Serotonin antagonist and reuptake inhibitor (SARI) antidepressant
Brand names: Desyrel, Trittico, Oleptro
Updated · Methodology
Second line
Second-line for major depressive disorder, particularly with concurrent insomnia and anxiety. NG222 (2022) and 2024 set SSRIs and SNRIs (sertraline, escitalopram, venlafaxine) as first-line. Trazodone is used when sedation is desired, at 150–400 mg/day with titration over 2 weeks. Not preferred due to marked sedation and orthostatic hypotension risk.
ICD-10: F32.9 · ICD-11: 6A70.Z
The drug is promoted for these uses outside international guidelines. Each entry below is analyzed against AEMPS, FDA, EMA, Cochrane and major RCTs.
Not recommended
Trazodone is a serotonergic antidepressant that in the US and several other countries is most often prescribed as a sleep aid at low doses (25–100 mg at bedtime), rather than as an antidepressant. International insomnia guidelines ( 2017, NG219) do not recommend trazodone as first-line for chronic insomnia in people without depression. A Cochrane meta-analysis (Yi 2018) in patients with major depression did not confirm trazodone's advantages over other antidepressants. The drug has specific risks: orthostatic hypotension (especially in older adults, with fall risk), priapism (a prolonged, painful erection requiring emergency care), and next-day sedation. The foundation of insomnia treatment is cognitive-behavioral therapy for insomnia (CBT-I); first-line medications include melatonin and, when indicated, benzodiazepine receptor agonists or orexin antagonists. If trazodone was prescribed for sleep, consider seeking a second opinion.
Sources
ICD-10: G47.0 · ICD-11: 7A00
A 5-HT2A serotonin receptor antagonist with concurrent (moderate) serotonin reuptake inhibition. Also blocks α1-adrenoreceptors and H1 histamine receptors – the source of marked sedation. Low doses (25–100 mg at bedtime) feature 5-HT2A and H1 blockade, producing hypnotic effect. Higher doses (150–400 mg/day) unfold antidepressant action. Half-life 5–9 hours.
Boxed warning
FDA boxed warning: antidepressants increase the risk of suicidal thoughts and behavior in children, adolescents, and young adults under 24 during the first weeks of treatment. Careful monitoring of mental status is needed, especially at initiation and dose change.
AEMPS summary of product characteristics (section 4.6): data on trazodone in pregnant women are limited (fewer than 200 term pregnancies), and animal studies at therapeutic doses do not indicate direct or indirect harmful effects on pregnancy, embryo-fetal development, parturition or postnatal development. As a precaution, it is preferable to avoid trazodone during pregnancy, and it is prescribed to pregnant women with care. When trazodone is used until delivery, newborns are monitored for withdrawal syndromes. Epidemiological data suggest that SSRI use in pregnancy, especially late in pregnancy, may increase the risk of persistent pulmonary hypertension of the newborn (about 5 cases per 1,000 pregnancies versus 1–2 per 1,000 births in the general population); this link has not been studied for trazodone, but the potential risk cannot be ruled out.
Milk concentrations are low. Acceptable when needed, with monitoring of infant sedation and weight gain.
Reference information, not a clinical decision. Discuss feeding pauses or changes with your physician or an IBCLC.
1 pair found. Sorted from critical to minor.
Mechanism
Trazodone prolongs the QT interval, and postmarketing reports include torsade de pointes at doses of 100 mg or less (trazodone label, US Food and Drug Administration, ). QT prolongation has been reported with quetiapine at therapeutic doses and in overdose (quetiapine summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The trazodone label warns that other QT-prolonging drugs may add to its QT effect (trazodone FDA label). Both drugs act on the central nervous system. Trazodone can intensify the sedative effect of antipsychotics, and both drugs cause somnolence and orthostatic hypotension (SmPCs of both drugs, AEMPS). Trazodone is a serotonergic agent, and quetiapine raises the risk of serotonin syndrome when combined with serotonergic drugs. Neuroleptic malignant syndrome, including fatal cases, has been reported when trazodone was given with neuroleptics (SmPCs of both drugs, AEMPS). Quetiapine and its metabolites do not inhibit the major cytochrome P450 (CYP) enzymes, and the labels give no pharmacokinetic study of this pair (quetiapine FDA label).
