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Abstract and Figures

Anxiety disorders range among the most prevalent psychiatric disorders and belong to the leading disorders in the study of the total global burden of disease. Anxiety disorders are complex conditions, with not fully understood etiological mechanisms. Numerous factors, including psychological, genetic, biological, and chemical factors, are thought to be involved in their etiology. Although the diagnosis of anxiety disorders is constantly evolving, diagnostic manuals rely on symptom lists, not on objective biomarkers and treatment effects are small to moderate. The underlying biological factors that drive anxiety disorders may be better suited to serve as biomarkers for guiding personalized medicine, as they are objective and can be measured externally. Therefore, the incorporation of novel biomarkers into current clinical methods might help to generate a classification system for anxiety disorders that can be linked to the underlying dysfunctional pathways. The study of metabolites (metabolomics) in a large-scale manner shows potential for disease diagnosis, for stratification of patients in a heterogeneous patient population, for monitoring therapeutic efficacy and disease progression, and for defining therapeutic targets. All of these are important properties for anxiety disorders, which is a multifactorial condition not involving a single-gene mutation. This review summarizes recent investigations on metabolomics studies in anxiety disorders.
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International Journal of
Molecular Sciences
Review
Metabolomic Biomarkers in Anxiety Disorders
Elke Humer * , Christoph Pieh and Thomas Probst
Department for Psychotherapy and Biopsychosocial Health, Danube University Krems, 3500 Krems, Austria;
christoph.pieh@donau-uni.ac.at (C.P.); thomas.probst@donau-uni.ac.at (T.P.)
*Correspondence: elke.humer@donau-uni.ac.at; Tel.: +43-2732-893-2676
Received: 26 June 2020; Accepted: 5 July 2020; Published: 6 July 2020


Abstract:
Anxiety disorders range among the most prevalent psychiatric disorders and belong to
the leading disorders in the study of the total global burden of disease. Anxiety disorders are
complex conditions, with not fully understood etiological mechanisms. Numerous factors, including
psychological, genetic, biological, and chemical factors, are thought to be involved in their etiology.
Although the diagnosis of anxiety disorders is constantly evolving, diagnostic manuals rely on
symptom lists, not on objective biomarkers and treatment eects are small to moderate. The underlying
biological factors that drive anxiety disorders may be better suited to serve as biomarkers for
guiding personalized medicine, as they are objective and can be measured externally. Therefore,
the incorporation of novel biomarkers into current clinical methods might help to generate a
classification system for anxiety disorders that can be linked to the underlying dysfunctional
pathways. The study of metabolites (metabolomics) in a large-scale manner shows potential for
disease diagnosis, for stratification of patients in a heterogeneous patient population, for monitoring
therapeutic ecacy and disease progression, and for defining therapeutic targets. All of these
are important properties for anxiety disorders, which is a multifactorial condition not involving a
single-gene mutation. This review summarizes recent investigations on metabolomics studies in
anxiety disorders.
Keywords: metabolomics; metabolites; anxiety; biomarkers
1. Introduction
Anxiety disorders are a prevalent global health problem, aecting the lives of almost 300 million
individuals suering from a range of anxiety disorders as well as society as a whole [
1
]. Anxiety
disorders are currently the most prevalent psychiatric disorder in the United States and Europe and
are ranked by the WHO as the sixth largest cause of disability worldwide and range among the
top ten causes of years lived with disability [
1
,
2
]. Anxiety disorders also lead to the subsequent
development of other psychiatric comorbidities, such as depression [
3
]. The prevalence of anxiety
disorders is aected by gender, with a higher prevalence in women than men [
4
]. Despite a trend
towards lower prevalence among older people (
80 years), prevalence rates are similar among age
groups [
1
,
5
]. The group of anxiety disorders is characterized by feelings of anxiety and fear and related
behavioral disturbances, such as avoidance behavior [
6
]. Due to the typically long-lasting duration of
the symptoms experienced by aected individuals, anxiety disorders represent more chronic-recurrent
than an episodic disorder [7].
Like all psychiatric disorders, anxiety disorders are diagnosed not on objective biomarkers,
but based on symptom lists, which refer to a single diagnosis, while patients commonly present
symptoms that fit multiple diagnoses [
2
]. The heterogeneous nature of the population of anxious
patients does not only impede diagnosis and discovery of the underlying etiological mechanisms [8],
but also contributes to the poor treatment response experienced in many patients [
9
,
10
]. Although
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Int. J. Mol. Sci. 2020,21, 4784 2 of 19
several established psychotherapeutic and medication-based treatments exist which are eective
on average [
11
13
], individual responses to treatments vary widely [
9
,
10
], limiting the validity of
assumptions that there is a single biological disturbance underlying anxiety in all patients [
14
,
15
].
Therefore, disturbances more likely dier among individuals [
16
], thus requiring the identification of a
broader array of biomarkers to gain better insights into patient-specific etiological mechanisms that
lead to more targeted treatments [17].
The inclusion of biomarkers that could help improve diagnosis might also help to generate
a classification system for psychiatric disorders that can be associated with the dysfunctional
pathways underpinning them, finally enabling more targeted treatments of anxiety disorders [
16
,
18
].
Among potential biomarkers, the study of metabolites (metabolomics) in a large-scale manner is
currently regarded as one of the most informative representations of biological functions, as these
molecules carry out or respond to most processes of the body [
19
,
20
]. More detailed information on
the use of metabolomics in the study of psychiatric disorders is summarized in the following chapter.
2. Metabolomics in Studies in Psychiatry
Recent advances in analytical technology enable the so-called “omics technologies”, referring
to bioinformatics studies on genes, transcripts, proteins, and metabolites [
21
,
22
]. Among these
technologies, the study of the metabolome represents the “ome”, which is closest to the phenotype [
23
].
The word “metabolome” refers to the total metabolite pool in a cell, tissue, or organism [
24
]. As such,
the metabolome consists of a diverse array of biomolecules that are the final products of interactions
between gene expression, protein function, and the cellular environment [
25
]. Metabolites represent
the final products and by-products of complex biosynthetic and catabolism pathways. Thus, the study
of metabolites in a large-scale manner represents a powerful technique to elaborate phenotypic changes
caused by exogenous stimuli more predictively than other omics technologies [2426].
Metabolomics aims to provide detailed and mechanistic insights into the pathology of diseases
by revealing altered metabolic pathways. As such, metabolomics is considered to hold potential for
the identification of pathways involved in the pathophysiology of diseases and for the diagnosis
of psychiatric illnesses [
27
,
28
]. Moreover, it oers new options for stratification of patients in a
heterogeneous patient population, for monitoring therapeutic ecacy and disease progression, and for
defining therapeutic targets [
27
,
28
]. All of these aspects have a particular value in complex pathological
states, such as psychiatric disorders, as almost all of them are multifactorial conditions, not involving
a single-gene mutation [
29
]. To sum up, metabolomics presents a tool to explore the mechanisms of
diseases from a holistic perspective [
29
]. Therefore, metabolite profiling seems promising to recognize
early biochemical changes in disease and, thus, provides an opportunity to develop predictive
biomarkers that can initiate earlier interventions [
30
,
31
]. The latest applications of metabolomics cover
various areas, including screening and diagnostic approaches, discovery and development of new
therapeutics, evaluation of drug toxicity and assessment of therapeutic ecacy, patient stratification,
and monitoring of patient response to treatment [
19
,
30
,
31
]. Thus, in the future, metabolomics might
help to reveal the biological bases of psychiatric symptoms and implement personalized care to patients
with mental disorders [32].
Studies based on metabolomic approaches attempt to ascertain biomarkers for diagnosis, disease
progression, and the treatment response. Advanced metabolomic platforms enable a global and
integrated evaluation of biochemical pathways and metabolic changes appearing in a diseased
state [
20
]. In this regard, the most relevant biological material for the
in vivo
study of the pathogenesis
of psychiatric disorders arguably derives from the brain [
33
]. Brain tissues, as well as cerebrospinal
fluid—which also reflects the metabolic status and biochemistry of the brain—are the most relevant
sampling substrates for identifying biomarkers of psychiatric diseases. These brain-derived samples
enable the study of causal links between a detected psychiatric pathology and aected molecular
pathways. However, such samples from humans are typically only available for analysis at autopsy [
20
].
Therefore, often animal models are used as tools that help to understand the pathogenesis of psychiatric
Int. J. Mol. Sci. 2020,21, 4784 3 of 19
disorders, as recently reviewed [
34
]. In humans, however, the use of plasma, serum, or urine has
increased in the metabolomic study of mental disorders, which also provides valuable information
about the biological signatures of psychiatric disorders. This corroborates to the whole-body concept
of psychiatry, based on the fact that although psychiatric disorders seem to be generated in the brain,
the eects of these illnesses can be observed throughout the body, as the brain is integrated into
virtually all physiological functions of the whole body [20].
Metabolomic studies have already been reported for several psychiatric disorders, including
depressive disorders, bipolar disorder, schizophrenia, and drug addiction [
19
,
35
]. However, fewer
studies have been carried out in anxiety disorders. The following chapters summarize studies on the
use of metabolomic platforms to reveal abnormalities and metabolic changes occurring in anxiety
disorders. In addition, studies on changes in metabolites due to the treatment of anxiety disorders
are summarized. To give a broader overview on changes in blood metabolites, the review is not only
limited to advanced metabolomic platforms but also considers studies investigating a smaller set of
metabolites by classical methods, such as photometric assays, high-performance liquid chromatography,
or gas chromatography.
