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Anxiety: Insights into Signs, Symptoms, Etiology, Pathophysiology, and

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East African Scholars Journal of Medical Sciences
Abbreviated Key Title: East African Scholars J Med Sci
ISSN 2617-4421 (Print) | ISSN 2617-7188 (Online) |
Published By East African Scholars Publisher, Kenya
Volume-2 | Issue-10| Oct -2019 |

Review Article

Anxiety: Insights into Signs, Symptoms, Etiology, Pathophysiology, and

Treatment
1 2 2*
Almokhtar A. Adwas , J.M. Jbireal and Azab Elsayed Azab
1
Department of Pharmacology, Faculty of Medicine, Sabratha University, Libya
2
Physiology Department, Faculty of Medicine, Sabratha University, Libya

*Corresponding Author
Azab Elsayed Azab

Abstract: Background: The anxiety disorders are the most common mental disorders. It is manifest by disturbances of
mood, as well as of thinking, behaviour, and physiological activity. It includes panic disorder, agoraphobia, generalized
anxiety disorder, specific phobia, social phobia, obsessive-compulsive disorder, acute stress disorder, and post-traumatic
stress disorder. Objectives: The aim of the current review is a high light on the anxiety signs, symptoms, etiology,
pathophysiology, treatment. The common symptoms of anxiety are accompanying disturbances of sleep, concentration,
social and/or occupational functioning. The anxiety is associated with restlessness, feeling keyed up or on edge, being
easily fatigued, difficulty in concentrating or mind going blank, irritability, muscle tension, and irritability. The etiology
of anxiety may include stress, physical condition, genetic, and environmental factors. Anxiety symptoms may be due to
disrupted modulation within the central nervous system. Many believe that low serotonin system activity and elevated
noradrenergic system activity are responsible for its development. Therefore, selective serotonin reuptake inhibitors and
serotonin-norepinephrine reuptake inhibitors that is the first-line agent for its treatment. Corticosteroids may increase or
decrease the activity of certain neural pathways, affecting not only behavior under stress, but also the brain's processing
of fear-inducing stimuli. Several studies have found elevated WBC count among anxious individuals there was a
negative association between red blood cell and mean corpuscular hemoglobin and symptoms of anxiety. A positive
association between anxiety symptoms and levels of hematological inflammatory markers including WBC and RDW.
Drugs to reduce anxiety have been used by human beings for thousands of years. Conclusion: It can be concluded that
anxiety is manifest by disturbances of mood, thinking, behaviour, and physiological activity and accompanying
disturbances of sleep, concentration, social and/or occupational functioning. Also, it is associated with restlessness,
feeling keyed up or on edge, being easily fatigued, difficulty in concentrating or mind going blank, irritability, muscle
tension, and irritability. The etiology of anxiety may include stress, diabetes, depression, genetic, and environmental
factors. Anxiety disorders should be treated with psychological therapy, pharmacotherapy, or a combination of both.
Keywords: Anxiety, Signs, Symptoms, Etiology, Pathophysiology, Treatment.

1. INTRODUCTION disorder), generalized anxiety disorder, specific phobia,

The anxiety disorders are the most common, or social phobia, obsessive-compulsive disorder, acute
frequently occurring, mental disorders (Munir et al., stress disorder, and post-traumatic stress disorder. In
2019). They encompass a group of conditions that share addition, there are adjustment disorders with anxiety
extreme or pathological anxiety as the principal features, and disorders due to general medical
disturbance of mood or emotional tone. Anxiety, which conditions and substance-induced anxiety disorders
may be understood as the pathological counterpart of (Greenberg et al., 1999).
normal fear, is manifest by disturbances of mood, as
well as of thinking, behaviour, and physiological Diagnostic criteria are include excessive
activity. The anxiety disorders include panic disorder anxiety and worry for at least six months, difficulty
(with and without a history of agoraphobia), controlling the worrying. The anxiety is associated with
agoraphobia (with and without a history of panic three or more of the following symptoms for at least 6
Quick Response Code Journal homepage: Copyright @ 2019: This is an open-access
http://www.easpublisher.com/easjms/ article distributed under the terms of the
Creative Commons Attribution license which
Article History permits unrestricted use, distribution, and
Received: 24.09.2019 reproduction in any medium for non
Accepted: 05.10.2019 commercial use (NonCommercial, or CC-BY-
Published: 19.10.2019 NC) provided the original author and source
are credited.

