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Antidepressants are medications that can help relieve depression symptoms, like fatigue and emotional numbness.

Several different kinds of antidepressants exist, but the most commonly prescribed are selective serotonin reuptake inhibitors (SSRIs).

Fluoxetine (Prozac) entered the market in 1988 as the first SSRI, and for the next 30 years, many experts considered SSRIs the “modern” antidepressant.

In 2019, the Food and Drug Administration (FDA) approved two new antidepressants, brexanolone and esketamine. There’s also been renewed interest in agomelatine, an antidepressant not currently available in the United States.

Read on to learn more about these new antidepressants, including how they compare to SSRIs, their side effects, and how to try them.

In 2019, the FDA approved brexanolone (Zulresso) as the first drug specifically designed to treat moderate to severe postpartum depression (PPD).

Experts consider some SSRIs safe to take while pregnant or nursing, but these medications may not lead to much improvement for several weeks. When you have PPD, symptoms don’t just affect your own well-being — they can also have long-term effects on your bond with your baby.

Brexanolone, however, begins to take effect immediately. According to two randomized clinical trials published in 2018, this medication can significantly reduce PPD symptoms — benefits that held when researchers followed up with participants 30 days after treatment.

Learn more about treatment for postpartum depression.

How it works

Brexanolone raises brain levels of the neurotransmitter gamma aminobutyric acid (GABA).

In a nutshell, GABA dampens the chemical activity in your neurons, almost like a dimmer switch for certain cells.

Scientists aren’t sure exactly how brexanolone treats PPD symptoms, but one theory suggests that with PPD, your GABA levels don’t recover quickly enough from pregnancy to manage your stress. Essentially, cortisol hormones rise unchecked, contributing to symptoms of depression. Brexanolone, then, may offer a “reset” by restoring your GABA levels.

You receive this medication as a one-time IV treatment over the course of 2 and a half days. You’ll remain in your healthcare center for the entire 60-hour treatment for monitoring.

Safety and side effects

Like other drugs that affect GABA levels, brexanolone can cause sedation. Roughly 1 in 4 people experience sedation-related side effects in the first 24 hours of treatment.

You may feel:

  • extremely sleepy, even during the day
  • unfocused and distractible
  • dizzy or faint

Your care team will check on you every 2 hours for extreme symptoms like fainting. If you experience serious side effects, they’ll stop the infusion. Sedation-related symptoms should stop within 15 minutes after the IV infusion stops.

How to get a prescription

You can only receive this treatment from approved healthcare centers, and you’ll need a doctor’s referral to join the treatment program.

The treatment can cost up to $34,000, though health insurance can help offset some of the cost. Companies like Aetna and Cigna require pre-authorization, so you’ll want to make sure your insurance provider covers the treatment before you check in to your clinic.

Keep in mind, too, that most insurance companies only cover one round of treatment, as research has yet to explore the potential benefits of additional rounds of treatment.

The company that makes brexanolone also offers several financial assistance programs, which could be worth considering if the price tag puts it out of reach.

Esketamine (Spravato) is a chemical cousin of the anesthetic ketamine. The FDA approved esketamine in 2019 to treat treatment-resistant depression, or depression that persists after you try at least two different antidepressant treatments.

During clinical trials, doctors gave participants a nasal esketamine spray or a placebo spray. All participants also took an oral antidepressant they hadn’t tried before. Compared to people who took an oral antidepressant and used a placebo spray, those who used the esketamine spray reported greater symptom relief and longer symptom-free periods.

How it works

Esketamine sets off a chain reaction of chemicals that ultimately raises your levels of brain-derived neurotrophic factor (BDNF). BDNF helps your neurons make new connections, which in turn enables you to form memories, learn new information, and develop different habits.

Depression typically involves low BDNF levels, and your brain may have difficulty adapting to changes. Esketamine helps restore BDNF levels, along with overall brain plasticity.

As with brexanolone, you have to take esketamine in the presence of a healthcare professional. Your doctor or clinician will give you a dose between 56–84 milligrams (mg), which you spray into your nostrils. You then relax in a chair for 2 hours. Your care team will monitor your blood pressure and heart rate during this time.

This medication works quickly, with many people noticing relief right away. Treatment requires multiple sessions, typically twice a week for the first 28 days and then spaced out over time. The effects usually last until your next dose.

Safety and side effects

In clinical trials, participants tended to report mild to moderate side effects. You may feel sleepy, dizzy, or a bit “out of it” during your treatment session. These side effects often go away within 90 minutes after you take your dose.

