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PSYCHOSOMATIC MEDICINE—VOL. I, NO. 3,.

JULY, I939

AUTONOMIC INTEGRATION IN SCHIZOPHRENIA

AUTONOMIC STATUS DETERMINED STATISTICALLY, THE THYROID FACTOR,


AND A POSSIBLE THYROID-OYPOTHALAMUS MECHANISM

JOSEPH C. RHEINGOLD, M.D.*

THE STUDIES IN THIS SERIES deal w i t h PROCEDURE AND RESULTS


problems of autonomic function in
schizophrenia. The aim is ultimately to Since schizophrenia presumably is
formulate the characteristic defect or not a disease entity, a reasonable de-
defects of homeostasis. gree of homogeneity of a schizophrenic
As a basis for an experimental ap- group must be demonstrated before its
proach it is necessary first to define the statistical analysis may be profitably
vegetative pathoplasia of the disease. undertaken. The criteria of reasonable
The contributions of the Memorial homogeneity are probably satisfied
Foundation for Neuro-Endocrine Re- when the cases are classified by a uni-
search do not serve the present purpose form practice, one body type pre-
because its findings are derived mainly ponderates, the age range is not too
from study of long-hospitalized male great, the subjects are in about the
patients and the need here is the de- same stage of the disease, the extremes
scription of an unselected schizophrenic of psychomotor activity are eliminated,
population in early stages of the psy- and each sex and each clinical sub-
chosis. There seems, indeed, to be no group is analyzed separately.
report in the literature on objective The patients in the present group
findings in a group of incipient cases were admitted to the Psychiatric Insti-
large enough to assure the validity of tute between the years 1931 and 1936.
a statistical analysis (jo). The classification in each instance was
To determine the vegetative charac- made by Dr. H. Douglas Singer and
ters of schizophrenia, first a survey was was confirmed by the State hospitals
made of the organic data in the records to which some of the patients were
of 129 schizophrenic subjects. The re- later transferred. Of the 129 patients,
sults are reported in this paper to- 43.4 per cent were males and 56.6 per
gether with an attempt to appraise the cent, females. The sex distribution in
influence of the thyroid gland in the the several clinical subgroups is shown
production of the schizophrenic syn- in Table II. The charts show histograms
drome. Then a single patient was stud- of age, weight, pulse rate, blood pres-
ied over a period of a year by the daily sure, oxygen consumption rate, and
administration of a battery of tests. blood chemical findings in 129 cases of
These results will be presented in a schizophrenia—ordinates represent fre-
subsequent paper. quency; solid line, males; broken line,
females. The histogram of age shows
* From the Psychiatric Institute (Dr. H. Douglas that the subjects bulk in the third
Singer, Director) of the University of Illinois College
of Medicine.
decade of life. The paranoid group is
398 JOSEPH C. RHEINGOLD

TABLE I
ORCANIC FINDINGS IN 129 CASES OF SCHIZOPHRENIA TABULATED FOR EACH SEX AND TOTAL GROUP

Males Females Total Group

Weight—
Mean 140.7 107.5 124.1
% Cases under 69.0 81.0 75.0
Means lbs. under 22.5 22.5 22.5
% of prediction 13-8 16.4 15.1
% Cases normal 17.0 5.0 11.0
% Cases over 14.0 14.0 14.0
Mean lbs. over 38-9 15-5 26.4
Pulse R a t e - 76 82 79
Blood Pressure— —
Systolic "5 105 no
Diastolic 76 72 74
Pulse Pressure 39 33 36
Oxygen Consumption—
-I
Mean minimal rate 5-7 -16.7 — 16.2
% Cases below —10 53-o 69.0 61.0
Mean — 22.5 — 21.2 -21.8
% Cases —10 to +10 47-o 29.0 38.0
Mean — 2.1 0 - 1.05
% Cases above +10 0 1.56 0.78
Mean - + 11 + 11
Blood Chemistry—
N. P. N. 29.7 30.3 30.0
Dextrose 91.7 89.7 90.7
Cholesterol 194.9 218.8 206.8
Carbon-Dioxide C.P. 56.4 53-9 55-i
Blood Cytology— 81.8 =
Hemoglobin % 86.8 77-4 13.08 Gm.
R. B. C. (millions) 4.86 4-37 4.62
Color Index 0.89 0.87 0.88
W. B. C. 8,010. 7,840. 7,920.
% Neutrophils 61.2 59-9 60.4

distinguisheld by a mean age which is II). Photographs of the patients in the


about eight years greater than the nude suggest a preponderance of the
mean ages of the other groups (Table leptosomic habitus. The mean duration
TABLE II
ORGANIC FINDINGS IN 129 CASES OF SCHIZOPHRENIA TABULATED FOR EACH CLINICAL SUB-GROUP

