BMC Psychiatry BioMed Central

Research article Open Access

Thyroid function in clinical subtypes of major depression: an
exploratory study
Konstantinos N Fountoulakis*1, Apostolos Iacovides2,
Philippos Grammaticos3, George St Kaprinis4 and Per Bech5

Address: 1Laboratory of Psychophysiology, 3rd Department of Psychiatry, Aristotle University of Thessaloniki, University Hospital AHEPA,
Thessaloniki Greece, 23rd Department of Psychiatry, Aristotle University of Thessaloniki, University Hospital AHEPA, Thessaloniki Greece,
3Laboratory of of Nuclear Medicine, Aristotle University of Thessaloniki, University Hospital AHEPA, Thessaloniki Greece, 43rd Department of

Psychiatry, Aristotle University of Thessaloniki, University Hospital AHEPA, Thessaloniki Greece and 5Frederiksborg General Hospital Department
of Psychiatry, Hillerod Denmark
Email: Konstantinos N Fountoulakis* - kfount@med.auth.gr; Apostolos Iacovides - kfount@med.auth.gr;
Philippos Grammaticos - kfount@med.auth.gr; George St Kaprinis - kfount@med.auth.gr; Per Bech - gabean@fa.dk
* Corresponding author

Published: 15 March 2004 Received: 15 September 2003

Accepted: 15 March 2004
BMC Psychiatry 2004, 4:6
This article is available from: http://www.biomedcentral.com/1471-244X/4/6
© 2004 Fountoulakis et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in
all media for any purpose, provided this notice is preserved along with the article's original URL.

depressionthyroid functionpsychoneuroendocrinologyautoimmune disorders.

Background: Unipolar depression might be characterized by a 'low-thyroid function syndrome'.

To our knowledge, this is the first study which explores the possible relationship of DSM-IV
depressive subtypes and the medium term outcome, with thyroid function.
Methods: Material: Thirty major depressive patients (DSM-IV) aged 21–60 years and 60 control
subjects were included. Clinical Diagnosis: The SCAN v 2.0 and the IPDE were used. The
psychometric Assessment included HDRS the HAS and the GAF scales. Free-T3, Free-T4, TSH,
Thyroid Binding Inhibitory Immunoglobulins (TBII), Thyroglobulin antibodies (TA) and Thyroid
Microsomal Antibodies (TMA) were measured in the serum. The Statistical analysis included 1 and
2-way MANCOVA, discriminant function analysis and Pearson Product Moment Correlation
Coefficient.
Results: All depressive subtypes had significantly higher TBII levels in comparison to controls.
Atypical patients had significantly higher TMA in comparison to controls. No significant correlation
was observed between the HDRS, HAS and GAF scales and thyroid indices. Discriminant function
analysis produced functions based on thyroid indices, which could moderately discriminate
between diagnostic groups, but could predict good response to treatment with 89.47% chance of
success.
Conclusion: Although overt thyroid dysfunction is not common in depression, there is evidence
suggesting the presence of an autoimmune process affecting the thyroid gland in depressive patients

Page 1 of 9
(page number not for citation purposes)
BMC Psychiatry 2004, 4 http://www.biomedcentral.com/1471-244X/4/6

Background however studies are inconclusive and fail to differentiate

It is believed that depression might be characterized by a between different clinical subtypes of depression.
'low-thyroid function syndrome' [1-3]. Hypothyroidism
might be associated with anxiety [4] or refractory depres- The present study aimed to investigate the relationship
sion, suggesting that this characterizes one biological sub- between subtypes of unipolar major depression, medium
type of refractory depression. However, screening thyroid term (2 years) outcome and thyroid function in patients
tests are often routine for depressed inpatients, and data and controls. To our knowledge, this is the first study
suggest that thyroid screening may add little to diagnostic which explores the possible relationship of DSM-IV
evaluation. Overt thyroid disease is rare among depressed depressive subtypes and the medium term outcome, with
inpatients [5], and the role of thyroid hormones in the thyroid function.
pathophysiology of affective disorders remains to be clar-
ified [6]. Methods
Material
Depression is traditionally classified into two opposite Thirty patients (10 males and 20 females) aged 42.43 ±
poles [7-10], today named 'melancholic' [11] or 'somatic' 11.82 years (range 21–60) suffering from Major Depres-
syndrome [12] and 'atypical' features, that is 'reverse neu- sive disorder according to DSM-IV [11], and 60 normal
rovegetative symptoms' (increased appetite, weight gain, controls (25 males and 35 females aged 41,01 ± 9.72 years
increased sleep etc) and interpersonal rejection sensitivity (range 25–58) entered the study. Ten patients fulfilled
[13-15]. atypical features (according to DSM-IV), 12 melancholic
features (according to DSM-IV) and 8 did not fulfill crite-
It is reported that in melancholia, the autonomous nerv- ria for any specific syndrome ('undifferentiated' patients).
ous system and the stress response seem hyperactive [16].
Patients are anxious, dread the future, lose responsiveness Patients and controls were free of any medication for at
to the environment, have insomnia, lose appetite, there is least two weeks and were physically healthy with normal
a diurnal variation with depression at its worst in the clinical and laboratory findings (Electroencephalogram,
morning. Corticotropine Releasing Hormone (CRH) sys- blood and biochemical testing, test for pregnancy, B12
tem may be hyperactive. On the contrary growth hormone and folic acid).
and reproductive axes may have diminished activities.
Patients with atypical depression present with a constella- No patient with catatonic or psychotic features or seasonal
tion of symptoms that seems the antithesis of melancho- affective disorder was included and no-one fulfilled crite-
lia [10]. They are lethargic, fatigued, hyperphagic, ria for another DSM-IV axis-I disorder, except from gener-
hypersomnic, reactive to the environment, and show diur- alized anxiety disorder and panic disorder. No-one had
nal variation of depression that is at its best in the morn- history of manic or hypomanic episode in the past, or had
ing. Some authors suggest that there is a down-regulated prior history of lithium or thyroid hormones treatment.
hypothalamic-pituitary adrenal axis and CRH deficiency
of central origin present in atypical depression [17]. The normal control group was composed by members of
the hospital staff, and students. A clinical interview con-
On the other hand, it is suggested that conditions associ- firmed that they did not suffer from any mental disorder
ated with significant changes in stress system activity, such and their prior history was free from mental and thyroid
as acute or chronic stress or even cessation of chronic disorder.
stress, severe exercise, pregnancy, the postpartum period,
and anxiety and mood disorders, may suppress or poten- All patients were followed up for a period of 2 years. Dur-
tiate autoimmune diseases activity and/or progression ing that period they received an adequate dose of one or
through modulation of the systemic or local pro/antiin- more antidepressant agent (SSRI or SNRI). According to
flammatory cytokine balance [18]. It has been also their course during that period, they were divided in two
reported that patients affected by celiac disease tend to groups: Nineteen (N = 19, 63.33%, 8 melancholics, 5
show a high prevalence of personality and major depres- atypicals, 6 undifferentiated) of them were considered to
sive disorders. Association with subclinical thyroid dis- be Responders (those with full or almost full remission
ease appears to represent a significant risk factor for these and no relapse during the whole 2 year period) and 11
psychiatric disorders [19,20]. (36.67%, 4 melancholics, 5 atypicals, 2 undifferentiated)
were considered to be partial responders (those with par-
Thus, there is a lot of evidence suggesting the presence of tial attenuation of symptomatology without full remis-
an underlying autoimmune disorder in unipolar depres- sion or with relapses of episodes). The follow-up was
sion, with the possible involvement of the thyroid gland, done in an open naturalistic way.

