Q: How do you conceptualize the differences and similarities between MDD and ADHD with respect to cognition?

Some people claim that attention deficit disorder didn’t really exist until the second half of the 20th century, when expected classroom-based behaviors and workplace demands really pushed a subset of the population, to tax their innate abilities to organize, cope, and stay on-task. I think the same thing might be true in terms of understanding how people recover from depression.

In the modern era, we are now seeing patients with MDD who are better on treatment but who are having subtle difficulties that do really get in the way of their lives. So, that is how I think of the association of persistent cognitive impairment and psychosocial disability. If you are not back to your “best self” or your “well self” then you are not able to perceive subtlety, you may not have your same sense of humor, you may not be able to execute problem solving strategies as efficiently, and you certainly may not have the creative capacity to rise above the circumstances to come up with a unique explanation or a unique solution. And if all of those things—or even just a few of those things—are true, then you are not really yourself. You are a shadow of yourself, and that’s going to affect how you feel, and it’s going to affect your relationships.

I agree very much with what Dr Thase said. I think it is commonplace in clinical practice, when one sees that “you’re not yourself yet,” to assume that that is purely clinical depression and then to treat the depression further (eg, by raising the dose of the current antidepressant or adding an adjunctive treatment for the depression). This may sometimes be very helpful; I don’t know that that there is much in the way of data from randomized clinical trials that examines exclusively the residual symptoms, or subthreshold symptoms. I don’t know that anyone has targeted cognitive symptoms as the focus of treatment after a response (ie, not a remission, but a response) in MDD; to try to tease apart the things that Dr Thase just described (ie, not simply the sequelae, or the residual elements, of a partially treated depression).

Q:Duloxetine and vortioxetine are both agents that have been studied specifically for their cognitive profiles in patients with MDD. What do you make of these studies and/or comparisons?

Dr Thase:
The folks who introduced duloxetine, to their credit, did some studies with objective measures of cognition. And, so when there were preclinical data suggesting that vortioxetine may have effects that differ from SSRIs, in Europe, duloxetine was the antidepressant comparator of choice, because it was still “a new guy” and its value yet to be determined, and so the original comparisons of vortioxetine and duloxetine were done essentially by necessity. And the results tended to favor vortioxetine (even though, to my eye, duloxetine had a somewhat stronger antidepressant effect in those studies; not in a large, clinically meaningful way, but perhaps in a 1-point difference-in-aggregate-data sort of way, that might translate to a 5% better response rate).

As relates to these duloxetine and vortioxetine studies, the more striking part for me has been that 2 separate sponsors replicated the findings, and we know that, when a pharmaceutical company sponsors a study, this tends to increase the chances of success for the sponsored agent. The outcome that was observed when duloxetine was studied, in studies by Joel Raskin, MD, and colleagues (and that was a different patient population, and of course the methodology was different, the objective measures weren’t identical), but the outcome was that there was a pro-memory effect with duloxetine, but essentially no effect in the remaining 3 domains of cognition—and this was replicated by 2 separate sponsors.

So, to me, this is something that has not been emphasized but that somehow I think may be relevant—and it gives a little bit more credibility to the possibility that there may be some differences between vortioxetine and duloxetine in some of these cognitive domains.

Dr Goldberg:
Just before leaving the noradrenergic system, with respect to bupropion, if one thinks of it as mimicking what atomoxetine does as far as being a norepinephrine reuptake inhibitor, if you like a secondary amine tricyclic without the anticholinergic effects…

Dr Thase:
Yes, like with the ability of older men to initiate their urine stream.

Dr Goldberg:
Yes, well, one must pick and choose.

Dr Thase:
I certainly have favored bupropion as an antidepressant for my younger patients with ADHD over the years. When one does use it in combination with a stimulant, one has to watch blood pressure, but it certainly does have an attention enhancing effect that can be complemented by psychostimulants. And I think these are some of the subtleties that you run into when you mix and match medications in particular patients. I wouldn’t necessarily think that the procognitive effects that are demonstrated in studies of depression with vortioxetine would be universally useful for all people with ADHD—I think that in many patients there may be a different kind of cognitive impairment.