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Effect of lithium citrate on adrenocortical activity in manic-depressive illness
Effect of Lithium Citrate on Adrenocortical Activity in Manic-depressive Illness By RUSSELL NOYES, JR., IRVINGC. RINGDAHL,ANDN. J. C. ANDREASEN
T
HE THERAPEUTIC EFFECTIVENESS OF LITHIUM SALTS in manicdepressive illness has been demonstrated consistently. Alterations in electrolyte balance and adrenocortical activity in this illness have also been demonstrated by a number of investigators. In an attempt to correlate these findings this investigation was designed to explore the effect of lithium upon l7-hydroxycorticosteroid (17-OHCS) production and upon urinary excretion and serum levels of sodium, potassium, and lithium in both the manic and depressed phases of the illness. A number of reports have consistently indicated that depressed patients produce corticosteroids at a relatively high rate that declines with recovery.1-3 Some investigators have hypothesized that the high rate reflects stress or struggle with illness, not unique to depression.4-6 In manic patients two different patterns of steroid production have been described. Studies comparing admission with discharge steroid levels among these patients have revealed an apparent decline in adrenal activity with recovery similar to that found in depressed patients .T-8 However, longitiudinal studies of cycling manic-depressive patients have shown lower levels of adrenal activity during the manic phase than during the depressive phase of the illness.9-11 Several investigators have explored the effect of lithium on adrenal activity. Platman and Fieve have noted among manic patients that plasma cortisol tends to increase transiently after lithium administration despite the overall trend of steroid levels to decline with recovery.s Sachar et al. observed the effects of lithium administration on cortisol production rates and plasma levels in a group of patients with affective disorders who were in remission.12 They were unable to demonstrate any meaningful changes produced by the ion. Electrolyte metabolism has also been observed to be altered in manic-depressive illness. Coppen et al. demonstrated a tendency for sodium to accumulate intracellularly in depressed patients. A normal distribution of the ion was restored upon recovery.13-14 They found this tendency toward increased residual sodium to be even greater in manic patients.15 Their studies of the effects of lithium upon sodium retention and excretion have, however, been inconc1usive.1G-17 Trautner et al. and Greenspan et al. have both suggested that manic patients tend to retain lithium, probably intracellularly, during the acute phase of their illness and to excrete the retained lithium as the mania ‘%reaks.“1*-19 Baer et al, confirming some of Trautner’s other findings, demonRUSSELLNOYES, JR., M.D.: Assistant Professor of Psychiaty, The University of Iowa, Department of Psychiatry, State Psychopathic Hospital, Iowa City, Iowa. IRVINGC. RUGDAHL, M.D.: The University of Iowa, Department of Psychiatry, State Psychopathic HOSpita& Iowa City, Iowa. N. J. C. ANDREASEN,M.D.: The University of Iowa, Department of Psychiatry, State Psychopathic Hospital, Iowa City, Iowa. COMPREHENSIVE PSYCHIATRY,VOL. 12, No. 4 (JULY), 1971
337
NOYES,
338
RINGDAHL,
AND ANDREASEN
strated that lithium administration is associated with an increased excretion of water, sodium, and potassium.“o Following these leads, this study explored four discrete areas: ( 1) The excretion of 17-OHCS in manic and depressed patients was compared longitudinally at the height of illness, the beginning of lithium administration, the point of recovery, and the substitution of placebo after recovery; (2~) the levels of serum and urinary potassium and sodium were observed during the course of lithium treatment to determine whether or not their fluctuations reflected the physiologic effects of corticosteroids; (3) a similar longitudinal comparision was made of patterns of lithium retention and excretion, testing the hypothesis that manic and depressed patients metabolize lithium differently; (4) the effect of high doses of lithium upon the clinical course of both manic and depressed patients was observed. MATERIALS
AND METHODS
The sample consisted of 13 consecutive admissions to the Iowa State Psychopathic Hospital diagnosed independently by two staff psychiatrists as having manic-depressive illness. All of the eight manic patients showed at least six of the following 10 characteristics: hyperactivity, euphoric mood, rapid stream of thought, increased sociability, increased energy, exaggerated optimism, pressure of speech, increased level of interest, distractibility, and increased interest in sex. All of the five depressed patients showed at least six of the following 10 characteristics: depressed mood, loss of interest, sleep reduction, loss of self-esteem, reduced sociability, loss of appetite, guilt feelings, motor retardation, loss of energy, and loss of hope. One manic patient was dropped after being admitted to the study due to a toxic response to the initial dose of lithium. Seven of the remaining manic patients and three of the depressed patients were of the bipolar type. Two of the depressed patients were of the umpolar type. The entire group of patients had required a mean of 6.5 previous hospitalizations following the onset of illness 16 yr earlier (mean). Five women having a mean age of 54 yr comprised the depressed group, while five women and two men having a mean age of 52 yr comprised the manic group. With the exception of one woman with diabetes mellitus, controhed by diet, all patients were in good physical health. Patients were restricted to a six-bed research ward where a special diet was provided and where 24-hr urines were collected daily. Placebo, identical in appearance to the active drug, was administered during an initial drug free period of 1 wk following admission. Thereafter each patient received 0.357 meq/kg of lithium in citrate form daily. This dose, equivalent to approximately 900 mg of lithium carbonate for a 70 kg individual, was increased after 1 wk to 0.714 meq/kg. Once patients beacme symptom-free, placebo was substituted for lithium citrate during a 2 day period. Lithium citrate administration was resumed thereafter. It became necessary to administer chlorpromazine to a few patients initially in order to achieve behavioral control. No other drugs were administered. All patients received 100 mg of NaCl/kg body weight. The daily fluid intake for all patients was a constant 2500 CC per patient. The potassium intake was 3500 mg daily. Measurements were made upon blood and 24-hr urine samples collected twice weekly during the entire course of hospitalization. A white blood and differential count was obtained from whole blood. Serum was analyzed for lithium, potassium, sodium and glucose. Electrolyte assays were performed with a Beckman Model B flame photometer. Glucose was measured colorimctrically by the Somogyi-Nelson metbod.al Twenty-four hour urine samples were analyzed for 17-OHCS, lithium, sodium, and potassium. The coritcosteroids were determined by the Porter-Silber method. *a Chlorpromazine, known to distort determinations, was removed by resin columnsa The completeness of 24-hr urine collections was determined by analying the creatinine content of all samples. Twice weekly assessments of the level of mood disturbance were made independently by two investigators at the time of blood and urine sampling. Specially developed objective
LITHIUM
CITRATE AND ADRENOCORTICAL ACTIVITY
339
rating scales for mania and depression were used. The Nurses’ Observation Scale for InPatient Evaluation was completed by the research ward personnel daily.24 A daily record was kept of any toxic symptoms of lithium. RESULTS
Eleven of the 12 patients in this study became symptom-free while receiving lithium. Disturbed behavior emerged l-3 days following the substitution of placebo in three manic and two depressed patients. These patients were asymptomatic before lithium was discontinued. The symptoms, which in every instance were of the same type as those present before treatment, persisted for 2-7 days. Despite the reintroduction of lithium one patient required an extended period of treatment to again become asymptomatic. These behavioral disturbances, for the most part, reached moderate proportions although one manic patient became delusional. One additional depressed patient who had improved moderately with lithium treatment became agitated and delusional when the treatment was discontinued. Most of the patients attributed these changes in behavior to psychological or situational factors. During the 24-hr period following the introduction of lithium an increased 17-OHCS excretion occurred in four of the manic and all of the depressed patients. Three manic patients showed no change. The mean increase in 17OHCS excretion was statistically significant for these patients, using the paired t test, at the 0.01 level. This dramatic initial response to lithium was not sustained 3 days later but reappeared during the 24 hr that followed the doubling of the dose, The pattern shown by nine patients is illustrated in Figs. 1 and 2. During the first 24 hr after the substitution of placebo a fall in 17-OHCS excretion occurred in six manic and five depressed patients. One manic patient No’ -210 -160 K+ 60 --150 4 8
45--120
Fig. L-The excretion of 17-OHCS, sodium, potassium, and lithium of a representative manic patient during lithium treatment.
