What is Trazodone? Understanding Its Uses, Side Effects, and More

Trazodone is a prescription medication primarily used in the treatment of major depressive disorder. Classified as a serotonin antagonist and reuptake inhibitor (SARI), it stands out as a versatile antidepressant that can be used alone or in combination with other treatments, including medications and psychotherapy. Trazodone’s mechanism of action is multifaceted, impacting serotonin levels in the brain and also blocking histamine and alpha-adrenergic receptors. This comprehensive action makes it effective for depression and also leads to its use in various off-label applications. This article delves into the details of trazodone, exploring its approved and off-label uses, how it works, administration guidelines, potential side effects, and important considerations for patients and healthcare providers. Understanding “What Is A Trazodone” is crucial for both individuals seeking information and healthcare professionals managing patient care.

Indications for Trazodone

Trazodone has received approval from the Food and Drug Administration (FDA) for a primary indication, and it’s also commonly used for other conditions in clinical practice.

FDA-Approved Uses of Trazodone

The primary FDA-approved use for trazodone is the treatment of major depressive disorder (MDD). It is effective as both a standalone treatment (monotherapy) and as part of a comprehensive treatment plan that may include other medications or therapeutic approaches like psychotherapy. For individuals struggling with depression, trazodone can help alleviate symptoms and improve overall mood and daily functioning.

Off-Label Uses of Trazodone

Beyond its FDA-approved indication, trazodone is frequently prescribed for insomnia. Although not officially approved by the FDA for sleep disorders due to the need for more robust clinical trials specifically for sedation, its sedative properties make it a common choice for sleep issues. Trazodone is utilized off-label to aid sleep in patients experiencing various forms of insomnia.

Furthermore, trazodone is used off-label for a range of other conditions, leveraging its unique pharmacological profile. These off-label uses include:

• Anxiety Disorders: Trazodone’s effects on serotonin receptors and reuptake can be beneficial in managing symptoms of anxiety.
• Alzheimer’s Disease: It can be used to manage behavioral symptoms and sleep disturbances that often accompany Alzheimer’s disease.
• Substance Use Disorders: Trazodone may be used in managing certain aspects of substance misuse and withdrawal.
• Bulimia Nervosa: In some cases, trazodone is used in the treatment of bulimia, potentially due to its effects on neurotransmitter systems involved in eating disorders.
• Fibromyalgia: Trazodone’s effects on pain pathways and sleep may provide relief for individuals with fibromyalgia.
• Post-Traumatic Stress Disorder (PTSD): While Selective Serotonin Reuptake Inhibitors (SSRIs) are typically first-line treatments for PTSD, trazodone can be considered, especially for managing nightmares associated with PTSD. Studies have indicated that doses between 50 to 200 mg can reduce nightmare frequency and improve sleep quality in PTSD patients. The American Academy of Sleep Medicine (AASM) suggests trazodone for treating PTSD-related nightmares. However, it’s important to note that some patients with panic symptoms might experience symptom exacerbation with trazodone, making SSRIs the preferred initial treatment for PTSD in many cases.
• Obstructive Sleep Apnea (OSA): Research suggests trazodone can improve apnea and hypopnea episodes in OSA patients without worsening hypoxemia. It is believed to raise the respiratory arousal threshold, potentially reducing respiratory instability.

Trazodone: Mechanism of Action Explained

To understand “what is a trazodone” fully, it’s important to understand how it works in the body. Trazodone’s therapeutic effects stem from its complex mechanism of action, primarily involving the modulation of serotonin activity in the brain. It belongs to the Serotonin Antagonist and Reuptake Inhibitor (SARI) class of antidepressants.

