Thyroid hormones, serotonin and mood: Of synergy and significance in the adult brain

Abstract

The use of thyroid hormones as an effective adjunct treatment for affective disorders has been studied over the past three decades and has been confirmed repeatedly. Interaction of the thyroid and monoamine neurotransmitter systems has been suggested as a potential underlying mechanism of action. While catecholamine and thyroid interrelationships have been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal of this article is to review the literature on the relationships between thyroid hormones and the brain serotonin (5-HT) system, limited to studies in adult humans and adult animals. In humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-HT responsiveness that is reversible with thyroid replacement therapy. In adult animals with experimentally-induced hypothyroid states, increased 5-HT turnover in the brainstem is consistently reported while decreased cortical 5-HT concentrations and 5-HT2A receptor density are less frequently observed. In the majority of studies, the effects of thyroid hormone administration in animals with experimentally-induced hypothyroid states include an increase in cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT1A receptors in the raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermore, there is some indication that thyroid hormones may increase cortical 5-HT2 receptor sensitivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid economy has a modulating impact on the brain serotonin system. Thus it is 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 area, and by increasing 5-HT2 receptor sensitivity.

Full text

Molecular Psychiatry (2002) 7, 140–156
2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00
www.nature.com/mp
REVIEW ARTICLE
Thyroid hormones, serotonin and mood: of synergy and
significance in the adult brain
M Bauer
1
, A Heinz
2
, and PC Whybrow
1
1
University of California Los Angeles (UCLA), Neuropsychiatric Institute & Hospital, Department of Psychiatry and
Biobehavioral Sciences, 760 Westwood Plaza, Los Angeles, CA 90024, USA;
2
Central Institute of Mental Health,
Department of Addictive Behavior and Addiction Research, 68159 Mannheim, Germany
The use of thyroid hormones as an effective adjunct treatment for affective disorders has
been studied over the past three decades and has been confirmed repeatedly. Interaction
of the thyroid and monoamine neurotransmitter systems has been suggested as a potential
underlying mechanism of action. While catecholamine and thyroid interrelationships have
been reviewed in detail, the serotonin system has been relatively neglected. Thus, the goal
of this article is to review the literature on the relationships between thyroid hormones and
the brain serotonin (5-HT) system, limited to studies in adult humans and adult animals. In
humans, neuroendocrine challenge studies in hypothyroid patients have shown a reduced 5-
HT responsiveness that is reversible with thyroid replacement therapy. In adult animals with
experimentally-induced hypothyroid states, increased 5-HT turnover in the brainstem is con-
sistently reported while decreased cortical 5-HT concentrations and 5-HT
2A
receptor density
are less frequently observed. In the majority of studies, the effects of thyroid hormone admin-
istration in animals with experimentally-induced hypothyroid states include an increase in
cortical 5-HT concentrations and a desensitization of autoinhibitory 5-HT
1A
receptors in the
raphe area, resulting in disinhibition of cortical and hippocampal 5-HT release. Furthermore,
there is some indication that thyroid hormones may increase cortical 5-HT
2
receptor sensi-
tivity. In conclusion, there is robust evidence, particularly from animal studies, that the thyroid
economy has a modulating impact on the brain serotonin system. Thus it is 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-HT
1A
autoreceptors in the raphe area, and by
increasing 5-HT
2
receptor sensitivity.
Molecular Psychiatry (2002) 7, 140–156. DOI: 10.1038/sj/mp/4000963
Keywords: thyroid system; T
4
;T
3
; serotonin system; adult brain; 5-HT receptor; mood modulation;
affective disorders; depression
Introduction
The thyroid system and mood modulation in
affective illness
Disorders of the thyroid gland are frequently associated
with severe mental disturbances.
1,2
This intimate
association between the thyroid system and behavior
has been the impetus for exploring the effects of thy-
roid hormones in modulating affective illness, and the
role of the hypothalamic-pituitary thyroid (HPT) axis
in the pathophysiology of mood disorders.
3
Thyroid
hormones (TH) have a profound influence on behavior
and mood, and appear to be capable of modulating the
phenotypic expression of major affective illness.
3–6
Correspondence: M Bauer, MD, PhD, Department of Psychiatry
and Biobehavioral Sciences, University of California Los Angeles
(UCLA), 300 Medical Plaza, Suite 2330, Los Angeles, CA 90095,
USA. E-mail: mjbauer@mednet.ucla.edu
Received 14 March 2001; revised 7 June 2001; accepted 15
June 2001
Thyroid supplementation is now widely accepted as
an effective treatment option for patients with affective
disorders.
7–9
Actions of thyroid hormones in the adult brain
It is well established that thyroid hormones are essen-
tial for both the development and maturation of the
human brain, affecting such diverse events as neuronal
processing and integration, glial cell proliferation,
myelination, and the synthesis of key enzymes
required for neurotransmitter synthesis.
10,11
Thyroid
deficiency during the perinatal period results in irre-
versible brain damage and mental retardation. How-
ever, despite this accepted body of knowledge and in
disregard of the clinical and therapeutic observations
in association with affective illness, the action of thy-
roid hormones in CNS function in adults has not been
widely acknowledged by general endocrinologists.
This lack of interest seems to have originated in the
1950s and 1960s, when early physiological studies sug-

