Greg Mattingly, MD on A New Generation of Antidepressant Treatments

A group of new, fast-acting antidepressants has a different mechanism of action than traditional antidepressants. Here, Greg Mattingly, MD, discusses the new medication class.

Additional Resources:

Can Brain Changes That Occur in Chronic Depression Be Reversed?

Dr. Greg Mattingly on the Neurological Impacts of Chronic Depression

Unmet Needs in the Treatment of Depression

Dr. Mattingly is Associate Clinical Professor, Washington University, St. Louis, Missouri, principal investigator in clinical trials for Midwest Research Group and founding partner of St. Charles Psychiatric Associates, St. Charles, Missouri.


For 20, 30, or 40 years, for most of us throughout our training, maybe it was in residency, maybe it was in nursing school, maybe it was in our internship, we learned about antidepressants, and the lecture we had was the monoamines. We talked about serotonin. We talked about norepinephrine. We talked about dopamine.

For years, we talked about the ability to block the reuptake and raise those chemicals in the brain. We then moved into a generation of antidepressants that were receptor modulators. Instead of raising the chemicals, they modulated the monoamine receptors themselves.

We've now moved into a new generation of antidepressants. This new generation of antidepressants, we call, as a group, the fast‑acting antidepressants because they have the ability to improve depressive symptoms not in matter of weeks to months, but within a matter of hours to days.

This new group of fast‑acting antidepressants tend to modulate the GABA‑glutamate interface, and we know that in basic science labs, they change arborization of nerve cells within hours to days.

When we've looked at this group of medicines in clinical trials, we're now seeing that instead of having to wait months or weeks for a response for an antidepressant, this new group of medicines can cause changes by the very next day.

We now have medicines that we can do intranasally that stimulate glutamate. We have medicines that we can do intravenously for women with postpartum depression that modulate that GABA‑glutamate interface where we see improvement, remission after several days of treatment.

We have a group of fast‑acting oral antidepressants in development that once again show remission of depressive symptoms within several days to several weeks.

This fast‑acting group of antidepressants is going to offer hope where many of our patients haven't had hope. It's going to offer speed of onset for patients where it's taken weeks to months to improve their treatments in depression, and it'll throw out something totally novel.

These fast‑acting antidepressants are now being looked at for as‑needed treatment for depression. Instead of having to take a medicine for a lifetime, you may take a medicine for each episode, drive that episode into remission, and then take another treatment if you should have another episode.

Much more like an antibiotic model for somebody that has recurrent pulmonary infection or a nasal infection. You take it when you need it, you take it for several weeks, and then you may not need it again for months to years.

This group of fast‑acting antidepressants, novel mechanism of action, faster onset, remission, where other medicines maybe haven't worked, and then finally, the possibility of an as‑needed treatment instead of a chronic lifelong treatment.