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17    ELECTROLYTES AND MENTAL ILLNESS

by ALEC COPPEN, M.D. D.P.M.*

Medical Research Council, Surrey, England

 

I MUST START by delimiting the scope of this review. I will be dealing with work carried out, for the most part in the past decade, into electrolytes and the affective disorders, for it is in this area that most work has been recently devoted.

Electrolytes have an extraordinarily central place in biological processes. Physiological research has shown the fundamental importance of electrolytes in the functioning of the cell. According to the ionic theory, the resting and action potentials of nerve and muscle cells depend on potassium, sodium, chloride and other ions having a different concentration inside the cell from the concentration they have in the extracellular fluid. The cell membrane is freely permeable to potassium and chloride, but is much less permeable to sodium, and there is active transport of sodium which keeps the sodium concentration within the cell at about 1/l0 of the concentration of sodium in the extracellular space. Because of this uneven distribution of sodium and the presence within the cell of impermeable anions {such as glutamic acid), potassium and chlorine are also unevenly divided between the cell and the extracellular fluid; potassium has a very high intracellular concentration and chlorine a low intracellular concentration compared to their concentration in the extracellular space.

Investigations over the last 20 years on invertebrate giant nerve fibers have shown the role of electrolytes in the nervous system. Although the study of the giant axon of the squid seems remote from any investigation that we may be able to carry out on our patients, radioactive-isotope techniques enable us to study the intra-and extracellular concentrations of electrolytes in man. In the clinical field the study of disturbances of intracellular ions is still in its early stage. We do not yet know the physiological processes controlling the intracellular concentration of sodium and other electrolytes, nor do we know the functional consequences of alterations in their distribution, except that in certain very limited disorders, such as periodic paralysis, these effects may be profound. The concentration of electrolytes in cells and the extracellular water can influence other important biochemical processes, such as transport of amino acids across cell membranes and many intracellular metabolic processes. It is possible that any widespread abnormality of electrolytes could in themselves alter cellular excitability and produce further biochemical abnormalities. It is worth remembering this when considering the role of electrolytes in depression, as it must be remembered that there is increasing evidence of changes in amine metabolism as well as in electrolytes in the affective disorders.

Balance Studies

The study of water and electrolytes in affective disorders goes back for half a century,1 and the earlier studies were of the balance type. They are reviewed by Gibbons.22 Mostly they are confined to the rather rare type of patient who suffers from regularly recurring mania or depression. Most investigators have found that there are varying changes in water and salt excretion with mood, although these are not the same from patient to patient. These cases, although illuminating, are very uncommon, and it is uncertain what relationship they bear to the more usual type of depression of gradual onset which may last for weeks or months.

Russell29 studied water, sodium and potassium balance in 15 depressed patients for several weeks during recovery from a depressive illness. Eleven of these patients recovered clinically during the period of study while they were treated by electroconvulsive therapy. It was found that there was no significant change in sodium, potassium or water balance during this time. The only significant finding was a transient retention of sodium and water on the day that electroconvulsive therapy was administered, and it was probable that this was related to an emotional reaction to ECT.

The Distribution of Electrolytes Measured by Isotope Dilution Studies

The balance studies have various limitations: it is difficult to measure the intake and excretion in mentally disturbed patients for days or weeks on end. Moreover, the balance studies give no information about the distribution of electrolytes between cells and the extracellular fluid, which, as we have seen, is of such fundamental biological importance.

The distribution of electrolytes is measured in man by techniques based on the principle of isotope dilution. This principle may be illustrated as by considering the simple example of the measurement of total body water {TBW) by using tritiated water, that is, water labelled with the radioactive isotope of hydrogen. The subject drinks a carefully measured amount of tritiated water which is allowed to mix thoroughly with his body water {this is usually complete within 6 hours) .The concentration of tritium is then measured in a sample of body water obtained from blood or urine. As the amount of administered isotope is known, it is easy to calculate the volume of body water in which it was diluted:

  (Administered dose) - (urine losses of tritiated water)
TBW =
  concentration of isotope in sample

It is not so easy to measure extracellular water (ECW) because this test requires a tracer substance that mixes rapidly and completely within the ECW, yet does not enter the cells. No substance is known which fulfils all these conditions. In the present investigations we have used radioactive bromine, 82Br. This tracer has the advantage that it can be given by mouth, is easy to estimate and has been used extensively in estimating ECW,34 but it is not exclusively extracellular in its distribution. Normally, however, it gives one of the most satisfactory measures of ECW.