The primary mechanisms of action include:

• Serotonin Reuptake Inhibition: Trazodone inhibits the serotonin transporter (SERT), which is responsible for removing serotonin from the synapse (the space between nerve cells). By blocking this reuptake, trazodone increases the availability of serotonin in the synaptic cleft. This increased serotonin availability is thought to contribute to its antidepressant effects.
• 5-HT2 Receptor Antagonism: Trazodone is a potent antagonist at serotonin 5-HT2A and 5-HT2C receptors. Blocking these receptors is believed to contribute to its therapeutic effects in depression and anxiety. Notably, antagonism of 5-HT2A receptors is also linked to its sedative properties, making it useful for insomnia. Unlike some other antidepressants, this 5-HT2 receptor antagonism profile is thought to be associated with a lower incidence of sexual dysfunction, a common side effect with SSRIs and SNRIs.
• Alpha-1-Adrenergic and Histamine Receptor Blockade: Trazodone also blocks alpha-1-adrenergic receptors and histamine (H1) receptors. Blockade of these receptors contributes to some of its side effects, such as orthostatic hypotension (due to alpha-1 blockade) and sedation (due to H1 blockade). However, the H1 receptor blockade also adds to its sleep-promoting effects.

Comparison to Other Antidepressants:

Clinical studies have shown that trazodone’s effectiveness in treating major depressive disorder is comparable to other classes of antidepressants, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, trazodone often exhibits better tolerability than some second-generation SSRIs, which are frequently associated with side effects like insomnia, anxiety, and sexual dysfunction. Trazodone’s unique combination of SERT inhibition and 5-HT2A/2C receptor antagonism helps mitigate these common issues seen with SSRI and SNRI treatments.

Further Insights into Mechanism:

Recent research has also explored additional aspects of trazodone’s mechanism. Studies on human astrocytes suggest that trazodone may have anti-inflammatory effects in the brain. It has been shown to reduce the release of inflammatory mediators and support neuronal health during inflammation, which is increasingly recognized as a factor in major depression.

Pharmacokinetics of Trazodone:

Understanding the pharmacokinetics of trazodone is essential for optimizing its use.

• Absorption: Trazodone is rapidly absorbed after oral administration, reaching peak plasma concentrations within approximately 1 hour. Its bioavailability is high, around 100%.
• Distribution: Trazodone is highly protein-bound in plasma, with 89% to 95% binding to plasma proteins.
• Metabolism: The drug is extensively metabolized in the liver, primarily by the CYP3A4 enzyme. It has an active metabolite, meta-chlorophenylpiperazine (m-CPP). CYP2D6 plays a minor role in its metabolism.
• Excretion: Trazodone is mainly excreted in the urine. It has a terminal elimination half-life of 5 to 9 hours.

Administration and Dosage of Trazodone

Trazodone is administered orally and is available in immediate-release tablets. It is available in various strengths: 50 mg, 100 mg, 150 mg, and 300 mg tablets of trazodone hydrochloride in the United States. Taking trazodone after meals can help reduce the occurrence of lightheadedness and postural hypotension.

Dosage for Major Depressive Disorder:

• Immediate-Release Formulation: The typical starting dose is 50 to 100 mg taken orally two or three times daily. Treatment often begins at a lower dose of 25 to 50 mg two or three times daily, gradually increased in increments of 50 mg per day every 3 to 4 days.
• Maximum Dosage: For outpatients, the maximum recommended daily dose is 400 mg. For hospitalized inpatients, this can be increased to 600 mg daily.
• Extended-Release Formulation: An extended-release formulation is also available, typically administered once daily in the evening. Starting doses range from 75 to 150 mg before bedtime, with potential increases every three days, up to 300 mg daily. In hospitalized settings, doses can reach 600 mg per day. The extended-release formulation is designed to improve patient compliance by simplifying dosing to once a day.
• Discontinuation: When discontinuing trazodone, it is important to taper the dose gradually to minimize withdrawal symptoms.

Dosage for Insomnia:

• For insomnia, lower doses of trazodone are typically effective, often ranging from 50 to 100 mg per day. Studies have shown that a 100 mg dose is particularly effective for improving sleep in nonorganic insomnia related to depressive disorders.

Available Formulations:

Trazodone is primarily available in immediate-release (IR) tablets. In some countries, other formulations such as prolonged-release tablets, oral drops, and injection solutions may be available.

