Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Background to An Oral History of the First Fifty Years
Neuropsychopharmacology (Volume Five): 2. Psychotoxic metabolites
Bulletin 49

            In the 1950s psychoanalysis dominated psychiatric teaching in North America and psychomimetics were used mainly as adjuvants to various forms of psychotherapy (Ban 1969; Brill and Patton 1957; Leuner 1962; Shorter 1997). Yet it was in the mid-1950s that the shift in the site of psychiatric practice from psychiatric hospitals to the community began with the introduction of effective psychotropic drugs (Ban 200).  It followed the transformation of the diagnostic distribution of hospitalized psychiatric patients, resulting from the introduction of causal treatments in the 1940s,such as nicotinic acid for pellagra and penicillin for cerebral syphilis, as well as the introduction of diphenylhydantoin for controlling epilepsy and thiamine for treating the amnestic syndrome (Elvehjem, Madden, Strong and Wooley 1937; Fleming1929; Fouts, Helmer, Lepkowsy and Jukes 1937;  Putnam 1970; Stokes, Seinberg, Schwartz, Mahoney, Moore  and Wood 1944). With these changes priorities for psychiatric research turned from the so-called “organic” to the “functional” psychoses (Ban 2006). 

            The idea that some “functional psychoses” are metabolic in origin was first entertained in the mid-19^th century after the introduction of lithium in the treatment of gout by Alfred Baring Garrod in London (Garrod 1958; Johnsone 1984). Given that acute symptoms of gout develop suddenly and persist if untreated, in the early 1870s William Hammond in New York assumed that mood disorders might be a form of cerebral gout and introduced lithium in their treatment (Hammond 1871). In the mid-1880s Carl and Fritz Langein Copenhagen also started to use lithium salts in the treatment of periodic mood disorders (Lange 1886; Rybakowski 2009).

            Rolv Gjessing was first, in the mid-1930s, to identify an “endogenous psychosis 2009”assumed to be the result of faulty metabolism induced “auto-intoxication” (Gjessing 1932; Moebius 1893; Yeragani and Gershon 1986). By recording biochemical measures in a group of patients characterized by recurrent catatonic (psychotic) manifestations with “more or less lucid” intervals in between, Gjessing found a periodic change in nitrogen balance passing from a peak of retention to a trough of loss, with the nitrogen cycles having the same duration as the mental cycles, even if the phases did not always coincide (Gjessing1932; Moebius 1893; Thudichum 1864; Ungvari 2006; Weil-Malherbe and Szara 1971). He attributed the psychotoxicity to urea, a substance that in the late 1940s was identified by John Cade as the likely culprit for the enhanced toxicity of urine from manic depressed patients in guinea pigs, leading to the rediscovery of the effectiveness of lithium in the treatments of manic-depressive disease (Cade 1949, 1970; Gjessing 1934, 1938). Gjessing also detected changes in biological measures:temperature, pulse rate, basal metabolic rate, 17-corticosteroids and glucocorticoid excretion, and oxygen saturation of capillary bloodthat corresponded with the different phases of nitrogen metabolism and mental state during the “attacks” (Gjessing 1964, 1967). Furthermore, in spite of the fact that patients were euthyroid, Gjessing found that retention of nitrogen and the occurrence of psychotic episodes could be prevented by the administration of thyroxine (Gjessing 1938). Rolv Gjessing’s findings were complemented by Leiv Gjessing in the 1960s. He demonstrated an increased excretion of vanylmandelic acid, metanephrine and normetanephrine during the catatonic phase of the disease and had also shown that depletion of catecholamines by reserpine could abort the catatonic phasewhereas the administration of α-methyldopa could only mitigate it (Gjessing 1964, 1965, 1967a) He also showed that “periodic catatonia” was distinct from manic-depressive disease in lithium responsiveness (Gjessing 1967b, 1974, 1975).

            Harley-Mason was first, in 1952, to entertain the possibility that the cause of schizophrenia was autointoxication with a mescaline-like substance, such as 3, 4-dimethoxyphenylalanine (DMPEA), a transmethylation product of catecholamine metabolism, produced in the body (Harley-Mason, Laird and Smythies 1958; Osmond and Smythies 1952). At the time the only finding indicating that DMPEA might have mental effects was Noteboom’s demonstration in the early 1930s that it induced experimental catatonia (Noteboom 1934). For about 10years, Harley-Mason’s proposition was dormant, but in the 1960s, after the reported presence of a “pink spot,” identified as DMPEA in acute schizophrenia but not in chronic schizophrenia, a controversy arose (Faurbye and Pind 1964). It was argued that DMPEA was not specific for schizophrenia, was present at a low level in all urines, was not present in either schizophrenic or normal urine, was not an endogenous substance but a dietary artefact, and finally, that the “pink spot” was not DMPEA (Feldstein 1970; Siegel and Tefft 1971).  In the midst of this controversy Fujimori and Halpern found  that in subjects pre-treated with MAOIs, DMPEA had psychomimetic effects, and  Bourdillonand his associates demonstrated that by dividing patients on the basis of their psychopathology the “pink spot” was present in more than fourof fivepatients in the non-paranoid  group of patients diagnosed as schizophrenia on the basis of Schneider’s first rank symptoms  but in less than oneof fivepatients in the paranoid group (Bourdillon, Clarke,  Ridges, Sheppard, Harper and Leslie 1965;  Fujimori and Alpern 1971; Ridges and Bourdillon1967;  Schneider 1929).

