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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.[1] 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).[1]
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.[2] 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.
History
[edit]Early discovery and development of antidepressants
[edit]In the 1950s, Fox and Gibas (1953) synthesized iproniazid accidentally from a new antitubercular agent, isoniazid.[3] The unintended effect of improving appetite and sleeping quality was reported in 70% depressed patients by Loomer, Saunders, and Kline (1957).[4] Iproniazid was later classified as monoamine oxidase inhibitor (MAOI), the first antidepressant medication.[5]
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.[6] While no antipsychotic effects were observed, imipramine showed clinical improvements in severely depressed patients with no serious side effects resulting, indicating advantage over MAOIs.[6] 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.[5]
First selective serotonin reuptake inhibitor (SSRI), fluoxetine, was synthesized and reported by pharmaceutical company Eli Lily in 1974.[5] After approval by FDA in 1987, few more SSRIs like sertraline, paroxetine, escitalopram have entered the market.[5]
In 1993, the first selective serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine, entered the market as an atypical depressant drug.[5] SNRIs 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.[5]
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.
| Type | Description |
|---|---|
| Generalized anxiety disorders (GAD) | The anxiety symptoms are usually persistent and constant. Patients of this disorder could experience excessive anxiety for a long duration, commonly over 6 months and the symptoms could occur without any specific triggers. |
| Panic disorder | This disorder specifically refers to the suffering from panic attacks and also the fear of repetitive attacks. Commonly found in agoraphobia patients ( the fear of difficulty in leaving a confined venue). Panic attacks are sudden upsurge in anxiety level usually with unexplained reasons. |
| Social phobia | This refers to the fear of staging in social situations where one experiences public observation among people or performs in front of the public. The fears are often unexplained and persistent. The fear could also be attributed to the possible humiliation in front of others due to poor performance or awkward social interactions. |
| Specific phobias | Persistent fear towards a specific object, either tangible or intangible. This leads to undeniable avoidance or thought of escape from the object or endurance of the object in immense levels of anxiety. |
| Post-traumatic stress disorder (PTSD) | PTSDs develop due to experience of severe trauma or life-threatening events. Specific symptoms include flashbacks of the traumatic events during the encounter to the similar situations and avoidance of these situations. The fear of re-experiencing the event is also associated with feelings of helplessness or horror. |
| Obsessive-compulsive disorder (OCD) | Person with OCD would experience compulsive impulses of removing an obsession. One common example is the obsession with impurities or contamination. The person would have compulsion or urge in sterilizing the environment to remove the contamination. Another example is the obsession with orderliness. The person would manipulate the surroundings including visual presentations to ease their compulsion. |
There currently are six groups of anti-anxiety medications showing significant clinical evidence in different types of anxiety disorders.
Both SSRIs and SNRIs 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). TCAs cause more significant adverse effects compared to the first-line treatment, limiting its application as second-line treatment. Benzodiazepines 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.
| Drug Class | Examples |
|---|---|
| Antidepressants | SSRI, SNRI, MAOIs, TCAs |
| Benzodiazepines | Lorazepam, diazepam , alprazolam |
| Buspirone | Buspirone |
| Antiepileptics | Pregabalin |
| Antipsychotics | Olanzapine, risperidone |
| Beta-adrenoceptor antagonists | Propranolol |
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.[5] 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.[8]
SSRIs and SNRIs are the most commonly used and effective first-line anti-anxiety drugs, beneficial in long-term treatment of wide ranges of anxiety disorders.[8]
SSRI increases the serotonin level by inhibiting serotonin reuptake pumps in presynaptic neurons.[8] 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.[8]
SNRIs have similar mechanisms as SSRIs except that SNRIs block the reuptake of norepinephrine besides serotonin.[8] Accumulation of increasing norepinephrine stimulates more noradrenergic activities, leading to side effects limited to SSRIs, like elevated blood pressure and heart rate.[9]
Generally, 4-6 weeks are needed for both SSRIs and SNRIs to exert their full effect, as the nerve fibers at first respond to the surge of neurotransmitters by inhibiting its further secretion, yet is eventually desensitized after the prolonged rising amount of neurotransmitters.[10]
Using SSRIs and SNRIs 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.[11] 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.[11] Long half-life drugs like fluoxetine and its active metabolite causes the least withdrawal symptoms.[11]