Published By East African Scholars Publisher, Kenya 580

Almokhtar A. Adwas et al., East African Scholars J Med Sci; Vol-2, Iss-10 (Oct, 2019): 580-591
months: restlessness, feeling keyed up or on edge, being event. The latter occurs in the short term, while the
easily fatigued, difficulty in concentrating or mind former describe a more chronic version of the disorder
going blank, irritability, muscle tension, sleep (Kessler et al., 1995).
disturbance, and irritability (Munir et al., 2019).
Obsessive-compulsive disorder (OCD) is
2. Signs and Symptoms characterized by repeated behaviors (compulsions),
A subjective experience of distress with which serve to reduce anxiety connected to unwanted,
accompanying disturbances of sleep, concentration, intrusive thoughts (obsessions). Commonly seen
social and/or occupational functioning are common behaviors are cleaning or washing in response to
symptoms in many of the anxiety disorders. Despite concerns about contamination, or repeatedly checking
their similarities, these disorders often differ in to see if a stove is turned off in response to concerns
presentation, course and treatment. Patients often over a fire starting. Some people repeatedly check work
present with complaints of poor physical health as their or seek excessive reassurance due to obsessive self-
primary concern. This may temporarily distract from doubt (Eddy and Walbroehl, 1998).
the underlying anxiety symptoms. This is particularly
common in panic disorder, which is characterized by a 2. Etiology and psychological basis of anxiety
short period of intense fear and a sense of impending, The etiology of anxiety may include stress,
doom, with accompanying physical symptoms, such as physical condition such as diabetes or other co-
chest pain, dizziness and shortness of breath morbidities such as depression, genetic, first-degree
(Markowitz et al., 1989). When complicated by relatives with generalized anxiety disorder (25%),
agoraphobia, the individual fears have a panic attack in environmental factors, such as child abuse, and
a place that prevents escape. This results in the patient substance abuse (Munir et al., 2019). The anxiety
avoiding such situations, with subsequent disturbances disorders are so heterogeneous that the relative roles of
in functioning (Magee et al., 1996). The ancient term these factors are likely to differ. Some anxiety
agoraphobia is translated from Greek as fear of an open disorders, like panic disorder, appear to have a stronger
marketplace. Agoraphobia today describes severe and genetic basis than others (National Institute of Mental
pervasive anxiety about being in situations from which Health [NIMH], 1998), although actual genes have not
escape might be difficult or avoidance of situations such been identified. Other anxiety disorders are more rooted
as being alone outside of the home, traveling in a car, in stressful life events.
bus, or airplane, or being in a crowded area (Magee et
al., 1996). It is not clear why females have higher rates
than males of most anxiety disorders, although some
Most people who present to mental health theories have suggested a role for the gonadal steroids.
specialists develop agoraphobia after the onset of panic Other research on women‘s responses to stress also
disorder. Agoraphobia is best understood as an adverse suggests that women experience a wider range of life
behavioral outcome of repeated panic attacks and the events as stressful as compared with men who react to a
subsequent worry, preoccupation, and avoidance more limited range of stressful events, specifically those
(Barlow, 1988). affecting themselves or close family members
(Maciejewski et al., 2001).
Generalized anxiety disorder (GAD) rarely
occurs without a co-morbid psychiatric disorder, with What the myriad of anxiety disorders have in
the patient experiencing consistent worry over multiple common is a state of increased arousal or fear. Anxiety
areas of his or her life for at least 6 months (Schweizer, disorders often are conceptualized as an abnormal or
1995 ). exaggerated version of arousal. Much is known about
arousal because of decades of study in animals and
Social phobia describes fear and anxiety in humans of the so-called ―fight-or-flight response,‖
social situations leading to avoidance of social which also is referred to as the acute stress response.
interaction (Ballenger et al., 1998). Specific phobia is The acute stress response is critical to understanding the
characterized by similar symptoms and behavior, but is normal response to stressors and has galvanized
triggered by a specific object or situation, such as a fear research, but its limitations for understanding anxiety
of certain animals (especially snakes, rodents, and have come to the forefront in recent years (Barbee,
dogs); birds, insects (especially spiders and bees or 1998).
hornets); heights; elevators; flying; automobile driving;
water; storms; and blood or injections (Marks, 1969). In common parlance, the term ―stress‖ refers
either to the external stressor, which can be physical or
Post-traumatic stress disorder and acute stress psychosocial in nature, as well as to the internal
disorder occur after a patient experiences a traumatic response to the stressor. Yet researchers distinguish the
event with subsequent physiological arousal in the face two, calling the stressor the stimulus and the body‘s
of stimuli that trigger memories of the event; avoidance reaction the stress response. This is an important
of such stimuli; and a sense of re-experiencing the distinction because in many anxiety states there is no

