Trazodone

• Major Depressive Disorder
• Insomnia
• Anxiety Disorders
• Sleep Disorders

Trazodone (Desyrel) is a serotonin antagonist and reuptake inhibitor (SARI) originally approved in 1981 for major depressive disorder. In contemporary practice, it is more commonly prescribed off-label at low doses (25 to 100 mg) for sleep-onset and sleep-maintenance insomnia, particularly when comorbid depression or anxiety is present. The medication's mixed pharmacology — combining serotonin reuptake inhibition with strong 5-HT2A, alpha-1 adrenergic, and histamine H1 antagonism — produces sedation that is useful clinically but also accounts for most of its side-effect profile. Unlike benzodiazepines and Z-drugs, trazodone is not a controlled substance and carries no abuse potential or physiologic dependence in the conventional sense.

Mechanism of Action

Trazodone has a multimodal pharmacologic profile that varies meaningfully by dose. At low doses (25 to 150 mg), the dominant actions are 5-HT2A receptor antagonism, alpha-1 adrenergic blockade, and histamine H1 antagonism — all of which promote sedation, decrease arousal, and stabilize sleep architecture. The 5-HT2A antagonism in particular increases slow-wave (deep) sleep and reduces nocturnal awakenings without producing the REM suppression typical of older antidepressants.

At antidepressant doses (150 to 400 mg daily), serotonin transporter (SERT) inhibition becomes clinically meaningful, raising synaptic serotonin in cortical and limbic regions over weeks. The combination of SERT inhibition with 5-HT2A and 5-HT2C blockade is hypothesized to be more antidepressant than SSRIs alone in some patients, though comparative trials show similar overall efficacy. The alpha-1 antagonism explains orthostatic hypotension, especially in elderly patients, and contributes to the rare but serious adverse effect of priapism — sustained painful erection requiring emergency urologic evaluation. Trazodone has minimal anticholinergic activity, distinguishing it from older tricyclic antidepressants and making it generally better tolerated in older adults. The NIMH depression resource and the American Academy of Sleep Medicine offer additional context for the dual indication.

Clinical Use

For depression, trazodone at full antidepressant dose (typically 150 to 400 mg in divided doses, or extended-release 150 to 375 mg at bedtime) is a reasonable option but is rarely first-line because the sedation at therapeutic doses is dose-limiting. SSRIs such as sertraline, escitalopram, and fluoxetine, or SNRIs such as duloxetine, are preferred initial options based on superior tolerability and similar efficacy. Trazodone moves up the algorithm in patients with prominent insomnia accompanying depression, where its sedation becomes a feature rather than a bug.

For insomnia, trazodone 25 to 100 mg at bedtime is widely prescribed off-label as a non-controlled alternative to benzodiazepines, zolpidem, and other sedative-hypnotics. The American College of Physicians chronic insomnia guideline recommends cognitive behavioral therapy for insomnia (CBT-I) as first-line treatment, with pharmacotherapy reserved for patients in whom CBT-I is unavailable, ineffective, or insufficient. When pharmacotherapy is used, trazodone is a reasonable option, particularly in patients with mood symptoms, in older adults at fall risk on Z-drugs, and in patients with substance use history. Comparative evidence for trazodone in primary insomnia is modest; the sleep hygiene article, the circadian rhythm guide, and the screen time and sleep article cover non-pharmacologic foundations that should precede pharmacologic intervention. Our psychiatric team coordinates both indications and screens carefully for untreated obstructive sleep apnea, restless legs syndrome, depression, anxiety, and chronic pain — each of which can present primarily as insomnia and require treatment of the underlying problem rather than a sedative-hypnotic.

How to Take It

For insomnia, take 25 to 100 mg by mouth 30 minutes before the desired bedtime. Take with food or a light snack to reduce dizziness; the half-life is about 7 hours, so morning sedation is possible at higher doses and warrants taking the dose earlier in the evening or reducing the amount. For depression, immediate-release tablets are taken in divided doses (often half in the morning and half at bedtime) to reduce daytime sedation and preserve adherence; extended-release tablets are taken once daily at bedtime on an empty stomach. If a dose is missed, take it as soon as remembered the same evening; if it is the next morning, skip and resume — do not double up.