Page 2 of 9
(page number not for citation purposes)
BMC Psychiatry 2004, 4 http://www.biomedcentral.com/1471-244X/4/6

All patients and controls provided written informed con- The statistical analysis included one and two-way Multi-
sent before participating in the study. The protocol was ple Analysis of Covariance (MANCOVA) with Scheffe as
approved by the Investigational Review Board of the post-hoc test. Age, the presence of personality disorder
hospital. and the presence of anxiety disorder served as covariates.
Two Discriminant function (stepwise method) analyses
Method were performed with diagnostic group and outcome as
The clinical diagnosis was reached by consensus of two grouping variables and thyroid indices as dependent vari-
examiners. The Schedules for Clinical Assessment in Neu- ables. Discriminant function analysis produces one func-
ropsychiatry version 2.0 [21,22] were directly applied and tion for each group by using the dependent variables
the International Personality Disorders Examination [23- appropriately weighted. In this way each case obtains a
26] was retrospectively applied to the data. score (a function of its weighted dependent variables; in
our case of weighted thyroid indices) that corresponds to
The psychometric assessment included the Hamilton every group, and is classified in the group in whose func-
Depression Rating Scale (HDRS) [27,28], the Hamilton tion obtains the highest score. The forward stepwise
Anxiety Scale (HAS) [29], and the Global Assessment of method reduces the number of dependent variables used
Functioning Scale (GAF) [30]. in these functions to a minimum. The Pearson Product
Moment Correlation Coefficient was also calculated.
Assessment of thyroid function Since 2 MANCOVAs were performed and 21 correlation
Free-T3 (FT3) was assessed by an AMERLEX-MAB™ Immu- coefficients were calculated, the Bonferroni correction led
noradiometric Assay (RIA) kit The sensitivity of the assay to the adoption of the p < 0.0021 level (0.05/23 = 0.0021)
is 0.7 pmol/lt. Normal are values 3.3–8.2. Free-T4 (FT4) as the level for significance for all tests (including post-
was assessed by an AMERLEX-MAB™ Immunoradiometric hoc tests)
Assay (RIA) kit The sensitivity of the assay is 0.6 pmol/lt.
Normal are values 11–25 pmol/lt. The Thyroid Stimula- Results
tion Hormone-TSH was assessed with an Ortho-Clinical No patient had FT3, FT4, or TA levels outside the normal
Diagnostics™ Immunoradiometric Assay (RIA). The sensi- range. The plot of FT4 values vs. a logarithmic TSH values
tivity of the assay is 0.04 µIU/mlt. The specificity was < (figure 1) suggests that all depressed patients and controls
0.001% for FSH, LH and Hcg. Normal values are 0.3–3 are located in the normal reference area, away from pri-
mU/lt. Thyroid Binding Inhibitory Immunoglobulins- mary hypo- and hyperthyroidism. Four patients (13.3%)
TBII were measured with a BRAHMS Diagnostica GmbH had increased TSH levels (1 melancholic-8.31% and 3
DYNOtest® TRAK human kit Radio Receptor Assay (RRA). undifferentiated-37.5%), 12 patients (26.6%) had
The test has 98.8% sensitivity and 99.6% specificity. The increased TMA levels (5 atypicals-50%, 6 melancholics-
analytical sensitivity of the assay is 0.3 IU/lt, and the func- 50% and 1 undifferentiated-11.1%), and 5 (16.6%) had
tional assay sensitivity (20% inter-assay variation coeffi- increased TBII levels (2 atypicals-20% and 3
cient) is 0.9 IU/lt. Normal are values below 10%. undifferentiated-37.5%).
Thyroglobulin antibodies-TA were assessed by a RADIM™
Immuroradiometric Assay (RIA). The analytical sensitivity
of the assay is 15 U/mlt and the functional sensitivity
(with 20% inter assay variation coefficient is 40 IU/mlt.
Normal are values below 100 U/ml. Thyroid Microsomal
Antibodies-TMA (or autoantibodies to Thyroid Peroxi-
dase-anti-TPO) were assessed by a MEDIPAN DIAGNOS-
TICA™ radiolingand assay. The functional assay sensitivity
(10% within assay and 20% between assay variation coef-
ficient) is 35 IU/mlt. Normal are values below 50 IU/ml.
All measurements concern the serum levels of patients.
The ratio FT4/FT3 was also calculated.

