M.

Bauer1, 2
E. D. London2, 3, 4
D. H. S. Silverman3 Thyroid, Brain and Mood Modulation in Affective
N. Rasgon5
J. Kirchheiner6
Disorder: Insights from Molecular Research and
P. C. Whybrow2 Functional Brain Imaging

The efficacy resulting from adjunctive use of supraphysiological
doses of levothyroxine has emerged as a promising approach to
therapy and prophylaxis for refractory mood disorders. Most pa-
tients with mood disorders who receive treatment with supra-
Original Paper
transmitters (particularly serotonin and norepinephrine), which
putatively play a major role in the regulation of mood and behav-
ior, may contribute to the mechanisms of mood modulation. Re-
cent functional brain imaging studies using positron emission

Downloaded by: University of Queensland. Copyrighted material.

physiological doses of levothyroxine have normal peripheral thy-
roid hormone levels, and also respond differently to the hormone
and tolerate it better than healthy individuals and patients with
primary thyroid diseases. Progress in molecular and functional
brain imaging techniques has provided a new understanding of
these phenomena, illuminating the relationship between thyroid
function, mood modulation and behavior.
Thyroid hormones are widely distributed in the brain and have a
multitude of effects on the central nervous system. Notably
many of the limbic system structures where thyroid hormone re-
ceptors are prevalent have been implicated in the pathogenesis
of mood disorders. The influence of the thyroid system on neuro-
tomography (PET) with [18F]-fluorodeoxyglucose demonstrated
that thyroid hormone treatment with levothyroxine affects re-
gional brain metabolism in patients with hypothyroidism and bi-
polar disorder. Theses studies confirm that thyroid hormones are
active in modulating metabolic function in the mature adult
brain, and provide intriging neuroanatomic clues that may guide
future research.
Key words
Thyroid hormone ´ levothyroxine ´ mood disorders ´ depression ´
bipolar disorder ´ positron emission tomography ´ brain imaging
S215

Introduction
Since the early 19th century, physicians have recognized that ade-
quate thyroid function is essential for normal brain development
and mental functioning. Observations of behavioral changes in
hypothyroid patients culminated in a classic report from the
Clinical Society of London in 1888, describing a variety of mental
disturbances including irritability, agoraphobia, dementia and
depression [24]. Nonetheless, it has been only during the past
50 years that scientific and technological progress has illumina-
ted the relationship between thyroid function and behavior. As
technology advanced, the chemical dissection of the thyroid hor-
mone system gained specificity, by identifying the neuroregula-
tory negative feedback loop as well as by the localization of brain
thyroid hormones, nuclear thyroid hormone receptors (TR), and
thyroid-related peptides (e. g., TRH) [reviewed in 13, 14].

Affiliation
1
Department of Psychiatry and Psychotherapy, CharitØ ± University Medicine Berlin,
Campus CharitØ-Mitte (CCM), Berlin, Germany
2
Neuropsychiatric Institute & Hospital, and the Department of Psychiatry and Biobehavioral Sciences,
David Geffen School of Medicine, University of California at Los Angeles (UCLA), Los Angeles, CA, USA
3
Department of Molecular and Medical Pharmacology, Ahmanson Biological Imaging Center,
David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
4
Brain Research Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
5
Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Palo Alto, CA, USA
6
Institute of Clinical Pharmacology, CharitØ ± University Medicine Berlin, Campus CharitØ-Mitte (CCM),
Berlin, Germany

Correspondence
Michael Bauer, M.D., Ph. D. ´ Department of Psychiatry and Psychotherapy ´
CharitØ ± University Medicine Berlin ´ Campus CharitØ-Mitte (CCM) ´ Schumannstr. 20/21 ´ 10117 Berlin ´
Germany ´ Phone: +49-30-450 51 70 70 ´ Fax: +49-30-450-51 79 62 ´ E-Mail: michael.bauer@charite.de

Bibliography
Pharmacopsychiatry 2003; 36 Suppl 3: S215±S221 ´  Georg Thieme Verlag Stuttgart ´ New York ´ ISSN 0936-9528
 Psychiatric and behavioral manifestations in thyroid
disorders
It is now well established that significant disturbances of the
thyroid economy in the mature brain may profoundly alter
mental function, influencing cognition and emotion. In adult life
both excess production (hyperthyroidism) and inadequate thy-
roid hormone production (hypothyroidism) are associated with
changes in mood and intellectual performance; and severe hypo-
thyroidism can mimic melancholic depression and dementia
[56, 57, 59]. The neurocognitive impairments accompanying dys-
function of the thyroid gland are usually reversed rapidly follow-
ing return to euthyroid hormone status, although severe hypo-
thyroidism, if left untreated, may result in irreversible dementia
Original Paper
[14].