Simple Hebephrenic Catatonic Paranoid Other Types


No. of Males 11 33 9 8 5
Mean Age 24.6 25.7 27.7 35-4 26.8
No. of Females 7 19 8 22 17
Mean Age 27.0 25.4 25.0 31-7 26.1
Weight, % cases under 78 89 73 54 78
Weight, mean lbs. under *5-3 22.5 22.4 22.5 19.8
Pulse Rate 77 78 79 78' 83
Systolic B. P. 114 106 107 114 109
Diastolic B. P. 78 71 72 73 74
Pulse Pressure
B. M. R., % cases below —10
B. M. R., Mean
36
57
20.2
35
65
27.4
u
16.0
41
65
19.9
35
64
25-7
Cholesterol 196.4 200.3 221 .7 227.5 185.9
N. P. N. 27.2 3O-5 3O.1 30-4 31.2
Dextrose 88.0 91-3 87.5 94.2 92.4
Carbon-Dioxide C.P. 54.2 57.0 55- 1 56.3 53-2
Hemoglobin % 79 81 84 83 82
R. B. C. (millions) 4.65 4-55 4.69 4.68 4-56
Color Index 0.85 0.89 0.89 0.88 0.89
W. B. C. 6,940 • 7.550. 8,250. 7,440- 9.43O.
% Neutrophils 57-7 60.4 61.2 57-6 65-3
AUTONOMIC INTEGRATION IN SCHIZOPHRENIA 399

r—

* f c -J

IZ 15 7a 21 24 27 Id 33 36 5? 7z 45 4S 5>

POUNDS UNDZRWE/GHT OR
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SI

l&
N0NPR0TE1N
15 NITROG-EN
IZ

ri
•5

Eg JO 3Z
i n
CfTVT"
400 JOSEPH C. RHEINGOLD

28

M ....

Zc DEXT/2OSE

IZ
ii i
6

o
to 45 W 75 fio 55 Too ^ Tio 775 T^o 7^5 7«o Taj

a i CHOLESTEROL
j..-^ . . . . .

• i i ""*"!

:F llo >+5 /bo


hL
MGM.
Zo5 ZZO 235 zSo
PER QENT
ZiS

CARBON- DIOXIDE
COMBINING
POWER

Si, 40 fo¥ 48
VOLUME'S PER CENT
AUTONOMIC INTEGRATION IN SCHIZOPHRENIA 401

a
pi OXYGEN
7
CONSUMPTION
'"] RATE
5

4 r—

n
i

...J . . . .

h40 *4 <8 7* 74 flO S^ 58 W % /.. /O4- 'OS

3t

Z6
J
Z4

Zo D/ASTOLIC
/fc
L...
3. P.
11

a
Jb J-*- ^<9 iZ t,(> JO 74 7(5 QZ QL to fj. fg>

24

r ....
Zl
I r—i
Id
1 i ; sysroL/c
IS | 1 | J a ^ ^^

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o
402 JOSEPH C. RHEINGOLD

PULSE RATE

55 io TO 75 8o 85 <fo

of the psychosis prior to admission was metabolic (oxygen consumption) rate,


about five months and, in more than blood chemistry, and blood cytology.
half of the cases, less than one month. Body temperature and respiratory rate
Clinical and laboratory examinations were excluded because they were not
were made within the two weeks follow- determined under standard conditions.
ing admission. Psychomotor activity is Urinalysis was qualitative only. Cere-
a random error in a large series of cases brospinal fluid findings were in general
but in any event the more stuporous normal. Insurance statistics served as
and more excited patients tend to ex- standards of weight. The rate of oxy-
clude themselves because of non-co- gen consumption was measured by the
operation. This exclusion, apart from Benedict-Roth metabolimeter using
geographic selection, is the only selec- the Boothby-Sandiford modification of
tion factor. Patients with complicating the Du Bois standards. In 53 per cent
physical illness affecting metabolic of the cases two to fourteen readings
status were not included in the study. were made. In these instances, the
One may therefore venture to say minimal rate, rather than the average
that the findings for each sex, as shown of the several readings was taken as the
in Table I, characterize a homogeneous more reliable index of basal metabo-
schizophrenic population. That sex is lism. The blood content of nonprotein
a significant variable is demonstrated nitrogen was determined by the modi-
by the consistently greater tendency fied Koch-McMeekin Method; dex-
of the females to hypometabolism. trose, by the modified Benedict
In the case of the sub-groups (Table II) Method; cholesterol of the whole blood,
the numbers of subjects in each classi- by the modified Bloor Method; and
fication, certainly in each sex-sub- carbon-dioxide combining power of the
group class, are too few to warrant plasma, by the Van Slyke and Cullen
statistical analysis. It will be observed, Method. Hemoglobin was measured by
however, that despite differences at the the Dare instrument and blood counts
clinical level, the sub-groups yield very were made in the usual way. This
similar metabolic pictures. battery of tests was not always ad-
The data reported on comprise ministered on the same day but never
weight, pulse rate, blood pressure, basal over a period of more than a week.
AUTONOMIC INTEGRATION IN SCHIZOPHRENIA 403