Thyroid serotonin relationship
M Bauer
et al
141
gested that oxygen consumption in the mature human
brain did not change with changing thyroid status.
12–14
Thus, in contrast to our understanding of thyroid
hormone’s critically important role in the development
of the CNS, until recently, little has been known about
the function and effects of thyroid hormones in the
mature mammalian brain.
15
However, with improved
methods in basic research the action of thyroid hor-
mones in the mature brain has become a subject of
greater interest.
16
There are several lines of evidence
suggesting that thyroid hormones affect mature brain
function. First, thyroid hormone receptors are preva-
lent in the mature brain. Nuclear receptors for T
3
, the
thyroid hormone with the highest biological activity,
are widely distributed in adult rat brain with higher
densities of nuclear T
3
receptors in phylogenetically
younger brain regions—in the amygdala and hippo-
campus—and lower densities in the brain stem and
cerebellum.
17,18
Asecond line of evidence pertains to
brain thyroid hormone metabolism. The process of 5-
deiodination by which both thyroid hormones, T
4
and
T
3
, are metabolized to inactive iodothyronines has
been demonstrated to be different in the adult brain
from that in peripheral tissues. Specifically, the type
D2 and type D3 deiodinases catalyze these metabolic
processes in spatially distinct patterns in the central
nervous system and appear to be segregated into spe-
cific cell types.
19
D2 is expressed primarily in the brain
and anterior pituitary gland where it metabolizes T
4
to
the active thyroid hormone form, T
3
. The activity of D2
in distinct regions of the brain varies widely, with the
highest levels found in cortical areas and lesser activity
in the midbrain, pons, hypothalamus and brainstem.
20
In rat brain D2 is expressed in neurons, in particular
in the nerve terminals, but also in astrocytes.
21
Third,
thyroid hormones have been detected in relatively high
(nanomolar) concentrations in cortical tissue.
22
In con-
trast to peripheral tissue where T
4
concentrations usu-
ally far exceed those of T
3
, in the brain T
4
and T
3
con-
centrations are in an equimolar range.
Monoamines and mood
Over the past two decades it has become apparent that
the monoamines, specifically norepinephrine and sero-
tonin play a major role in mood modulation.
23–27
These
long track systems which begin in the brainstem and
extend through the midbrain into the limbic system
and cortex modulate the activity of many of the brain
regions related to emotion and memory. The inter-
dependence of these long tracks—including the dopa-
mine system—with thyroid hormone metabolism has
become better understood as our technology has
improved.
The catecholaminergic system was initially investi-
gated largely because of the known physiological
association between sympathetic activity and thyroid
hormones.
26
Thyroid hormones appear to play an
important role in regulating central noradrenergic (NA)
function and it has been suggested that thyroid dys-
function may be linked with abnormalities in central
NA neurotransmission.
27
Evidence for a thyroid–NA
Molecular Psychiatry
interaction derives largely from immunohistochemical
mapping studies demonstrating that T
3
is concentrated
in both nuclei and projection sites of central NA sys-
tems.
28
Recent evidence that T
3
is also delivered from
the locus coeruleus to its NA targets via anterograde
axonal transport indicates that T
3
may function as a
cotransmitter with norepinephrine in the adrenergic
nervous system.
29
However, the neuropharmacological effects and
functional pathways underlying the therapeutic effects
of thyroid hormones in patients with affective dis-
orders are still unclear. One of the most intuitive
hypotheses postulates the existence of a brain thyroid
hormone deficiency in affective illness. Thyroid hor-
mone therapy can then be considered a replacement
therapy with a possible mechanism of action being its
pharmacological effects on monoamine neuro-
transmitter systems, eg, by increasing
␤
-adrenergic
receptor activity and thus promoting the action of cat-
echolamines at central receptor sites.
27
The CNS serotonin system
As with the noradrenergic and dopaminergic systems,
the bulk of the CNS serotonergic nerve terminals orig-
inate in the neuronal cell bodies of the brainstem raphe
nuclei and project, both rostrally and caudally, to neu-
roanatomically discrete areas throughout the brain but
with extensive innervation of the cerebral cortex and
the limbic system.
30
Although the serotonin system has
been given prominence in recent deliberation regard-
ing mood modulation, particularly since the advent of
drugs that specifically interfere with serotonin neu-
ronal reuptake systems, there has been little investi-
gation of the relationship of this system to the thyroid
system. This paper analyzes the existing literature per-
taining to this relationship and explores areas which
may be fruitful for further study.
The brain serotonin system and its role in depression
Basic and clinical research of the past three decades
has yielded compelling evidence that the serotonergic
system is intimately involved in the pathogenesis of
depression.
23,25,31,32
Changes in serotonergic neuro-
transmission have been repeatedly associated with the
therapeutic response to antidepressant and mood stabi-
lizing medication.
23,33
Almost all currently employed
treatments for depression, including the tricyclic anti-
depressants, the SSRIs, the MAO inhibitors, lithium
and ECT, directly or indirectly augment serotonergic
neurotransmission.
34
Another line of evidence derives
from the tryptophan-depletion paradigm, a procedure
that lowers central serotonin levels, and which
produces a rapid relapse of SSRI-responsive
depression.
33,35
Other support comes from studies
demonstrating lowered levels of 5-hydroxyindoleacetic
acid (5-HIAA), a metabolite of 5-HT whose levels
reflect central serotonin activity, in the CSF in unmedi-
cated depressed patients.
25
In brain imaging studies,
clinical depression was associated with reduced sero-
tonin transporter availability.
36,37

Thyroid serotonin relationship
M Bauer
et al
142
Molecular Psychiatry
Objectives and elements of this review
This article explores the hypothesis that the mood
modulating activity of thyroid hormones may be
mediated in part by interaction with the brain sero-
tonin system, specifically by enhancing cortical sero-
tonergic neurotransmission. Because of the specific
organization of the brain serotonin system, an analysis
of the literature has been divided into anatomical
areas: specifically the brainstem, the midbrain, the lim-
bic system, and the cortex; those studies that were not
specified in regard to brain area, as were many of the
early studies, are referred to as ‘whole brain studies’.
The other important element running through these
analyses is the technical advance which has occurred
over the 25 years that are the subject of our review.
Specifically, many early studies were based upon
crude analyses of levels of serotonin and its metab-
olites in homogenized brain tissue of animals that had
been previously exposed to hypo- or hyperthyroid
states. As technology advanced and our chemical dis-
section of thyroid hormone system metabolism gained
specificity, more sophisticated studies emerged that
have improved our understanding of turnover and
receptor activity. In the 1990s, ligand studies and stud-
ies of transporter systems began to complement the
earlier studies, and most recently, microdialysis tech-
niques have provided new insights by measuring levels
of serotonin in vivo. We have tried to reflect this techni-
cal advance in the analysis of the papers that are
reviewed.
Methods of literature research
An attempt was made to identify all reports studying
the interaction between thyroid hormones and the
brain serotonergic system both in animals and in
humans, but with a focus on studies in the adult brain.
A computer-aided search of the National Library of
Medicine MEDLINE database for 1966 to August 2000
using the subject headings ‘thyroid hormones’,‘sero-
tonin’,‘brain’and ‘affective disorders’was performed,
supplemented by the bibliographies of reports ident-
ified.
Results of the review
Effects of experimentally-induced hypothyroid states
on brain serotonin system in animals
Historical perspective: studies in neonatal animals Sti-
mulated by the essential role of thyroid hormones in
brain development, the effects of hypothyroidism on
serotonergic neurotransmission were originally studied
in neonatal rats. In these studies, 5-hydroxytryptamine
(5-HT, serotonin) and 5-HIAA, the main 5-HT metab-
olite, were found to be significantly elevated and the
serotonin precursor 5-hydroxytryptophan (5-HTP) to
be decreased compared to euthyroid controls indicat-
ing an increased serotonin turnover rate in the neonatal
period.
38
Other data have demonstrated that neonatal
hyperthyroidism induced by daily application of T
3
also resulted in an increased turnover of 5-HT.
39
Measurements of 5-HT and its metabolites in adult
hypothyroid animals In the adult rat brain, hypothy-
roidism generally induced lesser changes in the sero-
tonergic system compared to the studies in neonatal
animals. Thirteen studies were identified that meas-
ured the effects of experimentally-induced hypothy-
roidism on the serotonergic system. The methods and
results of these studies are shown in Table 1. One early
study measured brainstem 5-HT concentrations and
did not find significant differences compared to euthy-
roid animals.
40
Later, using more sensitive assay tech-
niques, five studies measured 5-HT and 5-HIAA con-
centration or the 5-HIAA/5-HT ratio as an indicator of
the serotonin turnover and reported increased 5-HT
metabolites in the brainstem
41–45
(notice: one study cal-
culated the inverse ratio, 5-HT/5-HIAA
41
). Reduced 5-
HT concentrations in the cortex,
46,47
and reduced con-
centrations of the serotonin precursor 5-HTP were
reported in the whole brain
48
of hypothyroid adult rats.
These findings of increased 5-HT turnover in the brain-
stem and decreased levels of 5-HT and its precursors
in the cortex/whole brain are in accordance with the
hypothesis that increased brainstem 5-HT turnover
might activate raphe 5-HT
1A
autoreceptors and sub-
sequently decrease serotonin release in the cortical
projection areas.
23
Receptor studies: changes in 5-HT
1A
and 5-HT
2
recep-
tors in the adult hypothyroid brain Among the many
5-HT receptor subtypes with different regional distri-
butions throughout the CNS, it is the 5-HT
1A
and 5-
HT
2
receptor densities that have been most studied in
experimentally-induced hypothyroid animals. The 5-
HT
1A
receptor subtype, predominantly located on the
cell bodies and dendrites of the serotonergic neurons
in the raphe nuclei, functions as a control point of
activity for these neurons. In contrast, the postsynaptic
entities of 5-HT neurotransmission consist of several
subtypes of 5-HT
2
receptors located in distinct projec-
tion areas of the 5-HT neurons.
In experimentally-induced hypothyroid states the 5-
HT
1A
(presynaptic) receptor density in the brainstem
and midbrain was not altered
49–52
(Table 1). Studies on
the density of 5-HT
1A
(postsynaptic) receptors outside
the brainstem yielded contradictory results. An
increase in cortical and hippocampal 5-HT
1A
(postsynaptic) receptors was observed by Tejani-Butt et
al
50
but not by Hong et al
49
and Kulikov et al,
51
who
found no significant differences compared to euthyroid
adult rodents.
An early study by Mason et al
52
found a decrease in
5-HT
2
receptor density in the striatum but not in the
cortex of hypothyroid adult rats. However, when 5-
HT
2A
receptors were assessed selectively in severely
hypothyroid rats, a significant cortical reduction was
recently reported by Kulikov et al.
51
Hence in summary, several lines of evidence indicate
that an experimentally-induced hypothyroid state in

