The Relationship of Anxiety and Depression
to Symptoms of Hyperthyroidism Using
Operational Criteria
R. G. Kathol, M.D.
University of Iowa, Departments of Psychiatry and Infernal Medicine,
J. W. Delahunt, F.R.A.C.P.
Department of Endocrinology, Wellingfon Hospital,
Abstract: Twenty-six females and seven males with newly
diagnosed,untreated hyperthyroidism were administered a
structured questionnaire designed to identify anxiety and de-
pression using operational criteria. By DSM 111criteria, 20
patients were found to have depression and 15 anxiety. The
number of anxiety symptoms paralleled the number of hyper-
thyroid symptoms whereas depressive symptoms did not. Prior
history of psychiatric disease and family history of psychiatric
disease did not predict anxiety or depression in patients with
hyperthyroidism. The number with depression and anxiety was
felt to be artificially inflated by the concurrent presence of
somatic thyroid symptoms. Psychiatric practitioners should be
careful to exclude patients with hyperthyroidism before a prima-
y psychiatric diagnosis is made.
Introduction
In 1941 thioureas were first synthesized [l] and by
the late 1940s they were being used clinically. The
introduction of this medication coupled to the mea-
surement of protein-bound iodine (PBI) in 1950
meant that hyperthyroidism could not only be
identified earlier but could also be quickly and suc-
cessfully controlled in the majority of patients. It is
not surprising to find then that the psychiatric
symptoms of “exhaustion psychosis” and acute de-
lirium [2-41 became less commonly identified while
Gemml Hospital Psychiatry 8, 23-28, 1986
8 1986 Elsevier Science Publishing Co., Inc.
52 Vanderbilt Avenue, New York, NY 10017
Iowa City, Iowa
Wellington, New Zealand
depression and anxiety were described more often
(Table 1).
Studies designed to identify psychiatric features
of hyperthyroidism since 1940 yield only limited
information about these behavioral problems be-
cause they fail to define accurately what is meant by
the disorders they report. Even if the descriptions
of the behavioral syndromes were operationally de-
fined, profound crossover of symptoms in hyper-
thyroidism, anxiety, and depression (as demon-
strated in Table 2) leads to the conflict: to which
disorder do the symptoms truly belong? Are they
merely the result of the hyperadrenergic state seen
in hyperthyroidism, artifactually giving the illusion
of anxiety and depression, or are anxiety and de-
pressive disorders commonly found in hyper-
thyroidism? This study examines this question by
reviewing the relationship of depression and anx-
iety as currently defined to the degree of symptoms
and severity of laboratory abnormalities in hyper-
thyroidism and by comparing the incidence of pre-
existing psychiatric disease and family history of
psychiatric disease in patients with and without
anxiety or depression. It was hypothesized that if
anxiety and depression are only a reflection of the
physiologic changes seen in hyperthyroidism then
one would expect the severity of symptomatology
of hyperthyroidism to parallel the symptoms of
23
ISSN 01658343/86/$3.50
R. G. Kathol and J. W. Delahunt

Table 1. Symptoms (antithyroid drug era: after 194Os)@

N M:F Age Severity Comments

Lidz [13] 15 3:12 30’s Not stated 9114 depressed; no description of criteria given
Robbins and Vinson [14] 10 37 42 Not stated 1110 psychosis, l/10 anxious; no criteria
Wilson [15] 26 1:25 37 Not stated 15126 dysphoric; 2l26 elated; 6126 anxious; no
criteria
Hermann and Quarton [16] 24 NS NS Not stated Anxiety a sensory phenomenon
Artunkal and Togrol[17] 20 0:20 36 Not stated Increase on depression and anxiety score on
MMPI; not changed with treatment
Whybrow [18] 10 3:7 43 Mean PBI 14.6 2110depression; 2/10 anxiety; 2llOparanoia on
(N = 3.5 - 8.8) MMPI; 4/10 confusion: “subjective mental
disturbance”
MacCrimmon [19] 19 0:19 39 All T4 11.5 High depression scores on MMPI and Pre-
All 1311uptake 60% sent State Schedule
Rockey [20] 14 3:ll 40 T,-all elevated 1114 depressed; psychiatric dignoses not spe-
cifically looked for