15--60
I&.Lilt. Lib PlfC. Jlh. Increase
WEEKS OF HOSPlTALlZATlOti
340
NOYJZS,
RINGDAHL,
AND
ANDREASEN
Na+
Fig. B.-The excretion of 17-OHCS, sodium, potassium, and lithium of a second representative manic patient during lithium treatment.
5
3 t
;
Plac. Lith.
;
Lith. Increase
6
:+
Plac. Lith.
WEEKS OF HOSPITALIZATION showed an increase. The fall in 11 patients persisted for 24-48 hr but after the reintroduction of lithium the steroid excretion returned to preplacebo levels. Like the mean increase on initial administration of lithium, the mean decrease in 17-OHCS excretion upon the substitution of placebo amounted to approximately 30% of the mean starting level. This mean decrease was statistically sign&ant for these patients at the 0.05 level. A trend in the direction of increasing I7-OHCS excretion over the course of treatment was evident in six manic patients. Control samples were taken on the fourth to the seventh day of hospitalization before treatment was begun. The values from these samples, which represented excretion during the maximally symptomatic period after acclimatization to the hospital, were compared with those obtained from samples representing the symptom free period immediately prior to the introduction of placebo. Samples from the systom-free period yielded substantially higher values in these patients. The mean increase, which is statistically significant at the 0.05 level for the seven manic patients, may be seen in Fig. 3. It should be noted that the statistical tests reported are not independent. Two depressed patients showed a fall in excretion values over the course of treatment while one manic and three depressed patients showed no change. As may be noted from the mean excretion values for the depressed patients in Fig. 4, the early corticosteroid response to lithium in this group was more dramatic than that seen in the manic group. A marked diuresis occurred in all patients during the first 24 hr following the introduction of lithium. A mean increase in urine volume of 47% occurred for all patients. A compensatory reduction in urine volume was evident 3 days later. During the 24 hr following the abrupt discontinuation of lithium a marked reduction of urine volume occurred. This reduction, amounting to a 32% decrease in the mean urine volume, was followed by a return to normal during the subsequent 24 hr. Thus the effect upon urine volume was shortlived.
LITHIUM
CITRATE
17-OHCS
AND
ADRENOCORTICAL
Excretion
341
ACTIVITY
n= 7
in Monies
incrca$e Weeks of Hospitalization Fig. 3.-The mean excretation of 17-OHCS during lithium treatment for the manic group of patients. The first value in week four represents the average of two or more values in those cases where the length of the patient’s hospitalization exceeded 6 wk. The excretion of lithium rose rapidly in all patients, reaching an early peak within 3-10 days. In five patients this initial peak occurred 3 days after the introduction of lithium. In two manic patients, both men, the excretion of lithium rose gradually to a peak 10 days after lithium had been started and in one of them a second peak, higher than the first (43 meq/24 hr to 60 meq/ 24 hr), appeared 19 days following the introduction of lithium. Following the substitution of placebo, a sharp fall in excretion occurred in 10 patients lasting 2448 hr. The reintroduction of lithium resulted in every instance in a return to preplacebo levels of excretion within 48 hr. In five manic and one depressed patients a further increase in lithium excretion was observed 5-8
17-OHCS
Excretion
in
Depressed
n=5 l!llilll
increase
Weeks of Hospitalization Fig. I.-The mean excretion of 17-OHCS during lithium treatment for the depressed group of patients.
342
NOYES,
45-
Lithium
Excretion
in Monies
RINGDAHL,
AND
ANDREASEN
n=7
increase
Weeks
Fig. 5.-The patients.
of Hospitolizotion
mean excretion of lithium during treatment for the manic group of
days after the reintroduction of lithium. These increased values, which in four patients exceeded the lithium intake, were the highest recorded while these patients were observed. This trend may be seen in Fig. 5 where the mean values of all manic patients are presented. Four depressed and two manic patients did not show this post placebo rise in excretion although, as mentioned, one of these manic patients showed a peak excretion in the symptomfree period immediately prior to the introduction of a placebo. The mean lithium excretion values for the five depressed patients is shown in Fig. 6. Serum lithium levels during the symptom-free period were quite uniform among the depressed patients, 0.95 to 1.17 meq/liter, but quite variable among
45-
Lithium
Excretion
n=5
in Depressives
40a $ 35\ &30F ?. v
25-
9r 20$ 3 15Plctcebo 1
U&n
2
l_M?ium increase
3
Weeks Fig. &-The of patients.