Thyroid hormones in treatment of mood disorders
The noted evidence for a relationship between thyroid disease
states and psychiatric symptoms has sparked interest in using
thyroid hormones to treat mood disorders. The therapeutic use
of thyroid hormones in modern psychiatry has existed since Nor-
wegian physicians in the 1930 s used hypermetabolic doses of
dessicated sheep thyroid gland in successful treatment of pa-
tients with cyclic mood disorders and periodic catatonia [32].
Subsequently, with the identification of triiodothyronine (T3)
and levothyroxine (L-T4) as the natural thyroid hormones in the
1950 s, and their subsequent availability as pharmaceutical
agents, the effects of synthetic thyroid hormones alone and in
combination with traditional psychotropic drugs have been
studied in the treatment of affective disorders [14,15].
S216
Initial efforts to employ thyroid hormones alone as therapeutic
agents were rarely successful [30, 62]. Nonetheless, since Pran-
ge's classic triiodothyronine (T3) acceleration studies in the late
1960 s [43], a series of open and controlled clinical trials have
confirmed the therapeutic value of adjunctive treatment with
thyroid hormones in mood disorders. Specifically, there is good
evidence that T3 can accelerate the therapeutic response to
tricylic antidepressants [1], and some double-blind studies sug-
gest that T3 may augment the response to tricyclic antidepres-
sants in treatment-resistant depressed patients although the re-
sults have been inconsistent [3,15]. In a series of open-label stud-
ies, adjunctive treatment with supraphysiological doses of L-T4
appeared to be effective and well tolerated in maintenance
treatment of patients with rapid cycling and otherwise prophy-
laxis-resistant bipolar disorders [4, 6,12,17,19, 53]. Augmenta-
tion with supraphysiological doses of L-T4 may also have im-
mediate therapeutic value in antidepressant-resistant bipolar
and unipolar depressed patients during a phase of refractory de-
pression, and in patients with chronic depression [9, 47]. In these
studies, a substantial number of severely ill and refractory pa-
tients experienced remission from affective symptomatology.
Data from these studies also suggest that women benefit more
from supplementation with thyroid hormone than men [1, 61].
Bauer M et al. Thyroid, Brain and ¼ Pharmacopsychiatry 2003; 36 Suppl 3: S215 ± S221
Differential response and tolerability of thyroid hormone in
psychiatric and primary thyroid conditions
The hypothesis driving these therapeutic studies was that indi-
viduals who responded to adjunctive thyroid hormone treat-
ment had a failing thyroid economy or subclinical thyroid dis-
ease. Indeed indices of disturbed peripheral thyroid metabolism
are demonstrable in some patients with affective disorder, and
an increased incidence of frank hypothyroidism accompanies
the rapid cycling phenotype [16]. It is now recognized, however,
that most patients who respond to thyroid supplementation do
not have peripheral thyroid disease. Research has also yielded
other intriguing observations.
The majority of patients with affective disorders treated with su-
praphysiological doses of L-T4 not only have normal peripheral
thyroid hormone levels, they also respond differently to the hor-
mone than do healthy control subjects. The doses of L-T4 required
to achieve therapeutic effect in these studies are higher (250 ±
Downloaded by: University of Queensland. Copyrighted material.