There was of course no planned con- systolic pressure is reduced relatively


trol study but what may be used for more than the diastolic, producing a
this purpose are the ranges of variation diminished pulse pressure. From Krae-
(2p) for blood chemical and cytological pelin on, almost all investigators have
determinations made in thousands of agreed that schizophrenia is character-
subjects in the clinical laboratories of ized by a lowering of the blood pres-
the Illinois Research and Educational sure. The literature was reviewed in
Hospital of which the Psychiatric Insti- 1932 by Freeman, Hoskins, and Sleeper
tute is a part. Unless the control sub- (9), who also reported a mean blood
jects match the schizophrenic patients pressure of 104.5/54.5 in 180 male
in at least the sex ratio, age range, and schizophrenics. The 323 control sub-
incidence of leptosomes there is prob- jects likewise yielded low mean read-
ably little point in setting up a special ings (115.7/71.2). The difference in
control group. systolic levels between patients and
In the statistical analysis of the normal subjects (11.2) is about the
data the mean is used as the expression same as the difference between the
of central tendency (Tables I and II) male patients in the present series and
and the histogram as the expression of the general population (12.6). The
variability (see Charts). lower readings at Worcester may be
Weight: Three-fourths of the pa- due to the more nearly basal conditions
tients are about 15 per cent below of testing.
standard weight. Hoskins (21) found Oxygen Consumption: Low metabolic
the mean weight of 57 male schizo- rates are frequent in patients of the
phrenics 16 per cent below prediction. Psychiatric Institute. Readings in the
Since this degree of underweight may range of minus 40 to minus 30 are not
be characteristic of the leptosome, one uncommon amongst the schizophrenic
need not conclude that a higher inci- subjects. In the present group 61 per
dence of malnutrition exists in the cent of the patients have a mean rate
schizophrenic group than in a normal of minus 21.8 per cent and only two
group. Nor does low mean weight patients have rates (single determina-
mirror chronicity since the incidence of tions) above the conventional upper
underweight men (69 per cent) in this limit of plus 10. This result is in con-
series is greater than that of patients formity with almost all other reports
in Hoskins' series (55 per cent) who of basal metabolism in schizophrenia.
were hospitalized a mean of 5.9 years. The literature was summarized by
Pulse Rate: Mean values are within Hoskins (if) who later reported a mean
a normal range but group variability minimal rate of minus 18.9 per cent in
is probably greater than normal. Hos- his own series of 114 male schizo-
kins and Sleeper (20) found an average phrenics (19).
pulse rate of 59.2 in 57 schizophrenic An interesting finding is the lowering
men. The discrepancy may possibly be of the basal metabolic rate following
accounted for by the practice at the exercise in 11 of 30 cases included in
Worcester State- Hospital of determin- the present series. The basal rates and
ing pulse rate, as well as blood pressure, the rates after exercise were not deter-
under basal conditions. mined on the same day but the differ-
Blood Pressure: The mean systolic ence between the two is too great to be
and diastolic levels are lower than those accounted for by lower basal levels on
of the general population (127.6/83.5 in the days of the experiment with exer-
150,000 life insurance applicants). The cise. Thus patient H-B. had rates of
404 JOSEPH C. RHEINGOLD

minus 17, minus 6, and minus 4 under phrenia.) The blood picture is charac-
basal conditions on three successive terized by mild secondary anemia,
days, but on the fourth, after stepping normal absolute leucocyte count, and
on and off a chair for one minute, had low normal percentage of neutrophils.
a rate of minus 34. Worcester {4) reports the following
Nonprotein Nitrogen: The mean re- findings in 57 men: R.B.C., 4,957,000;
sults are within a normal range and the Hb, 15.3 gm.; W.B.C., 10,477; and
curve of distribution approaches a neutrophils, 59.6 per cent.
normal frequency curve. Worcester
(20), too, finds a normal N.P.N. level.
Dextrose: Mean values are again DISCUSSION
normal. The literature was reviewed by
W. Freeman (//) in 1933. He reports Summarizing the foregoing results
a mean of 96.6 mgm. per cent for 347 one may say that this group of schizo-
determinations in 59 patients and a phrenic patients shows trends to sub-
mean of 95.4 in 31 control subjects. standard weight; reduced oxygen con-
Cholesterol: Looney and Childs (j/) sumption; normal pulse rate; lowered
m I
933 collected the literature on systolic, diastolic, and pulse pressures;
blood cholesterol determinations in normal blood nonprotein nitrogen and
both normal and schizophrenic persons. dextrose levels; high normal or slightly
With the exception of two reports, elevated blood cholesterol content; low
normal subjects do not yield mean normal carbon-dioxide combining
values above 200 mgm. per cent, no power of the blood plasma; mild sec-
matter what method is used. The re- ondary anemia; normal absolute leuco-
sult of 206.8 in our schizophrenic group cyte count; and low normal percentage
may therefore indicate a trend to high of neutrophilic leucocytes. The dis-
normal or slightly elevated blood placements from normal means consti-
cholesterol content. Five authors have tute one of the features of the disturb-
reported mean values over 200 in ance of homeostasis in schizophrenia.
schizophrenia but three have reported Another feature is the greater than
mean values between 140 and 200, and normal range of variation of every
seven, below I40. Looney and Childs measurement. This is demonstrated
found a mean level of 158 in 50 schizo- mathematically by the Worcester find-
phrenic men and that of 175 in 26 ing of greater standard deviations for
normal men. almost every determination in patients
Carbon-Dioxide Combining Power: as compared with the same determina-
The means falls at the lower limit of tion in normal control subjects. Mul-
the normal range. Variability is pro- tiple determinations in the same pa-
nounced with a preponderance of fe- tient also reveal increased variability.
male cases in the 46 to 50 class inter- This "physiologic clumsiness" may be
val. Worcester measures carbon-di- the fundamental aspect of the homeo-
oxide content, not combining power. static fault. Hoskins (2/) ventures the
Looney and Freeman ( J J ) recently re- prediction that in many cases of schizo-
ported a venous content of 57.8 per phrenia "the essential etiology will
cent in both 112 male patients and 67 ultimately prove to be defects of inte-
control subjects. gration . . . reflected in extreme varia-
Blood Cytology: (The histograms are tion and atypical inter-action of vari-
reserved for a future paper dealing ous functions". In the present paper,
with the blood morphology in schizo- however, the discussion is based on
AUTONOMIC INTEGRATION IN SCHIZOPHRENIA 405

