BIOL PSYCHIATRY 1992;32:104-107


roleptic MalignantSyndrome, a case for ECT. Postgrad bled J 66:49-5 I.

Adityanjee DAP (1990): ECT in neuroleptic malignantsyndrome (letter). Br J Psychiatry 157:778. Harland CC, O'Leary MM, Winters R, et ai (1990): Neu-

Guerrero RM, ShifrarKA. (1988): Diagnosis and treatment of neuroleptic malignant syndrome (clinical conference). Clin Pharmacy 7:697-701.

Calcium, Lithium, and Circadian Rhythms

flux using rat uterus tissues. Chronic lithium treatment can also activate calcium pumps and increase calcium efflu~ from cells (Meltzer, 1986). Thus, serum (extracellular) calcium levels can be increased during lithium treatment. The measurement of parathyroid hormone and intracellular calcium levels may be useful to determine which mechanism increased serum calcium levels in their lithium-treated hamsters. Moreover, it may give a clue to elucidating why further calcium supplementation was needed for hamsters with lithium plus 0.1% calcium diet, in which serum calcium levels were within normal range, to prevent some adverse effects of lithium. Clinically, parathyroid adenomas have been found in lithium-treated patients (Garfinkel et al 1973; MacGregor 1977; Ananth et al 1991). Calcium supplementation is likely to mask the occurrence of hyperparathyroidism, and parathyroid adenomas, if present, can be overlooked during lithium treatment in some patients.

To the Editor: I read with interest the article by Klemfuss et al (1992). In their study, plasma calcium levels were increased from 3.0 +- 0. I mEq/L (0. I% calcium diet) to 4.0 --- 0.2 mEq/L (0. I% calcium plus lithium diet) in their hamsters. As pointed out by Kiemfuss et al (1992), it has been shown that lithium can increase serum calcium levels. With regard to the mechanism, first, it is possible that hyperparathyroidism occurred during lithium treatment as previously reported (Herman 1981; Davis et al 1981; Prasad 1984), although Klemfuss et al (1992) did not show parathyroid hormone levels. Shen and Sherrard (1982) suggested that lithium treatment resets the inverse correlation between serum calcium levels and parathyroid hormone levels, and the regression line is shifted to the right (Set-Point Theory). Second, there is a possibility that lithium blocked calcium channels and thereby decreased intracellular calcium levels while extracellular (serum) calcium levels were increased. We examined lithium effect on 45Ca2+ influx to cultured bovine adrenal medullary cells (Terao et al 1992). Lithium-treated (I .27 mEq/L of intracellular lithium level for 7 days) or non-treated cells were incubated with 1.5 ~Ci45CaC12 at 37°C for 5 min in the presence of carbachol (0.3 mmol/L). The cells were rapidly washed 4 times and solubilized with 2 ml of Triton X-100, and the radioactivity was counted by a liquid scintillation counter. As a result, lithium treatment decreased carbachol-stimulated influx of 45Ca2+ (non-treated cells, 4.04 +_ I. 15 versus lithium-treated cells, 2.51 -+ 0.47 [nmoles/4 × 106 cells]; t = 2.74, df = 10, p < 0.05). Our finding suggests that chronic lithium treatment decreases calcium influx to cells, although Freer and Smith (1979) could not identify acute lithium effect on 45Ca2+ in-

Takeshi Terao

Department of Psychiatry School of Medicine University of Occupational and Environmental Health Iseigaoka 1-1, Yahatanishi-Ku Kitakyushu 807, Japan

References Ananth J, Wohl M, Zegers C, Remmel R (1991): Hyperparathyroid adenoma with lithium therapy. Lithium 2:5457. ChristenssonTAT (1976): Lithium, hypercalcemia, and hyper-parathyroidism. Lancet ii:144. Davis BM, Pfefferbaum A, Kmtzik S, Davis KL (1981): Lithium's effect on parathyroid hormone. Am J Psychiatry 138:489-492.