4
Placebo+
L)ithium5
6
of Hospitalization
mean excretion of lithium during treatment for the depressed group
LITHIUM
CITRATE
AND
ADRENOCORTICAL
ACTIVITY
343
the manic patients, 0.59 to 1.76 meq/liter. A similar tendency toward greater variability within the manic group was observed in almost all measures, Following the introduction of lithium four manic and four depressed patients showed increases in sodium excretion in the first 24 hr. This increase was not evident 3 days later but three manic and four depressed patients showed an increased excretion when the dose was doubled. The patients who responded in this fashion showed a pattern of sodium excretion during the first week and a half of lithium administration similar to that shown in Fig. 1. This pattern paralleled that for the excretion of 17-OHCS during that same period. The mean increase during the first 24 hr of lithium administration was statistically significant using the paired t test at the 0.05 level. When placebo was substituted four manic and four depressed patients retained sodium during the first 24 hr. In all but two of these patients a compensatory rise in excretion to preplacebo levels occurred within 48 hr. A peak in sodium excretion occurred in two manic and two depressed patients on the second placebo day. Such a peak in four manic and two depressed patients occurred during the first 48 hr after the reintroduction of lithium. The mean decrease in sodium excretion for all 12 patients during the first 24 hr following the substitution of placebo was statistically significant at the 0.05 level. Comparing sodium excretion values prior to treatment with those prior to placebo administration, three manic and two depressed patients showed a definite increase, three manic and two depressed patients showed no change, and one manic and one depressed patient showed a fall. No effects were observed upon the serum level of sodium as a result of the introduction or withdrawal of lithium. Changes in potassium excretion in response to lithium administration were initially less marked than those of sodium but were sustained for a longer period of time. Five manic and three depressed patients showed an increase in excretion during the first 24 hr following the introduction of lithium. The mean increase in all patients was statistically significant at the 0.05 level. In seven of these patients values remained above pretreatment levels 3 days later. In three manic and three depressed patients the initial increase was augmented by increasing the dose of lithium. This second increase in excretion was observed 3 days after the doubling of the dose. The pattern of potassium excretion followed in eight patients was that shown in Fig. 2. Two manic and two depressed patients showed no change in potassium excretion during the first 24 hr following the substitution of placebo. One depressed and three manic patients showed an increase; two depressed patients showed a decrease. An increase in five manic and three depressed patients was evident on the second placebo day. Eight patients showed no change in potassium excretion over the course of treatment; two showed an increase and two a decrease. No change was observed in the serum levels of potassium as a result of lithium administration or withdrawal. The only positive findings from blood were from the samples taken 3 days after the introduction of lithium. Nine patients showed an increase in blood sugar (mean increase of 4.6 mg/lOO cc from 77.4 to 82.0 mg/lOO cc) and nine patients demonstrated an increase in white blood count (mean increase from 8,120 to 10,46O/cc).
344
NOYES,
RINGDAHL,
AND
ANDREASEN
DISCUSSION The favorable clinical response on the part of the depressed patients in this study was striking and suggests, as did Plain-ran and Fieve, that high doses of lithium may enhance the antidepressant action of this ion.25 The emergence of symptoms within 2448 hr upon the abrupt withdrawal of lithium, which has been reported in manic patients, may also occur in depressed ones.“6 This observation suggests that lithium may, in certain depressed patients, have a specific therapeutic action. The five patients who responded to the abrupt withdrawal of lithium by a brief behavioral disturbance were younger than the mean patient age in this series. It is perhaps important to note in this regard that the particular population studied was relatively advanced in age and chronic. The three manic and two depressed patients who responded in this fashion were among the patients who responded to the introduction and withdrawal of lithium in the manner described as typical in terms of urinary excretion of 17-OHCS, sodium, and potassium. The values obtained for two of these patients are shown in Fig. 1 and 2. In each of the three manic patients, who showed this clinical response, maximum lithium excretion occurred beginning with, or following, the symptom-free period. The diuresis which occurred in all patients during the first 24 hr of lithium administration was accompanied by an increased excretion of 17-OHCS, sodium, and potassium. With the exception of potassium these effects were no longer evident on the fourth day of lithium administration but reappeared when the dose was doubled on the eighth day. The evidence for a temporary increase in steroid production identified in this study is consistent with the findings of Platman and Fieve. 8 The elevation of plasma cortisol, they observed, resulted from administering larger doses of lithium and, perhaps for this reason, persisted longer. When lithium was discontinued the effects were the reverse of those noted above. During the first 24 hr the volume of urine was reduced, as was the excretion of 17-OHCS and sodium. These effects, which persisted for 24-48 hr, were promptly reversed upon the reintroduction of lithium. Potassium excretion showed little change until after 24 hr of placebo substitution but then showed a striking increase. Despite the reintroduction of lithium this increase in potassium excretion persisted 5-11 days. Steroid excretion among the manic patients showed a tendency to increase over the course of lithium treatment. Like the depressed patients they showed a definite steroid response to the initial administration of lithium and again to the doubling of the dose but, unlike the depressed patients, their excretion of 17-OHCS failed to return to the pretreatment baseline. This finding suggests that lithium treatment is associated with increased production of steroids in manic patients. It could not be accounted for on the basis of clinically evident lithium toxicity. By careful control of water and electrolyte intake it was possible to demonstrate a tendency among manic patients to retain lithium during the symptomatic phase of their illness and eliminate it at an increased rate after becoming symptom-free. Only one depressed patient showed this tendency and, taken as a group, these patients on an equivalent dosage of lithium excreted the
LJTXUUM CITRATE AND ADRENOCOR’IXXL
ACTIVITY
345
