Erythrocyte membrane cation carrier, relapse rate of manic-depressive illness and response to lithium.

Biochemical studies of manic-depressive psychosis usually correlates biochemical findings with current affective state and hence any significant findings could be secondary to mood change. The present study attempts to correlate measures of the erythrocyte membrane cation carrier with clinical events, remote in time from the biochemical assay. Eprythrocyte sodium concentration, ouabain-sensitive potassium influx and Na-K ATPase were estimated in 11 patients before and after the cross-over point in a 2-year double blind clinical trial ratio tended to suffer most episodes of affective illness in the 2 years. Patients who had a low initial Na-K ATPase or a high initial flux sodium ATPase ratio, or in whom this ratio fell most with lithium or whose Na-K ATPase rose most with lithium, clinically responded best to lithium.     

Altered in vitro adaptive responses of lymphocyte Na+,K(+)-ATPase in patients with manic depressive psychosis.

When lymphocytes from healthy subjects are incubated in lithium (8 mM) or ethacrynate (1 microM) they show a time-dependent adaptive response, which consists of a significant increase in the number of Na+,K(+)-ATPase molecules in the lymphocyte membrane. We have studied the lymphocytes from nine euthymic drug-free patients with a history of manic depressive psychosis, and have found that this normal adaptive response was absent. It was also absent from the lymphocytes of euthymic patients taking lithium. We conclude that this altered in vitro adaptive response of lymphocyte Na+,K(+)-ATPase represents an enduring trait marker in manic depressive psychosis.     

Prediction of clinical course of bipolar manic depressive illness treated with lithium

A group of bipolar manic depressive patients attending a routine lithium clinic were investigated. The results suggest that, when on treatment with lithium, manic depressive patients with a good prognosis tend to have a higher erythrocyte Na-K ATPase and higher plasma and erythrocyte lithium concentrations than those with a poor prognosis. There was no evidence to suggest that the erythrocyte: plasma lithium ratio was useful in predicting clinical response to lithium therapy. There was also a positive correlation between plasma lithium concentration and Na-K ATPase activity, confirming that in manic depressive subjects lithium produces a rise in erythrocyte Na-K ATPase activity.     

Further evidence for a potassium-like action of lithium ions on sodium efflux in frog skeletal muscle

1. The efflux of labelled sodium as well as net sodium and lithium changes were studied in aged high sodium sartorius muscles of the South American frog Leptodactilus ocelatus.2. In the presence of 2.5 mM potassium in the media, the replacement of external sodium with lithium or magnesium resulted in an increase in sodium efflux. The magnitude of such increase was always larger in lithium.3. With the absence of potassium in the media, the response of sodium efflux to replacement of external sodium varied with the cation used as a substitute. In lithium Ringer there was always a noticeable increase, whereas in magnesium there was always a marked reduction. The same results were observed when calcium was substituted for magnesium.4. The replacement of 60 mM external sodium with sucrose did not prevent the stimulating effect of 5 mM potassium on sodium efflux, nor the inhibitory action of 10(-4)M ouabain. This indicates that neither sucrose by itself, nor the lowering of the ionic strength, modified to an appreciable extent the function of the sodium pump.5. Net sodium extrusion took place against an electrochemical gradient in potassium-free - 50 mM sodium - mM lithium Ringer. About 75% of this efflux was ouabain sensitive.6. Muscles made both sodium and lithium rich and incubated in potassium-free - 60 mM sodium - 50 mM lithium Ringer also showed net sodium extrusion against an electrochemical gradient, which was 85% ouabain sensitive. This extrusion took place even under conditions where the changes in free energy favouring lithium entry were always lower than the changes in free energy opposing sodium going out. This indicates that a sodium-lithium exchange by a counter-transport process is unlikely.7. External potassium reduced the ouabain sensitive lithium influx in muscles incubated in lithium Ringer. The values found were 5.90 +/- 0.39 mu-mole/g.hr and 2.66 +/- 0.43 mumole/g.hr in potassium-free and 15 mM potassium respectively. At the same time potassium had no effect on the ouabain-insensitive lithium uptake.8. Muscles incubated in potassium-free-magnesium Ringer had a residual sodium efflux which could not be accounted for by passive movement. About 40% of it was abolished by 10(-4)M ouabain. This ouabain-sensitive part could be a consequence of some stimulation of the sodium pump by potassium leaking out of the cells. If this is correct it should be inhibited by external sodium and should not contribute to the total sodium efflux in potassium-free sodium media.9. Magnesium was used as the reference cation to study the sodium-stimulated sodium efflux under potassium-free conditions. The total sodium efflux amounted to 0.668 hr(-1) (rate constant) and was 71% ouabain sensitive.10. The present experiments demonstrated that lithium ions have a direct stimulating effect on sodium efflux in high sodium skeletal muscle, and strongly support the notion that this effect is produced by an activation of the sodium pump through a potassium-like action.     

