Major depressive disorder (MDD) is a mental health condition featuring persistent low mood, reduced pleasure capacity, and a lack of interest in enjoyable activities.

Living with depression means more than feeling sad or disengaged. It can also mean:

  • poor concentration
  • changes in appetite
  • sleep problems
  • fatigue
  • low self-esteem or feelings of worthlessness
  • irritability
  • thoughts of self-harm

MDD impacts approximately 280 million people worldwide and is considered a leading cause of disability.

Despite the heavy disease burden, traditional antidepressant medications only improve symptoms in an estimated 20 out of 100 people within 6 to 8 weeks of treatment.

Approved by the Food and Drug Administration (FDA) in August 2022 to treat MDD in adults, dextromethorphan-bupropion (Auvelity) works in a fraction of that time — as soon as after one week of treatment. This makes it the first and only rapid-acting oral medication available for MDD.

Dextromethorphan-bupropion (Auvelity) is an extended-release antidepressant medication that combines two active medications, dextromethorphan (a cough suppressant) and bupropion (an antidepressant).

It’s currently only available in tablet form and is typically taken by mouth once a day to start.

Dosing may increase to twice a day as your treatment plan continues.

Antidepressants work by influencing neurotransmitters, the chemical messengers in your brain.

Traditional antidepressants target the neurotransmitters dopamine, serotonin, and norepinephrine. Dextromethorphan-bupropion affects the neurotransmitter glutamate by blocking N-methyl-D-aspartate (NMDA) and activating sigma-1 receptors.

The importance of NMDA receptors’ role in treating depression was part of a research discovery process involving ketamine.

Ketamine, a controlled substance, is a medication primarily used as an anesthetic but frequently misused as a recreational drug due to its dissociative properties.

The ability of ketamine to influence the brain made it a medication of interest decades ago for the treatment of mental health conditions such as depression. When put to the test, ketamine was effective extremely quickly.

After years of research, scientists discovered that ketamine’s ability to block NMDA receptors was part of what made it so potent. But ketamine was found to be too unsafe for regular use as a depression treatment.

Dextromethorphan, one part of the extended-release antidepressant, also blocks NMDA receptors but without the safety concerns associated with ketamine.

Bupropion, the other half, keeps dextromethorphan in your system longer by inhibiting the enzyme in your body that breaks it down.

Dextromethorphan-bupropion is also a norepinephrine-dopamine reuptake inhibitor, part of a commonly used class of typical antidepressants, which adds the function of a traditional antidepressant to its novel formulation.

Dextromethorphan-bupropion may be an option for you if you’re living with MDD and are over the age of 21.

This medication isn’t approved for use in people who are considered pediatric (age 21 or younger) and hasn’t been tested in patients over the age of 65 in clinical trials.

The FDA approval of dextromethorphan-bupropion was based on results from two clinical trials.

In the GEMINI clinical trial, researchers compared the efficacy of dextromethorphan-bupropion against a placebo. They measured depressive symptom improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS).

MADRS scores were compared after 6 weeks. The group using dextromethorphan-bupropion saw scores drop by an average of 16 points, while the placebo group saw an average drop of 12 points.

Additionally, 40% of the dextromethorphan-bupropion group achieved remission of symptoms, compared to 17% of those taking a placebo.

The trial data also indicate that significantly more symptom improvement was seen in the dextromethorphan-bupropion group compared to the placebo group as soon as 1 week after starting the treatment.

The ASCEND clinical trial for dextromethorphan-bupropion used MADRS scores to compare its effectiveness as a dextromethorphan-bupropion combination against the use of bupropion alone.

In the randomized, double-blind control study, people taking dextromethorphan-bupropion saw MADRS scores decrease by an average of 14 points, compared to an average 9-point decrease among those taking only bupropion.

Like the GEMINI trial, dextromethorphan-bupropion also had a higher rate of symptom remission (47%) than bupropion alone (16%).

Both clinical trials demonstrated that dextromethorphan-bupropion was well-tolerated and had similar side effects compared to other oral antidepressants, such as:

  • dizziness
  • nausea
  • dry mouth
  • decreased appetite
  • anxiety

Additional research

Though dextromethorphan-bupropion was recently approved for treating MDD, it may have other applications.

A 2022 paper comparing its mode of action to the Alzheimer’s disease medication, memantine, suggests that the two prescriptions have almost identical processes in the brain.

Researchers indicate this might make dextromethorphan-bupropion a candidate for use in Alzheimer’s disease, just as it may make memantine a possible option for MDD.

Dextromethorphan-bupropion is only approved for use in MDD. It can be used as a first-time medication for MDD or as the next step in your treatment process.

If you’re living with MDD and are experiencing treatment resistance with other medications, your doctor might recommend trying this antidepressant due to its non-traditional mode of action.

As the only fast-acting medication approved for MDD, your doctor might also suggest dextromethorphan-bupropion if your symptoms are severe and impacting your relationships, academics, or occupation.

Dextromethorphan-bupropion is a prescription-only medication. Taking this without consulting with your healthcare team, especially in conjunction with other medications, could cause serious health complications.

Dextromethorphan-bupropion (Auvelity) is a fast-acting oral antidepressant recently approved by the FDA. It focuses on NMDA receptors in your brain, providing the same level of symptom relief seen throughout the years in ketamine studies but with higher safety margins.

You can use this medication if you’re over the age of 21 and have received a diagnosis of major depressive disorder. Your doctor may also prescribe it if you’re experiencing treatment-resistant depression or need immediate symptom relief.