Use of Antidepressants for MDD

Andrew J. Cutler, MD: Sagar, when do we think about using a second-generation antidepressant or a multimodal or a newer one? And when do you think about augmentation?

Sagar V. Parikh, MD, FRCPC: Well, we don’t really have any good evidence to say that there’s any clear winner out of all the antidepressants. So that’s too bad. I think we all wish we had a blood test that would match people to an antidepressant, just like a strep test would match somebody with a sore throat to penicillin, or something like that. We don’t have that, so I think it makes sense, also in these economic times, that we start with something that is already readily available and well tested, typically like a selective serotonin reuptake inhibitor [SSRI] or one of the older serotonin-norepinephrine reuptake inhibitors [SNRIs].

After you’ve tried at least one of those, I think that’s when you start thinking, “Well, what else can I do?” I’m a big fan of augmentation and even traditional augmentation agents such as aripiprazole on top of an SNRI or SSRI—but in low doses. The old teaching about augmentation was really too much, too heavy in the dosing of agents like aripiprazole.

So if someone’s having some benefit with their initial antidepressant, rather than switching, I want to build on that, add an augmenting agent, and go from there. If they’re having intolerable adverse effects even from the first agent, of course I’m going to switch.

Some people even before you get to the treatment-resistant depression situation...will tell you there’s a particular adverse effect they want to avoid. It may be sexual dysfunction, or it may be forgetfulness. We have some antidepressants like bupropion that are much cleaner on sexual dysfunction. We have some agents that may have some degree of cognitive improvement; some vortioxetine studies show that.

So those are some of the considerations. After you’ve tried 2 or 3 of the standard agents and you’ve tried at least 1 augmentation strategy, that’s when I think truly novel agents would play a role.

Andrew J. Cutler, MD: That certainly makes sense. With augmentation, the evidence is best probably for atypical antipsychotics, as you’ve mentioned. But Greg, people do other various combinations. What are they trying to accomplish here?

Gregory Mattingly, MD: I think we’re taking a multimodal approach in the same way we do with other health conditions. My mom and dad are both on blood pressure pills right now, Andy, and they don’t take a blood pressure pill with a single mechanism. They’re combining multiple mechanisms to get the best treatment for their blood pressure. The same thing is done with type 2 diabetes. Hitting 1 mechanism quite often doesn’t work as well as hitting 2 mechanisms.

And I think we’re learning the same thing about neural circuits in the brain. So I may start with a medicine that modulates serotonin. I say, “OK, listen, I’d like to modulate a little dopamine along with that.” So maybe I do a little bupropion as Sagar was saying or maybe layer an atypical and a psychotic on top of that. There was a fantastic article I know we’ve all read that was published in JAMA [The Journal of the American Medical Association] and written by Ronald W. Pies, MD, and Maurizio Fava, MD, saying if we did a STAR*D2 20 years after the original study, what would it look like now, given our current treatment options?

Andrew J. Cutler, MD: It’d be interesting.

Gregory Mattingly, MD: Their article still says even now, Sagar, we’d probably start with an SSRI, but something you said, we’d layer it right away with online digital cognitive behavior therapy. It’s freely available, and doesn’t cost much, so why not go ahead and augment with that? They then went to step 2; instead of trying another monoamine, they said probably step 2 based on the current data would be augmentation, and probably with a low dose of an atypical would be step 2. And then step 3 becomes those truly novel agents.

Andrew J. Cutler, MD: The intranasal NMDA [N-methyl-D-aspartate] antagonists based on ketamine, if you will. And there’s even a brand-new medicine on the market right now that’s a combination of dextromethorphan bupropion that has multimodal activity, including NMDA antagonism and sigma-1 agonism. So we do have some of these other options.

Transcript edited for clarity