Anxiety Disorder

Anxiety is something that may affect many of us throughout our lifetime. It is estimated that almost 24% of Canadians will experience some form of anxiety in their lifetime ¹. Anxiety may be due to several different reasons, and there are many different types of anxiety that people may experience, these include social anxiety disorder, panic disorders, anxiety due to substance use or other medical conditions and generalized anxiety disorder, just to list a few. It is something that affects the way patients think, feel and act in society. It is a condition that is expressed in many different ways, which can be shown and expressed physically, psychologically and functionally. Physical signs and symptoms include: insomnia, loss of energy, palpitations, sweating, muscle tensions, tremors, shaking, nausea and vomiting, “butterflies” in stomach and stomach pain. Psychological signs and symptoms include fear, worry, restlessness, poor concentration and irritability. Functional signs and symptoms include a decrease in productivity, social isolation away from others and poor coping skills ².

Causes of Anxiety Disorder

There are some known socioeconomic causes of anxiety. These include a low level of education, isolation, a traumatic life event and lack of parenting, or over protection from ones parents ³. Family history and having a personal history of different types of anxiety disorders are also risk factors. Females are more likely than men to have anxiety as well ³, but this could also be due to the fact that females are more open and willing to talk about mental illnesses when compared to men.

Anxiety is a response to a certain situation. Becoming “alert” and having motivation to get up and ready to go is a part of the fight or flight response, which is a natural human instinct. However, with anxiety this danger or threat causes an overwhelming response, and this response results in impairments of daily functioning and results in a poor quality of life.

From a physiological perspective, the parts of the brain that are thought to be involved in anxiety disorders include the locus coeruleus, which senses the fear; the amygdala, which assesses the fear; the hypothalamus, which decodes information being relayed to it to from the amygdala; and the hippocampus, which is involved in memory ². Several theories are proposed for the cause of anxiety from a neurological perspective. These include an excessive release of norepinephrine from the locus coeruleus and amygdala, which is a result of their over activity within the brain ². Others include an over activity of the hypothalamus, which results in the release corticotropin releasing factor (CRF) ², downstream effects of this is a excessive release of cortisol, which is an important component of the stress response. Lastly, it is proposed that a decrease in serotonin could also play a role in anxiety because serotonin helps regulate the norepinephrine and CRF levels within the brain ².

In addition, there are some known mediation causes of anxiety as well. Some common medications that may cause anxiety include Salbutamol, Synthroid, Caffeine, and ADHD medication such as Adderall and Ritalin.

Diagnosis of Anxiety Disorders

There are several different types of anxiety disorders, and your physician may diagnose you with one type, or more than one type of anxiety disorder. Physicians use the DSM-5 (diagnostic and statistical manual of mental disorders) to aid with the diagnosis. A summary of the different types of anxiety disorders defined in the DSM-5 can be found in Table 1 below. Anxiety disorders usually begin in childhood or adolescents for most patients, however traumatic life events or other changes in one’s socioeconomic status may trigger an anxiety disorder later in life. For example, many veterans coming back from war suffer with PTSD.

Table 1: Classification of Anxiety Disorders ⁴

Type of Anxiety Disorder	Clinical Features
Separation anxiety disorder	Childhood onset of fear of separation from attachment figures (parents, siblings) that is excessive for the developmental stage.
Selective mutism	Childhood onset of failure to speak in school or other social situations when the individual does speak in other settings. May impede academic progression.
Specific phobia	Severe anxiety triggered by a specific feared object or situation (e.g., spiders, flying, heights) often leading to avoidance behaviour.
Social anxiety disorder (social phobia)	Intense anxiety provoked by social or performance situations in which embarrassment might occur; often leads to avoidance behaviour.
Panic disorder	Recurrent unexpected abrupt panic attacks with persistent anxiety concerning recurrence.
Agoraphobia	Marked fear or anxiety of 2 or more situations: public transportation, open spaces, closed spaces, crowds, being outside of home alone. Leads to avoidance of these situations.
Generalized anxiety disorder	Excessive worry and anxiety about a number of events or activities on more days than not over a period of ≥6 months.
Anxiety disorder due to another medical condition	Anxiety or panic attacks directly caused by a medical condition, e.g., thyroid dysfunction, hypoglycemia, heart failure, arrhythmia, COPD, vitamin B12deficiency, encephalitis.
Substance/medication-induced anxiety disorder	Anxiety or panic attacks directly caused by use or discontinuation of a substance (e.g., alcohol, amphetamines, anticholinergics, caffeine, cannabis, cocaine, corticosteroids, hallucinogens) capable of producing the symptoms of anxiety.