Specific Patient Populations:

• Hepatic Impairment: Use trazodone with caution in patients with liver impairment as it is primarily metabolized in the liver. Studies in this population are lacking, and careful monitoring is advised.
• Renal Impairment: Similar to hepatic impairment, use trazodone cautiously in patients with renal impairment due to limited studies and its excretion pathways.
• Pregnancy: Pregnant patients with depression should be registered with the National Pregnancy Registry for Antidepressants. Current research suggests that trazodone use during pregnancy is not associated with increased risks of miscarriage, congenital disabilities, or adverse maternal or fetal outcomes. It is crucial to weigh the risks of untreated depression against potential medication risks during pregnancy and postpartum.
• Breastfeeding: Trazodone is excreted in breast milk. Limited data suggests no identified adverse effects on breastfed infants, but caution is advised, especially for newborns. Consider the maternal need for trazodone against the benefits of breastfeeding.
• Pediatric Patients: Antidepressants, including trazodone, carry a boxed warning regarding an increased risk of suicidal thoughts and behaviors in pediatric patients. The safety and efficacy of trazodone in this population have not been well-established.
• Older Patients: A reduced dose of 100 mg per day is recommended for older patients. Serotonergic antidepressants like trazodone should be used cautiously in the elderly due to an increased risk of hyponatremia.

Side Effects of Trazodone

Like all medications, trazodone can cause side effects. It’s essential to be aware of these potential effects before starting treatment.

Common side effects of trazodone include:

• Central Nervous System Effects:
  • Headache
  • Fatigue
  • Dizziness
  • Drowsiness
  • Somnolence (sleepiness)

Other potential side effects, although less common, can be more serious:

• Anticholinergic Effects: Dry mouth can occur, though less pronounced compared to tricyclic antidepressants.
• Cardiovascular Effects:
  • Orthostatic hypotension (drop in blood pressure upon standing)
  • Syncope (fainting)
  • QT prolongation (an electrical heart rhythm issue)
  • Torsade de pointes (a dangerous type of arrhythmia) – These risks are linked to trazodone’s interaction with hERG potassium channels.
• Priapism: A prolonged and painful erection, is a rare but serious side effect. Men with conditions like sickle cell anemia, multiple myeloma, leukemia, or Peyronie’s disease may be at higher risk.
• Increased Suicidal Thoughts and Behaviors: As with other antidepressants, trazodone carries a boxed warning about the increased risk of suicidal thinking, especially in younger adults, adolescents, and children.

Other Considerations Regarding Side Effects:

• Orthostatic Hypotension: This is more common in older adults, particularly those with pre-existing heart conditions, due to alpha-1-adrenergic receptor blockade.
• Somnolence and Hypotension: These side effects are often most prominent during the first week of treatment.
• Visual Hallucinations: In rare cases, visual hallucinations have been reported, which typically resolve upon discontinuing trazodone.
• Mania: Trazodone-induced mania has been reported, so it’s important to assess for personal or family history of bipolar disorder before starting treatment.
• Bleeding Risk: While lower than with some other antidepressants, there is a potential for increased bleeding risk.

Boxed Warning:

Antidepressants, including trazodone, carry an FDA boxed warning about the increased risk of suicidal thoughts and behaviors in young adults and pediatric patients. Close monitoring for suicidal ideation and behaviors is essential for all patients treated with trazodone, especially at the beginning of treatment or with dose changes.

Contraindications for Trazodone Use

There are specific situations where trazodone should not be used due to potential risks.

Trazodone is contraindicated in patients:

• Taking Monoamine Oxidase Inhibitors (MAOIs): This includes MAOIs like phenelzine, tranylcypromine, isocarboxazid, and selegiline, as well as linezolid and intravenous methylene blue. Combining trazodone with MAOIs can lead to serotonin syndrome, a serious and potentially life-threatening condition due to excessive serotonin levels. Patients must be MAOI-free for 14 days before starting trazodone.
• Hypersensitivity: Known allergy to trazodone or any of its formulation components.

