Characteristics of the in vivo RBC: Plasma lithium ratio in a clinical setting

Brief Reports

Rybakowski J, Potok E, Strzyzewski W, Chlopocka WM (1983): The effects of lithium treatment on cation transport process in erythrocytes of patients with affective illness. Pol J Pharmacol Pharm 35:209-215.

Sapru MK, Geetha H, Shetty KT (1987): A single reagent method of phosphate estimation in phosphatase(s) assay. Ind. J Biochem Biophys 24:340343.

Sanui H (1974): Measurement of inorganic orthophosphate in bioiogic~ materials: extraction properties of butyl acetate. Anal Biorhem ~:489-5~. Sengupta N, Datta SC, Sengupta D, Bal S (1980): Platelet and erythrocyte membrane adenosine tri-

BIOL PSYCHIATRY 1989;26:533-537

537

phosphatase activity in depressive and manic-depressive illness. Psychiatry Res 3:337-347. Spitzer RL, Endicott J, Robins E (1978): Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatry 35:773-782.

Thakar JH, Lapierre YD, Waters BG (198.5): Erythrocyte membrane sodium-potassium and magnesium ATPase in primary affective disorders. Biol Psychiatry 201734-740.

WhaIleyLJ, ScottM, ReadingHW, ChristieJE (1980): Effect of elec~oconvu~s~ve therapy on erythrocyte adenosine ~iphosphat~e activity in depressive illness. Br J Psychiatry 137:343.

Characteristics of the In Vivo RBC: Plasma Lithium Ratio in a Clinical Setting William G. Ryan, James M. Richards, and Jeanette Y. Lee

Since Elizur et al. (1972) noted lower erythrocyte:plasma lithium ratios (LR) in bipolar patients during their illness phase and Mend& and Frazer (1973) reported that an anti-

depressant response to lithium correlated with a higher LR, the measurement of lithium in the red blood cell has been an area of research interest. The question of whether or not the LR is of value in predicting the outcome of lithium therapy has been addressed by many investigators (reviewed by Carroll 1979; Jefferson et al. 1987), with findings both pro and

From the Department of Psychiatry (W&R.), the Division of Hematology-Oncology, Department of Medicine (J.Y.L.). and the Office of Educational Development (J.M.R.), School of Medicine, University of Alabama at Birmingham, Bi~n~am, AL. Portions of this report were presented at the American Academy ot Ciincal Psycbiatzists Annual Meeting, Seattle, WA, October 1988. Address reprint requests to Dr. W. G. Ryan, 392 North Wing, University Hospital, University Station, Birmingham, AL 35294. Received August 25. 1988; revised December 12, 1988.

con, but the consensus has been that the LR is not useful. Controversy has also arisen about the nature of the ratio and what processes may affect it. in p~~cul~, doubts have been raised about the utility of the LR based on its variability (Rybakowski et al. 1974; Lippmann et al. 1983). Several studies have found that the LR varies with the plasma level, increasing when the plasma level increases, (Rybakowski et al. 1974; Lee et al. 1975; Schreiner et al. 1979), although others (Cooper et al. 1979) have found this effect to be minimal. it has also been suggested that the LR, at least in vitro, increases with the duration of lithium therapy (Numberger et ai. 1983). Another potential source of viability in the LR that would argue against its use in predicting outcome is cotherapy with antipsychotic drugs. One in vitro study (Pandey et al. 1979) and one in vivo study (Knorring et al. 1982) have

538

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BIOL PSYCHIATRY 1989;26:537-540

found that the administration of neuroleptics is associated with higher LRs, though one other in vitro study did not find this (Kim et al. 1978). Other investigators have found that being female (Lyttkens et al. 1976; Rybakowski et al. 1976, 1977; Zaremba and Rybakowski 1986), having bipolar disorder (Knorring, et al 1976, Lyttkens, et al 1976, Rybakowski et al. 1978), and being black (Opaku et al. 1980; Chang et al. 1984) may be associated with higher LRs. In a number of studies, however, female gender (Rybakowski et al. 1974) and bipolar diagnosis (Rybakowski et al. 1974; Soucek et al. 1974; Andrews and Chiu 1978; Cooper et al. 1979) were not associated with a higher LR. Clearly, the above factors could influence the potential utility of the LR. As these questions about the stability and variability of the LR are still unanswered, we undertook this project as part of a long-term retrospective study of the LR in an ordinary clinical setting.