ion at a higher rate than the manics through the first 2% wk of the treatment. These findings confinn those of Trautner et al. who first reported this unique aspect of the metabolism of lithium in manic patients.l* Each of the five manic patients who showed the tendency toward lithium retention during the symptomatic phase of their illness also showed an increased 17-OHCS excretion associated with the treatment. Three manic patients promptly developed a recurrence of symptoms upon the withdrawal of lithium which was followed by a return to a symptom-free state when lithium was reintroduced. In these patients lithium’s clinical effectiveness was adequately demonstrated. All three showed increased excretion of 17-OHCS, sodium, and lithium in the symptom free period as compared with pretreatment base-line values. The trends in two of these patients are illustrated in Fig. 1 and 2. No such trends were observed in the two depressed patients who became symptomatic when lithium was withdrawn. The short-lived shifts in 17-OHCS excretion which were associated with changes in electrolyte excretion occurring in the same direction may indicate that lithium affects adrenal and renal function independently, According to its physiologic action, an increased production of 17-OHCS might be expected to be associated with retention of water and sodium even though the effects of glucocorticoids on mineral metabolism are relatively weak. Conversely, a decreased production of 17-OHCS might be expected to be associated with diuresis and increased sodium excretion, The data show the opposite effects, which makes it less probable that the electrolyte changes are secondary to steroid change. Adrenal cortical activity might, however, represent a secondary response to electrolyte shifts associated with lithium administration. Such a response might serve to compensate for the temporary disturbance in electrolye metabolism resulting from lithium treatment. On the other hand, the shifts in 17-OHCS excretion might, as Platman and Fieve suggest, simply represent a stress response to lithium. An increase in steroid excretion over base-line values was demonstrated in manic patients in the symptom-free period. This increase developed in association with clinical improvement and lithium accumulation and retention. It may have been primarily related to one or even both of these events. Again, however, the trend toward increased sodium excretion would suggest that the steroid response was not primary. The depressed patients did not show the increased steroid excretion, a finding which differentiated the two groups metabolically. SUMMARY Twelve manic-depressive patients were treated with lithium citrate on a research ward where fluid and electrolyte intake was controlled. The following findings were noted: Four of the five depressed patients became symptom free as did all seven manic patients. The substitution of placebo during the symptom-free period was associated within 244S hr with recurrence of depressive or manic symptomatology in three manic and two depressed patients. In addition to its well
346
NOYES,
RINGDAHL,
AND
ANDREASEN
established effect upon mania, lithium, in these cases, had a specific therapeutic effect upon depression as well. The introduction of lithium was associated with a temporary increase in 17-OHCS excretion along with an increased excretion of water, sodium, and potassium. These effects were not sustained, in some instances, beyond 24 hr. The substitution of placebo for lithium during the course of treatment resulted in changes in excretion which were in the opposite direction. The direction of the changes in steroid excretion suggests that lithium’s effect upon electrolyte metabolism is not secondary to its action upon the adrenal cortex. Manic patients showed a tendency to retain lithium while symptomatic and to excrete amounts in excess of that administered after becoming symptomfree. This retention of lithium tended to differentiate the manic from the depressed patients. Manic patients treated with lithium showed a higher rate of 17-OHCS excretion after they had become symptom-free than before administration of lithium. This increase may have been secondary to clinical improvement or to retention of lithium. The depressed patients did not show this trend towards increased steroid excretion. REFERENCES 1. Bridges, P. K., and Jones, M. T.: The diurnal rhythm of plasma cortisol concentration in depression. Brit. J. Psychiat. 112: 1257, 1966. 2. Gibbons, J. L.: Cortisol secreation rate in depressive illness, Arch. Gen. Psychiat. (Chicago) 10:572, 1964. 3. Rubin, R. T., and Mandell, A. J.: Adrenal cortical activity in pathological emotional states: A Review. Amer. J. PSYchiat. 123:4, 1966. 4. Bunney, W. E., and Hamburg, D. A.: Correlations between behavioral variables and urinary I7-hydroxycorticosteroids in depressed patients. Psychosom. Med. 27:299, 1965. 5. Sachar, E. J.: Corticosteroids in depressive illness. Arch. Gen. Psychiat. (Chicago) 17:554, 1967. 6. Schwartz, M., Mandell, A. J., Green, R., and Ferman, R.: Mood, motility, and 17hydroxycorticoid excretion; a polyvariable case study. Brit. J. Psychiat. 112:149, 1966. 7. Brooksbank, B. W. L., and Coppen, A.: Plasma 17-hydroxycorticosteroids in affective disorders. Brit. Psychiat. 113:395, 1967. 8. Platman, S. R., and Fieve, R. R.: Lithium carbonate and plasma cortisol response in the aifective disorders. Arch. Gen. Psychiat. (Chicago) 18:591, 1968. 9. Burmey, W. E., Jr., and Hartman, E. L.: Study of a Patient with 48-Hour Manic-
Depressive (Chicago)
Cycles. Arch. 12:619, 1965.
Gen.
Psychiat.
10. Gibbons, J. L., and McHugh, P. R.: Plasma cortisol in depressive illness. Psychiat. Res. 1:162, 1962. 11. Rizzo, N. D., Fox, H. M., Laidlaw, J. C., and Thorn, G. W.: Concurrent observations of behavior changes and of adrenocortical variations in cyc’othymic patient during a period of twelve months. Ann. Intern Med. 41:798, 1954. 12. Sachar, E. J., Helhnan, L., Kream, J., Fukushima, D. K., and Gallagher, T. F.: Effect of lithium-carbonate therapy on adrenocortical activity. Arch. Gen. Psychiat. ( Chicago ) 22: 304, 1970. 13. Coppen, A., and Shaw, D. M.: Mineral metabolism in melancholia. Brit. Med. J. 2: 1439, 1963. 14. Coppen, A.: affective disorders. 1133, 1965.
Mineral Brit. J.
metabolism in Psychiat. 111:
15. Coppen, A., Shaw, C. M., Malleson, A., and Costa@ R.: Mineral metabolism in mania. Brit. Med. J. 1:71, 1966. 16. Coppen, A., Malleson, A., and Shaw, D. M.: Effects of lithium carbonate on electrolyte distribution in man. Lancet 1: 682, 1965. 17. Coppen, A., and Shaw, D. M.: The distribution of electrolytes and water in pa-
LITHIUM
CITRATE
AND
tients after taking lithium
ADRENOCORTICAL
carbonate.
Lancet
2: 805, 1967. 18. Trautner, E. M., Morris, II., Roach, C. H., and Gershon, S.: The excretion and retention of ingested lithium and its effect on the ionic balance of man. Med. J. August 42: 280, 1955. 19. Greenspan, K., Goodwin, F. K., Bunney, W. E., Jr., and Durrell, J.: Lithium ion retention and distribution. Arch. Gen. Psychiat. (Chicago) 19:664, 1968. 20. Baer, L., Platman, S. Ft., and Fieve, R. R.: The role of electrolytes in affective disorders. Arch. Gen. Psychiat. (Chicago) 22: 108, 1970. 21. Somogyi, M.: Determination of blood sugar. J. Biol. Chem. 160:69, 1945.
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347
22. Silber, R. H., and Porter, C. C.: The determination of 17, 21-dihydroxy-26-ketosteroids in urine and plasma. J. Biol. C&em., 210: 923, 1954. 23. McEvoy, D.: Proceedure developed using a Dowex column at the Eastern Pennsylvania Psychiatric Institute. 24. Honigfeld, G., Gillis, R. D., and Klett, C. J.: NOSIE-30: A treatment-sensitive ward behavior scale. Psychol. Rep. 19:180, 1966. 25. Platman, S. R., and Fieve, R. R.: Lithium retention and excretion. Arch. Gen. Psychiat. (Chicago) 20:285, 1969. 26. Bunney, W. E., Jr., Goodwin, F. K., David, J. M., and Fawcett, A.: A behavioralbiochemical Study of Lithium Treatment, Amer. J. Psychiat. 125:499, 1968.
