Biochemistry of Schizophrenia

Abstract

Specific Hypotheses THE last ten years have witnessed an enormous increase in the amount of work carried out in this field and, after many years of disappointment, at long last some positive findings are beginning to emerge. It is too early to make the claim that any definite cause of the illness is known but evidence is now to hand that suggests quite strongly the type of biochemical abnormality that may be involved. Progress in research depends to a great extent on the formulation of adequate hypotheses that can be tested experimentally. The recent progress in schizophrenia research has depended partly on the development of such. hypotheses and partly on ad hoc observations both on the metabolism of schizophrenic patients and on the mode of action of psychotomimetic drugs. The First Specific Hypothesis One key to understanding the biochemical basis of schizophrenia may lie in the chemical formula of the psychotomimetic drugs. These are compounds that can induce in normal people many of the signs and symptoms of an acute schizophrenic illness without causing any delirium or clouding of consciousness. The first such drug to be discovered was mescaline in i886. This is a close relative of adrenaline being 3,4,5-trimethoxyphenylethylamine (Fig. i). This chemical relationship formed the basis of the first specific biochemical theory of schizophrenia published in 1952 by Osmond and Smythies. This theory postulated that schizophrenia might be caused by a derangement of adrenaline metabolism whereby the phenolic hydroxyl groups of the latter would be methylated to form dimethoxyphenylethanolamine (Fig. 2) Recently a fair amount of evidence has accumulated bearing on this hypothesis.(i) It was demonstrated (Axelrod and Tomchick, 1958; Armstrong, McMillan and Shaw, I957) that the normal method of metabolizing adrenaline in the human is by methylating one of the phenolic hydroxyl groups to give metanephrine (Fig. 3) which in turn is deaminated to give VMA.(ii) It was shown by Harley-Mason, Laird and Smythies (I958) that a minor metabolite of mescaline in the human is 3-methoxy-4,5-dihydroxyphenylethylamine (Fig. 3). Thus the metabolites of mescaline and adrenaline are even more alike than their parent substances and one can see how mescaline could act by some interference between its own metabolism and that of adrenaline.(iii) Anxiety-prone individuals, who possess a high level of tone in their sympathetic nervous systems, tend to react more severely to mescaline than do less anxiety-prone individuals and their symptoms are much more akin to those seen in actual schizophrenia. Thus a condition of stimulation of the sympathetic system seems to facilitate the psychotic process. Furthermore the symptomfree relatives of schizophrenic patients react in a much more psychotic (paranoid) manner to LSD than do normal controls.(

The Pink Spot

“…This finding together with other recent experimental work has provided evidence that schizophrenia may be associated with an abnormality of the transmethylating mechanisms of the body (e.g. Pollin et al 1961, Brune & Himwich 1962, Smythies 1963, Greiner & Nicolson 1965. Later reports concerning DMPE excretion have been contradictory and have resulted in considerable confusion.…”

Nutrition and Depression: The Role of Folate

“…SAMe, in turn, is widely distributed throughout the CNS as an intermediary of more than 35 transmethylation reaction^.^^,^' In 1963, Smythies hypothesized a defect in the mechanism of the one-carbon cycle as an underlying factor in some psychotic and mood disorders. 26 Although the "transmethylation hypothesis" of schizophrenia as outlined by Smythies has not been well supported by subsequent research, evidence for a role of the one-carbon cycle in processes relevant to the expression of affective disorders continues to accrue. This includes the work of Tolbert and c0lleagues,2~ who observed that the RBCs of unipolar depressives had lower levels of activity of MAT compared with erythrocytes from controls.…”

S-Adenosyl Methionine and Transmethylation Pathways in Neuropsychiatric Diseases Throughout Life

“…The hypothesis that there might be a relationship between the disorders of 1-carbon metabolism (and transmethylation) with the genesis of psychiatric disorders was first forwarded by Smythies as early as 1963 [107]. Several studies demonstrated that MAT, the critical enzyme of the 1-carbon cycle to produce SAMe, was significantly underactive in patients with schizophrenia (SZ) [108].…”