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112 The APA Publishing Textbook of Mood Disorders, Second Edition
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response in these patients during winter, but not in summer, compared with healthy
control subjects, even though the evidence on this specific subtype of depression is
still insufficient. Focusing on age, in a meta-analysis on elderly patients (older than
60 years), Belvederi Murri et al. (2014) found significantly higher cortisol levels in patients with depression compared with healthy control subjects, and this effect was even
higher when analyzing cortisol levels after patients took dexamethasone. As the au
thors suggest, this effect could be due to a number of different mechanisms related to
aging and may be only collaterally linked to depression. In addition to patients’ de
pression subtype and age, their sex may partly mediate neuroendocrine dysfunctions,
even though results are sometimes conflicting. Sanches et al. (2013) found significantly
higher cortisol levels in depressed males, but not females, compared with healthy
control subjects. This finding further confirms the complexity of the relationship between the HPA axis and depression, which may involve other neuroendocrine mechanisms, including the HPG axis.
It is widely recognized that women in the perinatal period, including both preg-
nancy and postpartum, have a higher risk of developing depression (Sawyer et al.
2019). This could be due to the massive HPA axis alterations that are typical in this pe
riod. During a normal pregnancy, the HPA axis is hyperactive, mainly due to placental
production of CRH, with reduced GR function and GC resistance (Glynn et al. 2013).
Notably, these alterations are more marked when depressive symptoms occur during
pregnancy (Katz et al. 2012; Pariante 2014). In the postpartum period, there is a drop
in CRH levels, leading to low levels of ACTH. This HPA “refractory period” may rep
resent a risk factor for the development of depression, and may persist for weeks,
months, or even years (Dickens and Pawluski 2018; Glynn et al. 2013). This lingering
refractory period could be due to the HPA axis modifications during pregnancy, and
especially to the fall in cortisol and CRH levels in the postpartum period. Further
more, depression during pregnancy is associated with increased cortisol response to
stress in the offspring at 1 year of age (Osborne et al. 2018).
Another intriguing topic is the predictive value of HPA axis alterations in mediating the development of depression. Pariante and Lightman (2008) proposed that HPA
axis alterations are not simply a consequence or epiphenomenon of depression, but
also a risk factor predisposing to it. In an interesting 10-year study of patients hospitalized for MDD, Tsuru et al. (2013) found no correlation between baseline measures
of HPA axis activity (combined dexamethasone and CRH [DEX/CRH] levels) and the
future recurrence of depressive symptoms (within 10 years). However, an increased
cortisol awakening response has been associated with the recurrence of MDD, suggesting an increased vulnerability to depression (Hardeveld et al. 2014). Dysfunctions
in the HPA axis also could predict nonresponse to treatment. Juruena et al. (2009), in
addition to confirming higher cortisol levels in patients with depression compared
with control subjects, found higher cortisol levels after a prednisolone suppression
test and a lower percentage of suppression in patients with depression who did not
respond to subsequent treatment compared with responders.
Finally, early life stress, including childhood maltreatment, can chronically activate the HPA axis (Cousins and Goodyer 2015). This sustained hyperactivation, with
increased CRH and impaired GR-mediated negative feedback, may be an independent predisposing factor in the development of depression during adolescence and
adulthood (Cousins and Goodyer 2015; Pariante and Lightman 2008; van Bodegom
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et al. 2017). In this context, NR3C1 has been found to be susceptible to epigenetic
modification, specifically DNA methylation (Smart et al. 2015). Early life adversities
could also influence cortisol regulation during pregnancy, with a larger cortisol awak
ening response, and also moderate the effect of depressive symptoms on diurnal
slope (Epstein et al. 2020).