Symptoms
QT interval prolongation itself causes no symptoms and shows only on the electrocardiogram (ECG). A ventricular arrhythmia causes palpitations, dizziness and fainting. The added sedative and blood pressure-lowering effects cause somnolence, dizziness on standing, fainting and falls, more often in older people (summaries of product characteristics of both drugs). Serotonin syndrome presents with agitation, hallucinations, tremor, muscle jerks, fever and a fast pulse (trazodone label). Neuroleptic malignant syndrome presents with high fever, muscle rigidity, confusion and unstable pulse and blood pressure (quetiapine summary of product characteristics).
Management
The labels of both drugs from the US Food and Drug Administration () say to avoid combining them with drugs that prolong the QT interval. Each of the two prolongs QT according to its own documents (quetiapine and trazodone FDA labels; quetiapine summary of product characteristics, SmPC, Spanish Agency of Medicines and Medical Devices, AEMPS). The Spanish SmPCs of both drugs are softer and ask for caution with this combination (quetiapine and trazodone SmPCs, AEMPS). Avoid both drugs in bradycardia, low potassium or magnesium, congenital QT prolongation or a history of arrhythmias (quetiapine and trazodone FDA labels). Use quetiapine with caution in older people and in heart failure or cardiac hypertrophy (quetiapine SmPC, AEMPS). Trazodone can intensify the sedative effect of antipsychotics, and its SmPC recommends a dose reduction in that case (trazodone SmPC, AEMPS). If orthostatic hypotension occurs, consider a lower quetiapine dose or a slower titration (quetiapine SmPC, AEMPS). Monitor somnolence and blood pressure closely after the start and before and after each dose increase. Tell the patient not to drive until they know how the drugs affect them (trazodone SmPC, AEMPS; FDA labels of both drugs). If serotonin syndrome or neuroleptic malignant syndrome is suspected, stop trazodone at once and start supportive treatment (trazodone SmPC, AEMPS). In neuroleptic malignant syndrome, stop quetiapine as well (quetiapine SmPC, AEMPS).
Sources
Verbatim lines from the interaction sections, in the language of the label
«CONTRAINDICATIONS: Patients taking, or within 14 days of stopping, monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue, because of an increased risk…»FDA, section 4 · Open on DailyMed
«CONTRAINDICATIONS: Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4 ).»FDA, section 4 · Open on DailyMed
«Inhibidores de la monoaminoxidasa: Ocasionalmente, se ha informado de la posible interacción con los inhibidores de la monoaminoxidasa. Aunque algunos médicos las prescriben concomitantemente, no se…»AEMPS, section 4.5 · Open on CIMA
«Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Tablets: Intervention: Avoid the use of trazodone in combination with other drugs known to prolong QTc [see Warnings and…»FDA, section 7 · Open on DailyMed
«Inhibidores CYP3A4: Es probable que los inhibidores potentes de CYP3A4 puedan dar lugar a aumentos sustanciales de las concentraciones plasmáticas de trazodona. Se ha confirmado en estudios in vivo…»AEMPS, section 4.5 · Open on CIMA
«Interferencia con pruebas de orina: Se recomienda precaución en pacientes que toman agentes serotoninérgicos como trazodona concomitantemente con agentes anticoagulantes y/AEMPS, section 4.4 · Open on CIMA
«Síndrome serotoninérgico/AEMPS, section 4.4 · Open on CIMA
«Interferencia con pruebas de orina: Se recomienda precaución en pacientes que toman agentes serotoninérgicos como trazodona concomitantemente con agentes anticoagulantes y/AEMPS, section 4.4 · Open on CIMA
«Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Tablets: Intervention: Inform patients of the increased risk of bleeding with the concomitant use of trazodone and…»FDA, section 7 · Open on DailyMed
