Desyrel (Trazodone)
trazodone hydrochloride tablets
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Major Depressive Disorder (MDD) | Adults | Monotherapy | FDA Approved |
Trazodone is a serotonin antagonist and reuptake inhibitor (SARI) first approved by the FDA in 1981 as an antidepressant. It was the first non-tricyclic, non-MAOI antidepressant approved in the United States. In 2023, trazodone was the 21st most commonly prescribed medication in the US and the fifth most common antidepressant, with over 24 million prescriptions. While approved solely for MDD, trazodone is far more commonly prescribed at low doses for insomnia than at antidepressant doses. Its unique dose-dependent pharmacology produces primarily sedative and anxiolytic effects at low doses (25–100 mg) and antidepressant activity at higher doses (150–600 mg). Trazodone’s favourable sleep profile and low risk of sexual dysfunction distinguish it from SSRIs, though clinicians must weigh these benefits against risks of orthostatic hypotension, QT prolongation, and priapism.
Insomnia: The most common clinical use of trazodone; typically 25–150 mg at bedtime. Cochrane review found low-dose trazodone effective for short-term insomnia treatment. AASM 2017 guidelines recommended against use due to limited quality evidence, but clinical practice remains widespread. Evidence quality: Moderate (short-term).
Anxiety disorders (GAD, PTSD, panic): Anxiolytic properties from 5-HT2A antagonism and 5-HT1A partial agonism. Used adjunctively or as monotherapy. Evidence quality: Low-Moderate.
Agitation in dementia: Used at low doses for nocturnal agitation and sundowning in elderly patients with dementia. Evidence quality: Low.
Antidepressant-induced insomnia: Commonly added at bedtime to SSRIs/SNRIs that cause sleep disruption. Evidence quality: Moderate.
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDD — outpatient (IR) | 150 mg/day in divided doses | 150–400 mg/day in divided doses | 400 mg/day | Increase by 50 mg/day every 3–4 days; give major portion at bedtime Take shortly after a meal or light snack to reduce orthostatic hypotension |
| MDD — inpatient (IR, severely depressed) | 150 mg/day in divided doses | 150–600 mg/day in divided doses | 600 mg/day | Same titration; higher ceiling for inpatients under close monitoring QT monitoring recommended at higher doses |
| Insomnia — off-label | 25–50 mg at bedtime | 50–100 mg at bedtime | 150 mg at bedtime | Take on empty stomach for faster onset of sedation; lower doses work primarily via H1 and 5-HT2A antagonism Not FDA-approved for insomnia; prescribing reflects widespread clinical practice |
| Elderly patients | 25–50 mg at bedtime | 50–150 mg/day | 100 mg/day (initial target) | Increased risk of orthostatic hypotension, falls, syncope, hyponatremia Use lowest effective dose; monitor blood pressure |
| MDD — with strong CYP3A4 inhibitor | Reduce dose based on tolerability | CYP3A4 inhibitors increase trazodone exposure and QT risk; ritonavir increases AUC 2.4-fold | ||
| MDD — with strong CYP3A4 inducer | Increase dose based on therapeutic response | Carbamazepine reduces trazodone levels by 60–74% | ||
| MDD — discontinuation / tapering | Gradual dose reduction recommended | Discontinuation syndrome: dizziness, nausea, paresthesia, anxiety, agitation, insomnia, electric shock sensations | ||
Trazodone’s clinical profile is fundamentally different at low versus high doses. At low doses (25–100 mg), the potent 5-HT2A antagonism (Ki = 35.6 nM), α1-adrenergic blockade (Ki = 153 nM), and H1 histamine antagonism dominate, producing sedation and anxiolysis with minimal antidepressant effect. At antidepressant doses (150–600 mg), serotonin reuptake inhibition (Ki = 367 nM for SERT) contributes meaningfully, and the combination of reuptake inhibition with 5-HT2A blockade and 5-HT1A partial agonism produces the full antidepressant effect. This explains why trazodone is used at completely different dose ranges for insomnia versus depression. When prescribing for insomnia, patients should understand that the low dose is for sleep, not for treating their depression.