Therefore, a literature search was conducted using Scopus, PubMed, and APA Psycinfo databases.
Research articles in scientific journals on experiments using animal models or human subjects were
considered. The search was conducted on 29 May 2020, with no limitations on the publication date.
Articles were identified by searching for titles using the following search terms: “(metabolom* OR
metabolite OR lipidom OR lipid* OR biomarker) AND (anxi*)”. The search returned 170 records after
duplicates were removed.
3. Metabolomics to Dierentiate Healthy and Anxiety Subjects
As the diagnosis of anxiety disorders still relies rather on symptom checklists than on empirical
objective laboratory analyses, eorts have been made to dierentiate healthy from anxious subjects by the
analysis of metabolites as summarized in Table 1. Anxiety disorders are complex conditions. Numerous
factors, including genetic, neurobiological, neurochemical, and psychological factors, are thought
to be involved in their development [
3
]. To elucidate the pathways aected by anxiety disorders,
and to identify possible biomarkers, animal studies using brain tissue were conducted. For more
detailed information regarding the design of animal studies to serve as models for human anxiety
disorders, we refer to our previous review article [
34
]. In brief, oxidative stress, alterations in lipid and
energy metabolism (i.e., mitochondrial regulation), glutamine metabolism, and neurotransmission [
36
]
seem to be involved in anxiety disorders. This overlaps with depressive disorders—which often
occur comorbid in individuals with anxiety disorders—where changes in the glutamate–glutamine
cycle, as well as changes in lipid and energy metabolism, have also been found to be related to the
pathogenesis of major depressive disorder [30].
Table 1. Possible biomarkers identified to dierentiate healthy and anxiety subjects.
Subject Sampling
Material
Analytical
Platform Metabolites Identified Pathways Involved/Functions Reference
Mice Plasma GC-MS 1Myo-inositol, glutamate,
tricarboxylic
cycle-intermediates
Mitochondrial energy pathways,
inositol pathways, HPA 2-axis,
glutamate metabolism
[37]
Mice Brain GC-MS Dehydroascorbate, xylose,
succinic acid
Energy metabolism,
mitochondrial import and
transport, oxidative stress,
neurotransmission
[38]
Mice Brain and
plasma LC-MS/MS 3
1-methyl histidine,
deoxyuridine, kynurenic acid,
2-hydroxygluterate, carnitine,
acetylcarnitine, cytosine
Oxidative stress, energy
metabolism, amino acid
metabolism neurotransmitter
metabolism
[39]
Int. J. Mol. Sci. 2020,21, 4784 4 of 19
Table 1. Cont.
Subject Sampling
Material
Analytical
Platform Metabolites Identified Pathways Involved/Functions Reference
Dogs Plasma LC-MS 4Glutamine,
γ-glutamyl–glutamine Glutamine metabolism [40]
Humans Plasma LC-MS/MS Phosphatidyl-cholines (PC O
36:4), ceramides (CER 20:0)
Phospho- and sphingolipid
metabolism [41]
Humans Plasma
Photometric
assays,
immuno-assays
Cholesterol (HDL 5, LDL 6),
fructosamine, triglycerides,
free fatty acids,
dehydro-epiandrosterone-sulfate,
adrenocorticotropic hormone
Lipid and carbohydrate
metabolism [42]
Humans Plasma not specified Cholesterol, triglycerides,
apolipoproteins B Lipid metabolism [43]
Humans Urine GC-MS
N-methylnicotin-amide,
amino-malonic acid, azelaic
acid, hippuric acid
Tryptophan–nicotinic acid
metabolism, lipid metabolism,
tyrosine–phenylalanine pathways
[44]
1
GC-MS, gas chromatography–mass spectrometry.
2
Hypothalamus–pituitary–adrenal.
3
LC-MS/MS, liquid
chromatography–tandem mass spectrometry.
4
LC-MS, liquid chromatography–mass spectrometry.
5
HDL,
high-density lipoproteins. 6LDL, low-density lipoproteins.
In human studies, mainly plasma sNamples were used for the study of metabolites. Overall, many
early anxiety metabolomics studies focused on lipids (lipidomics), as there is a known connection
between lipids and neuronal signaling and disease [45].
Negative correlations between anxiety and high-density lipoprotein (HDL) levels were observed,
while higher triglyceride levels were observed in patients with depression and comorbid anxiety
compared to depressive patients without anxiety [
46
]. Furthermore, serum triglycerides, very-low-density
lipoprotein (VLDL)-cholesterol and free-cholesterol were higher in patients with anxiety disorders as
compared to healthy controls, whereas the opposite was observed for esterified cholesterol [
47
]. A study
conducted in menopausal women observed no correlation between lipid profiles (total cholesterol,
HDL, VLDL, low-density lipoproteins (LDL), triglycerides) and anxiety [
48
]. In young women, on the
other hand, low lipid and lipoprotein levels (cholesterol, LDL, total cholesterol, ratio of total cholesterol
to HDL) were inversely correlated with anxiety scores [
49
]. Huang et al. [
50
] observed dierences
in HDL cholesterol and the ratio of total cholesterol to HDL with regard to an anxious state in men.
In healthy men, levels of total cholesterol and LDL cholesterol were higher in those who scored higher
on an anxiety inventory [
51
]. Thus, several studies support the role of lipids in anxiety disorders,
although dierences with respect to gender and hormonal status likely exist.
Increasing evidence suggests a crucial role for membrane lipids and lipid oxidation in the
pathogenesis of anxiety disorders. Membrane lipids play a pivotal role in the barrier and signaling
function of membranes [
52
]. As dysfunctions in neuronal proteins and peptide activities are considered
as a primary cause of anxiety disorders, brain lipids are essential for transmitter signaling. Lipids
essential for membrane formation, i.e., n-3 polyunsaturated fatty acids, phospholipids, glycerolipids,
and sphingolipids, are assumed to be involved in the pathogenesis of anxiety disorders, especially [
53
].
The lipid composition of neuronal membranes is highly dynamic and likely aects the assembly of
signaling proteins and, thus, neuronal signaling and function [54].
Omega-3 fatty acids serve as precursors for the synthesis of eicosanoids, which might induce
perturbations of the system of inflammatory mediators. Anxiety disorders have been linked to
inflammation. Thus, the consumption of specific fatty acids or leukotriene receptor antagonists might
also contribute to the maintenance of the anxiety symptoms [55].
Given the ubiquitous distribution of lipids at synapsis in the brain, membrane-forming lipids are
believed to have high potential in the treatment of anxiety disorders [
53
]. As such, lipid-based therapies
might oer new individualized treatment approaches, such as targeted dietary supplementation of n-3
polyunsaturated fatty acids [
56
]. Another mode of function might be pharmacological interference of
lipids, i.e., glycerolipids, with lipid-regulating enzymes [57].
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Observed changes in phospho- and sphingolipids related to anxiety symptoms pinpoint overactive
ether lipid cleavage/turnover in the brain in the etiology of anxiety disorders, which likely relate to
inflammatory processes [41].
The hypothesis of the association of anxiety with systemic inflammation corroborates a recent
finding, showing an association of the inflammation marker C-reactive protein (CRP) [
58
], with increased
risk of suicide in patients with anxiety disorders [
59
]. Thus, metabolites indicative of poor metabolic
health might serve as distal biomarkers for anxiety. Indeed, metabolic health, as indicated by the analysis
of 36 biomarkers (e.g., leptin, brain-derived neurotrophic factor, tryptophan), which have been shown
to be related to anxiety disorders, revealed the highest occurrence of this mental disorder in individuals
with poor metabolic health (the so-called “overweight” class). Therefore, metabolites indicative of poor
metabolic health might serve as distal biomarkers for anxiety [
60
]. However, contrasting results on the
association between inflammation and anxiety disorders have been reported. In elderly participants,
for instance, a number of systemic inflammation markers (e.g., CRP, interleukins, serum amyloid A,
tumor-necrosis factor alpha) were not associated with anxiety symptoms [
61
]. In another study with
apparently healthy women, high-sensitivity CRP and fibrinogen contents were negatively associated
with anxiety, whereas no association was observed in men [
62
]. Therefore, associations of anxiety
and micro-inflammation markers also seem to dier with regard to gender and age, which might also
contribute to the equivocal results regarding the association of lipid metabolism and inflammation
with anxiety symptoms.
Studies also indicate a role of nitro-oxidative stress driving lipid oxidation and lowered
lipid-antioxidant defenses in anxiety disorders. More specifically, increased superoxide dismutase,
lipid hydroperoxides, nitric oxide metabolites (NOx), and uric acid were measured in individuals with
general anxiety disorders than in those without anxiety disorders. Those changes were accompanied
by a decrease in HDL and paraoxonase-1 [
63
]. It is suggested that the inflammation due to the
overproduction of NOx is involved in the pathology of anxiety disorders [
64
]. However, while studies
focusing on NOx levels in acute stress models observed associations between anxiety and NOx [
65
],
a study analyzing salivary NOx in daily psychological stress in humans and anxiety observed only
correlations between stress and anxiety, but not between salivary NOx and anxiety [64].
