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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