T
HE THERAPEUTIC EFFECTIVENESS OF LITHIUM SALTS in manicdepressive illness has been demonstrated consistently. Alterations in electrolyte balance and adrenocortical activity in this illness have also been demonstrated by a number of investigators. In an attempt to correlate these findings this investigation was designed to explore the effect of lithium upon l7-hydroxycorticosteroid (17-OHCS) production and upon urinary excretion and serum levels of sodium, potassium, and lithium in both the manic and depressed phases of the illness. A number of reports have consistently indicated that depressed patients produce corticosteroids at a relatively high rate that declines with recovery.1-3 Some investigators have hypothesized that the high rate reflects stress or struggle with illness, not unique to depression.4-6 In manic patients two different patterns of steroid production have been described. Studies comparing admission with discharge steroid levels among these patients have revealed an apparent decline in adrenal activity with recovery similar to that found in depressed patients .T-8 However, longitiudinal studies of cycling manic-depressive patients have shown lower levels of adrenal activity during the manic phase than during the depressive phase of the illness.9-11 Several investigators have explored the effect of lithium on adrenal activity. Platman and Fieve have noted among manic patients that plasma cortisol tends to increase transiently after lithium administration despite the overall trend of steroid levels to decline with recovery.s Sachar et al. observed the effects of lithium administration on cortisol production rates and plasma levels in a group of patients with affective disorders who were in remission.12 They were unable to demonstrate any meaningful changes produced by the ion. Electrolyte metabolism has also been observed to be altered in manic-depressive illness. Coppen et al. demonstrated a tendency for sodium to accumulate intracellularly in depressed patients. A normal distribution of the ion was restored upon recovery.13-14 They found this tendency toward increased residual sodium to be even greater in manic patients.15 Their studies of the effects of lithium upon sodium retention and excretion have, however, been inconc1usive.1G-17 Trautner et al. and Greenspan et al. have both suggested that manic patients tend to retain lithium, probably intracellularly, during the acute phase of their illness and to excrete the retained lithium as the mania ‘%reaks.“1*-19 Baer et al, confirming some of Trautner’s other findings, demonRUSSELLNOYES, JR., M.D.: Assistant Professor of Psychiaty, The University of Iowa, Department of Psychiatry, State Psychopathic Hospital, Iowa City, Iowa. IRVINGC. RUGDAHL, M.D.: The University of Iowa, Department of Psychiatry, State Psychopathic HOSpita& Iowa City, Iowa. N. J. C. ANDREASEN,M.D.: The University of Iowa, Department of Psychiatry, State Psychopathic Hospital, Iowa City, Iowa. COMPREHENSIVE PSYCHIATRY,VOL. 12, No. 4 (JULY), 1971
337
NOYES,
338
RINGDAHL,
AND ANDREASEN
strated that lithium administration is associated with an increased excretion of water, sodium, and potassium.“o Following these leads, this study explored four discrete areas: ( 1) The excretion of 17-OHCS in manic and depressed patients was compared longitudinally at the height of illness, the beginning of lithium administration, the point of recovery, and the substitution of placebo after recovery; (2~) the levels of serum and urinary potassium and sodium were observed during the course of lithium treatment to determine whether or not their fluctuations reflected the physiologic effects of corticosteroids; (3) a similar longitudinal comparision was made of patterns of lithium retention and excretion, testing the hypothesis that manic and depressed patients metabolize lithium differently; (4) the effect of high doses of lithium upon the clinical course of both manic and depressed patients was observed. MATERIALS
AND METHODS
The sample consisted of 13 consecutive admissions to the Iowa State Psychopathic Hospital diagnosed independently by two staff psychiatrists as having manic-depressive illness. All of the eight manic patients showed at least six of the following 10 characteristics: hyperactivity, euphoric mood, rapid stream of thought, increased sociability, increased energy, exaggerated optimism, pressure of speech, increased level of interest, distractibility, and increased interest in sex. All of the five depressed patients showed at least six of the following 10 characteristics: depressed mood, loss of interest, sleep reduction, loss of self-esteem, reduced sociability, loss of appetite, guilt feelings, motor retardation, loss of energy, and loss of hope. One manic patient was dropped after being admitted to the study due to a toxic response to the initial dose of lithium. Seven of the remaining manic patients and three of the depressed patients were of the bipolar type. Two of the depressed patients were of the umpolar type. The entire group of patients had required a mean of 6.5 previous hospitalizations following the onset of illness 16 yr earlier (mean). Five women having a mean age of 54 yr comprised the depressed group, while five women and two men having a mean age of 52 yr comprised the manic group. With the exception of one woman with diabetes mellitus, controhed by diet, all patients were in good physical health. Patients were restricted to a six-bed research ward where a special diet was provided and where 24-hr urines were collected daily. Placebo, identical in appearance to the active drug, was administered during an initial drug free period of 1 wk following admission. Thereafter each patient received 0.357 meq/kg of lithium in citrate form daily. This dose, equivalent to approximately 900 mg of lithium carbonate for a 70 kg individual, was increased after 1 wk to 0.714 meq/kg. Once patients beacme symptom-free, placebo was substituted for lithium citrate during a 2 day period. Lithium citrate administration was resumed thereafter. It became necessary to administer chlorpromazine to a few patients initially in order to achieve behavioral control. No other drugs were administered. All patients received 100 mg of NaCl/kg body weight. The daily fluid intake for all patients was a constant 2500 CC per patient. The potassium intake was 3500 mg daily. Measurements were made upon blood and 24-hr urine samples collected twice weekly during the entire course of hospitalization. A white blood and differential count was obtained from whole blood. Serum was analyzed for lithium, potassium, sodium and glucose. Electrolyte assays were performed with a Beckman Model B flame photometer. Glucose was measured colorimctrically by the Somogyi-Nelson metbod.al Twenty-four hour urine samples were analyzed for 17-OHCS, lithium, sodium, and potassium. The coritcosteroids were determined by the Porter-Silber method. *a Chlorpromazine, known to distort determinations, was removed by resin columnsa The completeness of 24-hr urine collections was determined by analying the creatinine content of all samples. Twice weekly assessments of the level of mood disturbance were made independently by two investigators at the time of blood and urine sampling. Specially developed objective
LITHIUM
CITRATE AND ADRENOCORTICAL ACTIVITY
339
rating scales for mania and depression were used. The Nurses’ Observation Scale for InPatient Evaluation was completed by the research ward personnel daily.24 A daily record was kept of any toxic symptoms of lithium. RESULTS
Eleven of the 12 patients in this study became symptom-free while receiving lithium. Disturbed behavior emerged l-3 days following the substitution of placebo in three manic and two depressed patients. These patients were asymptomatic before lithium was discontinued. The symptoms, which in every instance were of the same type as those present before treatment, persisted for 2-7 days. Despite the reintroduction of lithium one patient required an extended period of treatment to again become asymptomatic. These behavioral disturbances, for the most part, reached moderate proportions although one manic patient became delusional. One additional depressed patient who had improved moderately with lithium treatment became agitated and delusional when the treatment was discontinued. Most of the patients attributed these changes in behavior to psychological or situational factors. During the 24-hr period following the introduction of lithium an increased 17-OHCS excretion occurred in four of the manic and all of the depressed patients. Three manic patients showed no change. The mean increase in 17OHCS excretion was statistically significant for these patients, using the paired t test, at the 0.01 level. This dramatic initial response to lithium was not sustained 3 days later but reappeared during the 24 hr that followed the doubling of the dose, The pattern shown by nine patients is illustrated in Figs. 1 and 2. During the first 24 hr after the substitution of placebo a fall in 17-OHCS excretion occurred in six manic and five depressed patients. One manic patient No’ -210 -160 K+ 60 --150 4 8
45--120
Fig. L-The excretion of 17-OHCS, sodium, potassium, and lithium of a representative manic patient during lithium treatment.