Several studies in animals and humans have demonstrated a potential link of anxiety disorders with
oxidative stress and lipid peroxidation, as neurochemical causes of anxiety disorders. Lipid peroxidation
was enhanced in children with anxiety disorders as compared to a control group, as indicated by
increased serum levels of lipid hydroperoxide. Thus, lipid hydroperoxide has been speculated as a
potential biomarker for anxiety disorders [
3
]. Oxidative stress as indicated by elevated levels of lipid
hydroperoxide and lower paraoxonase activity (an HDL associated enzyme protecting lipids from
peroxidation [
66
]) have been observed in individuals with generalized anxiety disorder (GAD) without
any comorbid psychiatric disorder [
67
], further supporting the role of lipid peroxidation and oxidative
stress in the etiopathogenesis of GAD. Thus, lipid hydroperoxide has been speculated as a potential
biomarker for anxiety disorders [3,67].
The association between anxiety and oxidative stress has often been related to nutritional eects.
However, other factors might also serve as a source of oxidative stress, such as mobile phone
electromagnetic field radiation, vibration and ringtone, which have been found to induce oxidative
stress and anxiety-like behavior in rats [68].
As many studies highlight the association between stress and anxiety disorders, salivary cortisone
was suggested not only as a stress biomarker but also as a marker of state anxiety [
69
]. Salivary
alpha-amylase—a maker of sympathetic nervous system activity [
70
]—was observed to be higher
in adults with a higher dental anxiety score, thus showing potential to serve as a biomarker of
dental anxiety [
71
]. However, a study conducted in children with and without temporomandibular
disorders observed higher anxiety symptoms in children with the disorder, but no dierence in salivary
alpha-amylase and also salivary cortisol [
72
]. However, elevated hair cortisol was found to predict later
development of anxious behavior in response to a major life stressor in infant monkeys, thus showing
Int. J. Mol. Sci. 2020,21, 4784 6 of 19
some potential as a biomarker for stress-related mental problems [
73
]. In healthy volunteers exposed
to a psychosocial stressor, the anxiety score was associated with salivary alpha-amylase, but not to
salivary cortisol or chromogranin-A [
74
]. Therefore, further studies are needed to clarify whether
cortisol, cortisone, and alpha-amylase show potential as biomarkers for anxiety disorders.
The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is assumed to be
involved in stress response and has been suggested as a biomarker for the severity of stress-related
psychiatric disorders [
75
]. Serum PACAP analysis in male and female individuals diagnosed with
GAD compared to healthy controls revealed no overall association between circulating PACAP and
GAD, but an association in women [
76
], supporting prior work suggesting potential sex dierences in
PACAP eects, likely due to estrogen-dependent regulation of this pathway [75].
The neurotrophin fibroblast growth factor-2 (FGF2)—a protein involved in stress regulation
and neurogeneration [
77
]—is also considered as an endogenous regulator of fear expression. Thus,
FGF2 might also serve as a potential biomarker for anxiety disorders [
78
]; however, further research
is required to elucidate the potential of FGF2 to identify vulnerable individuals and to establish
preventative interventions.
Studies also aimed to integrate biopsychosocial aspects of stress, immune markers, and behavior
in the development of anxiety symptoms. Chronic stress causes perturbations in the hypothalamus–
pituitary–adrenal (HPA)-axis, which might mediate the relationship between cardiovascular
diseases and aective disorders [
79
]. One study investigated relations between stress, HPA-axis,
and mother–child interaction patterns on the development of anxiety in children exposed to chronic
trauma [
80
]. Trauma-exposed children exhibited more anxiety symptoms, which might be explained
by three bio-behavioral paths: a mediated biological pathway through HPA-axis functioning (higher
salivary cortisol in trauma-exposed mothers and also children), another biological pathway via the
immune system (higher salivary immunoglobulin A (IgA) in trauma-exposed mothers and also
children), and a third path with a behavioral link from diminished maternal supply to exposure
to child anxiety. Moreover, anxiety in children exposed to continuous wartime trauma integrating
endocrine and behavioral measures from mother and child was researched previously [
81
]. The study
revealed that maternal physiology and behavior impacted child anxiety and three possible pathways
were defined: augmentation of child anxiety through increased maternal salivary IgA, which led to
enhanced child IgA; reduced social repertoire of the child due to reduced maternal oxytocin—and,
in turn, reduced child oxytocin; and a direct impact of increased maternal anxiety on child anxiety.
Previous studies also attempted to reveal biological aspects of the higher prevalence of anxiety
disorders in women. Dierences in the hormonal status, i.e., with respect to the steroid pattern, have
been speculated to be a reason behind. Higher levels of estrogens in women with anxiety disorders,
when compared to women with depression, have been observed [82].
In one study, a specific analysis of the steroid metabolome in the blood of men with anxiety or
depression compared to healthy controls was carried out. Conjugated steroid forms, i.e., sulfates, such
as pregnenolone sulfate, diered between all three groups, and, thus, also provide an opportunity to
serve as biomarkers to dierentiate depressed from anxious individuals [
83
]. Among the previously
considered steroids as being neuroactive, steroid sulfates, such as pregnenolone sulfate, are reported to
act as negative gamma-aminobuytric acid (GABA) receptor modulators [
84
], which might explain the
lower pregnenolone sulfate concentration in anxious and depressive men.
Besides plasma analysis, metabolomics analyses were also conducted on urine samples.
Zheng et al. [44]
used dierent metabolomics approaches to profile urine samples from healthy controls
and patients with depression and anxiety disorders. Overall, four biomarkers—N-methylnicotinamide,
aminomalonic acid, azelaic acid, and hippuric acid—were identified as being able to distinguish healthy
from depressed/anxious individuals. Those biomarkers were mainly involved in three metabolic
pathways (tryptophan–nicotinic acid metabolism, lipid metabolism, tyrosine–phenylalanine pathways)
and five molecular and cellular functions (cell cycle, amino acid metabolism, molecular transport,
cellular growth and proliferation, small molecule biochemistry).
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Further specific studies investigated comorbid anxiety disorders in specific disorders, such as
autism, cancer, complex regional pain syndrome, or Cushing’s syndrome. Only a few recent studies
related to these specific diseases are summarized below.
Central and peripheral metabolites in patients with complex regional pain syndrome were
analyzed for their association with psychological disorders, including anxiety [
85
]. Specific associations
were observed, which might show pathological interactions between a painful body and increases
in anxiety in this population. Strong positive correlations between valine/N-acetylaspartylglutamate
(val/tNAA) and anxiety in the right thalamus were observed. Lower NAA levels have been related to
dysfunctional cell death related to neurons and glia cells. As lower NAA levels have been observed
in patients with complex regional pain syndrome before, neuronal cell death may aect anxiety
symptoms in this population [
86
,
87
]. In addition, peripheral CO
2
was positively associated with
anxiety, which might be explained by an increase in sensory pain levels due to increased partial CO
2
pressure causing a synergistic boost of neuropsychiatric symptoms, such as anxiety [85].
An investigation in individuals with Cushing’s syndrome evaluated the deleterious eects of
excessive glucocorticoid exposure on neuronal changes related to anxiety [
88
]. Metabolomic analyses
revealed a negative correlation of N-Acetyl-aspartate (a marker of neuronal integrity and viability [
89
])
and creatinine (a marker for brain cell density in glial and neuronal cells, and energetic systems [
90
])
with anxiety, suggesting that long-term exposure to excessive glucocorticoid levels causes metabolic
alterations in the prefrontal cortex associated with anxiety [88].
A study in patients with colorectal cancer undergoing three dierent stages of therapy, observed
clinically relevant anxiety and/or depression levels in all patients [
91
]. Serum levels of fractaline
(a chemokine involved in the progression of dierent types of tumors [
92
] and also in the inhibition of
neurotransmission related to anxiety [
93
]) were positively correlated with anxiety scores. Therefore,
fractaline might serve as a biomarker for the detection of anxiety disorders in cancer patients,
and they might also assist in the development of personalized anxiolytic treatment strategies for cancer
patients [91].
4. Metabolomics in the Study of the Role of the Gut Microbiome in Anxiety Disorders
The gut microbiome is suggested to play a pivotal role in the induction of anxiety-like behavior,
through stress-induced dysbiosis [
4
]. The link of the gut microbiome and stress-related conditions
has largely been investigated in studies with germ-free animals. A recent study in rats subjected
to chronic unpredictable stress revealed that changes in the gut microbiome were accompanied by
dysregulation of plasma metabolites related to metabolism of glycerophospholipids, glycerolipids, fatty
acyls, and sterols [
94
]. The authors suggest that lactate produced from gut microbes might possibly
promote anxiety-like behavior through the modulation of fatty acid metabolic pathways, resulting in
low levels of plasma fatty acids. It was suggested that the future development of treatment strategies
for anxiety disorders should consider targeting sphingolipid receptors.
In a further study with germ-free animals, these subjects had higher serotonin metabolite levels
compared to conventionally raised controls. It was also suggested that the gut microbiome can aect
the serotonergic neurotransmission in the central nervous system, through a humoral route, based on
the finding of higher concentrations of the serotonin-precursor tryptophan in the plasma of germfree
animals [95].
Furthermore, gender-dierences in anxiety disorders have been observed in animal studies [
4
].