Other specified anxiety disorder	Symptoms of anxiety disorders not meeting full diagnostic criteria, e.g., limited-symptom panic attacks, generalized anxiety occurring on fewer days than not.
Unspecified anxiety disorder	Distressing anxiety symptoms that fail to meet diagnostic criteria for specific anxiety disorders.

Moreover, your physician may use special monitoring scales, which are completed by you in order to assess your progression of anxiety or the effectiveness of the treatment that is being used to treat your anxiety. Table 2 lists some common self-administered tests that are used in practice.

Table 2: Self-Administered Scales Used for Anxiety Disorders

 

Type of Anxiety	Scale
Panic Disorder	Panic and Agoraphobia Scale (PAS)
Generalized Anxiety Disorder	Generalized Anxiety Disorder 7 Item Scale (GAD-7)
Social Anxiety Disorder	Social Phobia Inventory (SPIN)

The figure (figure 1) below is an example of the GAD-7 Scale, and Table 3 shows the interpretation of each score.

 

Figure 1: Generalized Anxiety Disorder 7 Item Scale (GAD-7)⁵.

Table 3: Interpretation of GAD-7 Scores⁵

GAD-7 Score	Level of Anxiety
0-4	Minimal
5-9	Mild
10-14	Moderate
15-21	Severe

Non-Pharmacological Treatment

Cognitive behavioral therapy (CBT) plays an important role in those who have anxiety, and it should always be used alongside those who require pharmaceutical treatment as well ⁶. Stress reduction techniques such as breathing exercises and aerobic exercises are also useful ways with dealing with stress and anxiety. Caffeine in the form of coffee and teas are also very common in todays society, however higher doses of these could also lead to some of the anxiety that some patients have, hence a reduction in caffeine intake could also be beneficial for some⁶. Good sleep hygiene is also another great way to reduce anxiety as well ⁶.

Pharmacological Treatment

CBT is usually used as a first line agent, however when the anxiety is moderate to severe, or if CBT was not effective, a trial of antidepressants can be used. Selective serotonin reuptake inhibitors and (SSRI) and selective serotonin and norepinephrine reuptake inhibitors (SNRI) are the mainstay of treatment. The reason for this is because they have a higher tolerability and lower side effect profile when compared to other antidepressants like the tricyclic antidepressants (TCA). Unlike depression, where one may see improvement in their symptoms within two to four weeks, the timeframe for symptom improvement for anxiety takes up to eight weeks, and in some cases may even take up to twelve weeks before symptoms of anxiety start to improve⁶. In some cases, your physician may prescribe benzodiazepines to help with anxiety. For people who have an acute onset of anxiety, the benzodiazepines may be effective for them. In other cases, the benzodiazepines may be used until the antidepressants have a full effective in the treatment of anxiety. In both cases, the benzodiazepines are used for the shortest period possible due to the possibility of dependence and abuse ⁶. Figure 2 shows an approach that your physician or other healthcare providers may use when helping you deal with your anxiety. This algorithm was taken from the Compendium of Therapeutics

 

Figure 2: Management of Anxiety Disorders ⁶.

It is important to note that this is just a general approach. Your physician and healthcare team may do something different other than what it listed in this algorithm depending on several factors, including what kind of anxiety you have, the severity and other considerations such as cost. Once an effective medication and dose is determined, it is recommended that it be used for a minimum of one year before discontinuing the medication.

The following will go only into first line agents for each type of anxiety disorder. A full list of treatment options, including second and third line agents can be found in the Compendium of Therapeutics ⁶. Second line agents for most anxiety disorders consist of TCA’s such as imipramine and clomipramine. Third line agents consist of monoamine oxidase inhibitors such as phenelzine and tranylcypromine and second-generation antipsychotics such at ripseridone, olanzapine and quetiapine. Benzodiazepines will also be briefly touched upon considering that they are still regularly prescribed for some conditions that give patients a lot of anxiety (examples include dental procedures and flights), however their long term use is something that is becoming phased out.