Precautions:

Trazodone should be used with caution in patients with:

• Liver or Kidney Dysfunction: Due to its metabolism and excretion pathways.
• Cardiac Conditions: Due to the risk of QT prolongation and orthostatic hypotension.
• History of Mania or Bipolar Disorder: As trazodone can potentially induce mania.
• Conditions Predisposing to Priapism: Such as sickle cell anemia, multiple myeloma, or Peyronie’s disease.
• Concomitant use of other serotonergic drugs: such as SSRIs, SNRIs, triptans, TCAs, fentanyl, and St. John’s Wort, due to increased risk of serotonin syndrome.

Monitoring During Trazodone Therapy

Regular monitoring is important to ensure safe and effective trazodone treatment.

Recommended monitoring includes:

• Baseline Liver Function Tests: Assess liver function before starting trazodone and periodically during therapy, especially in patients with potential liver issues.
• Monitoring for Suicidal Ideation and Behavior: Closely monitor all patients, particularly at the start of treatment and after dose adjustments, for any signs of worsening depression or suicidal thoughts.
• Serotonin Syndrome Monitoring: Be vigilant for signs and symptoms of serotonin syndrome, especially when trazodone is used with other serotonergic medications or CYP3A4 inhibitors.
• Cardiovascular Monitoring: Monitor blood pressure and heart rate, especially in older adults and those with pre-existing heart conditions, due to the risk of orthostatic hypotension and QT prolongation.
• Therapeutic Response: Regularly assess the patient’s response to trazodone therapy to determine if it is effective. If response is inadequate, consider dose adjustment, augmentation strategies, or switching to another antidepressant.
• Digoxin Levels: For patients also taking digoxin, therapeutic drug monitoring is recommended due to potential interactions.
• PT/INR Monitoring: If trazodone is used with warfarin, monitor PT/INR levels due to potential interactions affecting anticoagulation.

Trazodone Toxicity and Overdose

While generally safe when used as prescribed, trazodone overdose can be serious.

Toxicity Concerns:

• Serotonin Syndrome: Although rare, serotonin syndrome is a potentially life-threatening condition associated with excessive serotonin activity. Symptoms include mental status changes, neuromuscular abnormalities (tremor, clonus), and autonomic instability. Management involves stopping serotonergic agents, supportive care, and potentially medications to manage agitation.
• Drug-Induced Liver Injury: Idiopathic drug-induced liver injury is a rare but possible complication of trazodone. Liver damage typically occurs within the first three months of treatment, and in severe cases, liver transplantation may be required.

Overdose Symptoms:

Trazodone overdose can lead to:

• Arrhythmias
• Respiratory arrest
• Coma
• Seizures
• Priapism
• Cerebral edema
• Hyponatremia (low sodium levels)

A fatal overdose has been reported with ingestion of 6.45 grams of trazodone.

Overdose Management:

Treatment for trazodone overdose is primarily supportive and symptomatic:

• Supportive Care: Manage hypotension and excessive sedation.
• Priapism Management: If priapism occurs, urgent intervention by a urologist is necessary, often involving intracavernosal injection of phenylephrine.
• Hyponatremia Correction: Monitor and correct serum sodium levels if hyponatremia occurs.
• Poison Control: Contact the local poison control center for the most current guidance on managing trazodone overdose.

Enhancing Healthcare Team Outcomes with Trazodone

Optimizing patient outcomes with trazodone requires effective collaboration among healthcare professionals.

Interprofessional Team Approach:

• Prescribers (Psychiatrists, Primary Care Physicians): Initiate and manage trazodone therapy for appropriate indications, considering patient history, comorbidities, and potential drug interactions.
• Pharmacists: Review prescriptions for appropriate dosing, check for drug interactions, and counsel patients on medication use and potential side effects.
• Nurses: Educate patients on medication adherence, potential adverse effects, and monitor for therapeutic response and side effects.
• Clinical Psychologists and Therapists: Provide psychotherapy as part of a comprehensive treatment plan for depression and related conditions, and monitor patient progress and mental status.