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Almokhtar A. Adwas et al., East African Scholars J Med Sci; Vol-2, Iss-10 (Oct, 2019): 580-591
immediate external stressor. The following paragraphs and depression (Nolen-hoeksema et al., 1999 ).
describe the biology of the acute stress response, as well
as its limitations, in understanding human anxiety. 4. Pathophysiology
Emerging views about the neurobiology of anxiety, The exact mechanism is not entirely known.
attempt to integrate and understand psychosocial views Anxiety can be a normal phenomenon in children.
of anxiety and behavior in relation to the structure and Stranger anxiety begins at seven to nine months of life
function of the central and peripheral nervous system. (Munir et al., 2019). Anxiety symptoms and the
resulting disorders are thought to be due to disrupted
There are several major psychological theories modulation within the central nervous system. Physical
of anxiety: psychoanalytic and psychodynamic theory, and emotional manifestations of this dysregulation are
behavioral theories, and cognitive theories (Thorn et al., the result of heightened sympathetic arousal of varying
1999). Psychodynamic theories have focused on degrees (Kaplan and Sadock, 1995).
symptoms as an expression of underlying conflicts
(Rush et al., 1998; Thorn et al., 1999). Although there Several neurotransmitter systems have been
are no empirical studies to support these implicated to have a role in one or several of the
psychodynamic theories, they are amenable to scientific modulatory steps involved. The most commonly
study (Kandel, 1999) and some therapists find them considered are the serotonergic and noradrenergic
useful. For example, ritualistic compulsive behavior can neurotransmitter systems. In very general terms, it is
be viewed as a result of a specific defense mechanism thought that an under activation of the serotonergic
that serves to channel psychic energy away from system and an over activation of the noradrenergic
conflicted or forbidden impulses. Phobic behaviors system are involved (Ressler and Nemeroff, 2000,
similarly have been viewed as a result of the defense Munir et al., 2019). These systems regulate and are
mechanism of displacement. From the psychodynamic regulated by other pathways and neuronal circuits in
perspective, anxiety usually reflects more basic, various regions of the brain, resulting in dysregulation
unresolved conflicts in intimate relationships or of physiological arousal and the emotional experience
expression of anger. of this arousal (Ressler and Nemeroff, 2000). Many
believe that low serotonin system activity and elevated
More recent behavioral theories have noradrenergic system activity are responsible for its
emphasized the importance of two types of learning: development. It is, therefore, selective serotonin
classical conditioning and vicarious or observational reuptake inhibitors (SSRI) and serotonin-
learning. These theories have some empirical evidence norepinephrine reuptake inhibitors (SNRI) that are the
to support them. In classical conditioning, a neutral first-line agent for its treatment (Munir et al.,
stimulus acquires the ability to elicit a fear response 2019). Disruption of the gamma-aminobutyric acid
after repeated pairings with a frightening (GABA) system has also been implicated because of the
(unconditioned) stimulus. In vicarious learning, fearful response of many of the anxiety spectrum disorders to
behavior is acquired by observing others‘ reactions to treatment with benzodiazepines (Nutt, 2001). There has
fear-inducing stimuli (Thorn et al., 1999). With general been some interest in the role of corticosteroid
anxiety disorder, unpredictable positive and negative regulation and its relationship to symptoms of fear and
reinforcement is seen as leading to anxiety, especially anxiety. Corticosteroids may increase or decrease the
because the person is unsure about whether avoidance activity of certain neural pathways, affecting not only
behaviors are effective. behavior under stress, but also the brain's processing of
fear-inducing stimuli (Korte, 2001). Cholecystokinin
Cognitive factors, especially the way people has long been viewed as a neurotransmitter involved in
interpret or think about stressful events, play a critical regulating emotional states (Korte, 2001).
role in the etiology of anxiety (Barlow et al., 1996;
Thorn et al., 1999). A decisive factor is the individual‘s There is such careful orchestration between
perception, which can intensify or dampen the response. these neurotransmitters that changes in one
One of the most salient negative cognitions in anxiety is neurotransmitter system invariably elicit changes in
the sense of uncontrollability. It is typified by a state of another, including extensive feedback mechanisms.
helplessness due to a perceived inability to predict, Serotonin and GABA are inhibitory neurotransmitters
control, or obtain desired results (Barlow et al., 1996). that quieten the stress response (Coplan and Lydiard,
Negative cognitions are frequently found in individuals 1998; Rush et al., 1998). All of these neurotransmitters
with anxiety (Ingram et al., 1998). Many modern have become important targets for therapeutic agents.
psychological models of anxiety incorporate the role of
individual vulnerability, which includes both genetic Many studies indicate that a genetic
(Smoller & Tsuang, 1998) and acquired (Coplan et al., predisposition to developing an anxiety disorder is
1997) predispositions. There is evidence that women likely. However, environmental stressors clearly play a
may ruminate more about distressing life events role, in varying degrees. All of the disorders are
compared with men, suggesting that a cognitive risk affected in some way by external cues and how they are
factor may predispose them to higher rates of anxiety processed and reacted to (Kaplan and Sadock, 1995).