Bipolar Disorder
Growing evidence also suggests a hyperactive HPA axis in patients with bipolar disorder (Daban et al. 2005). In a study using the combined DEX/CRH suppression test,
Schmider et al. (1995) found a significantly increased ACTH response in patients with
bipolar disorder in both manic and depressive phases compared with control sub
jects. A significantly increased cortisol response to the DEX/CRH test was reported
even in remitted patients with bipolar disorder (Watson et al. 2004). A more recent
comprehensive meta-analysis (Belvederi Murri et al. 2016) supported these findings,
confirming significantly higher basal cortisol—at awakening, and similarly when
measured over 12 or 24 hours—and higher ACTH levels in patients with bipolar dis
order compared with control subjects. Although the majority of evidence points toward an increased cortisol response in patients with bipolar disorder, opposite results
have been reported as well. For example, Yatham (1996) found no difference in corti
sol response to fenfluramine (a serotonin-releasing agent formerly used as an appetite
suppressor) in a comparison of patients with bipolar disorder and healthy control
subjects.
Importantly, HPA axis activity has been shown to change in accordance with the
different phases of bipolar disorder, which could account for the inconsistencies in re
search findings on these patients. In a fascinating study, Feng et al. (2019) compared
measures of neuroendocrine function between untreated first-episode patients with
MDD and those with bipolar disorder. The authors found significantly higher cortisol
and ACTH levels in patients with MDD than in patients with bipolar disorder. Even
if patients with MDD were consistently more numerous than patients with bipolar
disorder, and patients with bipolar disorder were mostly in depressive episodes,
these findings confirm a difference in neuroendocrine functioning between unipolar
and bipolar depression. A possible explanation for these findings is that either melancholic or atypical symptoms are common in bipolar depression (Belvederi Murri et
al. 2016). As we discussed in the previous subsection on depression, melancholic and
atypical depression present with opposing biological correlates and HPA axis activity
(Lamers et al. 2013). Therefore, when evaluating the role of the endocrine system, one
needs to consider that changes will differ during mania, depression and its subtypes,
and mixed episodes.
As also seen in patients with depression, the changes in HPA axis activity in patients with bipolar disorder is due to decreased GR function, seen through decreased
levels of GR protein (Bei et al. 2009) or GR-α mRNA (Matsubara et al. 2006). De-
creased GR-α mRNA was also identified in healthy first-degree relatives of patients
with bipolar disorder, and it has been linked to irregular GR splicing and transcrip
tional activity (Bei et al. 2009; Watanuki et al. 2008), altered heat shock proteins (Bei et
al. 2013), and epigenetic modulation of the FKBP5 gene (Fries et al. 2014).
Longitudinal studies further support these findings, suggesting that HPA axis abnormalities might also influence and predict the development of bipolar disorder,
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and vice versa. Previously high mean daytime cortisol levels significantly predicted
the development of depression and bipolar disorder in a 3-year follow-up study of
young adults (Ellenbogen et al. 2011). This relationship could be bidirectional; in fact,
another study showed that patients with bipolar disorder who had more previous
manic or depressive episodes had higher mean cortisol levels and a blunted response
and flatter diurnal slopes compared with those with fewer previous episodes (Haver
mans et al. 2011).
Finally, salivary cortisol levels were found to be higher in offspring of parents with
bipolar disorder compared with offspring of parents with no mental health disorder
(Ellenbogen et al. 2004, 2010). The findings were not influenced by confounders such
as medication or differences in affective diagnosis, but sex was not accounted for.
However, findings have not been consistent within research, and there is also evidence of no significant difference in cortisol levels between the offspring of patients
with bipolar disorder and offspring of healthy control subjects (Deshauer et al. 2006).
Hypothalamic-Pituitary-Thyroid Axis
Depression
Another well-established neuroendocrine alteration in patients with depression involves abnormalities in the HPT axis (Nemeroff and Evans 1989). Even if no conclusive data support an overt thyroid dysfunction in depression, it is clear that thyroid
abnormalities are often present in patients with depression (Fountoulakis et al. 2006).
Thyroid function generally appears to be hypoactive in depression (Swaab et al. 2005).