only the deviations from normal cen- recently by Hoskins (2j). The use of
tral tendencies. sedatives has been invoked as explana-
The most striking departure from tion, but although they make for qui-
normality is the low oxygen consump- escence and more nearly representative
tion rate. A consistently elevated basal readings, no evidence can be found
metabolic rate in a schizophrenic sub- that they depress the actual basal rate.
ject is practically unknown. Since 1908 Positively, the reversal of the metabolic
the literature has been concordant on tendencies, the uniformity of the find-
the finding of a lowered basal metabolic ing of low oxygen consumption rate,
level. "Schizophrenia", says Hoskins the degree of reduction, and the tend-
(/<?), "is a condition characterized ency in most cases to rise of the rate
among other physiologic abnormalities with clinical improvement (21) leave
by a systematic downward displace- little doubt that the lowered basal me-
ment of the oxygen consumption rate". tabolism is an important feature of the
This trend is made more impressive by schizophrenic disorder.
the difficulty of obtaining standard Investigation of the pathogenesis of
conditions of testing in psychotic sub- schizophrenia therefore requires con-
jects: According to Hoskins (23) "the sideration of causes antecedent to the
true basal rate in most cases is prob- diminished use of oxygen. Three sets
ably considerably lower than the rate of such causes may be postulated:
actually determined". 1) insufficient supply of oxygen to the
It seems reasonable to assume that tissues, 1) derangement of the chemo-
this depressed level of basal metabolism dynamic processes within the celkj and
is an integral part of the disease pic- 3) disturbance of the mechanisms con-
ture. It is not a characteristic of the trolling cell respiration.
person predisposed to schizophrenia. The abnormality is probably not in
In fact, the normal leptosome (43) with the transport of oxygen. The arterial
his tendency to elevated basal meta- blood of patients contains as much
bolic rate, as well as tendencies to lower oxygen as that of normal persons and
blood cholesterol content, increased the tissues of the patients abstract even
capillary permeability, greater oxida- more oxygen from the blood than do
tive preponderance, increased thyroid- the tissues of the control subjects (33).
adrenal activity, and more distinctly Blood volume is reduced, but the devi-
sympathicotonic reaction to epineph- ation from normal disappears when
rine, shows trends opposite to those schizophrenic subjects are matched by
observed in the schizophrenic subject. "nutritional index" (23). The de-
That inanition is not a factor in the creased blood mass may be incidental
diminished oxygen use is shown by to the hypoplastic vascular system of
absence of correlation between weight the leptosome. Finally, although, H.
and basal metabolic rate (r = .i2). It is Freeman (/o) has twice reported di-
only in states of severe inanition as in minished velocity of the blood flow
anorexia nervosa that basal metabo- under basal conditions, Finesinger et
lism falls to levels comparable to those al. (6), using the same method, found
found in schizophrenic patients (5). the average circulation time in 130
Hospitalization as a cause of the patients to be within normal limits.
altered metabolic status is ruled out in Oxygen may be supplied to the tis-
the present group of incipient cases; sues in adequate amount and at an
that it plays no part in even long- adequate rate but may fail to enter into
hospitalized patients has been shown chemical reactions within the cells be-
406 JOSEPH C. RHEINGOLD

cause of a disturbance of enzyme ac- gested itself to several investigators.


