New antidepressants, like esketamine and brexanolone, have a fresh approach to treating depression and offer options when other medications may not work.

Serotonin reuptake inhibitors (SSRIs) changed the face of depression treatment with their arrival in the 1980s. They offered an improvement over older antidepressants, like tricyclics, because they had fewer side effects.

But since that time, many new developments have been made in antidepressants.

Treatment for depression typically involves a combination of therapy and medication. But studies show that about one-third of people with depression don’t respond to current medications.

New antidepressants may help fill that gap. The latest antidepressants use new mechanisms to pick up where older antidepressants left off.

Three new antidepressants are on the market to treat depression:

Unlike SSRIs and other antidepressants, these newer medications can start relieving symptoms in a few hours or days instead of a few weeks.


Approved in 2019 by the Food and Drug Administration (FDA), brexanolone is used to treat postpartum depression in adults who aren’t pregnant.

How does brexanolone work?

Progesterone and allopregnanolone are hormones that peak in your body during the third trimester of pregnancy. Allopregnanolone is a metabolite (byproduct) of progesterone. After you have your baby, progesterone and allopregnanolone levels drop abruptly and significantly.

Scientists believe the sudden hormone level drop may contribute to postpartum depression.

The exact way brexanolone works isn’t fully understood. But since it’s a solution of allopregnanolone, it’s thought to help activate gamma-aminobutyric acid (GABA) receptors and raises GABA levels in your brain.

People with depression tend to have lower GABA levels and lower activity in the GABA receptors.

How do you take brexanolone?

Brexanolone is given as an intravenous (IV) infusion for a total of 60 hours (2.5 days). At this time, brexanolone can only be administered in a hospital setting.

You’ll likely start with a low dose, which will gradually increase until your allopregnanolone levels are at what’s typically seen during the third trimester of pregnancy.

During the last 8 hours of the infusion, the dose will gradually be decreased.

What are the side effects of brexanolone?

The most commonly reported side effects of brexanolone include:

  • dry mouth
  • flushing
  • loss of consciousness (passing out)
  • sleepiness

What should I watch for while taking brexanolone?

You may lose consciousness while receiving your brexanolone infusion. A healthcare professional will monitor you closely for excessive sleepiness and loss of consciousness.

Like other antidepressants, brexanolone may increase the chance of suicidal thoughts or behaviors in people ages 24 years and younger. It’s recommended that you monitor your symptoms while on this medication.


Esketamine is a new antidepressant drug approved in 2019 by the FDA to treat depression that hasn’t improved with other medications.

It belongs to the class of medications called N-methyl D-aspartate (NMDA) receptor blockers. It’s derived from ketamine — a drug used for anesthesia. This new antidepressant works differently than other commonly prescribed antidepressants.

How does esketamine work?

In clinical studies, scientists discovered that ketamine relieves depression in ways that traditional antidepressants don’t. Compared to other commonly used antidepressants, people who took ketamine showed improvement in depression symptoms within a few hours versus a few weeks.

It’s not fully understood how esketamine works, but it may work similarly to ketamine. Both medications are NMDA receptor blockers. By blocking NMDA receptors, esketamine triggers the production of glutamate.

Glutamate is a chemical in your brain that helps form new brain cell connections. Scientists believe creating new brain cell connections can help people with depression develop new positive thoughts and behaviors.

How do you take esketamine?

Esketamine comes in a nasal spray. A mental health professional will show you how to use it and how much medication to take. You will likely use esketamine once or twice a week, along with another oral antidepressant.

After taking esketamine, a healthcare team will observe you for about 2 hours. They will let you know when it’s safe for you to leave the facility.

What are the side effects of esketamine?

The side effects most commonly seen with esketamine include:

  • anxiety
  • dizziness
  • drowsiness
  • feeling detached from yourself
  • feeling inebriated
  • increased blood pressure
  • nausea
  • numbness in part of your body
  • sluggishness
  • vomiting

What should I watch for while taking esketamine?

Esketamine may cause you to feel drowsy or disconnected from yourself, your thoughts, or space and time (dissociation). There’s also a chance that you may become dependent on esketamine. For this reason, esketamine is only administered in a healthcare facility setting.

After taking esketamine, a healthcare professional will monitor you for at least 2 hours for an increase in blood pressure and signs of excessive sleepiness or dissociation. It’s recommended that you avoid driving or operating machinery after taking esketamine for 24 hours.

Like other antidepressants, esketamine may increase the risk of suicidal thoughts and actions in young adults.


Agomelatine is an antidepressant that works in two unique ways. It blocks serotonin receptors so that you have more serotonin freely available in your brain. It also stimulates melatonin receptors to help you sleep.

Agomelatine is approved to treat depression in Europe and Australia. But the FDA hasn’t yet approved the medication for use in the United States due to negative results seen in late-stage trials. The possibility of liver damage is also a concern.

New antidepressants open new avenues in depression treatment that haven’t been explored before. However, older antidepressants are still the first choice for antidepressant medication. Here are the five most common antidepressants.

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs remain the most prescribed antidepressants. Fluoxetine (Prozac) was the first SSRI approved by the FDA to treat depression.

Other commonly prescribed SSRIs include:

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

SNRIs are also frequently prescribed antidepressants. Levomilnacipran (Fetzima) was approved by the FDA in 2013 for depression.

Other commonly used SNRIs include:

Noradrenergic and specific serotonergic antidepressants (NaSSAs)

Similar to SSRIs and SNRIs, these medications affect serotonin and norepinephrine, but they also block receptors of the stress hormone epinephrine.

They are often prescribed for depression, anxiety, and personality disorders. The most commonly used NaSSA is mirtazapine (Remeron).

Tricyclic antidepressants (TCAs)

Because TCAs may have some unpleasant side effects, they are less often prescribed for depression. However, TCAs are still used for other conditions, such as trouble sleeping and some types of chronic pain. Commonly used TCAs include:

Atypical antidepressants

Atypical antidepressants are those that don’t fall into other categories. Each one works slightly differently than other antidepressants and even other atypical antidepressants.

Examples of atypical antidepressants include:

Whether you’re looking for a new depression medication or thinking of changing your current treatment, finding the right drug for you can take some time.

Taking steps to learn more about new antidepressants can help you find the proper medication for you. Consider reaching out to a mental health professional. They can help you choose an antidepressant that fits your unique symptoms.

Remember that you do not have to go through depression alone. Help is available. You can check out our “How to Find Mental Health Support” page for a list of mental health resources and hotlines.