Q: How is the current thinking shifting in regard to treating all of the symptoms of MDD?

We have traditionally focused on symptoms of depression, giving much less importance to cognition and the impact of depression, per se, on other things such as effects on work productivity, performance in other areas of life, and essentially psychosocial quality of life. Thus, some patients whom we define as having shown good responses to therapy have done so based on symptom rating scales like the Hamilton Rating Scale for Depression (HRSD) or the Montgomery-Åsberg Depression Rating Scale (MADRS), but these patients are not necessarily fully recovered.

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. 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.

For me, the question has always been: what is it that mediates and moderates psychosocial outcomes? I have a particular interest in the workplace, and we know from the extant literature that functional outcomes for depression just haven’t been sufficient in the workplace. This challenge clearly has implications on so many levels. Over the last 3 to 5 years, I’ve been quite struck by the data from various studies showing that, across the panoply of depressive symptoms, cognitive symptoms may disproportionately account for impairments in work productivity and attendance.

Cognitive symptoms in MDD clearly march in a similar direction as mood symptoms, but they don’t march in an identical direction. There is this notion that if the depression improves, then the cognition should improve concomitantly – and vice versa may also apply. But cognition and depression are also very much dissociable. The dissociability, in fact, can be cascaded down right into the substrates that subserve these phenomena. Cognitive symptoms may even predate the onset of depression in some people, and cognitive symptoms may persist in people who have had a previous depressive episode, in the absence of “mood symptoms.”

Dr Trivedi:
We need to really target the additional things such as cognition and the impact of these additional symptoms and impairments on a patient’s life, work productivity, and psychosocial function.

We should be thinking of something more, in addition to the impact that our traditional monoaminergic antidepressants like a selective serotonin reuptake inhibitors (SSRIs) or a 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.

I completely agree with you, Dr McIntyre, about the problem of patients who have a range of depressive symptoms and additional impairments that persist after therapy with an SSRI or an SNRI. And so what are we to do with that? This is a very important area to be focused on in MDD. If you examine the definitions of remission, they do not necessarily include these impairments, and that is why I agree with you totally.

Coming from the bipolar disorder world, there is some suggestion that cognitive deficits are endophenotypic (ie, heritable) or expressed in first-degree relatives in a more diminutive fashion, and may even be a marker of an illness subtype.

To me, what’s always fascinating is teasing apart the extent to which cognitive complaints are the representation of dementia with depression in a younger patient: someone who is having difficulty with associative fluency, attentional processing, and short-term memory. The challenge is identifying whether that is a state-dependent phenomenon or there is a baseline risk for even subtle cognitive deficits that may be a harbinger of this broader, underlying problem.

And then, just to make things more complicated, we get into the correlations between subjective cognitive complaints and objective cognitive performance, and the extent to which someone may misidentify, say, anxiety or depression as a memory symptom (or vice versa), or comorbidity. For example, a patient may say, “I think I have attention-deficit/hyperactivity disorder. It struck at age 45, along with my first depression, and I am concerned that it is not just 1 overarching ailment, but 2.” The clinician is then trying to tease apart whether this is 2 elements or 1.

However, I am pleased that the field is talking more about not just reducing a primary outcome score on depression severity, but also looking at recovery and embracing more of the functional, symptomatic, and syndromal aspects of outcomes.

In the real world, patients may be told, in essence, “Well, your Hamilton Rating Scale for Depression (HAM-D) score has dropped below a certain number – and that’s good, but you are still not quite able to get back to work and not really functioning at home with your responsibilities.” I think this really comes up short. Those more real-world outcome definitions that I see being discussed and described more in the literature bring us that much closer to the goals of treatment.