Auvelity is a combination oral tablet for depression containing dextromethorphan and bupropion that works differently from other antidepressants because it has a direct effect on the N-methyl-D-aspartate (NMDA) receptor as well as possibly other traditional neurotransmitter effects. It also works much faster than traditional antidepressants, and it does appear to be more effective.

Dextromethorphan, more commonly known for its traditional role as a cough suppressant, works by blocking the NMDA receptor. NMDA receptors are located on nerve cells, mostly at excitatory synapses, and research has shown that they can become overstimulated when glutamate levels are high. This is the basis for the glutamate hypothesis of depression. Glutamate is an excitatory neurotransmitter that is important for memory, cognition, and mood. It gets released during excitement or stress, but in some people, this system can be turned on for hours, days, or months at a time. When levels of glutamate are high all the time, they overstimulate the NMDA receptor which results in two main effects:

• The NMDA receptor loses its responsiveness and needs more and more glutamate to get activated
• All this extra glutamate cascades over and is toxic, damaging nerves, synapses, and supporting cells.

Usually, the body has a way of removing extra glutamate and recycling it, but this process can become ineffective if levels of glutamate remain high for prolonged periods. Previous studies have shown that antagonists of the NMDA receptor have antidepressant effects. For example, infusions of low-dose ketamine, which is an NMDA receptor antagonist, are associated with significant decreases in depression symptoms.

Bupropion has traditionally been thought to work on noradrenergic and dopaminergic pathways in the brain, although the exact way it works is unknown. In Auvelity, perhaps its main role is that it boosts concentrations of dextromethorphan in the blood by competitively inhibiting cytochrome P450 2D6, an enzyme in the liver that breaks it down.

Trials have also shown that Auvelity works faster than other antidepressants, with rapid symptom improvement being noted in as early as 1 week. In addition, more people experienced symptom remission by week 2 than those taking placebo. Continued effects were seen at week 6. Symptom improvement was based on the overall change in a depression symptom scale that evaluated: sadness, inner tension, reduced sleep and appetite, difficulty concentrating or doing daily activities, lack of interest, lack of energy/motivation and ability to feel, pessimism, and thoughts of suicide.