Herbert L. Meltzer

Repression of a lithium pump as a consequence of lithium ingestion by manic-depressive subjects.

The lithium pump in human erythrocyte membranes, which is responsible for extrusion of lithium against a concentration gradient, has been found to be reversibly repressed during periods of lithium carbonate administration. The pump activity of patients prior to lithium therapy is not different from controls. The onset of repression may require several days to several weeks and occurs at specific individual threshold levels of lithium carbonate dosage. Reactivation of the lithium pump occurs sometime after the dosage is discontinued. We postulate that repression of the lithium pump results from systemically available factors which alter membrane structure, and suggest that if such changes also occur in the central nervous system, they may provide insight into one means by which lithium produces its psychotropic affects.

Abnormal calmodulin-activated CaATPase in manic-depressive subjects

CaATPase of human erythrocyte membranes exists in both a basal and a calmodulin-activated form, each of which can be further activated by monovalent ions such as sodium, potassium or lithium. We have measured the extent of such activation in erythrocyte membranes obtained from 14 manic-depressive outpatients under treatment with lithium carbonate, nine such patients not treated with lithium carbonate, and eight normal controls. The principal findings were as follows: (1) when further activation of the calmodulin-dependent enzyme was measured in the presence of a sub-optimal concentration of lithium ions, greater activation was observed for all manic-depressive subjects, whether or not treated with lithium carbonate, than for controls. We interpret this observation to mean that a biochemical abnormality exists in this patient population with respect to controls; (2) when activation was measured in the presence of optimal concentrations of sodium and potassium ions, the control and the untreated patient groups each showed lesser activity than the lithium carbonate treated groups, indicating that this treatment sensitized the membrane enzyme to monovalent cations. Overall, both of these results indicate that calmodulin-activated CaATPase is abnormal in manic-depressive patients.

Rubidium chloride ingestion by volunteer subjects: initial experience.

The authors report on the first metabolically controlled study of rubidium chloride administered to humans. Four subjects were given doses of 8.2–12.4 meq. RbCl in a single day, and biological half lives calculated from urinary excretion ranged from 21–55 days. A long term study of chronic rubidium loading in one of these subjects demonstrated no undesirable clinical side effects. After ingestion of a total dose of 268 meq. within a period of 75 days a plasma level of 0.16 meq./liter rubidium was obtained. Urinary excretion proceeded at a rate consistent with a 50 day half life.The authors speculate on the potential usefulness of RbCl for modification of behavior and affect.

Calmodulin-Activated Calcium ATPase in Bipolar Illness

Calmodulin-activated calcium ATPase is a transport enzyme which establishes the normal level of intracellular ionized calcium in most cells. We have determined values for three parameters of this enzyme: E-t, the concentration in the membrane; Vmax, the maximal velocity, and Ka, the binding affinity for calmodulin. We assayed these parameters in erythrocyte membranes from lithium carbonate-treated bipolar subjects and from normal controls. Bipolar subjects have significantly increased levels of E-t compared with normal controls.

Lithium elimination half‐life and duration of therapy

The elimination half‐life (t½E) of lithium carbonate in red blood cells, plasma, and urine was measured in 30 patients hospitalized for primary affective disorder. Duration of Li treatment at time of sampling was found to have a direct effect on lengthening time course. Patients on their initial course of Li had the lowest t½s: 1.12 (urine), 1.28 (plasma), and 1.22 days (red blood cells); those less than 1 yr on Li had intermediate values: 1.85, 1.65, and 1.75 days; and those more than 1 continous year on Li had the longest mean t½s: 2.40, 2.43, and 2.24 days. These results for urine (p < 0.01) and plasma (p < 0.05) are further evidence that Li may stimulate the production of an endogenous regulator of Li efflux. This regulator may prove to be an important factor in planning of long‐term Li prophylaxis.

Active efflux of lithium from erythrocytes of manic-depressive subjects

Abstract Lithium transport kinetics, studied under physiological conditions in erythrocytes obtained from manic-depressive patients, are characterized by asymmetric rate constants of efflux and influx. The efflux constants, which are more than twice as large as the influx constants, correlate well with the in vivo distribution of lithium between erythrocytes and plasma. The efflux process, which is not inhibited by ouabain and is therefore distinct from the sodium-potassium pump, is characterized by Michaelis - Menten kinetics and a large energy of activation. There appears to be a normal endogenous inhibitor which regulates the activity of the postulated lithium pump.

The behavioral effects of nicotinamide adenine dinucleotide in chronic schizophrenia

SummaryTwo grams of NAD were administered orally to ten chronic schizophrenic patients for twenty-one days. Five of the patients were also receiving thioridazine. There was no gross clinical improvement noted in any of the patients despite the fact that related experiments suggested that the NAD was absorbed. In those patients who were not also receiving phenothiazines there was a distinct tendency towards increased hostility, aggressiveness and irritability beginning one week after the initiation of NAD treatment and lasting for nearly two weeks after the NAD was discontinued.

Inhibition of calmodulin-activated Ca2+-ATPase by propranolol and nadolol

Propranolol, at concentrations ranging from 0.05 to 0.5 mM, inhibits the calmodulin-activated Ca2+-ATPase of human erythrocyte membranes. In the same concentration range it is without effect on the basal Ca2+-ATPase. The inhibition is competitive and appears to be due to membrane binding, rather than to combination with cytoplasmic calmodulin as is the case for phenothiazines. This effect of propranolol may explain its ability to open the calcium-gated potassium channel, and could also be related to its action as a beta-adrenergic blocker. Nadolol, another beta-adrenergic blocker, is also an inhibitor of calmodulin-activated Ca2+-ATPase.

Repression and reactivation of lithium efflux from erythrocytes

Efflux of lithium from human erythrocytes was studied in patients before, during, and after discontinuation of administration of lithium carbonate. Onset of lithium-induced repression of efflux took approximately 10 days and was significantly shorter in patients who had had lithium therapy previously. Reactivation took a longer period of time--approximately 2 week--and was found to be related to duration of lithium therapy. Theoretical pathways of lithium flow through membranes are discussed.

Enhanced activation of human erythrocyte Ca2+-ATPase by calmodulin after storage or brief exposure to disulfite

Ca2+-ATPase of human erythrocyte membranes which are prepared from freshly drawn human blood can be activated by the calmodulin present in the hemolysate to 1.5-times the basal level. However, when the membranes are prepared from blood stored for 5-14 days the activation by calmodulin reaches 2.5-times the basal level. An enhanced reactivity to calmodulin of similar magnitude was produced by brief exposure of fresh erythrocytes to 25 mM Na2S2O5 prior to isolation of the membranes. Reincubation of the activated cells in a disulfite-free medium restored the membrane-bound Ca2+-ATPase to a state of normal reactivity to calmodulin. It is hypothesized that these results are related to the level of cytoplasmic Ca2+ which is partly controlled by complex formation with 2,3-diphosphoglycerate, the concentration of which is diminished when its specific phosphatase is activated by Na2S2O5.