Anxiety is a natural and often unobtrusive response to a perceived danger which then elicits a cascade effect of adaptive physical and hormonal responses; however, in some individuals, anxiety can be much more detrimental and even hamper everyday life and the ability to deal with situations that the average person may find menial (Steimer, 2002). Some authors state that fear and anxiety are inseparable, co-occurring reactions to threats and/or conflict, whereas other authors perceive the two traits to be distinct experiences.(Steimer, 2002) In general, anxiety appears to be a generalized reaction to a seemingly intangible conflict or unknown danger (Craig, Brown, & Baum, 1995). Contrastingly, some authors pose that anxiety is a continuation of fear and that it is a mechanism by which animals begin to learn and prepare for upcoming events that may similarly evoke any previously induced fears (Barlow, 1988, 2000). The most common symptoms of anxiety include any combination of the following sense or states of being: panic, feeling weak, hot flashes, nauseated, difficulty breathing, increased heart rate, and/or loss of control (American Psychiatric, American Psychiatric, & Force, 2013). It is of great importance to understand and to further conduct research about anxiety because anxiety disorders are the most common disorders amid adolescents and adults (Cassano, Rossi, & Pini, 2002; Merikangas, Nakamura, & Kessler, 2009).
Although the effects and types of anxiety have been well-studied, the exact causes of pathological or “trait” anxiety (anxiety that is sustained and affects everyday life) are not as well-understood (Spielberger, 2010). The most common types of pathological anxiety are obsessive-compulsive disorders (OCD), panic disorders (PD), social anxiety disorders (SAD), generalized or specific phobias, generalized anxiety disorders (GAD), and post-traumatic stress disorder (PTSD) (Association & DSM-IV., 2000; Clement, Calatayud, & Belzung, 2002). In general, the two factors most cited as being the root of such anxiety are biological and psychological. The biological source of anxiety is due to the genetic makeup of an individual, whereas the psychological aspect is derived from an individual’s early life exposures and the events or circumstances that henceforth act as triggers (Barlow, 2000; Steimer, 2002). Furthermore, disorders such as phobias, obsessive-compulsive disorders (OCD), and panic attacks seem largely tied to psychologically-derived anxiety. In contrast, generalized anxiety disorders are most likely related to the genetic makeup (biological), whether they are directly inherited from parental lineages or genetic expressions caused by various environmental exposures that happen during natal development.
Because the use of humans in scientific studies that are manipulative and intrusive is largely prohibited, in order to understand how biological and physiological aspects of anxiety in humans, researchers typically use mice and rats but have also used cats and monkeys to answer their hypotheses about the sources, causes, functionalities, and results of anxiety, and they then relate their findings to humans (Belzung & Griebel, 2001; Lister, 1990). With the use of these non-human models, researchers have identified the major physiological components of the brain that are most-affected by fear and anxiety. For example, it is now known that external stimuli are processed in the amygdala (parts of the brain associated with decision-making and emotional responses), the hypothalamus (synthesizes and secretes neurohormones), and the peraqueductal gray (involved with defensive responses) and subsequently lead to various regulations in hormones (glucocorticoids, cortisol, and corticosterone) and anxiety-related behaviors (Chorpita, Brown, & Barlow, 1998; Gray & McNaughton, 1996; Sullivan, Coplan, Kent, & Gorman, 1999; Sullivan, Kent, & Coplan, 2000). In response to these stimuli, these aforementioned parts of the brain lead to states widely known to be associated with anxiety and fear such as the responses of freezing, escaping, panting, being startled, and release of bodily waste(Steimer, 2002).
Although many diseases, particularly those affecting the nervous system, have been determined to be genetically-induced, unraveling all genotypic causes for disorders is very difficult because several syndromes or disorders (phenotypes) can be produced by several genes, and isolating a particular single locus or chromosomal region responsible for a disorder can take an inordinate amount of time and money. To add to this difficulty and from the converse perspective, a particular genotype can result in many different phenotypes which makes it hard to associate a particular disorder (phenotype) with a specific genotype (Clement et al., 2002).
