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DIVALENT CATIONS IN PREDICTING ANTIDEPRESSANT RESPONSE TO LITHIUM
1454 DIVALENT CATIONS IN PREDICTING ANTIDEPRESSANT RESPONSE TO LITHIUM SIR,-Increasing recognition that lithium carbonate has acute antidepressant,2 as well as antimanic properties, has led to attempts to characterise, and hence to predict, the individual who will respond to lithium. Response to lithium was reported to be more common in depressed patients with a history of mania (bipolar) 3,4and in patients who had greater initial ingress of lithium into their red blood-cells.r; Several workers have reported increases in plasma magnesium g-12 or calcium 13-16 during the initial phase of lithium treatment. In an earlier study from this laboratory, it was noted that the lithium-induced increase in plasmamagnesium was significantly more likely to occur in
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"
cyclic " compared to non-cyclic " depressed patients.17 In the present study of depressed patients in hospital, we have examined the relation between magnesium and calcium and subsequent antidepressant response to lithium; both the pre-treatment plasma magnesium and calcium levels and changes in these ions during the first five days of lithium therapy were examined. 33 inpatients who met the criteria for primary affective disorder 18 were studied in research units at the National Institute of Mental Health. Lithium was administered for at least three weeks, with blood-levels maintained between 0-7 and 1-2 meq. per litre. Blood was drawn at 8 A.M. and total plasma calcium and magnesium were determined by atomic-absorption spectrometry. The mean of three baseline drug-free calcium and magnesium determinations was compared with the mean of three determinations during the first five days of lithium administration. Behaviour was evaluated twice daily under double-blind conditions, using a modified Bunney-Hamburg scaled Antidepressant response was defined as a sustained decrease of at least 2 points in the global depression scale (maximum effective range 9 points). Equivocal responders were excluded and only definite lithium responders and non-responders were analysed, so that the biochemical differences between the two groups were
highlighted.
(P=0-05). The
most accurate
prediction of subsequent lithium
however, from an analysis of the magnesium
and calcium changes occurring during the first five days of lithium treatment. An initial increase in magnesium 1.
2. 3. 4.
5. 6. 7. 8. 9.
10. 11. 12. 13. 14.
15. 16.
17. 18.
accurately predicted response. Thus, 18 of the 22 patients with an initial increase in magnesium turned out to be responders, while all but 1 of the 11 patients with an initial decrease in magnesium were subsequently shown to be non-responders. Of the 16 patients who demonstrated an increase in both cations, all but one were responders, whereas among the 17 patients in whom there was a decrease in either or both ions, 13 were non-responders. In other words, there was only one " false positive " when the increases in magnesium and calcium were used together, whereas there was only one " false negative " when a decrease in magnesium was the only prediction of nonresponse. There were no significant differences between unipolar and bipolar depressed patients in these calcium/ magnesium/lithium interactions. The clinical value of these findings must first be confirmed in larger studies, but the low frequency of false positives and false negatives suggests that these changes should be clinically useful. It is not yet known whether acute antidepressant response (i.e., the subject of this study) will be predictive of ultimate prophylactic response. Furthermore, patients in our study were pre-selected for relatively clear-cut response
The pre-treatment calcium/magnesium ratio was significantly related to subsequent antidepressant response to lithium. Thus, of the 24 patients with a baseline ratio greater than 2-62, 17 were responders, whereas of the 9 patients with ratios below 2-62, 7 were non-responders
response came,
PLASMA MAGNESIUM AND CALCIUM AND ANTIDEPRESSANT RESPONSE TO LITHIUM
Goodwin, F. K., Murphy, D. L., Bunney, W. E., Jr. Archs gen. Psychiat. 1969, 21, 486. Mendels, J., Secunda, S. K., Dyson, W. L. ibid. 1972, 26, 154. Goodwin, F. K., Murphy, D. L., Dunner, D. L., Bunney, W. E., Jr. Am. J. Psychiat. 1972, 129, 44. Baron, M., Gershon, E., Rudy, V., Buchsbaum, M., Jonas, Z. Unpublished. Mendels, J., Frazer, A.J. psychiat. Res. 1973, 10, 9. Aronoff, M. S., Evens, R. G., Durell, J. ibid. 1971, 8, 139. Nielson, J. Acta psychiat. scand. 1964, 40, 190. Dunner, D. L., Bogan, G. A., Goodwin, F. K. Unpublished. Goodwin, F. K., Murphy, D. L., Bunney, W. E., Jr. Scient. Proc. Am. psychiat. Ass. 1968. Haavaldsen, R., Ingvaldsen, P. Lancet, 1973, i, 1390. Birch, N. J., Jenner, F. A. Br. J. Pharmac. 1973, 47, 586. Mellerup, E. T., Plenge, P., Rafaelson, O. J. Int. Pharmacopsychiat. 1973, 8, 178. Birch, N. J. Lancet, 1973, ii, 46. Andreoli, V. M., Villani, F., Brambilla, G. Psychopharmacologia, 1972, 25, 77. Mellerup, E. T., Plenge, P., Ziegler, R., Rafaelson, O. J. Int. Pharmacopsychiat. 1970, 5, 258. Tupin, J. P., Schlagenhauf, G. K., Creson, D. L. Am. J. Psychiat. 1968, 125, 128. Goodwin, F. K., Murphy, D. L., Bunney, W. E., Jr. Scient. Proc. Am. Psychiat. Ass. 1968, 121, 233. Feighner, J. P., Robins, E., Guze, S. B., Woodruff, R. W., Jr., Winokur, G., Munoz, R. Archs gen. Psychiat. 1972, 26, 57.
