oral medicine Editor: JAMES W. LITTLE, D.M.D., M.S.D. Department of Oral Diagnosis and Oral Medicine University of Kentucky Lexington, Kentucky 40506
Salivary lithium concentration-A tool for monitoring psychiatric patients H. Ben-Aryeh, Ph.D.,* H. Naon, M.D., ** R. Szargel, MSc., D. Gutman, D.D.S.,*** A. Hefetz, M.D., **** Haifa, Israel RAMBAM
MEDICAL
and
CENTER
Salivary and serum lithium concentratiins were measured simultaneously in 118 manic-depressive patients. Lithium concentration in saliva was 2.24 rt 0.35 times htgher than in serum. An eWttbn to calculate serum lithium concentration from salivary measurements was derived: L&,,,.,,,,,=0.36 Lisariva + 0.13. Psychotropic drugs had no effect on the salivary:serum ratio. Eighteen patients were followed for several weeks. A significant correlation coefftclent between salwary and serum lithium concentrations was found in thirteen of the eighteen patients studied.
L ithium therapy is used for treatment of the manic
phaseof bipolar affective disorders and for prophylaxis of recurrent depression.’ It is necessaryto monitor the levels of lithium during the treatment since the therapeutic range (0.7 to 1.2 mEq/L in serum) is close to the toxic range (above 1.5 mEq/L). At present lithium therapy is monitored by measurementsof lithium concentration in the serum. Several studies concerning the possibility of lithium monitoring by measurementsof salivary lithium concentration were performed. The results are contradictory, depending on the mode of collection of saliva and on the population examined.2-s The present study was undertaken in view of this discrepancy in the published data. Our purpose was to examine again the possibility of monitoring lithium therapy by salivary measurements. Submitted by Dr. Naon in partial fulfillment of the requirementsfor the M.D. degree, Faculty of Medicine, Technion, Haifa, Israel. *Head, Laboratory of OraI Biology, Department of Oral and Maxillofacial Surgery. **Biochemist at Laboratory of Oral Biology. ***Head of Department of Oral and Maxillofacial Surgery. ****Head of Department of Psychiatry.
00304220/80/080127+03$00.30/0
@ 1980 ‘he C. V. Mosby Co.
METHODS
The population studied consisted of 118 manicdepressive patients of the psychiatric outpatient clinic in our hospital. Their mean age was 5 1.8 2 10 years (range 36 to 74 years). Seventy-six were women and 42 were men. All the patients were treated at least 3 months with lithium carbonate. The range was from 3 months to 7.5 years. They received from 300 mg. to 1,800 mg. lithium carbonateper day. About 50 percent of the patients were being treated with other drugs as well (Table I). Eighteen patients were followed for several weeks, and serial blood and saliva sampleswere drawn (from three to nine samplesper subject). Unstimulated whole saliva was collected by a standard metl~od.‘~The patients were instructed to accumulate saliva in their mouths and to spit into a test tube. Unstimulated saliva was used since stimulation alters salivary composition in general” and lithium secretion in particular.12 The salivary and blood sampleswere centrifuged and diluted 1: 10 with 200 ppm potassium chioride. Lithium concentration was measured with a Perk&Elmer 107 flame photometer. The results were analyzed statistically by standard 127
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Fig. 1. Lithium concentrationin serumandsaliva.The straightline represents the significantlylinearcorrelation betweensalivary and serumlithium concentrationsin the 118 manic-depressive patientstreatedwith lithium carbonatefor at least 3 months.The correlationcoefficientis r = 0.87 (p < 0.001). The equationfor the regressionline is Y = 0.36 X + 0.13.
Table I. Salivary and serum lithium concentration* No. Patients treated with:
Lithium carbonate only Chlorimipramine (Anafranil) Dibenzepin (Novetil) Amitriptyline (Elatrol) Thioridazine (Mellaril) Desipramine (Pextoftane) SUmmarY
of
p&en@ 64 25 15 10
a 4 118
Salivary lithiumt
1.57 f 0.54 1.47 + 0.39 1.43 + 0.46 1.74 + 0.41 1.85 2 0.36 1.40 1.54 r 0.51
Serum lithium~
0.70 -’ 0.21 0.68 + 0.20 0.61 + 0.21 0.73 f 0.14 0.73 f 0.066 0.61 0.69 it 0.21
Salivary1 serum lithium~
2.23 + 0.34 2.18 r 0.39 2.37 -t- 0.37 2.34 + 0.23 2.50 + 0.34 2.29 2.24 + 0.35
of 118 manic-depressivepatients @eatedwith lithium carbonateonly or with additional *Lithium concentrationsin mEq/L in saliva and serum psychotropic drugs. The duration of treatment with lithium was at least 3 months. tMean 2 standarddeviation. *The ratio between salivary and serum lithium concentrationswas calculated for each patient individually, and then the mean and standard deviation wem derived.
