Upsala J Med Sci 81: 123-128, 1976 Relation between Erythrocyte and Plasma Lithium Concentrations as an Index in Psychiatric Disease L E I F LYTTKENS, U L F SODERBERG and LENNART WETTERBERG From the Psychiatric Research Center, Ullerzker Hospital, University of Uppsala, and Department of Psychiatry, Karolinska Institute, S t . Goran's Hospital, Stockholm, Sweden ABSTRACT In longitudinal and transverse studies, lithium was measured in plasma, serum and red blood cells (eryth- rocytes) of healthy male and female subjects as well as in patients of both sexes suffering from manic-depressive disease or schizophrenia. The results confirm that lith- ium in erythrocytes is lower than in plasma in all groups. The lithium concentration gradient between plasma and erythrocytes is not caused by a slow rate of diffu- sion through the erythrocyte membrane. The new result of the present study is the importance of sex, disease and age on the erythrocyte/plasma lithium ratio, which is significantly higher in female subjects with manic-depressive disease. This difference persists even during long-term lithium therapy. Older female schizophrenics also have a higher ratio of erythrocyte to plasma lithium than males of the same age. The findings emphasize the importance of endocrine in- vestigation in mental disease and support the view that plasma lithium in humans does not always reflect the intracellular levels. The erythrocyte plasma ratio may also be of value in revealing diagnostic subgroups within the classical psychiatric framework. INTRODUCTION Even if lithium is assumed to be distributed mainly within intra- and extracellular water compartments of the body, its distribution is not uniform for several reasons. It can be transported actively through cell membranes and it influences and com- petes with several other ions such as sodium, po- tassium, calcium and magnesium. (For review, see Johnson, 1975 (1 l).) The distribution is strongly dependent on the lithium level in the plasma and possibly also on the duration of the lithium treat- ment. The therapeutic level of lithium is low and less than 1 % of plasma sodium is exchanged for lithium. The lithium tissue/serum distribution ratios also unexpectedly exceed 1 . O in several tissues, such as muscle, bone, brain and kidney (21), al- though intracellular sodium is known to be low. In addition, since blood lithium varies rapidly be- tween doses, and its transport into cells vanes from tissue to tissue and is sometimes slow, part of the uneven distribution depends on the absence of a true distribution equilibrium. Several reports have claimed that manic patients retain more lithium than healthy controls even after a single dose (1). This is the basis for attempts to link the clinical picture of patients receiving lithium and the erythrocyte/plasma concentra- tion ratio. It has been preliminary reported that female manic-depressive patients had higher erythrocyte/plasma lithium ratio than healthy volunteers (14, IS), and that manic patients with acute attacks have such an elevated ratio (7). Correlations with response to treatment (4, 18) and with disease have been proposed (25), but also criticized (20). Part of the disagreement may de- rive from the observed dependence of the erythro- cytelplasma lithium ratio on the plasma lithium level (12). Fully aware of these difficulties, we further extended our previous material (14, 15) to include healthy male subjects and patients from both sexes with schizophrenia, i n order to investi- gate whether or not some disagreement in the litera- ture could be traced to distribution variations aris- ing from differences in sex, age and disease; especially so, since preliminary findings revealed the possibility that differences in lithium distribu- tion between erythrocytes and plasma are not ex- clusive to manic-depressive disease. MATERIAL The studies included longitudinal and transverse assays of lithium in plasma, serum and red blood cells. Lithium Upsala J Med Sci81 124 L . Lyttkens et ai. mcqll 0.6 0.4 .- E, .- 5 -t 0.2 0 T - Plasma -10- RBC Lithium 8 meq x 3 doily Fig. 1 . Concentration of lithium in plasma and erythrocytes in 8 healthy females in response to lith- ium administration for 2 weeks. was analysed with a Perkin-Elmer 306 atomic absorption spectrophotometer. Plasma and haemolysed blood were diluted 50 to 100 times for the analyses. The venous blood samples were drawn in the morning with the sub- jects fasting before the first dose of lithium was given. Lithium was administered as lithium carbonate. In the healthy individuals and in the patients comprising the longitudinal studies, a dose of 8 mEq three times daily was given. The patients comprising the transverse studies were given dosages that gave plasma levels between 0.6 and 1.2 mEq/l. MATERIAL Healthy persons Two groups of apparently healthy subjects were exam- ined, one comprising 8 female nurses and the other 8 male ambulance drivers from a hospital a t Ludvika, Dalecarlia. Their ages varied between 20 and 40 years. No other medication than lithium was taken during the trial period. Blood samples were taken in the morning, twice before lithium was given and 13 times during the following 18 days. In addition the sedimentation rate, leukocyte count, platelet count, plasma creatinine and glucose in whole blood were assayed before, during and after the lithium test. There was no restriction in diet or special control of salt intake. Upsala J Med Sci 81 Pafients The patients were all treated at Ullergker Hospital, Uppsala, Sweden. Thirty-seven patients with manic- depressive disease (23 women, 14 men) were examined; most of them had symptoms (in-patients), but some were in remission and were having lithium as prophylaxis (out- patients). Their ages ranged from 20 to 68 years. These patients had received lithium therapy for periods varying from 2 months to several years. A further 8 males and 8 females diagnosed as having chronic schizophrenia (in- patients) were treated in therapeutic trial at the hospital with dosages comparable to those given to the above- mentioned healthy subjects. Blood samples were taken in the same sequence as in the healthy subjects. The schizophrenic patients, however, also received their usual antipsychotic medication during the trial period. The diet was not restricted and there was no special control of salt intake. RESULTS Healthy subjects During the test period lithium concentrations in plasma and erythrocytes followed the same time course, though the level was lower in erythrocytes than in plasma (see Fig. 1). A steady state between Lithium in erythrocytes and plasma 125 Table 1 . Half-lives (T+) of lithium in plasma during the elimination phase Subjects Number (hours) Half-life Healthy females 8 19f 1 Healthy males 8 23+1 Schizophrenic females 8 19f2 Schizophrenic males 8 21f3 plasma and erythrocytes was rapidly attained, and no significant delay in the erythrocyte level was noted with the present sampling routine. The plasma levels reached 95% of the steady state within 4 days of treatment with lithium. After dis- continuation of lithium therapy the half-life was computed from the slope of the concentration curve obtained during the elimination period the first point being the measurement 24 hours after the last dose. The half-lives thus obtained were not significantly different in the two sexes (men 23k2 and women 19f2 hours; Table I). Likewise the groups of healthy persons showed no sex difference (Table 11). The sedimentation rate, leukocyte and platelet counts, creatinine in plasma and glu- cose in blood were not significantly affected by the lithium intake. Pa tien ts The relation between the erythrocyte and plasma levels of lithium in the manic-depressive patients of both sexes can be seen in Table 11. Females with manic-depressive disease showed a probably significant higher erythrocyte/plasma ratio of lith- ium than healthy females (P