Thyroid serotonin relationship
M Bauer
et al
143
Table 1 Effects of experimentally-induced hypothyroid states on brain serotonin system
Author
a
Species/ Treatment to achieve Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area)
method
b
hypothyroidism
Levels of 5-HT Receptors Levels of 5-HT and Receptors
and metabolites metabolites
5-HTT, 5-HT
1A
5-HTT, 5-HIAA/5-HT, 5- 5-HT
1A
5-HT
2c
5-HIAA/5-HT, HTP levels, TPH activity
5-HTP levels,
TPH activity
Jacoby et al
48
Rat (1) TXT, 25 days n.d. n.d. 5-HTP: whole brain ↓n.d. n.d.
Schwark & Rat (1) TXT, 4–6 wks 5-HT: brainstem n.d. 5-HT: basal ganglia →n.d. n.d.
Keesey
40
→hypothalamus ↑
Ito et al
46
Rat (1) TXT, 3 wks n.d. n.d. 5-HT: cortex ↓n.d. n.d.
mesodiencephalon ↓
Savard et al
41
Rat (2) PTU, 42 days 5-HT/5-HIAA n.d. 5-HT/5-HIAA ratio: n.d. n.d.
ratio: n. interstitialis striae
n. dorsalis terminalis ↓
raphe ↓n. preopticus med. and lat.
n. medianus ↓
raphe ↓n. lat. hypothalamus ↓
infundibulum ↓
medial forebrain bundle ↓
Mason et al
52
Rat (3) TXT, 21–35 days n.d. n.d. n.d. n.d. cortex →
striatum ↓
Henley et al
42
Rat (2) TXT, 3 wks 5-HIAA/5-HT n.d. 5-HIAA/5-HT ratio: n.d. n.d.
ratio: spinal cord ↑
rostral
brainstem ↑
Henley & Rat (2) (1) TXT, 2 wks (1) and (2) 5- n.d. (1) and (2) 5-HIAA/5-HT: n.d. n.d.
Bellush
43
(2) METH, 2 wks HIAA/5-HT: spinal cord ↑
(3) TXT +PCPA, 2 wks brainstem ↑(3) 5-HT: spinal cord ↓↓
(3) 5-HT:
brainstem ↓↓
Hong et al
49d
Rat (3) PTU, 2 wks n.d. Brainstem →n.d. cortex, n.d.
hippocampus,
hypothalamus,
striatum →
(continued)
Molecular Psychiatry

Thyroid serotonin relationship
M Bauer
et al
144
Molecular Psychiatry
Table 1 Continued
Author
a
Species/ Treatment to achieve Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area)
method
b
hypothyroidism
Levels of 5-HT Receptors Levels of 5-HT and Receptors
and metabolites metabolites
5-HTT, 5-HT
1A
5-HTT, 5-HIAA/5-HT, 5- 5-HT
1A
5-HT
2c
5-HIAA/5-HT, HTP levels, TPH activity
5-HTP levels,
TPH activity
Upadhyaya & Rat (4) Carbimazole, 15 days n.d. n.d. 5-HT: cortex ↓n.d. n.d.
Agrawal
47
hypothalamus ↓
Tejani-Butt et Rat (5) TXT, 7, 14 and 35 days 5-HTT: n. dorsalis 5-HTT: day 7 and 35: n.d.
al
50
n. dorsalis raphe →cortex, hypothalamus, cortex ↑
raphe →hippocampus →hippocampus ↑
hypothalamus →
Henley & Rat (2) (1) METH, 3 wks (2) and (3): n.d. n.d. n.d. (1)–(3) autonomic
Vladic
44
(2) METH, 3 wks +5-HT1A 5-HIAA (cardiovascular)
agonist (8-OH-DPAT) brainstem ↑response ↓
(3) METH, 3 wks +5-HT2 5-HT brainstem
agonist (DOI) →
Henley et al
45
Rat (2) (1) TXT, 3 wks (1) to (3): 5- n.d. (1) to (3): 5-HIAA/5-HT n.d. n.d.
(2) PTU, 3 wks HIAA/5-HT spinal cord ↑
(3) METH, 3 wks brainstem ↑
Kulikov et al
51
Rat (3) TXT, 7 days 5-HTT & TPH: midbrain →5-HTT: hippocampus →hippocampus →5-HT
2A
:
+iodine-free diet, 24 days midbrain →TPH: hippocampus →frontal cortex ↓
Frontal cortex →
a
In order of the year published.
b
Methods: (1–4,6) =in vitro, homogenized brain tissue, (7) in vivo.1=Liquid chromatography/(spectro-)fluorometry, 2 =HPLC (high-performance liquid chromatography),
3=radioligand binding, 4 =autoradiographic in vitro receptor binding, 5 =behavioral response experiments, 6 =radioimmunoassay (RIA), 7 =microdialysis/HPLC, 8 =
neuroendocrine test.
c
5-HT
2A
: neocortex, basal ganglia, olfacto-limbic areas, spinal cord.
d
Only abstract available.
↑=significant increase; ↓=significant decrease; →=no significant change; n.d. =not done.
Non-Standard Abbreviations: DOI =2,5-dimethoxy-4-iodoamphetamine; 5-HIAA =5-hydroxyindoleacetic acid; 5-HT =5-hydroxytryptamine (serotonin); 5-HTP =5-hydroxy-
tryptophan; 5-HTT =hydroxytryptamine (serotonin) transporter; METH =Methimazole; n. =nucleus; 8-OH-DPAT =8-hydroxy-2-(di-n-propylamino)tetralin; PCPA =p-
chlorophenylalanine (5-HT synthesis blocker); PTU =propylthiouracil; TPH =tryptophan hydroxylase; TXT =thyroidectomy.