600 mg/d) than those used in the treatment of primary thyroid
disorders, e. g., hypothyroidism (typically 75 ± 150 mg/d) [55],
and thus may be of concern to clinicians. When L-T4 was first in-
troduced in clinical practice for replacement treatment of pri-
mary thyroid disorders in the late 1950 s, however, the recom-
mended doses were far higher (200 ± 400 mg/d) than they are to-
day [45]. Furthermore, supraphysiological doses of L-thyroxine
(up to 1000 mg/d) or large amounts of desiccated thyroid extracts
have been administered in studies to healthy control subjects
without major adverse effects [20, 21, 25].
Nonetheless, patients with affective disorders tolerate high do-
ses of L-T4 surprisingly well, and no serious disadvantages from
the hyperthyroxinemia, including loss of bone mineral density
[7, 33, 34], were observed even in patients treated for extended
periods [6,12, 60]. This low incidence of adverse effects and high
tolerability reported by patients with affective disorders who are
receiving high dose thyroid hormone therapy contrasts with that
typically seen in patients with primary thyroid disease. For ex-
ample, patients with thyroid carcinoma treated with high doses
of L-T4 to achieve suppression of TSH commonly complain of the
symptoms of thyrotoxicosis. Under well-controlled conditions,
as part of an ongoing effort to define the efficacy and safety
parameters of supraphysiological doses of L-T4, we also observed
significant differences in the response of healthy control subjects
and depressed patients [5]. The peripheral thyroid hormone indi-
ces (total thyroxine, free thyroxine, total triidothyronine) in de-
pressed patients were less elevated in response to supraphysio-
logical doses of L-T4 than in the healthy controls, and the patients
suffered significantly fewer side effects [5], suggesting a possible
syndrome of peripheral resistance to thyroid hormone [44].
Thyroid hormone status and treatment outcome
There is also growing evidence that thyroid hormone levels in
the low-normal range or below the normal range (thyroid hy-
pofunction) may result in a less than optimal treatment out-
come. Frye et al. [31] reported that a low level of free thyroxine
(fT4) (even if within the ªnormalº range) was associated with
more affective episodes and greater severity of depression dur-
ing prophylactic lithium treatment in patients with bipolar dis-
order. It appears, therefore, that a higher fT4 level is of advan-
tage for treatment with lithium. In a recent study, lower free
thyroxine index (FTI) values and higher TSH values within the
normal range were significantly associated with a poorer treat-
ment response in bipolar patients during the acute depressed
phase [26].
It has been suggested that altered thyroid hormone availability in
the CNS might contribute to failure of standard antidepressant
treatment. Transthyretin (TTR) plays an important role in the
transport and distribution of thyroid hormone in the CNS [39]
(Fig.1), and lower TTR concentrations in CSF may result in altered
CNS thyroid hormone homeostasis. Reduced levels of TTR, as de-
tected in the CSF of depressed patients [54], might disrupt delivery
of thyroid hormones to regions inside the blood-brain barrier, de-
spite functioning of thyroid hormone feedback to the hypothala-
mus and pituitary gland to maintain peripheral hormone levels. It
has been hypothesized that a lack of TTR might account for ªbrain
hypothyroidismº with normal peripheral (serum) thyroid hor-
mone concentration in patients with major depression [54].
In a study by Gyulai et al. [35], a 4-week challenge with thera-
peutic doses of lithium, an established drug for the treatment of
mood disorders with established ªantithyroidº properties, resul-
ted in significantly higher delta TSH levels after TRH stimulation
in unmedicated rapid cycling bipolar patients compared to heal-
thy controls. The investigators postulated that if a ªcentralº thy-
roid hypofunction is induced by lithium treatment or any other
mechanism, then increasing the availability of thyroid hormone
to the brain may be therapeutic, with consequent modification of
the mood state and improved clinical outcome [35].
