Jack Durell

Catecholamine metabolism in affective disorders: I.: Normetanephrine and VMA excretion in depressed patients treated with imipramine

INTRODUCTION DATA deriving both from studies in man and laboratory animals suggest that the antidepressant actions of imipramine may be mediated through its effect on the metabolism of catecholamines. l-14 Such a mechanism of action of imipramine would be compatible with the hypothesis that some depressions may be associated with an absolute or relative functional deficiency of catecholamines, especially norepinephrine, at specific brain receptor sites, whereas elations may be associated with an excess of such amines.1~2J~4J5J6 Clinical studies relevant to the catecholamine hypothesis of affective disorders are limited, however, and it is not possible either to confirm definitively or to reject this hypothesis on the basis of data currently available.l~2~4,16-21 In a previous study of depressed patients, it was found that imipramine (like the monoamine oxidase inhibitors) also decreased the excretion of 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid) (VMA), the major urinary metabolite of norepinephrine.2 Most VMA is believed to derive from norepinephrine which has been synthesized in the nerve cell, and deaminated intracellularly by mitochondrial monoamine oxidase and thereby inactivated without necessarily having exerted a physiological effect.22123 The decrease in VMA excretion during treatment with imipramine, a drug which does not chemically inhibit monoamine oxidase, therefore suggested the possibility that imipramine by a mechanism of action other than chemical inhibition of monoamine oxidase might also decrease the intracellular deamination of norepinephrine and thereby increase the norepinephrine available for use at receptor sites .2 This reasoning led to the prediction that

Effect of lithium salts on electrolyte metabolism

Abstract Lithium carbonate was administered to 18 patients with recurrent affective or schizoaffective disorders and a number of parameters of water and electrolyte metabolism and related adrenal cortical functions were studied longitudinally. Serum K + and Mg ++ levels increased significantly while patients were on lithium but serum Na + and Ca ++ levels did not change. There were transient increases in urinary volume and 24-hr Na + and aldosterone output, but no change in urinary 17-hydroxycorticosteroids. There were also sustained increases in urinary volume and urinary aldosterone output. Eleven of the patients had repeated measurements of 24-hr exchangeable sodium as well as several measurements of extracellular space. There was a significant increase in 24-hr exchangeable sodium mass and space during lithium administration. These changes were much larger in patients whose affective disorders improved while on lithium, whether they were manic or depressed when treatment began. The interrelationship between some of these changes is analyzed and discussed in detail.

Studies on the acetylcholine-stimulated incorporation of radioactive inorganic orthophosphate into the phospholipid of brain particulate preparations. II. Subcellular distribution of enzymic activity.

IT HAD been demonstrated by HOKIN and HOKIN (1958) that acetylcholine stimulates the incorporation of 32Pi into the phosphatidic acid of brain microsome fractions. This observation was confirmed and extended in a previous report from our laboratory (DUKELL and SODD, 1964) in which it was shown that 32Pi was not incorporated into free adenosine triphosphate (ATP) on the pathway of the former’s incorporation into phosphatidic acid. It was concluded that if ATP were an intermediate on the pathway of acetylcholine-stimulated incorporation of 32Pi into phosphatidic acid, it was contained within a compartment and could not pool with the ATP of the medium. The further demonstration that dinittophenol was a potent inhibitor of the labelling of phosphatidic acid suggested the involvement of mitochondria. Therefore, it seemed desirable to re-examine the question of the subcellular localization of the acetylcholinestimulated reaction in an attempt to reconcile the possible participation of mitochondria with the apparent optimal effect in the ‘microsome’ fraction. Differential and density gradient centrifugation were employed to obtain better resolution of subcellular components, and each of the fractions was assayed for activity of the acetylcholine-stimulated incorporation of 32Pi nto phosphatidic acid.

The enzymic hydrolysis of phosphatidyl inositol by guinea pig brain: Sub-cellular distribution and hydrolysis products.