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Several studies have found elevated WBC amygdala as critical to fear responses. Sensory
count among depressed and anxious individuals information enters the lateral amygdala, from which
(Pitsavos et al., 2006; Kobrosly and van Wijngaarden, processed information is passed to the central nucleus,
2010; Duivis et al., 2013; Aydin et al., 2016; Shafiee et the major output nucleus of the amygdala. The central
al., 2017). Shafiee et al., 2017 reported that the mean nucleus projects, in turn, to multiple brain systems
WBC count increased with increasing severity of involved in the physiologic and behavioral responses to
symptoms of depression and anxiety among men. Men fear. Projections to different regions of the
(but not women) with severe anxiety symptoms had hypothalamus activate the sympathetic nervous system
significantly higher values of RDW (p <0.001). and induce the release of stress hormones, such as
Moreover, there was a negative association between red CRH. The production of CRH in the paraventricular
blood cell (RBC) and mean corpuscular hemoglobin nucleus of the hypothalamus activates a cascade leading
(MCH) and symptoms of depression/anxiety. Pitsavos to release of glucocorticoids from the adrenal cortex.
et al. (2006) observed that anxiety score is positively Projections from the central nucleus innervate different
correlated with WBC count in women, but not in men. parts of the periaqueductal gray matter, which initiates
Since WBC count is an independent predictor of descending analgesic responses (involving the body's
atherosclerosis and cardiovascular diseases (Loimaala endogenous opioids) that can suppress pain in an
et al., 2006; Madjid et al., 2004, Shafiee et al., 2017). emergency, and which also activates species-typical
RDW is a strong predictor of mortality and has defensive responses (e.g., many animals freeze when
association with a variety of cardiovascular and fearful) (Davis, 1997 ).
thrombotic disorders (Montagnana et al., 2012; Patel et
al., 2009, Shafiee et al., 2017). Therefore, higher levels Anxiety differs from fear in that the fear-
of RDW among depressed and anxious individuals may producing stimulus is either not present or not
predict greater risk of developing cardiovascular immediately threatening, but in anticipation of danger,
diseases in these patients (Shafiee et al., 2017). the same arousal, vigilance, physiologic preparedness,
and negative affects and cognitions occur (LeDoux,
Shafiee et al., 2017 concluded that a positive 1996). Different types of internal or external factors or
association between depression/anxiety symptoms and triggers act to produce the anxiety symptoms of panic
levels of hematological inflammatory markers including disorder, agoraphobia, post-traumatic stress disorder,
WBC and RDW, which persisted despite adjustment by specific phobias, and generalized anxiety disorder, and
potential confounders. the prominent anxiety that commonly occurs in major
depression. It is currently a matter of research to
5. Biochemical Basis of Anxiety determine whether dysregulation of these fear pathways
An exciting new line of research proposes that leads to the symptoms of anxiety disorders. It has now
anxiety engages a wide range of neurocircuits. This line been established, using noninvasive neuroimaging, that
of research catapults to prominence two key regulatory the human amygdala is also involved in fear responses
centers found in the cerebral hemispheres of the brain— (Breiter et al., 1996). Fearful facial expressions have
the hippocampus and the amygdala. These centers, in been shown to activate the amygdala in MRI studies of
turn, are thought to activate the hypothalamic-pituitary- normal human subjects (Breiter et al., 1996). Functional
adrenocortical (HPA) axis (Goddard & Charney, 1997; imaging studies in anxiety disorders, such as PET
Coplan & Lydiard, 1998; Sullivan et al., 1998). studies of brain activation in phobias (Rauch et al.,
Researchers have long established the contribution of 1995), are also beginning to investigate the precise
the HPA axis to anxiety but have been perplexed by neural circuits involved in the anxiety disorders.
how it is regulated. They are buoyed by new findings
about the roles of the hippocampus and the amygdala. What is especially exciting is that
neuroimaging has furnished direct evidence in humans
The hippocampus and the amygdala govern of the damaging effects of glucocorticoids. In people
memory storage and emotions, respectively, among with post-traumatic stress disorder, neuroimaging
their other functions. The hippocampus is considered studies have found a reduction in the size of the
important in verbal memory, especially of time and hippocampus. The reduced volume appears to reflect
place for events with strong emotional overtones the atrophy of dendrites—the receptive portion of nerve
(McEwen, 1998). The hippocampus and amygdala are cells—in a select region of the hippocampus. Similarly,
major nuclei of the limbic system, a pathway known to animals exposed to chronic psychosocial stress display
underlie emotions. There are anatomical projections atrophy in the same hippocampal region (McEwen &
between the hippocampus, amygdala, and Magarinos, 1997). Stress-induced increases in
hypothalamus (Jacobson & Sapolsky, 1991; Charney & glucocorticoids specially corticosterone are thought to
Deutch, 1996; Coplan & Lydiard, 1998). be responsible for the atrophy (McEwen, 1998). If the
hippocampus is impaired, the individual is thought to be
Studies of emotional processing in rodents less able to draw on memory to evaluate the nature of
(Rogan & LeDoux, 1996) and in humans with brain the stressor (McEwen, 1998).
lesions (Adolphs et al., 1998) have identified the