Literature data show patients with depression may have a disruption of the HPT axis
at different levels. Central alterations—hypothalamic and pituitary—have been reported, mainly with reduced TSH secretion and increased TRH activity, and therefore
an abnormal TSH response to TRH (Hage and Azar 2012). Alterations in thyroid func
tioning also may occur at the peripheral level, with elevated T
positive antithyroid antibodies (Hage and Azar 2012). Moreover, serotonin (5
hydroxytryptamine [5-HT]) plays an important role in HPT axis regulation, mainly
inhibiting TRH secretion. Accordingly, the 5-HT depletion typical of depression could
lead to increased secretion of TRH and blunted TSH response (Duval et al. 2002), confirming the extensive interconnections between neuroendocrine systems and mood
disorders. However, the majority of patients with depression have no overt abnor
malities in thyroid function, even though they probably have a greater prevalence of
subclinical hypothyroidism compared with the general population (Bauer et al. 2008).
Brouwer et al. (2005) reported higher TSH levels in depressed outpatients compared
with matched control subjects, suggesting a dysregulation of TSH levels rather than
a clear decrease or increase. Interestingly, Tsuru et al. (2013) found significantly
higher TSH responses to TRH in patients whose clinical depression later recurred
within 10 years after remission.
The relationship between depression and thyroid illness is bidirectional, as we can
observe by also analyzing the high prevalence rates of depression in thyroid illnesses.
Classically, hypothyroidism has been associated with an increased risk of depression.
However, there is also evidence showing an increased risk of depression in patients
with hyperthyroidism (Bauer et al. 2008). Results are more controversial regarding
subclinical hypothyroidism. In their meta-analysis, Zhao et al. (2018) showed an as
levels, low T3, and
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sociation between subclinical hypothyroidism and depression only in younger patients. On the other hand, low TSH levels that are still within the normal range have
been linked to future development of depression in elderly patients (Medici et al.
2014). In addition, in a recent cross-sectional study in patients with MDD, Shen et al.
(2019) found higher serum levels of TSH, TGAb, and TPOAb in suicide attempters
compared with non–suicide attempters.
Autoimmunity may also be involved in HPT axis disruption in depression.
TPOAbs have been extensively associated with a higher prevalence of depression.
These findings were also confirmed by analyzing specific clinical subgroups, such as
those with postnatal depression (Wesseloo et al. 2018) and subclinical hypothyroidism (Jucevičiūtė et al. 2019). However, there are discrepancies; some studies did not
find any association between TPOAbs and depression, but also higher concentration
of TRAbs have been reported in patients with depression compared with control sub
jects (Fam et al. 2015).
Lastly, it has been proposed that thyroid dysfunction in depression may result
from an impairment of the thyroid hormone receptor. A preclinical study found that
mice with receptor-mediated hypothyroidism—caused by an unliganded thyroid
hormone receptor alpha 1—presented a depressive phenotype that was responsive to
continuous T
substitution (Pilhatsch et al. 2010).
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Bipolar Disorder
Despite the absence of clear evidence for a direct causal relationship, patients with bipolar disorder may have an increased risk of thyroid abnormalities compared with
healthy individuals, and thyroid alterations have been reported in patients with bi
polar disorder (Barbuti et al. 2017). Patients with bipolar disorder have been reported
to be particularly sensitive to variations in thyroid function within the normal range,
and lower thyroid function may predict slower response to treatment for bipolar depression (Cole et al. 2002). Hypothyroidism is a frequent finding in patients with bipolar disorder, and it has been associated with more severe clinical presentations, such
as rapid cycling (Bauer et al. 1990). Patients with bipolar disorder had higher mean
thyroid volumes and TSH levels in comparison with healthy control subjects (Ezzaher et al. 2011; Ozsoy et al. 2010), as well as higher TSH levels compared with patients
with unipolar depression and schizophrenia (Wysokiński and Kloszewska 2014).
Moreover, increased TSH is associated with increased risk of manic relapse (Amann
et al. 2017), and low T
manic and depressive) and severity of mania (Frye et al. 1999). In addition, an association between bipolar disorder and increased T
These findings suggest that an imbalance in thyroid function may be related to all
phases of bipolar disorder.
