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Introduction
One of the common symptoms of hypothyroidism is a depressed mood. However, most
patients with major depression are biochemically euthyroid. On closer examination,
a number of subtle abnormalities in the hypothalamus-pituitary-thyroid (HPT) axis
occur in a large proportion of depressed patients, including alterations in serum
concentrations of thyroid hormones and TSH. In addition, a number of clinical
studies have suggested a therapeutic role for thyroid hormone co-medication in
patients with depression who are biochemically euthyroid. The lack of insight
into the pathogenesis of the neuroendocrine changes in the HPT axis, together
with the uncertainty about a possible role for thyroid hormone treatment in depression
have made the field somewhat controversial. In this paper, the need for larger
and well-designed clinical studies on a possible role for T3 in the treatment
of depression is discussed, while a hypothesis is put forward on the pathogenesis
of HPT axis changes in major depression.
The hypothalamus-pituitary-thyroid (HPT) axis in depression.
There is abundant evidence that patients with major depression exhibit changes
in the activity of both the hypothalamus-pituitary-thyroid (HPT) axis and the
hypothalamus-pituitary-adrenal (HPA) axis. Serum T4 levels above the reference
range have been reported in approximately 25% of the patients, with kinetic
studies pointing to an increased daily production rate of T4 (1). Serum T3 is
often normal, but may be decreased in a proportion of patients. Since the daily
thyroid production rate of T3 was reported to be normal, a reduction in the
deiodination of T4 into T3 in extrathyroidal compartments may be involved. The
cause of increased T4 production is unknown at present. Serum TSH is low, but
mostly within the normal range. The diurnal variation of serum TSH is attenuated,
with a decreased nocturnal surge in untreated patients (1). Apparently, increased
serum T4 is not the consequence of increased stimulation by TSH. Recently, Kalsbeek
et al (2) reported sympathetic and parasympathetic innervation of the rat thyroid
gland via multisynaptic autonomic pathways from the hypothalamus. Some of these
autonomic neurons in the PVN were TRH-immunoreactive. Therefore, autonomic activation
which may occur in a subset of patients with depression is a possible mechanism
for non-endocrine stimulation of the thyroid.
The attenuation of the diurnal TSH rhythm in major depression suggests changes
in the hypothalamic regulation of TSH secretion, since the hypothalamic suprachiasmatic
nucleus (SCN) generates the diurnal variations in serum thyroid hormones (2).
Both increased and unaltered CSF levels of TRH have been reported in depression,
with a lack of correlation between CSF TRH levels and TRH-stimulated serum TSH
(3,4). This discrepancy may result from the fact that only a small proportion
of TRH neurons is involved in the neuroendocrine regulation of serum thyroid
hormones. In the hypothalamic PVN of patients with major depression we recently
found decreased TRH mRNA as assessed by quantitative mRNA in situ hybridisation
(5) which may contribute to decreased serum TSH in a subgroup of patients.
Apart from neuroendocrine changes in the HPT axis of patients with major depression,
various authors have pointed to immunological changes related to the HPT axis
in this patient group. Especially in patients with bipolar depression, the prevalence
of thyroid peroxidase autoantibodies (TPO antibodies) is increased which may
explain the association between bipolar disorder and hypothyroidism. Recently,
the presence of TPO antibodies during gestation were found to be an independent
marker for subsequent depression postpartum (15).
Thyroid hormones in the treatment of depression
Although major depression in itself is not associated with primary hypothyroidism
as is apparent from decreased serum TSH and high serum T4, a number of studies
have focussed on improving efficacy of treatment with antidepressants, mainly
tricyclic antidepressants (TCA) by co-administration of thyroid hormone. The
rationale for this type of research may have originated from the similarities
between mental changes in hypothyroidism and depression. Early studies with
TRH have been largely inconsistent and the pharmacokinetics of orally administered
TRH-like peptides may have been an important source of variance. One double-blind
crossover study reported strong and positive effects of intrathecal TRH in refractory
depressed patients (6), but the number of patients was rather small.