Although anti-TPO Ab assay by monoclonal antibody-

assisted RIA appears to be more sensitive and specific for Figure 1scatterplot between TSH and FT4 levels
Bivariate
thyroid autoimmune diseases than other methods [31] Bivariate scatterplot between TSH and FT4 levels. All
unfortunately it was not available in our laboratory at the depressed patients are located within the area of non-thyroi-
time the study took place. dal illness

Page 3 of 9
(page number not for citation purposes)
BMC Psychiatry 2004, 4 http://www.biomedcentral.com/1471-244X/4/6

Table 1: 1-way MANCOVA between the diagnostic groups in terms of thyroid results, with age, 2-way MANCOVA between the short
term outcome (factor 1) and diagnostic groups (factor 2) in terms of thyroid results

Wilks' Lambda Rao's R df 1 Df 2 p-level

1-Way MANCOVA 1: Type of depression

1 0.325 5.052 21 221 0.000
2-Way MANCOVA 1: Outcome 2: Type of depression
1 0.430 2.835 7 15 0.043
2 0.073 5.772 14 30 0.000
12 0.275 1.942 14 30 0.062
Normal Depressed Atypical Melancholic Undifferentiated Responders Partial
Controls patients features features N=8 N = 19 responders
N = 60 N = 30 N = 10 N = 12 N = 11

Mean S.D Mean S.D Mean S.D Mean S.D Mean S.D Mean S.D Mean S.D

FT4 16.32 2.69 14.59 1,59 15.50 1.28 14.15 1.45 14.13 1.83 14.04 1.39 15.55 1.52
FT3 6.03 1.56 5.85 1,00 6.57 1.16 5.30 0.50 5.76 0.85 5.83 1.18 5.88 0.61
TS 1.31 0.74 1.52 1,21 0.92 0.33 1.42 0.71 2.43 1.92 1.58 0.99 1.43 1.57
H
TBII 0.89 1.16 8.67 7,93 7.64 3.13 6.31 1.30 13.49 14.41 7.66 2.29 10.40 12.95
TM 18.80 3.42 124.8 295, 272.14 477. 51.35 66.9 51.04 116.07 151.17 362.54 79.43 111.1
A 6 08 98 4 3
TA 15.26 8.52 20.41 9,91 18.23 4.51 23.72 13.9 18.19 6.71 19.05 5.71 22.77 14.72
3
T4/ 2.81 0.64 2.54 0,33 2.41 0.39 2.68 0.31 2.46 0.20 2.46 0.35 2.66 0.28
T3
rati
o

In both analyses, age, the presence of anxiety disorder and the presence of personality disorder as covariates. Scheffe test served as post-hoc test

The means and standard deviations for each group are falsely classified) however the success rate is far lower for
shown in table 1. depressives (around 60% for all subtypes), however is still
higher than chance (which would be 25% success).
MANCOVA results revealed a main effect for the type of
depression alone (p < 0.001, table 1). Post hoc analysis However, the success in discriminating between respond-
(table 2) revealed significant differences between all ers and poor responders is far higher. The functions suc-
depressed subtypes and controls in terms of TBII levels (p ceeded in an 80.00% correct classification of depressed
< 0.0021) and between atypicals and controls in terms of patients on the basis of thyroid indices. If we subtract the
TMA (p < 0.001). two functions, then we obtain the following function:
20.86-1.52*(FT4)-0.98*(TSH)+0.74*(FT3)-0.07*(TBII).
These results should be considered a true effect of the type When this function takes values above zero, then the
of depression since age, the presence of anxiety disorder respected depressed patient is predicted to be a responder
and the presence of personality disorder were used as with an 89.47% chance of success. These rates are clearly
covariates. higher than the 50% (by chance).

There were no significant correlations between the HDRS,

the HAS and the GAF scales and thyroid indices. No cor- Table 2: Scheffe Post Hoc test results.
relation was significant even at p < 0.05.
Index Groups compared P

Discriminant function analysis results are shown in table TBII Undifferentiated vs. Normal controls <0.001
3 for depressed subtypes and in table 4 concerning the Atypicals vs. Normal controls <0.001
short-term outcome. Melancholics vs. Normal controls 0.002
TMA Atypicals vs. Normal controls <0.001
Discriminant functions may discriminate controls from
depressives with 98.33% accuracy (only one control is Only significant results are shown at p < 0.0021

Page 4 of 9
(page number not for citation purposes)
BMC Psychiatry 2004, 4 http://www.biomedcentral.com/1471-244X/4/6

Table 3: Results of Discriminant function analysis (forward stepwise method) with diagnostic groups as the grouping variables.

