Atypical antidepressants are antidepressants that don’t fall under any of the 4 main classes of antidepressants. They’re most often prescribed if you’ve tried other types of antidepressants, and they didn’t work for you. But they can also be used as a first-line treatment, depending on your symptoms and whether you are experiencing other mental health conditions in addition to depression.
Like other mental health medications, they work by restoring the balance of the chemicals in your brain (neurotransmitters). Each medication works on different chemicals and affects them differently.
Bupropion (brand names: Wellbutrin, Zyban)
Bupropion might be the most “atypical” antidepressant on this list. Unlike most antidepressants, bupropion has no effect on serotonin. Instead, it boosts dopamine and norepinephrine, two other neurotransmitters that affect energy level, motivation, and attention.
Doctors often prescribe bupropion to target specific symptoms, like oversleeping, weight gain, and fatigue . It can also help improve concentration in people with depression and/or ADHD . It also helps people quit smoking .
Many antidepressants can decrease a person’s sex drive and lead to drowsiness and weight gain. Bupropion is unlikely to do any of these things—in fact, it is often prescribed alongside another antidepressant to counteract these side effects .
However, bupropion can have its own side effects. Common ones include:
- Dry mouth
- Trouble sleeping
- Headache and nausea
- Weight loss
- Restlessness or anxiety
- Dizziness and fatigue
Trazodone is an antidepressant, but it is commonly prescribed for sleep problems, such as trouble sleeping or nightmares due to PTSD .
Like many other antidepressants, it works by boosting serotonin levels in the brain. It is less likely than many antidepressants to cause symptoms such as sexual dysfunction, insomnia, or anxiety.
Common side effects include:
- Headaches and fatigue
- Drowsiness and sleepiness
- Dry mouth
- Dizziness or fainting
- Rarely, hallucinations or irregular heartbeat
Some of these side effects go away after the first week or so of taking trazodone.
Mirtazapine (brand name: Remeron)
Mirtazapine works boosting both serotonin and norepinephrine, a neurotransmitter that affects energy levels. It helps with depression but also improves sleep. It may work more quickly than most antidepressants. It’s being studied for potential use in anxiety disorders and other mental health conditions as well .
Mirtazapine is unlikely to have any negative sexual side effects. Possible side effects include:
- Increased appetite and weight gain (this may be a positive thing, if you are already underweight or have an eating disorder)
- Dry mouth
- Sleepiness and fatigue
Vortioxetine (brand names: Trintellix, Brintellix)
Vortioxetine is a newer medication (approved by the FDA in 2013). Although it’s considered “atypical,” it has a similar effect to many other antidepressants . It works by boosting serotonin levels in the brain.
Common side effects  include nausea, constipation, and vomiting. More serious side effects are rare, but may include:
- Serotonin syndrome
- Increased bleeding or bruising when injured
- Changes in vision, or swelling or pain near the eyes
- Low sodium levels
- Patel et al. (2016). Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Therapeutic Advances in Psychopharmacology 6(2), pp. 99–144. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837968/
- Acheson & de Wit. (2008). Bupropion improves attention but does not affect impulsive behavior in healthy young adults. Experimental and Clinical Psychopharmacology, 16(2), 113–123. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270475/
- Holm & Spencer. (2000). Bupropion: A Review of its Use in the Management of Smoking Cessation. Drugs 59, pp. 1007–1024. Retrieved from https://doi.org/10.2165/00003495-200059040-00019
- Shin and Saadabadi. (2020). Trazodone. StatPearls Publishing, Treasure Island, Florida. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK470560/
- Croom, et al. (2009). Mirtazapine: A Review of its Use in Major Depression and Other Psychiatric Disorders. CNS Drugs 23, pp. 427-452. Retrieved from https://doi.org/10.2165/00023210-200923050-00006
- D’Agostino, et al. (2015). Vortioxetine (Brintellix): A New Serotonergic Antidepressant. Pharmacy and Therapeutics, 40(1), pp. 36-40. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296590/
- Takeda Pharmaceuticals America, Inc. (2016). Medication Guide: Trintellix (vortioxetine) Tablets. Retrieved from https://www.fda.gov/media/98043/download