Q: How do deficits in the various individual domains of cognition impact patients with MDD?

As relates to cognition and the 4 domains we talk about (ie, executive function, memory, attention, and processing speed), I think that this type of mediational approach may be instructive from the patient-reported outcome or the functional perspective. And much of this is going to be intuitive, since there is not yet that level of refinement in this area.

When one looks at cognition and health outcomes in mood disorders, one knows that the depression is relevant, but taking separate domains and distilling things down based on the individual domains—there has been a bit less work done on that sort of thing. I do recall that when Judith Jaeger, PhD, published her paper, one of the first studies in MDD examining cognition 6 months after discharge from an inpatient visit, that there were select domains of cognition that were more or less correlative of (and some were to be predictive of) functional outcomes.

When considering the cognitive domains and their impact on outcomes, this would also depend on what the individual patient’s level of functioning was to begin with—and what their job is. Clearly, if one is a schoolteacher, or an accountant, or a worker on the assembly line at General Motors, there are potentially going to be very different implications on the effects of a single cognitive deficit. Something else that is interesting is that if a person is higher-functioning but has MDD, he or she may be more likely to achieve remission, all else being equal, when compared with someone who has a lower level of function at baseline. And we see this in STAR*D and other studies.

When we examined the data for vortioxetine, it we saw that performance across these 4 cognitive domains was even greater in people who where higher functioning to begin with. So, in addition to the effect of cognitive deficits on a person’s function, it also seems to be the case that a person’s function may influence the changeability of their cognitive performance; so, it is somewhat bidirectional.

One of the overarching issues here is that it depends on how you define cognition and what rightfully belongs under that category. Dr McIntyre has spoken eloquently elsewhere about, things that we traditionally think of as “depression symptoms” may more rightfully be subsumed under cognition. Even symptoms such as anhedonia and reward-based behaviors may speak to executive pathways and prefrontal cortical functioning.

When one talks about “responders” to a pharmacological treatment for MDD, the patient may have residual symptoms, as is common, or the patient may even have a rating scale score in the single digits, but not zero; and then, one looks at the functional outcomes that lag behind. When one looks at what we are calling residual symptoms of depression, this might actually be slowed information processing, impaired concentration, anhedonia, and associative fluency.

There is, therefore, something akin to a Venn diagram of overlap between the cognitive symptoms of depression (ie, in the neuropsychological sense) and the things that we conceptualize separately as elements of cognition, irrespective of mood. Those may be the things that lead patients to lag behind (ie, as relates to planning, organization, follow through, motivation, reward-based behaviors, and implementing and executing their plans and intentions) despite the fact that their energy might improve after treatment for other symptoms of 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 some 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.