On rare occasions, people have reported more severe side effects like:

  • vomiting
  • anxiety and confusion
  • worsening depression or suicidal thoughts

Esketamine can also lead to significant increases in blood pressure during the treatment session, which is why you’ll need monitoring for 2 hours. If you have hypertension or another vascular condition, make sure to tell your doctor before receiving treatment.

How to get a prescription

You can only receive this treatment at an approved healthcare center, so you’ll need to ask your doctor or psychiatrist if you’d like to try esketamine.

The course of treatment instead depends on the severity of your symptoms — and how much you’re able to pay. As of 2021, a standard 56-mg dose of esketamine costs $590, and a large dose of 84 mg costs $885.

The initial month of therapy is often the most expensive since treatment guidelines recommend twice-weekly treatment for the first month. This first month can cost anywhere from $4,800 and $6,800 dollars.

To date, no official guidelines set an ideal length of treatment.

According to the company that produces Spravato, some insurance programs cover most of the cost of esketamine. You’ll only need to pay a $10 copay per session until you hit the benefits cap of $7,150 per year.

Agomelatine (Valdoxan), an oral antidepressant, has been available in some other countries since 2009, though you can’t get this medication in the United States.

You take agomelatine as a 25-mg pill once a day at bedtime. If your depression symptoms don’t respond, a doctor may increase the dose to 50 mg per day.

Agomelatine may have particular benefit for depression that:

How it works

Agomelatine has two main effects on your brain. It increases activity at melatonin nerve receptors, which helps you sleep. It also decreases activity at specific serotonin receptors and helps increase dopamine and norepinephrine in the frontal cortex.

Increasing melatonin levels can improve sleep-related issues. In a small 2018 study that included 24 young adults, researchers found that the more agomelatine shifted the participants’ circadian rhythms, the more their depression symptoms improved.

Experts don’t yet know exactly how decreasing serotonin fits into the picture.

That said, older animal research from 2014 suggests boosting melatonin and decreasing serotonin binding to receptors simultaneously may help protect newly created neurons by shielding them from the damage caused by chronic stress.

Safety and side effects

Agomelatine may cause:

  • nausea and vomiting
  • constipation, stomach pain, and diarrhea
  • drowsiness or difficulty sleeping
  • headaches

But many people only experience mild side effects while taking agomelatine, which may partially explain the renewed interest in this antidepressant.

After all, if you don’t experience severe side effects, you’ll probably feel more inclined to continue taking the medication.

How agomelatine compares

A 2018 review including 522 trials with a total of 116,477 participants compared 21 antidepressants.

When the review authors considered dropout rates specifically due to adverse reactions, they discovered all included antidepressants had a higher dropout rate than the placebo — except agomelatine.

Incidentally, researchers also listed agomelatine as one of seven most effective antidepressants among those studied.

With many antidepressants, you may experience flu-like symptoms if you suddenly stop taking the medication. This phenomenon, called discontinuation syndrome, doesn’t occur with agomelatine. You can easily stop even long-term agomelatine use.

So, you might wonder: If this medication works so well, what’s holding up approval in the United States?

Agomelatine does have the potential to cause one very severe side effect: liver toxicity. The medication raises the levels of liver amino acids called transaminases, causing liver damage for up to 4.6% of people who take it. People taking this medication need to have their liver function tested at weeks 3, 6, 12, and 24 of treatment.

Other antidepressants can have a similar impact on your liver, but at much lower rates:

  • placebo: 2.1%
  • escitalopram (Lexapro): 1.4%
  • paroxetine (Paxil): 0.6%
  • fluoxetine (Prozac): 0.4%

How to get a prescription

Currently, you can’t get a prescription for agomelatine in the United States or Canada, as regulatory agencies have deemed the risk of liver injury too high to allow the drug on the market.

It’s possible that agomelatine could become more widely available in the future if researchers identify a way to minimize the risk of liver toxicity.

Doctors in Europe and Australia may prescribe this medication.

Brexanolone and esketamine appear to have the most benefit for postpartum depression and treatment-resistant depression, respectively. These medications also come with a high price tag that can make them harder to access.

Agomelatine can effectively treat a wider range of depression subtypes. But it also carries a risk of liver toxicity, and it hasn’t been approved for use in the United States.

To sum up, these medications likely won’t replace SSRIs as the first line of treatment for other types of depression anytime soon. Still, their existence opens up possibilities for future advances in depression treatment.

Emily Swaim is a freelance health writer and editor who specializes in psychology. She has a BA in English from Kenyon College and an MFA in writing from California College of the Arts. In 2021, she received her Board of Editors in Life Sciences (BELS) certification. You can find more of her work on GoodTherapy, Verywell, Investopedia, Vox, and Insider. Find her on Twitter and LinkedIn.