‘N = number; M = male; F = female; NS = not stated; MMPI = Minnesota Multiphasic Personality Inventory.

depression and anxiety. Additionally there should Methods

also be no increase in prior psychiatric history or
family history in patients with anxiety or depres-
sion over those without.
This report represents the largest cohort of pa-
tients with hyperthyroidism who were examined
for psychiatric disease using operational criteria.
Among patients who presented with untreated hy-
perthyroidism at a general endocrinology clinic
during a 10 month period, 26 females and 7 males
were identified. The mean age of the patients was
47 years with a range of 29 to 82. After informed

Table 2. Comparison of hyperthyroid to anxiety and depressive symptoms

Hyperthyroid Anxiety/panic Depressive

Shaky Shaky
Palpitations Palpitations
Insomnia Insomnia Insomnia
Fatigue/weakness Fatigue Fatigue/weakness
Shortness of breath Dyspnea
Weight loss Weight loss/anorexia
Nervousness Anxiety
Irritability Irritability Irritability
Impaired concentration Impaired concentration Impaired concentration

Other Symptoms

Heat intolerance Sweating Agitation/retardation

Impaired memory Chest pain Loss in interest
Menstrual change Faintness Worthlessness/guilt
Change in face Choking Thoughts of death/suicide
Change in hair Fear of dying
Change in skin Dizziness
Unreality
Paresthesias
Hot/cold flashes

24
 Anxiety, Depression, and Hyperthyroidism

consent was obtained these patients were adminis- Table 4. Characterization of thyroid disease
tered a structured questionnaire by one of the in-
vestigators (RK 19; JWD 14) that was designed to Diagnosis Graves’ disease 28
determine the clinical degree of hyperthyroidism as Toxic multinodular 3
well as the presence or absence of major depres- Thyroiditis 2
History of thyroid disease Yes 10
sion, organic affective syndrome, and anxiety dis-
No 23
order, using DSM-III criteria [S], and depression
Thyroid symptoms Mild (<4) 6
and anxiety disorder, using Feighner criteria [6]. (possible total = 19)~ Moderate (5-8) 19
For purposes of symptom identification and com- Severe (>9) 8
parison the DSM-III and Feighner criteria excluding Free thyroid index (FTI) Above 540 5
patients with medical illness preceding or parallel- (iv = 60-160) 450-540 7
ing the psychiatric syndromes of depression and 360-450 1
anxiety were not used. All patients in this study 270-360 6
would obviously have been excluded for this rea- 180-270 9
son. The questionnaire also allowed assessment of 160-180 1
below 160 3
the presence of depression according to criteria that
attempted to adjust for the overlap of somatic com- ITachycarcIia,tremor, sweating, hyperactivity, goiter, thyroid
plaints seen in depressed and hyperthyroid pa- bruit, exophthalmos, lid lag, ophthalmoplegia, dermopathy,
tients (Table 3). Three patients were questioned by myopathy, decreased menstruation, diarrhea, splenomegaly,
gynecomastia, acropachy, heat intolerance, dyspnea, orbital
both raters in separate interviews to improve inter- edema.
rater reliability. In these patients the few dif-
ferences on individual items did not affect the diag-
nosis according to DSM III or Feighner criteria or wide range of thyroid disease was represented. It
composite thyroid symptomatology. was necessary to drop one patient from the analysis
All patients demonstrated a thyrotropin (TSH) of emotional status because her history was consid-
response to thyrotropin-releasing hormone (TBH) ered unreliable.
of less than 2.2 IU/ml. Basal TSH levels were all less Statistical analysis was performed using Fisher’s
than 2 IUIml. Other characteristics of thyroid dis- Exact Test for nonparametric data and Student’s t
ease in these patients can be found in Table 4. A test for parametric data when comparing patients
with anxiety to those without and patients with
Table 3. Criteria for depression depression to those without.
in hyperthyroidism

