Q: What is the relative importance of individual cognitive deficits to functional outcomes in MDD?

I would approach this conceptually as follows: we have 9 symptoms in the polythetic list of depression (ie, in the DSM-5). Mediational work would now suggest that some of these symptoms are more likely than others to account for patient-reported outcomes, and I think that level of thinking may be valuable. I also think we need to zoom in even further, bringing more granularity to our approach for those 9 individual symptoms. For example, anhedonia is one of the criteria, but all of us here today would recognize that anhedonia is actually a conflation of several different phenomena subserved by differing neurobiological systems (eg, liking vs wanting). And you could even get more refined than that.

We look at cognition and health outcomes (in people with mood disorders), and we know that it is relevant; however, taking the separate domains of cognition and distilling things down based on that one domain—there has been a little less work done in that area.

I do recall that Judith Jaeger, PhD, in her paper, one of the first in depression looking at cognition 6 months after discharge from an inpatient visit, reported that some domains of cognition were more or less correlative of—and some perhaps predictive of—functional outcomes. 

And the impact of individual cognitive deficits would likely depend on that person’s level of functioning to begin with—and what his or her job is. Obviously, if someone is a schoolteacher, or an accountant, or a worker on the assembly line at General Motors, there are going to be very different implications in terms of how a single cognitive deficit might impact that patient.

You know, the Cognition Performance and Function Questionnaire (CPFQ) that Maurizio Fava, MD, and his colleagues composed is a nice, simple, straightforward, valid measure that does give patients the chance to self-appraise. It is a self-report scale with a modest number of items in each of those domains, and it does give patients the chance to let you know how they feel they are doing. However, as we have discussed, there is an imperfect correlation between how patients appraise themselves and how they might perform on objective tests of memory and other cognitive domains.

That, in fact, is what I believe is most admirable about the vortioxetine program: the investigators included both subjective appraisals of cognitive function and numerous objective tests of cognition to evaluate the hypothesis. That is, the hypothesis that the potentially complex mechanism of action of vortioxetine—something more than just an SSRI-type mechanism—might really make a difference, not just in subjective measures but also in objective measures of cognition.

I would add a comment in regard to isolating out executive dysfunction in depression, and the idea of cognitive rigidity and cognitive flexibility. I think it can be challenging, yet important, to understand the ability of the individual patient to shift sets or think of things differently than he or she might otherwise, or to exercise some manageability over his or her biases and have an openness to new concepts. It is a difficult thing to do if one is trying to accomplish something that is technical or that involves acquiring new information. I think it is difficult if you are struggling with any task that really demands seeing alternative perspectives. And, in a really clinical way, this can have implications: a colleague of mine published a paper about 10 years ago looking at patients with MDD who attempted suicide, there were some measures of executive functioning (ie, Stroop test, Wisconsin Card Sort) and there was a strong correlation between suicidal thinking and executive dysfunction. The hypothesis was that it may just be harder for these patients to see alternative solutions.