Determination of the erythrocytoplasma lithium ratio. Analytical considerations and clinical applications (author's transl)]

During eleven months the authors studied the erythrocytoplasma lithium ration in 46 patients on chronic lithium maintenance. They observed that the individual variations of this ratio are of the same magnitude in "cycloid psychosis" and in chronic schizophrenia. But, furthermore these variations are significantly more important than in neurosis. They report that this ratio increases significantly in manic depressive illness during the active manic or depressive phases, and they compare their results to those of the literature.     

Osmotic behavior of erythrocytes from patients with a major affective disorder. A freeze-fracture electron microscopic study

Previously we have demonstrated a state-dependent decrease in the number of membrane vesicles in erythrocytes from patients with a major depressive episode. We now report an increase in the number of membrane vesicles during a manic episode as well as a reduction during lithium treatment and we also present data suggesting that the number of erythrocyte membrane vesicles in the affective disorders is dependent on osmotic shrinkage due to the freezing for freeze-etch electron microscopy. Although caution is required since the interrater reliability of the measurement of osmotic strain was insufficient in the mid range where it was tested, we do not think this invalidates the differences in osmotic strain found in the low and high ranges during depressive and manic episodes respectively. These findings warrant the use of more precise techniques in studies of the osmotic behavior of erythrocytes from patients with a major affective disorder.     

Vanadium: a possible aetiological factor in manic depressive illness

The effect of Vitamin C in manic-depressive psychosis was assessed by a double-blind, placebo controlled, crossover trial. Both manic and depressed patients were significantly better following a single 3 g dose of Vitamin C than following a placebo. Preliminary results of a double-blind, crossover comparison of normal vanadium intake with reduced intake in manic and depressed subjects are reported. Both manic and depressed patients were significantly better on reduced intake. These results are in keeping with the suggestion that vanadium may be an aetiological factor in manic depressive illness.     

The influence of chloride on the ouabain-sensitive membrane potential and conductance of crayfish giant axons

1. Resting potential and current-voltage relation were measured in crayfish giant axons bathed in chloride-free and sodium-free solutions with and without ouabain. 2. Chloride-free solution caused a transient depolarization but did not alter the steady-state membrane potential. Utilizing isethionate as an anion substitute, the membrane resistance increased 12.5%. 3. In the absence of extracellular chloride, ouabain (0.5-1 mM) depolarized the axon 6-7 mV. The shape of the current-voltage relation did not change but the curve was shifted along the current axis. 4. These results indicate that ouabain inhibits a steady-state hyperpolarizing electrogenic pump current of approximately 3 muA/cm2. 5. Extracellular sodium removal from axons equilibrated in chloride-free solutions transiently hyperpolarized the membrane 6-7 mV without a change in membrane resistance. The transient hyperpolarization was ouabain and temperature sensitive. The steady-state potential reached in sodium-free and chloride-free solution was not ouabain sensitive. Temperature sensitivity of the steady-state membrane potential was greatly reduced. 6. The transient hyperpolarization produced by extracellular sodium removal was metabolically driven and may present the expression of a sodium efflux transport current of 7.0-7.5 muA/cm2. 7. Using electrophysiologically measured parameters, sodium and potassium conductance, influx and efflux currents and the coupling ratio for sodium/potassium transport are calculated from a modification of the conductance equation. 8. The sodium/potassium transport coupling ratio for steady-state conditions was estimated at 5:3 (1.67:1).     