For instance, dietary supplementation with the n-3 polyunsaturated fatty acid docosahexaenoic acid (DHA)
in male socially isolated mice reduced anxiety behaviors compared to controls, whereas no differences
occurred in female mice [
96
]. In addition, a sex-specific interaction of the DHA-supplementation with
the gut microbiome was observed, showing a significant effect on the microbiome in male but not in
female mice.
Besides animal studies, human studies with respect to the role of the gut microbiome were also
conducted, which mainly relied on correlative analysis. In this regard, Stevens et al. [
97
] investigated fecal
Int. J. Mol. Sci. 2020,21, 4784 8 of 19
microbiota in humans with anxiety or depressive disorders as compared to control reference subjects.
Gut dysbiosis in anxious and depressed individuals and over-representation of lipopolysaccharide
(LPS) biosynthesis genes in the gut microbiome were reflected in changes in metabolic pathways of
mood neurotransmitters as well as deleterious metabolism of intestinal protective mucin and elevation
of plasma LPS, and epithelium integrity molecules. These results support the notion that LPS might
compromise the integrity of the gut barrier, causing systemic manifestations, including the brain [
98
].
The microbiota–gut–brain axis is also assumed to play a central role in the etiology of depression,
showing that disturbances in the gut microbiome disturb metabolic homeostasis [
30
]. Several studies
provide support that dysregulation of the enteric microbiome does not only produce detrimental
metabolites but also causes increased bacterial translocation across the intestinal tract. These processes
are assumed to be involved in the pathophysiology of anxiety and depressive disorders through
proinflammatory cytokines and neuroinflammation, the HPA-axis, and vagal nerve activation, as reviewed
recently [
94
]. Overall, based on these studies, future studies should elucidate the role of the gut as a novel
target for the treatment of anxiety disorders.
5. Metabolomics in the Study of the Role of Nutrition in Anxiety Disorders
Several animal studies were conducted to evaluate the impact of different diets on anxiety.
Some studies investigated the effect of maternal diet on the offspring. For instance, one study investigated
the eect of maternal consumption of conjugated linoleic acid during gestation and lactation on cerebral
lipid peroxidation and anxiety behavior in rats [
99
]. Higher levels of the antioxidant glutathione
together with a lower concentration of the lipid peroxidation marker malondialdehyde were observed
in brain tissues in the ospring of rats receiving conjugated linoleic acid. Maternal intake of conjugated
linoleic acid also caused an anxiolytic eect in the ospring. Therefore, results imply that an adequate
supply of essential fatty acids during pregnancy plays an important role in facilitating the development
of the nervous system and protecting the ospring from neuronal changes, such as those leading
to anxiety.
In a further study, the ospring of rats received a diet consisting of high contents of simple
carbohydrates, saturated or trans-fats, sodium, and low protein and fiber contents (a so-called “cafeteria
diet”) during lactation and/or post-lactation compared to rats receiving a control diet [
100
]. The eects
of this cafeteria diet on physiological parameters and anxiety were investigated. The highest triglyceride
levels were found in the ospring of rats receiving post-lactation cafeteria diet or total cafeteria diet.
The ospring also presented higher levels of anxiety compared to the control groups and groups with
only a lactational cafeteria diet. Thus, the study provides some evidence that the ingestion of a cafeteria
diet after lactation might trigger metabolic (increase in serum triglycerides and oxidative stress) and
behavioral alterations (anxiogenic eects) in rats.
A broad range of studies investigated nutritional biomarkers and anxiety during pregnancy and
postpartum in humans, as recently systematically reviewed by Trujillo et al. [
101
]. Most relevant
studies are briefly described in the following.
One study related to anxiety disorders during pregnancy to nutritional biomarkers. Associations
between polyunsaturated fatty acids and anxiety disorders in early pregnancy were observed, showing
an inverse relation of serum DHA levels and anxiety disorders in the first trimester [
102
]. Furthermore,
associations between cholesterol and anxiety in the postpartum period were investigated, as total lipids
decrease considerably after delivery as compared to pregnancy [
103
]. Overall, only moderate negative
associations between total cholesterol and HDL cholesterol and anxiety symptoms were observed in
the postpartum period [104].
Next to the eects of fatty acids, a possible association between amino acids and anxiety was also
studied [
105
], showing an inverse relationship of the ratio of plasma tryptophan and the sum of the
levels of valine, leucine, isoleucine, and phenylalanine with anxiety. Moreover, changes in plasma
phenylalanine were correlated with changes in anxiety scores from the 3rd to 6th day before delivery
Int. J. Mol. Sci. 2020,21, 4784 9 of 19
to the 1st and 3rd postnatal day; however, these associations should be interpreted with caution, as
only low correlations (r =0.16, p=0.04) were observed [106].
The role of micronutrients has hardly been investigated so far, showing no association of vitamin
D with anxiety in pregnancy [
107
] and also no correlation between zinc levels and anxiety during
pregnancy and in the postpartum period [108].
Further studies investigated possible associations between obesity/metabolic syndrome and
anxiety disorders using animal models. For instance, in rats fed a high-saturated fat or a high-fat
and high-fructose diet, behavioral alterations toward anxiety-like behavior were observed [
109
].
These behavioral alterations correlated with dyslipidemia (increased serum triglycerides and
cholesterol), lipid peroxidation, and metabolic parameters. Long-term feeding of high-fat diets
has also shown to increase malondialdehyde concentrations and to decrease glutathione levels in the
serum of rats, which went along with increases in anxiety-like behavior [110].
In humans, a cross-sectional study investigated associations of anxiety and metabolic syndrome
components in metabolic syndrome patients. Waist, body mass index, and degree of obesity, and the
hypertension component could be linked to systolic blood pressure, pulse pressure, total cholesterol,
and trait anxiety, but not to state anxiety. Thus, cholesterol metabolism, blood pressure, and high
trait-anxiety likely interact in the pathophysiology of hypertension in metabolic syndrome [76].
Studies conducted in animals and humans reveal an inverse relationship of the dietary total
antioxidant capacity with oxidative stress biomarkers as well anxiety [
111
]. Therefore, lipid peroxidation
does not only seem to play a role during pregnancy/early life, but also in adults.
Overall, research indicates that nutrition—mainly associated with lipid peroxidation, inflammation,
and metabolic alterations—plays a role in translating diet-induced metabolic alterations into anxiety
disorders. Therefore, fatty acids, such as n-3 polyunsaturated fatty acids, or the provision of antioxidants,
are also considered as new treatment options [53,110,111].
6. Metabolomics in the Study of Anxiolytic Eects
Metabolomics was also applied in the field of drug discovery, including natural product research.
Several studies used metabolomics analyses to characterize the composition of anxiolytic
drugs/natural products [
112
], which will not be described in more detail as it does not fall within
the scope of this review. However, in some studies, changes in brain or plasma metabolites due to
drug administration were also assessed, as summarized in Table 2. These studies highlight the role of
the eects of anxiolytic drugs on neurotransmitter metabolism, but also on antioxidant mechanisms.
Several studies pinpoint the involvement of changes in serotonergic activity in the anxiolytic eect
of several drugs, showing increasing serotonin contents in rodent brains [
113
,
114
]. In addition,
the role of dopamine in anxiety has been reported before, revealing increasing concentrations in
the prefrontal cortex during stressful and anxiogenic situations [
113
], and a decrease after the
administration of anxiolytic drugs, such as afobazole [
114
]. However, for other drugs, such as
diazepam, no eect on the dopamine content was observed, despite their anxiolytic activity [
113
].
Next to serotonin and dopamine, the glutamate–glutamine cycle in the brain plays an essential
role in mental disorders [
115
], as glutamate represents the primary and most abundant excitatory
neurotransmitter in the central nervous system. The functionality of the glutamate–glutamine cycle
is essential for glutaminergic neurotransmission [
116
]. Furthermore, glutamine is not only essential
as a precursor for the neurotransmitter glutamate but also for the neurotransmitter GABA [
115
] and
the antioxidant glutathione [
117
]. The dysfunction of the glutamate–glutamine cycle is suggested to
be involved in dierent forms of anxieties [
40
]. Therefore, several anxiolytic drugs might pose their
anxiolytic eects via their impact on this cycle, as summarized in Table 2.
In the following, only a few recent studies using metabolomic approaches in the study of anxiolytic
eects are reported in more detail.
The ethanol extract of Passiflora edulis Sims F. flavicarpa was tested in comparison to a positive
drug control (diazepam) in a randomized trial using an anxiety model in rats. Administration
Int. J. Mol. Sci. 2020,21, 4784 10 of 19
of P. edulis extract enhanced GABA concentrations in the brain and exhibited an anxiolytic-like
eect. Thus, it is assumed that P. edulis extracts might function as positive allosteric modulators of
GABA. Using metabolomics approaches, secondary metabolites were investigated and correlated with
measured activities. However, no correlation of the dierent metabolites was observed, suggesting that
the anxiolytic eect is not attributable to a single metabolite, but rather to an additive or synergistic
eect of several entities [118].
In line with the research indicating a role of oxidative stress in the etiology of anxiety disorders,
a meta-analysis by Aponso et al. [
119
] reported anxiolytic eects of inhaled essential oils as well
reduced oxidative stress. Moreover, extracts of Hypericum Scabrum—a phyto drug with antioxidant
properties—were shown to be able to reverse diet-induced alterations related to oxidative stress [
110
].