When the amount of sodium in the body is to be measured an extension of the principle of isotope dilution is used. Instead of volumes of distribution the "exchangeable sodium" is measured. A radioactive isotope of sodium is given--either the short-lived isotope 24Na or the long-lived isotope 22Na, and the mass of sodium in the body with which the sodium mixes or "exchanges" in a given time is determined. It used to be thought that the isotope of sodium had mixed completely with the body sodium within 24 hours, but we were able to show that complete mixing took considerably longer than this.15 Twenty-four hours is the usual time allowed and the results so obtained are referred to as the "twenty-four hour exchangeable sodium."

Body potassium can be estimated by the isotope dilution technique using the short life isotope of potassium, 42K. However, in our work we were able to use a method of determining body potassium from the amount of the naturally occurring radioactive isotope of potassium, 40K, in the subject. All potassium contains 0.012 per cent of this isotope, and radioactivity due to 40K can be determined by means of a very sensitive body counter. By careful calibration of the body counter the total potassium in the body is calculated. It should be remembered that this method has the advantage that it measures total body potassium and not exchangeable potassium, as is the case of the isotope dilution techniques. We have described these techniques in detail elsewhere.11,15

The main fluid compartments of the body can be illustrated by considering those of a normal individual. TBW is made up of 16 litres of ECW and 19 litres of intracellular water (ICW) .The bulk of the exchangeable sodium is in the ECW, where the concentration of this ion is about 10 times that of its concentration in the cells. If the volume of ECW is known and the concentration of sodium therein is measured, it is possible to estimate the mass of sodium in the ECW. When this mass of extracellular sodium is subtracted from the exchangeable sodium, the remaining mass of sodium is termed "residual sodium." This consists of intracellular sodium together with a small amount of exchangeable bone sodium. Similarly potassium, which is mainly an intracellular ion, can be divided into an extracellular and residual portion.

The first to apply the isotope dilution technique to measure exchangeable sodium and potassium in depression was Gibbons.21 His investigation was prompted by the report by Schottstaedt et al.31 that periods of depression in normal people were accompanied by a decreased urinary excretion of sodium. Gibbons measured the 24-hour exchangeable sodium and potassium in a group of 24 adult patients who showed the clinical picture of severe depression. Estimations were carried out initially just after admission when all the patients were depressed and later, after several weeks, when 16 of the patients had recovered; 8 of the patients who had failed to respond to treatment were also retested. 24-hour exchangeable sodium decreased, on the average by 10 per cent after recovery; the patients who did not recover showed no significant alteration in exchangeable sodium. Dietary factors were not thought to produce these results; patients suffering from malnutrition were not investigated in the series, and 10 of the patients, who were on a constant intake of sodium and potassium for balance studies, showed the same changes as the group as a whole. Exchangeable potassium showed no significant alteration with recovery.

These findings stimulated us to carry out an investigation into electrolyte distribution between cells and the extracellular fluid by means of the isotope dilution techniques and whole body counting of 40K. First, the changes in body water. Altschule and Tillotson,2 using the thiocyanate method for measuring extracellular space, found a significant increase on recovery from depression. Dawson et al.16 found a reduction compared to their normal state in extracellular space in 4 patients during both depression and mania. Hullin et al.24 found an increase in extracellular water and total body water following recovery from a depressive illness.

In our study,11 using tritiated water and 82Br, we found that the extracellular water significantly increased by 0.5 liter after recovery and total body water by 1.2 liter. The findings of other workers and ourselves therefore support the notion that there is a decrease in extracellular water and total body water during depression, and that clinical recovery is accompanied by an increase in both total body water and extracellular water.