tion. A profitable investigation of this The literature was brought together by
possibility must await more exact Hoskins and Sleeper {18) in 1930. Since
knowledge of biologic oxidation. Some then increased experimental and clini-
doubt is cast upon the possible exist- cal knowledge has strengthened the
ence of a primary intracellular dys- assumption and a restatement of the
function in schizophrenia by the re- "case" for the thyroid seems war-
sults of the administration of dinitro- ranted.
phenol. Looney and Hoskins (32) found It is now recognized that hypo-
that although the drug produced an in- thyroidism may exist as a part-syn-
crease in the basal metabolic rate of drome and that uncomplicated hypo-
about 50 per cent, there was no con- thyroidism presents a variety of clinical
current change in temperature, pulse pictures more or less distinct from
rate, or blood pressure, only a tem- classical myxedema. Reviews of the
porary increase of the nonprotein nitro- subject may be found in papers by
genous blood constituents, and no con- Warn"eld (52) and by Seward (48). In
sistent trend in the blood cholesterol general, these recently described forms
and lactic acid values. Presumably no of thyroid hypofunction are distin-
clinical improvement was observed. If guished by the absence of skin infiltra-
the phenomena of schizophrenia were tion and other gross signs of Gull's
consequent to an altered ability of the disease even when the basal metabolic
cells to metabolize oxygen, correction rate is less than minus 40.
of this fault should restore the vital The symptomatology of non-myxe-
signs and body chemistry to normal dematous hypothyroidism is strikingly
and effect clinical change. similar to that of schizophrenia. Com-
There remains then the possible role mon to both is a usually insidious on-
of the mechanisms that regulate the set, a chronic course, absence of a
speed of metabolism—the trinity of definite group of symptoms or charac-
autonomic nervous system, endocrine teristic physical signs, lowering of the
glands, and non-hormonal chemical sense of well-being, tendency to under-
substances. Out of the almost infinite weight (in the first half of life), loss of
permutations of the interdependent strength, fatigability, susceptibility to
functions of these vegetative mecha- infection, carious teeth, sensitivity to
nisms Qne may, a priori, isolate the cold, anorexia, constipation, abdominal
factor of thyroid insufficiency. Thyroid complaints, headache, insomnia, vaso-
disorders and schizophrenia grow out motor disorders of the skin and its
of the same constitutional soil. The in- appendages, disturbances of menstrua-
fluence of the thyroid secretion upon tion, and loss of sexual desire. The pa-
the brain is proved by experimental tients reported here offered subjective
work (46) and clinical observation. The complaints in the following order of
degree of reduction of basal metabolism frequency: constipation, general poor
in schizophrenia suggests thyroid de- health, fatigability, weakness, loss of
ficiency; in fact it is now considered weight, anorexia, headache, sensitivity
likely that a persistent change in the to cold, frequent colds, insomnia, and
metabolic rate implies altered thyroid abdominal distress. Lack of uniformity
function (57). in recording the results of physical
The possibility of thyroid insuffi- examination makes it somewhat diffi-
ciency as a factor in the hypometabolic cult to appraise the thyroid factor from
status of the schizophrenic has sug- the objective data. Little importance
AUTONOMIC INTEGRATION IN SCHIZOPHRENIA 407

probably is to be attached to a 28 per mals the carbon-dioxide combining


cent incidence of goiter in patients from power trends to low levels (50). The
the Great Lakes region (5.2). More sig- blood cytological picture was: Hb, 87
nificant perhaps is the finding ofexoph- per cent; R.B.C., 4,840,000; C.I., 0.9;
thalmos in 8.5 per cent of the cases. W.B.C., 7,500; and neutrophils, 56 per
A pasty complexion was noted in five cent. In the respects of lower systolic
instances, non-pitting edema in one. blood pressure, smaller pulse pressure,
A pale, cold, moist skin is one of the lower blood sugar level, and secondary
commonest observations. Dilatation of anemia the schizophrenic patients may
the pupils (not measured) was recorded be said to be more "hypothyroid" than
in 18 per cent of the cases. Both sweat- the patients of Lawrence and Rowe.
ing and pupillary dilatation, usually The correspondence between the two
included in lists of the physical signs of conditions is seen further in the pres-
schizophrenia, are among the few phe- ence in schizophrenia of tendencies to
nomena not part of the symptoma- reduced lung volume (20), depression
tology of thyroid failure. Hypertri- of the specific dynamic action of pro-
chosis and inverted hair distribution, tein food (<?), low heat production in
found in 23 per cent of the female sub- response to cold (7), hypochlorhydria
jects, are more suggestive of pituitary- (2), and delayed emptying-time of the
ovarian hypofunction. Menstrual dis- colon {21), all of which are part of the
orders were noted in 22 per cent of the hypothyroid syndrome (4).
women and tremors of the fingers, So similar are the physical symp-
tongue, or lips in 31 per cent of all toms, signs, and laboratory findings in
the patients. Dental caries was com- the two diseases that in reading the
mon. literature on hypothyroid states one
The concordance of the laboratory has the impression of an ambiguous
findings in schizophrenia and in hypo- figure: now it is hypothyroidism, now
thyroidism may be judged by com- schizophrenia. This agreement is based
paring the data in Table I with the mainly on statistical results. To what
results obtained by Lawrence and extent does analysis of individual cases
Rowe (28) in 126 cases of uncompli- of schizophrenia bear out the thyroid
cated thyroid deficiency (males, 29 per factor ? To ascertain this, the cases were
cent; females, 71 per cent). One-third summarized and, where possible, an
of the patients were underweight, 14 endocrine diagnosis was made. Hypo-
per cent of prediction. Decreased thyroidism was considered probable in
weight, rather than obesity, is charac- 39.5 per cent of the cases. The sum-
teristic of the hypothyroid patient in maries were reviewed by Dr. William
the first half of life (21). Pulse rate was F. Petersen, Professor of Pathology,
66. In more recent reports the pulse and Dr. S. A. Levinson, Assistant Pro-
rate is described as slow or normal or fessor of Medicine and Director of the
rapid. Blood pressure was 114/71, pulse Hospital Laboratory, of the University
pressure 43. The mean basal metabolic of Illinois College of Medicine, both of
rate of all cases was minus 24. Blood whom regarded the data consistent
N.P.N. was 31, dextrose, 96. Blood with the diagnosis in the full 39.5 per
cholesterol and carbon-dioxide com- cent of the patients, and by Dr. S.
bining power were not determined. Soskin, Assistant Professor of Physi-
Hypercholesterolemia, it is well known, ology, University of Chicago, who
is a regular concomitant of thyroid de- checked 22.5 per cent of the cases as
ficiency, and in thyroidectomized ani- hypothyroid. The following are sum-
408 JOSEPH C. RHEINGOLD