Bauer M et al. Thyroid, Brain and ¼ Pharmacopsychiatry 2003; 36 Suppl 3: S215 ± S221
Effects of thyroid hormone on brain metabolism
Despite evidence of a close relationship between thyroid status
and behavioral disturbances, metabolic effects of thyroid hor-
mones in the adult mammalian brain have rarely been investiga-
ted in vivo. This disinterest may be traced to reports in the 1950 s
and 1960 s, which suggested that oxygen consumption in the
mature human brain did not change with thyroid status [50, 52].
Although no methods for direct in vivo measurement of brain
thyroid metabolism exist, functional brain imaging techniques
to evaluate cerebral blood flow and metabolism, are a starting
point. In this regard, recent studies offer some promising insights
into the thyroid-brain relationship.
Original Paper
In animal studies, autoradiographic analysis revealed signifi-
cantly lower levels of 14C-2-deoxyglucose uptake in hypothyroid
adult rats compared to euthyroid controls throughout the brain,
except for the brainstem and pons, indicating a general decline in
metabolic and functional activity during thyroid hormone defi-
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ciency [23]. Subsequently patients who had undergone total
thyroidectomy for thyroid carcinoma were examined with posi-
tron emission tomography (PET) with [18F]-fluorodeoxyglucose
(FDG) both when euthyroid and hypothyroid after thyroid hor-
mone withdrawal; and brain activity was globally reduced in se-
vere hypothyroidism [27]. Most neuroimaging studies in patients
with mood disorders, however, have not considered thyroid sta-
tus [29]. There is one study of euthyroid patients with major de-
pression, in which serum TSH (putatively the best marker of thy-
roid status) was inversely related to both global and regional cer-
ebral perfusion and glucose metabolism, indicating lower rela-
tive metabolic activity in the prefrontal cortex, particularly in
the dorsolateral and medial areas [41].
S217
Following the lead of our earlier clinical studies, we have recently
investigated the effects of adjunctive supraphysiological doses of
L-T4 on relative brain activity as a surrogate index of cerebral glu-
cose metabolism in euthyroid women with bipolar depression
Fig. 1 Thyroid Hormone Metabolism in the
Brain and Candidate Genes for Interindivi-
dual Variability in Thyroid Function. Abbre-
viations: BBB = blood-brain barrier; DNA =
desoxyribonucleic acid; TH = thyroid hor-
mone; T3 = triiodothyronine; T4 = thyro-
xine; TTR = transthyretin; TR = thyroid
hormone receptor; 5¢D = deiodinase
 using PET with FDG. At baseline (pre-treatment), bipolar depres-
sed women had functional abnormalities in prefrontal and lim-
bic brain areas compared to healthy controls. Over seven weeks,
the treatment with L-T4 significantly improved mood and was
accompanied by significant changes in relative brain activity. In
particular, L-T4 treatment was associated with a widespread rela-
tive deactivation of limbic and subcortical structures, including
the amygdala, hippocampus, caudate nucleus, ventral striatum,
thalamus and cerebellar vermis [10]. The findings suggest that
L-T4 produces mood improvement by actions on specific limbic
and subcortical circuits that have been implicated in the patho-
physiology of mood disorders [22, 28, 29, 37].
In another study, we investigated the regional metabolic changes
Original Paper
in the adult human brain associated with hypothyroidism
[11, 51]. Regional brain activity was assessed with FDG and PET
in 14 patients with hypothyroidism suffering from neuropsy-
chiatric symptoms (e. g., depression, cognitive impairment) that
are commonly seen in hypothyroid patients. Corresponding
measurements were acquired in an age- and gender-matched
comparison group of healthy individuals. We hypothesized that
metabolic change would accompany changes in behavior during
recovery. At baseline, pre-treatment brain activity in the superior
portion of the prefrontal cortex was correlated inversely with se-
verity of hypothyroidism as assessed by TSH levels, while activity
in the inferior portion of the prefrontal cortex was correlated
with severity of associated depression, as assessed by Hamilton
Depression Rating Scale (HDRS) scores. To further elucidate the
relationships between changes in neuropsychiatric and thyroid
function tests and cerebral metabolic changes, these previously
untreated hypothyroid patients underwent PET imaging with
FDG after having achieved euthyroid status with L-T4 treatment.