Along with mapping the chemical and neurological cascade effects in the brains of mammals, there is also evidence that establishes genetic and/or environmental factors as predisposition for anxiety-related disorders (Clement et al., 2002; Steimer, 2002). One method of uncovering the linkage between anxiety and one’s or genetic makeup has been to target gene mutations in mice. By manipulating the genotype of mice, researchers have shown that expression of certain genes can consequently lead to the outward expression of anxiety-related behaviors (Clement et al., 2002; Tarantino & Bucan, 2000). As previously mentioned, the use of human subjects in certain types of studies is rarely allowed, but it is important to note that observational human studies have occurred (Battaglia et al., 1995; Reich, Lyons, & Cai, 1996; Weissman, 1993), and these studies shed light on the fact that there is a suggested genetic association with anxiety disorders. By studying families, twins, and adoption cases, researchers are able to account for some of the variability seen among individuals who suffer from symptoms of anxiety and that some anxiety is likely to be heritable(Clement et al., 2002).
In conjunction with biological influences, numerous studies have examined an abundance of environmental factors that possibly cause or increase the risk of anxiety. Brook and Schmidt (2008) have identified several of these environmental factors from the literature that deserve attention when considering how individuals develop or respond to their surroundings. In particular, Brook and Schmidt reference the importance of parenting and family environment, parental psychopathology, adverse life events, and societal and cultural factors.
At the forefront of biological research on mental illnesses are findings within the last few years that associate mental health with gut microbiomes (commensal intestinal bacteria). Specifically, these scientists are beginning to show how microbiota influence stress-related behaviors such as anxiety and depression. Their findings suggest that normal, healthy brain function is partially associated with the types and quantity of commensal intestinal bacteria. Such a relationship has been coined the “gut-brain axis”(Clarke et al., 2013; Heijtz et al., 2011; K.-A. M. Neufeld, N. Kang, J. Bienenstock, & J. A. Foster, 2011; K. M. Neufeld, N. Kang, J. Bienenstock, & J. A. Foster, 2011; Sudo et al., 2004). One major finding from several of the gut-brain axis studies is that a key inhibitory neurotransmitter (GABA) in the central nervous system is produced from glutamate by bacteria (Lactobacillus and Bifidobacterium), and this is important because dysfunctions in the GABA signaling with the central nervous system have been linked to anxiety (Barrett, Ross, O’Toole, Fitzgerald, & Stanton, 2012; Cryan & Kaupmann, 2005; Foster & McVey Neufeld, 2013; Higuchi, Hayashi, & Abe, 1997)
As mentioned before, there are key components of the brain that control reactions to stimuli. For people with pathological anxiety, these crucial brain structures have been found to be dysfunctional in some regards. For example, the amygdala and hippocampus play important roles in the ability of mammals to learn, process, and cope with anxiety and emotions. Some studies have associated environmental factors to changes within these structures in the brain which can produce alterations in people’s types or levels of anxiety. Bremner et al. (1995) found that the hippocampus had been reduced in size for people who had experienced military combat. Because of these findings, other researchers have proceeded with trying to decode what role a reduced hippocampus may play for people with post-traumatic stress disorder who experience painful flashbacks or memory fragmentation/loss (Karl et al., 2006; Stein, Hanna, Koverola, Torchia, & McClarty, 1997; Wignall et al., 2004).
The right hemisphere hypothesis posits that the right hemisphere of the brain is the dominant source for processing emotional stimuli, and some studies have examined whether or not this processing is associated with anxiety (V. J. Bourne & Watling, 2015). Borod (1992) found that facial expressions are mostly processed by the right hemisphere of the brain which is most often measured by using by using chimeric faces test (CFT) (Workman, Chilvers, Yeomans, & Taylor, 2006). When V. J. Bourne and Watling (2015) evaluated emotion lateralization and fear of negative evaluation (FNE) in people, they found that there is a positive relationship between the strength of lateralization and FNE when individuals processed basic facial emotions. Additionally, they found that females tend to have a stronger lateralization of the right hemisphere when processing fearful facial emotions. These findings are consistent with an earlier study that determined that individuals with high levels of trait anxiety were lateralizing the processing of facial emotions more strongly in the right hemisphere (Victoria J. Bourne & Vladeanu, 2011). On the other hand, Victoria J. Bourne and Vladeanu (2011) found that for people with reported social anxiety, there was less right hemisphere lateralization and even tended to be more lateralized to the left hemisphere when processing facial emotions.