The majority of studies addressing the use of thyroid hormones in depression
have involved T3 and, less frequently, T4 (7). T3 monotherapy in depressed patients
has been the subject of only two studies lacking a placebo group (1). Most studies
have focussed on the question whether co-medication of antidepressants with
thyroid hormone increases efficacy of TCA. A meta-analysis on the use of T3
co-medication in the treatment of depression showed that T3 may indeed increase
response rate and decrease depression scores in a subgroup of patients refractory
to TCA (8). The authors concluded that there is a clear need for larger placebo-controlled
studies involving not only TCA but also selective serotonin reuptake inhibitors
(SSRI). Interestingly, a recent review and meta-analysis (9) supported the efficacy
of T3 in accelerating clinical response to TCA in patients with nonrefractory
depression. This might be a partial answer to the problem of the delayed onset
of therapeutic response to antidepressants. If indeed T3 increases efficacy
of treatment with SSRI, it would be very important to identify those patients
that are likely to respond to T3 co-medication rather than to SSRI alone.
Pathogenesis
| Legend to figure |
| A schematic representation of observed and hypothesized changes
in HPT- and HPA axis regulation in major depression |
Key events:
1) decreased serotonin and 2) increased CRH |
Consequences: increased CRH results in hypercortisolism,
leading to a) inhibition of D2, thereby decreasing intracerebral T3 which
reinforces decreased serotonin, and to b) decreased hypothalamic TRH and
inhibition of TSH release. The model links HPA and HPT axis changes to serotonin
as a key player in the pathegenesis of depression
Criticism: increased T4 is unexplained. Activation of the autonomic
innervation of the thyroid may possibly explain the dissociation between
TSH and thyroid hormones |
A number of authors have suggested that in major depression, the bioavailability
in the central nervous system (CNS) of the biologically active thyroid hormone
T3 may be decreased in the context of systemic euthyroidism (7). This is
certainly an attractive idea since it may explain that T3 co-medication
increases efficacy of TCA in some, but not all patients. Unfortunately,
no data are present to directly support this hypothesis. One might assume
an important role for the enzymes that play a key role in the regulation
of the concentration of T3 in the CNS, i.e., the iodothyronine deiodinases.
Specifically, type 2 deiodinase (D2) is important for deiodination of T4
to T3 in the brain, and therefore for the production of T3. Type 3 deiodinase
(D3) is important for deiodination and, therefore, inactivation of T3 to
T2. Interestingly, a number of different classes of antidepressants (lithium,
TCA, and SSRI) enhance D2 activity and decrease D3 activity in rat brain,
both resulting in increased local T3 concentration (for review see 1). For
example, the SSRI fluoxetine was shown to enhance D2 activity and to inhibit
D3 activity in rat cortex, limbic forebrain and striatum, matching areas
with high 5-HT2 receptor density (10). It should be noted, however, that
various pharmacological and nonpharmacological treatments affect D2 and
D3 activities in a highly treatment-specific and region-specific way (11).
That a local increase of the concentration of T3 may affect serotonergic
neurotransmission was strongly suggested by pharmacological experiments
showing increased serotonin concentrations in the cerebral cortex of rats
acutely or chronically treated with T3 (12). Therefore, T3 seems to enhance
serotonergic neurotransmission and vice versa.
If indeed decreased D2 activity in the CNS of a subset of patients with
major depression contributes to decreased bioavailability of T3 in the brain
which may be reversed to some extent by antidepressants, the question is
what the cause of decreased D2 activity in depression might be. One possible
explanation is the mild hypercortisolism that occurs in some 40% of these
patients (13), while increased serum T4 may also contribute. Glucocorticoids
inhibit D2 activity in cultured human placental cells (14). No data are
available on in vivo effects of cortisol on D2 activity in the hypothalamus.
Conclusion and hypothesis
Subtle changes occur in the hypothalamus-pituitary-thyroid axis in approximately
25% of patients with major depression. Consistent changes are high or
increased serum T4, normal serum T3 and low, or decreased serum TSH with
an attenuated diurnal variation. The pathogenesis of these changes is
unclear, but may involve both neuroendocrine changes (activation of the
hypothalamus-pituitary-adrenal axis) and neural mechanisms (activation
of the autonomic innervation of the thyroid gland, functional changes
in the hypothalamic SCN). At the level of the CNS, depression may involve
decreased bioavailability of T3 in a subset of patients, which may reinforce
decreased cortical serotonin levels. SSRI may not only facilitate serotonergic
neurotransmission but also enhance T3 production via an effect on D2 activity.
Co-medication with T3 appears to increase efficacy and to accelerate response
of TCA, but larger studies involving SSRI are needed. The identification
of patients who are likely to benefit from thyroid hormone comedication
would be important in view of the high prevalence of major depression
and the relatively high rate of nonresponders to antidepressants (30-40%).
References
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