More specifically, detrimental eects of high levels of saturated fats on oxidative status and anxious
behavior were observed in rats. A long-term high-fat diet enhanced serum malondialdehyde levels,
decreased glutathione levels, and enhanced anxiety. The extract of H. scabrum inversed these
diet-induced alterations and decreased anxiolytic eects. Therefore, it is expected that phytomedical,
natural therapeutic agents with antioxidant properties might oer preventative and/or curative
measures in anxiety disorders.
The linkage of psychological stress and production of free radicals with anxiety disorders was
also used to investigate oxidative metabolites as biomarkers for monitoring the response to treatment
with anxiolytics in a randomized placebo-controlled study [
120
]. Biopyrrins, the oxidative metabolites
of bilirubin, were investigated in urinary samples of mice receiving the anxiolytic alprazolam subjected
to acute stress. In addition, corticosterone levels in serum were analyzed. An increase in biopyrrins in
stressed mice and a decrease after the anxiolytic treatment, as well as a correlation between urinary
biopyrrins and serum corticosterone levels, were observed, thus showing some potential for urinary
biopyrrins to serve as biomarkers for the assessment of the response to anxiolytics.
Indicators of stress and lipid peroxidation were also investigated in the brain of psychologically-
stressed mice receiving anxiolytic and anxiogenic drugs [
121
]. The content of thiobarbituric acid
reactive substances—an index of lipid peroxidation activity—was enhanced in the brain, but not in
the liver or serum after stress exposure. The oxidative brain damage in the brain lipids went along
with the enhanced production of nitric oxidase through the mediation of non-selective nitric oxidase
synthase. The stress-induced detrimental eects were suppressed by anxiolytic drugs. Thus, drugs
with benzodiazepine or a serotonin receptor agonist profile might pose anxiolytic eects due to their
protective eects on stress-induced oxidative brain damage.
Further studies point at the pivotal role of the antioxidant eects of anxiolytics. For instance,
the anxiolytic-like eect and the possible neuronal mechanism of action of the chemical isopentyl
ferulate (IF) were investigated in a randomized trial in mice with a negative control group. Overall,
the calming eect of IF went along with a decrease in hippocampal nitrite and lipid peroxidation
levels and an increase in glutathione and antioxidative enzymes (glutathione peroxidase, superoxide
dismutase, catalase). Further investigations regarding possible involvement of the GABAergic system
in the anxiolytic eect of IF yielded some evidence that IF might show neuroprotective eects through
the GABAergic transmission pathway [122].
Anxiolytic eects of satins—drugs that are used to lower LDL levels—were also discussed in
a recent review article [
123
]. The mechanisms behind it are assumed due to a modulation of the
N-methyl-d-aspartate (NMDA) receptors in the brain, which show a close correlation with anxiety-like
behavior. Statins can disable these NMDA receptors due to their role in the disruption of membrane/lipid
rafts, finally disabling the NMDA receptor-mediated anxiety.
Int. J. Mol. Sci. 2020,21, 4784 11 of 19
Table 2. Overview of metabolomic studies in the study of anxiolytic eects.
Subject Sampling
Material
Analytical
Platform Anxiolytic Drug Metabolites Identified Pathways
Involved/Functions Reference
Mice Brain NMR 1Specific herbal
formula (Fu Fang
Jin oral liquid)
ATP, fumarate, malate, lactate,
glycine, GABA 2,
N-acetyl-aspartyl-glutamate
Energy metabolism,
choline metabolism,
neuro-transmitter
metabolism
[124]
Mice Brain HPLC 3(Z)-3-hexenol,
Diazepam
Serotonin
(5-hydroxy-tryptamine; 5-HT
4
),
5-hydroxyindoleacetic acid
Neuro-transmitter
metabolism [113]
Rats Brain not specified Afobazole,
Ladasten
3,4-dihydroxy-phenylacetic
acid, homovanillic acid, 5-HT,
5 oxytryptophan,
5-hydroxyindoleacetic acid,
l-3,4-dihydroxy-phenylalanine
Neuro-transmitter
metabolism [114]
Rats Brain HPLC-ED 5Imipramine
5 oxytryptophan,
homovanillic acid,
dihydroxyphenylacetic acid
Neuro-transmitter
metabolism [125]
Rats Brain UPLC-MS 6Passiflora edulis
Sims F. flavicarpa,
diazepam
GABA Neuro-transmitter
metabolism [118]
Mice Urine,
serum
Immuno-assays
Alprazolam Biopyrrins, corticosterone Oxidative stress [120]
Mice Brain Antioxidant
assays Isopentyl ferulate
Nitrite and lipid peroxidation
markers, glutathione,
glutathione peroxidase,
superoxide dismutase,
catalase
Oxidative stress,
neuro-transmitter
metabolism
[122]
1
NMR,nuclearmagneticresonancespectroscopy.
2
GABA,gamma-aminobuytricacid.
3
HPLC,high-performanceliquid
chromatography.
4
5-HT, serotonin, 5-hydroxytryptamine.
5
HPLC-ED, high-performance liquid chromatography—
electrochemical detection. 6UPLC-MS, ultra-performance liquid chromatography—mass spectrometry.
In a case study in a patient with a treatment-refractory substance use disorder and comorbid anxiety
and depressive symptoms, repeated transcranial magnetic stimulation was successful in reducing
anxiety symptoms [
126
]. It was speculated that enhanced glutamate transmission in the corticostriatal
pathways occurred due to the stimulation of the dorsolateral prefrontal cortex. This might, in turn,
modulate the GABA/glutamate balance within the basal ganglia, which, in turn, promotes dopamine
release in the mesocortical pathways, finally reducing psychiatric symptoms.
Lifestyle changes, such as nutritional changes or exercise, have been proposed as possible
complementary modalities to prevent and cure disorders, and the combination of both approaches,
i.e., dietary supplementation with polyunsaturated fatty acids in combination with physical exercise,
showed synergistic eects on brain function and behavior [
127
,
128
]. A study in mice investigated the
eect of voluntary running on anxiety-like behavior and the lipid metabolome in the brain and blood
corticosterone levels. Compared to sedentary mice, the running group displayed lower anxiety-like
behavior, which went along with dierences in blood corticosterone and a region-specific cortical
decrease in the palmitate (C16:0) and a concomitant increase in arachidonic acid and DHA. Therefore,
it is assumed that the anxiolytic eects of physical exercise derive from exercise-induced activation
of cortical signaling cascades involving or dependent on bioactive lipids [
129
]. In humans, physical
exercise (strength and endurance training) reduced anxiety, which went along with a reduction in
CRP, an indicator of cardiac veins inflammation [
130
], with the latter being stronger aected by
strength than endurance training [
131
]. Tai Chi Chuan is often viewed by Chinese people as physical
exercise to improve mind–body health, therefore, making it an interesting research target in the field
of cardiovascular health and anxiety symptoms. Thus, a randomized-controlled trial was conducted
to evaluate the eect of a Tai Chi Chuan exercise program on anxiety status and blood lipid profile
in individuals with hypertension as compared to healthy subjects [
132
]. As an increase in HDL and
a decrease in total cholesterol, LDL, and triglycerides went along with decreases in trait and state
anxiety, it was suggested that Tai Chi might be used as an alternative treatment in patients with
anxiety disorders.
Int. J. Mol. Sci. 2020,21, 4784 12 of 19
7. Conclusions
The aforementioned studies on the use of metabolomics in anxiety disorders are promising
for diagnosis, gaining insight into the etiology of the disorders and the development of treatment
strategies. Overall, metabolites related to oxidative stress, inflammatory processes, lipid and energy
metabolism, glutamine metabolism, and neurotransmission seem to pose the potential to serve as
biomarkers for anxiety disorders; however, to date, the application in clinical practice is not feasible
due to several limitations. The main limitation is that, so far, no references for normal ranges of
metabolites exist [
30
]. Furthermore, variables, such as gender, diet, or lifestyle, aect the metabolic
profile and also medical comorbidities and the use of medications or drugs need to be considered
and, thus require further research [
133
,
134
]. Furthermore, many findings of this systematic review are
based on animal studies. Those studies on human anxiety were also prevalent beneath other disorders.
It must be taken into account that the group of anxiety disorders is from the clinical and etiological
point of view very dierent. Thus, a more specific approach, according to the dierent categories of
anxiety disorders, might be more ecient. There is also a lack of research on whether metabolomic
biomarkers can predict or moderate treatment response to anxiolytic medication and psychotherapy.
However, in major depressive disorders, for instance, studies indicate predictive potential of the
pretreatment metabolomics profile of the response to antidepressant medication [
135
], and also one
pilot psychotherapy study revealed that several plasma metabolites might serve as moderators of
the outcome of psychotherapy [
136
]. Future studies should also explore metabolomics changes in
anxiety due to psychotherapy treatment, which might also help to understand better the mechanistic
underpinnings of the eect of psychotherapy on symptom change and whether these changes are
associated with metabolomics alterations. Therefore, more research is needed to reveal whether
metabolomics can provide biomarkers to improve treatment selection and personalized treatment for
patients with anxiety disorders.
Author Contributions:
Conceptualization, E.H.; Methodology, E.H., C.P., T.P.; Investigation, E.H.;
Writing—original draft preparation, E.H.; Writing—review and editing, C.P., T.P.; Supervision, C.P., T.P. All authors
have read and agreed to the published version of the manuscript.
