If your practice is anything like mine, trazodone is your go-to hypnotic. As an antidepressant, it’s an afterthought, dismissed as ineffective or intolerable since its release in 1981. Four decades and over 200 clinical trials later, it’s a good time to see if we’ve missed any opportunities in this forgotten antidepressant.

How trazodone works
Trazodone is a serotonergic antidepressant that is classified as a 5HT₂ antagonist, but other mechanisms of action include serotonin reuptake inhibition, 5HT_1A agonism, and blockade of histamine, alpha-1, alpha-2, 5HT_2A, and 5HT_2C receptors. (See our 4/27/20 podcast for a discussion of 5HT_2A and 5HT_2C.)

Pros and cons
Trazodone has several advantages in that it is weight neutral, has few sexual side effects, and improves sleep. What has limited its use is daytime sedation, which affects about 1 in 3 patients who take it in the antidepressant dose. It can also cause dizziness, orthostasis, nausea, and cardiac arrhythmias. Priapism is a rare but dreaded side effect occurring in 1 in 6000 patients. This is more than just a painful, prolonged erection. Left untreated, it can lead to penile necrosis, and it can affect the clitoris in female patients as well.

Evening dosing
Trazodone has a short half life of 7–10 hours, and when it was first released, twice-daily dosing was recommended. That aggressive daytime dosing resulted in dizzy, sleepy patients who couldn’t tolerate the drug. And it probably wasn’t necessary, as the medication’s antidepressant actions are delayed and aren’t yoked to its serum levels. All-at-night dosing was later proven to work just as well as divided dosing, with significant gains in tolerability (Raatjes B and Dantz B, Psychiatric Annals 2011;42(3):148–157). However, by that time trazodone had been largely forgotten as an antidepressant, and interest shifted toward a branded, controlled-release version of trazodone, Oleptro.

Released in 2010, Oleptro attempted to resurrect trazodone for use in depression. By reducing the peak plasma levels, Oleptro claimed to cause less daytime sedation than instant-release trazodone. Unspoken in those claims was the fact that the manufacturer was comparing it to twice-daily dosing of trazodone. Oleptro, however, was discontinued in 2015, so controlled-­release dosing is no longer an option.

Depression
More than two dozen double-blind placebo-controlled studies have shown trazodone (150–600 mg per day) to be as effective as other antidepressants, from the tricyclics to the SSRIs. It has also worked well in hospitalized patients with severe depression. The drug works better when titrated slowly, possibly because rapid titration can lead to spikes in the depressogenic metabolite, m-chlorphenylpiperazine (mCPP) (­Schatzberg A, DeBattista C. Schatzberg’s Manual of Clinical ­Psychopharmacology. Washington, DC: American Psychiatric Publishing; 2019).

Can trazodone cause depression?
Trazodone does not cause depression, but a handful of papers have linked its metabolite, mCPP, to dysphoria and anxiety, as well as to self-harm in adolescents (Shamseddeen W et al, J Child Adolesc Psychopharmacol 2019;29(7):573). mCPP is a 5HT_2C agonist that can have antidepressant effects when its levels are stable, but when those levels rise too quickly, anxiety and dysphoria can result.

mCPP is excreted from the body through CYP2D6 metabolism, so managing this problem means dosing trazodone cautiously in patients who are slow metabolizers at CYP2D6. That includes those on CYP2D6 inhibitors (eg, duloxetine, fluoxetine, paroxetine, quinidine, ritonavir) and those with genetic variations at CYP2D6 (more common in African American and Hispanic patients). You can raise the dose more slowly in these populations (eg, using half the usual dose at each step of the titration) but still aim for the same target dose.

Insomnia
Trazodone works in primary insomnia as well as insomnia secondary to depression (Jaffer KY et al, Innov Clin Neurosci 2017;14(7–8):24–34). It increases total sleep time by 30–50 minutes, more than many on-label hypnotics. Importantly, trazodone improves sleep quality, increasing the deep stages: 3, 4, and slow-wave sleep. Few on-label hypnotics can claim that. On the contrary, there’s evidence that sleep architecture can worsen with benzodiazepines, particularly in high doses.

Despite these advantages, The American Academy of Sleep Medicine recommended against trazodone as a hypnotic. Their reasoning was that it lacked solid evidence, but their bar for acceptable evidence was very high (Sateia MJ et al, J Clin Sleep Med 2017;13(2):307–349). Trazodone can worsen next-day cognition and comes with a risk of falls in the elderly that is surprisingly similar to other hypnotics (Warner MD et al, Pharmacopsychiatry 2001;34(4):128–133; Watt JA et al, CMAJ 2018;190(47):E1376–E1383).

Trazodone has adrenergic effects that are similar to prazosin, and uncontrolled studies suggest it improves sleep and reduces nightmares in PTSD (Brownlow JA et al, Curr Psychiatry Rep 2015;17(6):41). Some experts use it first line for insomnia and nightmares in PTSD. It’s also a preferred hypnotic in sleep apnea because it can lower the hypopnea index (Smales ET et al, Ann Am Thorac Soc 2015;12(5):758–764). Trazodone is often used for insomnia in bipolar disorder, but there are case reports of hypomania even at the low dose. Recently, an epidemiologic study raised questions about suicidality risks when trazodone is used as a hypnotic, which we cover in this issue’s Research Update on page 6.

Anxiety, akathisia, and beyond
For treating generalized anxiety disorder, trazodone worked better than placebo but worse than imipramine in a large randomized controlled trial (average dose 225 mg divided tid) (Rickels K et al, Arch Gen Psychiatry 1993;50(11):884–895). It relieved antipsychotic-induced akathisia in a small, placebo-controlled trial at 100 mg qhs (Stryjer R et al, Clin Neuropharmacol 2010;33(5):219–222). There is little evidence to support its use in panic disorder and OCD.

Managing side effects
If daytime fatigue persists with evening dosing, have the patient take trazodone 2–3 hours before bedtime. Orthostasis may improve by dividing the dose or taking it with food to reduce peak plasma levels. Taking trazodone after a meal can mitigate nausea. Priapism is best handled by education and screening for high-risk patients such as those with sickle cell anemia, leukemia, hypercoagulable states, and cocaine or methamphetamine use. Frequent morning erections are a warning sign, and an erection lasting longer than 2–4 hours mandates a trip to the emergency room.

How to use trazodone in depression
Some guidelines list trazodone as a first-line agent, and while I generally wouldn’t start there, it’s worth trying if your top 2 choices fail. Patients with insomnia, PTSD, sleep apnea, or anxiety are good candidates, as are those who want to avoid weight gain and sexual side effects. I’ll also consider moving to an antidepressant dose (150–600 mg) when the patient is already on it for insomnia. Those at risk for hypotensive falls or cardiac disease are less ideal.

Start with 25–50 mg at bedtime and increase slowly to 150 mg at bedtime within 7–10 days. At that point, you can wait to see if your patient responds or increase by 50–75 mg per week to a total of 300 mg, all at bedtime. The maximum dose is 600 mg, and some patients respond to doses as low as 150 mg.

TCPR Verdict: Trazodone is an effective antidepressant whose tolerability is greatly improved with nightly dosing, even in instant-release form. Its novel mechanism of action is a promising avenue for treatment-resistant patients, and its lack of weight gain and sexual side effects is a welcome advantage for others. Daytime somnolence, orthostasis, and drug interactions make it a second- or third-line option.