Effective Communication and Collaboration:

• Clear Communication: Ensure clear communication among all team members regarding patient status, treatment plans, and any concerns.
• Patient Education: Provide comprehensive education to patients about trazodone, its benefits, risks, and the importance of adherence.
• Shared Decision-Making: Involve patients in treatment decisions, considering their preferences and concerns.
• Open Communication Channels: Establish open channels for communication among team members to facilitate timely intervention and adjustments to the treatment plan.

By fostering a collaborative, interprofessional approach, healthcare teams can maximize the benefits of trazodone therapy while minimizing potential risks, leading to improved patient safety and outcomes.

References

1.Schwasinger-Schmidt TE, Macaluso M. Other Antidepressants. Handb Exp Pharmacol. 2019;250:325-355. PubMed: 30194544

2.McQuaid JR, Buelt A, Capaldi V, Fuller M, Issa F, Lang AE, Hoge C, Oslin DW, Sall J, Wiechers IR, Williams S. The Management of Major Depressive Disorder: Synopsis of the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline. Ann Intern Med. 2022 Oct;175(10):1440-1451. PubMed: 36122380

3.Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017 Feb 15;13(2):307-349. PMC free article: PMC5263087 PubMed: 27998379

4.Khouzam HR. A review of trazodone use in psychiatric and medical conditions. Postgrad Med. 2017 Jan;129(1):140-148. PubMed: 27744763

5.Morgenthaler TI, Auerbach S, Casey KR, Kristo D, Maganti R, Ramar K, Zak R, Kartje R. Position Paper for the Treatment of Nightmare Disorder in Adults: An American Academy of Sleep Medicine Position Paper. J Clin Sleep Med. 2018 Jun 15;14(6):1041-1055. PMC free article: PMC5991964 PubMed: 29852917

6.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

7.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

8.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

9.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

10.Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, Eckermann G, Egberts K, Gerlach M, Greiner C, Gründer G, Haen E, Havemann-Reinecke U, Hefner G, Helmer R, Janssen G, Jaquenoud E, Laux G, Messer T, Mössner R, Müller MJ, Paulzen M, Pfuhlmann B, Riederer P, Saria A, Schoppek B, Schoretsanitis G, Schwarz M, Gracia MS, Stegmann B, Steimer W, Stingl JC, Uhr M, Ulrich S, Unterecker S, Waschgler R, Zernig G, Zurek G, Baumann P. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry. 2018 Jan;51(1-02):9-62. PubMed: 28910830

11.Odagaki Y, Toyoshima R, Yamauchi T. Trazodone and its active metabolite m-chlorophenylpiperazine as partial agonists at 5-HT1A receptors assessed by [35S]GTPgammaS binding. J Psychopharmacol. 2005 May;19(3):235-41. PubMed: 15888508

12.Wen B, Ma L, Rodrigues AD, Zhu M. Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metab Dispos. 2008 May;36(5):841-50. PubMed: 18238857

13.Kale P, Agrawal YK. Pharmacokinetics of single oral dose trazodone: a randomized, two-period, cross-over trial in healthy, adult, human volunteers under fed condition. Front Pharmacol. 2015;6:224. PMC free article: PMC4591485 PubMed: 26483693

14.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

15.Menza MA. Withdrawal syndrome in a depressed patient treated with trazodone. Am J Psychiatry. 1986 Sep;143(9):1195. PubMed: 3752308

16.Nagler EV, Webster AC, Vanholder R, Zoccali C. Antidepressants for depression in stage 3-5 chronic kidney disease: a systematic review of pharmacokinetics, efficacy and safety with recommendations by European Renal Best Practice (ERBP). Nephrol Dial Transplant. 2012 Oct;27(10):3736-45. PubMed: 22859791