The most striking abnormality we found during depression lay in "residual sodium," which is the sodium outside the extracellular space consisting mainly of intracellular sodium and a small amount of exchangeable bone sodium. Residual sodium was increased on average by about 50 per cent during the depressive illness and returned to normal after recovery. Total body potassium and intracellular potassium were low and did not change with clinical recovery. The average intracellular potassium concentration was about 135 mEq. per liter, which is considerably lower than the normal value found by this method of 165 mEq. per liter.32 One limitation of this latter investigation was that data for normal subjects were obtained from other laboratories because of the restriction now imposed on the administration of radioactive isotopes to normal subjects. It should be noted that in depression there is no change in either extracellular potassium or sodium concentrations, which are normal both in plasma and in cerebrospinal fluid.17

These findings, it should be emphasized, are on the whole body, and it is not known whether similar changes take place in the central nervous system, although recent findings by Shaw et al.,33 in this research unit, on the brains of depressives who died by suicide suggest that this may be so. Again it should be emphasized that the isotope dilution techniques provide only indirect evidence about intracellular electrolytes. For example, the measurement of extracellular water is fraught with difficulty because it is difficult to find a suitable marker for this space. However, if one takes these results as indicating alterations in intracellular electrolytes, then we have calculated that these could cause changes in both the resting and action potential of about 7 millivolts and that these changes would have considerable functional consequences.

These changes in intracellular electrolytes suggest there may be some deficiency in sodium transport mechanism across the cell membrane. Although the movement of sodium between cells and extracellular water is not easily studied in man, its rate of transfer from the blood to the cerebrospinal fluid can be studied. The rate of transfer of sodium from blood to cerebrospinal fluid was estimated, using 24Na, in a series of 20 patients. In these patients the transfer rate was found to be half the normal rate when they were depressed, while after recovery the transfer rate of sodium was normal.

Anderson and Dawson3,4 described a group of depressed patients who had high blood concentrations of acetyl-methyl carbinol. The depressed patients who showed this elevation were characterized by certain features of depression, such as retardation in speech and preoccupation with depressive ideas. These findings are of particular interest, since it is thought that a raised fasting blood concentration of acetyl-methyl carbinol is associated with increased intracellular sodium.

Magnesium and Calcium in Depression

There have been few studies of magnesium and calcium in depression. Flach18 followed the urinary excretion of calcium in depressed patients maintained on a constant intake of calcium and phosphorus before and during recovery from their illness. He found that patients who recovered showed a significant decrease in the urinary excretion of calcium, but patients suffering from neurosis did not show such a change. In a more recent study, Flach,19 using balance studies and the radioisotope 47Ca, was able to calculate the body retention of the isotope and also to estimate the bone resorption rate. In a small series of 6 patients, Flach found a decrease in the bone resorption rate and an increased retention of 47Ca on clinical recovery. However, Gour and Chaudrey23 found plasma calcium normal in depression. Cade8 reported significantly raised plasma magnesium concentrations in depressed patients, before and after recovery, and also in schizophrenia, but these observations are as yet unconfirmed. However, recent work in our Laboratory20 found normal total and increased calcium and magnesium in depression.

Electrolytes in Mania

There are few investigations of electrolytes in mania. In a series of 22 patients we13 measured the distribution of sodium and water by a technique similar to that we used in the investigation of depression. We found that residual sodium showed an average 200 per cent increase over normal when the patients were manic; some of the manic patients became depressed, and these patients then showed a 50 per cent increase in residual sodium-i.e. similar to the levels found in patients suffering from a depressive illness. After recovery the patients' residual sodium returned to normal. Manic patients, therefore, showed a similar but greater deviation from normal than depressive patients.

The Significance of Electrolyte Abnormalities

The etiological significance of these changes is at present obscure. In the remainder of this discussion I will assume that these findings represent changes in intracellular sodium and potassium and that these whole body changes include the brain, although none of these assumptions can be taken as entirely substantiated.

Very little is known about factors that can alter the distribution of electrolytes; obvious possibilities are steroid hormones such as cortisol, aldosterone or estrogens, and also the posterior pituitary hormones. However, the only hormone extensively studied is cortisol, and our conclusion is that although the secretion of this hormone is slightly increased in depression, its secretion shows little correlation with mental state. In mania, where the electrolyte changes are so marked, we found normal plasma cortisol.6

Are these changes in electrolytes causal or secondary to the changes in mood? It will only be possible to ascertain the role of electrolytes in depression when we can manipulate them and restore their normal distribution. There are, however, some reports indicating that changes in water and electrolyte distribution may alter mood. Bòssow7 gave water and vasopressin to patients suffering from mania or depression and found that both the manic and the depressive patients became very much worse. Karstens25 repeated the same procedure on six normal subjects and produced some of the symptoms of a depressive illness.

