expert roundtables

“Remission” With Persistent Cognitive Symptoms

by Charles Debattista, MD, Ira D. Glick, MD, Roger McIntyre, MD, Madhukar Trivedi, MD


Cognitive disturbances certainly overlap with emotional and somatic symptoms in patients with major depressive disorder (MDD), and improvements in one sphere often do parallel improvements in others. However, these symptoms are also clearly dissociable, which can have a profound impact on functional outcomes. A paradox may occur, whereby the domains of cognitive function that seem to be more affected in depression (ie, working memory, reaction time, and speed of response) result in deficits that may be quite subtle, so as to escape clinical detection. Yet, these very subtle deficits often have the largest impact on what is most valued and cherished by patients, including their productivity.

Q: Are the multiple symptoms of MDD (ie, emotional, somatic, cognitive) dissociable, and how important is it to address all of the symptoms?

Roger McIntyre, MD

Professor of Psychiatry and Pharmacology
University of Toronto
Head, Mood Disorders Psychopharmacology Unit
University Health Network
Toronto, Ontario

“Cognitive symptoms in MDD clearly march in a similar direction as mood symptoms, but they don’t march in an identical direction.”

Roger McIntyre, MD

There is a conceptual and clinically relevant shift that is occurring in the assessment and treatment of MDD, insofar as greater attention being paid to dimensions/domains of psychopathology. Several factors are providing the impetus for this shift, including, but not limited to, the need to develop new treatments informed by empirically supported disease models.

Results from the vortioxetine studies indicate that, in addition to mitigating symptoms of depression, there is improvement in other dimensions, including anhedonia, low energy, and cognitive function. It is strongly believed that multidimensional efficacy is more likely to result in relevant improvements in patient-reported outcomes, eg, psychosocial function.

With respect to cognitive symptoms, I think that what’s been happening with MDD over the last 5 years is what happened in bipolar disorder over the previous 10-15 years, and with schizophrenia long ago. And that is, a greater appreciation that cognitive disturbances, broadly, are clearly an overlapping entity, ie, they overlap with other domains vis-à-vis the symptoms that make up the depressive episode criteria.

A conceptual notion or heuristic that has been very much engrained in many of us is that depression, mood symptoms, and cognitive symptoms are so intertwined that they are basically one conflated entity: if the depression improves, then the cognition should improve concomitantly, and vice versa. Cognitive symptoms in MDD clearly march in a similar direction as mood symptoms, but they don’t march in an identical direction.

But they’re also very much dissociable. The dissociability, in fact, can be cascaded down right into the substrates that subserve these phenomena. There’s plenty of evidence now to show that. 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 Debattista, I was just thinking about the patient type you mentioned in an earlier discussion: a high-functioning Silicon Valley CEO. Many of these high-functioning people because they are so high functioning, are particularly susceptible to a decrease in cognitive “capital,” so to speak. And so a person of this type will notice these changes. The cognitive demand that is placed on such an individual is significant, so he or she will notice even a small effect or decrease in cognitive ability. Even though there might not be overt mood symptoms, an individual of this type might encounter a significantly decreased level of function.

Also, there has been recognition that the old moniker of pseudodementia (ie, cognitive impairment as merely an epiphenomenon of depression) may only be an appropriate characterization in somepatients; I think it’s been convincingly established now that the cognitive symptoms of depression also, in fact, have a dissociable aspect about them.

Madhukar Trivedi, MD

Professor of Psychiatry
Director, Center for Depression Research and Clinical Care
Peter O’Donnell Jr. Brain Institute
UT Southwestern Medical Center
Dallas, TX

It’s also very interesting that the domains of cognitive function that seem to be more affected in MDD and bipolar disorder (BD) are things like working memory, reaction time, and speed of response. That actually is, in a way, more complicated than it seems, because these are deficits that can really be so much subtler in depression than in some of the more dramatic cognitive disorders, and yet they have the biggest impact on things that are really valued and important to patients, as well as to productivity.

So, it is a very interesting range of cognitive dysfunctions you see in patients with mood disorders and especially the group of patients for whom symptoms are getting better, but the cognitive performance is not. Those patients find themselves actually puzzled because their symptoms are better, they are sleeping better, their mood is better, but their ability to perform at work remains significantly impaired. Psychomotor speed, executive function, and working memory are emerging as the most frequently reported symptoms.


Ira D. Glick, MD

Professor of Psychiatry and Behavioral Sciences, Emeritus
Stanford University Medical Center
Stanford, CA

Overall, in treating depression, I have been teaching that we typically get partialresponses. There are very few people who have virtually no response, but the degree of the partial response varies. Then you have your family history, genetic and any environmental issues, or stressors, on top of that. So, I am keeping an eye on all of those spheres, and I find that things tend to go relatively consistently – the cognitive, the mood, and the somatic symptoms often go hand-in-hand, but that doesn’t mean that the response will be complete in each area.

When I start treatment, I always try to identify and target symptoms that will and will not respond. There are people who, let’s say, have a particular depressive symptom stick with them while everything else is improving. This scenario is unusual, and symptoms that are not responding at all are often part of a longstanding condition that precedes, by far, the onset of the depressive episode; and these symptoms may have other causes (eg, substance abuse, or another concomitant disorder).

Charles Debattista, MD

Professor of Psychiatry and Behavioral Sciences
Stanford University Medical Center
Stanford, CA

“We know that depressed patients tend to have difficulties with attention, processing speed, and executive functioning; but outside of clinical studies, very few of us actually routinely assess cognition.” 

Charles Debattista, MD

And I think that cognition is one of those symptoms that may not respond wellto our standard treatments, and unfortunately it is also a symptom that most clinicians don’t measure regularly, except in the most cursory manner. We know that depressed patients tend to have difficulties with attention, processing speed, and executive functioning; but outside of clinical studies, very few of us actually routinely assess cognition.

But, clearly, our experience is that depression and cognition may not improve together. And, in fact, there’s a subset of patients with significant cognitive deficits around processing speed and attention and so forth that tend to do worse vocationally and interpersonally over time.


Cha DS, Carmona NE, Subramaniapillai M, et al. Cognitive impairment as measured by the THINC-integrated tool (THINC-it): association with psychosocial function in major depressive disorder. J Affect Disord. 2017;222:14-20.

McIntyre RS, Cha DS, Soczynska JK, et al. Cognitive deficits and functional outcomes in major depressive disorder: determinants, substrates, and treatment interventions. Depress Anxiety. 2013;30(6):515-527.

McIntyre RS, Harrison J, Loft H, et al. The effects of vortioxetine on cognitive function in patients with major depressive disorder: a meta-analysis of three randomized controlled trials. Int J Neuropsychopharmacol. 2016;19(10):pyw055. 

Russo M, Mahon K, Burdick KE. Measuring cognitive function in MDD: emerging assessment tools. Depress Anxiety.2015;32(4):262-269.

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