Panic Disorder and Agoraphobia

Though according to the new DSM-5 guidelines panic disorders and agoraphobia are considered two distinct forms of anxiety (refer to table 1), the treatment for them is still the same. The first line agents include SSRI’s, which can be seen in Table 4A. Other medications that are prescribed for panic disorders include benzodiazepines, which can be seen in table 4C.

Specific Phobias

Some people may have extreme fears of animals, natural disasters or some sort of object. The first line for this is exposure therapy, which is being exposed to the object that results in fear and anxiety. However, some patients may benefit from a benzodiazepine before exposure therapy, which can be found in table 4C. 

Generalized Anxiety Disorder

CBT is one of the most effective treatments for generalized anxiety disorder, however having access to CBT can get expensive, or may be harder for some patients to have access to in smaller communities. SSRIs and SNRIs are the first line treatments for when it comes to treating generalized anxiety disorders, which can be found in table 4A and table 4B, respectively. One drawback to the use of SSRIs and SNRIs is that it usually takes eight to twelve weeks to have an effect on the patient⁶. Because of this, another first line agent, pregabalin, is usually recommended because it has a faster onset of action and patients start to notice improvements within one week⁷. Refer to table 4D for dosing of pregabalin.

Social Anxiety Disorder

Social anxiety disorder is one of the more common types of anxiety that people may face. It results in people looking shy in front of others, or them avoiding social situations all together, such as social gatherings, or having to speak in front of larger groups of people. SSRIs and venlafaxine are the first line agents for treating social anxiety disorder, which can be found in table 4A and table 4B. Another first line agent is pregabalin, however a higher dose is usually required, which results in more side effects (with sedation being the biggest one), hence it is usually used when SSRIs and SNRIs fail. A third line agent that is commonly prescribed for those who have stage fright, or a fear of public speaking is propranolol or atenolol (refer to table 4E). This is usually taken 30 minutes prior to the anxiety causing event, and has been shown to be effective for those with the fear of public speaking or stage fright.

Table 4: First Line Medications and Dosages Used in Anxiety Disorders

Table 4A: SSRIs ⁶

SSRI	Type of Anxiety it is Used For	Dosage
Citalopram	Agoraphobia Panic Disorders Generalized Anxiety Disorder Social Anxiety Disorder	Initial: 10 mg/day PO Target: 20–40 mg/day PO Maximum: 40 mg/day PO and 20 mg/day PO in ≥65 years
Escitalopram	Agoraphobia Panic Disorders Generalized Anxiety Disorder Social Anxiety Disorder	Initial: 5 mg/day PO Target: 10–20 mg/day PO Maximum: 20 mg/day PO and 10 mg/day PO in ≥65 years
Fluoxetine	Agoraphobia Panic Disorders Social Anxiety Disorder	Initial: 10 mg/day PO Target: 20–60 mg/day PO
Fluvoxamine	Agoraphobia Panic Disorders Social Anxiety Disorder	Initial: 25 mg/day PO Target: 100–300 mg/day PO
Paroxetine	Agoraphobia Panic Disorders Generalized Anxiety Disorder Social Anxiety Disorder	Initial: 10 mg/day PO Target: 20–60 mg/day PO   Controlled Release Initial: 12.5 mg/day PO Target: 25–50 mg/day PO
Sertraline	Agoraphobia Panic Disorders Generalized Anxiety Disorder Social Anxiety Disorder	Initial: 25 mg/day PO Target: 50–200 mg/day PO

• SSRIs
  • Mechanism of Action
    • SSRIs work by increasing the amount of serotonin in the brain. The serotonin helps regulate the levels of norepinephrine and CRF, both of which play a role in anxiety.
  • Side effects
    • Common side effects include: nausea, insomnia, agitation, sweating, dry mouth, headaches, and sexual dysfunction. When starting a SSRI it is important to watch for serotonin syndrome. Common signs of this include increased body temperature, tremor, sweating and dilated pupils.
  • Pregnancy and Lactation
    • Citalopram, fluoxetine, sertraline and fluvoxamine are safe to use during pregnancy, however when used during the third trimester, it may lead to something known as behavioral syndrome, which results in tremors and agitation in the newborn⁸. Paroxetine should be avoided in pregnancy because it could cause cardiac abnormalities in the newborn⁶.
    • When breast feeding, the most common SSRI that is prescribed is sertraline. Lower amounts of sertraline get into the breast milk, suggesting that it is safe to use while breast feeding⁸.

