A Fast Acting Antidepressant

Auvelity claims to be the first “rapid acting oral antidepressant,” and that claim is true, but it is not a new medication. It is a combination of two older meds: bupropion (also known as Wellbutrin, released in 1985) and dextromethorphan (released in 1958). At the Mood Treatment Center, we’ve been using dextromethorphan to help people with treatment resistant depression for nearly a decade. Let’s look at what this new combination pill brings to the table.

How it works

Most antidepressants work through some combination of serotonin, norepinephrine, and dopamine, and Auvelity covers all three. By adding dextromethorphan, it also brings something new: glutamatergic modulation. Glutamate is a neurotransmitter involved in depression, and it is behind the rapid-acting antidepressant effects of ketamine and esketamine (Spravato).

Bupropion is one of the better tolerated antidepressants, as it does not cause weight gain, sexual dysfunction, fatigue, or withdrawal problems. Besides treating depression, bupropion has mild benefits at improving concentration, weight loss, and sleep quality.

Research on dextromethorphan in depression began in 2012. It can work on its own or in combination with bupropion, but together the two have an edge that goes beyond their complimentary effects on neurotransmitters.

Dextromethorphan has a very short half-life of 4 hours, which means the body gets rid of the medication quickly. Bupropion slows this excretion down, stretching its half-life to nearly 24 hours, allowing its therapeutic effects to settle in throughout the day.

Who can benefit from Auvelity?

Auvelity’s main advantage is its rapid onset (the word rhymes with “velocity”). If you need to get better quickly, perhaps to stay on the job or stay out of the hospital, it may be a good choice. While most antidepressants take 2-4 weeks to start working, Auvelity kicks in within the first week. Auvelity is also more effective than bupropion. After a 6 weeks, people who took Auvelity were 3 times more likely to recover from depression than those who took bupropion alone (47% vs 16%).

Auvelity was only studied in regular (non-bipolar) depression, and it may not be a good idea for people with bipolar disorder. Antidepressants like bupropion can cause mixed or manic symptoms in bipolar disorder, making people more agitated, anxious, and irritable. This is a controversial area that needs to be personalized, as some people with bipolar disorder do respond to antidepressants. Auvelity’s other ingredient, dextromethorphan, has a small risk of triggering mania, but on the other hand it has been tested in bipolar depression with good effects.

At this point, savvy readers may wonder how a drug with such a short half-life can work? Dextromethorphan can also be paired with quinidine, an anti-malaria medication that – like bupropion – slows down dextromethorphan’s excretion. Quinidine has no major risks or psychiatric effects, and this strategy has been used successfully in another dextromethorphan product, Nuedexta, which is used to stabilize mood symptoms in neurologic disorders.

What are the risks?

Auvelity is generally well tolerated. 1 in 16 patients stopped the medication due to side effects, most commonly tiredness, nausea, dizziness, headache, and dry mouth. The tiredness is a side effect of dextromethorphan, as energy tends to improve when bupropion is used on its own.

There are a few rare risks that did not show up in the clinical trials of Auvelity but are known to occur with its two ingredients. These are seizures, mania, hallucinations, and addictive behaviors. Like most antidepressants, bupropion has a small risk of causing seizures, a risk that is much more serious at high doses beyond 450 mg. Dextromethorphan has been misused recreationally at doses much higher than what were used in the depression studies. At those high doses, the medication can make people feel dissociated.

The Bottom Line

Auvelity is faster and more powerful than traditional antidepressants, but by combining two medications together it also brings more side effects.

Want to read more? Two of our providers, Brian McCarthy, PMH-NP, and Chris Aiken, MD, have published research reviews of Auvelity in the Journal of Clinical Psychopharmacology and Neuroscience and the Carlat Psychiatry Report.


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