Trazodone

Article Author:
Justin Shin
Article Editor:
Abdolreza Saadabadi
Updated:
6/5/2019 1:30:08 PM
PubMed Link:
Trazodone

Indications

Trazodone is an FDA-approved antidepressant for treating major depressive disorders.[1] It can be used as part of a combination therapy with other drugs or psychotherapies or used by itself for treating depression. Non FDA-approved use is meant 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 been shown to reduce episodes of a nightmare as well as improving sleep habits in studies involving PTSD patients. However, various studies show panic symptoms have been exacerbated in certain cases, which is why SSRIs, instead of trazodone, are preferred as the first-line treatment for PTSD. In addition, trazodone has been shown 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 risk of respiratory instability.[3]

Mechanism of Action

Trazodone is an antidepressant that works by inhibiting both serotonin transporter and serotonin type 2 receptor. 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. In addition, 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 is commonly seen 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 is administered orally. 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 a 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 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 tablet, and in some cases, oral drops and injection solution.

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 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 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 indicated 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 has been associated with visual hallucinations.[7] Hallucinations were found to resolved with discontinuation, and physicians should change to a different antidepressant medication.

Contraindications

Trazodone is to be used with care 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 should be used with 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 therapy 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 increase in drug levels of trazodone increasing risk of serotonin syndrome and cardiovascular adverse effects.[9]

Toxicity

Due to the metabolism of trazodone in the liver and kidney, special care is recommended 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 3 months, but reported cases require liver transplantation. 

Enhancing Healthcare Team Outcomes

To properly administer medications for the appropriate population, presence of clear communication and instruction is necessary. In addition to healthcare providers being able to communicate with each other, patients must be feel comfortable enough to be involved in the treatment process. Providers having appropriate empathy for patients is necessary for patients to communicate their needs to providers. [11]


References

[1] Schwasinger-Schmidt TE,Macaluso M, Other Antidepressants. Handbook of experimental pharmacology. 2018 Sep 8;     [PubMed PMID: 30194544]
[2] Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold., Smales ET,Edwards BA,Deyoung PN,McSharry DG,Wellman A,Velasquez A,Owens R,Orr JE,Malhotra A,, Annals of the American Thoracic Society, 2015 May     [PubMed PMID: 25719754]
[3] Trazodone increases the respiratory arousal threshold in patients with obstructive sleep apnea and a low arousal threshold., Eckert DJ,Malhotra A,Wellman A,White DP,, Sleep, 2014 Apr 1     [PubMed PMID: 24899767]
[4] New-Generation, non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmacological Interactions. Part 1: SNRIs, SMSs, SARIs, Mandrioli R,Protti M,Mercolini L,, Current medicinal chemistry, 2017 Jul 12     [PubMed PMID: 28707591]
[5] Rediscovering trazodone for the treatment of major depressive disorder., Fagiolini A,Comandini A,Catena Dell'Osso M,Kasper S,, CNS drugs, 2012 Dec     [PubMed PMID: 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. Rivista di psichiatria. 2018 Sep-Oct;     [PubMed PMID: 30353201]
[7] Distressing Visual Hallucinations after Treatment with Trazodone., Santos G,Moreira AM,, Case reports in psychiatry, 2017     [PubMed PMID: 28702268]
[8] Acute Liver Failure due to Trazodone and Diazepam., Carvalhana S,Oliveira A,Ferreira P,Resende M,Perdigoto R,Barroso E,, GE Portuguese journal of gastroenterology, 2017 Jan     [PubMed PMID: 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]. Psychiatria polska. 2011 Jul-Aug;     [PubMed PMID: 22232986]
[10] Jurek L,Nourredine M,Megarbane B,d'Amato T,Dorey JM,Rolland B, [The serotonin syndrome: An updated literature review]. La Revue de medecine interne. 2018 Sep 19;     [PubMed PMID: 30243558]
[11] Nichol JR,Nelson G, Medical History 2018 Jan;     [PubMed PMID: 30484996]