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Trazodone

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Last Update: May 28, 2020.

Continuing Education Activity

Trazodone is a medication used in the management and treatment of major-depressive-disorder. It is in the serotonin-antagonist-and-reuptake-inhibitor class of medications. This activity reviews the indications, action, and contraindications for trazodone as a valuable agent in the management of major depression. This activity will highlight the mechanism of actions, adverse effects, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions), pertinent for members of the interprofessional team in the treatment of patients with depression and related conditions.

Objectives:

  • Identify the pathophysiology of developing orthostatic hypotension as a side effect.
  • Describe the common adverse effects associated with trazodone use.
  • Review the treatment considerations for patients with monoamine oxidase inhibitors use
  • Explain the importance of collaboration and communication amongst interprofessional team members to improve outcomes for patients affected by severe hepatic impairment who are candidates for trazodone use.
Earn continuing education credits (CME/CE) on this topic.

Indications

Trazodone is an FDA-approved antidepressant for treating major depressive disorders.[1] It can be used as part of combination therapy with other drugs or psychotherapies or used by itself for treating depression. Non-FDA-approved use is to induce sedation in patients with sleep problems. These patients may or may not have concurrent depression. Because of a lack of sufficient clinical data for justifying its use as a sleep aid, trazodone is not FDA-approved for sleep disorders. Trazodone is also used off-label for anxiety, Alzheimer disease, substance abuse, bulimia, and fibromyalgia due to its serotonergic receptor antagonism and serotonin reuptake inhibiting effects. Trazodone has also been used for post-traumatic stress disorder (PTSD) if the first-line treatment use of SSRIs does not show efficacy. The dose of 50 mg to 200 mg of trazodone has demonstrated to reduce episodes of a nightmare as well as improving sleep habits in studies involving PTSD patients. However, various studies show panic symptoms have suffered exacerbation in some instances, which is why SSRIs, instead of trazodone, are preferred as the first-line treatment for PTSD. Additionally, research has shown trazodone to improve apnea and hypopnea episodes in patients with obstructive sleep apnea (OSA), and the drug does not worsen hypoxemic episodes.[2] It raises the respiratory threshold, lowering the risk of respiratory instability.[3]

Mechanism of Action

Trazodone is an antidepressant that works by inhibiting both serotonin transporter and serotonin type 2 receptors. It is a triazolopyridine derivative. Trazodone inhibits the reuptake of serotonin and blocks the histamine and alpha-1-adrenergic receptors. It also induces significant changes in 5-HT presynaptic receptor adrenoreceptors. The full spectrum of trazodone’s mechanism of action is not fully understood, which could explain its off-label uses. Trazodone is in the category of SARI drugs[4], (serotonin antagonist and reuptake inhibitors), with other members being phenylpiperazine, etoperidone, lorpiprazole, and mepiprazole. 

Clinical studies have shown trazodone to be comparable in efficacy to other drug classes, such as TCAs (tricyclic antidepressants), SSRIs (selective serotonin reuptake inhibitors), and SNRIs (serotonin-norepinephrine receptor inhibitor) in treating major depressive disorders. Also, trazodone has better tolerance than second-generation SSRIs, which are highly associated with insomnia, anxiety, and sexual dysfunction.[5] The unique property of trazodone, where it simultaneously inhibits SERT, 5-HT2A, and 5-HT2C receptors, is that it avoids the issue of sexual dysfunction, insomnia, and anxiety that commonly presents with SSRIs and SNRIs therapy. Trazodone reduces levels of neurotransmitters associated with arousal effects, such as serotonin, noradrenaline, dopamine, acetylcholine, and histamine. Low dose trazodone use exerts a sedative effect for sleep through antagonism of 5-HT-2A receptor, H1 receptor, and alpha-1-adrenergic receptors. 

Furthermore, a recent study on human astrocyte showed trazodone helps to decrease inflammatory mediator release, and overall helps with normalizing trophic and metabolic support during inflammation of neurons, which is associated with major depression.

Administration

Trazodone administration is via the oral route. It may be administered after meals to decrease lightheadedness and postural hypotension. Begin with evening administration, of 75 mg to 150 mg before bedtime, as a prolonged-release once a day administration. This regiment helps to optimize its purpose as an antidepressant, and it elicits higher compliance.[6] The dose may be increased every third day, up to 300 mg per day. The dose may be up to 600 mg/day in hospitalized patients. The dose in the elderly should be down to 100 mg/day. Results of multi-drug regiment studies showed the use of citalopram and fluoxetine with trazodone had no significant impact on any alteration of serum level, and no increased risk of a headache, sedation, or serotonin syndrome.

Studies showed that administration of 50 mg to 100 mg per day of trazodone helped nonorganic insomnia due to depressive disorder, with 100 mg dosage as most effective to improve sleep. Trazodone may be available as immediate-release (IR) tablets, prolonged-release tablets, and in some cases, oral drops and injection solutions.

Adverse Effects

The primary adverse effects of trazodone include headaches, fatigue, dizziness, and drowsiness/somnolence. Other risks include anticholinergic effects (dry mouth), orthostatic hypotension, QT prolongation, torsades, priapism, and an increase in suicidal thoughts. QT prolongation and arrhythmia risks are due to the interaction of trazodone with hERG potassium channels. Antidepressants are associated with an increased risk of suicidal thinking, especially in younger adults, adolescents, and children. Despite the presence of anticholinergic side effects, the risk is less than tricyclic antidepressants, such as imipramine or amitriptyline. The risk for orthostatic hypotension is higher in the elderly, especially in those with pre-existing heart conditions, and it is due to the adrenergic α1-receptor blockade. Patients show adverse effects of somnolence and hypotension during the first week of administration. Special care is necessary for men who have sickle cell anemia, multiple myeloma, leukemia, autonomic dysfunction, hypercoagulable state, or those who have a penile anatomic variation as angulation, cavernosal fibrosis, or Peyronie disease, as it can cause priapism.