Thyroid serotonin relationship
M Bauer
et al
145
adult rodents is associated with an increased 5-HT
turnover rate in the brainstem, but not with a change
in 5-HT
1A
autoreceptor density in the raphe area. There
is also some evidence that hypothyroid states result in
a decrease in cortical 5-HT serotonin concentrations
and 5-HT
2A
receptor density.
Effects of thyroid hormone application on brain
serotonin system in animals
Fourteen studies were located that measured the acute
effects of thyroid hormone (T
3
and/or T
4
) on 5-HT
and/or L-tryptophan, 5-hydroxytryptophan (5-HTP),
and 5-HIAA concentrations in adult rodent brain (for
methods and results see Table 2).
Acute effects of thyroid hormones on levels of 5-HT
and its metabolites in the brainstem and mid-
brain Rastogi and Singhal
53
observed an increase in
the 5-HT precursor L-tryptophan (L-TP), and Heal and
Smith
54
found an increase in both 5-HT and 5-HIAA in
the midbrain after T
3
application in euthyroid animals.
In contrast, Henley et al
42,45
examined animals after
thyroidectomy, which resulted in an elevated sero-
tonin turnover rate; in these animals, T
3
replacement
resulted in a significant decrease in the 5-HIAA/5-HT
ratio in the brainstem. In the two studies of thyroid
replacement after thyroidectomy, T
3
replacement for
longer than 3.5 days reduced the 5-HT turnover in cau-
dal brainstem to completely normal values. The
activity of tryptophan hydroxylase (TPH), the rate-lim-
iting enzyme in the synthesis of 5-HT, was found
unaltered in the midbrain after T
3
application.
51,53
Acute effects of thyroid hormones on levels of 5-HT
and its metabolites in cortex and whole brain More
consistent than the effects of ‘micro-dissection’
reported above were the results of studies that meas-
ured the effects of thyroid hormone on levels of 5-HT
and its metabolites in the cortex or in the whole brain.
Thyroid hormone application to euthyroid rodents
increased cortical or whole brain 5-HT, 5-HTP and 5-
HIAA concentrations in 10 studies.
41,46–48,54–59
These
results indicating increased cortical 5-HT turnover
were consistent despite changing technologies over a
25-year period, and may be considered robust. In only
one study did the whole brain 5-HT level not increase
after thyroid hormone administration.
60
Chronic effects of thyroid hormones on levels of 5-HT
and its metabolites in cortex and whole brain Fewer
studies assessed the effects of a single vs multiple T
3
or T
4
application on cortical serotonergic neuro-
transmission in euthyroid rodents
54,55,58,59
(Table 2). In
three of four studies, increases in cortical or whole
brain 5-HT, 5-HTP and 5-HIAA contents were observed
only after repeated (chronic) thyroid hormone appli-
cation.
54,55,59
Thus, the increased concentration of 5-HT and its
precursors and metabolites in the cortex or whole brain
that were observed in the majority of studies were more
Molecular Psychiatry
pronounced after repeated (chronic) thyroid hormone
application. Similar studies investigating the effects on
5-HT levels in the brainstem and midbrain are less con-
sistent (Table 2).
Effects of thyroid hormones on 5-HT
1A
receptor density
and sensitivity Three autoradiographic studies have
reported that thyroid hormone application induces no
significant reduction in raphe and midbrain 5-HT
1A
receptor density.
49–51
However, a recent study by Gur et
al
59
indicated a loss of autoinhibitory 5-HT
1A
receptor
sensitivity mediated by T
3
(Table 2). Gur et al,
59
for the
first time in the study of the 5-HT-thyroid interaction,
used an in vivo microdialysis technique that allows the
measurement of 5-HT concentrations in the brain with
a high degree of accuracy in the living animal. In this
study, the decrease in hippocampal and cortical sero-
tonin release that follows the application of a 5-HT
1A
agonist via the activation of inhibitory autoreceptors
was significantly reduced by T
3
alone, or T
3
combined
with clomipramine administration in euthyroid rats.
59
Effects of thyroid hormones on 5-HT
2
receptor density
and sensitivity The database concerning changes in 5-
HT
2
receptor density after thyroid hormone application
reveals contradictions. Mason et al
52
observed an
increase in 5-HT
2
receptor density in the striatum, hip-
pocampus and cortex of thyroidectomized rats only
after long-term application of a relatively high dose of
either T
3
(250–1000
␮
gkg
−1
for 7–10 days) or T
4
(250–
500
␮
gkg
−1
for 7–10 days). Kulikov et al
51
showed that
T
4
application in thyroidectomized animals returned
cortical 5-HT
2A
receptor densities to normal levels,
irrespective of whether a replacement or high T
4
dose
was applied (15
␮
gkg
−1
vs 200
␮
gkg
−1
T
4
for 21 days
each). Lower doses and shorter duration of T
3
appli-
cation yielded different results: Sandrini et al
58
found
no significant effect on 5-HT
2
receptor density in the
hippocampus and a decrease in cortical 5-HT
2
receptor
density after application of T
3
in euthyroid rats
(100
␮
gkg
−1
for 3–7 days). In the study of Heal and
Smith
54
the same T
3
dose applied to euthyroid rats
(100
␮
gkg
−1
for 10 days) also decreased cortical 5-HT
2
receptor density. A reduction in prefrontal 5-HT
2A
receptors was observed after coadministration of T
3
and the antidepressant desipramine.
61
A thyroid hormone-induced change in receptor sen-
sitivity was observed for cortical 5-HT
2
receptor func-
tion in adult euthyroid rats. Heal and Smith
54
observed
an increase in 5-HT
2
receptor sensitivity after short-
term T
3
application, and Atterwill
60
reported similar
findings after both short- and long-term T
3
application
(Table 2). Under stress conditions, on the other hand,
administration of high doses of T
4
(350
␮
gkg
−1
for 7
days) resulted in a blunting of the immobilization
stress-induced activation of hypothalamic 5-HT
2
recep-
tors.
62
Effects of low vs high doses of thyroid hormones on the
5-HT system Some studies compared the effects of a
low (replacement) vs a high dose of thyroid hormone