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Almokhtar A. Adwas et al., East African Scholars J Med Sci; Vol-2, Iss-10 (Oct, 2019): 580-591
6. Treatment of anxiety In 1986, the FDA approved the 5-HT1A partial
Drugs to reduce anxiety have been used by agonist, buspirone for generalized anxiety disorder.
human beings for thousands of years. One of the first This drug was the first to challenge the benzodiazepines
anxiolytics and one that continues to be used by humans for this patient group and was generally perceived as an
is ethanol. A number of other drugs including the improvement because of the lack of benzodiazepine
barbiturates and the carbamates (meprobamate) were side effects. The efficacy of buspirone, however, was
used in the first half of the 20th century and some not the same as that of the benzodiazepines in terms of
continue to be used today. its delayed onset of action, and it is generally accepted
that when buspirone offers clinical benefit to GAD
6.1. Serotonin Receptor Modulators and Reuptake patients, it takes 3 to 4 weeks to match the efficacy of
Inhibitors benzodiazepines such as diazepam and alprazolam
Serotonin has long been viewed as a (Coplan et al., 1995). The 5-HT1A partial agonist
neurotransmitter involved in regulating emotional properties of buspirone are believed to account for its
states. Of the 14 or so mammalian serotonin receptor clinical effects, but it should be noted that the drug is
subtypes that have been described in the literature, at also a D2 antagonist and is extensively metabolized.
least four have been implicated in anxiety in various One of the major metabolites, 1-pyrimidinylpiperazine
animal models (Lucki, 1996). As reported by Lucki, (l-PP), may contribute to the pharmacologic activity of
1996 the original hypothesis implicating serotonin in buspirone (Mahmood and Sahajwalla, 1999). In a
anxiety surfaced from observations that reduced levels double-blind, placebo-controlled study of buspirone in
of serotonin can produce anxiolytic effects. One of the GAD patients (Laakmann et al., 1998), the drug was
receptor subtypes implicated in anxiety is the serotonin reported to be as efficacious as lorazepam at the end of
1A receptor subtype (5HT1A), which is an auto a 4-week treatment period. After the drugs were
receptor located presynaprically on serotonin neurons. discontinued, however, the lorazepam-treated patients
When stimulated, this receptor inhibits the synthesis worsened whereas the buspirone-treated subjects
and secretion of serotonin. The 5-HT1A receptor maintained clinical improvement. Thus, there continues
agonist buspirone exhibits anxiolytic effects in animals to be evidence that buspirone is effective in GAD.
and was approved by the Food and Drug Administration
(FDA) in 1986 for human generalized anxiety disorder. The development of selective serotonin
Other serotonin receptors potentially involved in reuptake inhibitors (SSRIs) in the 1980s and 1990s
anxiety include the 5-HT2A, 5-HT2C and 5-HT3 widely expanded the treatment for depressive disorders,
receptors. Antagonists for the 5-HT2A receptor, like and these drugs (fluoxetine, sertraline, venlafaxin,
ritanserin, exhibit anxiolytic effects in some animal paroxetine) have recently made inroads in treating
models (Critchley and Handley, 1987; Gleeson et al., anxiety disorders such as panic, obsessivecompulsive
1989). Likewise, blockade of the 5-HT2C receptor disorder, social phobia, and GAD. Successful treatment
produces anxiolytic effects in animals and prevents the of GAD with a class of drugs working through the
anxiogenic effects of m-CPP (Kennett et al., 1989). serotoninergic system will come from the SSRIs (Rocca
Finally, the 5-HT3 receptor antagonist ondansetron was et al., 1997).
reported to be anxiolytic in some animal models
(Costall and Naylor, 1991). OCD is a chronic, disabling anxiety disorder.
In a review of the diagnosis and treatment of OCD,
Advances in molecular biology has led to the Goodman, 1999 states that the backbone of
development of serotonin receptor gene knockout pharmacologic treatment for OCD is a 10- to 12-week
methodology, which generates mice lacking the 5- trial with an SSRIs in adequate doses. It is clear from a
HT1A receptor, allowing for the evaluation of this review of the role of the 5-HT1A receptor (Coplan et
receptor subtype in a variety of measurable behaviors. al., 1995) in OCD that partial agonists such as
Ramboz et al., 1998 reported results consistent with the buspirone are generally ineffective in treating OCD.
5-HT1A agonist's data cited above. Mice lacking this The authors also note that in studying the potential to
receptor displayed less exploratory activity in an open augment efficacy of the standard OCD medication,
field and more anxious behavior than the wild types in buspirone was not different from placebo as an
the elevated plus maze. According to the serotonin augmenting agent. Drugs that work through other
hypothesis of anxiety (Johnson and file, 1986), serotonin receptor subtypes also appear to be ineffective
removing the negative feedback control of 5-HT with in treating OCD. Thus, drugs modifying the 5-HT1A, 5-
the 5-HT1A receptor knockout animals should result in HT1D and 5-HT3 receptors appear ineffective in
increased levels of 5-HT in the synaptic cleft, which treating OCD symptoms and rule out a critical
would be expected to lead to the anxiogenic behavior. involvement of these receptor subtypes in OCD
However, Ramboz et al. 1998, reported normal levels (Broocks et al., 1998; Pian et al., 1998).
of 5-HT, which confuses the issues related to anxiety
modulation and serotonin levels.

