Effect of Epinephrine on the Adrenocortical Activity of Psychotic Patients

Transcription

1 Effect of Epinephrine on the Adrenocortical Activity of Psychotic Patients HAROLD WERBIN, Ph.D.; S. M. SEIDLIN, M.D.; LESTER COHEN, M.D.; and JOSEPH S. A. MILLER, M.D. J.HE work of the Worcester Foundation Group (, 12) indicates that there is a lower level of adrenocortical response in chronic schizophrenic patients to such stresses as: 1) the pursuit-meter, 2) the Target-ball frustration test, 3) ACTH, and 4) the Exton-Rose oral glucose tolerance test. On the basis of their data, they inferred that the patients were suffering from a "relative hypoadrenalism." This hypothesis seems to be contradicted by the work of Parsons et al. They found that both normals and psychotics responded with a lymphocytopenia of about the same magnitude, similar to that resulting from insulin and electroshock treatment. Since lymphocytopenia is believed to be one of the pituitary-adrenocortical responses to stress (4), they concluded that the adrenocortical activity of the psychotic individual was adequate in its response to physiological stresses but diminished in its reaction to psychological stresses. Recently Altschule et al. showed that the response of the adrenal cortex to ACTH in schizophrenic or depressed patients was comparable to that of psychoneurotic patients. From the Department of Biochemistry, Hillside Hospital, Glen Oaks, New York. This work was supported by a grant from the Dazian Foundation for Medical Research. After this manuscript had been prepared, a paper by Bliss et al. appeared on the effects of adrenalin on the adrenocortical function in man. We were pleased to find their conclusions in agreement with our own. The technical assistance of Mr. Stanley S. Kline, Miss Charlotte Greenberg, and Mr. John Croghan is acknowledged. Received for publication May 21, VOL. XIV, NO. 6, 1952 This work was performed on a group of patients during chronic and acute phases of their psychoses. In view of the contradictory results among the several workers in the field, it seemed worthwhile to pursue the problem further. The purpose of the present investigation was to determine whether a quantitative difference exists in adrenocortical responses to epinephrine stress between psychotic and normal individuals. The use of subcutaneous injections of epinephrine as a physiological stress seemed justified because: 1) the drug was readily available, 2,) its administration would involve a minimum of psychological factors (only those involved in the test procedure itself), and 3) considerable evidence in the literature indicates that epinephrine activates the adrenal cortex indirectly by effecting the release of ACTH from the anterior pituitary. The work of Recant et al. on men, dogs, and rats presents convincing evidence for the support of such a theory. They proposed the use of an "Epinephrine Test" to measure the ability of the pituitary-adrenal system to respond to stress. This test consists of measuring the drop in number of circulating eosinophiles following subcutaneous injection of 0.3 mg. of epinephrine or intravenous administration of 0.2 mg. of the drug in 200 ml. of saline solution. The former procedure was chosen as a stress for the present study because there appeared to be fewer psychological factors with which to contend. In addition to the eosinophile count, other indices of adrenocortical activity were concurrently determined. These included blood uric acid, potassium and sodium, urine uric acid, creatinine, neutral 17-

2 470 RESPONSE TO EPINEPHRINE ketosteroids, potassium, and sodium. Blood sugars were run in order to check on the metabolic activity of the epinephrine. Details of the Test Procedure The patient was awakened at 6 a.m., voided, and drank one glass of water; two more glasses followed, one at 7 and one at a.m. Urine collections were made from 6 to a.m. in one bottle (pre-epinephrine) and from to 12 noon in a second bottle (postepinephrine). A pre-epinephrine sample of venous blood of blood was found by the method of Thorn etal. (19). 2. True glucose was assayed on a Somogyi filtrate using the colorimetric procedure of Nelson. 3. Uric acid was determined by following the procedure of Archibald. 4. Theflamephotometer was used to measure sodium and potassium. Urine Analysis 1. Archibald's directions were chosen for the uric acid determinations. TABLE 1. MEAN VALUES OF UIUNE AND BLOOD MEASUREMENTS OMITTING EPINEPHRINE ADMINISTRATION Index URTNE: Uric acid (U) mg./hr. Creatinine (C) mg./hr. U:C ratio 17-Ketosteroid: Men I [mg./hi Preepinephrine Normal Postepinephrine '. Vo Diff." «t 9 4 Preepinephrine Patient Postepinephrine %Diff.* J »t WomenJ BLOOD: Uric acid mg. % Total eosinophiles per cu. mm. True Glucose VPre-PostN \n Pre f Number of analyses. X This value differs significantly from the pre-epinephrine value at the 5 per cent level of confidence. 9 7 was withdrawn at a.m., and immediately thereafter, 0.3 ml. of 1:00 epinephrine hydrochloride was administered subcutaneously in the upper arm. Postepinephrine samples of blood were taken at 9 a.m. and 12 noon. The patient had no breakfast and fasted from p.m. of the previous night. 2. The procedure of Peters was followed for the creatinine analyses. 3. The method employed for the hydrolysis and extraction of neutral 17-ketosteroids was essentially that of Robbie and Gibson. The Pincus (11) colorimetric reagent was used to develop the color. Methods Blood Analysis i. The total number of eosinophiles per cc. Experimental Results A series of normals and patients were subjected to the entire epinephrine test omitting PSYCHOSOMATIC MEDICINE