A. Sustained definite mood change of greater than 2 weeks

Results
and less than 6 months.
B. Two or more of the following: incidence of Depression and Anxiety
Four or more of the following: The criteria used for the diagnosis of depression
a. Irritability significantly affects the percentage of patients who
b. Hopelessness receive the diagnosis. When major depressive dis-
c. Increased crying
order was defined according to DSM-III, 10 of 32
d. Suicidal thoughts or gestures
patients were identified as having depression. The
e. Loss of sense of humor
f. Decreased activity because of sadness
criteria were modified by excluding the “not due to
g. Slowed concentration organic disease” category for purposes of this
Significant (not just mild) decrease in social ac- study. This was done to allow clinicians to under-
tivity stand and compare symptoms with patients who
Four or more of the following: have primary psychiatric disease. One additional
a. Unable to perform usual tasks patient could have been added had DSM-III criteria
b. Tired all the time for organic affective syndrome been used. The
c. Recent insomnia number identified as depressed according to
d. Decreased appetite Feighner criteria was six. When somatic symptoms
e. 2 kg or more weight loss in last 3 months
were de-emphasized and significant social inca-
f. Unable to perform daily tasks
pacity was added, as was done using the criteria
g. Decreased sexual activity
created for depression in hyperthyroidism, only

25
R. G. Kathol and J. W. Delahunt

three patients could be called depressed. Alter-
natively when DSM-III criteria were loosened to
include those with features of depression but no
dysphoria, i.e., “masked” depression, 14 of 32 pa-
tients with hyperthyroidism would have received a
diagnosis of depression.
Of our 32 patients, 20 claimed to be more ner-
vous than prior to the occurrence of their thyroid
disease. When specifically asked about the pres-
ence of symptoms of anxiety as found in DSM-III,
15 noted there was an increase. Thirteen patients
had sufficient symptoms to diagnose panic attacks;
however, the symptoms tended not to occur in
discrete episodes, as one would expect with an
anxiety disorder. Interestingly, only 8 of the 13
patients with more than four panic symptoms re-
ported increased anxiety, whereas only 8 of the 15
with generalized anxiety had panic symptoms.
Only two patients met criteria for anxiety disorder
according to Feighner. The absence of the specific
and restricted panic symptoms in these criteria was
the major reason for the paucity of patients diag-
nosed by this method.
Features ofDepression
Patients who had major depressive disorder as de-
fined by DSM-III when compared to those with
hyperthyroidism but no depression showed no sta-
tistical differences in a variety of parameters (Table
5). Analyzing these data when depression is de-
fined by Feighner criteria, no new differences
emerged. Patients with depression according to
Feighner criteria also had a lower percentage of
prior history of depression and family history of
psychiatric disease than those with DSM-III diag-
nosed depression. The three patients who met the
more stringent criteria for depression were not sig-
nificantly different from the group as a whole, but
this group was too small for meaningful interpreta-
tion.
Features of Anxiety
Patients defined as anxious by DSM-III showed no
statistical differences in sex distribution, history of
depression, history of anxiety, or family history of
emotional problems (Table 5). They were, however,
significantly younger, had higher free thyroxine
levels, and had more symptoms of hyperthyroid-
ism. When the number of symptoms of anxiety
were compared to the number of symptoms of hy-
perthyroidism using linear regression, a highly sig-
nificant correlation was found (r = 0.61; p < 0.001).
Relafionship of Depression to Anxiety
The ten patients with depression using DSM-III
criteria tended to have more panic symptoms (4.1+
2.0) than those without (3.2 ? 2.6), but this did not
approach significance. On the other hand, patients
with generalized anxiety had significantly more
symptoms of depression than those without (F =
1.017; df = 14; 16; p = 0.03). Patients who had
depression associated with hyperthyroidism were
more likely to have generalized anxiety disorder as
well as depression, whether the depression was
diagnosed by DSM III @/lo; p < 0.05) or Feighner