15--60
I&.Lilt. Lib PlfC. Jlh. Increase
WEEKS OF HOSPlTALlZATlOti
340
NOYJZS,
RINGDAHL,
AND
ANDREASEN
Na+
Fig. B.-The excretion of 17-OHCS, sodium, potassium, and lithium of a second representative manic patient during lithium treatment.
5
3 t
;
Plac. Lith.
;
Lith. Increase
6
:+
Plac. Lith.
WEEKS OF HOSPITALIZATION showed an increase. The fall in 11 patients persisted for 24-48 hr but after the reintroduction of lithium the steroid excretion returned to preplacebo levels. Like the mean increase on initial administration of lithium, the mean decrease in 17-OHCS excretion upon the substitution of placebo amounted to approximately 30% of the mean starting level. This mean decrease was statistically sign&ant for these patients at the 0.05 level. A trend in the direction of increasing I7-OHCS excretion over the course of treatment was evident in six manic patients. Control samples were taken on the fourth to the seventh day of hospitalization before treatment was begun. The values from these samples, which represented excretion during the maximally symptomatic period after acclimatization to the hospital, were compared with those obtained from samples representing the symptom free period immediately prior to the introduction of placebo. Samples from the systom-free period yielded substantially higher values in these patients. The mean increase, which is statistically significant at the 0.05 level for the seven manic patients, may be seen in Fig. 3. It should be noted that the statistical tests reported are not independent. Two depressed patients showed a fall in excretion values over the course of treatment while one manic and three depressed patients showed no change. As may be noted from the mean excretion values for the depressed patients in Fig. 4, the early corticosteroid response to lithium in this group was more dramatic than that seen in the manic group. A marked diuresis occurred in all patients during the first 24 hr following the introduction of lithium. A mean increase in urine volume of 47% occurred for all patients. A compensatory reduction in urine volume was evident 3 days later. During the 24 hr following the abrupt discontinuation of lithium a marked reduction of urine volume occurred. This reduction, amounting to a 32% decrease in the mean urine volume, was followed by a return to normal during the subsequent 24 hr. Thus the effect upon urine volume was shortlived.
LITHIUM
CITRATE
17-OHCS
AND
ADRENOCORTICAL
Excretion
341
ACTIVITY
n= 7
in Monies
incrca$e Weeks of Hospitalization Fig. 3.-The mean excretation of 17-OHCS during lithium treatment for the manic group of patients. The first value in week four represents the average of two or more values in those cases where the length of the patient’s hospitalization exceeded 6 wk. The excretion of lithium rose rapidly in all patients, reaching an early peak within 3-10 days. In five patients this initial peak occurred 3 days after the introduction of lithium. In two manic patients, both men, the excretion of lithium rose gradually to a peak 10 days after lithium had been started and in one of them a second peak, higher than the first (43 meq/24 hr to 60 meq/ 24 hr), appeared 19 days following the introduction of lithium. Following the substitution of placebo, a sharp fall in excretion occurred in 10 patients lasting 2448 hr. The reintroduction of lithium resulted in every instance in a return to preplacebo levels of excretion within 48 hr. In five manic and one depressed patients a further increase in lithium excretion was observed 5-8
17-OHCS
Excretion
in
Depressed
n=5 l!llilll
increase
Weeks of Hospitalization Fig. I.-The mean excretion of 17-OHCS during lithium treatment for the depressed group of patients.
342
NOYES,
45-
Lithium
Excretion
in Monies
RINGDAHL,
AND
ANDREASEN
n=7
increase
Weeks
Fig. 5.-The patients.
of Hospitolizotion
mean excretion of lithium during treatment for the manic group of
days after the reintroduction of lithium. These increased values, which in four patients exceeded the lithium intake, were the highest recorded while these patients were observed. This trend may be seen in Fig. 5 where the mean values of all manic patients are presented. Four depressed and two manic patients did not show this post placebo rise in excretion although, as mentioned, one of these manic patients showed a peak excretion in the symptomfree period immediately prior to the introduction of a placebo. The mean lithium excretion values for the five depressed patients is shown in Fig. 6. Serum lithium levels during the symptom-free period were quite uniform among the depressed patients, 0.95 to 1.17 meq/liter, but quite variable among
45-
Lithium
Excretion
n=5
in Depressives
40a $ 35\ &30F ?. v
25-
9r 20$ 3 15Plctcebo 1
U&n
2
l_M?ium increase
3
Weeks Fig. &-The of patients.
