Trazodone: What you should know

Ashley Y, PharmD

June 1, 2025

Trazodone is one of those meds we see on sooo many patient profiles, but it doesn’t always get the deep-dive it deserves. You’ve probably wondered "why do we see trazodone so much, and what should we actually need to watch out for as health care providers?"

While trazodone is approved for the treatment of major depressive disorder (MDD), it’s typically considered a second-line option for depression—most often when insomnia is a prominent symptom. First-line therapies for depression in Canada, such as SSRIs, SNRIs, bupropion, and mirtazapine, are generally preferred for their stronger evidence base and more favorable tolerability profiles. That said, trazodone’s sedating properties make it a reasonable choice when sleep disturbance is a significant concern in the context of depression.

Mechanism of Action: The Reason Behind its Effects and Side-Effects

Trazodone is a serotonin antagonist and reuptake inhibitor (SARI). It works by:

• Inhibiting serotonin reuptake, increasing serotonin levels in the brain.

• Blocking 5-HT2A receptors and histamine H1, which contributes to its antidepressant and sedative effects.

• Blocking alpha-1 adrenergic receptors, leading to side effects such as potential orthostatic hypotension

Getting to the Right Dose

We usually like to titrate up to reach at least 150mg/day to have benefit as an antidepressant. Start at 50mg and titrate every 3-4 days as needed so that the body can get used to it. Maximum dose: 400 mg/day

For off-label use insomnia, I usually only see doses around 25-100mg at bedtime.

Note that higher doses are required to achieve antidepressant effects (hence try to titrate up to at least 150mg if using for depression before ruling out trazodone as a failed therapy). I always like to let my patients know to not give up too early. Keep in mind that it can take 8-12 weeks to see a 50% reduction in depressive symptoms once you're at the desired dose of at least 150mg.

Contraindications: When Trazodone Is a No-Go

• Hypersensitivity to trazodone or any of its components.

• Concurrent use with MAOIs or within 14 days of discontinuing an MAOI.

• Recent myocardial infarction

Counseling Tips: What Patients Need to Know

I usually start by telling them about the more transient side effects such as drowsiness (which may be a plus for some), dizziness, dry mouth, nausea. I like to let them know these symptoms usually get better over time (1-2 weeks), and I like to follow up with them in 2-4 weeks to see if they've experienced any of these side effects, and if so, if they still persist.

After going through those more common side effects, I usually go through a few red flags they should watch out for, where if they do experience it, they should contact myself (pharmacist) or doctor right away.

Suicidal Thoughts and Behaviors

Like other antidepressants, trazodone carries a risk of increasing suicidal ideation, particularly in young adults. Close monitoring is essential during the initial treatment period (the first 2-4 weeks) and during dosage adjustments.

Priapism

A rare (<1%) but serious side effect, priapism (prolonged and painful erection e.g >4 hours), has been associated with trazodone use. Please tell Chad that no, this is not a fun time and is a MEDICAL EMERGENCY. Please go to the hospital so everything can stay where it needs to stay...

Serotonin Syndrome

I counsel on this when a patient is on multiple medications for mood. I counsel that this usually feels like increased sweating, GI symptoms, and can be more serious where it turns into agitation, hallucinations, rapid heart rate, and muscle rigidity.

Cardiac Arrhythmias

Trazodone has been linked to QT prolongation and other cardiac arrhythmias. Use caution in patients with pre-existing heart conditions or those on other QT-prolonging drugs. For women, I am very cautious when their QTc is >470ms, and men >450ms. Anything over >500ms has a high risk of Torsades de Pointes (TdP).

Final Thoughts: Balancing Benefits and Risks

Trazodone remains a valuable medication to keep in our pharmacological arsenal, particularly for patients struggling with depression and insomnia. However, what's most important is that the patient is aware of why they're taking it, the expectations, and when to reach out if they don't think its the right medicine for them. As pharmacists, we can help our patients stay informed and help them navigate them closer to achieving their mental health goals.