Thyroid serotonin relationship
M Bauer
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Molecular Psychiatry
Table 2 Effects of thyroid hormone application on brain serotonin system
Author
a
Species/ Thyroid hormone treatment Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area)
method
b
Levels of 5-HT Receptors Levels of 5-HT and Receptors
and metabolites metabolites
5-HTT, 5-HT
1A
5-HTT, 5-HIAA/5-HT, 5- 5-HT
1A
5-HT
2c
5-HIAA/5-HT, HTP L-TP, 5-HTP levels,
L-TP, 5-HTP TPH activity
levels, TPH
activity
Engstro
¨met Mouse (1) T4 (1 mg kg
−1
,1–4 injections n.d. n.d. more than 1 injection: n.d. n.d.
al
55
s.c.), 12 h interval 5-HTP: whole brain ↑
Jacoby et al
48
Rat (1) T4 (15
␮
g 100 g
−1
, i.p.), n.d. n.d. 5-HTP: whole brain ↑n.d. n.d.
25 days
Rastogi & Rat (1) T3 (10
␮
g 100 g
−1
, s.c.), L-TP: midbrain ↑n.d. 5-HT: cerebellum, n.d. n.d.
Singhal
53
30 days TPH: midbrain striatum ↓
→5-HIAA: cerebellum,
striatum ↓
hippocampus (↑)
Ito et al
46
Rat (1) T4 (400
␮
gkg
−1
, s.c.), 17 days n.d. n.d. 5-HT: cortex ↑n.d. n.d.
Stro
¨mbom et Mouse (1) T4 (1 mg kg
−1
, 4 injections s.c.), n.d. n.d. 5-HTP: striatum ↑, cortex ↑n.d. n.d.
al
56
12 h interval limbic system ↑
Atterwill
60
Rat (1,3,6) (1) T3 (100
␮
gkg
−1
, s.c.), 10 days n.d. n.d. (1) 5-HT: whole brain →n.d. (2)–(5) hyperactivity
(2) T3 (100
␮
gkg
−1
, s.c.) response ↑↑
1 day +MAOI (TCP) and L-TP
(3) T3 (100
␮
gkg
−1
, s.c.),
10 days +MAOI (TCP) and L-TP
(4) T3 (100
␮
gkg
−1
, s.c.),
1 day +5-HT agonist (quipazine
or 5-MeODMT)
(5) T3 (100
␮
gkg
−1
, s.c.),
10 days +5-HT agonist
(quipazine or TCP +5-MeODMT)
Savard et al
41
Rat (2) T4 (50
␮
g 100 g
−1
, s.c.), n.d. n.d. 5-HT/5-HIAA ratio: n.d. n.d.
14 days n. medialis habenulae ↑
n. amygdaloideus basalis
pars lat. ↑
area ventralis tegmenti ↑
n. preopticus medialis ↓
(Continued)

Thyroid serotonin relationship
M Bauer
et al
147
Table 2 Continued
Author
a
Species/ Thyroid hormone treatment Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area)
method
b
Levels of 5-HT Receptors Levels of 5-HT and Receptors
and metabolites metabolites
5-HTT, 5-HT
1A
5-HTT, 5-HIAA/5-HT, 5- 5-HT
1A
5-HT
2c
5-HIAA/5-HT, HTP L-TP, 5-HTP levels,
L-TP, 5-HTP TPH activity
levels, TPH
activity
Mason et al
52
Rat (3) TXT +n.d. n.d. n.d. n.d. (1) and (3) cortex,
(1) T4 (50–100
␮
gkg
−1
, i.p.), 10 striatum →
days hippocampus →
(2) T4 ‘high dose’(250–500
␮
g (2) striatum ↑(250,
kg
−1
, i.p.), 7–10 days 500
␮
g)
(3) T3 (15–50
␮
gkg
−1
, i.p.), 10 hippocampus ↑(250
days
␮
g)
(4) T3 ‘high dose’(250–1000
␮
g cortex ↑(500
␮
g)
kg
−1
, i.p.), 7–10 days (4) cortex ↑(500,
1000
␮
g)
Heal & Smith
54
Mouse (2,3) (1) T3 (100
␮
gkg
−1
, s.c.), (1) 5-HT: n.d. (1) 5-HT & 5-HIAA: 8-OH-DPAT Receptor density:
1 day midbrain →forebrain →hypothermia: (1) cortex →; (2)
(2) T3 (100
␮
gkg
−1
, s.c.), 5-HIAA: (2) 5-HT: forebrain →1) →cortex ↓
10 days mid/hindbrain ↑5-HIAA: forebrain ↑2) ↓5-MeODMT-induced
(2) 5-HT, 5- 5-HT and 5-HIAA: whole head-twitches:
HIAA brain ↑(1) receptor
mid/hindbrain ↑sensitivity ↑
(2) receptor
sensitivity →
Henley et al
42
Rat (2) TXT +T3 (100
␮
gkg
−1
, s.c.), 3.5 5-HIAA/5-HT: n.d. 5-HIAA/5-HT: spinal cord n.d. n.d.
days brainstem →
restored (↓)
(normalized
after TXT)
Hong et al
49d
Rat (3) T3-induced hyperthyroidism, 2 n.d. brainstem →n.d. hippocampus ↑n.d.
wks
d
cortex ↓
hypothalamus,
striatum →
Suzuki et al
57
Rat (2) T3 (25
␮
gkg
−1
, s.c.), 5 days n.d. n.d. 5-HIAA: whole brain ↑n.d. n.d.
5-HT: whole brain →
(Continued)
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Table 2 Continued
Author
a
Species/ Thyroid hormone treatment Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area)
method
b
Levels of 5-HT Receptors Levels of 5-HT and Receptors
and metabolites metabolites
5-HTT, 5-HT
1A
5-HTT, 5-HIAA/5-HT, 5- 5-HT
1A
5-HT
2c
5-HIAA/5-HT, HTP L-TP, 5-HTP levels,
L-TP, 5-HTP TPH activity
levels, TPH
activity
Tejani-Butt et Rat (5) TXT +(1) and (2) (1) and (2) (1) and (2) (1) 28 days: n.d.
al
50
(1) T4 replacement (15
␮
g 5-HTT 7 and 28 days: 5-HTT: hippocampus CA1 &
kg
−1
, p.o.), 7 and 28 days n. dorsalis n. dorsalis cortex →dentate gyrus ↑
(2) T4 ‘high dose’(200
␮
g raphe →raphe →hippocampus →(2) 7 and 28 days:
kg
−1
, p.o.), 7–28 days hypothalamus →cortex: restored (↑),
hippocampus CA1
and dentate gyrus ↑,
hypothalamus ↑
Upadhyaya & Rat (4) T4 (10
␮
g 100 g
−1
, i.p.), n.d. n.d. 5-HT: cortex ↑n.d. n.d.
Agrawal
47
15 days hypothalamus ↑
Ramalho et Rat (7) T4 (350
␮
gkg
−1
, s.c.), n.d. n.d. n.d. n.d. hypothalamus:
al
62
7 days stress-induced
activation ↓
Sandrini et Rat (3,4) (1) T3 (100
␮
gkg
−1
, single n.d. n.d. 5-HT: (1) and (2) (1) and (2)
al
58
s.c. injection) (1) frontal cortex ↑frontal cortex →frontal cortex ↓
(2) T3 (100
␮
gkg
−1
, s.c.), hippocampus →hippocampus →hippocampus →
3–7 days (2) frontal cortex ↑
hippocampus →
Henley et al
45
Rat (2) TXT +T3 (s.c. implants 5-HIAA/5-HT: n.d. 5-HIAA/5-HT: spinal cord n.d. n.d.
2.5/5.0/7.5 mg), 7 days rostral ↓
brainstem ↓
(Continued)

