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 managing 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 indications for trazodone, including off-label indications.
• Describe the common adverse effects associated with trazodone use.
• Review the treatment considerations for patients on trazodone.
• 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.

Indications

FDA-approved 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 Uses

Trazodone is used 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.[2]

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 demonstrated to reduce episodes of nightmares as well as improve sleep habits in studies involving PTSD patients. However, various studies show patients with 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.[3] It raises the respiratory threshold, lowering the risk of respiratory instability.[4]

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, explaining its off-label uses. Trazodone is in the category of SARI drugs (serotonin antagonist and reuptake inhibitors), with other members being phenylpiperazine, etoperidone, lorpiprazole, and mepiprazole.[5]

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.[6] The unique property of trazodone, where it simultaneously inhibits SERT, 5-HT2A, and 5-HT2C receptors, 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 astrocytes showed trazodone helps decrease inflammatory mediator release and helps normalize trophic and metabolic support during inflammation of neurons, which is associated with major depression.

Administration

Trazodone administration is via the oral route. It is available in oral tablets of trazodone hydrochloride 50 mg, 100 mg, 150 mg, and 300 mg in the US. 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 regimen helps optimize its purpose as an antidepressant, eliciting higher compliance.[7] The dose may be increased every third day, up to 300 mg per day. The dose may be up to 600 mg per day in hospitalized patients. The dose in the elderly should be down to 100 mg per day. Results of multi-drug regiment studies showed that using citalopram and fluoxetine with trazodone had no significant impact on any alteration of serum level and no increased risk of headache, sedation, or serotonin syndrome.

Studies showed that administering 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 and, in some countries, prolonged-release tablets, oral drops, and injection solutions.

Pediatric Patients 

There is a boxed warning on an increased risk of suicidal thoughts and behaviors in pediatric patients with antidepressant medication use. However, effectiveness and safety in the pediatric population have not been established for trazodone. 

Geriatric Patients

It should be used carefully in elderly patients as serotonergic antidepressants are associated with hyponatremia in elderly patients, who are already at greater risk for this adverse reaction. 

Pregnancy Consideration

Healthcare providers should register pregnant patients with depression in the National Pregnancy Registry for Antidepressants by calling 1-844-405-6185, which monitors pregnancy outcomes in patients exposed to antidepressants during pregnancy. Published literature on trazodone use in pregnant women has not found any associated risks of miscarriage, major congenital disabilities, and adverse maternal or fetal outcomes.[8] The clinical study was conducted on 201 pregnant patients with major depressive disorder history who become euthymic while using antidepressants at the beginning of pregnancy. It showed that patients who discontinued antidepressants during pregnancy have more chances to experience a relapse of major depression than women who continued treatment with antidepressants. Therefore, it is advisable to consider the risk of untreated depression if planning to discontinue or change antidepressant treatment while a patient is pregnant or postpartum

Breastfeeding Consideration

Trazodone is excreted into human milk, and there is a lack of data on its effect on milk production.[9] Postmarketing reports have limited data, and it has not identified an association of adverse effects of trazodone use on the breastfed child. Maternal need of trazodone should be accessed along with risk on development and health benefits of breastfeeding to the child. According to the safety scoring system use of trazodone should be used cautiously while breastfeeding, especially infants.[10]

Hepatic Impairment

Trazodone use is not studied in patients with liver impairment, and it is recommended to use trazodone with caution in this population.

Renal Impairment

Trazodone use is not studied in patients with renal impairment, and it is recommended to use trazodone with caution in this population.[11]

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 those with pre-existing heart conditions, 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 with 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.[12]

In some cases, trazodone use has correlated with visual hallucinations. Hallucinations generally resolve with the discontinuation of trazodone, and physicians should switch the patient to another antidepressant medication.[13]

Contraindications

Trazodone therapy requires careful consideration for patients treated with any class of monoamine oxidase inhibitors (MAOIs), including linezolid or intravenous methylene blue. MAO inhibitors impair the metabolism of serotonin, and concurrent administration increases serum levels of serotonin. Therefore, one must have 14 days of the MAOI-free period to reduce the risk of serotonin syndrome before initiating treatment with trazodone. In addition, concomitant use of other serotonergic drugs, such as triptans, TCA, or fentanyl, will also increase serotonin levels. Trazodone use requires caution in patients with compromised liver function and renal function.[14]

Monitoring

Baseline liver functions require monitoring 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 increased levels of trazodone, increasing the risk of serotonin syndrome and cardiovascular adverse effects.[15] Health care providers should assess the response to trazodone therapy and consider augmenting or switching antidepressants if inadequate response.

Toxicity

Due to trazodone's hepatic and renal metabolism, 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. 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 certain antidepressants, antibiotics, migraine medications, antiemetics, and analgesics. The idiopathic drug-induced liver injury may result from trazodone administration. The timeframe typically is three months, but reported cases require liver transplantation.[16]

Trazodone overdose can precipitate arrhythmias, respiratory arrest, coma, and priapism. Treatment is usually symptomatic and supportive in the case of hypotension and excessive sedation. If priapism occurs, it requires urgent urologist interventuon. Intracavernosal injection (phenylephrine injection) is indicated in patients with ischemic priapism. The medical team should call the local poison center for up-to-date guidance on trazodone overdose.[17]

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.[18] An interprofessional healthcare team incorporating clinicians, mid-level practitioners, nurses, psychological professionals, and pharmacists will lead to optimal patient care with minimal adverse events. [Level 5]