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The effect of lithium (Li) and carbamazepine (CBZ) on erythrocyte lithium transport in vivo was investigated in 28 patients with affective or schizoaffective illness (14 given Li and 14 given CBZ). In 12 of them, Li or CBZ were added to current psychotropic treatment. The activities of erythrocyte lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC) and passive lithium diffusion (PLD) were assayed before and after 28 days of treatment. The administration of Li caused a significant decrease of LPC as well as PLD activity. The administration of CBZ resulted in a significant increase of the activity of LPC system. No systematic relationship was observed between Li or CBZ-induced alterations in erythrocyte transport and changes in clinical state of patients. The possible clinical implications of the dissimilar effect of Li and CBZ on erythrocyte lithium transport are discussed.

Erythrocyte cation fluxes were measured in 30 patients with endogenous depression, before and after 14 days of treatment with antidepressant drugs, imipramine or nomifensine. Assays were made of active (ouabain-sensitive) transport of sodium and potassium as well as of lithium-sodium countertransport, reflecting sodium exchange diffusion. All the parameters studied increased significantly on 14th day of the thymoleptic treatment. The mean increase in activity of cation fluxes was similar in patients receiving imipramine or nomifensine. Patients with good clinical response to the treatment (as rated by the reduction of the initial intensity of depression on the Hamilton Scale on 21st day of therapy) had greater increase in ouabain-sensitive sodium flux than "non-responders". A possible role of cation transport processes in the mechanism of action of antidepressant drugs is discussed.

Specific activities of erythrocyte membrane Na-K ATP-ase, Mg ATP-ase and Ca-Mg ATP-ase were measured in twenty-five patients with endogenous depression both during acute phase of the illness and in remission as well as in sixteen healthy subjects. The three ATP-ase activities were significantly lower during depressive phase than in remission period. The ATP-ase values of depressive patients in remission did not differ from those of healthy controls. No difference was found in respect to parameters studied between the group of patients with depression in the course of bipolar manic-depressive psychosis and patients with unipolar depression both in depression and remission. These data may suggest that the reduced activity of ATPases in depressed patients is not due to a primary genetic defect but is an episodic change associated with depression. In view of consistency of this phenomenon its diagnostic and research potential is worthy of further study.

Ouabain-sensitive cation fluxes in red blood cells were measured in 23 patients with endogenous depressive syndromes during acute phase of the illness and during remission period as well as in 17 healthy subjects. The intensities of both sodium and potassium net fluxes during depressive phase were significantly lower than during remission both in patients with depression in the course of manic-depressive psychosis and in patients with unipolar depression. They were also lower than the intensities of fluxes found in control subjects. The values of female patients in remission did not differ from those of control females, while male patients had higher values in remission than control males. It is hypothesized that impaired activity of cation transport may be related to somatic and psychopathologic symptoms of depression and its stimulation may play a role in the mechanism of action of antidepressant drugs.

When lithium carbonate is administered to individuals, there is considerable intersubject variation in the extent of accumulation of Li+ by erythrocytes. The primary reason for this is differences in the activity of a Li+-Na+ counterflow system, which, under clinical conditions, removes Li+ from the cell. It appears that some bipolar patients accumulate more Li+ in their red cells than either unipolar depressives or normal controls. The precise clinical characteristics of the bipolar patients who accumulate relatively large amounts of erythrocyte Li+ need to be clarified in future research. Finally, the measurement of red cell concentrations of Li+, in addition to the usual plasma measurement, can be used as an indicator of patient compliance.

The movement of the lithium ion (Li+) across the membrane of intact erythrocytes incubated in vitro was assessed under two different experimental conditions in which such transfer occurred primarily due to the activity of a lithium-sodium countertransport system. The 13 subjects on whom the in vitro procedures were done subsequently received lithium carbonate for 14 to 56 days, and the extent of accumulation of Li+ by erythrocytes in vivo was measured. While both in vitro procedures yielded data that correlated with the extent of accumulation of Li+ by erythrocytes in vivo, a system measuring the efflux of Li+ from Li+-loaded cells produced a much higher correlation (0.976). The magnitude of this correlation suggests that this in vitro system can be used for further investigations into the relevance of the erythrocyte accumulation of Li+ to the pathogenesis and treatment of affective disorders.