17.Einarson A, Bonari L, Voyer-Lavigne S, Addis A, Matsui D, Johnson Y, Koren G. A multicentre prospective controlled study to determine the safety of trazodone and nefazodone use during pregnancy. Can J Psychiatry. 2003 Mar;48(2):106-10. PubMed: 12655908

18.Saito J, Ishii M, Mito A, Yakuwa N, Kawasaki H, Tachibana Y, Suzuki T, Yamatani A, Sago H, Murashima A. Trazodone Levels in Maternal Serum, Cord Blood, Breast Milk, and Neonatal Serum. Breastfeed Med. 2021 Nov;16(11):922-925. PMC free article: PMC8817729 PubMed: 34348038

19.Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Apr 18, 2022. Trazodone. PubMed: 30000237

20.Viramontes TS, Truong H, Linnebur SA. Antidepressant-Induced Hyponatremia in Older Adults. Consult Pharm. 2016 Mar;31(3):139-50. PubMed: 26975593

21.Haria M, Fitton A, McTavish D. Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders. Drugs Aging. 1994 Apr;4(4):331-55. PubMed: 8019056

22.Santos G, Moreira AM. Distressing Visual Hallucinations after Treatment with Trazodone. Case Rep Psychiatry. 2017;2017:6136914. PMC free article: PMC5494093 PubMed: 28702268

23.Hu J, Lai J, Zheng H, Hu S, Xu Y. Fan the flame: trazodone-induced mania in a unipolar depressed patient with stable sertraline treatment. Neuropsychiatr Dis Treat. 2017;13:2251-2254. PMC free article: PMC5576708 PubMed: 28883733

24.Bixby AL, VandenBerg A, Bostwick JR. Clinical Management of Bleeding Risk With Antidepressants. Ann Pharmacother. 2019 Feb;53(2):186-194. PubMed: 30081645

25.Kurian BT, Ray WA, Arbogast PG, Fuchs DC, Dudley JA, Cooper WO. Effect of regulatory warnings on antidepressant prescribing for children and adolescents. Arch Pediatr Adolesc Med. 2007 Jul;161(7):690-6. PubMed: 17606833

26.Amari DT, Juday T, Frech FH, Wang W, Wu Z, Atkins N, Wickwire EM. Falls, healthcare resources and costs in older adults with insomnia treated with zolpidem, trazodone, or benzodiazepines. BMC Geriatr. 2022 Jun 04;22(1):484. PMC free article: PMC9166444 PubMed: 35658904

27.Farkas D, Volak LP, Harmatz JS, von Moltke LL, Court MH, Greenblatt DJ. Short-term clarithromycin administration impairs clearance and enhances pharmacodynamic effects of trazodone but not of zolpidem. Clin Pharmacol Ther. 2009 Jun;85(6):644-50. PubMed: 19242403

28.Otani K, Ishida M, Kaneko S, Mihara K, Ohkubo T, Osanai T, Sugawara K. Effects of carbamazepine coadministration on plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine. Ther Drug Monit. 1996 Apr;18(2):164-7. PubMed: 8721280

29.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

30.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

31.Rauch PK, Jenike MA. Digoxin toxicity possibly precipitated by trazodone. Psychosomatics. 1984 Apr;25(4):334-5. PubMed: 6718667

32.Small NL, Giamonna KA. Interaction between warfarin and trazodone. Ann Pharmacother. 2000 Jun;34(6):734-6. PubMed: 10860134

33.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

34.Avila JD. Fatal Cerebral Edema, Seizures, and Hyponatremia After Trazodone Overdose. Clin Neuropharmacol. 2017 Sep/Oct;40(5):221-223. PubMed: 28816830

35.Wen CC, Munarriz R, McAuley I, Goldstein I, Traish A, Kim N. Management of ischemic priapism with high-dose intracavernosal phenylephrine: from bench to bedside. J Sex Med. 2006 Sep;3(5):918-922. PubMed: 16942536

36.Nichol JR, Sundjaja JH, Nelson G. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 30, 2024. Medical History. PubMed: 30484996