Serotonin Antagonist and Reuptake Inhibitor (SARI)

4 min read · 9 sections

Serotonin antagonist and reuptake inhibitors are primarily indicated as antidepressant medications but are more commonly used to treat other conditions such as anxiety and insomnia.

Common side effects of these drugs include drowsiness, headache, dry mouth, dizziness, and blurred vision. Their use is associated with an antidepressant discontinuation syndrome, which means that people may experience certain withdrawal symptoms if the medication is stopped suddenly. There is also some risk of overdose and drug toxicity with SARIs.

Though these drugs have low potential for abuse, there have been reported cases of misuse in connection with polysubstance abuse.

What Are SARIs?

Serotonin antagonist and reuptake inhibitors (SARIs) are antidepressant medications approved for use in treating major depressive disorder. However, they are used off-label for the treatment of insomnia and anxiety. In fact, trazodone—perhaps the most commonly used SARI—is rarely used as the primary line of treatment for depression, and is more likely to be prescribed as a sedative or adjunct therapy in addition to other antidepressant treatments.1,2

SARIs may be particularly effective in individuals suffering from depression with symptoms of insomnia and/or psychomotor agitation.3

The two main SARIs prescribed in the United States are:3

  • Trazodone (previous trade names include Desyrel, Oleptro).
  • Nefazodone (previously marketed as Serzone).

How Do They Work?

SARIs work by inhibiting serotonin reuptake in the brain. They act as antagonists to inhibit a certain serotonin receptor—known as the 5HT2a receptor—and block the function of the serotonin transporter protein, thereby increasing the amount of active serotonin throughout the central nervous system (CNS). Trazodone use also results in some histamine and adrenergic receptor blockade in the brain; nefazodone additionally inhibits norepinephrine reuptake, though less potently than its effects on the serotonergic system.4,5

At low doses, trazodone can induce and help maintain sleep without causing daytime sleepiness or increased tolerance—largely due to its short half-life. Trazodone’s effectiveness as an  antidepressant is generally more pronounced at doses of 150mg to 600mg.4

These drugs may have an immediate effect on insomnia and anxiety but may take 2-4 weeks to have an effect on depression.5,6

What Are the Side Effects of SARIs?

Serotonin antagonist and reuptake inhibitors tend to have fewer side effects than some earlier generation antidepressants such as tricyclics and monoamine oxidase inhibitors (MAOIs).3

To counter the impact of the side effects, doctors may prescribe a smaller dose of the antidepressant initially and increase the dose as the individual’s body adjusts to the new medication.3

Do These Medications Have Withdrawal Symptoms?

People who take SARIs for at least several weeks may experience withdrawal symptoms if they stop taking them or lower the dose.

Studies that have looked at antidepressant withdrawal claim that symptoms generally appear within 3 days of quitting the medication and fade within 1 to 2 weeks. A case study found that nefazodone withdrawal symptoms completely resolved in 10 days.9,10

To avoid withdrawal symptoms, your doctor will probably taper or gradually reduce your dose of trazodone or nefazodone. The timeframe will depend on what your dose was and how long you took the medication.

Do They Interact With Other Drugs or Alcohol?

Yes. Both medications can interact with other drugs.

Trazodone can interact with:7

  • Non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or anticoagulants: may increase bleeding risk.
  • Warfarin (Coumadin): using trazodone with this drug can lead to difficulties with blood clotting.
  • Monoamine oxidase inhibitors: may enhance the risk of serotonin syndrome.
  • Serotonergic medications: when combined with trazodone, can increase the risk of serotonin syndrome.
  • Central nervous system depressants (alcohol and benzodiazepines): may increase certain effects of these drugs, including drowsiness and respiratory depression.
  • Digoxin or phenytoin: taking these drugs while on trazodone may lead to increased blood serum levels of the medications. Digoxin toxicity can lead to fatal cardiac arrhythmias. Phenytoin toxicity is associated with a range of neurologic complications.
  • CYP3A4 enzyme inhibitors (e.g., clarithromycin, nefazodone, ketoconazole): using these with trazodone may lead to the person requiring a lower dose; this combination may also cause trazodone toxicity at lower doses.
  • CYP3A4 inducers (e.g., carbamazepine): using these with trazodone may lead to the person requiring a higher dose of trazodone; the effects of trazodone will also likely be lowered at normal doses.

Nefazodone may interact with:5

  • Selective serotonin reuptake inhibitors (SSRIs): due to the CYP2D6 enzyme inhibition of these drugs, may increase the risk of nefazodone-related adverse side effects.
  • Monoamine oxidase inhibitors: may enhance the risk of serotonin syndrome.
  • Alprazolam (Xanax) and triazolam (Halcion): due to nefazodone’s CYP3A4 inhibition, may increase the half-life or duration of action for these drugs and heighten their effects.
  • Buspirone: due to nefazodone’s CYP3A4 inhibition, may increase blood plasma concentrations and increase the risk of adverse effects.
  • HMG CoA reductase inhibitors: due to nefazodone’s CYP3A4 inhibition, could increase serum concentration of certain statin drugs and increase the risk of rhabdomyolysis (breakdown of muscle tissue that can lead to kidney damage).
  • Haloperidol: when combined with nefazodone, may not be cleared from the body as quickly, necessitating a lower dose.
  • Pimozide (Orap): due to nefazodone’s CYP4A4 inhibition, can increase concentrations of the drug in a person’s system, increasing the risk of cardiac arrhythmias.