Rows: Observed classifications

Columns: Predicted classifications

Undifferentiated Atypicals Melancholics Normal controls

% Correct p = 0.088 p = 0.111 p = 0.133 p = 0.666

Undifferentiated 62.50 5 1 1 1
Atypicals 60.00 0 6 1 3
Melancholics 58.33 0 0 7 5
Normal controls 98.33 0 0 1 59
Total 85.56 5 7 10 68

Classification Functions (coefficients)

Undifferentiated Atypicals Melancholics Normal controls

p = 0.088 p = 0.111 p = 0.133 p = 0.666

TBII 1.04 0.57 0.49 0.14

TSH 6.78 4.03 4.47 3.87
TMA 0.01 0.01 0.00 0.00
TA 0.17 0.10 0.25 0.12
FT4 2.39 2.85 2.02 2.73
T4/T3 ratio 2.36 0.45 4.00 2.46
Constant -39.08 -31.56 -29.45 -29.58

The analysis succeeded in a 85.56% correct classification of all cases on the basis of thyroid indices. Only one control was falsely classified. Each case
is predicted to belong to the group in whose function obtains the highest value. The chance of success of this prediction depends on the group. The
four groups seems to lie on a continuum with melancholics closer to controls and undifferentiated being the group more distant to controls, and
atypicals in the middle.

Table 4: Results of Discriminant function analysis (forward stepwise method) with outcome as the grouping variables.

Rows: Observed classifications

Columns: Predicted classifications

Responders Partial responders

% Correct p = 0.633 p = 0.366

Responders 89.47 17 2
Partial responders 63.64 4 7
Total 80.00 21 9

Classification Functions

Responders Partial responders (Responders) -

(Partial Responders)
p = 0.633 p = 0.366

FT4 13.27 14.78 -1.52

TSH 12.21 13.19 -0.98
FT3 0.80 0.06 0.74
TBII 0.37 0.45 -0.07
Constant -106.96 -127.83 20.86

The analysis succeeded in a 80.00% correct classification of depressed patients on the basis of thyroid indices. If we subtract the two functions, then
we obtain the following function: 20.86-1.52*(FT4)-0.98*(TSH)+0.74*(FT3)-0.07*(TBII). When this function takes values above zero, then the
respected depressed patient is predicted to be a responder with a 89.47% chance of success.

Page 5 of 9
(page number not for citation purposes)
BMC Psychiatry 2004, 4 http://www.biomedcentral.com/1471-244X/4/6

Discussion ric diseases, and they may imply that cell-mediated

The present study reports that while FT3, FT4 and TSH of immune mechanisms are involved in the pathogenesis of
depressed patients are generally within the normal range certain mental disorders [19,20,36].
(figure 1), thyroid binding inhibitory immunoglobulin
levels were higher in depressed patients in comparison to The availability of thyroid testing led to a bulk of research
controls. Microsomal antibodies levels were higher in on thyroid dysfunction in non-thyroidal illness. Data sug-
atypical patients in comparison to controls. No differ- gest that within a given patient's status, change of thyroid
ences were detected when depressive subtypes were com- function is determined by the severity and duration of ill-
pared. The way discriminant function analysis classified ness as well as the presence of mitigating influences that
depressed patients is interesting. Melancholics are classi- are associated with the specific underlying disorders.
fied either correctly or as normals, atypicals are classified These thyroid disturbances in the frame of non-thyroidal
either correctly or as melancholics (N = 1) or normals (N illness is a diagnostic problem which needs focused atten-
= 3) and finally falsely classified 'undifferentiated' tion. Figure 1 represents a graphical solution suggested by
patients are classified one in each one of the three other Kaptein[37]. In this figure, it is evident that most
groups. This may mean that melancholics are a more depressed patients are clearly euthyroid, with some of
clearly defined and 'core' group, while atypicals and them falling in the 'non-thyroid illness' area.
undifferentiated patients may constitute groups that fur-
ther deviate away from normality and the 'melancholic There are several papers suggesting that the thyroid func-
core' of depression. Atypical patients were both more tion of depressed patients is within the normal range,
refractory to treatment and had higher microsomal anti- hypothyroidism and hyperthyroidism are extremely
bodies (apart from TBII). uncommon and that the presence of subtle thyroid func-
tion abnormalities does not have an impact on treatment
Microsomal antibodies are frequently present in patients outcome [38-43]. However, on the contrary there are even
with chronic lymphocytic thyroiditis, while thyroid bind- more papers supporting the idea of a subclinical thyroid
ing inhibitory immunoglobulines inhibit the binding of dysfunction, especially in melancholic or refractory
TSH to its receptor, and lead to hypothyroidism. patients, possibly of an autoimmune origin [44-55] sug-
gesting that subclinical hypothyroidism may lower the
Depressed patients may have an altered thyroid-stimulat- threshold for the occurrence of depression[56], or gener-
ing hormone response to thyrotropin-releasing hormone ally to any mental disorder [57-59]. It is reported that
(TRH), an abnormally high rate of antithyroid antibodies most patients with depression may have alterations in
and elevated cerebrospinal fluid (CSF) TRH concentra- their thyroid function including slight elevation of the
tions. Moreover, tri-iodothyronine has been shown con- serum FT4, blunted TSH response to thyrotropin-releasing
clusively to augment the efficacy of various hormone (TRH) stimulation[60], and loss of the noctur-
antidepressants. It has been suggested that the Hypothala- nal TSH rise and this may reflect brain hypothyroidism in
mus-Pituitary-Thyroid (HPT) axis alterations may be par- the context of systemic euthyroidism[61].
tially trait and partially state markers [32]. Other studies
suggest that depression (and especially bipolar depres- Concerning the role thyroid status may play in the aetio-
sion) is characterized by brain hypothyroidism despite pathogenesis and neurobiology of depression it has been
apparent euthyroidism indicated by routine peripheral suggested that most patients with depression, although
blood thyroid hormone results[33,34]. generally viewed as chemically euthyroid, have alterations
in their thyroid function which are generally reversed fol-
The finding that depression often co-exists with autoim- lowing alleviation of the depression [61-66].
mune subclinical thyroiditis suggests that depression may
cause alterations in the immune system, or that in fact it It is also believed (although not well documented) that
is an autoimmune disorder itself. Whereas acute stress depression is accompanied by various direct and indirect
may initiate a transient immunologically protective indicators of a moderate activation of the inflammatory
response, prolonged or poorly controlled psychosocial response system, especially in the frame of the stress-
stressors may result in depression of different components response activity. Increased production of proinflamma-
of the immune system. These responses may be related to, tory cytokines, such as interleukin-1, interleukin-6 and
or independent of, changes in the neuroendocrine system. interferon (IFNgamma), may play a crucial role in the
As the rather prolific literature in this infant area of psy- immune and acute phase response in depression[18-
choneuroimmunology reveals, there are many complex 20,67]. On the other hand, it is not known whether
levels of interaction that require further investigation [35], pathophysiological mechanisms other than 5-HT dysreg-
concerning a close relationship between delayed hyper- ulation could be involved in TSH blunting in major
sensitivity to neural tissue antigens and immunopsychiat- depressed patients. Some data suggest that the 5-HT