or
non-response to lithium and the
predictive value of these data in an unselected population (i.e., including those with partial or equivocal responses) is
known. These findings also provide further evidence consistent with the suggested importance of magnesium and/or calcium in the mechanism of action of lithium and ultimately in the pathophysiology of affective illness." not
Adult Psychiatry Branch, and Section on Psychiatry, National Institute of Mental Health, 9000 Rockville Pike,
Bethesda, Maryland 20014, U.S.A.
JOHN S. CARMAN ROBERT M. POST TERRY A. TEPLITZ FREDERICK K. GOODWIN.
INFLUENCE OF AGE ON NEUROHORMONAL RECEPTORS
SIR,-Every clinician knows how intensely old age can influence the sensitivity of neurohormonal receptors and therefore the response to stress or medication. Progress in clinical geriatrics is very slow for many reasons, and one of the most important sources of information for a geriatrician remains the comparison of data obtained from different age-groups. It is difficult to understand why information about the ages of the subjects investigated, essential in my opinion, is missing in some otherwise extremely interesting papers. This lack is even more striking if the subjects of the investigation are clearly geriatric as, for example, are those of Dr Carter and his colleagues (Oct. 26, p. 971) or those of Dr Benkert and others 19.
Carman, J. S., Post, R. M., Goodwin, F. K., Teplitz, T. A., Bunney, W. E., Jr. Annual Meeting, American Psychiatric Association, Detroit, Michigan, May, 1974.
’"
"
cyclic " compared to non-cyclic " depressed patients.17 In the present study of depressed patients in hospital, we have examined the relation between magnesium and calcium and subsequent antidepressant response to lithium; both the pre-treatment plasma magnesium and calcium levels and changes in these ions during the first five days of lithium therapy were examined. 33 inpatients who met the criteria for primary affective disorder 18 were studied in research units at the National Institute of Mental Health. Lithium was administered for at least three weeks, with blood-levels maintained between 0-7 and 1-2 meq. per litre. Blood was drawn at 8 A.M. and total plasma calcium and magnesium were determined by atomic-absorption spectrometry. The mean of three baseline drug-free calcium and magnesium determinations was compared with the mean of three determinations during the first five days of lithium administration. Behaviour was evaluated twice daily under double-blind conditions, using a modified Bunney-Hamburg scaled Antidepressant response was defined as a sustained decrease of at least 2 points in the global depression scale (maximum effective range 9 points). Equivocal responders were excluded and only definite lithium responders and non-responders were analysed, so that the biochemical differences between the two groups were
highlighted.
(P=0-05). The
most accurate
prediction of subsequent lithium
however, from an analysis of the magnesium
and calcium changes occurring during the first five days of lithium treatment. An initial increase in magnesium 1.
2. 3. 4.
5. 6. 7. 8. 9.
10. 11. 12. 13. 14.
15. 16.
