Lithium and erythrocyte membrane cation carrier studies in normal and manic depressive subjects.

Changes in the erythrocyte membrane cation carrier following lithium ingestion in normal human subjects were studied; ouabain sensitive potassium influx fell significantly during the lithium treated phase. Lithium was fed to rats and no change in erythrocyte Na-K ATPase was shown. These findings contrast with studies of lithium in manic depressive psychosis. The fluctuations in the erythrocyte membrane cation carrier were studied in 5 normal subjects over 12 weeks and the correlations between the parameters calculated. The erythrocyte sodium concentration correlated positively with the ouabain sensitive potassium influx. This too contrasts with findings in manic depressive psychosis.     

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.     

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.     

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)     

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.     

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.     

Lithium-induced inhibition of Na-K ATPase and Ca ATPase activities in rat brain synaptosome.

To explore the action mechanism of lithium in the brain, the author investigated the effects of lithium on Na-K ATPase and Ca ATPase in rat brain synaptosomes prepared from forebrains by the method of Booth and Clark. The activities of Na-K ATPase and Ca ATPase were assayed by the level of inorganic phosphate liberated from the hydrolysis of ATP. Lithium at the optimum therapeutic concentration of 1 mM decreased the activity of Na-K ATPase from the control value of 19.08 +/- 0.29 to 18.27 +/- 0.10 micromoles Pi/mg protein/h and also reduced the activity of Ca ATPase from 6.38 +/- 0.12 to 5.64 +/- 0.12 micromoles Pi/mg protein/h. The decreased activity of Na-K ATPase will decrease the rate of Ca2+ efflux, probably via an Na-Ca exchange mechanism and will increase the rate of Ca2+ entry by the depolarization of nerve terminals. The reduced activity of Ca ATPase will result in the decreased efflux of Ca2+. As a Conclusion, it can be speculated that lithium elevates the intrasynaptosomal Ca2+ concentration via inhibition of the activities of Na-K ATPase and Ca ATPase, and this increased [Ca2+]i will cause the release of neurotransmitters and neurological effects of lithium.     

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.     

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.     

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.     

Neuroendocrine studies in affective disorders. Part 1. Plasma prolactin response to thyrotropin-releasing hormone in affective disorders: effect of ECT

The plasma prolactin response to thyrotropin-releasing hormone, which is thought to be mediated by central 5-HT mechanisms, has been studied in patients with affective disorders. There was no difference between depressive patients (taken as a whole), bipolar patients undergoing a manic phase and controls in the prolactin response to thyrotropin-releasing hormone. When the depressive patients were divided on a genetic basis into familial pure and sporadic depressive disease it was found that the sporadic patients had an enhanced response. The results do not provide any strong evidence to suggest that central 5-HT mechanisms as measured by the prolactin response to thyrotropin-releasing hormone are abnormal in depressed patients or bipolar patients undergoing a manic phase. Patients after ECT had an increased prolactin response to thyrotropin-releasing hormone which may indicate increased sensitivity of central 5-HT receptors following this treatment.     

Plasma and erythrocyte electrolytes in affective disorders

Plasma and erythrocyte sodium (Na+), total and free (ultrafiltrable) plasma magnesium (Mg2+) as well as erythrocyte magnesium were measured in patients with affective disorders and in healthy control subjects. Depressed and manic patients had higher total plasma Mg2+ than did hospitalized healthy control subjects, but concentrations of ultrafiltrable Mg2+ did not differ. Although erythrocyte Mg2+ was significantly elevated in the depressed subjects in comparison with that found in the non-hospitalized healthy controls, this difference was not seen between the depressives and the hospitalized healthy controls. Depressed, manic or healthy control subjects did not differ with respect to either plasma or erythrocyte.     

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.     

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.     

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.     

The Misdiagnosis of Black Patients with Manic Depressive Illness

It has been shown repeatedly that, contrary to earlier beliefs, blacks may well demonstrate similar prevalence rates for manic depressive illness when compared with whites. Yet the authors believe that black manic depressive patients are frequently misdiagnosed as being chronic undifferentiated schizophrenics and treated with major tranquilizers when lithium is the drug of choice. This contention is supported by three case histories and some institutional dynamics that cause this form of iatrogenic morbidity to continue to prey upon black psychiatric patients.     

Plasma vanadium concentration in manic-depressive illness

133 samples of plasma taken from 9 normal control and 8 manic-depressive subjects were analysed for vanadium by atomic absorption spectrometry. Mean plasma vanadium concentrations were 0 . 15 microM in normal control, 0 . 34 microM in manic and 0 . 28 microM in depressed subjects, and 0 . 23 microM in manic-depressive subjects after recovery. The differences between normal subjects and manic and recovered subjects were statistically significant. Significant negative correlations were found between plasma vanadium concentration and the ratio of Na-K-Mg ATPase to Mg-ATPase in 2 manic-depressive subjects, but not in normal subjects. The results suggest that vanadium may be a cause of the variations in Na-K-Mg ATPase and sodium pump activity which are associated with manic-depressive illness.     

Cyclic AMP in cerebrospinal fluid of manic and depressive patients.

Cyclic 3',5'-adenosine monophosphate (c-AMP) was measured in cerebrospinal fluid (CSF) of manic and depressive patients with and without probenecid administration both before and during treatment with various psychotropic drugs. Oral probenecid (100 mg/kg) produced substantial c-AMP accumulations in CSF suggesting a probenecid-sensitive transport mechanism for c-AMP. Baseline and probenecid-induced accumulations of c-AMP were not significantly different in manic and depressed patients, while baseline levels in depressed patients were higher than those in neurological controls. Imipramine, amitriptyline, lithium, tryptophan, and electroconvulsant therapies did not significantly alter levels or accumulations of c-AMP in CSF of depressed patients.     

Predominant polarity in bipolar disorder: diagnostic implications

BACKGROUND: It has been reported that patients with bipolar disorder (BD) remain about 10 years symptomatic before the correct diagnosis is made. This fact is particularly important for patients with predominantly depressed polarity who tend to be diagnosed as suffering from unipolar major depressive disorder and treated with antidepressants. The present study was carried out to assess clinical differences between predominantly manic and depressed BD patients with a special focus on the time that patients remained undiagnosed. METHODS: Clinical and socio-demographic characteristics were obtained from a sample of 149 euthymic bipolar outpatients. Patients were divided into depressive or manic predominance of polarity. Clinical features, number of years undiagnosed (NYU) and occupational functioning were assessed in the two groups. RESULTS: Forty-five patients were classified as a "Depressive Polarity" whilst forty-seven were considered as "Manic Polarity". Depressive Polarity was associated with a longer delay to be diagnosed (F=14.43, df=89, p=0.001). The predominantly depressive patients tended to present a depressive onset of illness, earlier age of onset, longer duration of illness and higher number of suicide attempts than manic polarity patients. CONCLUSION: There was a marked clinical difference between predominantly manic and depressive bipolar patients. Predominantly depressive polarity is associated with a longer delay in receiving a correct diagnosis and effective treatment which has an important impact on the management of the illness.     

Course of bipolar disorder in eastern India.

The life course of affective episodes was determined for 95 consecutively admitted patients from eastern India fulfilling RDC criteria for definite mania during the current episode, using SADS-L interviews. There was a significantly greater frequency of manic compared to depressive relapses. Presentation as recurrent mania was very common. The total numbers of affective and manic episodes were significantly higher among those with recurrent mania and in cases where the first illness episode was manic.