Pharmacology
Mechanism of Action
Trazodone is classified as a serotonin antagonist and reuptake inhibitor (SARI), a pharmacological profile distinct from both SSRIs and tricyclic antidepressants. Its primary actions include potent antagonism of the 5-HT2A receptor (Ki = 35.6 nM), moderate serotonin reuptake inhibition via the serotonin transporter (SERT, Ki = 367 nM), partial agonism at the 5-HT1A receptor (Ki = 118 nM), and antagonism of 5-HT2B, 5-HT2C, α1A-adrenergic, α2C-adrenergic, and H1 histamine receptors. The 5-HT2A antagonism is approximately 10-fold more potent than the SERT inhibition, which is why sedation and sleep-promoting effects appear at much lower doses than antidepressant effects. Trazodone also blocks α1-adrenergic receptors, which accounts for orthostatic hypotension and contributes to the risk of priapism. Its active metabolite mCPP is a 5-HT2C agonist and may contribute to anxiogenic effects at higher doses.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Well absorbed orally; Tmax ~1 h (fasting), ~2 h (with food); food increases amount absorbed but decreases Cmax and delays peak; bioavailability ~65–80% | For insomnia: take on empty stomach for faster onset. For depression: take after food to reduce lightheadedness and orthostatic hypotension |
| Distribution | Protein binding 89–95% (therapeutic concentrations); Vd 0.8–1.5 L/kg; no selective tissue localization | High protein binding; lipophilic; crosses blood-brain barrier |
| Metabolism | Extensively hepatic; CYP3A4 (primary, to active metabolite mCPP via oxidative cleavage); CYP2D6 (minor, mCPP hydroxylation); <1% excreted unchanged | Highly susceptible to CYP3A4 inhibitors/inducers; mCPP levels ~10% of parent; mCPP has serotonergic activity and can cause false-positive MDMA urine screens |
| Elimination | Biphasic: t½ 3–6 h (distribution), 5–9 h (terminal elimination); 70–75% urine, ~21% feces | Relatively short half-life requires divided dosing for MDD or bedtime-only for insomnia; may accumulate in some patients |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Drowsiness | 41% (placebo 20%) | Most common side effect; dose-dependent; give major portion at bedtime; clinically leveraged for insomnia |
| Dry mouth | 34% (placebo 20%) | Despite minimal muscarinic affinity; may be partly related to α1 blockade; hydration and sugar-free gum |
| Dizziness / lightheadedness | 28% (placebo 15%) | Related to α1-adrenergic blockade and orthostatic hypotension; rise slowly; take with food |
| Headache | 20% (placebo 16%) | Modest excess over placebo (4%); responds to OTC analgesics |
| Blurred vision | 15% (placebo 4%) | Significant excess over placebo; evaluate if persistent |
| Nausea / vomiting | 13% (placebo 10%) | Usually transient; taking with food helps; less GI disturbance than SSRIs |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Constipation | 8% (placebo 6%) | Modest excess; fibre and fluid intake |
| Edema | 7% (placebo 1%) | Peripheral edema; monitor fluid status |
| Fatigue | 6% (placebo 3%) | Related to H1 and α1 blockade; timing at bedtime may help |
| Nasal / sinus congestion | 6% (placebo 3%) | Related to α1-adrenergic blockade causing vasodilation of nasal mucosa |
| Weight loss | 6% (placebo 3%) | Unusual among sedating antidepressants; weight gain also reported (5% vs 2%) |
| Abdominal / gastric disorder | 6% (placebo 4%) | Usually mild |
| Syncope | 5% (placebo 1%) | Related to orthostatic hypotension from α1 blockade; significant clinical concern, especially in elderly |
| Weight gain | 5% (placebo 2%) | Less weight gain than mirtazapine or most TCAs; variable effect on weight |
| Diarrhea | 5% (placebo 1%) | Related to serotonergic effects on GI tract |
| Aches / pains (musculoskeletal) | 5% (placebo 3%) | Usually self-limiting |
| Tremors | 5% (placebo 4%) | Minimal excess over placebo |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Priapism | Rare (estimated 1 in 6000–8000 males) | Any time during treatment | Medical emergency if erection >4 hours; discontinue immediately; urological emergency; untreated priapism can cause irreversible erectile damage |
| QT prolongation / Torsades de Pointes | Rare (postmarketing reports at doses ≤100 mg) | Any time | Avoid in patients with QT prolongation risk, cardiac arrhythmias, or concurrent QT-prolonging drugs/CYP3A4 inhibitors; ECG monitoring in at-risk patients |
| Orthostatic hypotension / syncope | 5% syncope (outpatients); up to 7% hypotension (inpatients) | Early treatment; dose-related | Warn patients; reduce antihypertensive dose if concurrent; fall risk assessment in elderly |
| Serotonin syndrome | Rare | Hours to days after initiation or dose increase | Discontinue trazodone and all serotonergic agents; supportive care |