People taking SARIs should avoid alcohol and other central nervous system depressants (CNS depressants) such as benzodiazepines and barbiturates. Not only can mixing SARIs with alcohol or CNS depressants lead to heightened sleepiness and dizziness, but it can also lead to an overdose. Fatal overdoses have occurred in people who took trazodone while drinking or using other CNS drugs.7

Can You Overdose?

An overdose is possible on SARIs.

Seek emergency attention in the event of an overdose. If you’re with the person who has overdosed, try to find out when the person took the drug and how much they took, and recover the pill bottle, if possible, for the emergency response team.

Treating an overdose usually involves:7

  • Heart monitoring; frequent, serial vital sign monitoring.
  • Airway maintenance and breathing support (when needed) via supplemental oxygen or assisted ventilation.
  • Gastric lavage (stomach pumping).
  • Activated charcoal to prevent the digestive tract from further absorbing the medication into the body.

Can SARIs Be Abused?

These drugs appear to have low potential for abuse, according to studies.

A 2014 literature review investigated the abuse and misuse of antidepressants and found no published cases of trazodone or nefazodone abuse.11 Similarly, clinical studies of Oleptro, a former brand-name formulation of trazodone, found no evidence of drug-seeking behavior among participants.7

Another study found that trazodone had less abuse potential than many other prescription drugs used for sleep disorders, including zolpidem (Ambien) and triazolam (Halcion). The study recommended it as alternative to the 2 other drugs in people with histories of alcohol or drug abuse.12
However, there have been reported cases of trazodone abuse by people using multiple drugs. One case study looked at an individual who overdosed on trazodone while actively using cocaine and experienced an episode of painful priapism—a side effect of both drugs. The study commented on trazodone’s potential for misuse by polydrug users.13 Another case study documented an incident of serotonin syndrome in a man who was abusing tramadol (Ultram) while taking both trazodone and sertraline (Zoloft).14

Part of Comprehensive Treatment

While SARIs and other antidepressants can be valuable components of treatment for certain mood disorders and related conditions, they are often prescribed as part of a more comprehensive treatment plan—complete with therapy and overall lifestyle changes to best manage depression.

Many individuals struggling with depression benefit from a combination of antidepressant medications and behavioral therapy. In fact, the National Alliance on Mental Illness states that people are more likely to achieve better results with a combination of therapy and medications than with either alone. Types of therapies used to treat depression include cognitive behavioral therapy (CBT), interpersonal therapy (IPT), and psychodynamic therapy. Support groups for depression offer a way for people to share experiences and coping strategies, which can also be helpful in managing depression.15

Whether you are seeking treatment solely for depression or as part of substance abuse treatment, know that recovery is possible. If you are struggling with both depression and addiction, dual diagnosis treatment programs can treat both conditions simultaneously, which may improve treatment outcomes and lower the risk of relapse.


  1. Fasipe, O. (2018). Neuropharmacological classification of antidepressant agents based on their mechanisms of action. Yenepoya University Archives of Medicine & Health Sciences, 6(1), 81-94.
  2. ScienceDirect. Trazodone.
  3. Medscape. Initial Antidepressant Treatment: Balancing Effectiveness and Tolerability.
  4. Jaffer, K. et al. (2017). Trazodone for Insomnia: A Systematic Review. Innovations in Clinical Neuroscience, 14(7-8), 24-34.
  5. Source unknown. Nefazodone.
  6. Medline Plus. Trazodone.
  7. Food and Drug Administration. (2010). OLEPTRO.
  8. Centers for Disease Control and Prevention, National Center for Health Statistics. (2017). Antidepressant Use Among Persons Aged 12 and Older: United States, 2011-2014.
  9. Rajagopalan, M., Little, J. (1999). Discontinuation symptoms with nefazodone. Australian and New Zealand Journal of Psychiatry, 33(4), 594-597.
  10. Warner, C., Bobo, W., Reid, S., and Rachal, J. (2006). Antidepressant Discontinuation Syndrome. American Family Physician, 74(3), 449-456.
  11. Evans, E. and Sullivan, M. (2014). Abuse and misuse of antidepressants. Substance Abuse and Rehabilitation, 5, 107-120.
  12. Rush, C., Baker, R., and Wright, K. (1999). Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans. Psychopharmacology, 144(3), 220-233.
  13. Myrick, H., Markowitz, J., and Henderson, S. (1998). Priapism Following Trazodone Overdose with Cocaine Use. Annals of Clinical Psychiatry, 10(2), 81-83.
  14. Nayyar, N. (2009). Serotonin syndrome associated with sertraline, trazodone and tramadol abuse. Indian Journal of Psychiatry, 51(1), 68.
  15. National Alliance on Mental Illness. (2017). Depression.


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