Increase in plasma potassium concentration following indomethacin administration: absence of a role for membrane Na−K ATPase

To elucidate whether indomethacin-induced hyperkalaemia is due to an inhibition of Na–K ATPase in the membranes, indomethacin (25 mg t.d.s.) was administered to 7 normal subjects for 7 days. This resulted in an increase in plasma potassium concentrations in all 7 subjects: median (range) for the entire group increased from 4.19 (3.98–4.79) mmol/l to 4.29 (4.13–4.87) mmol/l. Leucocytes preparred from these subjects prior to and after indomethacin were tested for⁸⁶Rb influx and [³H]-ouabain binding (an index of Na–K ATPase sites). Neither⁸⁶Rb influx (total, ouabain sensitive and ouabain insensitive) nor [³H]-ouabain binding changed significantly following indomethacin. We conclude that (a) indomethacin-induced hyperkalaemia is not due to alterations in potassium influx into cells and (b) the modulation of Na–K ATPase sites/activity is in leucocytes not dependent upon prostaglandins.     

Lithium ratio and maintenance treatment response

Erythrocyte/plasma lithium ratios were determined in 41 polar manic depressive outpatients maintained on lithium for a mean of 64 months. Sixteen patients experienced affective episodes requiring additional pharmacologic intervention during periods when their plasma lithium averaged 0.7 meq/l or above for at least 3 preceding months and they were on no concurrent medication known to induce depression or mania. These patients considered to be a homogeneous group of non-responders to lithium, had a mean lithium ratio of 0.50 (range 0.15-1.16). Seven patients experienced affective symptoms at plasma levels below 0.7 meq/1 and/or while taking concurrent medication known to induce affective symptoms, and therefore could not be categorized clinically as lithium non-responders or responders. Eighteen remaining patients, who had no affective episodes during lithium maintenance, were found to have a mean erythrocyte/plasma ratio of 0.52 (range 0.19-1.05). This latter group of apparent responders should be considered heterogeneous in that it may include spontaneous remitters. The difference in mean ratios between the non-responder group and the apparent responder group was not statistically significant. These findings support the contention that the erythrocyte/plasma lithium ratio does not correlate with response of bipolar outpatients to maintenance lithium.     

Peripheral effects of thyroid hormones: Alteration of intracellular Na-concentration,ouabain-sensitive Na-transport,and Na-Li countertransport in human red blood cells

Summary To investigate the effect of thyroid hormones on erythrocyte cation transport systems and intracellular electrolyte content we have measured the activity of Na-K ATPase, Na-Li countertransport, as well as red cell sodium and potassium contents in patients with hyperthyroidism and in euthyroid controls. Intracellular Na- and K-concentrations were determined in erythrocytes washed three times in isotonic MgCl₂ solution. Ouabain-sensitive Na-transport was estimated as the increase of Na before and after addition of ouabain in an erythrocyte suspension in isotonic Na-free medium. Na-Li countertransport was measured according to the method described by Canessa et al. [2]. The patients with hyperthyroidism exhibited a significantly elevated intracellular sodium content as well as a highly increased Na-K ATPase activity. Intracellular potassium content was not altered in the hyperthyroid subjects, but Na-Li countertransport was markedly decreased as compared to the controls.The results indicate that different ion transport systems of the erythrocyte membrane are influenced by thyroid hormones. We suggest that the elevation of Na-K ATPase activity might be due to the increased intracellular sodium concentration which is caused by the diminished countertransport pathway. Furthermore, the activity of Na-K ATPase, Na-Li countertransport, and intracellular sodium content in erythrocytes might be a useful peripheral indicator of thyroid hormone excess.Supported by the Bundesministerium für Forschung und Technologie (MMT 27)     

The significance of psychotic features in manic episodes: a report from the NIMH collaborative study

