Trazodone is the antidepressant nobody uses as an antidepressant anymore. It is FDA-approved for major depression at doses of 150 to 400 milligrams, but at those doses the sedation is so severe that daytime functioning is usually impossible. What trazodone is used for, almost universally, is sleep — at doses of 25 to 100 milligrams at bedtime, off-label, and absolutely everywhere.
- Class
- Serotonin antagonist and reuptake inhibitor (SARI)
- Mechanism
- Weak SERT inhibition + strong 5-HT2A antagonism; also alpha-1 antagonism (orthostasis) and H1 antagonism (sedation)
- Typical dose
- For depression 150-400 mg/day. For insomnia 25-100 mg at bedtime (off-label).
- Half-life
- ~7 hours
- FDA indications
- MDD (FDA-approved). Off-label: insomnia (most common modern use).
- Key adverse effects
- Sedation, orthostatic hypotension, dry mouth, blurred vision, priapism (rare but emergent)
Most common modern use: off-label for insomnia at 25-100 mg. Priapism is rare but a true emergency — counsel male patients. Avoid for daytime depression dosing; sedation usually intolerable.
The mechanism explains the split personality. Trazodone is a "SARI" — serotonin antagonist and reuptake inhibitor. It weakly inhibits SERT, blocks 5-HT2A receptors strongly, antagonizes alpha-1 adrenergic receptors (causing orthostasis), and blocks H1 receptors (causing sedation). At low doses, the H1 and alpha-1 effects dominate — sleep, with some morning grogginess. At higher doses, the SERT inhibition contributes antidepressant effect, but the sedation persists.
For sleep, trazodone is a popular choice for several reasons. It is non-controlled — no DEA scheduling, no abuse liability, no requirement for refill restrictions. It does not produce tolerance the way benzodiazepines and z-drugs can. It can be used long-term without the dependence concerns of GABA modulators. It does not suppress REM sleep significantly. For a patient with chronic insomnia who needs a sleep aid but should not have a controlled substance, trazodone is a reasonable choice.
Trazodone is a second textbook case of dose-dependent recruitment — a hypnotic at low dose, an antidepressant only at high dose, because different receptors engage at different exposures.
Mechanism note: Trazodone's split personality by dose — hypnotic low, antidepressant high — is dose-dependent receptor recruitment in action. Know which mechanism the prescribed dose actually engages.
Side effects are mostly the H1 and alpha-1 effects. Morning grogginess is the most common complaint, especially with doses over 50 milligrams. Orthostatic hypotension is meaningful in older patients — dizziness on standing, fall risk. Dry mouth, headache, occasional nausea.
The signature serious adverse effect — rare but unforgettable — is priapism. Trazodone can produce sustained, painful erection from alpha-1 blockade in penile vasculature. Untreated for more than four hours, priapism can cause permanent erectile dysfunction. Counsel every male patient about this at the time of prescription: a prolonged painful erection is a urological emergency, not something to wait out. Document the counseling.
Dosing for sleep is simple. Start 25 to 50 milligrams at bedtime. Some patients need 100 milligrams. Above that, the daytime sedation usually becomes intolerable for sleep purposes. For antidepressant effect, doses are 150 to 400 milligrams divided — daytime use is hard.
- Cost
- Generic: ~$4-10/month. On most $4 lists.
- Generic status
- Generic since 1989. Universally available.
- Formulary typical
- Tier 1 generic. No PA.
- Access friction
- None for sleep doses. Higher doses for depression are rare.
Prescriber tip: Cheapest non-controlled sleep aid. Counsel every male patient about priapism — rare but emergent, and many patients hear it for the first time only after the prescription is filled.
Drug interactions are modest at sleep doses. The 5-HT2A blockade reduces concern for serotonin syndrome compared to pure serotonergic agents, but trazodone is still serotonergic enough to add to the burden if combined with MAOIs or other strongly serotonergic drugs.
When a patient asks for "something for sleep" that isn't addictive, trazodone is often the answer. When you offer it, mention the priapism risk explicitly to male patients, and start low.