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Trz3.8
Trazodone Research
Mostly mechanism / observational
13 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most Trazodone studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from medium-quality meta-analyses and randomised trials published 2011–2024 with a typical study size of 30 participants.
Based on 13 studies · 3 meta-analyses · 2 RCTs · 8,982 total participants
Confidence
High confidence
By outcome
Sleep & insomniaThe strongest (and still modest) signal: meta-analysis found significantly fewer awakenings on trazodone, and polysomnography in primary insomniacs showed fewer night-time awakenings — but no significant change in wake-after-sleep-onset or total sleep time, and the AASM guideline recommends against this use · 1-7 nights · In a 7-night crossover in 16 primary insomniacs, slow-wave sleep was greater than placebo on day 7, and Stage 1 sleep was lower across test days (day 1 showed no slow-wave difference). A single very small study — not a replicated finding · About 1 week · Essentially none on the evidence: the trazodone insomnia meta-analysis found NO significant difference from placebo in sleep latency, and the AASM guideline specifically suggests clinicians not use trazodone for sleep-onset insomnia · Not demonstrated
Mostly mechanism / observational7 studies
Safety profile
Mostly mechanism / observational4 studies
Cognitive function
Mostly mechanism / observational3 studies
Depression & mood
Mostly mechanism / observational3 studies
Therapeutic & clinical
Mostly mechanism / observational3 studies
Heart & blood pressure
Too few graded studies2 studies
Anxiety & stress
Too few graded studies1 study
Endurance & exercise performance
Too few graded studies1 study
2 more outcomes with fewer studies not shown.
Active research area
4 studies in the last 5 years · Latest meta-analysis: 2022
201120172024
1Systematic Review2017
In plain English: We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK).
Sateia, Buysse, Krystal, Neubauer, Heald · Journal of Clinical Sleep Medicine (2017)
The AASM commissioned a task force of four sleep-medicine experts, ran a systematic review of randomised controlled trials, and graded the evidence with GRADE
Trazodone received a WEAK recommendation AGAINST use for both sleep-onset and sleep-maintenance insomnia — the same recommendation given to diphenhydramine, melatonin, tryptophan, valerian and tiagabine
By contrast the guideline suggests clinicians USE doxepin for sleep-maintenance insomnia and suvorexant, eszopiclone, zaleplon, zolpidem, triazolam, temazepam and ramelteon for their respective indications (all WEAK)
In plain English: In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84).
In plain English: Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available.
De Crescenzo, D'Alò, Ostinelli, Ciabattini, Di Franco, Watanabe, Kurtulmus, Tomlinson, Mitrova, Foti, Del Giovane, Quested, Cowen, Barbui, Amato, Efthimiou, Cipriani · The Lancet (2022)
170 trials (36 interventions, 47,950 participants) in the systematic review; 154 double-blind RCTs (30 interventions, 44,089 participants) in the network meta-analysis
The agents found more efficacious than placebo for acute treatment were benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem and zopiclone (SMD 0.36-0.83) — trazodone was not among them
Trazodone is grouped with the licensed drugs carrying poor tolerability and/or absent long-term data
In plain English: New use of low-dose trazodone was no safer with respect to a risk of a fall-related injury than new use of benzodiazepines.
Bronskill, Campitelli, Iaboni, Herrmann, Guan, Maclagan, Watt, Rochon, Morris, Jeffs, Bell, Maxwell · Journal of the American Geriatrics Society (2018)
Retrospective propensity-score-matched cohort of 7,791 Ontario nursing-home residents aged 66+ newly dispensed low-dose trazodone versus newly dispensed benzodiazepines
Cumulative incidence of hospitalisation for a fall-related injury within 90 days: 5.7% with low-dose trazodone vs 6.0% with benzodiazepines (hazard ratio 0.94, 95% CI 0.83-1.08)
Findings were consistent across sensitivity analyses restricted to hip or wrist fracture and at 30, 60 and 180 days of follow-up
In plain English: There was no significant improvement for trazodone in SE% (SMD = 0.09, 95% CI -0.19 to 0.38, P = 0.53); patients receiving trazodone perceived better sleep quality than those receiving placebo (SMD = -0.41, 95% CI -0.82 to -0.00, P = 0.05).
Seven randomised placebo-controlled trials involving only 429 patients in total — the entire dedicated meta-analytic base for trazodone in insomnia
NO significant improvement in sleep efficiency (SMD 0.09, 95% CI -0.19 to 0.38, P = 0.53), and no significant difference from placebo in sleep latency, total sleep time, or wake time after sleep onset
Significant reduction only in the number of awakenings (SMD -0.51, 95% CI -0.97 to -0.05) and a borderline improvement in self-reported sleep quality (P = 0.05)
In plain English: Although trazodone is efficacious for sleep maintenance difficulties, its associated cognitive and motor impairments may provide a modest caveat to health-care providers.
