William Pollin

Effects of amino acid feedings in schizophrenic patients treated with iproniazid.

Large oral doses of individual amino acids were given three or four times daily for periods of 1 week to schizophrenic patients, some of whom were maintained on iproniazid. Marked alterations in behavior in some patients were associated with the administration of l-methionine and of l-tryptophan.

Reduced Monoamine Oxidase Activity in Platelets: A Possible Genetic Marker for Vulnerability to Schizophrenia

Monoamine oxidase activity in blood platelets was measured, with [14C]tryptamine as substrate, in 13 monozygotic twin pairs discordant for schizophrenia and in 23 normal volunteers. The monoamine oxidase activity of both schizophrenic and nonschizophrenic co-twins was significantly lower than it was for the normals, and it was highly correlated between twins. In addition, there was a significant inverse correlation between a measure of the degree of the schizophrenic disorder and the monoamine oxidase activity. These data suggest, but do not prove, that reduced platelet monoamine oxidase activity may provide a genetic marker for vulnerability to schizophrenia.

Biological, psychological and historical differences in a series of monozygotic twins discordant for schizophrenia

THERE is an old Chinese proverb that says: “The beginning of wisdom is to call things by their right names.” To begin with, let us try to make sure that we are using the “right” words, and at a minimum, mutually understood words, by briefly defining our thoughts concerning the two phenomena which together constitute the subject of this meeting: transmission and schizophrenia. When we use the term schizophrenia, we mean a behavioral syndrome which (a) is a disease process in that there is a demonstrable breakdown of normal function, comfort and effectiveness in a given individual; (b) has a set of common denominator symptoms (thought, affect, and action disorder, delusions, hallucinations and other psychotic manifestations) such that the “typical”, hardcore patient presents no diagnostic difficulty to psychiatric workers of many different points of view and nationalities; and (c) a behavioral syndrome which has very unclear limits, so that as one moves away from the hardcore cases there is an increasing degree of difficulty in arriving at diagnostic consensus. In regard to the other major concept with which we are concerned, i.e. transmission, Webster tells us that transmission is the act, operation or process of sending or transferring from one person to another; or passing on or down to others. Some question may be raised concerning how germane this concept is, at the present stage of our knowledge of schizophrenia. However, if we consider the various models that are implied by the concept of transmission of illness, its usefulness becomes clear. Illness can be transferred from one individual to another by means of the transfer of an active pathogen, as in bacteria1 infection; or by genetic transmission as in phenylketonuria. There is also a type of social transmission in the sense that children of poverty stricken, socially backward, slum dwellers have a much greater likelihood of coming down with tuberculosis, for example, not necessarily because their parents have transmitted to them a particular bacillus or a given genetic predisposition, but because they have been given a particular social heritage and have been reared in a particular environment which influences the susceptibility to the bacillus which is the prime source of the illness. Another model we need keep in mind demonstrates the fact that though children may very predictably show the behavior of their parents, this need not have any genetic component, as exemplified by the fact that children of French-speaking parents speak French, of English-speaking parents speak English, and so forth.

Heredity and environment in schizophrenia, revisited. The contribution of twin and high-risk studies.

Life history study of monozygotic (MZ) twins discordant for schizophrenia led to the 1967 hypothesis that phenotypic schizophrenia was an expression of genotypic vulnerability interacting with prenatal and/or perinatal environmental experience. This report is a selected review of partial answers to five questions facing research efforts that have attempted to clarify the interactive gene-environment model of schizophrenia. Follow-up study of the offspring of MZ twins with a diagnosis of schizophrenia and their MZ co-twins without schizophrenia demonstrated equal rates of schizophrenia; hence, each group of offspring carried equal genetic vulnerability for schizophrenia. Magnetic resonance imaging study of MZ discordant twins found that phenotypic schizophrenia was characterized by brain ventricular enlargement and hippocampal reduction in 87-93% of the schizophrenic twins, when compared with their nonschizophrenic co-twins. A longitudinal study of teenage children at differential risk for schizophrenia showed that brain ventricular enlargement in adulthood correlated significantly and positively with genetic risk for schizophrenia and number of perinatal complications, and negatively with birth weight. Significantly greater dysmorphological hand skin signs among schizophrenic MZ twins when compared with their nonschizophrenic co-twins have suggested an in utero second trimester fetal developmental abnormality for the schizophrenic subjects. Simultaneous neuroanatomic, neurophysiological, and neurocognitive evaluation of MZ twin pairs discordant for schizophrenia demonstrated decreased prefrontal physiological cerebral blood flow activation during Wisconsin Card Sorting Test for affected twins correlated with decreased hippocampal volume determined by magnetic resonance imaging. These neurocognitive studies have suggested that schizophrenia involves neocortical-limbic pathology and dysfunction implicated in performance of cognitive tasks requiring working memory. They support an interactive model of schizophrenia in which the likelihood of expression of the schizophrenic genotype is increased by intervening prenatal and/or perinatal factors, associated with subsequent adult brain changes.

The physiological and psychological effects of intravenously administered epinephrine and its metabolism in normal and schizophrenic men. II. Psychiatric observations.