| Suicidal ideation (age <25) | Uncommon | First weeks or dose changes | Close monitoring; FDA Black Box Warning; not approved for paediatric use |
| Hyponatremia / SIADH | Rare | Weeks to months | Monitor sodium if symptoms develop; elderly and diuretic users at highest risk |
| Cardiac arrhythmias (PVCs, ventricular couplets, VT) | Rare; more common in pre-existing cardiac disease | Any time | Avoid in initial recovery phase of MI; close monitoring in cardiac patients; contraindicated with Class IA/III antiarrhythmics |
| Bleeding events | Uncommon | Variable | Inform patients; monitor INR in warfarin users; caution with NSAIDs and antiplatelet agents |
Trazodone is the only commonly prescribed antidepressant with a clinically significant risk of priapism (painful erection >6 hours). This effect is mediated by α1-adrenergic blockade in the corpus cavernosum. All male patients must be warned about this risk before initiation. If an erection lasts >4 hours (painful or not), the patient should discontinue trazodone immediately and seek emergency urological care. Untreated priapism can lead to permanent erectile dysfunction. The risk is increased in men with sickle cell disease, multiple myeloma, leukemia, or anatomical deformation of the penis.
Drug Interactions
Trazodone is extensively metabolized by CYP3A4, making it highly susceptible to drugs that inhibit or induce this enzyme. Trazodone itself does not significantly inhibit CYP enzymes. Its serotonergic properties create serotonin syndrome risk with other serotonergic agents, and its QT-prolonging effects can be additive with other QTc-prolonging drugs. The combination of CYP3A4 inhibition and QT prolongation is particularly dangerous because it simultaneously increases trazodone exposure and QT risk.
Monitoring
- Blood PressureBaseline, then regularly
RoutineOrthostatic hypotension is a significant concern, especially in elderly. Include sitting and standing BP. Hypotension/syncope reported in 5–7% of patients. Reduce dose of concurrent antihypertensives if needed. - ECG / QTcBaseline in at-risk patients
Trigger-basedTrazodone prolongs QT/QTc. Post-marketing TdP reported at doses ≤100 mg. Obtain ECG in patients with cardiac disease, family history of QT prolongation, electrolyte abnormalities, or concurrent QTc-prolonging drugs. - Suicidality AssessmentWeekly for first 4 weeks, then at each visit
RoutineEspecially important in patients under 25. Monitor for clinical worsening, agitation, and suicidal ideation. - Priapism RiskAt each visit (males)
RoutineAsk male patients about prolonged or painful erections at every follow-up. Remind patients to seek emergency care if erection >4 hours. Higher risk in sickle cell disease, myeloma, leukemia, or penile deformity. - Serum SodiumAs indicated
Trigger-basedSIADH/hyponatremia reported; check if confusion, weakness, falls, or seizures develop. Elderly and diuretic users at highest risk. - Fall RiskBaseline and periodically (elderly)
RoutineCombination of sedation, orthostatic hypotension, and dizziness creates significant fall risk, particularly in elderly patients. Assess gait, balance, and home environment. - INR (warfarin users)When starting/stopping trazodone
Trigger-basedTrazodone may increase or decrease prothrombin time. Monitor INR closely when initiating, titrating, or discontinuing in warfarin-treated patients.
Contraindications & Cautions
Absolute Contraindications
- Concurrent MAOI use or use within 14 days of MAOI discontinuation in either direction (serotonin syndrome risk)
- Concurrent linezolid or IV methylene blue (reversible MAO inhibition)
Relative Contraindications (Specialist Input Recommended)
- Pre-existing cardiac arrhythmias or known QT prolongation: Trazodone is arrhythmogenic in patients with cardiac disease; TdP reported at ≤100 mg; not recommended during initial recovery phase of MI
- Concurrent CYP3A4 inhibitors that also prolong QT: Dual risk of increased exposure and additive QTc prolongation
- Conditions predisposing to priapism (males): Sickle cell disease, multiple myeloma, leukemia, anatomical penile deformation
- Untreated anatomically narrow angles: Pupillary dilation from antidepressants may trigger angle-closure glaucoma
Use with Caution
- Renal impairment: Not studied; use with caution
- Hepatic impairment: Not studied; use with caution (extensively hepatically metabolized)
- Elderly patients: Increased fall risk from orthostatic hypotension, sedation, and hyponatremia; start at low doses
- Bipolar disorder: Screen before initiation; may precipitate mania/hypomania
- Patients receiving anticoagulants or antiplatelet agents: Increased bleeding risk
- Patients with hypokalemia, hypomagnesemia, or symptomatic bradycardia: Increased TdP risk
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Trazodone is not approved for use in pediatric patients.