S218 Decreases in TSH levels over treatment time were most signifi-
cantly correlated with decreases in activity of the superior fron-
tal gyrus, a region that demonstrated abnormally high activity at
baseline. At the same time decreases in both the severity of phys-
ical symptoms and depression over treatment time (approxi-
mately three months) were most significantly correlated with
decreases in superior parietal activity (Fig. 2). A significant in-
verse correlation also existed between baseline posterior cingu-
late cortex (pCC) metabolism and improvement in a standard-
Bauer M et al. Thyroid, Brain and ¼ Pharmacopsychiatry 2003; 36 Suppl 3: S215 ± S221
ized measure of short-term memory. This latter finding is of
particular interest, as the pCC is the brain region most signifi-
cantly decreased in the earliest stages of Alzheimer's disease
[42], another condition marked by irreversible decline in short-
term memory abilities.
These represent the first studies using PET to demonstrate the ef-
fects of treatment with levothyroxine on regional brain metab-
olism in patients with hypothyroidism and bipolar disorder.
They confirm that thyroid hormones are active in modulating
metabolic function in the mature adult brain, and provide some
intriguing neuroanatomic clues regarding where to concentrate
our effort in the future.
Thyroid hormones in affective disorders:
mechanisms of action
Despite evidence that thyroid hormones affect mature brain
Downloaded by: University of Queensland. Copyrighted material.
function and response to psychotropic drugs, the cellular and
molecular mechanisms underlying these metabolic effects are
yet to be understood. The brain tightly controls its own thyroid
economy through the specific deiodination enzymes [38, 39].
The action of T3, the active hormone, is mediated through nucle-
ar receptors that are widely distributed in adult rat brain, with
higher densities of these receptors in phylogenetically younger
brain regions (e. g., amygdala and hippocampus) and lower den-
sities in the brain stem and cerebellum [48, 49]. The actions of T3
are mediated through the control of gene expression after inter-
action with receptors of the nuclear superfamily of ligand-modu-
lated transcription factors that includes receptors for steroid hor-
mones, vitamin D, and retinoic acid [39]. The T3-receptor com-
plex interacts with specific sequences in DNA regulatory regions,
known as thyroid hormone-response elements, and modifies the
expression of target genes [2] (Fig. 1). Recent molecular studies
have shown that the adult brain has various molecular loci that
are responsive to thyroid hormones. Genes that are controlled in
their expression by thyroid hormones are known to encode pro-
teins of myelin, neurotrophins and their receptors, transcription
factors, splicing regulators and proteins involved in intracellular
signaling pathways [18, 38, 39].
Fig. 2 Positron-Emission-Tomography (PET)
Images: Changes in Physical Symptoms
Scores, Hamilton Depression (HAM-D) Rat-
ings, and Superior Parietal Activity in a 35-
year-old Woman with Hypothyroidism be-
fore and After Thyroid Replacement Therapy
with Levothyroxine (L-T4)
The specific neuropharmacological basis and functional path-
ways for the modulatory effects of thyroid hormones on mood
are also unknown. Interactions of the thyroid and neurotrans-
mitter systems, primarily norepinephrine and serotonin, which
putatively play a major role in the regulation of mood and behav-
ior, may contribute to the mechanisms of action [8, 58]. There is
robust evidence, particularly from animal studies, that the thy-
roid economy has a modulating impact on the serotonin system
in the developing and mature brain. It was postulated that one
mechanism, among others, through which exogenous thyroid
hormones may exert their modulatory effects in affective illness
is via an increase in serotonergic neurotransmission, specifically
by reducing the sensitivity of 5-HT1A autoreceptors in the raphe
nuclei, and by increasing 5-HT2 receptor sensitivity [8]. But it is
not clear whether these 5-HT receptor modulations drive the
seminal disturbance that accounts for behavioral change in the
affective illness. Thyroid hormones interact with a broad spec-
trum of neurotransmitter systems (e. g., serotonin, norepine-
phrine, dopamine) thought to be involved in mood regulation,
including post-receptor and signal transducing processes, as
well as gene regulatory mechanisms [14, 36, 39]. Furthermore,
within the CNS, the regulatory cascade through which the thy-
roid hormones, particularly T3, exert their effects is not well un-
derstood: deiodinase activity, nuclear binding to genetic loci, and
ultimately protein synthesis may all be involved. What is becom-
ing clear, however, is that without optimal thyroid function in
brain (which we suspect sometimes is sub-optimal despite nor-
mal peripheral thyroid function) mood disturbance and other
psychiatric symptoms often emerge.