maries of cases which happened to be left lobe of thyroid gland. Moderate


listed first under each of the four exophthalmos. Unilateral Von Graefe
customary sub-groups: sign. Tremor of fingers. Weight normal.
1) Simple Type: Female, age 25. P 64, B.P. 100/65, B.M.R—29 per
History of loss of strength and energy, cent, Choi. 278, N.P.N. 38, CO2 46.
poor appetite, constipation, frequent Hb 80 per cent, R.B.C. 4,300,000, N
colds, scanty menstruation, and emo- 45 per cent. Urine, albumin one plus.
tional apathy. Skin cold and rough. Among 130 schizophrenic patients
Isthmus of thyroid gland enlarged. Hoskins and Sleeper (/<?) found a
Teeth carious. About 20 pounds under- group of 18 (13.8 per cent) that showed
weight. T 97.8, P 80, R 16, B.P. 110/75. thyroid deficiency, uncomplicated or
B.M.R. —24 per cent, Choi. 277, CO2 in association with other glandular
56. Hb 55 per cent, R.B.C. 3,330,000, disturbance.
N 58 per cent. No free HC1 in gas- The greater incidence of cases of
tric contents, fasting or after Ewald hypothyroidism in the patients of the
meal. Illinois Psychiatric Institute, as well
2) Hebephrenic Type: Male, age 27. as the larger percentage of patients in
Always delicate, frequent spells of this group with low basal metabolic
weakness, easy fatigue, constipation, rates and the tendencies to hyper-
headaches. Wore coat on ward in warm cholesterolemia, acidosis, and second-
weather. Thyroid gland normal to pal- ary anemia, suggests that the Institute
pation. Skin pale, hands and feet cold patients are more "hypothyroid" than
and moist. Tremor of fingers. About the patients in the Worcester State
35 pounds underweight. P very vari- Hospital. This difference was to be
able, frequently in 5o's. B.P. 112/80. expected. The inclusion of females in
B.M.R.—27 per cent (after exercise — the present series shifts the averages to
34 per cent). Choi. 333, CO2 52. Hb the left. Further, the patients in Chi-
70 per cent, R.B.C. 5,300,000, N 54 cago are selected from a goiter region,
per cent. those in Worcester from a non-goiter
3) Catatonic Type: Female, age 38. region.
Three previous episodes with improve- The total evidence seems to give
ment. Stuporous. Skin cold, rough, considerable warrant to the theory that
with many eczematous areas and scars. insufficient thyroid function plays an
Tendency to masculine hair distribu- important part in creating the vegeta-
tion. Teeth in very poor condition. tive status of schizophrenia. This
Thyroid gland diffusely enlarged and pathogenetic tie may exist more or less
soft. Amenorrhea. Drooling of saliva. in all cases of schizophrenia or may be
Deep reflexes increased, abdominals pertinent to a certain group only. The
not elicited. Vincent's angina. About relationship between hypothyroidism
40 pounds underweight. T 97.6, P 70, and the psychic phenomenology of
R 15, B.P. 98/70. B.M.R.—14 per cent schizophrenia is outside of the limits of
(single determination). Choi. 290, this discussion. But the suggestion is
N.P.N. 51, CO2 51. Hb 70 per cent, offered that, no matter whether the
R.B.C. 3,530,000, W.B.C. 10,700, N metabolic and the mental characters
63 per cent. arise simultaneously or in sequence, the
4) Paranoid Type: Male, age 31. Im- hypothyroid state once established is
pairment of general health for two capable of perpetuating the signs refer-
years prior to admission. Felt cold even able to the brain. Integrated brain
when wearing fur coat. Adenoma of function, as McFarland (j5) and Gell-
AUTONOMIC INTEGRATION IN SCHIZOPHRENIA 409