Table 5. Features of anxiety and depression

Anxious Nonanxious Depressed Nondepressed

(N = 15) (N = 17) (N = 10) (N = 22)
Mean * SD Mean f SD Mean 4 SD Mean + SD

Age (years) 40 2 17 54 * 151 45 f 17 48 2 18

Number of thyroid symptoms 8.1 r 2.8 54. k 2.Ob 7-c3 6t-3
Free thyroid index 418 r 137 288 + 132~ 361 f 160 347 f 145
Free triiodothyronine 4.7 -c 2.4 5.4 + 2.7 4.9 t 2.7 5.1 2 2.5
Sex (F:M) 11:4 14:3 7:3 18:4
History of depression (positive/N) l/15 5117 200 4l22
History of anxiety (positive/N) 3115 3117 l/10 5122
Family history of emotional problems (positive/N) 5114 5117 4i9 6122
Interviewer (RKzJWD) 78 11:6 5:5 13:9
“p< 0.05(anxiousvs. non-anxious)
bp< 0.01(anxiousvs. non-anxious)

26

(6/6; p < 0.01) criteria. It was difficult for patients to
retrospectively assess which emotion appeared
first-depression or anxiety.
Comments
The findings in our patients document the frequen-
cy with which anxiety and depression can be diag-
nosed in patients with hyperthyroidism using
operational criteria. Further it illustrates the wide
variability in the percentage being diagnosed as
such when different criteria are employed. We
found the incidence of depression could range from
9% using strict criteria to 44% when symptoms of
depression but no dysphoria was required. Like-
wise the incidence of anxiety ranged from 6% to
47%. These results help in understanding the vari-
ability in the frequency of depression (0%~64%)
and anxiety 0%-23%) seen in Table 1.
The main thrust of this article has been to ad-
dress the issue of whether depression and anxiety
represented true psychiatric syndromes or whether
they were artifically produced by the overlap of
symptoms common to each entity. We found that
the number of symptoms of hyperthyroidism and
the level of thyroxine excess was correlated with the
number of symptoms of anxiety but not depres-
sion. Both severe hyperthyroidism and anxiety
symptoms tended to occur in a younger age group
in our patients. The degree of severity of hyper-
thyroidism is not known to be associated with age
in hyperthyroidism although it is uncertain whet-
her this issue has been addressed. It is well known
that primary anxiety disorder has its onset before
the age of 40 [7] and thus the younger age of onset
in our patients would in this way be consistent with
the primary disorder. Our patients, however, differ
significantly in that their mean age was 40, with a
range from 19 to 69. Seven were over the age of 40.
The average age of onset for primary anxiety disor-
der is 25 [8].
Only 3 of the 15 patients with anxiety had a prior
history of anxiety disorder and in only 2 of these
was the history clearly prior to the onset of thy-
rotoxicosis. A prior history of anxiety disorder was
also found in 3 of 17 with no anxiety at interview.
There was also no difference in a family history of
psychiatric disease between our anxious and non-
anxious patients. This suggests that prior anxiety
disorder does not predispose to anxiety during hy-
perthyroidism and that there is no increased famil-
ial incidence. Both of these features are inconsistent
Anxiety, Depression, and Hyperthyroidism
with what one might find in primary anxiety disor-
epression was not related to the degree of hyper-
thyroidism in our patients. This supports the hy-
pothesis that depression in hyperthyroidism is a
distinct syndrome and not an artifact of symptom
crossover. If this is the case, the frequency of de-
pression in this group as defined by DSM-III or
Feighner is well above that reported for the normal
population [9] and is consistent with what Glass
found in a group of general medical outpatients
[lo]. Closer analysis, however, suggests that even
though the severity of hyperthyroidism does not
predict the presence of depression early phys-
iologic changes of thyrotoxicosis can lead to the
symptoms characterizing depression. Somatic
symptoms alone (sleep disturbance, decreased ac-
tivity, lack of energy, appetite disturbance, and
poor concentration) were enough in the “B” criteria
of major depressive disorder to include 7 of the 10
