Q: With the multiple symptoms of MDD, including cognitive ones, how do partial and incomplete responses relate to the risk for recurrence?

Cognitive impairment and its impact on work productivity is a big problem. In fact, for people who don’t have improvement of depressive symptoms, this translates to significant impairments that have an impact on the patient, family, employer, and society. And then, even in people who “get better” per symptom-rating instruments, a large proportion of them will not have fully recovered cognitive function, work productivity, and psychosocial function. That gap, I feel, is a very important target for treatment.

We should be thinking of something more, in addition to the impact that our traditional monoaminergic antidepressants like selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) have had, because we find that patients on these therapies improve, but they are not back to normal. And maybe that is where there is a great need for either different treatment or additional treatment – whether it may be a medication with a different pharmacologic profile, or perhaps an add-on therapy like a medication to augment the effect, exercise, psychotherapy, magnetic stimulation, or whatever.

With regard to unresolved symptoms, we’ve known since the 1990s that any residual symptoms are associated with an increased risk of relapse and also of decreased functional ability. In the 1990s, Lewis Judd was writing papers about this phenomenon.

I’d just like to point out that it is not unusual for a patient to have multiple residual symptoms after treatment. Even if a single symptom is low grade, it may still be decidedly sufficient to impact functioning. Each residual symptom – and every additional symptom ‒ seems to add to the risk of poorer vocational and interpersonal functioning, and also the risk of relapse.

In our practice, we see many people who used to be high-functioning workers (eg, business executives in leadership roles) who have had 1 or more episodes of depression. With treatment, they may achieve significant improvements in their depressive symptoms, allowing for a return to work – but not at the same level of functioning as before. So, we have executives who cannot function any longer as CEOs after experiencing a significant period of depression, or in some instances, multiple recurrences.

We know that depression is one of the leading causes of long-term disability in the developed world, and if anything, those rates seem to be increasing. If one can’t think, regardless of whether one is the head of a major company or stacking boxes in a warehouse, it becomes very difficult to work.

We published a paper about a year ago showing that, among individuals with depression who worked, the total depression symptom score accounted for relatively low variability in performance and attendance, whereas the cognition measures accounted for a very high proportion of variability in workplace performance.

And it’s interesting what happens when we take a sort of dimensional approach to thinking about depression. We are thinking in terms of disturbance in mood, mood valence, emotional valence, the chronobiology, or aspects of arousal, for instance, Or you can take the language that the Research Domain Criteria (RDoC) has put forward, just as one example. When you take this dimensional approach, it looks as though the cognitive domain may be the most susceptible to progressing, insofar as it seems to have a progressive deterioration.