Thyroid serotonin relationship
M Bauer
et al
149
Table 2 Continued
Author
a
Species/ Thyroid hormone treatment Brainstem/midbrain (raphe area) Whole brain, cortex, limbic system (outside raphe area)
method
b
Levels of 5-HT Receptors Levels of 5-HT and Receptors
and metabolites metabolites
5-HTT, 5-HT
1A
5-HTT, 5-HIAA/5-HT, 5- 5-HT
1A
5-HT
2c
5-HIAA/5-HT, HTP L-TP, 5-HTP levels,
L-TP, 5-HTP TPH activity
levels, TPH
activity
Gur et al
59
Rat (7) (1) T3 (100
␮
gkg
−1
, single From (5) and (6) n.d. 5-HT: n.d. n.d.
s.c. injection) indirect (1) frontal cortex →
(2) Clomipramine (10 mg evidence for ↓hippocampus →
kg
−1
, s.c.), 4 wks (2) +(3) frontal cortex ↑
(3) T3 (100
␮
gkg
−1
, s.c.), hippocampus →
7 days (4) frontal cortex ↑↑
(4) Clomipramine (10 mg hippocampus →
kg
−1
, s.c.), 4 wks +T3 (100 5-HT
1A
challenge:
␮
gkg
−1
, s.c.), 7 days (5) frontal cortex ↓↓
(5) 5-HT
1A
agonist (8-OH- hippocampus ↓↓
DPAT) (6) frontal cortex (↓)
(6) T3 (100
␮
gkg
−1
, s.c.), hippocampus (↓)
7 days +5-HT
1A
agonist
(8-OH-DPAT)
Kulikov et al
51
Rat (3) TXT +(1) and (2) (1) and (2) (1) and (2) (1) and (2) (1) and (2):
(1) T4 replacement (15
␮
g 5-HTT & TPH: midbrain →5-HTT: hippocampus →hippocampus →5HT
2A
frontal cortex
kg
−1
), 21 days midbrain →TPH: frontal cortex →restored (↑)to
(2) T4 high (200
␮
gkg
−1
), hippocampus →normal levels after
21 days TXT
Watanabe
61d
Rat
d
Desipramine and T3 (dose
d
) n.d. n.d. n.d. n.d. 5HT
2A
density ↓
prefrontal cortex
a
In order of the year published.
b
For methods: see Table 1.
c
5-HT
2A
: neocortex, basal ganglia, olfacto-limbic areas, spinal cord; 5-HT
2C
: brainstem, substantia nigra, amygdala, entorhinal cortex.
d
Only abstract available.
↑=significant increase; ↓=significant decrease; →=no significant change; n.d. =not done.
Non-Standard Abbreviations: DMI =desmethylimipramine; 5-HIAA =5-hydroxyindoleacetic acid; 5-HT =5-hydroxytryptamine (serotonin); 5-HTP =5-hydroxytryptophan;
5-HTT =5-hydroxytryptamine (serotonin) transporter; i.p. =intraperitoneal; L-TP =L-tryptophan; MAOI =monoamineoxidase inhibitor; 5-MeODMT =5-methoxy N,N-
dimethyltryptamine; n. =nucleus; 8-OH-DPAT =8-hydroxy-2-(di-n-propylamino)tetralin; p.o. =per os; s.c. =subcutaneous; TCP =tranylcypromine; T4 =levothyroxine;
T3 =triiodothyronine; TPH =tryptophan hydroxylase; TXT =thyroidectomy.
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Thyroid serotonin relationship
M Bauer
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Molecular Psychiatry
on 5-HT receptors.
50–52
The effects on the serotonergic
system were more pronounced with higher doses of
thyroid hormone in two out of three studies.
50,52
Cortical and hippocampal 5-HT
2
receptors.
52
and hip-
pocampal and hypothalamic (postsynaptic) 5-HT
1A
receptor density
50
were significantly increased after
administration of higher doses of T
3
or T
4
. However,
excess serum thyroid hormone in thyroidectomized
rats, achieved by administration of high doses of T
4
,
did not produce any changes in cortical 5-HT
2A
recep-
tors when compared to thyroidectomized animals with
normalized thyroid hormone levels.
51
In summary, 5-HT receptor studies in adult euthy-
roid rodents indicate that thyroid hormone application
may desensitize presynaptic 5-HT
1A
raphe autorecep-
tors, and thus increase cortical serotonin release, an
effect similar to that described after addition of the 5-
HT
1A
receptor antagonist pindolol to an ongoing SSRI
treatment.
63
The receptor studies also indicate that thy-
roid hormone application may increase cortical 5-HT
2
receptor sensitivity. This increase in 5-HT
2
receptor
function does not seem to be linear, as stress-induced
activation of hypothalamic 5-HT
2
receptors was
blunted in hyperthyroid rats.
62
Cortical 5-HT
2
receptor
densities were only increased after prolonged treat-
ment with relatively high doses of thyroid hormone in
thyroidectomized rats. In contrast, standard doses of T
3
in euthyroid rats resulted in a decrease in the number
of cortical 5-HT
2
receptors.
Clinical studies of the thyroid–serotonin interaction
The serotonin system in hypothyroid patients and
effects of thyroid hormone replacement In three
studies, parameters of the serotonergic system were
examined in hypothyroid patients (Table 3). Sjo
¨berg et
al
64
measured 5-HT, L-TP and 5-HIAA concentrations
in the CSF of seven hypothyroid patients before and
after T
4
replacement. A significant decrease in the sero-
tonin precursor L-TP after T
4
treatment was found
which may indicate increased conversion to 5-HT.
However, no significant increase in CSF 5-HT or 5-
HIAA concentrations after T
4
replacement was found.
Several studies in an effort to evaluate functional
components of the serotonergic system in humans have
examined the neuroendocrine responses to d-fenflur-
amine (D-FEN). D-fenfluramine stimulates the sero-
tonergic projecting pathways from the dorsal raphe
nuclei to the paraventricular nucleus of the central
hypothalamus and seems to release cortisol via acti-
vation of 5-HT
1A
or 5-HT
2
receptors.
65,66
Two such
challenge studies found a significantly decreased D-
FEN-induced cortisol response in hypothyroid
patients
65,67
(Table 3), which normalized with T
4
replacement.
67
This enhancement of central 5-HT
2
receptor activity after T
4
application in previously
hypothyroid patients
67
is in agreement with the find-
ings in animal studies of increased 5-HT
2
receptor sen-
sitivity after T
3
application.
54,60
The serotonin system in hyperthyroid patients One
study examined peripheral 5-HT concentrations and
the activity of the metabolizing enzyme monoamine
oxidase (MAO) before and after treatment in 45 hyper-
thyroid patients and compared the activity to that
present in healthy, euthyroid controls. Serotonin blood
levels were found to be increased, and MAO activity
decreased, in the hyperthyroid state
68
(Table 3). After
3 months of treatment with carbimazole and the asso-
ciated decline of plasma T
3
and T
4
concentrations
towards normal levels, MAO activity increased and
plasma serotonin concentrations decreased, however,
not to within the range of the normal control subjects.
68
These findings suggest altered serotonin metabolism
during the hyperthyroid state.
Serotonin-HPT system interaction in patients with
major depression The interaction of the 5-HT system
and thyroid axis function was investigated in patients
with major depression using the D-FEN stimulation
test
69
(Table 3). Patients with HPT system abnormali-
ties (as indicated by a blunted TSH response to the
TRH stimulation test suggesting ‘hyperactivity’of the
HPT system) had hormonal D-FEN responses compara-
ble to those of healthy controls, while patients without
HPT abnormalities showed reduced hormonal
responses to D-FEN compared to controls. The authors
suggested that the blunted TSH response to TRH stimu-
lation found in a subgroup of depressed patients might
be a compensatory mechanism for diminished central
5-HT activity.
69
Implications for thyroid hormone modulation of
mood disorder
Does the information reviewed here of the interaction
of thyroid hormones with serotonergic neurotransmis-
sion, have relevance for our understanding of the mood
modulating effects of thyroid hormones in the clinical
setting, and can it promote our understanding of the
pathophysiology and treatment of mood disorders?
The molecular mechanisms underlying the efficacy
of thyroid hormone treatment in patients with mood
disorders, and in patients with primary hypothyroid-
ism who have comorbid depression, are not known.
From the few studies in humans with thyroid dysfunc-
tion, there is some evidence from the neuroendocrine
challenge studies that hypothyroid status is associated
with a reduced 5-HT responsiveness. Furthermore, this
appears to be reversible with thyroid replacement ther-
apy.
65,67
However, given the small number of studies
in humans definitive conclusions cannot be drawn. Not
only is the number of studies limited but the sample
sizes in the studies were small and the methods
employed to assess central 5-HT function varied con-
siderably. It is also questionable whether the periph-
eral blood and CSF content of 5-HT and its metabolites
provide an index of brain serotonergic neurotransmis-
sion,
70
while neuroendocrine challenge studies pro-
vide only an indirect way of ‘probing’central 5-HT
function.
71
In contrast, results from studies in animals provide
strong evidence that thyroid status has a considerable