depressed patients. When one, however, adjusts
criteria to deemphasize somatic features of the dis-
ease, as was done using the criteria in Table 3, the
percentage demonstrating depression decreases to
a level more consistent with that found in the gen-
eral population. The fact that the percentage de-
pressed by DSM-III and Feighner criteria may be
inflated is supported by the finding that neither
prior depression nor family history of psychiatric
disease is increased in depressed as opposed to
nondepressed patients with hyperthyroidism, nor
is there a trend suggesting such.
No one reading this report should be surprised a
high percentage of patients with hyperthyroidism
are found to meet criteria for anxiety and depres-
sion using currently accepted operational defini-
tions. It has been suspected though not docu-
mented since they became available. Our data,
however, suggest the symptoms of both depression
and anxiety leading to these diagnoses are likely to
be due (at least in part) to the physical manifesta-
tions of the underlying disease that can be in-
terpreted as being the result of a psychiatric disor-
der. DSM-III has been promoted as a means by
which psychiatric diagnosis can be made on posi-
tive grounds rather than by exclusion. Indeed it has
increased reproducibility in syndrome identifica-
tion and the ability to predict response to treatment
in patients with primary psychiatric disorders.
Medical practitioners must remember, however,
that the disorders described by DSM-III are based
on the evaluation of patients with no medical ill-
ness. Our data would suggest that their use in
patients with physical conditions having symptoms
27
R. G. Kathol and J. W. Delahunt
in common with anxiety and depression such as
hyperthyroidism leads to false positive psychiatric
diagnoses.
More important, many of the patients in this
study presented with symptoms very similar to
patients with primary psychiatric disease. In fact,
several had received psychiatric treatment (usually
pharmacotherapy) and one had been hospitalized
for psychiatric features of what eventually turned
out to be thyrotoxicosis. Primary physicians should
be aware the syndromes of depression and anxiety
require a systematic investigation, including phys-
ical examination and laboratory evaluation of con-
ditions known to be related to their onset [ll]. This
is especially true of patients with depression since
the severity of hyperthyroidism does not appear to
be related to the occurrence of depressive symp-
toms. Psychiatric referral will not ameliorate this
need since less than 10% of psychiatrists perform
outpatient physical examinations and less than 40%
perform examinations on hospitalized patients [12].
This approach will prevent the administration of
inappropriate and ineffective treatments and lead
to early detection of treatable diseases related to the
symptomatology.
In conclusion, this report represents the largest
study of psychiatric symptoms in patients with hy-
perthyroidism since the introduction of antithyroid
medications in 1941. It is the only one that uses
operational criteria to define disease. If DSM-III
criteria are used to diagnose major depressive dis-
order or generalized anxiety disorder in this group
the incidence is 3 to 4 times that expected in the
general population. This figure may be artificially
inflated due to overlap of symptoms in each condi-
tion. Perhaps stricter criteria should therefore be
used in this group of patients. Since patients with
hyperthyroidism can present with symptoms so
similar to anxiety and depression, great care should
be used by physicians to exclude its presence before
treatment is initiated.
Tkeauthors wish fo thank Mary Ann Walter for her assistance in the
preparation
of this manuscript,Joss Fugerstromfor help withpatient
scheduling
and folluw-up, and Judy Travis for data compilation and
retrieval.
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Direct reprint requests to:
R. G. Kathol, M.D.
University of Iowa Hospitals and Clinics
Departments of Psychiatry and Internal Medicine
500 Newton Road
Iowa City, Iowa 52242