TCAs are first generation antidepressants indicated for anxiety disorders and depression.[8] Besides blocking the reuptake of serotonin and norepinephrine, TCAs also block histamine and muscarinic receptors, causing a wide range of anticholinergic side effects.[8] Therefore, TCAs are known as ‘dirty antidepressants’ and are replaced by the ‘clean antidepressants’, SSRIs and SNRIS with a much lower adverse effect profile and wide range of clinical applications.[8]
Long acting
[edit]Short acting
[edit]Benzodiazepine is a drug class that depresses the central nervous system to produce anti-anxiety, muscle relaxing, sedating, memory improving effects.[12] It works by binding to gamma amino butyric acid (GABA) type A receptors to enhance the bonding between GABA and its receptors.[12] GABA produces soothing effects on the brain by inhibiting excitation of neurons.[13]
Benzodiazepines can be used in managing panic attacks as needed.[12] 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.[12]
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.[12]
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.[12] Long term use should be monitored carefully if needed.[12] Also, using benzodiazepines with longer half life or consider combination treatments with SSRIs can help reduce the risk of adverse effects.[12]
Discontinuation of benzodiazepine requires gradual tapering depending on the current dose, indication and patient’ s situation to prevent potential withdrawal symptoms.[12]
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.”[14]
The use of benzodiazepine should be avoided in elderly if possible, given that benzodiazepine may increase their risk of confusional state and hip fractures.[12] If benzodiazepine is necessary to prescribe to the elderly, lorazepam, oxazepam and temazepam are relatively safer choices due to their non-oxidative hepatic metabolism.[12] Also, benzodiazepine should be carefully prescribed to pregnant women or women at childbearing age due to its class D teratogen nature.[12] In other words, benzodiazepine has the risk of causing irreversible damage to the fetus while having considerable benefits in women.[12]
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 is an atypical anxiolytic with partial serotonin agonism.[15] It is indicated for GAD patients who do not respond to first-line antidepressants in the long term.[15] Besides, patients contraindicated to benzodiazepine due to the substance use history can use buspirone as it does not cause an addictive and dependence problem.[15] No sedating, withdrawal effect and tolerance problems are observed in buspirone.[15]
It is effective in GAD due to the GABAergic properties.[16] Common side effects include sedation, dizziness and weight gain which are well-tolerated.[16] Usage in patients with opioid using history should be cautious due to the overdose death risk.[16]
Some atypical antipsychotics are suggested as adjunct therapy to antidepressants when the response to first-line anti-anxiety medication is not optimal.[17] For example, first-line anti-anxiety medications have limited benefits in PTSD patients; atypical antipsychotics like olanzapine and risperidone are supplemented to treat the psychotic symptoms.[18] Both olanzapine and risperidone are norepinephrine 𝛼1 antagonists that producing anxiolytic-like effects. Olanzapine also blocks serotonin (5HT2A and 5HT2C) receptors especially in combination with a SSRI, fluoxetine.[18]
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.[19] Antipsychotics should be carefully used in elderly and pregnant or breastfeeding women with evaluation of benefits and side effects.[19]
Beta blockers are originally used for heart disease, which is shown useful to provide symptomatic relief in acute anxiety attacks.[20] By blocking the epinephrine binding in nervous system, cardiovascular symptoms like heart rate and blood pressure can be solved.[20]
Compared to benzodiazepine, the mainstream short acting anti-anxiety medication, beta blocker is associated with less side effects, dependence and abuse problems.[20] 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.[20] The combination is generally well tolerated with common side effects like dry mouth, bradycardia, hypotension, dizziness and so on.[20]
References
[edit]- ^ a b O’Donnell, JM; Bies, R.R; Shelton, R.C (2017). "Drug therapy of depression and anxiety disorders". The Pharmacological Basis of Therapeutics. Brunton L.L., & Hilal-Dandan R, & Knollmann B.C.(Eds.), Goodman & Gilman's.
- ^ Gale, Christopher; Oakley-Browne, Mark (2004-05-01). "Generalised anxiety disorder". Evidence-Based Mental Health. 7 (2): 32–33. doi:10.1136/ebmh.7.2.32. ISSN 1362-0347.
- ^ Fox, H. Herbert; Gibas, John T. (1953-08). "Synthetic tuberculostats. V. Alkylidene derivatives of isonicotinyhydrazine". The Journal of Organic Chemistry. 18 (8): 983–989. doi:10.1021/jo50014a012. ISSN 0022-3263.
{{cite journal}}: Check date values in:|date=(help) - ^ Kline, Nathan S.; Saunders, John C. (1957-03). "Reserpine in Psychiatric and Neurologic Disorders". Medical Clinics of North America. 41 (2): 307–326. doi:10.1016/s0025-7125(16)34438-8. ISSN 0025-7125.
{{cite journal}}: Check date values in:|date=(help) - ^ a b c d e f g Hillhouse, Todd M.; Porter, Joseph H. (2015-02). "A brief history of the development of antidepressant drugs: From monoamines to glutamate". Experimental and Clinical Psychopharmacology. 23 (1): 1–21. doi:10.1037/a0038550. ISSN 1936-2293.