Thyroid serotonin relationship
M Bauer
et al
151
Table 3 Clinical studies in humans on the thyroid–serotonin interaction
Author
a
Subjects Sample size n Test procedure/treatment Results Conclusions by authors
(female/male)
Upadhyaya et al
68
Hyperthyroid patients vs 45 (25/20) vs blood: 5-HT levels and MAO patients vs controls: altered biogenic amine
healthy, euthyroid controls 46 (25/21) activity before and after pre-treatment 5-HT ↑, MAO ↓metabolism related to
treatment with carbimazole (3 post-treatment 5-HT (↑), MAO ↑; metabolism in
months) positive correlation between 5- thyrotoxicosis
HT and thyroid hormone levels;
no sex difference
Cleare et al
65
Hypothyroid patients (four 10 (8/2) vs d-FEN test: cortisol and hypothyroid patients: significant hypothyroidism =reduced
of 10 with major 10 (8/2) prolactin response to d-FEN reduced both cortisol and central 5-HT activity
depression) vs healthy, stimulation (centrally acting prolactin response vs controls
euthyroid controls 5-HT releasing agent)
Cleare et al
67
Hypothyroid patients (two 7 (6/1) d-FEN test before and after significant enhanced cortisol reduced 5-HT
of seven with major T4 replacement response post-T4 treatment responsiveness reversible
depression), no controls (euthyroid status) with T4 replacement
Sjo
¨berg et al
64
Hypothyroid patients, no 9 (7/2) CSF levels of tryptophan, 5- pre- vs post-treatment: interaction between thyroid
controls HT, 5-HIAA before and after tryptophan ↓function and CSF biogenic
T4 replacement 5-HT →amines
5-HIAA →
Duval et al
69
Euthyroid patients with 60 (33/27) vs d-FEN test (see above) & TSH TSH response to TRH ↓among HPT dysregulation may
major depression vs 20 (11/9) response to TRH stimulation patients with normal d-FEN compensate for reduced
healthy, euthyroid controls test response; TSH response to TRH sensitivity of 5-HT
normal in patients with reduced receptors
d-FEN response
a
In order of the year published.
↑=significant increase; ↓=significant decrease; →=no signficant change.
Non-Standard abbreviations: CSF =cerebrospinal fluid; d-FEN =d-fenfluramine; 5-HIAA =5-hydroxyindoleacetic acid; HPT =hypothalamic-pituitary-thyroid axis; 5-HT
=5-hydroxytryptamine; MAO =monoamineoxidase; T4 =levothyroxine; TRH =thyrotropin-releasing hormone; TSH =thyrotropin.
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Thyroid serotonin relationship
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Molecular Psychiatry
impact in serotonergic neurotransmission in the adult
brain. Experimentally-induced hypothyroid states
result in an increase in 5-HT turnover in the brainstem.
Increased 5-HT turnover in hypothyroid states may
lead to an increase in raphe 5-HT
1A
autoreceptor
activity and a decrease in cortical 5-HT concentrations
(Figure 1). This observation indicates that in the raphe
area increased serotonin turnover may activate inhibi-
tory autoreceptors on the serotonergic cell bodies and
thus, reduce serotonin turnover in the cortical and sub-
cortical projection areas of these serotonergic neurons.
The value of direct measurements of 5-HT and its
precursors/metabolites from homogenized brain
tissues is limited. However, in more recent receptor
studies, it was found that hypothyroid states result in
a decrease in cortical 5-HT
2A
receptor density, an
observation that reinforces the postulate that hypothy-
roidism is associated with a reduced cortical sero-
tonergic neurotransmission.
Thyroid hormone application may increase cortical
Figure 1 The thyroid–brain serotonin system interrelation-
ship in adult animals. (a) Experimentally-induced hypothy-
roidism. (b) Effects of thyroid hormone on the brain sero-
tonin system.
serotonergic neurotransmission via two independent
mechanisms: (1) by reducing the sensitivity of 5-HT
1A
autoreceptors in the raphe area, thus disinhibiting
cortical and hippocampal serotonin release; and (2) by
increasing cortical 5-HT
2
receptor sensitivity, a poten-
tially independent way of increasing 5-HT neuro-
transmission (Figure 1). These latter two potential
mechanisms for thyroid hormone modulation of sero-
tonin transmission warrant further elaboration. With
respect to the first mechanism, it is important to note
that in animal studies it has been demonstrated that
an acute blockade of serotonin transporters by SSRIs
increases raphe serotonin concentrations immedi-
ately.
72,73
However, application of SSRIs also activates
presynaptic 5-HT
1A
autoreceptors located on sero-
tonergic cell bodies in the raphe area and may thus
inhibit serotonin release in the cortical projection
areas.
23
Subsequently, an increase in frontal serotonin
release is only found after prolonged SSRI appli-
cation,
74
when increased synaptic serotonin concen-
trations in the brainstem induce a down-regulation of
5-HT
1A
autoreceptors, or after a drug-induced blockade
of 5-HT
1A
receptors.
75
This mechanism has been postu-
lated to be responsible for the delayed antidepressive
effects of SSRIs.
23
In accordance with this hypothesis,
a blockade of 5-HT
1A
receptors would facilitate the
antidepressive action of SSRIs in patients with major
depression.
63,76
A similar mechanism involving a
desensitization of presynaptic 5-HT
1A
autoreceptors
could be involved in the efficacy of thyroid hormones
to accelerate and augment antidepressant agents. This
could also explain why T
3
augmentation treatment in
patients with depression usually takes effect in the first
2 weeks after initiation of treatment. Thus, potential
similarities exist in the putative mechanism of action
of the 5-HT
1A
receptor antagonist pindolol and of thy-
roid hormones, and that both pindolol and T
3
are
found to speed recovery from depression.
7,63,76
With
respect to the potential second mechanism, it should
be noted that reduced 5-HT
2
receptor sensitivity has
been observed in most,
77–80
although not all studies of
patients with major depression.
81
Subsequently, treat-
ment with clomipramine or SSRIs increased 5-HT
2
receptor sensitivity.
82,83
Thus, thyroid hormone-
induced increases in 5-HT
2
receptor sensitivity might
potentiate the effects of antidepressant drugs on the 5-
HT
2
receptors, as has been demonstrated in studies
with animals
54,60
and humans.
65,67
However, a hypoth-
esis of 5-HT
2
receptor-mediated antidepressive effects
of thyroid hormones faces some limitations. First, the
serotonin receptor subtypes perturbed in the neuroen-
docrine challenge studies in humans are unknown. In
these clinical studies, the in vivo serotonin receptor
sensitivity is indirectly assessed by measuring cortisol
or prolactin release after serotonergic challenge with
various drugs (5-hydroxytryptophan, fenfluramine or
meta-chlorophenylpiperazine).
82–85
The observed effect
might be mediated via various contributions of both 5-
HT
2C
and 5-HT
1A
receptor stimulation.
66,86,87
Second,
autoradiographic and brain imaging studies, measuring
not the sensitivity but the density of 5-HT
2
receptors