Page 6 of 9
(page number not for citation purposes)
BMC Psychiatry 2004, 4 http://www.biomedcentral.com/1471-244X/4/6

reduced function is more pronounced in those patients lation between specific clinical symptoms and thyroid
without HPT axis abnormality. In this frame, HPT dysreg- indices. This is again in accord with the literature.
ulation may be regarded as a compensatory mechanism Depressed patients had higher Thyroid Binding Inhibitory
for diminished central 5-HT activity[68], which is a Immunoglobulins (TBII), which is suggestive of the pres-
suggestion similar to another one proposed concerning ence of an underlying autoimmune process in depression,
the Hypothalamus-Pituitary-Adrenal Axis[69]. This just and is independent of the clinical subtype. Response to
reflects the fact that the true relationship of peripheral treatment could be predicted on the basis of thyroid indi-
indices to brain function is always an open question[70]. ces alone with 89.47% chance of success, which is a rather
high success rate. Further study is necessary in order to
The most robust relationship between thyroid dysfunc- investigate the mechanisms of this process and the extent
tion and depression concerns gestation and the postpar- of this autoimmune activation.
tum period. Thyroid antibody-positive women are prone
to hypothyroidism, which is often preceded by transient The current study constitutes only an exploratory effort to
hyperthyroidism after delivery[71]. Also, lower range total search for the relationship between subtypes of unipolar
and free thyroxine concentrations during late pregnancy depression, thyroid function and clinical outcome. This
may be related to postpartum depressive symptoms[72]. effort is restricted both by the study sample as well as from
The presence of abnormal thyroid function tests is not limitation of the methodology employed. Further
related with a distinct clinical picture[73]. However, research is essential in order to arrive to solid conclusions.
again, the literature is split and the results are inconclusive
[74-76]. Competing interests
None declared.
Thus, the review of the literature suggests that there are no
conclusive data on the role of thyroid function in depres- References
sion. It is clear that depression is not characterized by an 1. Staner L, De La Fuente JM, Kerkhofs M, Linkowski P, Mendlewicz J:
Biological and clinical features of recurrent brief depression:
overt thyroid dysfunction. It is also clear that a subgroup a comparison with major depressed and healthy subjects.
of depressed patients may manifest subtle thyroid abnor- Journal of Affective Disorders 1992, 26:241-245.
malities, or an activation of an autoimmune process, 2. Legros S, Mendlewicz J, Wybran J: Immunoglobulins, autoanti-
bodies and other serum protein fractions in psychiatric
however the cause of this phenomenon and its implica- disorders. Eur Arch Psychiatry Neurol Sci 1985, 235:9-11.
tions are unclear. There is a strong possibility that the 3. Rao ML, Ruhrmann S, Retey B, Liappis N, Fuger J, Kraemer M, Kasper
presence of a subtle thyroid dysfunction is a negative S, Möller HJ: Low plasma thyroid indices of depressed patients
are attenuated by antidepressant drugs and influence treat-
prognostic factor for depression and may demand specific ment outcome. Pharmacopsychiatry 1996, 29:180-186.
therapeutic intervention. On the other hand, it should be 4. Iacovides A, Fountoulakis KN, Grammaticos P, Ierodiakonou C: Dif-
ference in symptom profile between generalized anxiety dis-
stressed that atypical patients are over-represented in the order and anxiety secondary to hyperthyroidism. International
'partial responders' group of the current study. Thus, the Journal of Psychiatry in Medicine 2000, 30:71-81.
results of the current study report a triangular relationship 5. Ordas DM, Labbate LA: Routine screening of thyroid function in
patients hospitalized for major depression or dysthymia?
between atypicality, thyroid dysfuction and refractory Annals of Clinical Psychiatry 1995, 7:161-165.
depression. It is not possible to arrive at a reliable causal 6. Joffe RT, Sokolov ST: Thyroid hormones, the brain, and affec-
tive disorders. Crit Rev Neurobiol, 1994, 8:45-63.
relationship at this stage. Further focused research is 7. Roth M: The phenomenology of depressive states. Can Psychiatr
necessary. Assoc J 1959, 4(suppl):32-54.
8. Van Praag HM, Uleman AM, Spitz JC: The Vital Syndrome
Interview. Psychiatr Neurol Neurochir 1965, 68:329-349.
The major advantage of the current study is the follow up 9. Overall JE, Hollister LE, Johnson M: Nosology of Depression and
period of 2 years in clearly and solidly diagnosed subtypes Differential Response to Drugs. JAMA 1966, 195:946-950.
of unipolar major depression. There is no other similar 10. Fountoulakis KN, Iacovides A, Nimatoudis I, Kaprinis G, Ierodia-
konou Ch: Comparison of the Diagnosis of Melancholic and
study in the literature. Atypical Features According to DSM-IV and Somatic Syn-
drome According to ICD-10 In Patients Suffering from
Major Depression. European Psychiatry 1999, 14:426-434.
The main disadvantage of the study is the relatively small 11. APA: Diagnostic and Statistical Manual of Mental Disorders,
study population which is at the limit of parametric meth- 4th Edition, DSM-IV. Washington DC, American Psychiatric Press;
ods. Thus, results should be accepted with caution. 1994.
12. WHO: The ICD-10 Classification of Mental and Behavioural
Disorders-Diagnostic Criteria for Research. Geneva; 1993.
Conclusion 13. Liebowitz MR, Quitkin FM, Stewart J, McGrath PP, Harrison W,
The results of the current study, in accord with the litera- Markowitz J, Rabkin J, Tricamo E, Goetz D, D Klein: Antidepressant
Specificity in Atypical Depression. Archives of General Psychiatry
ture, suggest that overt thyroid dysfunction is not com- 1988, 45:129-137.
mon in depressive patients. No significant differences can 14. Sargant W: Some Newer Drugs in the Treatment of Depres-
sion and their Relation to Other Somatic Treatments. Psycho-
be traced concerning the thyroid function between differ- somatics 1960, 1:14-17.
ent clinical subtypes of depression nor there is any corre- 15. Dally PJ, Rohde P: Comparison of Antidepressant Drugs in
Depressive Illnesses. Lancet 1961, 1:18-20.