4
Placebo+
L)ithium5
6
of Hospitalization
mean excretion of lithium during treatment for the depressed group
LITHIUM
CITRATE
AND
ADRENOCORTICAL
ACTIVITY
343
the manic patients, 0.59 to 1.76 meq/liter. A similar tendency toward greater variability within the manic group was observed in almost all measures, Following the introduction of lithium four manic and four depressed patients showed increases in sodium excretion in the first 24 hr. This increase was not evident 3 days later but three manic and four depressed patients showed an increased excretion when the dose was doubled. The patients who responded in this fashion showed a pattern of sodium excretion during the first week and a half of lithium administration similar to that shown in Fig. 1. This pattern paralleled that for the excretion of 17-OHCS during that same period. The mean increase during the first 24 hr of lithium administration was statistically significant using the paired t test at the 0.05 level. When placebo was substituted four manic and four depressed patients retained sodium during the first 24 hr. In all but two of these patients a compensatory rise in excretion to preplacebo levels occurred within 48 hr. A peak in sodium excretion occurred in two manic and two depressed patients on the second placebo day. Such a peak in four manic and two depressed patients occurred during the first 48 hr after the reintroduction of lithium. The mean decrease in sodium excretion for all 12 patients during the first 24 hr following the substitution of placebo was statistically significant at the 0.05 level. Comparing sodium excretion values prior to treatment with those prior to placebo administration, three manic and two depressed patients showed a definite increase, three manic and two depressed patients showed no change, and one manic and one depressed patient showed a fall. No effects were observed upon the serum level of sodium as a result of the introduction or withdrawal of lithium. Changes in potassium excretion in response to lithium administration were initially less marked than those of sodium but were sustained for a longer period of time. Five manic and three depressed patients showed an increase in excretion during the first 24 hr following the introduction of lithium. The mean increase in all patients was statistically significant at the 0.05 level. In seven of these patients values remained above pretreatment levels 3 days later. In three manic and three depressed patients the initial increase was augmented by increasing the dose of lithium. This second increase in excretion was observed 3 days after the doubling of the dose. The pattern of potassium excretion followed in eight patients was that shown in Fig. 2. Two manic and two depressed patients showed no change in potassium excretion during the first 24 hr following the substitution of placebo. One depressed and three manic patients showed an increase; two depressed patients showed a decrease. An increase in five manic and three depressed patients was evident on the second placebo day. Eight patients showed no change in potassium excretion over the course of treatment; two showed an increase and two a decrease. No change was observed in the serum levels of potassium as a result of lithium administration or withdrawal. The only positive findings from blood were from the samples taken 3 days after the introduction of lithium. Nine patients showed an increase in blood sugar (mean increase of 4.6 mg/lOO cc from 77.4 to 82.0 mg/lOO cc) and nine patients demonstrated an increase in white blood count (mean increase from 8,120 to 10,46O/cc).
344
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AND
ANDREASEN
DISCUSSION The favorable clinical response on the part of the depressed patients in this study was striking and suggests, as did Plain-ran and Fieve, that high doses of lithium may enhance the antidepressant action of this ion.25 The emergence of symptoms within 2448 hr upon the abrupt withdrawal of lithium, which has been reported in manic patients, may also occur in depressed ones.“6 This observation suggests that lithium may, in certain depressed patients, have a specific therapeutic action. The five patients who responded to the abrupt withdrawal of lithium by a brief behavioral disturbance were younger than the mean patient age in this series. It is perhaps important to note in this regard that the particular population studied was relatively advanced in age and chronic. The three manic and two depressed patients who responded in this fashion were among the patients who responded to the introduction and withdrawal of lithium in the manner described as typical in terms of urinary excretion of 17-OHCS, sodium, and potassium. The values obtained for two of these patients are shown in Fig. 1 and 2. In each of the three manic patients, who showed this clinical response, maximum lithium excretion occurred beginning with, or following, the symptom-free period. The diuresis which occurred in all patients during the first 24 hr of lithium administration was accompanied by an increased excretion of 17-OHCS, sodium, and potassium. With the exception of potassium these effects were no longer evident on the fourth day of lithium administration but reappeared when the dose was doubled on the eighth day. The evidence for a temporary increase in steroid production identified in this study is consistent with the findings of Platman and Fieve. 8 The elevation of plasma cortisol, they observed, resulted from administering larger doses of lithium and, perhaps for this reason, persisted longer. When lithium was discontinued the effects were the reverse of those noted above. During the first 24 hr the volume of urine was reduced, as was the excretion of 17-OHCS and sodium. These effects, which persisted for 24-48 hr, were promptly reversed upon the reintroduction of lithium. Potassium excretion showed little change until after 24 hr of placebo substitution but then showed a striking increase. Despite the reintroduction of lithium this increase in potassium excretion persisted 5-11 days. Steroid excretion among the manic patients showed a tendency to increase over the course of lithium treatment. Like the depressed patients they showed a definite steroid response to the initial administration of lithium and again to the doubling of the dose but, unlike the depressed patients, their excretion of 17-OHCS failed to return to the pretreatment baseline. This finding suggests that lithium treatment is associated with increased production of steroids in manic patients. It could not be accounted for on the basis of clinically evident lithium toxicity. By careful control of water and electrolyte intake it was possible to demonstrate a tendency among manic patients to retain lithium during the symptomatic phase of their illness and eliminate it at an increased rate after becoming symptom-free. Only one depressed patient showed this tendency and, taken as a group, these patients on an equivalent dosage of lithium excreted the
LJTXUUM CITRATE AND ADRENOCOR’IXXL
ACTIVITY
345