Thyroid serotonin relationship
M Bauer
et al
153
among patients with major depression, observed sig-
nificant decreases in frontocortical 5-HT
2
receptor
availability after antidepressive drug treatment.
88,89
Of
course, increases in receptor sensitivity may be
accompanied by decreases in receptor number to avoid
overstimulation of the monoamine neurotransmitter
system and this may be the explanation. Such a
hypothesis would be supported by the observation in
animal studies of Heal and Smith,
54
Sandrini et al
58
and Watanabe
61
that cortical 5-HT
2
receptor density
was reduced after thyroid hormone application, a pro-
cedure which has been shown to increase the sensi-
tivity of this receptor subtype.
54,60,65,67
Further considerations
Post-receptor and molecular actions of thyroid
hormones
While not the primary focus of this review, other sites
of thyroid hormone action that are important for under-
standing thyroid hormone effects on brain function,
include post-receptor, transcriptional, and gene regu-
latory mechanisms. A series of studies indicate that
these signaling pathways, downstream from receptors,
are also influenced by changes in thyroid status. In rats,
hypothyroidism induced a significant up-regulation of
G-protein complexes in synaptosomal membranes from
different brain regions.
90
Conversely, in studies of
euthyroid animals, treatment with T
3
decreased the
abundance of the alpha-subunits of G
i
in synaptosomal
membranes of the cerebral cortex.
91
Impaired signal
transduction via adenylate cyclase and inositol phos-
phatase has also been demonstrated in the adult brain
of hypothyroid rats. Hypothyroid rats also showed
enhanced inhibition of adenylate cyclase in synaptoso-
mal membranes by GTP,
92
and decreased formation of
inositol phosphate in response to the muscarinic chol-
inergic agonist carbachol.
93
Thus, it appears that thy-
roid hormones exert an important influence on the
activity and synthesis of G-proteins and the receptor/G-
coupling systems that serve the monoamine receptor
system. Thus thyroid hormone deficiency leads to an
impairment in adenylate cyclase activity and phospho-
inositide-based signaling pathways involved in tran-
scriptional activities in the adult CNS.
16,90,91
The molecular action of thyroid hormone is
mediated through specific nuclear TH receptors (TRs)
␣
and
␤
(
␤
1,
␤
2), functioning as ligand-dependent tran-
scription factors that increase or decrease the
expression of target genes.
94
Although the two genes
that encode the related TR
␣
and TR
␤
are differentially
expressed, the two receptors usually coexist in the
same cell type. The relative contribution of these two
TR genes encoding for TR
␣
and TR
␤
in mediating a
particular T
3
response is poorly understood because of
a lack of in vivo functional information. Knock-out
mouse models lacking a particular TR isoform have
been generated to explore the relative contribution of
each of the TR isoforms to the TH-mediated regulation
of various biological processes in different tissues.
However, the animals tested to date showed little overt
Molecular Psychiatry
behavioral or neuroanatomical abnormalities com-
pared with animals rendered hypothyroid by thyroid-
ectomy
95–98
suggesting that other TR forms may com-
pensate or substitute for lacking or defective receptors
in these knock-out mouse models. In contrast, a TR
knock-in mouse model with a T
3
binding mutation in
the TR
␤
locus resulted in severe neuroanatomical and
behavioral dysfunction (eg, abnormal hippocampal
gene expression of brain-derived neurotrophic factor
(BDNF), myelin basic protein (MBP), and tyrosine pro-
tein kinase receptor B (TrkB), learning deficiency, and
cerebellar dysfunction) indicating a specific and del-
eterious action of unliganded TR in the brain.
99
Recent studies have also indicated that the adult
brain has various genetic loci that are responsive to
thyroid hormones.
100
Among the most extensively
studied loci is RT3/neurogranin, a brain-specific gene
encoding a protein kinase C substrate that binds calmo-
dulin and is located in dendritic spines and forebrain
neurons;
101
in these studies, adult-onset hypothyroid-
ism led to a decrease of RC3/neurogranin, an effect that
was reversible with T
4
treatment.
102
Thyroid hormone
also modulates glucose transport processes across the
blood–brain barrier (BBB)
103
and in astrocytes,
104
and
may alter the expression of glucose transporter one
(GLUT-1) gene, the principal isoform responsible for
glucose transport across the BBB.
105
Furthermore, the
effects of thyroid hormones on CNS gene expression
have been demonstrated for various other neuroactive
peptides, eg, TRH,
106
corticotropin-releasing hormone
(CRH),
107
brain-derived neurotrophic factor, nerve
growth factor and neurotrophin 3,
108,109
angiotensin-
ogen,
110
and several structural brain-specific genes (eg,
myelin-associated glycoprotein, Pcp-2, microtubule-
associated proteins).
111
Of particular relevance is a
recently reported interaction between thyroid and sero-
tonin systems, indicating synergistic effects of T
3
and
5-HT
1A
receptors on hippocampal brain-derived neuro-
trophic factor (BDNF) expression. T
3
administration
prior to treatment with a 5-HT
1A
agonist caused a
downregulation of hippocampal BDNF mRNA
expression in adult rats.
111
These molecular studies
clearly indicate that thyroid hormones actively regu-
late a broad spectrum of genes in the adult brain
although the behavioral significance of such activity
is unknown.
Conclusions
In our review we found evidence, particularly from
results in animal studies, to support the hypothesis
that thyroid status impacts the serotonin system in the
adult brain, and that increasing thyroid hormone levels
increase serotonin neurotransmission. Given the
important role of the serotonin system in the pathogen-
esis of depression we speculate that the serotonin sys-
tem may be involved in the mood modulating effects
of thyroid hormones among patients with affective dis-
orders. This hypothesis would explain why thyroid
hormones are most effective in patients with affective
disorders when administered as an adjunctive treat-

Thyroid serotonin relationship
M Bauer
et al
154
Molecular Psychiatry
ment to antidepressants and/or mood stabilizers that
perturb the serotonin system. This is also supported by
evidence that thyroid hormones alone appear to have
limited clinical use in affective illness.
4,5
It must be emphasized however that this interaction
with the serotonin system is probably only one of the
mechanisms through which thyroid hormones may
have modulatory effects in mood disorders. Thyroid
hormones interact with a broad range of neuro-
transmitter systems thought to be involved in the regu-
lation of mood including post-receptor and signal
transducing processes, as well as gene regulatory
mechanisms.
Acknowledgments
We thank Georg Juckel, MD, and Faustino Lopez-Rodri-
guez, PhD, MD, for comments on the manuscript. This
work has been supported by a grant from the Deutsche
Forschungsgemeinschaft to MB (Ba 1504/3–1).
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