Page 7 of 9
(page number not for citation purposes)
BMC Psychiatry 2004, 4 http://www.biomedcentral.com/1471-244X/4/6

16. Fountoulakis K, Fotiou F, Iacovides A, Goulas A, Tsolaki M, Ierodia- 42. Harris B, Fung H, Johns S, Kologlu M, Bhatti R, McGregor AM, Rich-
konou Ch: Changes in Pupil Reaction to Light in Melancholic ards CJ, Hall R: Transient post-partum thyroid dysfunction and
patients. International Journal of Psychophysiology 1999, 31:121-128. postnatal depression. Journal Of Affective Disorders 1989,
17. Gold PW, Chrousos GP: Organization of the stress system and 17:243-249.
its dysregulation in melancholic and atypical depression: 43. Joffe RT: Antithyroid antibodies in major depression. Acta Psy-
high vs low CRH/NE states. Mol Psychiatry 2002, 7:254-275. chiatrica Scandinavica 1987, 76:598-599.
18. Elenkov IJ, Chrousos GP: Stress hormones, proinflammatory 44. Howland RH: Thyroid dysfunction in refractory depression:
and antiinflammatory cytokines, and autoimmunity. Ann N Y implications for pathophysiology and treatment. Journal of Clin-
Acad Sci 2002, 966:290-303. ical Psychiatry 1993, 54:47-54.
19. Carta MG, Hardoy MC, Boi MF, Mariotti S, Carpiniello B, Usai P: 45. Rao ML, Vartzopoulos D, Fels K: Thyroid function in anxious and
Association between panic disorder, major depressive disor- depressed patients. Pharmacopsychiatry 1989, 22:66-70.
der and celiac disease: a possible role of thyroid 46. Nemeroff CB: Clinical significance of psychoneuroendocrinol-
autoimmunity. J Psychosom Res 2002, 53:789-793. ogy in psychiatry: focus on the thyroid and adrenal. Journal of
20. Carta MG, Hardoy MC, Usai P, Carpiniello B, Angst J: Recurrent Clinical Psychiatry 1989, 50 Suppl:13-20.
brief depression in celiac disease. J Psychosom Res 2003, 47. Maes M, D'Hondt P, Blockx P, Cosyns P: A further investigation
55:573-574. of basal HPT axis function in unipolar depression: effects of
21. Wing JK, Babor T, Brugha T: SCAN: Schedules for Clinical diagnosis, hospitalization, and dexamethasone
Assessment in Neuropsychiatry. Archives of General Psychiatry administration. Psychiatry Research 1994, 51:185-201.
1990, 47:589-593. 48. Bunevicius R, Kazanavicius G, Telksnys A: Thyrotropin response
22. WHO: Schedules for Clinical Assessment in Neuropsychia- to TRH stimulation in depressed patients with autoimmune
try-SCAN version 2.0) Greek Version. Edited by: Mavreas V. Ath- thyroiditis. Biological Psychiatry 1994, 36:543-547.
ens, Research University Institute for Mental Health; 1995. 49. Banki CM, Vojnik M, Arato M, Papp Z, Kovacs Z: Dexamethasone
23. Loranger AW, Sartorious N, Andreoli Al: The World Health suppression and multiple hormonal responses (TSH, prolac-
Organisation/Alcohol, Drug Abuse and Mental Health tin and growth hormone) to TRH in some psychiatric disor-
Administration International Pilot Study of Personality ders. European Archives of Psychiatry and Neurological Sciences 1985,
Disorders. Archives of General Psychiatry 1994, 51:215-224. 235:32-37.
24. WHO: International Personality Disorders Examination. 50. Rupprecht R, Rupprecht C, Rupprecht M, Noder M, Mahlstedt J: Tri-
Geneva; 1995. iodothyronine, thyroxine, and TSH response to
25. Fountoulakis KN, Iacovides A, Kaprinis G, Ierodiakonou Ch: World dexamethasone in depressed patients and normal controls.
Health Organisation: International Personality Disorders Biological Psychiatry 1989, 25:22-32.
Examination, Greek Edition. Thessaloniki Greece. unpublished 51. Gewirtz GR, Malaspina D, Hatterer JA, Feureisen S, Klein D, Gorman
26. Fountoulakis KN, Iacovides A, Ioannidou Ch, Bascialla F, Nimatoudis JM: Occult thyroid dysfunction in patients with refractory
I, Kaprinis G, Janca A, Dahl A: Reliability and cultural applicabil- depression. American Journal Of Psychiatry 1988, 145:1012-1014.
ity of the Greek version of the International Personality Dis- 52. Marchesi C, Chiodera P, DeRisio C, Dassò L, Govi AM, DeFerri A,
orders Examination. BMC Psychiatry 2002, 2:6. Piagneri B, Minelli R, Bianconi L, Gnudi A: Dopaminergic control
27. Hamilton M: A rating scale for depression. J Neurol Neurosurg of TSH secretion in endogenous depression. Psychiatry Research
Psychiatry 1960, 23:56-62. 1988, 25:277-282.
