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Anti-anxiety medication is pharmacological therapy to treat anxiety disorder. They aim to reduce the anxiety symptom severity, frequency and duration as well as improving the overall functioning in patients by tackling the underlying pathophysiology of anxiety disorder, insufficient brain neurotransmitters. A total of six types of medications are available to increase the concentration of signal-relaying chemicals inside the brain, like norepinephrine, serotonin, dopamine, and gamma-aminobutyric acid (GABA).

Selection of anti-anxiety drugs is mainly based on the nature of the anxiety disorders, severity of the disease, patient’s medical history and preference. There are different clinical uses, adverse effects and drug-related problems like dependence and withdrawal effects of each type of anti-anxiety medications. Consultation with healthcare professionals like doctors and pharmacists should be done before using these medications.

Early discovery and development of antidepressants
In the 1950s, Fox and Gibas (1953) synthesized iproniazid accidentally from a new antitubercular agent, isoniazid. The unintended effect of improving appetite and sleeping quality was reported in 70% depressed patients by  Loomer, Saunders, and Kline (1957). Iproniazid was later classified as monoamine oxidase inhibitor (MAOI), the first antidepressant medication.

In 1959, the first Tricyclic antidepressant (TCA), imipramine, was synthesized by Hafliger and Schinder and supplied to Dr. Roland Kuhn to test the antipsychotic effects in patients. While no antipsychotic effects were observed, imipramine showed clinical improvements in severely depressed patients with no serious side effects resulting, indicating advantage over MAOIs. Nevertheless, TCAs were later found to have anticholinergic and antihistaminergic side effects due to their ability to interact with the related receptors. The findings led to development of drugs that selectively interact with the target receptors, serotonin and norepinephrine receptors.

First selective serotonin reuptake inhibitor (SSRI), fluoxetine, was synthesized and reported by pharmaceutical company Eli Lily in 1974. After approval by FDA in 1987, few more SSRI s like sertraline, paroxetine, escitalopram have entered the market.

In 1993, the first selective serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine, entered the market as an atypical depressant drug. SNRI s can target serotonin and norepinephrine transporters while imposing insignificant effect on other adrenergic (α1, α2, and β), histamine (H1), muscarinic, dopamine, or postsynaptic serotonin receptors.

== Nature and Aetiology == Anxiety is a naturally occurring emotion and an innate response of the body to the environmental stimuli. Mild to moderate anxiety would improve one’s performance. However, when anxiety levels exceed the tolerability of a person, anxiety disorders may occur. People suffering from anxiety disorders could present symptoms even without external stimuli, like defensive behaviors such as fear responses, high levels of alertness and negative emotions. Sufferers of anxiety disorders are often found to have concurrent psychological disorders, most commonly depression. Anxiety disorders are divided into six types in clinical recognition as follows.

Different types of anxiety disorders share some general symptoms while having their own distinctive symptoms. Therefore, sufferers of different types of anxiety disorders respond differently to different classes of anti-anxiety medications.

Classifications
There currently are six groups of anti-anxiety medications showing significant clinical evidence in different types of anxiety disorders.

Both SSRI s and SNRI s are first-line anti-anxiety medications, with the former one indicated for all types of anxiety disorders while the latter one indicated for generalized anxiety disorder (GAD). TCA s cause more significant adverse effects compared to the first-line treatment, limiting its application as second-line treatment. Benzodiazepine s are effective in emergent and short term treatment of anxiety disorders due to their fast onset. However, long term use of them may cause dependence problems. Buspirone is indicated for GAD, which has much slower onset but with the advantage of less sedating and withdrawal effects. The groups of medications are as follows.

Antidepressants
Antidepressants produce anti-anxiety effects based on the monoamine hypothesis, a psychopathology suggesting that depression is caused by the deficiency of three key monoamine neurotransmitters (serotonin, norepinephrine and dopamine) in the brain. Monoamines are produced and stored in the presynaptic neuron, after being released to activate the postsynaptic neuron upon excitation, they are reuptaken into the presynaptic neuron for recycling use.

SSRI

 * Citalopram
 * Escitalopram
 * Fluoxetine

SNRI

 * Venlafaxine
 * Duloxetine

SSRI s and SNRI s are the most commonly used and effective first-line anti-anxiety drugs, beneficial in long-term treatment of wide ranges of anxiety disorders.

SSRI increases the serotonin level by inhibiting serotonin reuptake pumps in presynaptic neurons. Although more serotonin accumulated leads to anti-anxiety effects, overstimulation of serotonin receptors can generate side effects like nausea, insomnia, sexual dysfunction and so on.

SNRI s have similar mechanisms as SSRI s except that SNRI s block the reuptake of norepinephrine besides serotonin. Accumulation of increasing norepinephrine stimulates more noradrenergic activities, leading to side effects limited to SSRI s, like elevated blood pressure and heart rate.

Generally, 4-6 weeks are needed for both SSRIs and SNRIs to exert their full effect, as the nerve fiber s at first respond to the surge of neurotransmitters by inhibiting its further secretion, yet is eventually desensitized after the prolonged rising amount of neurotransmitters.