3 WERBIN ET AL. only the administration of the drug. This was done to obtain some measure of the variation to be expected due to: i) individual variation, 2) stress of the test per se, and 3) experimental errors of the analyses. Table 1 presents the mean values of the urine and blood measurements which were performed. These data were subjectd to a statistical analysis. The significance of the difference between the means of pre- and postepinephrine Index URINE: Uric Acid mg./hr. Creatinine mg./hr. U:C ratio 17-Ketosteroid: Men ] lmg./hr. WomenJ Sodium mg./hr. TABLE 2. MEAN VALUES OF URINB AND BLOOD MEASUBEMENTS AFTER SUBCUTANEOUS INJECTIONS OF EPINEPHRINE 471 ference over the pre-stress value (t was significant at the 5 per cent level of confidence). The increase of the uric acid-creatinine ratio was indicative of a possible adrenocortical response on the part of the patients to the test. However, there was no significance between the means of the percentage differences of patients and controls for each index. Therefore, the results of this preliminary test indicated that if any significant differences were ob- Preepinephrine Potassium mg./hr BLOOD: Uric Acid mg. % 3.4 Total Eosinophiles percu. mm True Glucose mg. % 73.0 Serum Sodium me/ Serum Potassium 4.5 me/1. Normal Post- Mean epinephrine % Di/f.* 23.65f n Patient Pre- Post- Mean epinephrine epinephrine % Di/f." f 59.f 2.f t f 5.7t lean % Diff. = 1/n Pre t The postepinephrine values which are indicated by t differ significantly from the pre-epinephrine values at the 1 per cent level of confidence values for each index was determined using Student's t ratio. In addition, the mean percentage difference between the pre- and postepinephrine values were calculated for each index in both control and patient group. By employing the t ratio it was possible to evaluate any significant changes between the patient and control mean percentage differences. In all of the adrenocortical indices of normals there was no significant difference between the pre- and postepinephrine values. In the patient group only the post-stress uric acid-creatinine ratio showed a significant dif- VOL. xiv, NO. 6, 1952 served in the responses of psychotic patients and normals to epinephrine stress, these differences could probably be ascribed entirely to the effects of the epinephrine. A group of normal individuals from the hospital staff and patients were subjected to the epinephrine test. The latter group consisted of 13 schizophrenics, 11 manic-depressives, and involutional melancholia cases. Both male and female patients were used, two-thirds of whom had been ill for one year or less while one-third had been ill for more than one year.

4 t $ The postepinephrine values iihich are indicated by a t differ significantly from the pre-epinephrine values at the 1 per cent level of confidence; those with a $ dlffer at the 5 per cent level of confidence.. 5 The mean per cent difference data with a 5 differ significantly at the 5 per cent level of confidence from the mean per cent difference of the corresponding index in the control group. TABLE 3. MEAN VALUES OF URINE AND BLOOD MEASUREMENTS AFTER SUBCUTANEOUS INJECTIONS OF EPINEPHRINE Schizophrenia Pre- - Post- Mean Index epinephrine.. epinephrine.. % Dif.' URINE : Uric Acid mg./hr Creatinine mg./hr U:C ratio Ketosteroid: mg./hr. Women Sodium mg./hr Potassium mg./hr BLOOD: Uric Acid mg. % Total Eosinophiles per cu. mm True Glucose mg. % 6.0 lo.ot 55.9 Serum Sodium me/] Serum Potassium me/] Manic Depressive Pre- Post- Mean epinephrine epinephrine % Diff.' Involuticnal Melancholia Pre- Post- Mean epinephrine epinephrine % Diff.* n