In some cases, trazodone use has correlated with visual hallucinations.[7] Hallucinations generally resolve with discontinuation of trazodone, and physicians should switch the patient to a different antidepressant medication.

Contraindications

Trazodone therapy requires careful consideration for patients treated with any class of monoamine oxidase inhibitors (MAOIs), including linezolid or IV methylene blue. MAO inhibitors impair metabolism of serotonin, and concurrent administration increases serum levels of serotonin. One must have 14 days of the MAOI-free period to reduce the risk of serotonin syndrome before initiating treatment with trazodone. Concomitant use of other serotonergic drugs, such as triptans, TCA, or fentanyl, will also increase the level of serotonin. 

Trazodone use requires caution in patients with compromised liver function and renal function.[8]

Monitoring

Baseline liver function should be monitored before, or periodically during, therapy in patients taking trazodone. Patients receiving trazodone should also be monitored for suicide ideation, especially at the beginning of the treatment or when the dose is modified. Monitor also for signs or symptoms of serotonin syndrome. In addition, concomitant administration of CYP 3A4 inhibitors can lead to an increase in drug levels of trazodone, increasing the risk of serotonin syndrome and cardiovascular adverse effects.[9]

Toxicity

Due to the hepatic and renal metabolism of trazodone, special care is necessary for patients with severe hepatic impairment and severe renal impairment.

Serotonin syndrome, while rare, is potentially life-threatening, presenting as a triad of mental status alteration, neuromuscular abnormality, and autonomic instability.[10] Initial clinical suspicion varies from presenting tremor, clonus, or akathisia. The first step to address this should be discontinuation of serotonergic agents, hydration, and control of agitation with anxiolytics. The risk is higher with a certain antidepressant, antibiotics, migraine medications, antiemetic, and analgesics.

The idiopathic drug-induced liver injury may result from trazodone administration. Timeframe typically takes three months, but reported cases require liver transplantation. 

Enhancing Healthcare Team Outcomes

To properly administer medications for the appropriate population, the presence of clear communication and instruction is necessary. In addition to healthcare providers being able to communicate with each other, patients must feel comfortable enough to be involved in the treatment process. Providers having appropriate empathy for patients is necessary for patients to disclose their needs to providers.[11] An interprofessional approach will lead to optimal patient care with minimal adverse events. [Level 5]

Continuing Education / Review Questions

References

1.
Schwasinger-Schmidt TE, Macaluso M. Other Antidepressants. Handb Exp Pharmacol. 2019;250:325-355. [PubMed: 30194544]
2.
Smales ET, Edwards BA, Deyoung PN, McSharry DG, Wellman A, Velasquez A, Owens R, Orr JE, Malhotra A. Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold. Ann Am Thorac Soc. 2015 May;12(5):758-64. [PMC free article: PMC4418332] [PubMed: 25719754]
3.
Eckert DJ, Malhotra A, Wellman A, White DP. Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold. Sleep. 2014 Apr 01;37(4):811-9. [PMC free article: PMC4044741] [PubMed: 24899767]
4.
Mandrioli R, Protti M, Mercolini L. New-Generation, Non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmacological Interactions. Part 1: SNRIs, SMSs, SARIs. Curr Med Chem. 2018;25(7):772-792. [PubMed: 28707591]
5.
Fagiolini A, Comandini A, Catena Dell'Osso M, Kasper S. Rediscovering trazodone for the treatment of major depressive disorder. CNS Drugs. 2012 Dec;26(12):1033-49. [PMC free article: PMC3693429] [PubMed: 23192413]
6.
Fiorentini A, Rovera C, Caldiroli A, Arici C, Prunas C, Di Pace C, Paletta S, Pozzoli SM, Buoli M, Altamura AC. Efficacy of oral trazodone slow release following intravenous administration in depressed patients: a naturalistic study. Riv Psichiatr. 2018 Sep-Oct;53(5):261-266. [PubMed: 30353201]
7.
Santos G, Moreira AM. Distressing Visual Hallucinations after Treatment with Trazodone. Case Rep Psychiatry. 2017;2017:6136914. [PMC free article: PMC5494093] [PubMed: 28702268]
8.
Carvalhana S, Oliveira A, Ferreira P, Resende M, Perdigoto R, Barroso E. Acute Liver Failure due to Trazodone and Diazepam. GE Port J Gastroenterol. 2017 Jan;24(1):40-42. [PMC free article: PMC5553376] [PubMed: 28848778]
9.
Jarema M, Dudek D, Landowski J, Heitzman J, Rabe-Jabłońska J, Rybakowski J. [Trazodon--the antidepressant: mechanism of action and its position in the treatment of depression]. Psychiatr Pol. 2011 Jul-Aug;45(4):611-25. [PubMed: 22232986]
10.
Jurek L, Nourredine M, Megarbane B, d'Amato T, Dorey JM, Rolland B. [The serotonin syndrome: An updated literature review]. Rev Med Interne. 2019 Feb;40(2):98-104. [PubMed: 30243558]
11.
Nichol JR, Sundjaja JH, Nelson G. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Sep 7, 2020. Medical History. [PubMed: 30484996]
Copyright © 2021, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated.

Bookshelf ID: NBK470560PMID: 29262060

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