Effect of Xiaoyaosan on major depressive disorder

Hypotheses for MDD and functions of XYS

5-HT deficiency was the prevailing hypothesis for MDD 22], 23]. SSRIs were widely used, and accounted for about 60–80% of the total market share
of antidepressants 24]. XYS upregulated the 5-HT contents in the cerebral cortex of a chronic restraint
stress (CRS)-induced rat depression model 25], and increased the 5-HT contents in the hippocampus of rats with postpartum depression
26]. XYS could be a regulator of monoamine neurotransmitters 27].

The hypothalamic–pituitary–adrenal (HPA) axis is governed by secretion of corticotropin-releasing
hormone (CRH) from the hypothalamus to activate secretion of adrenocorticotropic hormone
(ACTH) from the pituitary gland. Corticoids (cortisol in humans and corticosterone
in rodents) are stimulated from the adrenal cortex and interact with their receptors,
such as glucocorticoid receptors, for negative feedback control 28]. HPA hyperactivity results from deficits in the negative feedback regulation of the
axis based on the failure of glucocorticoid receptor activation to decrease plasma
levels of cortisol 29]. XYS downregulated CRH-1 and upregulated CRH-2 expression in the hypothalamus of
a CRS-induced depressive rat model 30]. XYS decreased the expression of CRH-1 mRNA in paraventricular nuclei and increased
GR expression in the hippocampus of a chronic unpredictable mild stress-induced depressive
rat model 31]. Therefore, homeostasis of CRH receptors might be involved in improvement of the
disequilibrium in the HPA system.

HPA hyperactivity was observed in 30–50% of all acutely depressed patients 32]. Mitochondrial dysfunctions affected important functions in MDD pathogenesis 23]. Small deletions of mitochondrial DNA were observed in muscles from patients with
MDD 33]. Alterations in nuclear DNA-encoded mitochondrial mRNA and proteins in the cerebellum
of MDD patients were also reported 34]. MDD patients with serious somatic complaints exhibited low ATP production rates
in biopsied muscles 35]. These studies provide concrete evidence for the clinical relevance of an association
between low ATP supply arising through mitochondrial dysfunction and MDD. XYS was
reported by our group to ameliorate depressive-like behaviors in rats by regulating
mammalian target of rapamycin (mTOR), suggesting that XYS may exert its anti-depressive
effects through regulation of energy metabolism 36].

Inflammatory pathways were suggested to be involved in the pathophysiology of MDD
through increased blood and cerebrospinal fluid concentrations of pro-inflammatory
cytokines as well as acute phase proteins and their receptors 37]. Cytokines interact with mitochondria to increase the production of reactive oxygen
species (ROS). Increased expressions of pro-inflammatory mediators, neurotoxic factors,
and ROS contributed to the development of MDD 23]. XYS has been widely used for treating inflammatory diseases and depression comorbidities
in hepatitis 38]. Recently, we found that XYS significantly reduced the serum levels of tumor necrosis
factor-? and interleukin-6 in rats with depressive-like behaviors induced by chronic
unpredictable mild stress (unpublished data). MDD was associated with neuronal atrophy
and neuronal cell loss, especially in the hippocampus and cerebral cortex 39]. Decreased brain-derived neurotrophic factor (BDNF) was strongly associated with
an increased risk for MDD 40]. A clinical meta-analysis showed that BDNF levels were associated with changes in
depression 41]. BDNF was downregulated in the hippocampus of a CRS-induced rat depression model
42]. Reports from our group and others indicated that XYS increased BDNF expression in
the hippocampus 36], 42], 43]. These results suggest that XYS improves MDD by upregulating BDNF in specific encephalic
regions.

Epigenetic alterations were found in the frontal cortex of suicide victims with depression
44]. Antidepressants exerted some of their effects by causing epigenetic alterations
45]. Observed dysfunctions of biological clocks were related to MDD 46]. Patients with depression often showed altered circadian rhythms, sleep disturbances,
and variations in diurnal moods 47]. The degree of circadian misalignment was correlated with the severity of depressive
symptoms 47]. The actions of XYS on epigenetic modifications and circadian rhythms are significant,
because this medicinal formula is efficacious in the treatment of sleeping and mood
disorders.