5 WERBIN ET AL. Tables 2 and 3 summarize the mean values for the various measurements before and after epinephrine administration and the mean of the percentage differences between the postand pre-epinephrine values for each index. In Table 2 the data are presented for the patient group as a whole, while in Table 3 the patient group has been subdivided according to the type of psychosis. Within each group the t ratio for the difference between the mean post- and pre-epinephrine values was computed. The t ratio was also calculated to estimate the degree of significance between the mean percentage differences in the indices of the patient and control groups. After administration of epinephrine the following changes at the 1 per cent level of confidence were observed in the normal group: 1) a decline in urine uric acid, 2) a rise in blood uric acid, 3) a decline in blood eosinophiles, and 4) a rise in blood glucose. There appeared to be little correlation between the rise in blood uric acid and the decline in urine uric acid (r = 0.36). For the purpose of calculating Student's t ratio the patient group was compared to the normal group, first as a whole, then according to the type of psychosis. The patient group as a whole gave these significant changes, which occurred at the 1 per cent level of confidence: 1) a decreased output of neutral 17-ketosteroids among women, 2) a rise in blood glucose, and 3) a decline in the eosinophile count. When the patient group was divided into categories according to type of psychosis, all groups showed the significant drop in eosinophile count and the rise in blood sugar at the 1 per cent level of confidence. Furthermore, in the manic-depressive group there was a significant rise in blood potassium. Among the involutional melancholia group, a drop in urine potassium and neutral 17-ketosteroids was observed, both changes occurring at the 5 per cent level of confidence. When the means of the percentage differences for the indices of the patient group were compared with those of the control group, no significant changes were observed. In contrast to the decline in urine potassium VOL. xiv, NO. 6, 1952, 473 found in the normal group, the schizophrenic group showed a slight rise, while the involutional melancholia group manifested a much greater decline; both changes were significant at the 5 per cent level of confidence. Discussion If the decline in the total number of circulating eosinophiles is accepted as the most sensitive indicator of adrenocortical activity (15), the above data demonstrate that psychotics respond as well as normals to a single subcutaneous injection of 0.3 mg. epinephrine. This is true regardless of whether the patient group is treated as a whole or is subdivided according to the type of psychosis. Similar results were found by Parsons et al., Friedlander et al., and Altschule et al. In normal individuals none of the other indices studied showed any evidence of increased adrenocortical activity. This agrees with the results of Recant et al. (13) who found the uric acid-creatinine ratio unaffected and the urinary r 7-ketosteroid excretion slightly depressed in 3 normal individuals following the administration of as large a dose as 6 mg. of epinephrine over a 24-hour period. It is questionable if the small significant change ( 4.6 per cent) in serum uric acid of the control group is indicative of adrenocortical activity. Sayers et al. (16) found that the administration of a single dose of either 50 or 0 mg. of ACTH resulted in a rise in serum uric acid concomitant with an increase in urine uric acid. However, Forsham et al. noted a decrease in serum uric acid resulting from the single injection of 25 mg. of ACTH. The slight but significant decrease (9.4 per cent) in urine uric acid noted in normals may have been due to a diurnal variation, although it was not observed in the patient group. No significant changes in the electrolyte pattern of the blood or urine was observed in normal individuals following epinephrine administration. This seems to support the contention of Recant et al. (13) that epinephrine results in the release of a quantity of adrenocortical steroids insufficient to cause the