The first week typically brings noticeable next-morning grogginess, dry mouth, mild dizziness, and sometimes blurred vision; these usually attenuate over 1 to 2 weeks. Hydration, slow position changes, and consistent timing help. Avoid alcohol and other CNS depressants because the additive sedation can produce dangerous respiratory depression in vulnerable patients. Driving and operating machinery should be deferred until tolerance is clear, particularly during the first week and after any dose increase. Storage is at room temperature in the original container, away from heat and humidity, and out of reach of children and pets — overdose can produce profound sedation and dangerous hypotension requiring emergency care.

Monitoring and Follow-Up

Baseline assessment includes blood pressure, pulse, weight, comprehensive metabolic panel, and a depression severity scale such as the PHQ-9 if used for depression, or the Insomnia Severity Index for sleep. ECG is not routinely required at low doses but is reasonable in patients with cardiac history, on QT-prolonging medications, or at higher antidepressant doses. Follow-up at 1 to 2 weeks reviews tolerability, sedation, and emergent adverse effects.

For depression, recheck the PHQ-9 at 4 and 8 weeks; a reduction of at least 50 percent indicates response and a score below 5 indicates remission. For insomnia, sleep diaries or actigraphy can document time to sleep onset (target less than 30 minutes), wake after sleep onset (target less than 30 minutes), total sleep time (target 7 to 9 hours for most adults), and morning hangover. Blood pressure should be measured at each visit because orthostatic hypotension is dose-related and can cause falls. Sodium should be monitored within the first month in elderly patients due to a small SIADH risk; values below 130 mEq/L warrant evaluation. Sexual function, mood, and weight are tracked at each visit. The duration of low-dose trazodone for insomnia should be reviewed at least every 3 to 6 months with consideration of taper when sleep is consistently consolidated.

Special Populations

Elderly patients are especially sensitive to trazodone-induced orthostasis, sedation, falls, and urinary retention; start at 25 mg and titrate cautiously. Hepatic impairment increases exposure; lower doses are appropriate. Renal impairment generally requires no specific adjustment. Pregnancy data are limited but more reassuring than for many antidepressants; risk-benefit discussion is important and the lowest effective dose is preferred. Lactation transfer is documented at low levels; weigh individually. Pediatric use is not FDA-approved; the boxed warning for emergent suicidality in patients under 25 applies to all antidepressants. MAOIs are contraindicated within 14 days. Concurrent use with strong CYP3A4 inhibitors such as ketoconazole, ritonavir, or clarithromycin substantially increases trazodone exposure and may require dose reduction. CYP3A4 inducers such as carbamazepine and phenytoin can reduce levels. Concurrent serotonergic medications increase serotonin syndrome risk. The FDA trazodone label provides the complete safety profile.

When to Contact Your Doctor

Seek emergency care immediately for a sustained painful erection lasting more than 4 hours — this is priapism, a medical emergency that can cause permanent erectile dysfunction without prompt treatment. Other emergencies include thoughts of self-harm or suicide, agitation with high fever, rigid muscles, rapid heartbeat, sweating, and confusion (signs of serotonin syndrome), fainting, severe dizziness with falls, chest pain, irregular heartbeat, severe vomiting, seizure, or signs of allergic reaction (face or tongue swelling, hives, trouble breathing). Call promptly for persistent morning grogginess that interferes with safe driving, new urinary retention, persistent dizziness on standing, unusual bleeding or bruising, new or worsening depression rather than improvement, racing thoughts or new euphoria suggesting bipolar activation, or any new psychiatric symptom in the first weeks of therapy. Never stop the medication abruptly without discussing taper.

If depression, anxiety, or insomnia are interfering with daily life, contact us or schedule a visit so our team can evaluate underlying causes — including untreated medical conditions, sleep disorders, and substance use that often complicate symptoms — and decide whether trazodone or an alternative therapy is the right fit for your situation.