Patient Counselling
Purpose of Therapy
Trazodone is prescribed to treat depression by acting on serotonin pathways in the brain. It also improves sleep, which is often disrupted in depression. At low doses, it is frequently prescribed specifically for sleep difficulties. Improvement in sleep typically begins within the first few days, while improvement in mood at antidepressant doses takes 2 to 4 weeks. Continue taking the medication as prescribed even after symptoms improve.
How to Take
If prescribed for depression, take trazodone in divided doses throughout the day, with the largest portion at bedtime, shortly after a meal or light snack. Taking with food reduces lightheadedness. If prescribed for sleep, take the dose at bedtime. Tablets may be swallowed whole or split along the score line. Do not stop this medication abruptly without discussing with your prescriber.
Sources
- DESYREL (trazodone hydrochloride) Tablets. Full Prescribing Information. Pragma Pharmaceuticals, LLC. Revised June 2017. accessdata.fda.govPrimary source for all dosing, adverse reaction Table 2 data, contraindications, QT prolongation warnings, priapism warnings, pharmacodynamic data, and drug interactions cited in this monograph.
- RALDESY (trazodone hydrochloride) Tablets. Full Prescribing Information. Revised 2024. accessdata.fda.govMost recently approved trazodone IR formulation with updated pregnancy registry information and QT prolongation language.
- OLEPTRO (trazodone hydrochloride) Extended-Release Tablets. Full Prescribing Information. Revised 2014. accessdata.fda.govReference for extended-release formulation dosing, efficacy trial data, and adverse event profile from the 8-week controlled trial (n=406).
- Beasley CM Jr, Dornseif BE, Bosomworth JC, et al. Fluoxetine and trazodone, alone and in combination, in the treatment of major depression. Psychopharmacol Bull. 1991;27(1):45-52.Controlled trial comparing trazodone with fluoxetine and combination therapy, establishing clinical efficacy profile.
- Jaffer KY, Chang T, Vanle B, et al. Trazodone for insomnia: a systematic review. Innov Clin Neurosci. 2017;14(7-8):24-34.Systematic review evaluating evidence for trazodone as a sleep aid, finding benefit in both depressed and euthymic patients with insomnia.
- Lam RW, Kennedy SH, Adams C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2023 Update on Clinical Guidelines for Management of Major Depressive Disorder in Adults. Can J Psychiatry. 2024;69(9):641-687. doi:10.1177/07067437241245384Current guideline listing trazodone as a second-line antidepressant option for MDD.
- 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;13(2):307-349. doi:10.5664/jcsm.6470AASM guideline that recommended against trazodone for insomnia due to limited quality evidence, despite acknowledging widespread clinical use.
- Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009;14(10):536-546. doi:10.1017/S1092852900024020Detailed analysis of trazodone’s dose-dependent receptor pharmacology explaining the disconnect between sedative and antidepressant dose ranges.
- Rotzinger S, Fang J, Baker GB. Trazodone is metabolized to m-chlorophenylpiperazine by CYP3A4 from human sources. Drug Metab Dispos. 1998;26(6):572-575.Definitive study identifying CYP3A4 as the primary enzyme producing the active metabolite mCPP from trazodone.
- Trazodone. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. ncbi.nlm.nih.govComprehensive review of mechanism, PK parameters (half-life 5–9 h, protein binding 89–95%), clinical applications, and adverse effects.
- 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. doi:10.3389/fphar.2015.00224PK study characterizing trazodone absorption and bioavailability parameters in healthy volunteers.
- Greenblatt DJ, Friedman H, Burstein ES, et al. Trazodone kinetics: effect of age, gender, and obesity. Clin Pharmacol Ther. 1987;42(2):193-200. doi:10.1038/clpt.1987.132Landmark PK study characterizing age, gender, and body composition effects on trazodone disposition.