«Síndrome serotoninérgico/AEMPS, section 4.4 · Open on CIMA
«General: Se puede intensificar el efecto sedante de los antipsicóticos, hipnóticos, sedantes, ansiolíticos y antihistamínicos; se recomienda en estos casos una reducción de la dosis.»AEMPS, section 4.5 · Open on CIMA
«Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Tablets: Intervention: Inform patients of the increased risk of bleeding with the concomitant use of trazodone and…»FDA, section 7 · Open on DailyMed
«General: Se puede intensificar el efecto sedante de los antipsicóticos, hipnóticos, sedantes, ansiolíticos y antihistamínicos; se recomienda en estos casos una reducción de la dosis.»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: CNS Depressants: Trazodone may enhance effects of alcohol, barbiturates, or other CNS depressants ( 7 ).»FDA, section 7 · Open on DailyMed
«Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Tablets: Intervention: Patients should be closely monitored to see if there is a need for an increased dose of trazodone…»FDA, section 7 · Open on DailyMed
«DRUG INTERACTIONS: CYP3A4 Inhibitors: Consider Trazodone dose reduction based on tolerability ( 2.5 , 7 ).»FDA, section 7 · Open on DailyMed
«General: Se puede intensificar el efecto sedante de los antipsicóticos, hipnóticos, sedantes, ansiolíticos y antihistamínicos; se recomienda en estos casos una reducción de la dosis.»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Digoxin or Phenytoin: Monitor for increased digoxin or phenytoin serum levels ( 7 ).»FDA, section 7 · Open on DailyMed
«Síndrome serotoninérgico/AEMPS, section 4.4 · Open on CIMA
«Síndrome serotoninérgico/AEMPS, section 4.4 · Open on CIMA
«Inhibidores CYP3A4: Es probable que los inhibidores potentes de CYP3A4 puedan dar lugar a aumentos sustanciales de las concentraciones plasmáticas de trazodona. Se ha confirmado en estudios in vivo…»AEMPS, section 4.5 · Open on CIMA
«El uso concomitante de trazodona con fármacos que prolongan el intervalo QT puede aumentar el riesgo de arritmias ventriculares, incluyendo Torsade de Pointes. Se debe tener precaución cuando estos…»AEMPS, section 4.5 · Open on CIMA
«Síndrome serotoninérgico/AEMPS, section 4.4 · Open on CIMA
«DRUG INTERACTIONS: Digoxin or Phenytoin: Monitor for increased digoxin or phenytoin serum levels ( 7 ).»FDA, section 7 · Open on DailyMed
«Síndrome serotoninérgico/AEMPS, section 4.4 · Open on CIMA
«Anestésicos/AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: Warfarin: Monitor for increased or decreased prothrombin time ( 7 ).»FDA, section 7 · Open on DailyMed
«Antihipertensivos: Dado que trazodona es sólo un inhibidor muy débil de la recaptación de noradrenalina y no modifica la respuesta de la presión sanguínea a la tiramina, la interferencia con la…»AEMPS, section 4.5 · Open on CIMA
«Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Tablets: Examples: Class 1A antiarrhythmics: quinidine, procainamide, disopyramide; Class 3 antiarrhythmics: amiodarone…»FDA, section 7 · Open on DailyMed
«Drugs Having Clinically Important Interactions with Trazodone Hydrochloride Tablets: Examples: Class 1A antiarrhythmics: quinidine, procainamide, disopyramide; Class 3 antiarrhythmics: amiodarone…»FDA, section 7 · Open on DailyMed
«General: El metabolismo de los antidepresivos se acelera debido a los efectos hepáticos de los anticonceptivos orales, fenitoína, carbamazepina y barbitúricos. La cimetidina y algunos antipsicóticos…»AEMPS, section 4.5 · Open on CIMA
«DRUG INTERACTIONS: CNS Depressants: Trazodone may enhance effects of alcohol, barbiturates, or other CNS depressants ( 7 ).»FDA, section 7 · Open on DailyMed