28. Williams J: A structured interview guide for the Hamilton 53. Nemeroff CB, Simon JS, Haggerty JJ, Evans DL: Antithyroid anti-
Depression Rating Scale. Arch Gen Psychiatry 1988, 45:742-747. bodies in depressed patients. American Journal Of Psychiatry 1985,
29. Hamilton M: The Assessment of Anxiety States by Rating. 142:840-843.
British Journal of Medical Psychology. 1959, 32:50-55. 54. Kjellman BF, Ljunggren JG, Beck-Friis J, Wetterberg L: Effect of TRH
30. APA: Diagnostic and Statistical Manual of Mental Disorders. on TSH and prolactin levels in affective disorders. Psychiatry
4th (DSM-IV)th edition. Washington DC; 1994:32. Research 1985, 14:353-363.
31. Mariotti S, Caturegli P, Piccolo P, Barbesino G, Pinchera A: Antithy- 55. Haggerty JJ, Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ:
roid peroxidase autoantibodies in thyroid diseases. J Clin Endo- Subclinical hypothyroidism: a modifiable risk factor for
crinol Metab 1990, 71:661-669. depression? American Journal Of Psychiatry 1993, 150:508-510.
32. Musselman DL, Nemeroff CB: Depression and endocrine disor- 56. Haggerty JJ, Evans DL, Golden RN, Pedersen CA, Simon JS, Nemeroff
ders: focus on the thyroid and adrenal system. Br J Psychiatry CB: The presence of antithyroid antibodies in patients with
1996, (suppl)(30):123-128. affective and nonaffective psychiatric disorders. Biological
33. Sullivan GM, Hatterer JA, Herbert J: Low Levels of Transthyretin Psychiatry 1990, 27:51-60.
in the CSF of Depressed Patietns. American Journal of Psychiatry 57. O'Donnell M, Silove D, Wakefield D: Current perspectives on
1999, 156:710-715. immunology and psychiatry. Australian And New Zealand Journal Of
34. Bauer MS, Whybrow PC, Winokur A: Rapid Cycling Bipolar Psychiatry 1988, 22:366-382.
Affective Disorder I: Association with Grade I 58. Stein MB, Uhde TW: Autoimmune thyroiditis and panic
Hypothyroidism. Archives of General Psychiatry 1990, 47:427-432. disorder. American Journal Of Psychiatry 1989, 146:259-260.
35. Schindler BA: Stress, affective disorders, and immune 59. Loosen PT: The TRH-induced TSH response in psychiatric
function. Medical Clinics Of North America 1985, 69:585-597. patients: a possible neuroendocrine marker. Psychoneuroendo-
36. Jankovic BD: Neural tissue hypersensitivity in psychiatric dis- crinology 1985, 10:237-260.
orders with immunologic features. J Immunol 1985, 60. Jackson IM: The thyroid axis and depression. Thyroid 1998,
135(2suppl):853s-857s. 8:951-956.
37. Kaptein EM: Clinical Application of Free Thyroxine 61. Jackson IM: The thyroid axis and depression. Thyroid 1998,
Determinations. Clinical and Laboratory Medicine 1993, 13:653-672. 8:951-956.
38. Fava M, Labbate LA, Abraham ME, Rosenbaum JF: Hypothyroidism 62. Sagud M, Pivac N, Muck-Seler D, Jakovljevic M, Mihaljevic-Peles A,
and hyperthyroidism in major depression revisited. Journal of Korsic M: Effects of sertraline treatment on plasma cortisol,
Clinical Psychiatry 1995, 56:186-192. prolactin and thyroid hormones in female depressed
39. Joffe R, Segal Z, Singer W: Change in thyroid hormone levels fol- patients. Neuropsychobiology 2002, 45:139-143.
lowing response to cognitive therapy for major depression. 63. Konig F, Hauger B, vonHippel C, Wolfersdorf M, Kaschka WP: Effect
American Journal Of Psychiatry 1996, 153:411-413. of paroxetine on thyroid hormone levels in severely
40. Haggerty JJ, Silva SG, Marquardt M, Mason GA, Chang HY, Evans DL, depressed patients. Neuropsychobiology 2000, 42:135-138.
Golden RN, Pedersen C: Prevalence of antithyroid antibodies in 64. Szuba MP, O'Reardon JP, Rai AS, Snyder-Kastenberg J, Amsterdam JD,
mood disorders. Depression And Anxiety 1997, 5:91-96. Gettes DR, Wassermann E, Evans DL: Acute mood and thyroid
41. Pop VJ, Maartens LH, Leusink G, vanSon MJ, Knottnerus AA, Ward stimulating hormone effects of transcranial magnetic stimu-
AM, Metcalfe R, Weetman AP: Are autoimmune thyroid dys- lation in major depression. Biological Psychiatry 2001, 50:22-27.
function and depression related? Journal Of Clinical Endocrinology 65. Orth DN, Shelton RC, Nicholson WE, Beck-Peccoz P, Tomarken AJ,
And Metabolism 1998, 83:3194-3197. Persani L, Loosen PT: Serum thyrotropin concentrations and

