Understanding Cutting-Edge Treatments for Major Depressive Disorder That Target N-methyl-D-aspartate (NMDA)

NMDA-targeting drugs are generally used for people who have treatment-resistant depression. Typically, that means you’ve already tried two antidepressants at a moderate-to-high dose for at least a month and/or talk therapy, yet you still have symptoms of depression.  

Your doctor may suggest esketamine or ketamine if you have major depressive disorder with suicidal thoughts or actions. That’s because these drugs are more likely than conventional antidepressants to result in rapid relief from your symptoms.

What Is Esketamine Nasal Spray (Spravato)?

Esketamine is a prescription NMDA-receptor antagonist made from ketamine, a type of anesthesia given through a vein in your arm. At low doses, ketamine is sometimes used to treat severe depression. We'll talk more about IV ketamine later. 

The nasal spray is approved for people with treatment-resistant depression or major depressive disorder with suicidal thoughts or actions. It works by targeting NMDA receptors, indirectly raising glutamate levels. This extra glutamate boosts brain connections and leads to fast relief from depression symptoms. 

Dosing schedule. Each Spravato nasal spray device contains 28 milligrams of esketamine with two standard doses: one spray per nostril. Though you can give yourself esketamine, it must be done under medical supervision in a certified health care facility. You can’t take it home. 

In general, the dosing schedule for esketamine is:

• Weeks 1-4: Twice-a-week dosing of 56 milligrams or 84 milligrams (two or three devices)
• Weeks 5-8: Once-weekly dose of 56 milligrams or 84 milligrams (two or three devices)

After that, you may get a dose every other week. Your treatment routine is something to discuss with your doctor. 

Side effects. Common side effects from esketamine are typically mild and go away after treatment. They may include: 

• Nausea or throwing up
• Sleepiness
• Temporary rise in blood pressure
• Headache
• Loopiness or a drunk feeling

Your doctor can give you medicine for nausea during treatment if you start to feel sick or throw up. But you may feel groggy for a while, so you’ll need someone to drive you home afterward.

Esketamine is generally considered safe. But it’s not recommend for people who: 

• Have an aneurysm (a weak, bulging spot in a blood vessel, usually an artery) 
• Have arteriovenous malformation (an abnormal clump of blood vessels)
• Have had a recent heart attack 
• Have had a stroke, particularly one that caused bleeding in your brain
• Are pregnant

Talk to your doctor if you have high blood pressure, heart disease, or any other form of cardiovascular disease. They’ll let you know if esketamine is a safe choice for you. 

What Is Dextromethorphan/Bupropion (Auvelity)?

This is the first prescription NMDA-targeting oral antidepressant. Auvelity is a pill you take every day. It’s approved for adults with major depressive disorder.

Early studies show your symptoms may improve in as little as 1-2 weeks, which suggests that Auvelity works much faster than traditional antidepressants. You shouldn’t expect it to work as quickly as esketamine or ketamine. 

Each extended-release pill contains 45 milligrams of dextromethorphan and 105 milligrams of bupropion. Here’s more about how the two main ingredients work to treat depression: 

• Dextromethorphan. This medication is commonly used as a cough suppressant, but it’s also an NMDA receptor antagonist that can boost glutamate and a sigma-1 receptor agonist that can raise serotonin levels.  
• Bupropion. This is a type of antidepressant known as a norepinephrine-dopamine reuptake inhibitor (NDRI). But it also blocks CYP2D6. That’s a chemical in your body that quickly breaks down drugs, including dextromethorphan.

Some people take bupropion alone to treat depression. But in Auvelity, the antidepressant effects mainly come from how dextromethorphan acts in the body. Bupropion is mostly there to keep dextromethorphan in your bloodstream longer. 

Dosing schedule. When you start taking Auvelity, you’ll typically take one pill a day for the first three days. At some point, your doctor will probably have you take it twice a day, leaving at least eight hours between doses. Never take more than two pills within 24 hours. 

Side effects. Common side effects of Auvelity are typically mild and may go away as your body gets used to the drug. They’re similar to other oral antidepressants and may include: 

• Dizziness
• Headache
• Dry mouth
• Feeling sleepy
• Diarrhea 
• More sweating
• Low libido
• Trouble getting an erection or having an orgasm

Make sure you tell your doctor if you have other health conditions or are taking any medications. Bupropion can interact with other drugs. Auvelity isn’t safe if you have serious liver or kidney disease or are at an increased risk of seizures. 