Methods All adult patients taking lithium in an innercity, mental health center clinic run by an academic department of psychiatry were identified. If a patient had at least 3 recorded dete~inations of the LR [using atomic absorption spectrophotometry by the method of Frazer et al. (1972)] when the plasma level was >0.3 r&q/liter, at least 18 months of follow-up, and adequate information recorded on the chart, he or she was included. Information was abstracted. DSM-III diagnoses were made by the senior author, who was blind to the patients’ clinical diagnoses and LR, and all information was entered into the CLINFO computer system (of the General Clinical Research Center at University of Alabama at Birmingham, funded by NIH Grant 521627). Statistical analyses were performed using the SAS package, with r-tests utilized to determine the significance of differences between means, Pearson product-moment correlations calculated to estimate relationships between variables, and a linear regression analysis employed to evaluate the stability of the LR over time.

Results Initially, 262 patients records were reviewed, and 95 met criteria for inclusion. The final sample had a mean age of 42 It 12 years and included 33 men and 62 women. Sixty-two of the patients were black, and 32 were white. Diagnostically, 53 patients were bipolars and 42 had other diagnoses, including schizoaffective disorder (n = 20), atypical psychosis (n = 6), organic affective disorder (n = 5), unipolar depression (n = 2), schizophrenia (n = 3), and schizophrenifo~ disorder (n = 2). The patients were studied over a 4.14 + 1.25year period, and had 14.3 +- 7.7 determinations of the LR. Mean lithium ratios for men versus women and bipolar patients versus nonbipol~s (Table 1) were not significantly different. Black patients had a significantly higher LR than whites by t-test @ < 0.01). When the racial groups were further su~ivided by diagnosis, the black patients’ LRs were significantly greater than those of the white patients only among bipolars @ < 0.01). The LR was not correlated with plasma lithium for the group (r = 0.14, p = 0.17) or for any subgroups. The stability of the LR over time was assessed by evaluating time trends from the initial ratio with those determined at 6 t 1, 12 ? 1 or 18 -+ 1 months. Although not all patients had determination at each of the required times, no statistically si~ific~t changes with time were detected, implying that the LR was stable over time in this population. The variability of the LR was investigated by dividing the standard deviation by the mean ratio for each patient. This quotient was determined previousfy by Rybakowski (1974) in a group of 37 patients; lower values correspond with less variability in that patient. In the present study, only 3.2% of the patients had SDhean >0.3 (versus 18.9% in Rybakowski’s study), and 29.4% had an SD/mean BO.2 (versus 43.2% for Rybakowski). We also found that men had less variable LRs than women. A potential effect of antipsychotic drug administration on the LR was investigated. Only 10 patients had had no exposure to neuroleptics during the study period (ratio 0.49 versus 0.60

Brief Reports

Table f . in Vivo Lithium Ratios for Sample Subgroups n

plasmaLi

Mean RBC Li

LR (mean ? SD)

95 33 62

0.85 0.86 0.84

0.50 0.51 0.50

0.59 zt 0.18 0.59 It 0.20 0.60 rt 0.17 0.63 + 0.19 0.52 It 0.15

Mean Group Whole sample Men Women

t

-

df

P

-

-

0.2395

58.7

O.I(NS).