It is of particular relevance in this context to consider the therapeutic actions of lithium, which has been shown to be effective in the treatment of mania28 and to have a prophylactic action in patients prone to attacks of frequently recurring depression or mania.5 The mechanism of action of lithium is being actively investigated. It is possible that its action is on monoamine metabolism,30 but it may also affect water and sodium metabolism. The action of this salt has a very interesting and unique influence on sodium metabolism and sodium transport across biological membranes. Keynes and Swan (1959) have shown that during an action potential, when sodium normally enters the cell, lithium and sodium enter with equal facility, but lithium is removed from the cell at about one-tenth the rate of sodium. Coppen and Shaw12 investigated the effects of lithium carbonate given in prophylactic doses over a week (on water and electrolyte distributio). They found an average increase of 1.5 liters in TBW and increases in both intracellular and extracellular water. Since we see that total body water, extracellular water and intracellular water increase with clinical recovery and since it is possible that lithium salts alter the physiological mechanisms responsible for these changes in water, this effect may be related to the therapeutic and prophylactic actions of lithium.

There is now much evidence accumulating that indoleamine metabolism is abnormal in depression:10 the urinary excretion of tryptamine is low,14 the concentration of 5-hydroxyindoleacetic acid is reduced in the cerebrospinal fluid (Ashcroft et al., 1966; Dencker et al., 1966) , and there is a fall in 5-hydroxytryptamine concentration in the hind brains of depressed suicides.33

Now how are these changes in electrolytes related to the changes in amine metabolism? At this point it must be acknowledged that we enter the realm of pure speculation. However, it is possible that changes in electrolyte distribution could affect amino acid and amine metabolism. Intracellular potassium is known to be essential for many enzymatic processes within the cell.6 A direct effect of potassium deficiency on protein synthesis has been demonstrated by Lubin and Ennis.27 Changes in electrolyte distribution could also have important effects on the transport of amino acids into cells. Christensen et al.9 and Vidaver35 indicate that the sodium gradient between cells and their surrounding fluid is one of the determinants of the rate of transport of certain amino acids into cells.

The biochemistry of affective disorders is a rapidly expanding field of psychiatric research, and it is in this light that the changes in electrolytes must be reviewed. It is possible that electrolytes have only a secondary place in the etiology of depression and mania. I think we will not know until we are able to manipulate electrolytes and to examine the effects on mood of restoring them to normal. We need to know the endocrinological factors responsible for the changes in electrolyte distribution, and we also need to know the relationship between the changes in electrolytes and amine metabolism and possibly other biochemical changes responsible for depression as yet undescribed.

 

