The Consumer’s Guide to NMDA Receptor Antagonists for Major Depressive Disorder
What you should know about a unique approach to treating major depressive disorder.
D epression can be challenging to treat. Typical antidepressants, which affect levels of chemicals in the brain involved in mood regulation, have been evolving for decades, but research shows they don’t work for as many as 1 in 3 people with major depressive disorder (MDD). What’s more, researchers aren’t certain how they work or who’s most likely to benefit from them.
A class of drugs called NMDA (N-methyl-D-aspartate) receptor antagonists may be the answer for people with depression who don’t get relief from typical treatment. These drugs are safe and effective and tend to work more quickly than most antidepressants when taken under careful medical supervision.
If you’re dealing with MDD and have yet to find a medication that relieves your symptoms, consider asking your doctor about NMDA receptor antagonists. But first, learn all you can about them. The better informed you are going in, the easier it will be for you and your doctor to decide if an NMDA receptor antagonist is right for you.
How NMDA Receptor Antagonists Help Treat Depression
6 Essential Facts About NMDA Receptor Antagonists for MDD
1. There are two drugs for depression that contain an NMDA receptor antagonist.
One is a version of an anesthesia medication called ketamine, an NMDA receptor antagonist that is sometimes used as an intravenous (IV), off-label treatment for severe depression and can relieve symptoms quickly. The U.S. Food and Drug Administration (FDA) approved a nasal spray version called esketamine, or S-ketamine, in 2019, under the brand name Spravato.
A year later, the FDA expanded the approved uses of esketamine to include treating people with MDD who have attempted suicide or thought about it.
In 2022 the FDA approved a second medication, a combination drug with the brand name Auvelity. It’s composed of two active ingredients: bupropion (an antidepressant) and dextromethorphan (an NMDA receptor antagonist that’s also a common cough suppressant).
2. NMDA receptor antagonists are taken in different ways.
Esketamine nasal spray is a self-administered medication, but you’ll have to go to your doctor’s office to take it, according to Mark Niciu, MD, PhD, an assistant professor of psychiatry at the University of Iowa Carver College of Medicine in Iowa City.
After you do, you’ll need to stay for at least two hours so your doctor can monitor your vital signs — heart rate, blood pressure, temperature, and respiratory rate — and look out for side effects. Esketamine nasal spray is taken twice a week for the first four weeks and then once a week or every other week thereafter.
You can take the bupropion-dextromethorphan pill at home, but you’ll need to follow a specific schedule: once a day for the first three days and twice a day at 8-hour intervals going forward.
3. NMDA receptor antagonists work faster than traditional antidepressants.
Most people won’t feel significant relief for at least six to eight weeks after starting a typical antidepressant. NMDA receptor antagonists work more quickly: The effects of esketamine nasal spray often kick in within a week or two, although this can vary.
“Sometimes, patients respond after the second treatment, others after the fourth treatment, and so forth,” says Paul Kim, MD, PhD, an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine in Baltimore.
The bupropion-dextromethorphan pill usually takes a bit longer to take effect, but it still works faster than typical antidepressants. You may start to see results in two to four weeks, says Dan Iosifescu, MD, an associate professor of psychiatry at NYU Grossman School of Medicine and the director of clinical research at the Nathan Kline Institute for Psychiatric Research in New York.
4. NMDA receptor antagonists are considered safe but have been linked to side effects.
The possible side effects of esketamine nasal spray that doctors monitor most carefully for are excessive sleepiness and dissociation — feeling disconnected from your body, mind, or thoughts. People who take esketamine also have experienced increased blood pressure, headaches, and frequent, urgent, or painful urination.
The bupropion-dextromethorphan pill can cause slight hand tremors, difficulty sleeping, dizziness, increased heart rate, dry mouth, stomach pain, vomiting, and nausea. Keep in mind these drugs are relatively new, so there may be long-term side effects that haven’t turned up yet in studies.
5. NMDA receptor antagonists can be pricey.
Also because they’re new, NMDA receptor antagonists tend to be more expensive than typical antidepressants, most of which are available in generic form. Spravato, the only esketamine nasal spray option available, can cost upwards of $240 per dose but may be covered by insurance, says Dr. Niciu.
Auvelity, the bupropion-dextromethorphan combination drug, costs around $560 for 30 pills. Drug manufacturers often offer discounts and other ways to save on medication, so it may be worth checking their websites.
6. In the future there may be other NMDA receptor antagonists or similar medications for treating MDD.
Among those being studied:,
- A pill version of esketamine
- A once-daily pill variation of methadone, which, notes Dr. Iosifescu, works more like an NMDA antagonist than an opioid
- A pill that combines the antibiotic D-cycloserine and lurasidone, an antipsychotic
- A ketamine nasal spray and oral medication
When to Consider an NMDA Receptor Antagonist for MDD
Your doctor may recommend an NMDA receptor antagonist if you’ve tried two or more traditional antidepressants and they haven’t worked for you — an FDA requirement for the esketamine nasal spray.
“If someone came in with symptoms of major depressive disorder, we would want to try other treatments first, such as cognitive behavioral therapy,” says Niciu. In some cases, psychotherapy may be used along with medication, such as a selective serotonin reuptake inhibitor (SSRI), he notes. If you don’t respond to those medications, an NMDA receptor antagonist may be worth considering.
You could also consider the bupropion-dextromethorphan pill for long-term maintenance if you’ve responded well to the esketamine nasal spray and want to transition from having to go to a doctor’s office for treatment, says Niciu.
5 FAQs About NMDA Receptor Antagonists for MDD
Next Steps: Making the Decision to Take an NMDA Receptor Antagonist for MDD
Before your next doctor’s appointment, ask yourself these key questions:
- Am I satisfied with my current treatment?
- Have my symptoms gotten worse or better since my last doctor’s appointment?
- Am I downplaying my symptoms when I talk to my doctor?
- Are my symptoms interfering with my quality of life (for example, losing interest in spending time with friends or family)?
- Have I tried other treatments to manage my depression?
If you’d like to talk to your doctor about trying an NMDA receptor antagonist, it’s ideal to prepare ahead of time to make sure you get answers to all of your questions.
- Am I a good candidate for an NMDA receptor antagonist?
- How long will the medication take to work, and what can I expect to feel as it kicks in?
- What overall results should I expect?
- If an NMDA receptor antagonist works for me, how long will it last and how often will I need to take it?
- How long will I need to take the medication?
- What are the risks?
- What treatments other than NMDA receptor antagonists may be helpful?
- What else should I know before I try this medication?