Using SSRI s and SNRI s in the long term can lead to reduction of postsynaptic receptors, the brain is incapable of up regulating the number of postsynaptic receptors shortly if the medication is discontinued abruptly. This phenomenon contributes to high risk of withdrawal effects like headache and flu-like symptoms, which is more obvious in the second generation of antidepressants with short half-life. Long half-life drugs like fluoxetine and its active metabolite causes the least withdrawal symptoms.

TCA

 * Imipramine
 * Clomipramine

TCA s are first generation antidepressant s indicated for anxiety disorders and depression. Besides blocking the reuptake of serotonin and norepinephrine, TCA s also block histamine and muscarinic receptors, causing a wide range of anticholinergic side effects. Therefore, TCA s are known as ‘dirty antidepressants’ and are replaced by the ‘clean antidepressants’, SSRI s and SNRIS with a much lower adverse effect profile and wide range of clinical applications.

Long acting

 * Chlordiazepoxide
 * Diazepam

Short acting

 * Lorazepam
 * Oxazepam
 * Alprazolam

Benzodiazepine is a drug class that depresses the central nervous system to produce anti-anxiety, muscle relaxing, sedating, memory improving effects. It works by binding to gamma amino butyric acid (GABA) type A receptors to enhance the bonding between GABA and its receptors. GABA produces soothing effects on the brain by inhibiting excitation of neurons.

Benzodiazepines can be used in managing panic attack s as needed. Also, benzodiazepines are indicated for short term treatment (around 2-4 weeks) of three types of anxiety disorders namely GAD, social anxiety disorder, panic disorder as well as insomnia.

Although short term use of benzodiazepine is generally safe, some noticeable adverse effects like drowsiness, fatigue, unconsciousness, muscle tone reduction, weak control of muscle and voluntary movement may occur.

Benzodiazepine is generally not recommended for long term use (longer than one month) as it is associated with rebounding original symptoms, tolerance of therapeutic effects and benzodiazepine-related disorders. Long term use should be monitored carefully if needed. Also, using benzodiazepines with longer half life or consider combination treatments with SSRI s can help reduce the risk of adverse effects.

Discontinuation of benzodiazepine requires gradual tapering depending on the current dose, indication and patient’ s situation to prevent potential withdrawal symptoms.

In terms of contraindications, benzodiazepine should not be used in people with “myasthenia gravis, ataxia, sleep apnea syndrome, chronic respiratory insufficiency, spinal and cerebral ataxia, angle-closure glaucoma, or acute CNS-depressant intoxication.”

The use of benzodiazepine should be avoided in elderly if possible, given that benzodiazepine may increase their risk of confusional state and hip fractures. If benzodiazepine is necessary to prescribe to the elderly, lorazepam, oxazepam and temazepam are relatively safer choices due to their non-oxidative hepatic metabolism. Also, benzodiazepine should be carefully prescribed to pregnant women or women at childbearing age due to its class D teratogen nature. In other words, benzodiazepine has the risk of causing irreversible damage to the fetus while having considerable benefits in women.

The choice of the benzodiazepine depends on the pharmacological profiles, including its strength of effect and time taken for metabolism, which are diverse in all types of benzodiazepine.

Buspirone
Buspirone is an atypical anxiolytic with partial serotonin agonism. It is indicated for GAD patients who do not respond to first-line antidepressants in the long term. Besides, patients contraindicated to benzodiazepine due to the substance use history can use buspirone as it does not cause an addictive and dependence problem. No sedating, withdrawal effect and tolerance problems are observed in buspirone.

Antiepileptics

 * pregabalin

It is effective in GAD due to the GABAergic properties. Common side effects include sedation, dizziness and weight gain which are well-tolerated. Usage in patients with opioid using history should be cautious due to the overdose death risk.

Antipsychotic

 * Olanzepine
 * Risperidone

Some atypical antipsychotics are suggested as adjunct therapy to antidepressants when the response to first-line anti-anxiety medication is not optimal. For example, first-line anti-anxiety medications have limited benefits in PTSD patients; atypical antipsychotic s like olanzapine and risperidone are supplemented to treat the psychotic symptoms. Both olanzapine and risperidone are norepinephrine 𝛼1 antagonist s that producing anxiolytic-like effects. Olanzapine also blocks serotonin (5HT2A and 5HT2C) receptors especially in combination with a SSRI, fluoxetine.

Nevertheless, the use of atypical antipsychotic has limited effects with high discontinuation risks caused by the wide range of adverse effects like weight gain, oedema, joint stiffness, fever, sexual dysfunction and so on. Antipsychotics should be carefully used in elderly and pregnant or breastfeeding women with evaluation of benefits and side effects.

Beta-adrenoceptor antagonists

 * Atenolol

Beta blockers are originally used for heart disease, which is shown useful to provide symptomatic relief in acute anxiety attacks. By blocking the epinephrine binding in nervous system, cardiovascular symptoms like heart rate and blood pressure can be solved.

Compared to  benzodiazepine, the mainstream short acting anti-anxiety medication, beta blocker is associated with less side effects, dependence and abuse problems. It is suggested that beta blocker can be used in combination with antimuscarinic drugs to provide more comprehensive coverage of panic attack symptoms, including sweating, tremor, nausea, vomiting and so on. The combination is generally well tolerated with common side effects like dry mouth, bradycardia, hypotension, dizziness and so on.