REFERENCES

1. Allers, R.: Z. Ges. Neurol. Psychiat. 9:585, 1914.

2. Altschule, M. D., and Tillotson, K. J.: Amer. J. Psychiat. 105:829, 1949.

3. Anderson, W. McC., and Dawson, J.: J. ment. Sci. 108:80, 1962.

4. Anderson, W. McC., and Dawson, J.: Brit. J. Psychiat. 109:225, 1963.

5. Baastrup, P. C., and Schou, M.: To be published, 1967.

6. Brooksbank, B. W. L., and Coppen, A.: Brit. J. Psychiat. 113:395, 1967.

7. Büssow, H.: Arch. Psychiat. Nervenkr. 184:357, 1950.

8. Cade, J. F. L.: Med. J. Australia 1:195, 1964.

9. Christensen, H.N., Inui, Y., Wheeler, K. P., and Eavenson, E.: Fed. Proc. 25:592,1966.

10. Coppen, A.: In: Recent Advances in Pharmacology. In press, 1967.

11. Coppen, A., and Shaw, D. M.: Brit. Med. J. ii:1439, 1963.

12. Coppen, A., and Shaw, D. M.: Lancet ii:805, 1967.

13. Coppen, A., Shaw, D. M., Malleson, A., and Costain, R.: Brit. Med. J. i;.71, 1966.

14. Coppen, A., Shaw, D. M., Malleson, A., Eccleston, E., and Gundy, G.: Brit. J. Psychiat. 111:993, 1965.

15. Coppen, A., Shaw, D. M., and Mangoni, A.: Brit. Med. J. ii: 295, 1962.

16. Dawson, J. Hullin, R. P., and Crocket, B. M.: J. Ment. Sci. 102:168, 1956.

17. Eichhorn, O.: Nervenarzt. 25:207, 1954.

18. Flach, F. F.: Brit. J. Psychiat. 110:588, 1964.

19. Flach, F. F.: Excerpta Medica. International Congress Series No.117. IV World Congress of Psychiatry, 1966 p. 184.

20. Frizel, D., Coppen, A., and Marks, V.: To be published, 1968.

21. Gibbons, J. L.: Clin. Sci. 19:133, 1960.

22. Gibbons, J. L.: Postgrad. Med. J. 39:19, 1963.

23. Gour, K. N., and Chaudrey, H. M.: J. Ment. Sci. 103:275, 1957.

24. Hullin, R. F., Bailey, A. D., McDonald, R., Dransfield, G. A., and Milne, H. B.: Brit. J. Psychiat. 113:573, 1966.

25. Karstens, P.: Arch. Psychiat. Nervenkr. 186:231, 1951.

26. Kernan, R. P.: Cell K. London, 1965.

27. Lubin, M., and Ennis, H. L.: Biochem. Biophys. Acta. 81:614, 1964.

28. Maggs, R.: Brit. J. Psychiat. 109:56, 1963.

29. Russell, G. F. M.: Clin. Sci. 19:327, 1960.

30. Schildkraut, J. J., Schanberg, S. M., and Kopin, I. J.: Life Sci. 5:1479, 1966.

31. Schottstaedt, W. W., Grace, W. J., and Wolff, H. G.: J. Psychosom. Res. 1:287,1956.

32. Shaw, D. M., and Coppen, A.: Brit. J. Psychiat. 112:269,1966.

33. Shaw, D. M., Camps, F., and Eccleston, E.: Brit. J. Psychiat. (In press, 1967).

34. Staffurth, J. S., and Birchall, I.: Clin. Sci. 19:45, 1960.

35. Vidaver, G. A.: Biochemistry 3:803, 1964.


 

Discussion of Dr. Coppen's Paper

by JACK DURELL, M.D.

The Psychiatric Institute, Washington, D.C.

 

I AM VERY PLEASED to have the opportunity to discuss Dr. Coppen's masterly review of the field of electrolytes and mental illness. I myself have been interested in this field for a number of years and am presently engaged with several collaborators in further investigations in some of the areas discussed by Dr. Coppen. My own interest was largely stimulated by Dr. Coppen's body of imaginative and careful research. It was his work that led to the provocative hypothesis that subtle alterations in electrolyte gradients across cell membranes might be intimately related to the pathophysiology of affective disorders. Indeed, it has not seemed unreasonable to hypothesize that such changes in electrochemical gradients in specific areas of the nervous system might account for a good deal of the phenomenology of the affective disorders. There are several other observations that seem related and add to the interest in pursuing this hypothesis. The first is the now well-established clinical fact that lithium salts are remarkably effective and specific in the treatment of mania.1 In addition, there is increasing evidence that they are prophylactic in recurrent depressions.2 Lithium ion is a univalent cation closely related chemically to sodium and potassium; on a theoretical basis it might be expected to alter the efficiency of the sodium-potassium stimulated ATPase (the membrane "sodium pump"). There is some evidence to support this mode of action of lithium salts, which serves to focus our attention on the univalent electrolytes in affective disorders. Secondly, though uncorroborated, there is a report in the literature that certain schizophrenic patients show increased activity of the red cell membrane sodium-potassium stimulated ATPase.3 Miss O'Brien has attempted to confirm some of these observations in our laboratory and, though the initial observations per se could not be confirmed, there is a suggestion that with the exacerbation of a schizophrenic syndrome there is a change in the activity of this ATPase. Even though these findings relate to schizophrenic patients and not patients with affective disorders, they increase our interest in the possible importance of electrolyte gradients.

Dr. Coppen's review has been thoughtful and he has taken great pains to point out certain methodological problems and difficulties of interpretation. I wish to limit my discussion to the studies hearing upon the metabolism and distribution of sodium ion and to emphasize the areas in which the methodological problems do lead to ambiguity in interpretation, and where I might suggest interpretations alternative to those proposed by Dr. Coppen.