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In the past, tricyclic antidepressants (TCAss) certain guanine nucleotide binding proteins (G proteins)
and monoamine oxidase inhibitors, as well as high (Kaupmann et al., 1997). Through their activity on
potency benzodiazepines, have been used to treat other effector systems, G proteins can change second
patients with panic disorder. The SSRIs have also been messenger levels, altering signal transduction and gene
added to the list of effective agents for the disorder. In expression, or open ion channels that are dependent on
reviewing the pharmacotherapy of panic disorder, den the G-protein subunit activities (Wess, 1997). Both
Boer, 1998 notes that antidepressants are more effective excitatory and inhibitory activities are possible on a
than benzodiazepines in reducing associated depressive time scale that is longer than GABAA receptor
symptomatology and are at least as effective for mediated events. There is extensive heterogeneity in the
improving anxiety, agoraphobia, and overall structure of the GABAA receptor members of the
impairment. Bell and Nutt, 1998 remark that SSRIs ligand-gated superfamily. These receptors are the
improve 60% to 70% of panic patients, a similar targets of a number of widely used and prescribed drugs
percentage to those seen with the TCAs. for sleep, anxiety, seizure disorders, and cognitive
enhancement; they may also contribute to mediating the
Like OCD, panic disorder is well treated by effects of ethanol on the body.
SSRIs but does not appear to be effectively treated by
receptor specific compounds. Coplan et al., 1995 It is well established that the GABAA
reviewed the role of 5HT 1A drugs such as buspirone in receptors possess binding sites for the neurotransmitter
panic disorder and reported that buspirone does not GABA, as well as allosteric modulatory sites for
significantly treat panic in several well-controlled benzodiazepines, barbiturates, neurosteroids,
studies. Using the 5-HT1A receptor agonist flesinoxan, anesthetics, and convulsants (Tallman et al., 1980;
ikvan Vliet et al., 1996 reported a worsening of Tallman and Gallager, 1985).
symptoms in panic patients treated with high doses of
the drug. It has also been reported that the 5-HT2A/2C 6.3. Corticotrophin-Releasing Factor Modulators
antagonist ritanserin had no effects on panic attacks or Corticotrophin-releasing factor (CRF) is a 41
phobic avoidance, and a similar negative finding has amino acid peptide that plays an important role in
been reported with the 5-HT3 antagonist ondansetron. mediating the body‘s physiologic and behavioral
responses to stress (Koob et al, 1993). Figure (1)
6.2. Γ-Aminobutyric Acid Receptor Modulators illustrates that this role of CRF may be mediated by
(Benzodiazepines and Related Drugs) multiple sites of action. As a secretagogue, CRF
A majority of the synapses in the stimulates the release of adrenocorticotropic hormone
mammalian CNS use the amino acids I-glutamic acid, (ACTH) from the pituitary. In addition, CRF plays a
glycine, or γ-aminobutyric acid (GABA) for signaling. neurotransmitter or neuromodulatory role through
GABA is formed by the decarboxylation of I-glutamate, neurons and receptors distributed in diverse brain
stored in neurons, and released, and its action is regions (DeSouza and Grigoriadis, 1995). CRF neurons,
terminated by reuptake; GABA's action mimics the localized in the hypothalamic periventricular nucleus,
naturally occurring inhibitory transmission in the are a major mediator of stress-induced activation of the
mammalian nervous system. Because of these findings, hypothalamic-pituitary-adrenal (HPA) axis, whereas
it has been accepted for over 20 years that GABA pathways innervating limbic and cortical areas are
fulfills the characteristics of a neurotransmitter (Paul, thought to mediate the behavioral effects of CRF. There
1995). Along with I-glutamate, acetylcholine, and is a large body of both preclinical and clinical literature
serotonin, GABA possesses two different types of implicating a key role of CRF in affective disorders
receptor conserved across different species and phyla such as anxiety and depression. A significant clinical
that control both excitation and inhibition. Molecular literature suggests that dysfunctions of CRF in its role
biological studies of the receptors causing these effects as a hormone in the HPA axis or as a neurotransmitter
have indicated that GABA's effects on ionic in the brain may contribute to the etiology of a variety
transmission (ionotropic) and metabolism of psychiatric conditions, including anxiety and
(metabotropic) are mediated by proteins in two different depression (Gold et al., 1995). The link between CRF
superfamilies. The first superfamily (GABAAreceptors) and depression is particularly strong, as numerous
is a set of ligand-gated ion channels (ligand-gated clinical studies have demonstrated that depressed
superfamily) that convey GABA's effects on fast patients show elevated cerebrospinal fluid (CSF) levels
synaptic transmission (Siegharr, 1995). When a of CRF, elevated plasma cortisol, and a blunted ACTH
GABAA receptor is activated, an ion channel is opened response following intravenous CRF. Successful
(gated) and this allows chloride to enter the cell; the antidepressant treatment was shown to have a
usual result of chloride entry is a slowing of neuronal normalizing effect on CRF levels. A role of CRF in
activity through hyperpolarization of the cell membrane anxiety disorders has also been postulated, though the
potential. The second superfamily (GABAB) is slower, clinical evidence is not as strong as it is for depression
mediating GABA's action on intracellular effectors (Arborelius et al., 1999). Preclinical studies have
through a seven transmembrane spanning receptor demonstrated that CRF administered exogenously into
(serpentine superfamily) that modulates the action of the central nervous system (CNS) can produce