Ask your doctor about dextromethorphan/bupropion if you’re interested in learning more and they don’t bring it up. Auvelity is a new drug. Not all doctors know about it or have experience using it.  

What Is IV Ketamine (Ketalar)?

In 1970, the FDA approved ketamine (Ketalar) as an anesthetic (a drug that puts you under before a medical procedure). But ketamine also affects glutamate and other brain chemicals linked to mood, like dopamine, norepinephrine, acetylcholine, and serotonin. 

Ketamine isn’t FDA-approved to treat major depressive disorder. But doctors are allowed to use it “off-label.” You need a much smaller dose to treat depression than what’s used for anesthesia. 

One low dose of IV ketamine has been shown to improve depression symptoms within two hours, including suicidal thoughts. The effects may last up to two weeks.

You get ketamine through a vein in your arm. Once in your body, the drug quickly changes how brain cells send signals to each other. Like other NMDA-targeting drugs, ketamine boosts glutamate and strengthens connections between brain cells.  

You may get ketamine alone or as an add-on therapy (something you take while on other treatments). Your doctor may suggest it if conventional antidepressants or more advanced treatments, such as electroconvulsive therapy (ECT), haven’t worked for you. 

Dosing schedule. Since ketamine is used off-label for depression, there isn’t a standard guideline for health professionals to follow. Your doctor will tailor your dose based on things like your body size, severity of symptoms, and any health problems they need to consider.

In general, you’ll get a ketamine infusion once every three weeks or so. You may start to feel better right after the first session, with best results after three treatments. But the timing and effects are different for everyone. You’ll need to work with your doctor to fine-tune your dosing amount and schedule.

Like esketamine, you can only get IV ketamine treatment under medical supervision. A health professional will give you the infusion and check for side effects. Most are mild and brief, going away at the end of the session or within a few hours. 

A typical ketamine infusion takes around 40 minutes to an hour, followed by a 30-minute observation period. The treatment is safe when provided by a trained health professional. But your doctor will want to be sure you’re OK and don’t have any serious mental or physical side effects.  

Side effects. Common side effects of IV ketamine may include pain where the needle goes in along with: 

• Feeling spacey or like you’re disconnected from your body
• Intense happiness 
• Dizziness 
• Seeing or hearing things that aren’t there
• Sleepiness
• Headache
• Nausea or throwing up
• A temporary rise in blood pressure and heart rate

You’ll need someone to drive you home. And you’re not supposed to work the rest of the day. Since ketamine can cause short-term changes in how you think, don’t make any major legal decisions or operate heavy machinery the same day you get treatment. 

5 Things to Consider When Planning Your Treatment

Everyone’s experience with depression is different, so finding the right treatment may take some patience. Take your time and think through the pros and cons of each option. Remember, you’re not alone – your health care team is there to guide you every step of the way. 

Before you talk to your doctor next, here are five things to consider:

Your options. Your doctor can tell you which treatment might be best for you and why. It’s helpful to do some research ahead of time so you can understand the pros and cons of each choice, including how the treatments are given (IV, nasal spray, or pill). 

Possible side effects. Treatments that target NMDA are generally safe. But like all medications, they come with side effects. Talk to your doctor about how these drugs might affect you, especially if you’re on other medications or have health conditions. 

If you’re having suicidal thoughts. NMDA-targeting medications can ease serious symptoms of depression faster than traditional options. 

Long-term outcomes. Esketamine and ketamine work fast, often relieving depression symptoms in hours or days. But their effects don’t last as long as antidepressants you take every day, including dextromethorphan-bupropion. 

Cost. Since ketamine is used off-label to treat depression, insurance may not cover it. Esketamine (Spravato) and dextromethorphan/bupropion (Auvelity) are FDA approved to treat depression. But they’re new, so cheaper generics aren’t available yet. 

Contact your insurance to check your coverage, out-of-pocket costs, and if prior authorization is needed. You might also find copay assistance or savings cards through Spravato and Auvelity’s websites.