In my opinion, the most definitively established finding in this entire area is the decrease in 24-hour exchangeable sodium upon recovery from depression. This has been most clearly demonstrated in the carefully controlled studies of Gibbons.4 In Dr. Coppen's own studies there were changes in the same direction that were not statistically significant unless the results were corrected for changes in weights and total body water; corrected in that way, however, the results are almost identical with those of Gibbons. It is not as clear whether the decrease of 24-hour exchangeable sodium reflects a decrease in total body sodium or a redistribution of sodium. Studies undertaken by Russell and by Coppen failed to provide evidence for a decrease in total body sodium upon recovery from depression. They have by no means established, however, that such changes do not occur. Recently, in our laboratory, Dr. Leslie Baer, using total body counting, determined the sodium turnover rate on a constant sodium intake and found changes which are best interpreted as indicating a decrease in total body exchangeable sodium upon recovery from depression.5

Dr. Coppen's studies have led him to favor the interpretation that redistribution of sodium is associated with recovery from depression. The changes in residual sodium reported by Dr. Coppen, though small numerically, represent a large fraction of the residual sodium, are statistically significant, and lead directly to the hypothesis of an altered intracellular sodium. However, as Dr. Coppen himself stressed, the results depend heavily upon the validity of the measure of extracellular space, and he has utilized the radioactive bromide space. This measure, though as good as any other single method, like each of the others has its pitfalls. It is possible that the conclusions reached by the use of that method could be systematically biased, leading to the apparent change in residual sodium. One good candidate for a mechanism that could introduce a systematic error relates to the concentration of bromide in gastrointestinal fIuids. It is known that the bromide/chloride ratio in gastric secretions may be about five times that in the plasma.6 Increases

of 100 to 200 cc. in the mean gastric fluid contents (or its equivalent in terms of chloride and bromide) of the gastrointestinal tract occurring upon recovery from depression might account for the apparent changes

in residual sodium. Since changes in gastrointestinal function are known to occur in depression, and since it is possible that there is less gastric secretion in depression or that the bromide concentration in the gastric fluids is lower, it seems possible that this could result in a systematic error accounting for the observed differences in residual sodium. We are currently investigating this area, utilizing several measures of extracellular space including the early sodium space, a method that has been described previously and has been modified and utilized in our laboratory by Dr. Baer. It will be interesting to see whether the finding of an altered residual sodium in depression will be corroborated by independent methodology.

Dr. Coppen has reviewed the indirect evidence that leads him to the conclusion that the alterations in sodium metabolism associated with depression are not secondary to changes in adrenal cortical function. Dr. Baer's studies suggest the converse conclusion, in that each of the patients showing altered sodium turnover rate in depression also showed higher urinary excretion of 17-OHCS while depressed. The one patient who had a less severe neurotic depression and did not show significant changes in sodium turnover upon recovery also showed no significant changes in urinary 17-OHCS. It appears, therefore, that the matter of whether or not changes in sodium metabolism in depression are related to changes in adrenal cortical function remains an open and interesting question.

In considering mania, Dr. Coppen presents evidence that the alteration in sodium distribution is similar to that occurring in depression, but more marked--i.e., there is a higher residual sodium in mania than in depression. This is an interesting and provocative finding, but conclusions as to its validity and significance must be held in abeyance until confirmed independently. In those studies there is, as in the studies of depressed patients, the problem with the interpretation of the validity of the measurement of extracellular space. In addition, however, some of Dr. Coppen's manic patients have shown extraordinarily high values of 24-hour exchangeable sodium. The related studies in our laboratory are still in progress; but on the five manic patients studied to date we have not found particularly high values of 24-hour exchangeable sodium; nor have we been able to corroborate the occurrence of very large changes in residual sodium upon recovery from mania. These studies are not completed, however, and I mention them only in the interest of keeping the question open.

In conclusion, I wish to emphasize the very important hypotheses that have been generated in this field. Dr. Coppen's own work has been of major importance in focusing upon the potential importance of changes in electrolyte gradients in affective illness. There remain, however, I serious methodological problems necessitating that conclusions as to the significance of the findings be held in abeyance.

 

REFERENCES

1. Schou, M.: I. Psychiat. Res. 6, 1968 (in press).

2. Baastrup, P. C., and Schou, M. : Arch. Gen. Psychiat. 16,162, 1967.

3. Seeman, P. M., and O'Brien, E. : Nature 200:263, 1963. .

4. Gibbons, I. L.: Clin. Sci. 19:133, 1960.

5. Baer, L., Durell, J., Bunney, W. E., Levy, B. S., and Cardon, P. V.: Submitted to I. Psychiat. Res., 1968.

6. Gamble, J. L., Robertson, J. S., Hannigan, C. A., Foster, C. G., and Farr, L. E.: I. Clin. Invest. 32:483, 1953.


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