Funding: This research received Open Access Funding by the University for Continuing Education Krems.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
CER Ceramides
CRP C-reactive protein
DHA Docosahexaenoic acid
DOPA Dopamine
FGF2 Fibroblast growth factor-2
GABA Gamma-aminobuytric acid
GAD Generalized Anxiety Disorder
GC-MS Gas chromatography–mass spectrometry
HDL High-density lipoprotein
HPA Hypothalamus–pituitary–adrenal
HPLC High-performance liquid chromatography
HPLC-ED High-performance liquid chromatography–electrochemical detection
5-HT Serotonin
IgA Immunoglobulin A
LC-MS Liquid chromatography–mass spectrometry
LC-MS/MS Liquid chromatography–tandem mass spectrometry
LDL Low-density lipoprotein
LPS Lipopolysaccharides
NAA N-acetylaspartylglutamate
NMR Nuclear magnetic resonance spectroscopy
Int. J. Mol. Sci. 2020,21, 4784 13 of 19
NOx Nitric oxide metabolites
PACAP Pituitary adenylate cyclase-activating polypeptide
PC Phosphatidylcholines
UPLC-MS Ultra-performance liquid chromatography–mass spectrometry
VLDL Very low-density lipoprotein
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Bhattacharyya, S.; Dunlop, B.W.; Mahmoudiandehkordi, S.; Ahmed, A.T.; Louie, G.; Frye, M.A.;
Weinshilboum, R.M.; Krishnan, R.R.; Rush, A.J.; Mayberg, H.S.; et al. Pilot study of metabolomic clusters as
state markers of major depression and outcomes to CBT treatment. Front. Neurosci.
2019
,13, 926. [CrossRef]
[PubMed]
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
... In addition to defining the gut microbiota in anxiety-related disorders, several studies have attempted to identify biomarkers to differentiate between subjects with anxiety and healthy controls in mice, dogs, and human beings [14]. A variety of biomarkers have been identified in anxiety disorders, including neurotransmitters, neuropeptides, neurotrophic factors, and immunological factors, but none were specific or sufficient for diagnosis [15]. ...
... A number of metabolites that changed in response to the foods tested in this study are also implicated in anxiety disorders. In general, metabolites related to oxidative stress, glutamine metabolism, and neurotransmission pathways appear to be involved in anxiety disorders [14]. High anxiety in mice is associated with high levels of intracellular reactive oxygen species, and oxidative stress has been shown to lead to anxious behavior in mice [4,48]. ...
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A nutrition-based approach was utilized to examine the effects of fish oil and a polyphenol blend (with or without tomato pomace) on the fecal microbiota and plasma/fecal metabolomes. Forty dogs, aged 5–14 years, were fed a washout food, then randomized to consume a control (fish oil and polyphenol blend without tomato pomace) or test (fish oil and polyphenol blend with tomato pomace) food, then the washout food, and crossed over to consume the test or control food; each for 30 days. Several metabolites differed when comparing consumption of the washout with either the control or test foods, but few changed significantly between the test and control foods. Plasma levels of 4-ethylphenyl sulfate (4-EPS), a metabolite associated with anxiety disorders, demonstrated the largest decrease between the washout food and the control/test foods. Plasma 4-EPS levels were also significantly lower after dogs ate the test food compared with the control food. Other plasma metabolites linked with anxiety disorders were decreased following consumption of the control/test foods. Significant increases in Blautia, Parabacteroides, and Odoribacter in the fecal microbiota correlated with decreases in 4-EPS when dogs ate the control/test foods. These data indicate that foods supplemented with polyphenols and omega-3 fatty acids can modulate the gut microbiota to improve the profile of anxiety-linked metabolites.
... Having considered the complex conditions of anxiety to elucidate the affected pathways and to identify possible biomarkers, several animal studies using brain tissue samples were conducted to serve as a model for human anxiety (Humer et al. 2020). To date, the metabolites related to (Yadav et al. 2014) anxiety disorders seem to be involved in oxidative stress, alteration in lipid and energy metabolism, and neurotransmission (i.e., glutamate-glutamine cycle or GABA metabolism) (Humer et al. 2020a). Additionally, metabolites targeting poor metabolic health might serve as distal biomarkers for anxiety (Humer et al. 2020a). ...
... To date, the metabolites related to (Yadav et al. 2014) anxiety disorders seem to be involved in oxidative stress, alteration in lipid and energy metabolism, and neurotransmission (i.e., glutamate-glutamine cycle or GABA metabolism) (Humer et al. 2020a). Additionally, metabolites targeting poor metabolic health might serve as distal biomarkers for anxiety (Humer et al. 2020a). ...
Chapter
The metabolic syndrome (MetS) is a multifactorial disease developed due to the accumulation and persistence of several risk factors associated with disrupted metabolism. To date, there is lack of efficient tools to evaluate the stage of MetS and its risk factors including carbohydrate dysfunction, dyslipidemia, inflammation, oxidative stress, gut microbiota dysbiosis, and anxiety. Expectantly, nuclear magnetic resonance (NMR) metabolomics has emerged as a promising source of new molecular markers due to its advantages across other metabolomic approaches. This chapter highlights the six major risk factors associated with MetS and related diseases, discussing their potential and weaknesses as biomarkers according to the current evidence available in the literature. Together, it is proposed a profile of metabolites for each risk factor obtained from NMR approaches to assess the severity of the risk factors associated to MetS.
... Anxiety disorders are considered to be complicated conditions, whose etiology has been only partially understood. Studies indicate that their development is determined by numerous factors, including psychological, genetic, environmental, chemical and biological ones, as well as by the epigenetic relationships between them (5,6). ...
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Background Anxiety disorders are considered the sixth most important factor resulting in non-fatal health loss in the world. Moreover, they are among the first ten causes of years lived with disability (YLD) across the globe. Important clinical disorders include e.g., panic disorder, social anxiety disorder, generalized anxiety disorder and specific phobia. Objectives The study aimed to analyse the occurrence of level anxiety in students who start work at the time of the COVID-19 pandemic, with relation to the socio-demographic factors and health status, vaccination, conovirus infection, assistance of a psychologist or psychiatrist in the past, and using tranquilizers. Methods The study involved 255 students from Poland starting work with coronavirus patients during the pandemic. It was conducted using our own questionnaire, the Liebowitz Social Anxiety Scale (LSAS) and the State-Trait Anxiety Inventory (STAI). Results Fifty-one percent of subjects demonstrated symptoms of mild to severe social phobia. Level of trait anxiety among students correlated significantly with age and gender (females). The level of social anxiety in the evaluated students was significantly correlated with marital status, the self-assessment of the experienced fear, self-perceived health status, having had a coronavirus infection, fear of deterioration of one's health after starting work with coronavirus patients, and fear of contracting the disease while working with coronavirus patients, and using tranquilizers. Level of state anxiety significantly correlated with state anxiety, the self-assessment of professional preparedness for work with coronavirus patients, self-perceived health status, vaccination against coronavirus, and the assistance of a psychiatrist in the past. Conclusions The proportion of students showing social anxiety is alarming. Anxiety among the evaluated students during the COVID-19 pandemic was correlated with many factors.
... Tyrosine is closely related to serotonergic activity, which has a close relationship with anxiety (Zhang et al., 2020). Moreover, the reversed metabolic substances of myo-inositol and palmitic acid in the serum of the model mouse were shown to be strongly associated with anxiety-related behaviors (Zhang et al., 2011;Moon et al., 2014;Humer et al., 2020). Preclinical findings have suggested that glycerolipids in the brain play a crucial role in the induction of anxiety and hyperactivity (Müller et al., 2015). ...
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Myasthenia gravis (MG) comorbid anxiety seriously affects the progress of MG. However, the exact relationship remains poorly understood. Recently, our preliminary study has revealed that intestinal microbe disturbance is closely related to MG. Therefore, further exploration of whether the microbiome is involved in MG comorbid anxiety is warranted. In this study, gas chromatography-mass spectrometry metabolomics analysis was used to characterize the metabotype of feces, serum, and three brain regions involved in emotion (i.e., the prefrontal cortex, hippocampus, and striatum), which were obtained from mice that were colonized with fecal microbiota from patients with MG (MMb), healthy individuals (HMb), or co-colonization of both patients and healthy individuals (CMb). Functional enrichment analysis was used to explore the correlation between the “microbiota–gut–brain” (MGB) axis and anxiety-like behavior. The behavioral test showed that female MMb exhibited anxiety-like behavior, which could be reversed by co-colonization. Moreover, metabolic characterization analysis of the MGB axis showed that the metabotype of gut-brain communication was significantly different between MMb and HMb, and 146 differential metabolites were jointly identified. Among these, 44 metabolites in feces; 12 metabolites in serum; 7 metabolites in hippocampus; 2 metabolites in prefrontal cortex; and 6 metabolites in striatum were reversed by co-colonization. Furthermore, the reversed gut microbiota mainly belonged to bacteroides and firmicutes, which were highly correlated with the reversed metabolites within the MGB axis. Among three emotional brain regions, hippocampus was more affected. Therefore, disturbances in gut microbiota may be involved in the progress of anxiety-like behavior in MG due to the MGB axis.