As we discuss later (see “Clinical Implications”), lithium treatment is well known
to cause a significant disruption in thyroid functionality and thyroid volume, causing
hypothyroidism. However, HPT changes were also demonstrated in lithium-naïve patients with bipolar disorder. Compared with healthy control subjects, lithium-free patients with bipolar disorder had significantly higher mean thyroid volumes and lower
T
levels (Ozsoy et al. 2010). Kraszewska et al. (2019) showed that the rates of hypo-
4
thyroidism in lithium-treated and untreated patients were similar, suggesting that
is associated with mood instability (more mood episodes, both
4
has been found (Krishna et al. 2013).
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changes within the HPT axis may have other causes, and possibly are directly related
to bipolar disorder itself.
Increased circulating thyroid autoantibodies are frequently seen in patients with
bipolar disorder. As in studies of patients with unipolar depression, TPOAbs are the
most consistently studied in patients with bipolar disorder (Bocchetta et al. 2016);
however, there is an evident increase in both TGAbs and TPOAbs in patients with
bipolar disorder compared with healthy control subjects (Barbuti et al. 2017). The
majority of these increases were seen in specific subtypes of patients with bipolar dis
order—that is, in those with rapid cycling, mixed features, or bipolar depression.
Prevalence of TPOAbs has also been compared in twin studies, which further suggest
an inherited risk of bipolar disorder and thyroid autoimmunity. In one such study
(Vonk et al. 2007), patients with bipolar disorder had significantly higher levels of
TPOAbs compared with their co-twins without bipolar disorder. This suggests that
thyroid immunity may act as an endophenotype for bipolar disorder. However, results are contradictory, as other studies did not find the same results (Cobo et al.
2015). Children of parents with bipolar disorder have been shown to be more suscep
tible to thyroid autoimmunity. According to a study from Hillegers et al. (2007), a
larger percentage of offspring of parents with bipolar disorder were positive for
TPOAbs compared with healthy control subjects, and the majority of these TPOAbspositive offspring also had raised TSH. The susceptibility to thyroid autoimmunity
appeared to be independent from the child’s risk of developing a psychiatric disorder,
but further research is needed. In addition, there was increased statistical significance
when comparing female offspring with control subjects, suggesting that females are
at higher risk than males for developing thyroid autoimmunity. However, conflicting
evidence exists on the role of sex in the incidence of thyroid autoimmunity in patients
with bipolar disorder. For example, Cobo et al. (2015) found that TSH and T
were not affected by sex; however, women had a higher presence of TGAb and
TPOAb positivization. Other authors have not found a significant relationship between sex and the presence of thyroid autoantibodies (Kupka et al. 2002).
In summary, HPT axis abnormalities are quite common among patients with bipolar
disorder. However, the biological mechanisms behind this evidence are still unclear,
and the role of lithium in inducing HPT axis dysfunction is an important confounder.
levels
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Hypothalamic-Pituitary-Gonadal Axis
Depression
A correct balance in the levels of sex hormones appears to be crucial in mental health.
Estrogens are directly and indirectly implicated in the neurobiology of depression.
Estrogens regulate the synthesis, metabolism, receptor concentration, and trafficking
of neurotransmitters that are implicated in depression, including 5-HT, dopamine,
and norepinephrine. Moreover, estrogens regulate the neuroplasticity acting on the
levels of brain-derived neurotrophic factor (BDNF) (Schiller et al. 2016). Testosterone
also has been widely linked to depression. Overall, an imbalance in testosterone levels has been associated with an increased risk for depression, in both men and women
(Rohr 2002). In male patients with depression, lower levels of testosterone, mainly
free testosterone, have been reported (Almeida et al. 2008). Even though results are
sometimes conflicting, a recent meta-analysis confirmed significantly lower testoster-
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one levels in men with depression compared with healthy control subjects (Fischer et
al. 2019a).