What happens in the brain when one is afraid or anxious? The brain’s response to stress is encorporated into the activation of the hypothalamic-pituitary-adrenal (HPA) system which is responsible for releasing hormones and catecholamines(Pariante, 2003). The hormones, mainly glucocorticoids, are secreted by the adrenal glands and help mediate the stress response while also increasing the efficiency of the cardiovascular system(Bomholt, Harbuz, Blackburn-Munro, & Blackburn-Munro, 2004). The catecholamines act as neurotransmitters and are largely composed of dopamine, neorepinephrine, and adrenaline during a response to stress or danger(Paine, Watkins, Blumenthal, Kuhn, & Sherwood, 2015). These chemical neurotransmitters activate the amygdala in the brain, which then triggers an emotional response that subsequently releases neuropeptide S, thereby increasing alertness and anxiety. At the same time, the amygdala sends signals to the caudate nucleus and hippocampus in the brain, telling it to store the negative stimuli as a long-term memory.
To understand how the brain is reacting in response to anxiety, the main component that is often cited as being the reactionary center – the amygdala. The amygdala is responsible for the sensation of fear and anger; evolutionarily, it has allowed animals to adapt to stressful or dangerous events (Gold, Morey, & McCarthy, 2015; Hanson et al., 2015; Harrison & Adolphs, 2015; Koek et al., 2015; Maren, 2014; McDonald, 2014; Yilmazer-Hanke, 2015). When functioning properly, the amygdala is adaptive for survival; however, when the neurotransmitters in the brain are dysfunctional, the amygdala is maladaptive and leads to anxiety. Two neurotransmitters of utmost importance are the GABA and glutamate transmitters. If either one is increased (or over-reactive), then the brain proceeds to respond as if a threat is present. Another important neurotransmitter is dopamine. Dopamine is linked to concentration, aggression, and pleasure; abnormal levels of dopamine can also be linked to anxiety if either aforementioned neurotransmitter processes are abnormal.
To understand the biological response of anxiety disorders, we must examine how the sympathetic nervous system (SNS) responds to stimuli. The sense of sight and sound first get processed by the thalamus which then signals the cortex or amygdala. In contrast, stimuli from touch and smells are received directly by the amygdala. If a threat is perceived, the hypothalamus and pituitary gland signal the production of a steroid hormone called cortisol by the adrenal gland. For example, during a panic attack, the body’s sympathetic nervous system continues to be stimulated, adrenaline is produced and the senses become more alert which results in either the fight or flight response to the situation. Additionally, the heart begins to beat more rapidly as blood pressure and breathing rate increases. Because of an increase in breathing (hyperventilation in some instances) the body inhales more air and thereby increases the oxygen to carbon dioxide level in the blood (Coryell, Pine, Fyer, & Klein, 2006; Gorman et al., 2001; Kent et al., 2001). Moreover, the carbon dioxide necessary to break down the additional oxygen molecules is no longer available because it is being rapidly exhaled from the lungs; therefore, the oxygen remains in the blood stream (Coryell et al., 2006). Because carbon dioxide has decreased while oxygen has increased, the blood pH levels change (Wemmie, 2011). In addition to changing the oxygen/carbon dioxide ratios and pH levels, adrenaline is responsible for the constriction of blood vessels which decreases blood flow to the head(Kuno, 1925; Masaki, Furukawa, Watanabe, & Ichikawa, 1999; Mathew & Wilson, 1988). As blood flow to the head is reduced, individuals become dizzy and/or lightheaded. Other symptoms that are associated with anxiety include rapid heart rate, hot flashes, sweating, chill, trembling, dizziness, difficulty breathing, intestinal distress, tingling or numbness of the skin, and/or a sense of losing control.