horn (/<?) have shown, depends upon the cause or causes antecedent to thy-
adequate oxygenation of the brain. roid deficiency. It is now believed that
Anoxia induced in normal subjects the pituitary thyrotropic hormone
produces disorders of behavior re- exercises the chief control over thyroid
sembling the symptoms of schizo- secretion {34)- That the sympathetic
phrenia. (But are acute experiments nerves are not involved in the produc-
with low oxygen tension comparable to tion of the hypometabolic status of
the persistent deficiency of oxygen as- schizophrenia follows from Cannon's
similation assumed to exist in the finding that even total extirpation of
schizophrenic brain?) In addition to the sympathetic chains in cats does not
the direct metabolism-depressing ef- result in a significant lowering of basal
fect, hypothyroidism, through second- metabolism (3). Our path leads to the
ary disturbances of water and calcium anterior pituitary lobe; and there it
metabolism (16) may exert further ends, because the mechanisms that
dampering effect upon brain activity. regulate prehypophyseal function are
The assumption of thyroid insufficiency still too speculative to warrant con-
offers help too in accounting for certain sideration.
physiologic and physical anomalies in Another path opens up, however,
schizophrenia. Since the thyroid hor- when we bring into the discussion the
mone apparently controls the excita- remarkable resistance of schizophrenic
bility of the respiratory center (27), its patients to the effects of thyroid medi-
deficiency explains the schizophrenic's cation. The bulk of the evidence speaks
insensitivity to carbon-dioxide stimu- against the efficacy of thyroid medica-
lation, a finding upon which Golla (14) tion, although there are reported cases
builds a pathogenesis of the disease. of a clear association between a schizo-
The hypofunction of the sympathetic phrenic syndrome and thyroid defi-
nervous system, recently emphasized ciency, with recovery from the psy-
by Gellhorn (13), may be the result of chosis following the use of thyroid sub-
the decreased sensitization of the mech- stance (16a, 53, 54). Also, several in-
anisms upon which epinephrine acts. vestigators have had more or less suc-
That schizophrenic subjects are unable cess with thyroid therapy in unselected
to comply normally with the homeo- cases (18), and negative results, accord-
static principles concerned with the ing to Hoskins, are usually inconclusive
regulation of heat (15) follows from the (/<?). There is no report on the adminis-
part the thyroid hormone plays in tem- tration, of thyroxin intravenously in
perature regulation apart from its con- early cases. After a long experience with
trol over the total heat production of glandular treatment Hoskins (42) is
the body. Finally, hypothyroidism may impressed with the schizophrenic's high
account for reduced blood volume {16). tolerance for thyroid preparations even
The influence of the thyroid secretion in those cases showing the character-
on capillary growth and morphology istic hypothyroid picture, and by the
(26) may be the more basic cause, as exhaustibility of the effect, as well as
Olkon (41) finds a reduction in the by the diminishing efficacy with re-
number and size of the skin capillaries peated courses of treatment. If the
in schizophrenic patients. therapeutic test is the ultimate diag-
Since it is generally agreed that func- nostic criterion of hypothyroidism,
tional thyroid disorders do not arise ab must one conclude that the refractori-
initio within the gland, the investi- ness of the schizophrenic contradicts
gative problem becomes a search for the assumption of thyroid deficiency?
410 JOSEPH C. RHEINGOLD

Only if by thyroid deficiency is under- against the hormone. In Graves' dis-


stood just decreased production of the ease the titer of this principle is much
hormone. The above discussion has less than normal. The presence of an
been oriented to the premise of such an excess of the anti-body in schizophrenic
absolute deficiency because this is the patients would account for the hypo-
implicit assumption in the literature on thyroid state, the resistance to thyroid
hypo thy roidism. But a relative lack of ' feeding, and the diminishing efficacy of
the hormone—its deficient use by the repeated courses of treatment, and
cells—is not only theoretically possible would make unnecessary the assump-
but is beginning to receive attention as tion of overproduction of the thyro-
an explanation of the failure of some tropic hormone which is apparently
hypothyroid patients to respond to requisite for formation of the thyroid
thyroid therapy. If we suppose that the anti-hormone. Other substances with
schizophrenic is unable to use thyroid anti-thyroid action, recently enumer-
secretion, we resolve the antinomy be- ated by Oehme (40), need not be con-
tween hypothyroidism and resistance sidered because it is unlikely that any
to substitutive treatment. The defi- of them exists in excess in the schizo-
ciency is probably not wholly in the phrenic. Finally, the hormone may
utilization of the hormone since pa- reach the cells but may be unable to
tients in a goiter area appear to suffer exert its effect because of the absence
of a greater degree of hypothyroidism of a positive catalyst or the presence of
than those in a non-goiter area and a negative catalyst. It has already been
some patients respond to thyroid ad- pointed out that the results of the ad-
ministration, if only with temporary ministration of dinitrophenol speak
benefit. Inadequate iodine supply is a against such an assumption in schizo-
cause of lessened production of secre- phrenia.
tion and thus presumably a factor in There is question whether thyroxin
the liability to schizophrenia, but io- acts upon the peripheral cells at all.
dine metabolism may not be of funda- Experiments testing the effect of thy-
mental import because the major dis- roxin upon the oxygen consumption of
turbance apparently lies not in the living cells in vitro have yielded nega-
synthesis of the hormone but in its tive or uncertain results (jp). Isolated
availability to the body. organs are not sensitized to stimulation
What may interfere with the action by thyroxin, yet do show increased
of the thyroid hormone? Since the se- excitability if the animal is prepared
cretion of the thyroid gland is not with thyroxin beforehand {37). Cold-
identical with thyroxin and is effective blooded animals show none of the
only after a long latent period, it has effects of thyroxin administration (25).
been suggested that it undergoes modi- On the other hand, there is evidence
fication in the body before it acquires that the nervous system is the site of
physiologic potency (/<5). In the schizo- action of the thyroid hormone. Investi-
phrenic this final elaboration may not gators like Leon Asher and Hans H.
occur. It is possible too that the secre- Meyer subscribe to the theory of an
tion or the definitive hormone may be exclusive central action. On the as-
depotentiated by anti-hormone or by sumption that cold-blooded animals
some other anti-body. Anselmino and are insensitive to thyroxin because they
Hoffmann (/) have isolated an anti- lack vegetative centers for temperature
thyroid substance from normal blood regulation, Issekutz and Issekutz (25)
and tissues which exerts protection made cats poikilothermic by narcotiz-
AUTONOMIC INTEGRATION IN SCHIZOPHRENIA 411