... While significant evidence has identified objective biomarkers associated with anxiety [9], these biomarkers are individualized, which makes identifying individuals who report anxiety through biomarkers challenging, as reported by the null findings of Boeke and colleagues [10]. However, utilizing a person's gait is one area where researchers have successfully identified feelings of anxiety through objective measures. ...
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Literature suggests that anxiety affects gait and balance among young adults. However, previous studies using machine learning (ML) have only used gait to identify individuals who report feeling anxious. Therefore, the purpose of this study was to identify individuals who report feeling anxious at that time using a combination of gait and quiet balance ML. Using a cross-sectional design, participants (n = 88) completed the Profile of Mood Survey-Short Form (POMS-SF) to measure current feelings of anxiety and were then asked to complete a modified Clinical Test for Sensory Interaction in Balance (mCTSIB) and a two-minute walk around a 6 m track while wearing nine APDM mobility sensors. Results from our study finds that Random Forest classifiers had the highest median accuracy rate (75%) and the five top features for identifying anxious individuals were all gait parameters (turn angles, variance in neck, lumbar rotation, lumbar movement in the sagittal plane, and arm movement). Post-hoc analyses suggest that individuals who reported feeling anxious also walked using gait patterns most similar to older individuals who are fearful of falling. Additionally, we find that individuals who are anxious also had less postural stability when they had visual input; however, these individuals had less movement during postural sway when visual input was removed.
... In fact, depression along with anxiety are stress-related disorders with similar symptoms 17 . Anxiety disorders are a group of disorders characterized by feelings of anxiety and fear accompanied by behavioral disturbances 18 . Specific (isolated) phobias, panic disorder, social anxiety disorder and generalized anxiety are among the most common anxiety disorders. ...
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In today's modern society, it seems to be more and more challenging to cope with life stresses. The effect of psychological stress on emotional and physical health can be devastating, and increased stress is associated with increased rates of heart attack, hypertension, obesity, addiction, anxiety and depression. This review focuses on the possibility of an influence of psychological stress on the metabolism of selected antidepressants (TCAs, SSRIs, SNRIs, SARIs, NDRIs a MMAs) and anxiolytics (benzodiazepines and azapirone), as patients treated with antidepressants and/or anxiolytics can still suffer from psychological stress. Emphasis is placed on the drug metabolism mediated by the enzymes of Phase I, typically cytochromes P450 (CYPs), which are the major enzymes involved in drug metabolism, as the majority of psychoactive substances are metabolized by numerous CYPs (such as CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2A6, CYP2D6, CYP3A4). As the data on the effect of stress on human enzymes are extremely rare, modulation of the efficacy and even regulation of the biotransformation pathways of drugs by psychological stress can be expected to play a significant role, as there is increasing evidence that stress can alter drug metabolism, hence there is a risk of less effective drug metabolism and increased side effects.
... [25] With respect to multifactorial anxiety disorders, it is believed that both psychological and biological factors are involved in their aetiology, specifically genetic and chemical factors among the latter. [26] In short, Selye's concepts of stress and EMS are still valid today, although there are a number of nuances. These concepts, which are generally different for sociology and psychology compared to biomedicine, have been expanded and evolved significantly. ...
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Background and objectives: The public costs of self-reported mental stress and distress are enormous. And both the advance of neurobiology and the modern more biological approach of psychiatry as a whole are considerable. This work intends to provide an essential, updated and objective panoramic view on the neurobiology of all kinds of stress in relation to people’s mental health and pathologies. Method: Bibliographic indexes such as Pubmed, Psycinfo Journal and Índices CSIC, were consulted, among others. The matter being tackled is extremely profuse, varied and complex, therefore the found literature has been as numerous as heterogeneous. It is also so dispersed that we have conducted a narrative non-systematic review that is intended to be impartial and balanced. Results: This article will concisely discuss the available, prominent and reliable scientific information regarding the main cerebral structures involved in the experience of stress, such as the hippocampus, prefrontal cortex, amygdala and hypothalamus. It will also comment on stress physiology, neuroendocrinology and associated psychopathology, as well as specifically certain genetic variations and linked molecular and immune activities. Conclusion: We have synthesised the relevant and current scientific knowledge of the correlations among stress, mental health and neurobiology as well as of their reciprocal interactions. There is increasing knowledge of these correlations and interactions, but it remains limited. Accordingly, further research is required.
... Regarding the novel approaches for the identification of new potential biomarkers, omics profiling seems to be a promising methodology for the identification of early biochemical changes in disease and thus provides an opportunity to discriminate a footprint of candidate biomarkers that can favor the initiation of earlier interventions; for example, through personalized nutrition and life-style modifications to avoid future drug treatments [5,6]. In this sense, the most relevant biological material for the study of biomarkers in psychiatric disorders derives from the brain [7]. ...
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Stress disorders have dramatically increased in recent decades becoming the most prevalent psychiatric disorder in the United States and Europe. However, the diagnosis of stress disorders is currently based on symptom checklist and psychological questionnaires, thus making the identification of candidate biomarkers necessary to gain better insights into this pathology and its related metabolic alterations. Regarding the identification of potential biomarkers, omic profiling and metabolic footprint arise as promising approaches to recognize early biochemical changes in such disease and provide opportunities for the development of integrative candidate biomarkers. Here, we studied plasma and urine metabolites together with metagenomics in a 3 days Chronic Unpredictable Mild Stress (3d CUMS) animal approach that aims to focus on the early stress period of a well-established depression model. The multi-omics integration showed a profile composed by a signature of eight plasma metabolites, six urine metabolites and five microbes. Specifically, threonic acid, malic acid, alpha-ketoglutarate, succinic acid and cholesterol were proposed as key metabolites that could serve as key potential biomarkers in plasma metabolome of early stages of stress. Such findings targeted the threonic acid metabolism and the tricarboxylic acid (TCA) cycle as important pathways in early stress. Additionally, an increase in opportunistic microbes as virus of the Herpesvirales was observed in the microbiota as an effect of the primary stress stages. Our results provide an experimental biochemical characterization of the early stage of CUMS accompanied by a subsequent omic profiling and a metabolic footprinting that provide potential candidate biomarkers.
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Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials. An open-label clinical trial of an oral absorbent that sequesters phenolic molecules in the gut shows safety and tolerability in adolescents with autism, reduces levels of gut-derived metabolites in circulation and reduces anxiety and irritability.
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Objectives To identify the prevalence, lifestyle factors, chronic disease status, and assessing the metabolic profile, comparing key differences in a cohort of subjects aged at least 50 years old among depression combined anxiety, depression and anxiety in a multi-ethnic population in west China. Methods A large multi-ethnic sample of 6838 participants aged 50 years old (mean age 62.4 ± 8.3 years) from West China Health and Aging Trend (WCHAT) study was analyzed. We categorized all participants into four groups: (a) comorbid anxiety and depression symptomology (CAD), (b) anxiety only, (c) depression only, or (d) neither depression nor anxiety. Different variables like anthropometry measures, life styles, chronic disease and blood test were collected. Depressive symptoms were assessed using the 15‐item Geriatric Depression Scale (GDS-15). GDS‐15 scores ≥5 indicate depression. Anxiety status was assessed using Generalized Anxiety Disorder (GAD-7) instrument and the scores ≥5 was considered as having anxiety. Different variables like anthropometry measures, life styles, cognitive function and chronic disease comorbidities were collected and serum parameters were tested. Multivariable logistic regression adjusted for age, sex, and ethnicity was done to compare between those with the mental outcomes and without. Results: The proportions of CAD, anxiety and depression were 9.0%, 12.8% and 10.6% respectively with ethnic diversity. The 'comorbid' group shown greater frequency of being female, having a lower educational level, higher prevalence of being single/divorced/widowed, drinking alcohol and smoking, more chronic disease profile and cognitive decline compared with individuals with only one disorder. And the metabolic profile showed differences in albumin, total protein, creatinine, uric acid, thyroid hormones in comparing CAD symptomology and the 'neither symptomology'. Conclusions Yi, Qiang and Uyghur ethnic groups have a higher prevalence of mental disease compared with Han in west China. And these mental disease had a distinct risk factor profile in age, sex, educational level, chronic disease and cognitive function. Vitamin D levels were lower among those with mental disease compared to those without.
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Biomarkers are a recent research target within biological factors of psychiatric disorders. There is growing evidence for deriving biomarkers within psychiatric disorders in serum or urine samples in humans, however, few studies have investigated this differentiation in brain or cerebral fluid samples in psychiatric disorders. As brain samples from humans are only available at autopsy, animal models are commonly applied to determine the pathogenesis of psychiatric diseases and to test treatment strategies. The aim of this review is to summarize studies on biomarkers in animal models for psychiatric disorders. For depression, anxiety and addiction disorders studies, biomarkers in animal brains are available. Furthermore, several studies have investigated psychiatric medication, e.g., antipsychotics, antidepressants, or mood stabilizers, in animals. The most notable changes in biomarkers in depressed animal models were related to the glutamate-γ-aminobutyric acid-glutamine-cycle. In anxiety models, alterations in amino acid and energy metabolism (i.e., mitochondrial regulation) were observed. Addicted animals showed several biomarkers according to the induced drugs. In summary, animal models provide some direct insights into the cellular metabolites that are produced during psychiatric processes. In addition, the influence on biomarkers due to short- or long-term medication is a noticeable finding. Further studies should combine representative animal models and human studies on cerebral fluid to improve insight into mental disorders and advance the development of novel treatment strategies.