Because there are so many people (Gorman, Hirschfeld, & Ninan, 2002) affected by different types of anxiety disorders, it is important to understand and properly diagnose the disorder since newly-developed psychotropic medications are tailored to the diagnosis. In the beginning, benzodiazepines were the initial drugs of choice for anxiety disorders. Benzodiazepines work by enhancing the effect of GABA which was previously discussed as being an essential communication signal for the central nervous system. Benzodiazepines, although they are fast-acting, are no longer readily used to treat long-term anxiety disorders because they regularly lead to drug dependence, tolerance, withdrawal anxiety, and/or sedation (Lader, 2008; Lader, Tylee, & Donoghue, 2009; Saias & Gallarda, 2008). Another downfall of the benzodiazepines is that they tend to be metabolized slowly; therefore, their persistence in the body becomes a problem if they are taken for lengths of time. The most well-known benzodiazepines include Xanax, Valium, Klonopin, and Ativan.
In the treatment of general anxiety disorders, an alternative to benzodiazepines has been azapirone busiprone, also known as BuSpar. Like SSRIs, BuSpar increases the serotonin and decreases dopamine in the brain. The advantages of busiprone are that it does not cause sedation, dependence, withdrawal, tolerance like the benzodiazepines.(Cassano et al., 2002). Busiprone does not act as rapidly as the benzodiazepines, but it has a maintained efficacy period that lasts for several months(Rickels, Fox, Greenblatt, Sandler, & Schless, 1988; Rickels, Schweizer, Csanalosi, Case, & Chung, 1988).
In contrast to prescribing drugs for treating specific disorders, past use of selective serotonin reuptake inhibitors (SSRIs) have been found to work for many anxiety disorders even though they were initially administered to treat depression because they assist the brain in maintaining enough serotonin which is an important neurotransmitter (Cassano et al., 2002); SSRIs help prevent the neurotransmitters from being reabsorbed into nerve cells in the brain. By keeping high concentration levels of the neurotransmitters in the brain, communication between the nerve cells is improved. SSRIs are successfully used to treat obsessive compulsive disorders, post-traumatic stress disorders, phobias, panic disorders, and generalized anxiety disorders. Some of the downfalls of using SSRIs are that they have undesirable side-effects (nausea, anorexia, insomnia, headaches, dry mouth, and/or ejaculation failure)(Cassano et al., 2002). The effectiveness of SSRIs has lead to a decrease in the use of benzodiazepines. The most commonly used SSRIs are Prozac, Zoloft, Paxil, Luvox, Lexapro, and Celexa. For some common SSRI treatments, see table 1 (recreated from anxieties.com and http://www.nytimes.com/health/guides/symptoms/stress-and-anxiety/treatment.html). Serotonin and norepinephrine reuptake inhibitors (SNRIs) working in a similar way to SSRIs, but they also inhibit reuptake of the neurotransmitter, norepinephrine. Commonly used SNRIs are Cymbalta, Effexor, Khedezla, Fetzima, and Pristiq. Another drug, Wellbutrin, affects the reuptake of dopamine and norepinephrine, and is thus called a NDRI.
Baldwin, Woods, Lawson, and Taylor (2011) performed a meta-analysis to determine the efficacy and tolerability of drugs used to treat generalized anxiety disorder. For this meta-analysis, they evaluated nine drugs (duloxetine, escitalopram, fluoxetine, lorazepam, paroxetine, pregabalin, sertraline, tiagabine, and venlafaxine) and found that fluoxetine was most effective in terms of response and remission. Additionally, sertraline ranked highest compared to all other treatments in terms of tolerability (in terms of withdrawals) because of adverse events.