The effect of lithium administration on cation transport processes in erythrocytes was investigated in 26 patients with affective illnesses. The measures of ouabain-dependent sodium and potassium transport, Na+K+ATP-ase activity and lithium-sodium countertransport in erythrocytes were taken before and after 14 days of lithium therapy. In eleven patients an additional assay was made, following 3-12 months of continuous lithium administration. A significant increase in sodium and potassium transport as well as Na+K+ATP-ase activity was found after 14 days of lithium therapy, while the intensity of lithium-sodium countertransport markedly decreased. Maintenance treatment with lithium tended to stabilize these changes on the altered level. A role of cation transport in the mechanism of lithium action is discussed. It is suggested that an increment of erythrocyte active cation transport may accompany the normothymic effect of lithium.

Clinical and biochemical factors related to the activity of the erythrocyte lithium-sodium countertransport (LSC) system were investigated during lithium prophylaxis in 27 patients (13 male, 14 female) with bipolar affective illness. No relationship was found between erythrocyte LSC and such factors as age, gender, duration of lithium prophylaxis, quality of prophylactic lithium response, and family history of affective illness. There was a significant negative correlation between the activity of LSC and the magnitude of the erythrocyte lithium ratio both in whole group and in female patients. In seven patients with concomitant hypertension, the relationship between high activity of LSC and hypertension was not demonstrated. The levels of total cholesterol, HDL cholesterol, triglycerides, and potassium related neither to LSC activity nor to hypertension. Erythrocyte LSC in patients with lower TSH levels were significantly reduced compared to patients with higher TSH. The values of TSH were negatively correlated with T4 but not with T3. Concentrations of T3 were positively correlated with plasma total cholesterol levels. These results are discussed in the view of recent findings on erythrocyte LSC.

Water and electrolyte contents in plasma and red blood cells (RBC) were studied in 46 patients with depressive syndromes of various etiology (bipolar, unipolar, psychogenic) before and after 14 days of imipramine treatment. Initial low RBC sodium levels were characteristic of patients with bipolar depression. A significant increase in RBC sodium was observed after imipramine treatment in a group of good imipramine responders. RBC sodium changes in psychogenic patients after imipramine were different from those observed in endogenous (bipolar plus unipolar) ones. A fall in plasma calcium levels was shown in the course of imipramine administration mostly in patients with favourable response to the drug.

Clinical (psychometric), psychophysiological and biochemical (erythrocyte membrane transport) variables were studied in 44 patients with endogenous depression (unipolar/bipolar) during acute depressive episode and in remission. All parameters studied showed paralleled and unidirectional changes when depression was compared with remission period. During a depressive episode, unipolar patients had greater intensity of depression than bipolar patients. Ouabain-dependent sodium fluxes were significantly lower in female than in male patients during depression than in remission. In male bipolar patients, the indexes of active transport in erythrocytes showed significant correlations with clinical ratings and with results of psychophysiological tests. The results point to a possible relationship between various levels of physiological functioning in endogenous depression. This suggests a generalised "background" defect of energy-dependent membrane transport pertaining to both erythrocytes and nerve cells, which may be linked to disturbances of activational processes within the central nervous system.