One hypothesis on how sex hormones could affect mood involves the interaction
between the HPG and the HPA axes. There is a reciprocal relationship between these
two axes, as each one plays a role in the regulation and functioning of the other. In
creased GC levels suppress the release of GnRH and synthesis of gonadotropins,
while estrogen and testosterone regulate levels of cortisol (Toufexis et al. 2014). For
example, a common symptom of Cushing’s syndrome is amenorrhea (Zada et al.
2015); moreover, HPA axis hypoactivity may lead to chronic high testosterone levels
(Ludwig et al. 2019).
Women are more likely than men to develop depression, and this sex difference is
more evident during the reproductive years, peaking in adolescence and then declining
and remaining stable in adulthood (Salk et al. 2017). These findings suggest a potential
role of sex hormones in the pathogenesis of depression, even if a clear relation-ship has
not yet been established (Brummelte and Galea 2016; Hammarström et al. 2009). Perinatal depression clearly occurs together with great changes in levels of sex hormones.
During pregnancy and postpartum, estrogen and progesterone levels dramatically
fluctuate from high to hypogonadal status after parturition. Earlier in this chapter, we
discussed the relevance of HPA axis alterations in perinatal depression. Additionally,
Pařízek et al. (2014) found that levels of both estrogens and androgens during preg
nancy were involved in the development of mental changes in the postpartum period.
The onset of depression-like behaviors in postpartum rats may be partly attenuated by
a complex estrogen-mediated mechanism, mainly ER-α (Furuta et al. 2013). Using
combined mouse and human data, Guintivano et al. (2014) identified epigenetic alterations in estradiol-mediated signaling genes that are implicated in postpartum depression. These results confirm once again the firm connection between the HPA and HPG
axes and suggest that sex hormones may be of etiological importance in perinatal de
pression. Another well-known clinical condition that could affect women of reproductive age is premenstrual dysphoric disorder. In this disorder women experience
affective symptoms specifically during the luteal phase of the menstrual cycle (with
complete remission before and after it). The most supported etiopathological theory
suggests that women with premenstrual dysphoric disorder have higher sensitivity to
hormonal changes, particularly the fall in progesterone levels. In support of this hy
pothesis, selective serotonin reuptake inhibitors (SSRIs) are rapidly effective in this
disorder; even if the exact mechanism is not completely clear, this effectiveness is probably due to the action of SSRIs on sex hormones, neuromodulating estrogen or progesterone levels (Lanza di Scalea and Pearlstein 2017; Yonkers and Simoni 2018).
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Bipolar Disorder
High rates of reproductive disorders have been reported in women with bipolar disorder. Early-onset menstrual cycle dysfunction is significantly more likely to occur in
patients with bipolar disorder compared with patients with unipolar depression and
healthy control subjects, and this dysfunction occurs more commonly before the onset of bipolar disorder (Joffe et al. 2016). In their pilot study, Rasgon et al. (2000) suggested that menstrual dysfunction preceded the diagnosis and treatment of bipolar
disorder, thus implying a role for HPG axis dysfunction in bipolar disorder. In a larger
study from the same group, the authors confirmed this hypothesis in 50% of these
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women (Rasgon et al. 2005). Additionally, the study found that preexisting menstrual
abnormalities were associated with increases in 17-α-hydroxyprogesterone, LH/FSH
ratio, and free testosterone, which suggest HPG axis dysfunction in these patients.
However, most of these studies have reported small sample and effect sizes, limiting
the translational impact of these data in a clinical setting. Menstrual cycle dysfunction
in patients with bipolar disorder has also been associated with changes in testoster
one levels (O’Donovan et al. 2002; Rasgon et al. 2005). Interestingly, testosterone levels were found to be positively correlated with the number of manic episodes and the
number of suicide attempts, in both males and females (Sher et al. 2012). This latter
finding was further confirmed in a longitudinal study of the same group. In female
patients with bipolar disorder, higher baseline testosterone levels predicted suicide
attempts in a 2.5-year follow-up period (Sher et al. 2014). However, results are conflicting. Indeed, in the study by Feng et al. (2019) discussed earlier in the subsection
on the role of the HPA axis in mood disorders, the authors found that untreated firstepisode patients with bipolar disorder had reduced testosterone secretion.