17. 18.
accurately predicted response. Thus, 18 of the 22 patients with an initial increase in magnesium turned out to be responders, while all but 1 of the 11 patients with an initial decrease in magnesium were subsequently shown to be non-responders. Of the 16 patients who demonstrated an increase in both cations, all but one were responders, whereas among the 17 patients in whom there was a decrease in either or both ions, 13 were non-responders. In other words, there was only one " false positive " when the increases in magnesium and calcium were used together, whereas there was only one " false negative " when a decrease in magnesium was the only prediction of nonresponse. There were no significant differences between unipolar and bipolar depressed patients in these calcium/ magnesium/lithium interactions. The clinical value of these findings must first be confirmed in larger studies, but the low frequency of false positives and false negatives suggests that these changes should be clinically useful. It is not yet known whether acute antidepressant response (i.e., the subject of this study) will be predictive of ultimate prophylactic response. Furthermore, patients in our study were pre-selected for relatively clear-cut response
The pre-treatment calcium/magnesium ratio was significantly related to subsequent antidepressant response to lithium. Thus, of the 24 patients with a baseline ratio greater than 2-62, 17 were responders, whereas of the 9 patients with ratios below 2-62, 7 were non-responders
response came,
PLASMA MAGNESIUM AND CALCIUM AND ANTIDEPRESSANT RESPONSE TO LITHIUM
Goodwin, F. K., Murphy, D. L., Bunney, W. E., Jr. Archs gen. Psychiat. 1969, 21, 486. Mendels, J., Secunda, S. K., Dyson, W. L. ibid. 1972, 26, 154. Goodwin, F. K., Murphy, D. L., Dunner, D. L., Bunney, W. E., Jr. Am. J. Psychiat. 1972, 129, 44. Baron, M., Gershon, E., Rudy, V., Buchsbaum, M., Jonas, Z. Unpublished. Mendels, J., Frazer, A.J. psychiat. Res. 1973, 10, 9. Aronoff, M. S., Evens, R. G., Durell, J. ibid. 1971, 8, 139. Nielson, J. Acta psychiat. scand. 1964, 40, 190. Dunner, D. L., Bogan, G. A., Goodwin, F. K. Unpublished. Goodwin, F. K., Murphy, D. L., Bunney, W. E., Jr. Scient. Proc. Am. psychiat. Ass. 1968. Haavaldsen, R., Ingvaldsen, P. Lancet, 1973, i, 1390. Birch, N. J., Jenner, F. A. Br. J. Pharmac. 1973, 47, 586. Mellerup, E. T., Plenge, P., Rafaelson, O. J. Int. Pharmacopsychiat. 1973, 8, 178. Birch, N. J. Lancet, 1973, ii, 46. Andreoli, V. M., Villani, F., Brambilla, G. Psychopharmacologia, 1972, 25, 77. Mellerup, E. T., Plenge, P., Ziegler, R., Rafaelson, O. J. Int. Pharmacopsychiat. 1970, 5, 258. Tupin, J. P., Schlagenhauf, G. K., Creson, D. L. Am. J. Psychiat. 1968, 125, 128. Goodwin, F. K., Murphy, D. L., Bunney, W. E., Jr. Scient. Proc. Am. Psychiat. Ass. 1968, 121, 233. Feighner, J. P., Robins, E., Guze, S. B., Woodruff, R. W., Jr., Winokur, G., Munoz, R. Archs gen. Psychiat. 1972, 26, 57.
or
non-response to lithium and the
predictive value of these data in an unselected population (i.e., including those with partial or equivocal responses) is
known. These findings also provide further evidence consistent with the suggested importance of magnesium and/or calcium in the mechanism of action of lithium and ultimately in the pathophysiology of affective illness." not
Adult Psychiatry Branch, and Section on Psychiatry, National Institute of Mental Health, 9000 Rockville Pike,
Bethesda, Maryland 20014, U.S.A.
JOHN S. CARMAN ROBERT M. POST TERRY A. TEPLITZ FREDERICK K. GOODWIN.
INFLUENCE OF AGE ON NEUROHORMONAL RECEPTORS
SIR,-Every clinician knows how intensely old age can influence the sensitivity of neurohormonal receptors and therefore the response to stress or medication. Progress in clinical geriatrics is very slow for many reasons, and one of the most important sources of information for a geriatrician remains the comparison of data obtained from different age-groups. It is difficult to understand why information about the ages of the subjects investigated, essential in my opinion, is missing in some otherwise extremely interesting papers. This lack is even more striking if the subjects of the investigation are clearly geriatric as, for example, are those of Dr Carter and his colleagues (Oct. 26, p. 971) or those of Dr Benkert and others 19.
Carman, J. S., Post, R. M., Goodwin, F. K., Teplitz, T. A., Bunney, W. E., Jr. Annual Meeting, American Psychiatric Association, Detroit, Michigan, May, 1974.