Candidate genes potentially involved in response to
levothyroxine
Approximately 50 % of patients with refractory bipolar disorder
show significant improvement with the adjunctive use of
supraphysiological doses of L-T4 but clinical or neurobiological
factors which could serve as biomarkers to predict response are
lacking [4]. One of the major goals for future therapy is to iden-
tify those patients who will likely respond to high-dose L-T4
treatment.
Inherited factors may cause a thyroid dysfunction characterized
by fast degradation of thyroxine, lower peripheral thyroxine lev-
els and minimal signs of hyperthyroidism after high-dose treat-
ment with L-T4 in patients with mood disorders. The genes in-
volved in regulation of thyroid function are well characterized,
and functional polymorphisms in some of these genes are known
from other disorders. Candidate genes for interindividual varia-
bility in thyroid function and thereby for differences in response
to L-T4 treatment in mood disorders are shown in Fig. 1. As out-
lined earlier, thyroxine (T4) is transported across the blood-brain
barrier via active transport by the TTR protein. TTR function was
extensively studied in amyloidosis and many functional poly-
morphisms are known to alter activity of this transport molecule
[46]. The conversion of T4 to triiodothyronine (T3) is mediated by
enzymes called deiodinases, of which three isoenzymes (deiodi-
nase I-III) are known. Deiodinase I probably has a more promi-
nent role in the pituitary, thyroid, liver and kidney; whereas T3
production in the brain is mainly mediated by deiodinase type
Bauer M et al. Thyroid, Brain and ¼ Pharmacopsychiatry 2003; 36 Suppl 3: S215 ± S221
II, located in astrocytes and tanycytes [38 ± 40]. Furthermore,
deiodinase type III isoenzymes might be involved in cerebral me-
tabolism of T4 as well, since they were described to be located in
neurons (in vivo) and astrocytes (in vitro) [39].
The genetic variability of TTR, thyroid hormone receptors, and
deiodinase enzymes has not been studied in patients with
mood disorders to date, but seems worthwhile to study in pa-
tients with treatment refractory disorders and in those who re-
spond to thyroid hormone treatment.
Outlook
Original Paper
Treatment with supraphysiological doses of L-T4 in malignant
disorders of mood frequently provides remission, without ad-
verse physiological effects, where all else has failed. Therefore,
its adjunctive use appears to be one of the promising strategies
in severely ill patients with refractory mood disorders but re-
Downloaded by: University of Queensland. Copyrighted material.
mains experimental. Additional research using a more rigorous
scientific design (e. g., randomized, double-blind, placebo-con-
trolled) to confirm the results is underway. While it is not yet clear
whether monoamine systems include the common pathway
through which the behavioral effects of thyroid hormones are
expressed, investigating such questions using functional brain
imaging techniques, employing selective radioligands, is now pos-
sible. As we strive to learn more about the association of thyroid
dysfunction with behavior and mood, the adjunctive treatment of
mood disorders with thyroid hormones will remain a valuable
strategy for patients with refractory affective illness.
Acknowledgments S219
Grant support to M. Bauer by Deutsche Forschungsgemeinschaft
(Ba 1504/3-1), National Alliance for Research on Schizophrenia
and Depression (NARSAD) Young Investigator Award, The Stan-
ley Medical Research Institute (#02T-238), Thyroid Research Ad-
visory Council (TRAK) (SYN-0400-13), the UCLA General Clinical
Research Center (GCRC) grant M01-RR00865, and Forest Lab Inc,
New York.
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