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behaviors indicative of anxiety and depression, for studies have shown that exposure to early postnatal
example, heightened startle responses, anxiogenic separation stress in rat pups results in elevated levels of
behaviors on the elevated plus maze, decreased food CRF messenger RNA (mRNA) in brain regions
consumption, and altered sleep patterns. The anxiogenic including the paraventricular nucleus (PVN) and the
effects of CRF are not blocked by adrenalectomy, central nucleus of the amygdala (Heim et al., 1997;
suggesting that they are centrally mediated effects Plotsky and Meaney, 1993). CRF acts through two Gs-
occurring independently of the HPA axis (Berridge and protein coupled receptors, the CRF-1 and CRF-2
Dunn, 1989a). Other studies strengthening the link receptor subtypes (Perrin and Vale, 2000; Dieterich et
between CRF and anxiety include recent work by Kalin al., 1997). CRF-1 receptors show homology to a
et al. (2000) demonstrating that a ‗‗fearful‘‘ phenotype number of other neuropeptide receptors, including
in monkeys is associated with increased pituitary- vasointestinal peptide (VIP) and calcitonin (Perrin and
adrenal activity and increased brain CRF levels. Other Vale, 2000).

Figure1. The role of corticotrophin-releasing factor (DeSouza and Grigoriadis, 1995)

CRF-1 and CRF-2 receptors have different Much work has been carried out using the peptide
pharmacology and different localizations in the brain antagonists α-helical-CRF and D-Phe CRF. However,
and periphery. In situ hybridization and receptor these compounds have shortcomings in that they do not
autoradiography techniques have been used to map the penetrate the CNS and therefore have to be
relative distributions of CRF-1 and CRF-2 receptors in administered intracerebro-ventricular (icv).
the rat brain (Chalmers et al., 1995; Primus et al., Furthermore, they do not discriminate between CRF
1997). High expression of CRF-1 receptors was seen in receptor subtypes and therefore do not allow a
the pituitary, and in a number of brain regions including determination of their relative contributions to behavior.
the PVN of the hypothalamus, cerebral cortex, olfactory More recently, the development of selective,
bulb, cerebellar cortex, and basolateral and medial nonpeptidic antagonists of the CRF-1 receptor such as
amygdala. In contrast, high densities of CRF-2 are CP 154,526 (Schulz et al., 1996) have provided
found in more circumscribed regions, including the important pharmacologic tools for the analysis of CRF-
lateral septum, ventromedial nucleus of the thalamus, 1 receptor function. Mutation studies have
and choroid plexus. Moderate densities of CRF-2 demonstrated that peptide and nonpeptide antagonists
receptors were reported for the medial amygdala and bind to different domains of the CRF-1 receptor (Perrin
dorsal raphe nucleus (Sanchez and Young, 1999). CRF and Vale, 2000). To date, selective CRF-2 antagonists
receptors utilize 3',5'-cyclic adenosine monophosphate have not been described, though recently, non peptide
(cAMP) as a second messenger in the pituitary and dual antagonists of the CRF-1 and CRF-2 receptors
brain and can be regulated by chronic activation. have been described (Luthin and Rabinovich, 1999).
Thus, desensitization following exposure to CRF has Studies utilizing transgenic and knockout mouse models
been demonstrated both in vitro (Dieterich et al., 1966) have provided important information with regard to the
and in vivo (Hauger and Aguilera, 1993). Furthermore, contribution of CRF and CRF receptor subtypes to
chronic stress can down-regulate CRF receptors and processes including energy balance, emotionality,
decrease CRF-stimulated cAMP production in multiple cognition, and drug dependence (Contarino et al, 1999).
brain areas (Aguilera et al, 1987; Anderson and Kant, Over expression of CRF in transgenic mice produced
1993). Down-regulation of pituitary CRF receptors anxiogenic effects using either the black-white box test
following adrenalectomy presumably results from (Heinrichs, et al, 1997) or the elevated plus maze
decreased ACTH mediated inhibitory feedback, which (Stenzel-Poore et al, 1994). The latter effect was
produces excess CRF stimulation. There are a number reversed by central administration of the CRF receptor
of pharmacologic agents available for dissecting the antagonist a-helical CRF, but not by adrenalectomy,
functional significance of CRF-1 and CRF-2 receptors. supporting the role of central CRF pathways

