Treatment Options in MDD

Andrew J. Cutler, MD: Greg, could you summarize quickly, high level, what are the various treatment options? Maybe start with the classes of medications, talk about psychotherapy, and then neuromodulation.

Gregory Mattingly, MD: Certainly, and again, most of the antidepressants that we have available are around that monoamine theory of depression. So our older antidepressants that many of us grew up with, trained with, [are] the tricyclics. A simple way to think of tricyclics is they’re the old-fashioned serotonin and norepinephrine medications. They raise serotonin. They raise norepinephrine. Some give you a little more serotonin; some give you a little more norepinephrine, but in an overdose, they can have cardiac toxicity. We had the mono oxidase inhibitors that raised all 3 monoamines but had issues with hypertensive crisis. That then led to what we think of as the more modern groups of antidepressants. The selective serotonin reuptake inhibitors [SSRIs] primarily modulate and raise serotonin in the synapse, and the serotonin-norepinephrine reuptake inhibitors [SNRIs] hit both serotonin and norepinephrine. And then a few of our more novel medicines, as Sagar was talking about, things that raise norepinephrine and dopamine or hit specific monoamine receptor subtypes. All of those chemicals to date though have danced around that monoamine modulation.

We now have some newer-generation medicines. They come out and hit a whole different system. They hit the γ-aminobutyric acid [GABA] glutamate system. So we know that glutamate is one of the main excitatory chemicals in the brain. We know that GABA is one of the main inhibitory chemicals in the brain, and these new treatment options tend to reset that GABA glutamate junction. And so we have medicines now that we can use intranasally that modulate glutamate. We have some that are not FDA approved that you can give intravenously that modulate glutamate. And then finally, you said something that we don’t want to forget about: It is neuromodulation. We have both magnetic stimulation and electrical stimulation for the neuromodulation of neural pathways and circuits within the brain. What’s exciting right now is that there are a lot of other options and new mechanisms on the horizon.

Andrew J. Cutler, MD: What would you say are the most commonly used treatments, Greg, at this point?

Gregory Mattingly, MD: By far the most common are going to be the SSRIs. If you go out there and look at the treatment landscape, what is it Sagar, probably 70% of our patients, we’re going to start with SSRIs? The second or the third medicine we’re going to use, quite often it’s an SSRI second or third. Sometimes that may not make the best sense, but we know from practice paradigms and even studies like STAR*D when you switch either in class or out of class, the second antidepressant doesn’t make a whole lot of difference, to be quite honest with you. I think it was a little disappointing. We were hoping that switching to a different mechanism would make a difference, but monoamines are monoamines.

Andrew J. Cutler, MD: And I think part of it is, of course, we can’t forget about cost and access, and frankly, SSRIs tend to be the road of least resistance, if you will.

Transcript edited for clarity