BACKGROUND: Psychotic features in the context of major depressive syndromes have correlates in symptom severity, acute treatment response and long-term prognosis. Little is known as to whether psychotic features have similar importance when they occur within manic syndromes. METHODS: These data derive from a multi-center, long-term follow-up of patients with major affective disorder. Raters conducted follow-up interviews at 6-month intervals for the first 5 years and annually thereafter. A sub-set of probands participated in a family study in which all available, adult, first-degree relatives were interviewed as well. RESULTS: Of 139 who entered the study in an episode of mania, 90 patients had psychotic features. Symptom severity ratings at intake were more severe for this group. Though time to first recovery and time to first relapse did not distinguish the groups, psychotic features were associated with a greater number of weeks ill during follow-up and the strength of this association was similar to that seen for psychotic features within depressed patients described in an earlier publication. Patients with psychotic mania at intake did not differ significantly from those with nonpsychotic mania by response to acute lithium treatment, suicidal behavior during follow-up, or risks for affective disorder among first-degree relatives. Psychotic features within manic syndromes were not associated with high psychosis ratings during follow-up. In contrast, when psychotic features accompanied depressive syndromes, they strongly predicted the number of weeks with psychosis during follow-up, particularly among individuals whose episodes at intake were less acute. CONCLUSIONS: As with major depressive syndromes, psychotic features in mania are associated with greater symptom severity and higher morbidity in the long-term. Psychotic features are much less predictive of future psychosis when they occur within a manic syndrome than when they occur within a depressive syndrome.     

Treatment of mixed mania

Mixed mania (i.e., a manic syndrome accompanied by depressive symptoms) and its response to long-term preventive drug treatment was studied as part of a larger NIMH collaborative study. Following recovery from a manic episode, patients received either lithium, imipramine, or the combination of lithium and imipramine for a 2-year period. It was found that patients who had recovered from a mixed manic state were at significantly higher risk for recurrences than patients who had recovered from a pure (non-mixed) manic state. Lithium and the combination of lithium and imipramine were highly effective preventive treatments for the pure manic group and poor treatments for the mixed group. Imipramine was ineffective for both the pure and mixed groups. The need for identifying mixed mania in therapeutic trials and in evaluating alternative treatments for lithium with this subgroup is discussed.     

Erythrocyte membrane cation carrier in mania.

Erythrocyte sodium and potassium concentrations, erythrocyte membrane ATPase (Na-K specific and non-specific) and the rate of potassium influx into erythrocytes (ouabain-sensitive and insensitive) were estimated in a group of female patients suffering from mania and repeated on about two thirds of them when they had recovered. With recovery there was a statistically significant increase in the erythrocyte ouabain-sensitive potassium influx. The other parameters showed no significant overall change with recovery but the initial severity correlated significantly and negatively with the change in erythrocyte Na-K ATPase with recovery. The changes that occurred in the erythorcyte sodium concentration and Na-K ATPase activity were not random since they correlated significantly with changes in the active potassium influx.     

Sibling pairs with affective disorders: resemblance of demographic and clinical features

BACKGROUND: As part of a collaborative linkage study, the authors obtained clinical and demographic data on 160 families in which more than one sibling was affected with a bipolar illness. The aim of the study was to identify clinical characteristics that had a high degree of familiality. METHOD: Data on age at onset, gender, frequency of illness-episodes and proportion of manic to depressive episodes were examined to determine intra-pair correlations in affected sibling pairs. Dimension scales were developed measuring frequency and severity of lifetime mania, depression, psychosis and mood-incongruence of psychotic symptoms; degree of familial aggregation for scores on these dimensions was calculated. RESULTS: Sibling pairs correlated significantly for age at onset (p = 0.293, P < 0 001); dimension scores for psychosis (p = 0.332, P < 0.001); and proportion of manic to depressive episodes (p = 0.184, P = 0.002). These findings remained significant when correcting for multiple testing. Of the other test variables; mania (p = 0.171, P = 0.019); incongruence dimensions (p = 0.242, P = 0.042); .frequency of manic episodes (p = 0.152, P = 0.033); and frequency of depressive episodes (p = 0.155, P = 0.028) were associated with modest correlations but these were not significant after correction. Degree of familial aggregation was not significant for sex (kappa = 0.084) or dimension scores for depression (p = 0.078, P = 0.300). CONCLUSIONS: Significant but modest familial resemblance has been shown for some specific features of bipolar illness, particularly age at onset and degree of psychosis. Further research may establish the extent to which these findings are mediated by genetic and/or environmental factors.     