Abstract— 1 Phosphatidylinositol hydrolase activity of homogenates of guinea pig brain was studied by using [2‐3H]inositol labelled substrate and measuring the release of radioactivity into the acid soluble fraction. 2 Inositol phosphate and diglyceride were found to be the main hydrolysis products. The principal enzyme involved, therefore, is a phosphatidylinositol inositolphosphohydrolase. 3 Most of the enzymic activity (61 per cent) was found in the soluble fraction. Osmotic shock of the high speed particulate fraction resulted in release of an additional 23 1 per cent into the soluble fraction. However, as contrasted to lactate dehydrogenase, significant activity remained particulate bound.

Controlled study of effects of plasma of schizophrenic and non-schizophrenic psychiatric patients on chicken erythrocytes

THERE are a large number of reports, dating from about 1890, of the detection of abnormalities in the body fluids of schizophrenic patients by bioassay.r-3 These findings have been based largely on studies on chronic schizophrenic patients and the literature is replete with contradictions and failures at corroboration. Failure to control these studies for factors, such as diet, history of infectious diseases, and altered activity status, as well as the nonspecific nature of most of the assay procedures used, may account for the unreproducible results.2,3 More recently, FROHMAN et aZ.435 have reported a biochemical assay which could detect a difference between the plasma or serum of some schizophrenic patients and that of normal volunteers. When plasmas were incubated with chicken erythrocytes, high terminal ratios of lactate to pyruvate (L/P) were associated with some schizophrenic patients. These findings are of particular interest for a number of reasons. In the first place, the use of a cell suspension rather than an intact animal for the bioassay offers a greater possibility of exploring the mechanism of action of the postulated plasma factor. Secondly, these were among the very few studies which employed controls for a number of adventitious variables. Furthermore, similar results were obtained at two different hospitals, geographically far apart, so that the findings were not limited to one particular patient population.5 Two independent groups were unable to confirm the initial reports of FROHMAN et aZ.e*’ However, because of differences in methodology and the small number of subjects used in one study, these independent studies do not disprove that the plasmas of some schizophrenics have a different effect on chicken erythrocytes than do the plasmas of normal volunteers.* In preliminary studies we found it difficult to reproduce the bioassay results of Frohman and colleagues. It was established, however, that human plasma contains an antibody which produces a complement-linked immune lysis of chicken erythrocytes and an associated stimulation of aerobic glycolysis.**g The extent of the reaction

CONCORDANCE BETWEEN TWO METHODS OF ASSAYING THE PLASMA EFFECTS ON CHICKEN ERYTHROCYTE METABOLISM

IN THE previous communication, studies were reported describing the distribution of a plasma antibody among chronic schizophrenics, normal volunteers, and chronically hospitalized psychiatric patients with diagnoses other than schizophrenia.1 The plasma antibody had been previously shown to stimulate aerobic glycolysis of chicken erythrocytes through a mechanism associated with complement-linked immune lysis.2 By the biochemical assays used, it was not possible to distinguish schizophrenics from the other chronically hospitalized patients studied. The plasmas of normal volunteers tended to have a slightly lesser effect on chicken erythrocytes than did the plasmas of the other two groups. To interpret these findings and relate them to earlier reports of FROHMAN et a1.,3~4 it seemed desirable to compare the results obtained using our bioassay methods with those obtained in simultaneous studies by Frohman and his colleagues at the Lafayette Clinic. Collaborative studies were therefore undertaken with the Lafayette Clinic (L.C.) group. The two groups, using independent methods, tested simultaneously the plasmas of the same subjects to determine whether the rank order of results obtained by the method for estimating the terminal ratio of lactate to pyruvate (L/P) corresponded to the ranked results obtained using our method for measuring net lactate accumulation (AL). These studies were done in two parts. The first was conducted at the Northville State Hospital (Northville, Michigan) and the second at the Rockland State Hospital (Orangeburg, New York). The patients and volunteers used in the first part had been studied previously by FROHMAN and co-workers.374