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Major depressive disorder (MDD) is a common and disabling syndrome with multiple etiologies that is defined by clinically elicited signs and symptoms. In hopes of developing a list of candidate biological measures that reflect and relate closely to the severity of depressive symptoms, so-called “state-dependent” biomarkers of depression, this pilot study explored the biochemical underpinnings of treatment response to cognitive behavior therapy (CBT) in medication-free MDD outpatients. Plasma samples were collected at baseline and week 12 from a subset of MDD patients (N = 26) who completed a course of CBT treatment as part of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. Targeted metabolomic profiling using the AbsoluteIDQ® p180 Kit and LC-MS identified eight “co-expressed” metabolomic modules. Of these eight, three were significantly associated with change in depressive symptoms over the course of the 12-weeks. Metabolites found to be most strongly correlated with change in depressive symptoms were branched chain amino acids, acylcarnitines, methionine sulfoxide, and α-aminoadipic acid (negative correlations with symptom change) as well as several lipids, particularly the phosphatidlylcholines (positive correlation). These results implicate disturbed bioenergetics as an important state marker in the pathobiology of MDD. Exploratory analyses contrasting remitters to CBT versus those who failed the treatment further suggest these metabolites may serve as mediators of recovery during CBT treatment. Larger studies examining metabolomic change patterns in patients treated with pharmacotherapy or psychotherapy will be necessary to elucidate the biological underpinnings of MDD and the -specific biologies of treatment response.
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Biological membranes are key elements for the maintenance of cell architecture and physiology. Beyond a pure barrier separating the inner space of the cell from the outer, the plasma membrane is a scaffold and player in cell-to-cell communication and the initiation of intracellular signals among other functions. Critical to this function is the plasma membrane compartmentalization in lipid microdomains that control the localization and productive interactions of proteins involved in cell signal propagation. In addition, cells are divided into compartments limited by other membranes whose integrity and homeostasis are finely controlled, and which determine the identity and function of the different organelles. Here, we review current knowledge on membrane lipid composition in the plasma membrane and endomembrane compartments, emphasizing its role in sustaining organelle structure and function. The correct composition and structure of cell membranes define key pathophysiological aspects of cells. Therefore, we explore the therapeutic potential of manipulating membrane lipid composition with approaches like membrane lipid therapy, aiming to normalize cell functions through the modification of membrane lipid bilayers.
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Purpose: Depression is a complex psychiatric disorder. Various depressive rodent models are usually constructed based on different pathogenesis hypotheses. Materials and methods: Herein, using our previously established naturally occurring depressive (NOD) model in a non-human primate (cynomolgus monkey, Macaca fascularis), we performed metabolomics analysis of cerebrospinal fluid (CSF) from NOD female macaques (N=10) and age-and gender-matched healthy controls (HCs) (N=12). Multivariate statistical analysis was used to identify the differentially expressed metabolites between the two groups. Ingenuity Pathways Analysis and MetaboAnalyst were applied for predicted pathways and biological functions analysis. Results: Totally, 37 metabolites responsible for discriminating the two groups were identified. The NOD macaques were mainly characterized by perturbations of fatty acid biosynthesis, ABC transport system, and amino acid metabolism (eg, aspartate, glycine, serine, and threonine metabolism). Interestingly, we found that eight altered CSF metabolites belonging to short-chain fatty acids and amino acids were also observed in the serum of NOD macaques (N=13 per group). Conclusion: Our findings suggest that peripheral and central short-chain fatty acids and amino acids are implicated in the onset of depression.
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Accumulating evidence suggests that chronic stress could perturb the composition of the gut microbiota and induce host anxiety- and depression-like behaviors. In particular, microorganism-derived products that can directly or indirectly signal to the nervous system. This study sought to investigate whether high levels of Lactobacillus and lactate in the gut of rats under chronic unpredictable stress (CUS) were the factors leading to anxiety behavior. We collected faeces and blood samples in a sterile laboratory bench to study the microbiome and plasma metabolome from adult male rats age and environment matched healthy individuals. We sequenced the V3 and V4 regions of the 16S rRNA gene from faeces samples. UPLC-MS metabolomics were used to examine plasma samples. Search for potential biomarkers by combining the different data types. Finally, we found a regulated signaling pathway through the relative expression of protein and mRNA. Both lactate feeding and fecal microbiota transplantation caused behavioral abnormalities such as psychomotor malaise, impaired learning and memory in the recipient animals. These rats also showed inhibition of the adenylate cyclase (AC)-protein kinase A (PKA) pathway of lipolysis after activation of G protein-coupled receptor 81 (GPR81) by lactate in the liver, as well as increased tumor necrosis factor α (TNF-α), compared with healthy controls. Furthermore, we showed that sphingosine-1-phosphate receptor 2 (S1PR2) protein expression in hippocampus was reduced in chronic unpredictable stress compared to control group and its expression negatively correlates with symptom severity. Our study suggest that the gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway.
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Ethnopharmacological relevance: Essential oils (EOs) are extracts of organic, volatile metabolites of plants that are typically oily liquids at ambient temperatures. Inhalation of EOs can regulate brain health and functions associated with mood and neurodegeneration, reflecting their bioavailability to brain. The aim was to identify physicochemical properties that influenced Essential Oil (EO) volatility and pathways of brain uptake by inhalation. Materials and methods: Dose-dependency of effects, determined as: total EO intake (μg/g bodyweight-BW), and rate of EO intake (μg/hr/g-BW), was determined by meta-analysis of data from animal studies (10 studies, 12 EOs), measuring effects on anxiety, depression and selected biomarkers of oxidative stress and inflammation (OSI). Results: Results demonstrated benefits on animal behavior at EO intakes of 1-100 μg/g BW and 1-10 μg/h/g BW (Elevated Plus Maze and Forced Swimming tests) and <100 μg/g BW and 10-100 g/h/g BW (Marble Burying). EOs regulated OSI biomarkers at intakes of 10-100 μg/g BW and 1-10 μg/h/g BW, and a dose-dependent elevation of dopamine at >1000 μg/g BW and 100-1000 μg/h/g BW. Conclusion: The results support that EO 'aromatherapy' can promote dose-dependent regulation of anxiety, depression and OSI and that efficacy requires optimization of dose.
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Pituitary adenylate cyclase activating polypeptide (PACAP, gene Adcyap1) is a neuropeptide and hormone thought to play a critical role in stress response (Stroth et al., Ann NY Acad Sci 1220:49-59, 2011; Hashimoto et al., Curr Pharm Des 17:985-989, 2011). Research in humans implicates PACAP as a useful biomarker for the severity of psychiatric symptoms in response to psychological stressors, and work in rodent models suggests that PACAP manipulation exerts downstream effects on peripheral hormones and behaviors linked to the stress response, providing a potential therapeutic target. Prior work has also suggested a potential sex difference in PACAP effects due to differential estrogen regulation of this pathway. Therefore, we examined serum PACAP and associated PAC1R genotype in a cohort of males and females with a primary diagnosis of generalized anxiety disorder (GAD) and nonpsychiatric controls. We found that, while circulating hormone levels were not associated with a GAD diagnosis overall (p = 0.19, g = 0.25), PACAP may be associated with GAD in females (p = 0.04, g = 0.33). Additionally, among patients with GAD, the risk genotype identified in the PTSD literature (rs2267735, CC genotype) was associated with higher somatic anxiety symptom severity in females but lower somatic anxiety symptom severity in males (-3.27, 95%CI [-5.76, -0.77], adjusted p = 0.03). Taken together, the associations between the risk genotype, circulating PACAP, and somatic anxiety severity were stronger among females than males. These results indicate a potential underlying biological etiology for sex differences in stress-related anxiety disorders that warrants further study.
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Anxiety disorders are currently the most prevalent psychiatric diseases in Europe and the United States, the 6th highest cause of years of life lived with disability, and so a grave and ever-increasing burden on health care resources. Categorization of specific anxiety disorders is constantly evolving, but even the new Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) manual uses symptom lists, not objective biomarkers. The DSM-5 and International Classification of Diseases (10th ed.) also aim for single diagnoses, but patients present with mixed symptoms that fit multiple diagnoses. In 1 step toward a solution to this problem, we previously reported on a human electroencephalogram anxiety process biomarker, goal-conflict-specific rhythmicity (GCSR) in a stop signal task (SST). GCSR appears homologous with rodent rhythmical slow activity, 4-12 Hz "theta" rhythmicity that, in the rat hippocampus, predicts human clinical anxiolytic action with, so far, no false positives (even with sedatives) or negatives (even with drugs ineffective in panic or depression). However, within-task stability of GCSR is too variable for test-retest. Here we tested the stability of GCSR when a simple relaxation task preceded the SST. We found that prior exposure of participants (56 female, 39 male; mean age = 21.87 years; reporting no medical or psychological treatment or any type of emotional disorder in the last 12 months) to the relaxation task appeared to almost completely eliminate GCSR. We therefore conclude that, when elicited in the stop signal task, GCSR represents a labile emotional state and should be assessed alone or as the 1st test of a series. (PsycINFO Database Record (c) 2019 APA, all rights reserved).