BIOL PSYCHIATRY 1992:32:104-107

Freer RJ, Smith AB (1979): Lithium dissociation of calcium- and angiotensin-induced contractions in depolarized rat uterus. Am J Physiol 236:C171--C176. Garfinkel PE, Ezrin C, Stancer HC (1973): Hypothyroidism and hyperparathyroidism associated with iithium. Lancet ii:331.-332. Herman SP (1981): Lithium, hypercalcemia, and hyperparathyroidisn~. Biol Psychiatry 16:593-595. Klemfuss H, Bauer TT, Greene KE, Kripke DF (1992): Dietary calcium blocks lithium toxicity in hamsters without affecting circadian rhythms. Biol Psychiatry 31:315321 MacGregor GA (1977): Hyperthyroidism and a parathyroid adcnoma complicating lithium treatment. Lancet ii: 1129-1130. Meltzer HL (1986): Lithium mechanisms in bipolar illness and altered intracellular calcium functions. Biol Psy. chiatry 21:492-510. Prasad A (1984): Chronic lithium intake and hyperparathyroidism. Eur J Ciin Pharmacol 27:499-500. Shen FH, Sherrard DJ (1982): Lithium-induced hyperparathyroidism: An alteration of the "set-point". Ann int Med 96:63-65. Terao T, Yanagihara N, Abe K, lzumi F (1992): Lithium chloride stimulates catecholamine synthesis and secretion in cultured bovine adrenal medullary cells. Biol Psychiatry (in press)

Response to Terao: To the Editor: Dr. Terao's letter suggests two feasible biochemical mechanisms by which chronic lithium treatment might increase serum calcium, in our study (Klemfuss et al 1992), we found that dietary calcium treatment prevents polyuria and weight loss associated with serum lithium concentrations of I meq/L in hamstets, and that this concentration of lithium also increased serum calcium. Although our study was not intended to address the question of mechanism, we did collect tissue and serum from these animals. Ms. Greene measured Ca + +, Na+, and K + concentrations in erythrocytes, kidney, hypothalamus, and striatum from 30 animals used in the first replication. Lithium treatment did not significantly affect any ion in erythrocytes or kidney, but there was a trend for

an increase in calcium in both erythrocytes ( + 23%, p = 0.27) and kidney ( + 2 9 % , p = 0.39) after lithium treatment. Therefore, we do not think that serum calcium was increased at the expense of intracellular calcium, as proposed by Dr. Terao. Hypothalamic and striatal calcium concentrations were unaffected by calcium or lithium treatment. We also measured serum parathyroid hormone (PTH) concentrations from the same hamsters, through the courtesy of K. Smith and L. Deftos at the Veterans Affairs Medical Center in San Diego. Lithium treatment did not increase P'rH in hamsters fed 3% calcium (485 "*" 42 SEM pg/ml without lithium versus 461 ._4-_ 38 pgtml in lithium-fed animals), arguing against hyperparathyroidism as a mechanism. However, it is possible that lithium might alter the PTH setpoint without affecting PTH concentration in these animals. Alternatively, we may have missed an increase in PTH, as we killed animals during the day, and lithium might increase PTH specifically during the night, as reported by McEachron and colleagues (1982) in rats. We appreciate Dr. Terao's suggestions, and would welcome an explanation for the physiological interactions between calcium and lithium. Our limited data do not support involvement of either P'rH or intracellular calcium. Harry Klemfuss Daniel F. Kripke Veterans Affairs Medical Center 3350 LaJolla Village Drive San Diego, CA 92161

References Klemfuss H, Bauer Tr, Greene KE, Kripke DF (1992): Dietary calcium blocks lithium toxicity in hamsters without affecting circadian rhythms. Biol Psychiatry 3 ! :315321. McEachmn DL, Kripke DF, Eaves M, Lenhard L, Pavlinac D, Deflos L (1982): The interaction of lithium and timeof-day on calcium, magnesium, parathyroid hormone, and calcitonin in rats. Psychiatry Res 7:121-131.

Calcium, lithium, and circadian rhythms.

Correspondence References BIOL PSYCHIATRY 1992;32:104-107 105 roleptic MalignantSyndrome, a case for ECT. Postgrad bled J 66:49-5 I. Adityanjee D...
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