            As an alternative to DMPEA in 1954 Hoffer, Osmond and Smythies suggested that adrenochrome, an oxidation product of epinephrine, might be the culprit in schizophrenia (Hoffer, Osmond and Smythies 1954). At the time the only support for this was Green and Richter’s finding, in the mid-1930s, that adrenochrome was formed in vitro by treating epinephrine with various oxidants (Green and Richter 1937). It was only in the mid-1960s that adrenochrome’s psychomimetic effect was first demonstrated (Grof, Vojtechovsky, Vitek and Prankova 1963). It was about the same time that the enzyme that could catalyze adrenochrome formation from epinephrine was identified by Julius Axelrod in the cytoplasmic fraction of the salivary gland (Axelrod 194). Nevertheless, in 1970 Altschule and Yanak reported that the activity of Axelrod’s enzyme was below the normal range in schizophrenia (Altschule and Nayak 1970). The presence of adrenochrome in vivo could not be detected with the employment of even highly sensitive radioactive tracer techniques (Ban 1973; Weil-Malherbe and Szara 1971).

            The first data based “psychotoxic” hypothesis of schizophrenia was presented by Brune and Himwich who found in the early 1960s a decrease in N-methyl-nicotinamide excretion together with an increase in tryptamine, 3-indoleacetic acid and 5-hydroxyindoleacetic acid excretion in patients with acute or exacerbated schizophrenia (Brune 1967; Brune and Himwich 1963). They hypothesized that in schizophrenia a blockage of the kynurenine pathway of tryptophan metabolism reduced the biological formation of nicotinic acid and increased tryptophan metabolism along its serotonin and tryptamine pathways, leading to the formation of psychotoxic dimethylated metabolites; N,N dimethyl serotonin (bufotenin), and DMT (Brune 1967; Fabing and Hawkins 1956; Weil-Malherbe and Szara 1971). The psychotomimetic effect of bufotenin was uncertain but the psychotomimetic effect of DMT was unequivocally confirmed (Szara and Aitkens 1973; Weil-Malherbe and Szara 1971). Supportive of the hypothesis was the demonstration that urinary excretion of DMT was increased during aggravation of schizophrenic psychopathology (Heller, Narasimhachari, Spaide, Hescovec and Himwich 1970). Nevertheless, in 1971, Faurbye and Pind found that both DMT and bufotenin were present in normal urine (Faurbye and Pind 1971).

            Seymour Kety in the mid-1960 reformulated Harley-Mason’s transmethylation hypothesis of schizophrenia. He shifted emphasis from a psychotoxic substance to the biochemical process of methylation, aggravated by the formation of abnormally methylated psychotoxic compounds (Kety 1967). In keeping with the hypothesis were findings that incubating deproteinized blood with betain or methionine as a methyl donor and nicotinamide as a methyl acceptor yielded a much greater increase in N-methylnicotinamide formation in schizophrenic than in normal blood (Buscaino, Spadetta and Carella 1966). Also in keeping were findings that parenteral administration of catechol-O-methyl transferase, as well as combined administration of methionine and an MAOI, exacerbated the clinical symptoms of schizophrenia (Hall, Hartridge and Van Leuwen 1969; Pollin, Cardon and Kety 1971; Spaide, Nevel, Tolentino and Himwich 1969).

            The first report on the therapeutic effect of nicotinic acid in schizophrenia was published by Hoffer and his associates in 1957 (Hoffer, Osmond, Callbech and Kahan 1957). They hypothesized that in stressful conditions administration of nicotinic acid (NA), a substance that converts into nicotinamide, a methyl acceptor, would prevent excessive epinephrine production and thereby restrict the supply of αreporting on the favourable effects of nicotinic acid in the treatment of schizophrenia. (Hoffer 1962, 1963; Hoffer and Osmond1964). Findings in these studies could not be replicated in the Canadian Mental Health Association Collaborative Studies, a series of clinical trials in which NA was given alone and in combination with neuroleptics and other vitamins, pyridoxine andascorbic acid, to acute and chronic schizophrenic patients (Ban 1971a,b; Ban and Lehmann 1970).

            During the 1950s and 1960s several other toxic “factors” were isolated from plasma or serum of patients with schizophrenia (Weil-Malherbe and Szara 1971). One of these “factors,” taraxein, a protein, was shown to produce dramatic effects in monkeys and normal subjects with spiking and slow wave activity in the septal and hippocampal areasresembling the spontaneous electrical activity reported from those areas in schizophrenic patients by Heath and Martens (Heath and Leach 1962; Heath, Martens, Leach, Cohen and Angel 1957; Heath, Martens, Leach, Cohen and Fengley 1958). Another factor usually referred to as “plasma protein factor” or “Frohman factor,” an α-2 globulin was found to increase the lactate/pyruvate (L/P) ratio by allegedly changing membrane permeability in schizophrenia. The purified “plasma protein factor” produced striking behaviour changes in female spire monkeys; within 45 minutes after injection the animals became quiet, motionless and unresponsive to handling (Frohman, Goodman, Beckett, Latham, Senf and Gottlieb 1962; Frohman, Latham, Beckett and Gottlieb 1967). A third “factor,” a prealbumin, isolated by Walaas and his associates, was found to inhibit the incorporation of glucose into glycogen, and phenylalanine into protein, in the isolated rat diaphragm (Walaas, Lingjaerde, Soviket al.1965).  Ultimately, none of these “factors” proved to be specific for schizophrenia (Ban 1973).

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December 20, 2018