The components of the sodium efflux in frog muscle

1. In normal Ringer solution containing 2.5 mM-K only 37% of the efflux of labelled sodium from a freshly dissected frog muscle is blocked by treatment with ouabain; in sodium-loaded muscles the ouabain-sensitive fraction of the efflux increases to 75%.2. Under all conditions, the ouabain-insensitive component of the sodium efflux is markedly reduced if the sodium in the external medium is replaced by lithium; at least in sodium-loaded muscles, the ouabain-sensitive component is increased in lithium Ringer.3. Only the ouabain-sensitive component of the efflux is affected by the external potassium concentration.4. In the presence of 2.5 mM-K the sodium influx in a freshly dissected muscle is not significantly altered by ouabain, but in a K-free medium the influx and the efflux are both reduced by nearly 20%.5. The sodium efflux can therefore be regarded as consisting of (1) a sodium-potassium coupled component that is blocked by ouabain and involves a sodium-sodium exchange in the absence of external potassium, and (2) a potassium-insensitive component that is unaffected by ouabain and tends to reach saturation at relatively lower internal sodium concentrations.6. The evidence is considered for attributing component (1) to an efflux of sodium from the sarcoplasm proper, and component (2) to an efflux from the sarcoplasmic reticulum. Although such an interpretation is consistent with many of the observations, a definite identification of the possible sodium compartments in frog muscle cannot yet be made.     

Reversal of vanadate-induced inhibition of Na-K ATPase. A possible explanation of the therapeutic effect of carbamazepine in affective illness

There is evidence that carbamazepine is of therapeutic benefit in manic depressive illness. There is also evidence that raised vanadium levels may be of aetiological importance in manic depressive illness. The present study examined the effect, in vitro, of therapeutic concentrations of carbamazepine on the inhibition by ammonium metavanadate of the Na-K ATPase of erythrocytes from normal and from manic depressive subjects. The inhibition by vanadate was largely reversed by carbamazepine. This effect may be related to the therapeutic action of carbamazepine in manic depressive illness.     

Effect of lithium carbonate therapy on thyroid immune status in manic depressive patients: a prospective study

Serum thyroid autoantibodies to thyroglobulin (TG) and thyroid microsomes (M) were measured by ELISA prospectively in 37 manic depressive patients prior to receiving lithium carbonate and during therapy with this drug for a mean of 16.2 months. They were also measured once in 27 normal subjects and several times in five psychiatric patients not receiving lithium. Sixteen patients (43%) had either thyroglobulin, microsomal antibodies or both before receiving lithium therapy. During therapy significant fluctuations in antibody titre, both upwards and downwards were observed in ten out of 12 patients with M antibodies and in nine out of 11 with TG antibodies. The fluctuations in antibody titre are consistent with an immunomodulatory effect of lithium as has been shown in animal studies. It is suggested that psychiatric patients should have thyroid antibodies measured routinely before and during lithium therapy.     

Misdiagnosis of Black Patients with Manic Depressive Illness: Second in a Series

In a previous article (J Natl Med Assoc 72(2): 141, 1980), the authors proposed that, despite several attempts to lay to rest the myth that blacks do not demonstrate similar prevalence rates of manic depressive illness when compared to whites, many black patients with manic depressive illness are frequently misdiagnosed. In a survey of the outpatient psychiatric clinic at Jackson Park Hospital, it was found that black patients in this clinic have similar prevalence rates of manic depressive illness when compared to surveys of white patient populations. In addition, it was found that the demographic characteristics of this subgroup of manic depressive patients were very similar to those found in white manic depressive patients. Yet, when the past histories of these black manic depressive patients were reviewed, there were large numbers of patients who received a diagnosis of schizophrenia and, thus, were not considered for treatment with lithium.     

Effect of lithium and sodium valproate ions on resting membrane potentials in neurons: an hypothesis.

In an attempt to understand the therapeutic effects of lithium and sodium valproate in stabilizing the moods in manic depressive illness, the well-known Goldman-Hodgkin-Katz (G-H-K) equation is modified to include a fourth ion, such as a lithium ion or a sodium ion. The modified G-H-K equation is used to calculate the resting membrane potential in neurons. These calculations show that the resting membrane potential is depolarized depending upon the relative concentration of the lithium ion and upon its relative permeability. These calculations suggest that the resting membrane potential may be hyperpolarized in bipolar patients before treatment, and that the lithium ion perhaps depolarizes the resting membrane potential back to the normal level. They further support the prevailing hypothesis that manic-depressive illness may be caused by the hyperpolarization of the resting membrane potential, which, in turn, may be caused by the changes in ionic conductance (permeability) of the membranes. Sodium ions in sodium valproate do not significantly affect the resting membrane potential since they do not significantly change in the serum.