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independent of the HPA axis (Stenzel-Poore and Unger, 1995). This notion is supported by early positive
Heinrichs, 1994). Studies using antisense directed clinical findings using a selective neurokinin-l (NK-l)
against CRF in rats have produced evidence of antagonist for the treatment of depression and anxiety
anxiolytic activity (Skutella et al., 1998). Finally, over (Kramer et al., 1998). Tachykinins collectively refer to
expression of CRF-BP is anxiolytic, whereas binding small peptides that include substance P (SP), neurokinin
protein knockout mice (in which free CRF levels are A (NK-A), and neurokinin B (NK-B). These peptides
elevated) display an anxiogenic phenotype in the show preferential affinity for three receptors, designated
elevated plus maze (Ramesh et al., 1998). These data NK-l, NK-2, and NK-3, respectively, which are
generally support the link between CRF and anxiety. members of the seven-transmembrane, G-protein-
coupled family. Of these three receptors, NK-l and NK-
More recently, several studies have highlighted 3 are found in the brain, whereas NK-2 is primarily
the importance of the CRF-l receptor subtype in localized peripherally in smooth muscle of the
anxiety. CRF1 knockout mice demonstrated a respiratory, urinary, and gastrointestinal tracts.
diminished anxiogenic response on the elevated plus Neurokinin receptors are localized in a number of
maze and decreased ACTH and corticosterone different brain areas that are implicated in anxiety,
responses to restraint stress (Smith et al., 1999). Similar including the amygdala, hypothalamus, and locus
findings were reported, using the blackwhite box coeruleus.
anxiety paradigm (Timpl et al., 1998). Furthermore,
inactivation of the CRF-l receptor with an antisense Studies assessing the effects of direct
oligonucleotide was shown to reduce the anxiogenic administration of neurokinin agonists such as substance
effect of intraventricularly administered CRF (Skutella P into the nervous system are complicated by the
et al., 1998). Liebsch et al., 1995 provided evidence of findings that, depending on factors such as the site and
anatomic localization by showing anxiolytic activity dose, opposite effects on behavior may be achieved
from CRF-l antisense that was chronically infused into (Kramer et al, 1998).
the central nucleus of the amygdala, an area of the
limbic system shown by Davis M, 1997; LeDoux J, 6.5. Cholecystokinin B antagonists
1996, and others to be important in mediating fear and Cholecystokinin (CCK) is a peptide found
anxiety processes. Finally, CRF-2 knockout mice show extensively both in the gut (where it was originally
anxiety-like behavior and are hypersensitive to stress identified) and in the brain (Mutt and Jorpes, 1971).
(Bale et al., 2000), indicating that the CRF-2 receptor CCK exists in multiple forms, the most predominant of
has an opposite functional role to that of the CRF-l which is CCK octapeptide (CCK8) and, to a lesser
receptor. Thus, it could be argued that CRF-2 agonists, extent, CCK tetrapeptide (CCK4) (Hokfel et al., 1985).
rather than antagonists, might be potentially useful as CCK is colocalized with a number of different
anxiolytic agents. neurotransmitters, including serotonin, dopamine,
GABA, substance P, neuropeptide Y, and VIP. CCK-
Another potential use for CRF antagonists is in like immunoreactivity has been demonstrated in
the treatment of drug abuse. Several lines of evidence anatomic regions that include the amygdala, cerebral
suggest that during the period of withdrawal from drugs cortex, hippocampus, striatum, hypothalamus, and
of abuse such as ethanol, morphine, and cocaine, there spinal cord (Emson et al., 1982). There are two
is an activation of central CRF pathways. Anxiety is subtypes of CCK receptor, CCKA (sulfated CCK) and
among the many physical symptoms of drug CCKB (unsulfated CCK) (Moran et al., 1986). CCKA
withdrawal, and given the link that has been made receptors are localized in the nucleus accumbens,
between CRF and anxiety, it is not surprising that CRF- posterior hypothalamus, and area postrema. CCKB
l receptor knockout mice demonstrated decreased receptors are localized in cortex, olfactory bulb, nucleus
anxiety responses during withdrawal from alcohol accumbens, and other brain areas (Pisegna et al., 1992).
(Timpl et al., 1998).
7.CONCLUSION
6.4. Neurokinin Receptor Antagonists It can be concluded that anxiety is manifest by
There is an extensive literature demonstrating disturbances of mood, thinking, behaviour, and
that the peptide tachykinins such as substance P and physiological activity and accompanying disturbances
their associated receptors have a widespread of sleep, concentration, social and/or occupational
distribution in the brain, spinal cord, and periphery, and functioning. Also, it is associated with restlessness,
may play important roles in chronic pain and feeling keyed up or on edge, being easily fatigued,
inflammation processes (Otsuka and Yoshioka, 1993; difficulty in concentrating or mind going blank,
Khawaja and Rogers, 1996; Longmore et al., 1997; irritability, muscle tension, and irritability. The etiology
Mantyh et al., 1989; Tooney et al., 2000). In addition, of anxiety may include stress, diabetes, depression,
anatomic and physiologic evidence has also indicated genetic, and environmental factors. Drugs to reduce
that these peptides limbic structures that are involved in anxiety have been used by human beings for thousands
the regulation of mood, such as the amygdala, of years. The drugs were used to reduce anxiety,
hypothalamus, and periaqueductal gray (Culman and including the barbiturates and the carbamates

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(meprobamate) drugs were used for treatment of 14. Thorn,G.R., Chosak, A., Baker, S.L., & Barlow,
anxiety in the first half of the 20th century and some D.H. (1999). Psychological theories of panic
continue to be used today. Anxiety disorders should be disorder. In: Nutt DJ, Ballenger JC, Lepine JP
treated with psychological therapy, pharmacotherapy, (Editors), Panic disorder: Clinical diagnosis,
or a combination of both. management and mechanisms. London: Martin
Dunitz Ltd, pp. 93–108.
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