Table 1. SSRI Treatments
|Drug Name||Anxiety Disorders||Benefits||Disadvantages||Side Effects||Recommended Dosages|
|Prozac||· Panic· OCD
· Social anxiety
|May cause insomnia or different anxiety, 4-6 weeks until effective.||Nervousness and tremors, sweating, nausea, anxiety, diarrhea, difficulty falling asleep or frequent awakenings, difficulty achieving orgasm, decreased libido, headache, loss of appetite, postural hypotension, drowsiness or fatigue, upset stomach||Prozac comes in 10 and 20 mg capsules and liquid oral solution that the patient usually takes in the morning. If you have a side effect of upset stomach, take it with food. Typically the initial dose is low, at 2.5 to 5 mg per day and gradually raised to 20 mg per day. If there is no response to this dose after four to eight weeks, raise the dose by 20 mg a week until there is a response, to a maximum dose of 80 mg.|
|Zoloft||· Panic· OCD
· Social anxiety
|Low level of nervousness or agitation as side effect.||4-6 weeks until effective, physician approval during pregnancy or breast-feeding||Headache, dry mouth, sleepiness, dizziness, tremors, diarrhea, agitation, confusion, nausea, delayed ejaculation in men||Start with 50 mg in morning or evening. Maximum dose is 200 mg. Taper slowly.|
|Paxil||· Panic· OCD
· Social anxiety
|4-6 weeks until effective, Avoid alcohol. Do not take during pregnancy or breast-feeding.||Nausea, sleepiness, constipation, dry mouth, dizziness, insomnia, delayed orgasm, weight gain||Start with 10 mg once a day. If no response after several weeks, can increase 10 mg per week up to 60 mg. For OCD the minimum therapeutic dose is often 40 mg.|
|Luvox||· Panic· OCD
· Social anxiety
|4-6 weeks until effective, Avoid alcohol. Do not take during pregnancy or breast-feeding.||Nausea, sleepiness, insomnia, dry mouth, headache, dizziness, delayed ejaculation||Start at 50 mg at night. Increase to between 100 and 300 mg per day. Doses over 100 mg should be divided into morning and night, with larger dose at night. To reduce nausea, take with food.|
|Lexapro||· GAD· PTSD
· Social anxiety
|Nausea, diarrhea, constipation, loss of appetite, stomach pain, dizziness, drowsiness, trouble sleeping, fatigue, increased sweating, or dry mouth may occur||10 mg per day, may be increased to 20 mg.|
|Celexa||· OCD· GAD
· Social Anxiety
|Nausea, vomiting, lack of appetite, diarrhea, drowsiness, dizziness, trouble sleeping, dry mouth, muscle/joint pain, fatigue, or yawning may occur||Start with 10 mg per day, may be increased to 20-60 mg.|
Another source of antidepressant medications (tricyclic antidepressants) have also been used to treat anxiety disorders. Tricyclic antidepressants (TACs) act by enhancing neurotransmission by increasing the concentration of the transmitters needed for the facilitation of serotonin and norepinephrine (Gillman, 2007; Tatsumi, Groshan, Blakely, & Richelson, 1997). Specifically, TACs block the absorption of the neurotransmitters serotonin and norepinephrine; because these neurotransmitters are blocked, there are more of them available in the brain. This seems to help brain cells send and receive messages which in turn boosts mood. TACs are not favored due to their toxicity and side effects. Similarly, monoamine oxidase inhibitors (MAOIs) work by increasing the availability of neurotransmitters, but they are use much less frequently due to their potential reactions with drugs and food (McCabe-Sellers, Staggs, & Bogle, 2006). The most commonly used TACs are Amitripytline, Amoxapine, Norpramin, Doxepin, Tofranil, Pamelor, Vivactil, and Surmontil. The side effects of amitriptyline, doxepin and trimipramine are known to cause sleepiness, whereas Amitriptyline, Doxepin, and Tofranil are more likely to cause weight gain. Overall, TACs have a wide range of side effects such as dry mouth, blurred vision, constipation, urinary retention, drowsiness, weight gain, decreased blood pressure, lightheadedness, increased sweating (Nelson, 2009). Less common side effects include disorientation, confusion, tremors, irregular heart rate, seizures, erectile dysfunction, and/or low sex drive (Nelson, 2009).