ing them with a dose of phenobarbital is ventured that in schizophrenia we


large enough to paralyze the vegetative deal, not with a disturbance of the
centers and found that they were to- pituitary-thyroid mechanism, but with
tally unresponsive to thyroxin. De- a dysfunction of the hypothalamus.
capitated animals and animals with Neither the naturally produced hor-
section of the cord in the third to the mone nor the exogenously introduced
fifth cervical segments were similarly hormone is effective because of the
unresponsive. Phenobarbital is capable elimination of the mechanism which in
of exerting protection against the sensi- some way is essential to the hormone's
tization by thyroxin to the effect of ultimate action. That the hypothala-
drugs which disturb the temperature- mus may be implicated not alone in
regulating center (44), and in humans, schizophrenia but in the psychoses
of depressing the calorigenic and di- generally has been suggested by per-
uretic action of thyroxin {36). It is also sons of such wide experience as Singer
known that resistance to the effects of {49), Hoskins (22), and Ingham (24).
administered thyroxin may accompany The postulate of a thyroid-hypothala-
certain brain diseases (36). mus relationship offers a way of ap-
Probably the most convincing evi- proach to the experimental testing of
dence that the localization of action of the role of the hypothalamus in the
the thyroid hormone is in the hypo- psychoses.
thalamus is offered by Schittenhelm
and Eisler (45) who found that after SUMMARY AND CONCLUSIONS
the injection of thyroxin into animals
the iodine-content of the tuber cine- As a point of departure in a study of
reum increases tenfold whereas other autonomic integration in schizophrenia
parts of the brain are unaffected. In the vegetative status was defined by
this connection it is interesting to note making a statistical analysis of the
that Morgan and Gregory (38), in a organic findings in a reasonably homo-
histologic study of various cell groups geneous group of 129 schizophrenic
in the thalamic and subthalamic re- patients. The most noteworthy ab-
gions and in the corpus striatum of the normality is a tendency to low oxygen
brains of psychotic subjects, twelve of consumption rate. Low blood pressure,
whom had been diagnosed schizo- slightly elevated blood cholesterol con-
phrenic, found pathologic changes only tent, low normal carbon-dioxide com-
in the tuber cinereum—the substantia bining power, and secondary anemia
grisea and the nucleus tuberis lateralis. attest to a state of general hypo-
Just how the hypothalamus mediates metabolism. The female subjects are
the effect of the thyroid hormone is not relatively more hypometabolic than
known. The sympathetic nerves would the male subjects. The clinical sub-
seem to be a necessary link between the groups show no consistent differences.
brain and the cells and a certain Low oxygen consumption is prob-
amount of evidence supports this as- ably an integral feature of the disease.
sumption, yet Ring, Dworkin, and Since it does not seem to be dependent
Bacq (47) have reported that removal upon an inadequate supply of oxyg'en
of the thoraco-lumbar chains in cats to the tissues or upon intracellular en-
does not prevent the usual rise in zyme dysfunction, a disturbance of the
metabolism after thyroxin. mechanisms regulating cell respiration
On the strength of this newer knowl- may be postulated.. Thyroid insuffi-
edge of thyroid physiology the opinion ciency is probably one factor in the
412 JOSEPH C. RHEINGOLD

tients witn
pathogenesis. T h e symptoms, physical dementia praecox to cold, J. Neurol. &
:
signs, and laboratory findings in schizo- t.^^^f ^^^vMetai^ bei
phrenia and in the non-myxedematous schizophrenen, Klin. Wchnschr. 6:1987,1927.
form of thyroid failure are very similar 9- FREEMAN, H. HOSKINS, R. G. and SLEEPER,
and in- the group of patients reported ^ ^X^^^™' ^
the diagnosis of hypothyroidism is be- 10. FREEMAN, H.: The arm-to-carotid circulation
time in
lieved tenable in 39.5 per Cent of the normal and schizophrenic subjects, Psy-
raw. These natienrs are nn-narenrlv chiatric Quart. 8: 290, 1934.
cases. Ihese patients are apparently FREEMAN> H . : Variability of circulation time in
more hypothyroid than patients normal and schizophrenic subjects, Arch. Neurol. &
studied in the Worcester State H o s - Psychiat.,^p.-488,1938.
niral whn are males evrlnsivelv anH n . FREEMAN, WILLIAM: The fasting blood sugar in
pitai wno are males exclusively and scmZophrenia, Am. J. M. Sc. 186:621,1933.
who are Selected from a non-gOlter 12. GELLHORN, ERNST: The integrated action of the
region organism exemplified by studies on anoxemia, Sigma
Thyroid hypofunction serves to ex-^ X ^ L a » o ^ R t; 9 3 7 E f f e c t s o f h y p o g l y c e m i a a n d
plain some of the mental as well as they \ anoxia on the central nervous system, Arch. Neurol.
&
metabolic phenomena and accounts for Psychiat. 40:125,1938.
l
certain physiologic abnormalities com- ^^^^Lt^^\^
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T h e schizophrenic's lack of response '5- GOTTLIEB, JACQUES S. and LINDER, FORREST E.:
B o d y tem era( ur
rn t-lwrnirl feerlino- rlnes n n t nereSQarilu P : es of persons with schizophrenia
teeClm g d eS n Ot n e c e s s a r i l
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pears to act through the hypothalamus ^ ^ ^ ^ w^ts? A^EW
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