Obviously, there is a substantial difference between male and female hormonal
physiologies. Wooderson et al. (2015) reported that women with bipolar disorder had
significantly higher testosterone levels compared with female control subjects,
whereas men with bipolar disorder had lower testosterone levels compared with
male control subjects. Thus, sex differences need to be considered for further research.
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Hypothalamic-Neurohypophysial System
HNS hormones also are important in mood disorders. Arginine vasopressin (AVP)
has been demonstrated to influence several CNS-related functions, including cogni
tive and behavioral ones (Surget and Belzung 2008). It has also been hypothesized to
have a depressogenic effect. In fact, higher AVP plasma levels (van Londen et al. 1998)
and increased AVP mRNA expression (Meynen et al. 2006) have been reported in patients with depression compared with control subjects. Interestingly, a major singlenucleotide polymorphism (SNP) haplotype of the AVP receptor has been found to be
protective against recurrent MDD (van West et al. 2004). Very few studies have analyzed AVP in patients with bipolar disorder, and no significant results have been reported (Rutigliano et al. 2016).
Oxytocin (T) may be involved in the development or maintenance of depression
(McQuaid et al 2014). Decreased OT levels have been associated with depression
(Lach et al. 2018). Ozsoy et al. (2009) found significantly lower OT levels in patients
with depression (unipolar and bipolar) compared with healthy control subjects, but
only in females. Also, perinatal depression and OT levels have been found to have a
reciprocal link: low OT levels during pregnancy are associated with risk of postnatal
depression, and antenatal depression is associated with low OT levels after birth
(Sawyer et al. 2019). Epigenetic studies showed that DNA methylation in the OT receptor gene was associated with postpartum depression (Kimmel et al. 2016), and
specifically with persistent symptoms (King et al. 2017). Also, studies in patients with
bipolar disorder reported heightened OT levels (Lien et al. 2017; Turan et al. 2013). In
a postmortem study of patients with a major psychiatric disorder, the authors found
that diagnoses of MDD or bipolar disorder were associated with significantly increased OT receptor mRNA levels in the dorsolateral prefrontal cortex (Lee et al.
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2018). Notably, in subjects with either MDD or bipolar disorder, a specific SNP of the
OT receptor gene was associated with suicide attempt history (Parris et al. 2018).
Interestingly, both neurohypophysial hormones can affect HPA axis activity (Engelmann et al. 2004) and consequently act on mood. AVP stimulates ACTH production synergistically with CRH, thus activating the HPA axis (Salata et al. 1988). This
has been proposed as a main depressogenic mechanism (Neumann and Landgraf
2012). OT may differently regulate HPA axis activity, by inhibiting basal HPA axis ac
tivity and potentiating it under conditions of stress (Neumann et al. 2000).
Clinical Implications
Overall, neuroendocrine functioning is crucial in mood disorders and has therefore
been studied for its clinical implications. The recognition of specific neuroendocrine
alterations in mood disorders may offer new possibilities for diagnosis, treatment,
and prevention of both depression and bipolar disorder. Several therapies currently
available for mood disorders act to varying extents on neuroendocrine systems, several treatments specifically targeting neuroendocrine systems at different levels are
currently being investigated for mood disorders, and new treatments may be devel
oped in the upcoming years. Even if this is a promising field, we still do not have conclusive results, and further research is needed.