Table 4B: SNRIs⁶

SNRI	Type of Anxiety it is Used For	Dosage
Duloxetine	Generalized Anxiety Disorder	Initial: 30 mg/day PO Target: 60–120 mg/day PO
Venlafaxine	Generalized Anxiety Disorder Social Anxiety Disorder	Initial: 37.5 mg/day PO Target: 75–300 mg/day PO

• SNRIs
  • Mechanism of Action
    • SNRIs work by increasing the amount of serotonin in the brain, and at higher doses they also help regulate the amount of norepinephrine in the brain. The serotonin helps regulate the levels of norepinephrine and CRF, both of which play a role in anxiety.
  • Side Effects
    • Common side effects include: nausea, insomnia, agitation, dizziness, drowsiness, sweating, dry mouth, headaches, and sexual dysfunction. When starting a SSRI it is important to watch for serotonin syndrome. Common signs of this include increased body temperature, tremor, sweating and dilated pupils⁶.
  • Pregnancy and Lactation
    • Similar to SSRIs, the use of SNRIs in the third trimester are contraindicated due to the potential risk of behavioral syndrome (refer to SSRIs)⁸.
    • Venlafaxine and Duloxetine are both excreted into breast milk. Though studies have shown minimum risk to the infant, and most studies show that the amount actually getting to the infant are minimum, there are still safer options to choose from before using an SNRI while breast feeding⁸.

Table 4C: Benzodiazepines Used in Anxiety Disorders^{6, 9}

Benzodiazepine	Type of Anxiety it is Used For	Dosage
Clonazepam	Agoraphobia Panic Disorders Generalized Anxiety Disorder Social Anxiety Disorder	Initial: 0.25–0.5 mg BID PO Target: 1–2 mg daily PO
Lorazepam	Agoraphobia Panic Disorders Generalized Anxiety Disorder	Initial: 0.5 mg TID-QID PO Target: 2–8 mg daily PO
Alprazolam9	Panic Disorder Anxiety Disorders	Usual dose: 0.25 – 0.5 mg TID9
Bromazepam9	Anxiety Disorders	Initial: 6 – 18 mg daily in divided doses9 Target: 6 – 30 mg daily in divided doses9
Clorezepate9	Panic Disorders Anxiety Disorders	7.5 – 15 mg BID to QID9
Chlordiazpoxide9	Anxiety Disorders	5 – 25 mg TID to QID9

• Benzodiazepines
  • Mechanism of Action
    • Benzodiazepines work by enhancing the effect of GABA neurotransmitters and GABA receptors within the brain. GABA is an inhibitory neurotransmitter, which results in a relaxing and calming effect.
  • Side Effects
    • Common side effects include drowsiness, fatigue, muscle weakness, reduced concentration and confusion⁶. It is important not to operate a car if you experience any of these side effects after taking a benzodiazepine.
  • Pregnancy and Lactation
    • The use of benzodiazepines is not recommended in pregnant females because it could result in something known as floppy infant syndrome. This is when the infant has low muscle tone and reduced muscle strength⁸.
    • Lorazepam and clonazepam cross into the breast milk, however studies have shown that there is no sedation in the infants after being breast-fed. However, when looking into resources, clonazepam seems to be a safer option and it gets a compatible rating whereas lorezapam has a potential for toxicity⁸.

Table 4D: GABA Derivatives Used in Anxiety Disorders⁶

GABA Derivative	Type of Anxiety it is Used For	Dosage
Pregabalin	Generalized Anxiety Disorder Social Anxiety Disorder	Initial: 50 mg TID PO Generalized Anxiety Disorder target: 150–600 mg daily PO in divided doses Social Anxiety Disorder target: ≥600 mg daily PO in divided doses

 GABA Derivatives

• • Mechanism of Action
    • Pregabalin binds to calcium channels in the brain, which results in a decrease in the release of excitatory neurotransmitters such as norepinephrine.
  • Side Effects
    • Common side effects include drowsiness, fatigue, dizziness, ataxia, nausea, headaches and tremor⁶. It is important to note that these side effects are usually dose related, and the higher the dose, the more prevalent the side effects come.
  • Pregnancy and Lactation
    • There is no human data on the use of pregabalin in pregnancy; hence it is best to avoid it⁸.
    • Pregabalin is freely secreted into the breast milk. Studies have shown that there were no adverse effects in the infants being breast-fed, however if a mother does decide to breast feed her infant while taking pregabalin, it is important to watch for the side effects listed above in the infant⁸.

