Definition

Anxiety is a state of worry or apprehension, feels that something bad will be coming (Nevid et al.,
2005). A certain amount of anxiety is normal and necessary, it can lead people to act on their concerns
and protect them from harm. In some situations, anxiety can even be essential for survival (Rector et
al., 2014). Anxiety is an appropriate response for threats but can become disorders if the level does not
match the proportions of the threat, or come without any cause (Nevid et al., 2005).
Anxiety disorders are characterized by excessive and unrealistic anxiety about a thing (Vildayanti et
al., 2018). Anxiety disorders, including panic disorders with or without agoraphobia, generalized
anxiety disorder, social anxiety disorder, separation anxiety disorder, and specific phobias, are the most
common mental disorders and are associated with large health care costs and a high burden of disease
(Bandelow and Michaelis, 2015).
Global Burden of Disease estimates that anxiety disorders contribute to 26,8 million causes of
disability per year in 2010 (Whiteford et al., 2013). Based on the other study, the lifetime prevalence
rate for adolescents aged 13 to 17 years old is 7,7% and 6,6% in adults aged 18 to 64,3 years old
(Bandelow and Michaelis, 2015). Anxiety disorders are the most common mental health problem in
women and are second only to substance use disorders in men. Anxiety disorders can make it hard for
people to work or study, to manage daily tasks and to relate well with others, and often result in financial
strain and profound personal suffering (Rector et al., 2014).

Etiology
The etiology of anxiety disorders is still unclear, but there are some factors involved in anxiety
disorders. Like the most mental health problems, anxiety disorders appear to be caused by a combination
of psychological, biological, genetic, medical and other factors (Rector et al., 2014).
Anxiety disorders may be caused by problems in the functioning of brain circuits that regulate fear
and other emotions. Studies have shown that severe or long-lasting stress can change the way nerve
cells within these circuits transmit information from one region of the brain to another. Other studies
have shown that people with certain anxiety disorders have changes in certain brain structures that
control memories linked with strong emotions (Soodan and Arya, 2015)

Pathophysiology
Anxiety involves three major neurotransmitters on its regulation such as serotonin (5-HT),
norepinephrine and gamma-aminobutyric acid. Serotonin plays a role in the regulation of mood,
aggression, impulses, sleep, appetite, body temperature and pain. Norepinephrine is involved in the
fight or flight response and the regulation of sleep, mood and, blood pressure. GABA plays a role in
helping to induce relaxation and sleep, and in preventing overexcitation (Bremner et al., 1996).
Serotonin
Serotonergic pathways arising from the raphé nuclei in the brainstem innervate a wide range of
structures thought to be involved in anxiety, including the frontal cortex, amygdala, hypothalamus, and
hippocampus (Soodan and Arya, 2015). During exposure to fear-conditioned stimuli, the 5-HT turnover
in the mPFC (medial prefrontal cortex) appears particularly sensitive to the severity of stress, increasing
as the aversiveness of the US and the magnitude of the conditioned fear behavioral response increases
(Davis et al., 2002). Studies show that patients with anxiety disorders may have genetic polymorphisms
in the 5-HT transporter or the 5-HT2A receptor and the 5-HT1A receptor. In patients with panic disorder
the number of 5-HT1A receptors in the limbic system was shown to be reduced (Rex and Fink, 2011).
Activation of 5-HT1A receptors is also involved in the induction of adrenocortical trophic hormone and
corticosteroid secretion in response to stress (Bremner et al., 1996).
Norepinephrine
Majority of noradrenergic neurons are found in the locus coeruleus. Altered noradrenergic signaling is
linked to anxiety disorders. Sustained stimulation of locus coeruleus results in the manifestation of
anxiety symptoms (Soodan and Arya, 2015). In people with anxiety disorders, especially those with
panic disorder, the system controlling the release of norepinephrine appears to be poorly regulated
(Rector et al., 2014).
Gamma Aminobutyric Acid (GABA)
GABA is the main inhibitory neurotransmitter in the CNS. There are 2 subtypes of GABA receptors
GABAA and GABAB. Benzodiazepines bind to the benzodiazepine receptor complex located on the
postsynaptic neuron. Such binding augments the effect of GABA leading to the opening of chloride ion
channels, causing an influx of the chloride ions into the cell resulting in neuronal membrane
stabilization (Ressler and Nemeroff, 2000).
GABA may also influence anxiety levels by mediating the release of other neurotransmitters such as
cholecystokinin and suppressing neuronal activity in the serotonergic and noradrenergic systems.
Neuroimaging studies have reported reductions in GABA levels and GABAA-benzodiazepine receptor
binding in patients with anxiety disorders (Soodan and Arya, 2015)
Corticotropin-releasing Factor
Some abnormalities in the- hypothalamic-pituitary-adrenal axis and central corticotropin-releasing
factor (CRF) neuronal functioning have been identified in several anxiety disorders. Patients with
anxiety disorders have a pattern of central overproduction of CRF, with low plasma cortisol and up-
regulation of lymphocyte corticosteroid receptors (Soodan and Arya, 2015).
Corticotropin-releasing Hormone
CRH is an important mediator of the stress response, as reflected by the stress-induced release of CRH
from the hypothalamus into the hypthalamic-pituitary portal circulation resulting in activation of HPA
axis and the increased release of cortisol and DHEA (Mathew et al., 2008). The secretion of CRH
increases LC neuronal firing activity and results in enhanced NE release in a variety of cortical and
subcortical regions (Davis et al., 2002)
HPA Axis
The HPA axis is an interactive system of hormones released in response to stress. The release of CRF
by the hypothalamus prompts the pituitary to disperse adrenocorticotropin-releasing hormone (ACTH)
into the bloodstream. ACTH is detected by the adrenal cortex, facilitating the release of glucocorticoids
such as cortisol. High levels of anxiety result in negative physiological manifestations, such as elevated
blood cortisol levels and increased blood pressure and heart rate, leading to slower wound healing,
diminished immune response, and increased risk of infection (Soodan and Arya, 2015).

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