Previous investigations have elucidated an erythrocyte lithium-sodium countertransport (LSC) system as the primary mechanism for extruding lithium from the cell, and this activity has been described in terms of Michaelis-Menten kinetics. In most clinical studies the maximum velocity (Vmax) of the LSC has been measured by estimating the rate of lithium efflux from lithium-loaded cells. To date, few studies have examined whether the affinity (Km) of the LSC for lithium might be altered in patients with affective disorders. In the present study we examined LSC kinetic parameters (Vmax, leak, Km, and in vitro lithium ratio) at baseline in 80 patients with affective disorder and 25 healthy control subjects, and after 6 weeks of lithium administration in 33 of the patients. No differences in Vmax were observed between any patient and control group, although Vmax was significantly lower in unipolar depressed men compared to bipolar men (P = 0.043). The affinity (Km) of the transport 'carrier' for lithium did not differentiate between patient and control groups. Chronic lithium administration caused a decreased Vmax in bipolar men (P = 0.015), an increase in the in vitro lithium ratio in bipolar men (P = 0.002) and bipolar women (P = 0.002), and a marginal increase in Km in bipolar men (P = 0.08) and bipolar women (P = 0.06). Although the present data do not demonstrate an underlying difference for Km between affectively ill patients and controls, they do indicate a decrease in the affinity of the transport 'carrier' for lithium after chronic lithium administration.

The active cation transport mechanisms (ouabain-dependent fluxes of sodium; ODS) and potassium (ODK), sodium-potassium adenosine triphosphatase ([Na+-K+]-ATPase) activity as well as lithium-sodium countertransport (LSC) reflecting sodium exchange diffusion, were studied in erythrocytes of forty-four patients with endogenous depression both in acute episode and in remission, and compared with thirty healthy control subjects. During depressive episodes, the activities of all mechanisms studied were significantly lower than those of control subjects. In female depressives the values of ODS and LSC were lower than in males. In remission, the activity of all mechanisms rose, reaching in most patients the values of control subjects. In female patients, activities of ODS and LSC were still lower than in male patients and female controls. The activities of ODS and LSC had the highest discriminating power between depressive patients and control subjects. It appears that membrane pathology may be an aetiologic factor in endogenous depression. A disturbance in erythrocyte transport presents most conspicuously during depressive episodes and in some patients may also persist to the normothymic period.

The activity of the lithium--sodium countertransport system in erythrocytes was estimated in 16 control subjects and 28 patients suffering from affective disorders (11 bipolar, 17 unipolar) during depression, mania and remission. In all the patients studied, mean estimates of countertransport were significantly lower during an episode than after remission, with low values occurring more frequently in mania than in depression in bipolar patients. The mean values in patients with affective disorders but who were in remission remained lower than those of control subjects. Lowest values occurred more frequently in patients with bipolar than in those with unipolar illness. the possible physiological significance of reductions in the activity of the lithium--sodium countertransport mechanism in red cells was discussed.

Erythrocyte lithium transport mechanisms--lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC) and passive lithium efflux (PLE)--were measured in 46 patients with bipolar affective disorder on prophylactic lithium therapy and in 20 healthy control subjects. Maximal velocity of LSC measured at saturating intracellular lithium concentration was lower in the patients than in the controls; this may concur with previous reports on possible links between impaired activity of LSC and bipolar affective illness. When measured at therapeutic lithium concentration, LSC was 4 times lower and Km for LSC was 5 times higher in lithium-treated affective patients than in control subjects. The in vivo erythrocyte:plasma lithium ratio was inversely correlated with LSC in lithium-treated patients; higher ratios were found in females than in males. No differences were found between affective patients and control subjects in other erythrocyte lithium transport measurements. The values for lithium transport were not related to age, duration of lithium therapy, concomitant neuroleptic treatment, hypertension or obesity. Lower activity of LSC was found in patients with lithium-induced thyroid enlargement than in the other patients. The results obtained are discussed in the light of contemporary findings concerning erythrocyte lithium transport mechanisms in affective disorders and other conditions.

The authors investigated lithium and magnesium levels in serum and RBC in 30 patients with affective disorders during lithium prophylaxis. No differences in magnesium levels were found in relation to diagnosis (unipolar, bipolar), sex and age. Mean RBC lithium index was higher in females than in males, particularly in bipolar patients. Magnesium levels in erythrocytes showed a significant negative correlation with RBC lithium and RBC lithium index. Serum magnesium levels did not correlate of lithium concentrations. It was concluded that RBC magnesium may play a role in lithium penetration of RBC and this was discussed in relation to clinical and pathogenetic factors.