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Atypical Antidepressants

Reviewed by: HU Medical Review Board | Last reviewed: September 2023

The most common types of drugs used to treat major depressive disorder (MDD) are selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). These are often called typical antidepressants. Atypical antidepressants, on the other hand, are a unique group of drugs that are used to treat depression.1

How do atypical antidepressants work?

Antidepressant drugs change the levels of certain neurotransmitters in the body. Neurotransmitters are chemicals the brain uses to send signals. These signals tell our body how to feel, think, and behave. They play a role in mood, digestion, movement, and more. Antidepressants may affect neurotransmitters such as serotonin, dopamine, and norepinephrine to treat symptoms of MDD.2-4

Atypical antidepressants impact many of the same neurotransmitters that typical antidepressant drugs do. But they do so in slightly different ways. This can lead to different efficacy, side effects, and risks.2,4-6

Examples of atypical antidepressants

Some of the most common atypical antidepressants are bupropion, mirtazapine, and serotonin modulators.

Bupropion (Wellbutrin®)

Bupropion impacts dopamine and norepinephrine. Unlike most other antidepressant drugs, it does not impact serotonin. Bupropion may help with many symptoms of MDD, like oversleeping, fatigue, and weight gain. It is also used to help people quit smoking. Bupropion may cause fewer sexual side effects (like low sex drive) and less weight gain than typical antidepressant drugs.2,5,7

Mirtazapine (Remeron®)

Mirtazapine affects several different neurotransmitters. Some of these include norepinephrine, serotonin, and histamine. Mirtazapine may work faster than other antidepressants. But the side effects can be especially bothersome.2,7

Trazodone (Desyrel®) and nefazodone (Serzone®)

Trazodone and nefazodone mainly impact serotonin. They increase the level and activity of serotonin to improve mood. These drugs are called serotonin modulators.6

Trazodone is unique because it does not lead to the same sexual side effects as most other antidepressants. These side effects include decreased sex drive, trouble achieving orgasm, and problems maintaining an erection. Trazodone also may help with sleep and anxiety. Trazodone is not typically used for depression due to its intense sedative nature.5,6

Vortioxetine (Trintellix) and vilazodone (Viibryd)

Like trazodone and nefazodone, vortioxetine and vilazodone are serotonin modulators. Vortioxetine may help with the thinking (cognitive) symptoms of depression, like memory problems. It may also impact other neurotransmitters like dopamine and norepinephrine.5-7

What are the possible side effects?

Side effects can vary depending on the specific drug you are taking. Common side effects of atypical antidepressants include:2,4-8

  • Headache
  • Nausea or vomiting
  • Trouble sleeping
  • Dry mouth
  • Restlessness
  • Constipation or diarrhea
  • Dizziness
  • Anxiety
  • Shakiness (tremors)
  • Sexual problems
  • Extreme tiredness (fatigue) or drowsiness
  • Blurry vision
  • Increased appetite and weight gain

All antidepressant drugs have a boxed warning, the strictest warning from the US Food and Drug Administration (FDA). This is because they may increase a person’s risk of suicidal thoughts or behaviors. This risk is highest for people under 25 years old who have just started treatment or who have recently had a dosage change.4

These are not all the possible side effects of atypical antidepressants. Talk to your doctor about what to expect when taking 1 of these drugs. You also should call your doctor if you have any changes that concern you when taking an antidepressant.

Other things to know

There are some rare side effects with atypical antidepressants. Your doctor will review those with you if you are prescribed an atypical antidepressant. If you notice new symptoms you are not used to, seek medical guidance on how to proceed.

Before starting to take 1 of these drugs, tell your doctor if you are pregnant or may become pregnant. Some antidepressant drugs may cause harm to an unborn baby.4

Most atypical antidepressants can interact with other drugs and supplements. Before starting a new atypical antidepressant, tell your doctor about all your health conditions and any other drugs or supplements you are taking. This includes over-the-counter drugs.4

Do not stop or change the dose of your antidepressant without first talking with your doctor. Your doctor will monitor you closely for any mental health side effects when you start or change doses of an antidepressant.4,6

If you are having thoughts of harming yourself or others, seek help right away from your doctor or a helpline like the Suicide & Crisis Lifeline. You can reach the Lifeline by calling or texting 988 anytime. Or you can chat with a counselor online.

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