Page 8 of 9
(page number not for citation purposes)
BMC Psychiatry 2004, 4 http://www.biomedcentral.com/1471-244X/4/6

bioactivity during sleep deprivation in depression. Archives of

General Psychiatry 2001, 58:77-83.
66. David MM, Owen JA, Abraham G, Delva NJ, Southmayd SE, Wooltor-
ton E, Lawson JS: Thyroid function and response to 48-hour
sleep deprivation in treatment-resistant depressed patients.
Biological Psychiatry 2000, 48:323-326.
67. vanWest D, Maes M: Activation of the inflammatory response
system: A new look at the etiopathogenesis of major
depression. Neuroendocrinology Letters 1999, 20:11-17.
68. Duval F, Mokrani MC, Bailey P, Correa H, Diep TS, Crocq MA,
Macher JP: Thyroid axis activity and serotonin function in
major depressive episode. Psychoneuroendocrinology 1999,
24:695-712.
69. Fountoulakis KN, Fotiou F, Iacovides A, Karamouzis M, Goulas A,
Demetriadou A, Kaprinis G: Relationship between pupillometric
findings, DST and melancholia. Acta Psychiatrica Belgica in press:.
70. Frye MA, Dunn RT, Gary KA, Kimbrell TA, Callahan AM, Lucken-
baugh DA, Cora-Locatelli G, Vanderham E, Winokur A, Post RM:
Lack of correlation between cerebrospinal fluid thyrotropin-
releasing hormone (TRH) and TRH-stimulated thyroid-
stimulating hormone in patients with depression. Biological
Psychiatry 1999, 45:1049-1052.
71. Harris B: Postpartum depression and thyroid antibody status.
Thyroid 1999, 9:699-703.
72. Pedersen CA: Postpartum mood and anxiety disorders: a
guide for the nonpsychiatric clinician with an aside on thy-
roid associations with postpartum mood. Thyroid 1999,
9:691-697.
73. Kent GN, Stuckey BG, Allen JR, Lambert T, Gee V: Postpartum
thyroid dysfunction: clinical assessment and relationship to
psychiatric affective morbidity. Clinical Endocrinology 1999,
51:429-438.
74. Harris B, Oretti R, Lazarus J, Parkes A, John R, Richards C, New-
combe R, Hall R: Randomised trial of thyroxine to prevent
postnatal depression in thyroid-antibody-positive women. Br
Psychiatry 2002, 180:327-330.
75. Lucas A, Pizarro E, Granada ML, Salinas I, Sanmarti A: Postpartum
thyroid dysfunction and postpartum depression: are they
two linked disorders? Clinical Endocrinology 2001, 55:809-814.
76. Kuijpens JL, Vader HL, Drexhage HA, Wiersinga WM, vanSon MJ, Pop
VJ: Thyroid peroxidase antibodies during gestation are a
marker for subsequent depression postpartum. European Jour-
nal of Endocrinology 2001, 145:579-584.

Pre-publication history
The pre-publication history for this paper can be accessed
here:

http://www.biomedcentral.com/1471-244X/4/6/prepub

Publish with Bio Med Central and every

scientist can read your work free of charge
"BioMed Central will be the most significant development for
disseminating the results of biomedical researc h in our lifetime."
Sir Paul Nurse, Cancer Research UK

Your research papers will be:

available free of charge to the entire biomedical community
peer reviewed and published immediately upon acceptance
cited in PubMed and archived on PubMed Central
yours — you keep the copyright

Submit your manuscript here: BioMedcentral

http://www.biomedcentral.com/info/publishing_adv.asp

Page 9 of 9
(page number not for citation purposes)