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Hypothalamic-Pituitary-Adrenal Axis
Several studies have been focused on the HPA axis as a potential target for treatment
of mood disorders. Different anti-GC compounds have been studied as antidepres
sants, although findings are not univocal and systematic research is still limited. In
their review, Holsboer and Ising (2008) reported the results of clinical studies on two
CRH type 1 receptor antagonists, NBI-30775/R121919 and NBI-34041. Results were encouraging: the first compound demonstrated a clinical profile comparable to that of the
antidepressant paroxetine, whereas the second one reduced the stress-elicited secretion
of cortisol. In contrast, Ferrier et al. (2015) reported negative findings in their clinical
trial of metyrapone augmentation in patients with treatment-refractory depression.
They found that this compound—a competitive inhibitor of 11β-hydroxylase (with re
sulting inhibition of cortisol)—was ineffective in the treatment of depression. Mifepristone, a potent competitive GR antagonist, has been evaluated both as augmentation
and as monotherapy in the treatment of MDD (Maric and Adzic 2013). Interestingly,
this compound has demonstrated effectiveness in reducing psychotic symptoms in depression with psychotic features (Block et al. 2018). Treatment with the mifepristone
has been investigated in bipolar depression as well, as an adjuvant to current treatment
(with mood stabilizers, antidepressants, and antipsychotics) (Young et al. 2004). A significant improvement in depression rating scores was seen in patients taking mifepristone compared to placebo. Furthermore, significant improvements in neurocognitive
functioning were observed. A recent meta-analysis by our research group (Lombardo
et al. 2019) involving both patients with depression and patients with bipolar disorder highlighted that among those treated with cortisol synthesis inhibitors, responders had significantly higher peripheral baseline cortisol levels compared with non-
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responders, supporting a potential role for cortisol as a predictive biomarker for treatment with cortisol synthesis inhibitors in patients with mood disorders.
The firm connection between the HPA axis and mood disorders is further supported by the fact that almost every psychotropic drug has an effect on the HPA axis,
as confirmed by a recent review (Subramaniam et al. 2019). Antidepressants are
mainly, but not always, associated with a reduction in both basal and post-DEX/CRH
cortisol levels, whereas psychostimulant medications are more frequently associated
with an increase (or no change) in basal cortisol levels (Subramaniam et al. 2019). It is
particularly important to highlight that antidepressants require the GR to exert their
action (Anacker et al. 2011). Whereas antidepressants activate the GR in order to in
crease neurogenesis, cortisol exerts the opposite effect (Pariante 2017). GR function is
therefore crucial to achieving an effective antidepressant response. In fact, Binder et
al. (2004) found FKBP5 SNPs to be associated with treatment response in patients
with depression. Ising et al. (2019) confirmed these findings, demonstrating increased
expression levels of the FKBP5 gene, and specifically its product FKBP51, to be associated with nonresponse to antidepressant treatment in patients with depression. Another recent systematic review (Fischer et al. 2019b) found that specific SNPs and
haplotypes in genes related to CRH (CRHBP, CRHR1) and melanocortins (POMC)
were predictive of nonresponse to antidepressants. However, the authors reported
equivocal findings on GR- and MR-related genes. Moreover, both antidepressants and
the HPA axis act on 5-HT receptors. Therefore, long-term treatment with antidepressants could modulate serotonergic transmission and lead to activation of the HPA axis,
which in turn unfavorably affects 5-HT receptor functioning. This mechanism could
cause, at least partly, sensitization and/or tolerance to treatment (Fornaro et al. 2019).
Finally, we have to mention the gut microbiota, which are profoundly linked to the
HPA axis and have an important clinical value. The gut microbiota, which include all
the indigenous microorganisms that live in the human gut, have an important role in
mediating the response to stress (Farzi et al. 2018; Sudo 2014). Hence, probiotics are
now emerging as a new potential adjunctive treatment for depression, also acting
through modulation of the HPA axis (Butler et al. 2019; Vlainić et al. 2016).
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Hypothalamic-Pituitary-Thyroid Axis
Every clinician should be aware of the importance of evaluating thyroid function
when assessing a patient with mood disorder. Thyroid hormone supplementation is
beneficial in improving depressive symptoms in patients with hypothyroidism and
may also benefit patients with normal thyroid function. Augmentation of conventional treatments for depression with T
resistant depression (Carvalho et al. 2009). Very few studies have examined the use of
T
in bipolar depression, but results are promising (Parmentier and Sienaert 2018).