Integrated hypothesis for MDD as a unified mechanism of XYS

Hypotheses for MDD include 5-HT depletion, neurotrophin deficiency, neuroinflammation,
mitochondrial dysfunction, HPA hyperactivity, epigenetic variation, and circadian
dysrhythmia. However, the pathophysiology of MDD has rarely been studied and the published
hypotheses are far from mutually exclusive.

The theory of inadequate monoamine neurotransmission, in which antidepressants increase
monoamine availability and produce long-term adaptive changes in monoaminergic receptor
sensitivity 48], is insufficient to explain MDD. Lowered plasma tryptophan reduced 5-HT synthesis
and aggravated MDD symptoms 49]. N-acetylserotonin, an intermediate product of melatonin formation from 5-HT, is a specific
agonist of BDNF receptors, and 5-HT is a substrate for melatonin biosynthesis. Melatonin
deficiency contributed to primary and depression-associated insomnia as well as disturbances
in circadian rhythms 50].

Neuroinflammation, which is characterized by increased production of interferon-?,
interleukin-6, and tumor necrosis factor-?, and induction of indoleamine 2,3-dioxygenase
(IDO) in the blood and brain, plays a role in depression 37]. Activation of IDO reduces plasma tryptophan and brain 5-HT and increases the levels
of tryptophan catabolites (TRYCATs), such as quinolinic and picolinic acids. Inflammation
increases CRH and ACTH secretion. Cortisol levels are increased to activate liver
tryptophan 2,3-dioxygenase, which further decreases plasma tryptophan and increases
TRYCAT production. TRYCATs generate ROS, cause mitochondrial dysfunctions, and interfere
with energy metabolism. They also potently activate NMDA receptors and induce pro-inflammatory
responses and neuron apoptosis. These findings imply a shift from tryptophan and 5-HT
depletion toward the detrimental effects of TRYCATs. IDO links the neuroinflammation
and neurotoxicity of TRYCATs, which jointly promote the development of depressive
symptoms 49].

Psychosocial stresses arising from life events can potentially induce continuous increases
in stress hormones, which impair negative-feedback mechanisms and lead to continuous
hyperactivity of the HPA axis. Pro-inflammatory cytokines are also potential activators
of the HPA axis, thereby increasing the secretion of glucocorticoids, which are markers
of glucocorticoid resistance. Glucocorticoids augment the alternative pathway for
IDO-catalyzed tryptophan and decrease the amount of 5-HT available in synapses by
increasing the expression of the serotonin transporter gene. Prolonged increases in
glucocorticoids desensitize their receptors on immune cells, such as macrophages.
Activation of macrophages in the periphery and brain occurred and pro-inflammatory
cytokines were released in MDD patients 37]. Psychosocial stresses decrease the levels of BDNF and other neurotrophic/growth
factors, while increasing the glucocorticoid concentration. Multiple interaction pathways
exist between pro-inflammatory immune functions, brain and neuronal structures, brain
serotonergic systems, and the HPA axis. The HPA axis is a key integrative component
that links primary biological and psychosocial theories 36].

Dysfunction of the hippocampus, cerebellum, insula, frontal cortex, and temporal cortex
could eventually contribute to the pathogenesis of MDD. The integrated model conjectures
a general-purpose co-processor, whose effects depend on the specific brain centers
to which individual modules are connected 51]. The disparate modules and different ideas on MDD emphasize the internal relationships
among the different hypotheses (Figure 2).

Figure 2. A simplified integrative model for the pathophysiology of MDD and the potential targets
for XYS. a–g Refer to seven major hypotheses for MDD. a 5-HT depletion, b neurotrophin deficiency, c circadian dysrhythmia, d neuroinflammation, e mitochondria dysfunction, f HPA hyperacbivity, g epigenetic variation, 5-HT 5-hydroxytryptamine, BDNF brain-derived neurotrophic factor, IFN-? interferon ?, TNF-? tumor necrosis factor ?, IL-6 interleukin 6, IDO indoleamine 2,3-dioxygenase, TDO tryptophan 2,3-dioxygenase, TRYCATs tryptophan catabolites, NMDA N-methyl-D-aspartic acid, GR glucocorticoid receptor, ACTH adrenocorticotropic hormone, CRH corticotropin releasing hormone.