3.0115

75.R

0.004

Black patients White patients

62 32

0.85 0.85

0.54 0.44

Bipolars Nonbi~l~s

53 42

0.86 0.84

0.52 0.48

0.61 rt 0.18 0.57 rt 0.18

-0.9093

86.4

Q,37(NS)

Neuroteptic rreatment No neuroteptic treatment

85 IO

0.86 0.78

0.52 0.36

0.60 + 0.19 0.49 I 0.08

-3.53

22.4

0.02

On neuroleptics months On neuroleptics months

s t8

35

0.85

0.51

0.57 rt 0.18

>18

60

0.86

0.52

0.61 I 0.18

- 0.9057

72.7

0.37(NS)

34 18

0.86 0.84

0.56 0.44

0.65 z!z O,t9 0.52 t 0.t2

3.1367

47.9

0.003

28 14

0.83 0.86

0.50 0.46

0.60 t 0.18 0.53 rf: 0.18

t 2088

26.1

0.23fNSf

Btack bipolars White bipolars Black n~nbi~t~s White nonbipolarr

for patients with some exposure, p = 0.002). Although this difference is clearly significant, the small number of patients in the neurolepticfree group makes its meaning unclear. As Pandey et al. (1979) noted that phenothiazines, but not haloperidol, were associated with higher LRs, we analyzed patients with and without phenothiazine or haloperidol dearest. No significant differences could be found.

f>iscussionlConcfusions The higher LR seen in bfack patients, especially among bipolars, is in accordance with the findings of other investigators, and although the underlying mechanism is not known, in vitro work (Opaku et al. X980) implies that a difference in membrane Li transport exists between the groups. Our failure to find higher ratios among bipolar patients in general, coupled with previous work (Johnston et al. 1974; Soucek et al. 1974; Andrews and Chiu 1978; Cooper et al. 19791, indicates that the LR is not a useful biologicaf marker for this diagnosis, although, as no normal controls were available, the possibility that

they would have a different ratio than bipolar patients cannot be absolutely ruled out. Some earlier research has implied that the LR is not reliable enough to be used to characterize patient samples. In contrast, our study shows that the LR is relativeIy independent from the plasma lithium level and duration of therapy. This and the evidence that the LR is not highly variabie in a given individual supports the position that the LR reflects factors intrinsic to the individual and, at Ieast ~eoretica~ly, could have utility in identifying subgroups of bipolar patients. The issue of the effect of neuroleptic administration should be resolved by studying groups with more neuroleptic-free patients. Although the naturalistic, uncontrolled nature of this study may limit the generality of the findings, the large sample size, the high number of determinations of the LR per patient, and the relatively long study period indicate that the finding are me~ingful and should be replicabie. ~though the clinical significance of the LR has yet to be determined, our results imply that research in this area may still be rewarding.

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BIOL PSYCHIATRY 1989;26:537-540

References Andrews S, Chiu E (1978): The intracellular lithium level: Is it of any use? In Johnson FN, Johnson S (eds), Lithium in Medical Practice, Lancaster, England: MTP Press, pp 421-427. Carroll BJ (1979): Prediction of treatment outcome with lithium. Arch Gen Psychiatry 36:870-878. Chang SS, Pandey GN, David JM, et al. (1984): Racial differences in plasma and RBC lithium levels (abstr). American Psychiatric Association Annual Meeting. Cooper TB, Gershon S, Kline NS (eds) (1979): Lithium: Controversies and Unresolved Issues. Amsterdam: Excerpta Medica. Elizur A, Shopsin B, Gershon S, et al. (1972): Intra:extracellular lithium ratios and clinical course in affective states. C/in Pharmacoi Ther 13:947952.

Brief Reports

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Frazer A, Secunda SK, Mendels J (1972): A method for the determination of sodium, potassium, magnesium and lithium concentrations in erythrocytes. Clin Chim Acta 36:499-509.

Rybakowski J ( 1977): Pharmacogenetic aspect of red blood cell lithium index in manic-depressive psychosis. Biol Psychiatry 12:425-429.

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Lee CR, Hill SE, Dimitrakoudi M, et al. (1975): The relationship of plasma to erythrocyte lithium levels in patients taking lithium carbonate, Br J Psychiatry 127:596-598.

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