Table 4E: Beta-Blockers Used for Anxiety Disorders – Third Line Agents⁶

Beta Blocker	Type of Anxiety it is Used For	Dosage
Propanolol	Social Anxiety Disorder related to a specific task – Eg. Stage fright	Initial: 10 mg PO 30–60 min before task PRN Target: 10–40 mg PO
Atenolol	Social Anxiety Disorder related to a specific task – Eg. Stage fright	Initial: 25 mg PO 60 minbefore task PRN Target: 25–50 mg PO

• Beta Blockers
  • Mechanism of Action
    • The beta-blockers bind to beta-receptors in the body, specifically the heart. This results in a decrease in ones heart rate, heart contraction and blood pressure. This all results in less anxiety when one is placed into a social situation that results in anxiety.
  • Side Effects
    • Common side effects include low blood pressure, which results in dizziness and drowsiness. Others include a slowed heart rate⁶.
  • Pregnancy and Lactation
    • Beta-blockers, specifically propranolol and atenolol have resulted in decreased birth weight in newborn infants, especially when used in the second and third trimester; hence they should be avoided in pregnancy⁸.
    • Propranolol and atenolol are both secreted into breast milk. There was one incident where an infant being breast-fed while the mother was taking atenolol resulted in a lower heart rate and blood pressure in the infant. If it is possible to avoid it, it is best to avoid it, but if taking a beta-blocker while breastfeeding it is important to monitor for respiratory depression and decreased heart rate in the infant.⁸

Natural Health Products

Some studied have shown that lavender taken orally may help with anxiety. There is evidence showing that lavender either taken orally as capsules, liquid and oil have resulted in a decrease in anxiety and have helped with sleep and in some cases depression as well¹⁰. Other options Ashwaghandha, which is a natural herb. Studies have shown that this also helps with stress and anxiety to a certain extent¹¹. Another option as a natural product that is getting more attention in recent years is Rhodiola rosea for generalized anxiety disorder. A pilot study had shown that when patients were diagnosed with generalized anxiety disorder, the use of Rhodiola rosea 340 mg daily for 10 weeks resulted in a decrease in anxiety¹². Though these studies show that natural products are able to decrease anxiety, stress and depression, it is important to note that there is a lot of variation in the products that were used. Moreover, the sample sizes in these studies were relatively small and having a larger sample size would result in more statistical power for these studies involving natural health products.

References

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3. Katzman MA, Bleau P, Blier P et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. BMC Psychiatry 2014;14(Suppl 1):S1.
4. American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-5. 5^e éd. Arlington (VA): American Psychiatric Publishing; 2013.
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6. Dion Nathalie & Filteau Marie-Josee In CTC [Internet]. Ottawa (ON) Anxiety Disorders. Compendium of Therapeutics 2019 [cited 2020 January 15].
7. Rickels K, Pollack MH, Feltner DE et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam.Arch Gen Psychiatry 2005;62(9):1022-30.
8. Briggs G.G., Freeman R.K., & Yaffe S. J. (2015). Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Tenth Edition. Philadelphia: Wolters/Kulwer/Lippinicott Williams & Wilkins Health.
9. CPS [Internet]. Ottawa, ON: Canadian Pharmacists Association; 2019 [cited 2020 Feb 3]. Benzodiazepine. Available from: http://www.e-therapeutics.ca. Also available in paper copy from the publisher.
10. Appleton Jeremy.Lavender Oil for Anxiety and Depression, review of literature on the safety and efficacy of lavender. Natural Medicine Journal. 2012, 4(2).
11. Morgan A. et al. An Alternative Treatment for Anxiety. A Systematic Review of Human Trial Results Reported for the Ayurvedic Herb Ashwagandha (Withania somnifera). Journal of Alternative and Complementary Medicine. 2014. 20(12): 901 – 908.Bystritsky A et al. A pilot study for Rhodiola rosea for generalized anxiety disorder (GAD). Journal of Alternative and Complementary Medicine. 2008. 14(2): 175 – 180.