«General: El metabolismo de los antidepresivos se acelera debido a los efectos hepáticos de los anticonceptivos orales, fenitoína, carbamazepina y barbitúricos. La cimetidina y algunos antipsicóticos…»AEMPS, section 4.5 · Open on CIMA
«Combination with Certain Drugs: Antidepressants including but not limited to: Other monoamine oxidase inhibitors (MAOIs) Selective serotonin reuptake inhibitors (SSRIs) and serotonin and…»FDA, section 4 · Open on DailyMed
«Established and Other Potentially Significant Drug Interactions: trazodone ↑ trazodone Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with…»FDA, section 7 · Open on DailyMed
«Established and Other Potentially Significant Drug Interactions: Antidepressants : Selective Serotonin Reuptake Inhibitors (SSRIs): paroxetine, sertraline Tricyclic Antidepressants (TCAs)…»FDA, section 7 · Open on DailyMed
«Established and Other Potentially Significant Drug Interactions: Antidepressant: trazodone ↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed following…»FDA, section 7 · Open on DailyMed
«Established and Other Potentially Significant Interactions: Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g., paroxetine Tricyclic Antidepressants (TCAs) e.g., amitriptyline…»FDA, section 7 · Open on DailyMed
«ANTIDEPRESIVOS: Paroxetina 20 mg una vez al día Sertralina 50 mg una vez al día Amitriptilina Desipramina Imipramina Nortriptilina Trazodona»AEMPS, section 4.5 · Open on CIMA
«Antidepresivos: Se detectó un au mento de la incidencia de reacciones adversas relacionadas con trazodona cuando se coadministró con ritonavir dosificado como agente antirretroviral o como…»AEMPS, section 4.5 · Open on CIMA
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Trazodone is evaluated for the following indications with varying evidence strength: Major depressive disorder (evidence tier B), Insomnia and sleep disorders (evidence tier F). See the full indication matrix with dosing and citations above on this page.
Common side effects of Trazodone (≥ 1 in 100): Drowsiness, daytime sedation, Dizziness, Orthostatic hypotension, Dry mouth, Fatigue, Nausea. See the Safety section for uncommon and serious reactions.
AEMPS summary of product characteristics (section 4.6): data on trazodone in pregnant women are limited (fewer than 200 term pregnancies), and animal studies at therapeutic doses do not indicate direct or indirect harmful effects on pregnancy, embryo-fetal development, parturition or postnatal development. As a precaution, it is preferable to avoid trazodone during pregnancy, and it is prescribed to pregnant women with care. When trazodone is used until delivery, newborns are monitored for withdrawal syndromes. Epidemiological data suggest that SSRI use in pregnancy, especially late in pregnancy, may increase the risk of persistent pulmonary hypertension of the newborn (about 5 cases per 1,000 pregnancies versus 1–2 per 1,000 births in the general population); this link has not been studied for trazodone, but the potential risk cannot be ruled out.
Milk concentrations are low. Acceptable when needed, with monitoring of infant sedation and weight gain.
Trazodone is contraindicated in: Trazodone hypersensitivity; Acute alcohol or hypnotic intoxication; Acute myocardial infarction; Severe hepatic impairment; Concurrent MAO inhibitors or within 14 days of stopping them. Full list in the Safety section.
FDA boxed warning: antidepressants increase the risk of suicidal thoughts and behavior in children, adolescents, and young adults under 24 during the first weeks of treatment. Careful monitoring of mental status is needed, especially at initiation and dose change.
Direct links to regulator labels. Open in a new tab.
Venlafaxine, Vinpocetine, Vortioxetine, 5-hydroxytryptophan (5-HTP), Bupropion, Fluoxetine, L-tryptophan, Phosphatidylserine