3
Evidence suggests that T
ing on BDNF, similarly to antidepressants (Hung et al. 2013). In this regard, Baek et
al. (2014) found higher TSH levels to be associated with lower baseline, as well as a
reduced increase in, BDNF levels during antidepressant treatment, thus suggesting
that the HPT axis is crucial in mediating the antidepressant response. In clinical trials
in patients with bipolar disorder, treatment of rapid cycling with levothyroxine (L-T
has resulted in significantly less time in a depressed or mixed state, and greater time
has been proven to be effective in treatment-
3
also may act as a neuroprotective agent in the CNS by act-
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euthymic, compared with placebo (Walshaw et al. 2018). In addition, subclinical hypothyroidism—and also higher TSH levels within the normal range (>2.5 μIU/mL)—
has been associated with poorer antidepressant response in both unipolar and bipolar
depression (Cohen et al. 2018). Thus, optimizing TSH levels with thyroid hormone
supplementation may be an effective treatment strategy in depressed patients with
high-normal TSH levels and poor antidepressant response (Cohen et al. 2018).
One of the most common side effects of long-term use of lithium—probably still
the most effective treatment for bipolar disorder—is hypothyroidism. Because lith
ium treatment has been seen to affect the level of thyroid hormones, it could also be
suggested that lithium plays a role in increasing thyroid autoantibodies in patients
with bipolar disorder. However, some studies (Barbuti et al. 2017; Kupka et al. 2002)
reported that the increased presence of TPOAbs in patients with bipolar disorder
compared with control subjects was not associated with lithium exposure. Also, other
psychotropic medications have been demonstrated to affect thyroid function. In a re
cent study in patients with bipolar disorder, Li et al. (2019) found no differences in
thyroid profiles among patients with different types of mood episodes, but they
found quetiapine treatment to affect thyroid function, significantly reducing levels of
thyroid hormones.
Hypothalamic-Pituitary-Gonadal Axis
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Obviously, sex differences are crucial when analyzing the role of sex hormones in
mood disorders. However, there is some evidence regarding the effects of both tes
tosterone and estrogens on mood, independent of a person’s sex. In their review,
McHenry et al. (2014) reported that testosterone has antidepressant effects in women,
men, and animals. The hippocampal mitogen-activated protein kinase pathway may
be the mediator of such protective effects. Supplementation with testosterone—administered in an intramuscular, transdermal, or oral formulation—has been proposed
as an adjunctive treatment for depressed men, especially for partial responders with
low or borderline testosterone levels (Kanayama et al. 2007). Pope et al. (2003) reported that a testosterone transdermal gel was effective in reducing depressive symptoms in male patients with refractory depression and low or borderline testosterone
levels. In a subsequent larger study by the same group (Pope et al. 2010), however,
testosterone supplementation failed to achieve a significant reduction in depressive
symptoms compared with placebo. Despite conflicting findings, a recent meta-analysis including 27 randomized placebo-controlled clinical trials confirmed the efficacy
and effectiveness of testosterone in reducing depressive symptoms in men, particularly in higher-dosage regimens (Walther et al. 2019). Interestingly, low-dose transdermal testosterone was found to improve depressive symptoms in women with
treatment-resistant depression (Miller et al. 2009). These findings suggest that women
may be more sensitive to androgens compared with men. Huang et al. (2008) reported
that menopausal status and ovarian steroid levels, but not age, were the main determinants of the antidepressant efficacy of repetitive transcranial magnetic stimulation
in women with treatment-resistant depression, both in MDD and in bipolar disorder.
Interestingly, depression occurring in perimenopausal women may be directly related to the decline in ovarian estrogen production (estradiol withdrawal), and hormone replacement therapy with estradiol may therefore be protective against the
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