6 474 marked metabolic changes observed after ACTH administration. The significant decrease in neutral urinary 17-ketosteroids in women of the entire patient group and of the involutional melancholia group is in sharp contrast to the normal decline in eosinophiles noted in these groups. There appeared to be some correlation (r = 0.64) between the declines in urinary 17-ketosteroids and potassium in the female involutional melancholia patients. The significant differences in urinary potassium between the control group and the schizophrenic and involutional melancholia patients may reflect a disturbance in the electrolyte balance of the latter groups. The inability of the epinephrine stress employed in this study to increase the excretion of urinary 17-ketosteroids and uric acid indicates that much less than 25 mg. of endogenous ACTH was released from the anterior pituitary as a result of this stimulation. It appears more likely that about 4 mg. of ACTH may have been released; this quantity of ACTH, when injected into man, will cause a 50 per cent decline in the number of circulating eosinophiles without effecting the other indices (1). This suggests that the stress employed here was a minimal one, probably incapable of taxing the functional capacity of the adrenal cortex. This may have been the reason for the insignificant differences between the declines in eosinophiles of patients and controls observed in this investigation. The data presented above do not reveal a pituitary-adrenocortical defect in psychotic patients. If endocrine dysfunction does exist in this group, the methods employed in this study apparently are insufficiently sensitive to permit its detection. Conclusions A group of 23 normals and 22 psychotics were subjected to a single subcutaneous injection of 0.3 mg. epinephrine; the changes in the basal values of various adrenocortical indices were measured. No significant difference between the decline in eosinophile counts RESPONSE TO EPINEPHRINE of psychotic and normal individuals was observed. Among the female involutional melancholia patients a significant decrease in neutral urinary 17-ketosteroids was observed following epinephrine administration. Significant differences were observed between the means of the percentage changes in urinary potassium of the control group compared with those of the schizophrenic and involutional melancholia groups. The epinephrine test appears to be either of insufficient intensity or inherently incapable of revealing any possible difference which may exist between the pituitary-adrenocortical mechanism of the normal and the psychotic individual. References 1. ALTSCHULE, M. D.; PROMISEL, E.; PARKHURST, B. H., and GRUNEBAUM, H. Effects of ACTH in patients with mental disease. Arch. Neurol. & Psychiat. 64:641, ARCHIBALD, J. Methods for Laboratory Technicians. United States Wat Department Technical Manual -227, 1946, p BLISS, E. L.; RUBIN, S.; GILBERT, T., and MILLER, R. Effect of adrenalin on adrenal cortical function. /. Clin. Endocrinol. 11:46, DOUGHERTY, T. F., and WHITE, A. First alteration in lymphoid tissue induced by adrenal cortical secretion. Am. ]. Anat. 77:1, FORSHAM, P. H.; THORN, G. W.; PBUNTV, F. T. G., and HILLS, A. G. Clinical studies with pituitary adrenocorticotrophin. J. Clin. Endocrinol. :15, FBIEDLANDER, J. H.; PERRAULT, R.; TURNER, W. J., and GOTTFRIED, S. P. Adrenocortical response to physiological stress in schizophrenia. Psychosom. Med. 12:6, NELSON, N. A photometric adaptation of the Somogyi Method for the determination of glucose. /. Biol. Chem. 153:375, PARSONS, E. H.; GILDEA, E. F.; RONZONI, E., and HULBERT, S. Z. Comparative lymphocytic and biochemical responses of patients with schizophrenia and effective disorders to electric shock, insulin shock, and epinephrine. Am. ] Psychiat. '05:573, PETERS, J. H. Determination of creatinine and creatine in blood and urine with a photoelectric colorimeter. ]. Biol. Chem. 146:179, PINCUS, G. Adrenal cortex function in stress. Ann. New York Acad. Sc. 50:635, PINCUS, G. New color reaction for certain PSYCHOSOMATIC MEDICINE

7 WERBIN ET AL. urinary 17-ketosteroids. Endocrinology 32:176, ' PlNCUS, G; HOAGLAND, H.; FREEMAN, A.; ELMADJIAN, F., and ROMANOFF, L. P. A study of pituitary-adrenocortical function in normal and psychotic men. Psychosom. Med. 11:74, RECANT, L.; HUME, D. M.; FOHSHAM, P. H.,. and Thorn, G. W. Studies on the effect of epinephrine on the pituitary-adrenocortical system. J. Clin. Endocrinol. :17, ROBBIE, W. A., and GIBSON, R. B. Rapid clinical determination of urinary 17-ketosteroids. /. Clin. Endocrinol. 3:200, SAYERS, G. The adrenal cortex and homeostasis. Physiol. Rev. 30:241, SAVERS, G.; BURNS, T. W.; TYLEH, R. H.; 475 JAGER, B. V.; SCHWARTZ, J. B.; SMITH, E. L.; SAMUELS, L. T., and DAVENPORT, H. W. Metabolic action and fate of intramuscularly administered adrenocorticotrophic hormone in man. J. Clin. Endocrinol. 9:593, SOMOGYI, M. Determination of blood sugar. ]. Biol. Chem. 160:69, > THORN, G. W., and FORSHAM, P. H. "Metabolic changes in man following adrenal and pituitary hormone administration." In Recent Progress in Hormone Research. New York, Academic Press, Inc., 1949, vol. IV, p THORN, G. W.; FORSHAM, P. H.; PRUNTY, F. T. G., and HILLS, A. G. A test for adrenal cortical insufficiency. J.A.M.A. 137:05, VOL. XIV, NO. 6, 1952