reports the effects on erythrocyte methionine adenosyltransferase (MAT) kinetics (Vmax) of a 2-week treatment in a population of patients housed on a psychiatric research ward. The drug-free schizophrenic patients and depressives had, upon admission, low Vmax values, and the drug-free manic patients had high Vmax values on admission. After 2 weeks of appropriate treatment, the values for all three patient samples showed significant normalization (i.e., the levels rose in schizophrenics and depressives and fell in manics). We have further shown that pretreatment low levels of erythrocyte membrane phosphatidylcholine in depressives and high levels in manics show statistically significant normalization following 2 weeks of pharmacotherapy. The significance of these results is discussed.

Medication effects on one-carbon metabolism in schizophrenia, mania, and major depression.

Erythrocyte methionine adenosyltransferase (MAT) activity (Vmax) and phosphatidylcholine (PC) levels previously have been found increased in manic patients and decreased in depressive and schizophrenic patients. To evaluate whether these abnormalities were the result of medication effects, erythrocyte MAT activity (Vmax) was assayed for paired samples from 29 schizophrenic, 16 manic, and 12 depressive patients, an erythrocyte PC levels were obtained for paired samples from 13 schizophrenic, seven manic, and seven depressive patients. Patients were medication free for at least 3 weeks. Vmax was significantly increased in schizophrenic and depressive patients (p less than 0.01; p less than 0.01) and significantly decreased (p less than 0.01) in manic patients after 2 weeks of psychotropic medication. Similar trends were found in PC levels. The findings of those one-carbon metabolism tests following medication are generally opposite to those reported to be related to specific disorders and tend toward normalization. Moreover, in vitro preincubation of erythrocytes of three normal subjects with the most commonly used neuroleptics had no consistent effects of MAT Vmax. These findings confirm previous studies that showed similarities in one-carbon metabolism of schizophrenic and depressed patients as opposed to manic patients and suggest that medications tend to correct or minimize rather than induce such abnormalities.

One-carbon metabolism disturbances in affective disorders. A preliminary report.

Methionine adenosyltransferase (MAT) activity (Vmax) and the relative amount of phosphatidylcholine (% PC) were measured in erythrocytes of up to 30 DSM-III diagnosed manic, 17 unipolar depressed patients, and 28 normal controls. Manic subjects had significantly higher and depressed subjects significantly lower MAT Vmax than normals. The relative amount of PC was in the low range for the depressives, and in the high range for the manics. Depressive patients present, in these tests, similar abnormalities to those seen previously in schizophrenic patients. Clinical and diagnostic implications of these findings are discussed.

A further note on the molecular structure of the acetylcholine receptor protein.

A modification is presented of a previous all beta structure for the AChR channel to a mixed alpha/beta structure based on more recent evidence-the alpha-structure being predominant in the trans-membrane portion and the beta-portion in the portion exterior to the outside of the membrane.

The role of the one-carbon cycle in neuropsychiatric disease.

This paper reviews and correlates three separate recent findings that implicate the one-carbon cycle in neuropsychiatric disease: (i) the demonstration by kinetic studies that the Vmax of methionine adenosine transferase (MAT) is reduced in some schizophrenics and depressives and is increased in some manics, and that the activity of serine hydroxymethyltransferase (SHMT) is reduced in a further subpopulation of schizophrenics; (ii) the demonstration that S-adenosylmethionine (the product of MAT) is an effective clinical antidepressant; and (iii) the reports that L-methionine is an effective treatment for certain of the symptoms of Parkinson's disease. These clinical findings may be correlated with recent findings that transmethylation reactions (lipid and carboxymethylation) play an important role in synaptic events (coupling of receptors to adenylate cyclase and release of neurotransmitters).

A structural study of the full amino acid sequence of subunits alpha, beta, and delta of the acetylcholine receptor protein.

A Chou and Fasman analysis of the complete amino acid sequence of the alpha, beta and delta subunits of the AChR protein is presented. This shows nine beta strands in comparable loci in all subunits, of which three have (in part) an amphiphilic structure in all subunits (and one has such in 2/3 subunits), giving a total of 12-15 amphiphilic strands. This supports a previous hypothesis that the structure of the ion channel in the AChR protein is a type of beta-barrel or complex of amphiphilic beta-sheets with an extensive hydrophilic surface lining the channel, and an extensive lipophilic surface forming the inside of a beta-sandwich. No other suitable locus for the actual ACh receptor was found on the alpha-subunit other than segment 2-6.

A revised model of the molecular structure of the acetylcholine receptor at the neuromuscular junction.

The recently reported amino acid sequence of the alpha subunit of Electrophorus indicates that a previous hypothesis presented of the molecular structure of the acetylcholine receptor at the neuromuscular junction based on the sequence of the alpha subunit of Torpedo is improbable: an "essential" glu (13) of Torpedo is replaced by ser (13) which cannot subsume the function for glu (13) postulated in the hypothesis. This paper presents a new hypothesis which is applicable to both Electrophorus and Torpedo. A mode of rigorously testing the hypothesis provided by the irreversible blocker, lophotoxin, is described.

Biological markers for the schizophrenic and atypical psychoses.

This is a review of the present state of knowledge in the area of biological markers that may delineate subpopulations of patients with major psychotic illness. Postmortem studies have revealed that schizophrenia is associated with an excess of dopamine (DA) receptors in the limbic system. A more clinically useful adaptation of this approach has been a study of DA D2 receptors in lymphocytes. Studies of monoamine oxidase, dopamine-beta-hydroxylase, and dimethyltryptamine have not fulfilled their early promise nor have the peptides provided useful information as to possible biological markers. Recent studies of the one-carbon cycle enzymes, methionine adenosyltransferase and serine hydroxymethyltransferase, suggest that underactivity of these, particularly the former, may be a reliable clinical marker for a subgroup of schizophrenics. The computerized axial tomography (CAT) scan abnormalities of schizophrenia establish useful indices of abnormal cerebral anatomy such as cortical atrophy with enlarged ventricles, cortical asymmetries, and atrophy of the cerebellar vermis. Positron emission tomography studies with 18F 2-deoxyglucose (2DG) have shown that many schizophrenics have a higher 2DG uptake in the occipital and temporal rather than the frontal cortex, thus reversing the normal patterns. The dexamethasone suppression test is a valuable biological marker for certain depressions. It may also be useful in identifying subgroups of the schizoaffective disorders, with some schizoaffectives showing an abnormal affective-like response and others not. These and other discriminating biological markers are discussed in this report.

Kinetic evidence for decreased methionine adenosyltransferase activity in erythrocytes from schizophrenics.

We have observed significantly lower kinetic parameters (KM and Vmax) for methionine adenosyltransferase activity in erythrocytes obtained from early onset schizophrenics when compared to samples from normal subjects. These differences are apparently not due to differences in S-adenosylmethionine (SAM) utilization. These results offer an explanation for the conflicting reports of previous investigators and support the concept that undermethylation may characterize some forms of schizophrenia. Methylation is involved in multiple aspects of metabolism and although similar differences in the MAT enzyme in the brain have not been reported, such a deficit could have profound effects on the nervous system. Decreased availability of SAM could decrease catecholamine metabolism or rates of phospholipid methylation.