{{cite journal}}: Check date values in:|date=(help) - ^ a b KUHN, ROLAND (1958-11). "THE TREATMENT OF DEPRESSIVE STATES WITH G 22355 (IMIPRAMINE HYDROCHLORIDE)". American Journal of Psychiatry. 115 (5): 459–464. doi:10.1176/ajp.115.5.459. ISSN 0002-953X.
{{cite journal}}: Check date values in:|date=(help) - ^ a b "Roger Walker and Clive Edwards, Clinical Pharmacy and Therapeutics (3rd Edition) London: Churchill Livingstone, 2003". Journal of Pharmacy and Pharmacology. 55 (12): 1709–1709. 2003-12. doi:10.1111/j.2042-7158.2003.tb02481.x. ISSN 0022-3573.
{{cite journal}}: Check date values in:|date=(help) - ^ a b c d e f g h Lorman, William J. (2018-10). "Pharmacology Update: The Selective Serotonin Reuptake Inhibitors". Journal of Addictions Nursing. 29 (4): 260–261. doi:10.1097/JAN.0000000000000250. ISSN 1548-7148.
{{cite journal}}: Check date values in:|date=(help) - ^ stork, CM (2019). Serotonin Reuptake Inhibitors and Atypical Antidepressants. Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank's Toxicologic Emergencies, 11e. McGraw Hill.
- ^ Lochmann, Dee; Richardson, Tara (2019), Macaluso, Matthew; Preskorn, Sheldon H. (eds.), "Selective Serotonin Reuptake Inhibitors", Antidepressants: From Biogenic Amines to New Mechanisms of Action, Cham: Springer International Publishing, pp. 135–144, doi:10.1007/164_2018_172, ISBN 978-3-030-10949-3, retrieved 2022-04-20
- ^ a b c Bandelow, Borwin; Michaelis, Sophie; Wedekind, Dirk (2017-06-30). "Treatment of anxiety disorders". Dialogues in Clinical Neuroscience. 19 (2): 93–107. doi:10.31887/dcns.2017.19.2/bbandelow. ISSN 1958-5969.
- ^ a b c d e f g h i j k l m Champion, Claire; Kameg, Brayden N. (2021-03). "Best practices in benzodiazepine prescribing and management in primary care". The Nurse Practitioner. 46 (3): 30–36. doi:10.1097/01.NPR.0000733684.24949.19. ISSN 0361-1817.
{{cite journal}}: Check date values in:|date=(help) - ^ Griffin, Charles E.; Kaye, Adam M.; Bueno, Franklin Rivera; Kaye, Alan D. (2013). "Benzodiazepine Pharmacology and Central Nervous System–Mediated Effects". The Ochsner Journal. 13 (2): 214–223. ISSN 1524-5012. PMC 3684331. PMID 23789008.
- ^ Soyka, Michael (2017-03-23). Longo, Dan L. (ed.). "Treatment of Benzodiazepine Dependence". New England Journal of Medicine. 376 (12): 1147–1157. doi:10.1056/NEJMra1611832. ISSN 0028-4793.
- ^ a b c d e Pepa, PA; Lee, KC (2019). Anxiety Disorders. Sutton S. eds. McGraw-Hill's NAPLEX® Review Guide,.
{{cite book}}: CS1 maint: extra punctuation (link) - ^ a b c Garakani, Amir; Murrough, James W.; Freire, Rafael C.; Thom, Robyn P.; Larkin, Kaitlyn; Buono, Frank D.; Iosifescu, Dan V. (2020). "Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options". Frontiers in Psychiatry. 11. doi:10.3389/fpsyt.2020.595584. ISSN 1664-0640. PMC 7786299. PMID 33424664.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ National Collaborating Centre for Mental Health (UK) (2011). Generalised Anxiety Disorder in Adults: Management in Primary, Secondary and Community Care. National Institute for Health and Clinical Excellence: Guidance. Leicester (UK): British Psychological Society. ISBN 978-1-904671-42-8. PMID 22536620.
- ^ a b Pae, Chi-Un; Lim, Hyn-Kook; Peindl, Kathleen; Ajwani, Neena; Serretti, Alessandro; Patkar, Ashwin A.; Lee, Chul (2008-01). "The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials". International Clinical Psychopharmacology. 23 (1): 1–8. doi:10.1097/YIC.0b013e32825ea324. ISSN 0268-1315. PMID 18090502.
{{cite journal}}: Check date values in:|date=(help) - ^ a b "MedicinesComplete". login.eproxy.lib.hku.hk. doi:10.18578/bnf.959187317. Retrieved 2022-04-20.
- ^ a b c d e "Overview | Generalised anxiety disorder and panic disorder in adults: management | Guidance | NICE". www.nice.org.uk. Retrieved 2022-04-20.