Twelve “normal control” volunteers and twelve chronic schizophrenic patients received intravenous of isotopically labelled epinephrine in a complex experimental situation permitting simultaneous study of multiple biological and psychological variables. The major psychological changes accompanying epinephrine infusion were: (a) increased arousal, (b) narrowing of the field of attention, (c) change of direction of attention toward inner body experience, (d) resultant difficulty in communication and concentration and (e) subjective feelings of anxiety. Some “normal control” volunteer subjects distinguished these anxiety feelings from actual life-situation anxiety. There was no qualitative difference in the psychological response of the schizophrenic and the “normal control” groups to epinephrine infusion. In neither “normal control” volunteers, nor schizophrenic patients, did epinephrine cause the appearance or exacerbation of psychotic symptoms. There were two instances of increase of psychotic behavior during or after the epinephrine infusion in schizophrenic patients, but these could not be attributed to the epinephine per se; and seemed more clearly related to situational variables. This result fails to support hypotheses which attribute the origin of schizophrenic symptoms to an abnormality in the metabolism of epinephrine. Quantitative differences between the schizophrenic and “normal control” subjects showed that, as a group, the schizophrenic subjects were much less able to cope with the experimental situation (p = <0·002), showed more anxiety in response to the situation (p = <0·02) but less in response to epinephrine (p = <0·02), and ranked lower on involvement-communication (p = <0·02). It is believed that a major factor in the smaller anxiety response during epinephrine infusion in the schizophrenic patient group, compared to the “normal control” group, was its higher situational anxiety baseline. Differences between schizophrenic and “normal control” subjects in their ability to cope with an experimental situation, and in their resultant situational anxiety, are judged to be widely prevalent in research studies comparing schizophrenic and “normal control” subjects. Such differences must be given careful consideration before concluding that a particular hypothesis being investigated has or has not been validated.

Serum creatine phosphokinase (CPK) activity in monozygotic twins discordant for schizophrenia: heritability of serum CPK activity.

Abstract Recent studies with normal monozygotic and dizygotic twins have established that serum creatine phosphokinase (CPK) activity in man is under genetic control (Meltzer, Dorus, and Davis, in preparation). This is of interest because of the reports that serum CPK activity is increased in many acutely psychotic patients, provided that they are studied in the first days after the onset of gross psychotic symptoms and throughout hospitalization. 1–12 The increases range from slightly above the 95% upper limits of normal to 50–75 times the limits for each race-sex group. Furthermore, 25%–30% of the first degree relatives of psychotic patients have slight but persistent increases in serum CPK activity. 2,3,7 These increases occur significantly more frequently in relatives of psychotic patients who have themselves had increases in serum CPK activity (Meltzer and Moretti, in preparation). Prior to the studies with normal twins which established that serum CPK activity is under some genetic control, we had the opportunity to study serum CPK activity in twins discordant for schizophrenia. These results will be reported here.

Relationships between platelet and plasma monoamine oxidase, plasma dopamine-B-hydroxylase, and urinary 3-methoxy-4-hydroxy phenylglycol

Abstract The activity of dopamine-B-hydroxylase in blood has recently been demonstrated to be under genetic control and to correlate closely with urinary catecholamine excretion. The results of the present study did not demonstrate any relationship between a major catecholamine metabolite in urine, 3-methoxy-4-hydroxy phenylglycol, and dopamine-B-hydroxylase activity in plasma, monoamine oxidase activity in platelets, or monoamine oxidase activity in plasma. Differences in the origin of urinary catecholamines and urinary 3-methoxy-4-hydroxy phenyglycol may be responsible for these divergent results.

Plasma dopamine-beta-hydroxylase in identical twins discordant for schizophrenia

Publisher Summary This chapter elaborates the plasma dopamine-beta-hydroxylase (DBH) in identical twins discordant for schizophrenia. The schizophrenic index twins had all been hospitalized on one or more occasions with the diagnosis of schizophrenia. DBH activity was measured by a coupled enzyme assay as described elsewhere but with a modified pH of 5.5. Thirty-four normal blood donors were matched for age, and served as controls. The DBH activity was 498 ± 78 units for the 34 controls. The mean values of the index twins and of the nonschizophrenic twins were almost identical, and both were slightly, but not significantly, elevated when compared with controls. There was a highly significant correlation between enzyme activities in schizophrenic and nonschizophrenic cotwins. Neither a relationship between the severity of impairment, and the levels of the enzyme activity nor an effect of the phenothiazines could be demonstrated. No pathophysiological relationship between plasma DBH activity and schizophrenia has been demonstrated.

Family studies of MZ twins discordant for schizophrenia: neurological findings.

Over the past six years the Section on Twin and Sibling Studies, NIMH, has conducted intensive studies of 16 families with MZ twins discordant for schizophrenia. In addition, 3 families in which both twins were schizophrenic and 4 with no known psychiatric illness have been similarly investigated. Each family is admitted to the Clinical Center, NIH, for two weeks of multi-disciplinary investigation. In the hope of shedding light on the question of neurologic findings in schizophrenic patients and their role in this disorder, detailed neurological examinations are performed on the twins by two neurologists. Patients with gross neurologic disturbance are screened out by our selection criteria. The examiners are therefore explicitly seeking minor deviations in neurologic status, rather than patterns of symptoms and signs leading to a specific neurologic diagnosis. Given this context, the neurologists recorded substantial numbers of signs. Yet, in none of the twins was there sufficient evidence to warrant a neurologic diagnosis. The pairs of neurologic reports were subjected to a variety of procedures, in an attempt to quantify the results. For example, 11 of the first 13 index schizophrenic twins, as compared with 1 of 13 cotwin controls, were rated as having “probable” or “definite” neurologic abnormality, based upon the senior authors analysis of the number and type of signs recorded and the degree of agreement between the examiners. Significant group differences on number of signs reported were found between schizophrenics and nonschizophrenics, schizophrenic indexes and their cotwin controls, and schizophrenics and normals. In contrast, there were no significant group differences in the number of signs found between the nonschizophrenic cotwin controls and the normal twins.