ion at a higher rate than the manics through the first 2% wk of the treatment. These findings confinn those of Trautner et al. who first reported this unique aspect of the metabolism of lithium in manic patients.l* Each of the five manic patients who showed the tendency toward lithium retention during the symptomatic phase of their illness also showed an increased 17-OHCS excretion associated with the treatment. Three manic patients promptly developed a recurrence of symptoms upon the withdrawal of lithium which was followed by a return to a symptom-free state when lithium was reintroduced. In these patients lithium’s clinical effectiveness was adequately demonstrated. All three showed increased excretion of 17-OHCS, sodium, and lithium in the symptom free period as compared with pretreatment base-line values. The trends in two of these patients are illustrated in Fig. 1 and 2. No such trends were observed in the two depressed patients who became symptomatic when lithium was withdrawn. The short-lived shifts in 17-OHCS excretion which were associated with changes in electrolyte excretion occurring in the same direction may indicate that lithium affects adrenal and renal function independently, According to its physiologic action, an increased production of 17-OHCS might be expected to be associated with retention of water and sodium even though the effects of glucocorticoids on mineral metabolism are relatively weak. Conversely, a decreased production of 17-OHCS might be expected to be associated with diuresis and increased sodium excretion, The data show the opposite effects, which makes it less probable that the electrolyte changes are secondary to steroid change. Adrenal cortical activity might, however, represent a secondary response to electrolyte shifts associated with lithium administration. Such a response might serve to compensate for the temporary disturbance in electrolye metabolism resulting from lithium treatment. On the other hand, the shifts in 17-OHCS excretion might, as Platman and Fieve suggest, simply represent a stress response to lithium. An increase in steroid excretion over base-line values was demonstrated in manic patients in the symptom-free period. This increase developed in association with clinical improvement and lithium accumulation and retention. It may have been primarily related to one or even both of these events. Again, however, the trend toward increased sodium excretion would suggest that the steroid response was not primary. The depressed patients did not show the increased steroid excretion, a finding which differentiated the two groups metabolically. SUMMARY Twelve manic-depressive patients were treated with lithium citrate on a research ward where fluid and electrolyte intake was controlled. The following findings were noted: Four of the five depressed patients became symptom free as did all seven manic patients. The substitution of placebo during the symptom-free period was associated within 244S hr with recurrence of depressive or manic symptomatology in three manic and two depressed patients. In addition to its well
346
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ANDREASEN
established effect upon mania, lithium, in these cases, had a specific therapeutic effect upon depression as well. The introduction of lithium was associated with a temporary increase in 17-OHCS excretion along with an increased excretion of water, sodium, and potassium. These effects were not sustained, in some instances, beyond 24 hr. The substitution of placebo for lithium during the course of treatment resulted in changes in excretion which were in the opposite direction. The direction of the changes in steroid excretion suggests that lithium’s effect upon electrolyte metabolism is not secondary to its action upon the adrenal cortex. Manic patients showed a tendency to retain lithium while symptomatic and to excrete amounts in excess of that administered after becoming symptomfree. This retention of lithium tended to differentiate the manic from the depressed patients. Manic patients treated with lithium showed a higher rate of 17-OHCS excretion after they had become symptom-free than before administration of lithium. This increase may have been secondary to clinical improvement or to retention of lithium. The depressed patients did not show this trend towards increased steroid excretion. REFERENCES 1. Bridges, P. K., and Jones, M. T.: The diurnal rhythm of plasma cortisol concentration in depression. Brit. J. Psychiat. 112: 1257, 1966. 2. Gibbons, J. L.: Cortisol secreation rate in depressive illness, Arch. Gen. Psychiat. (Chicago) 10:572, 1964. 3. Rubin, R. T., and Mandell, A. J.: Adrenal cortical activity in pathological emotional states: A Review. Amer. J. PSYchiat. 123:4, 1966. 4. Bunney, W. E., and Hamburg, D. A.: Correlations between behavioral variables and urinary I7-hydroxycorticosteroids in depressed patients. Psychosom. Med. 27:299, 1965. 5. Sachar, E. J.: Corticosteroids in depressive illness. Arch. Gen. Psychiat. (Chicago) 17:554, 1967. 6. Schwartz, M., Mandell, A. J., Green, R., and Ferman, R.: Mood, motility, and 17hydroxycorticoid excretion; a polyvariable case study. Brit. J. Psychiat. 112:149, 1966. 7. Brooksbank, B. W. L., and Coppen, A.: Plasma 17-hydroxycorticosteroids in affective disorders. Brit. Psychiat. 113:395, 1967. 8. Platman, S. R., and Fieve, R. R.: Lithium carbonate and plasma cortisol response in the aifective disorders. Arch. Gen. Psychiat. (Chicago) 18:591, 1968. 9. Burmey, W. E., Jr., and Hartman, E. L.: Study of a Patient with 48-Hour Manic-
Depressive (Chicago)
Cycles. Arch. 12:619, 1965.
Gen.
Psychiat.
10. Gibbons, J. L., and McHugh, P. R.: Plasma cortisol in depressive illness. Psychiat. Res. 1:162, 1962. 11. Rizzo, N. D., Fox, H. M., Laidlaw, J. C., and Thorn, G. W.: Concurrent observations of behavior changes and of adrenocortical variations in cyc’othymic patient during a period of twelve months. Ann. Intern Med. 41:798, 1954. 12. Sachar, E. J., Helhnan, L., Kream, J., Fukushima, D. K., and Gallagher, T. F.: Effect of lithium-carbonate therapy on adrenocortical activity. Arch. Gen. Psychiat. ( Chicago ) 22: 304, 1970. 13. Coppen, A., and Shaw, D. M.: Mineral metabolism in melancholia. Brit. Med. J. 2: 1439, 1963. 14. Coppen, A.: affective disorders. 1133, 1965.
Mineral Brit. J.
metabolism in Psychiat. 111:
15. Coppen, A., Shaw, C. M., Malleson, A., and Costa@ R.: Mineral metabolism in mania. Brit. Med. J. 1:71, 1966. 16. Coppen, A., Malleson, A., and Shaw, D. M.: Effects of lithium carbonate on electrolyte distribution in man. Lancet 1: 682, 1965. 17. Coppen, A., and Shaw, D. M.: The distribution of electrolytes and water in pa-
LITHIUM
CITRATE
AND
tients after taking lithium
ADRENOCORTICAL
carbonate.
Lancet
2: 805, 1967. 18. Trautner, E. M., Morris, II., Roach, C. H., and Gershon, S.: The excretion and retention of ingested lithium and its effect on the ionic balance of man. Med. J. August 42: 280, 1955. 19. Greenspan, K., Goodwin, F. K., Bunney, W. E., Jr., and Durrell, J.: Lithium ion retention and distribution. Arch. Gen. Psychiat. (Chicago) 19:664, 1968. 20. Baer, L., Platman, S. Ft., and Fieve, R. R.: The role of electrolytes in affective disorders. Arch. Gen. Psychiat. (Chicago) 22: 108, 1970. 21. Somogyi, M.: Determination of blood sugar. J. Biol. Chem. 160:69, 1945.
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347
22. Silber, R. H., and Porter, C. C.: The determination of 17, 21-dihydroxy-26-ketosteroids in urine and plasma. J. Biol. C&em., 210: 923, 1954. 23. McEvoy, D.: Proceedure developed using a Dowex column at the Eastern Pennsylvania Psychiatric Institute. 24. Honigfeld, G., Gillis, R. D., and Klett, C. J.: NOSIE-30: A treatment-sensitive ward behavior scale. Psychol. Rep. 19:180, 1966. 25. Platman, S. R., and Fieve, R. R.: Lithium retention and excretion. Arch. Gen. Psychiat. (Chicago) 20:285, 1969. 26. Bunney, W. E., Jr., Goodwin, F. K., David, J. M., and Fawcett, A.: A behavioralbiochemical Study of Lithium Treatment, Amer. J. Psychiat. 125:499, 1968.