Roth, McCall, Liguori · Journal of Sleep Research (2011)
Sixteen primary insomniacs (mean age 44, insomnia confirmed by polysomnography with sleep efficiency ≤ 85%) received trazodone 50 mg 30 min before bed for 7 days in a 3-week within-subjects randomised double-blind placebo-controlled design
Versus placebo, trazodone reduced night-time awakenings, minutes of Stage 1 sleep, and self-reported difficulty sleeping
On day 7 ONLY, slow-wave sleep was greater and objective daytime sleepiness (MSLT) lower than placebo
In plain English: Compared with the placebo group, trazodone users slept 42.5 more minutes per night and had their nighttime percent sleep increased 8.5 percentage points according to actigraphic data post-treatment.
Camargos, Louzada, Quintas, Naves, Louzada, Nóbrega · The American Journal of Geriatric Psychiatry (2014)
Double-blind randomised placebo-controlled trial in 30 community-dwelling patients with probable Alzheimer disease and sleep disturbance (15 trazodone, 15 placebo), 50 mg at 10:00 PM for 2 weeks
Trazodone increased actigraphic total sleep by 42.5 minutes per night and night-time percent sleep by 8.5 percentage points
Neither trazodone nor placebo induced significant daytime sleepiness or naps, and there were no effects on cognition (MMSE, digit span, letter-number sequencing, arithmetic, digit symbol-coding, symbol search) or functionality (Katz index)
In plain English: The hypnotic action of this medication at lower doses is attributed primarily to the antagonism of the 5-HT2A receptors, H1 receptors, and alpha-1 adrenergic receptors.
Schwasinger-Schmidt, Macaluso · Handbook of Experimental Pharmacology (2019)
Trazodone is a 5-HT2A and 5-HT2C receptor antagonist and a selective serotonin reuptake inhibitor, FDA-approved only for major depressive disorder but used off-label for insomnia, anxiety, dementia, substance abuse, schizophrenia, bulimia and fibromyalgia
In the United States trazodone is the second most commonly prescribed agent used to treat insomnia
The most active metabolite is m-chlorophenylpiperazine (mCPP), produced by CYP3A4, which is a more profound inhibitor of serotonin reuptake than trazodone itself
In plain English: Although not in the "Known Risk" category, mirtazapine, amitriptyline, diphenhydramine, and trazodone had a statistically significant association with QTc > 500 ms.
Retrospective review of 1,125 regional poison-centre exposures (2014-2019) to substances on the CredibleMeds 'Known Risk of Torsades de Pointes' list; 760 had a documented QTc
QTc ≥ 500 ms was reported in 138 of 760 cases (18.2%)
Trazodone — though not itself on the 'Known Risk' list — showed a statistically significant association with QTc > 500 ms, as did mirtazapine, amitriptyline and diphenhydramine
In plain English: These adverse effects are also observed with the serotonin-reuptake modulators, nefazodone and trazodone, but seldomly with vortioxetine and vilazodone.
Calvi, Fischetti, Verzicco, Belvederi Murri, Zanetidou, Volpi, Coghi, Tedeschi, Amore, Cabassi · Frontiers in Cardiovascular Medicine (2021)
Review of antidepressant effects on blood pressure across drug classes
Orthostatic hypotension and falls are identified as adverse effects of the serotonin-reuptake modulators nefazodone and trazodone, in contrast to vortioxetine and vilazodone where they are seldom seen
SSRIs have limited autonomic effects and the lowest blood-pressure impact, making them the safest class in elderly and cardiovascular patients on this axis
In plain English: While trazodone is approved for the treatment of depression, the off-label use of this medication for insomnia has surpassed its usage as an antidepressant.
PRISMA systematic review of 45 studies from 1983-2016 covering RCTs, meta-analyses, observational studies and placebo-controlled trials of trazodone for primary or secondary insomnia
Off-label use of trazodone for insomnia has surpassed its use as an antidepressant — the drug's actual clinical role is not its approved one
Earlier studies (1980-2000) used high doses (≥100 mg/day) in depressed populations; since the 2000s the use has expanded to low-dose treatment of secondary insomnia in non-depressed populations
12Case Studyn=19 · very small study2019
In plain English: However, priapism can occur at nearly any age and with any dose. Clinicians must be aware of the risk and reports of early signs, such as prolonged erections, should be taken seriously.
Greiner, Schneider, Regente, Toto, Bleich, Grohmann, Heinze · The World Journal of Biological Psychiatry (2019)
Nineteen cases of priapism likely caused by psychotropics, drawn from the AMSP pharmacovigilance database, plus a review of published case reports
Trazodone is named alongside typical and atypical antipsychotics as a known cause of priapism
The most common assumed mechanism is the alpha-adrenergic blocking effect of the drugs
In plain English: We report a case that details the presentation and treatment of a 25-year-old man who developed serotonin syndrome in the setting of rapid titration of risperidone, trazodone, and sertraline.
Martino, Elfessi, Szaflarska, Suh, Antonishina · Journal of Pharmacy Practice (2024)
A 25-year-old man developed serotonin syndrome after rapid titration of risperidone, trazodone and sertraline, presenting with acute agitation, diaphoresis, altered mental status, lower-extremity myoclonus, tremor, temperature 100°F and heart rate 103
He was treated successfully with benzodiazepines and discharged after 4 days
Serotonin syndrome is a potentially life-threatening toxic excess of serotonin whose classic triad is neuromuscular excitation, autonomic instability and altered mental status; because it is a diagnosis of exclusion it is under-recognised and its true incidence is unknown