techniques of determination of correlation coefficients and Student’s t test of significance. RESULTS
The salivary and serum lithium concentrations of the 118 patients examined are presented in Fig. 1. The equation for calculating serum lithium from saliva lithium measurements was derived from the graph: Y = 0.36 X + 0.13 (Y = serum lithium concentration, X = salivary lithium concentration). The patients were divided into six subgroupsaccord-
ing to the psychotropic drugs they were receiving in addition to lithium carbonate. The mean lithium concentrations of saliva and serum are presentedfor each group (Table I). The salivary to plasmaratio was calculated and found to vary between 2.18 and 2.37. The averagesaliva to serum lithium ratio of all the patients studied was 2.24 + 0.35. The results of the follow-up study of eighteen patients are summarized in Table II. The correlation coefficient of salivary to serum lithium concentrations for each patient was calculated and found to be significant
Salivary lithium concentration
Volume 50 Number 2
Table II. Plasma/saliva lithium correlation
coefficients* Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
No. of samples
Correlation coeficient
3 3 4 3 5 3 3 4 3 3 3 I 9 11 7 7 8 9
0.88t 0.55
0.9wS 0.99t 0.93t 0.18 0.84 0.99t 0.94-t 0.59 0.64 0.97t 0.93t 0.88t 0.98t 0.94t 0.91t 0.98t
*In eighteen of the 118 patients the salivary and serumlithium concentration was measuredseveral times a week. The correlation coefficient and the regressionline were calculated for each patient and compared with the general line. tp < 0.05. #Different from the general regression line.
in thirteen of the eighteen patients (at the level of significance of p < 0.05). DISCUSSION
The possibility of using salivary lithium concentrations for lithium monitoring of psychiatric patients was studied in 118 patients by standarizedunstimulated saliva collection. The results show that lithium concentrations are higher in saliva (2.24 f 0.35) than in serum (Table I, Fig. 1). The serum concentration may be calculated from an equation derived from Fig. 1. The results are similar to reported by Shopsin, Verghese,6and Preskorn,9and their associatesbut differ from those of Sims’ and Neus and their colleagues. Psychotropic drugs did not affect the concentration of salivary lithium and the salivary : serum ratio. The follow-up study shows a significant correlation coefficient between salivary and serum lithium concentrations in thirteen of the eighteen patients (p < 0.05). Preskom and associate9 found a significant cor-
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relation in only seven of their twenty-three patients, and Sims and co-workers’ found varying lithium salivary concentrations in their three patients. The difference could be causedby the mode of salivary collection or the duration of lithium therapy. It has to be noticed that at the beginning of the treatment the salivary: serum ratio is unstable. The present results demonstrate the possibility of using salivary lithium measurementsfor monitoring patients on prolonged lithium therapy. This method is uninvasive; saliva can be collected by the patient at home and mailed to the laboratory for analysis, thus enabling the psychiatrist to adjust his treatment regime on the patient’s visit. REFERENCES 1. Schou, M.: Lithium in Psychiatric Therapy and Prophylaxis, J. Psychiatr. Res. 6: 67, 1968. 2. Shopsin, B., Gershon, S., and Pinckney, L.: The Secretion of Lithium in Human Mixed Saliva: Effects of Ingested Lithium on Electrolyte Distribution in Saliva and Serum, Int. Pharmacop sychiatry 2: 148-169, 1969. 3. Spring, K. R., and Spirtes, M. A.: Salivary Excretion of Lithium: II. Functional Analysis, J. Dent. Res. 48: 550-554, 1969. 4. Sims, A. C. P.: Saliva and Serum Lithium Estimations in Psychiatric Patients, Br. J. Psychiatry 124: 106-107, 1974. 5. Neu, Carlos, Dimascio, Alberto, and Williams, David: Saliva Lithium Levels: Clinical Applications, Am. J. Psychiatry 132: __ 66-68, 1975. 6. Verghese, A., Indrani, N., Kuruvilla, K., and Hill, P. G.: Usefulness of Saliva Lithium Estimation, Br. J. Psychiatry. . . 130: 148-150, 1977. I. Sims, A., White, A. C., and Garvey, K.: Problems Associated With the Analysis and Interpretation of Saliva Lithium, Br. J. Psychiatry 132: 152-154, 1978. 8. Neu, Carlos, and Dimascio, Alberto: Saliva Lithium Levels: Clinical Applications, Psychopharmacol.Bull. 13: 55-57, 1977. 9 Preskom, S. H., Abemethy, D. R., and McKnelly, W. V., Jr.: Use of Saliva Lithium Determination for Monitoring Lithium Therapy, J. Clin. Psychiatry 756/33-758/35, 1978. 10. Ciutman, D., Ben-Aryeh, H.: The Influence of Age on Salivary Content and Rate of Flow, Int. J. Oral Surg. 3: 314-317, 1974. 11. Hall, H. D.: Diagnosisof Diseaseof the Salivary Glands, J. Oral Surg. 27: 15-25, 1969. 12. Spring, K. R., and Spirtes, M. A.: Salivary Excretion of Lithium. I. Human Parotid and Submaxillary Secretions, J. Dent. Res. 48: 546-649, 1969. Reprint requests to: Dr. H. Ben-Aryeh Laboratory of Oral Biology Department of Oral and Maxillofacial Surgery Rambam Medical Center Haifa, Israel