expert roundtables

Antidepressants and Cognition: A Story Beginning to Unfold

by Roger McIntyre, MD, Madhukar Trivedi, MD


How much is truly known about antidepressants and cognition, and are strategies for selecting antidepressants formulated with careful consideration of cognition? Experts note several instances of clinical concepts in this area that are not grounded in level 1 evidence but have nevertheless gained relatively widespread acceptance. Panelists also address current challenges in matching patients to the right antidepressant therapy. Major depressive disorder (MDD) is considered a genetically complex disease; researchers are still in the early stages of exploration. Continued discovery of “depression genes,” however, and a better understanding and classification of the underlying pathophysiological mechanisms of MDD promise to move the field forward toward a more personalized approach to therapy.

Q: Do current MDD treatment algorithms reflect what is known about different antidepressant drug mechanisms at the molecular and/or receptor level?

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

I think it is becoming clear that the serotonin reuptake blockers (SSRIs) do not seem to be as significant in their impact directly on cognitive performance and cognitive function.

There are short-term and long-term studies that may begin to give us some explanation, some based on the fact that the cognitive performance and cognitive function effects relate to the efficacy of SSRIs. The other piece is that there is a proportion of patients – probably small, but significant – for whom continued serotonin reuptake blockade may actually lead to some associated apathy and cognitive performance issues. That phenomenon, I think, is something that we’ve known about for some time, and I think it plays out in terms of long-term studies with SSRIs.

Roger McIntyre, MD

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

“I think that there does seem to be a cognition story beginning to unfold in certain areas.” 

Roger McIntyre, MD

I’d have to agree with that, Dr Trivedi. I think that the impression has been that the SSRIs, as a broad class, are unequivocally capable of reducing anxiety and dysphoria, and perhaps one could extend that into a sort of affective reactivity, or maybe even an affective impulsivity, in some people. And that overlaps with – but is different from – general, cold, cognitive processes. The evidence is insufficient to allow one to say, with the utmost of certainty, that SSRIs don’t improve cognition.

I think, in fairness, SSRIs haven’t been subjected to the appropriate scrutiny, with the appropriate study design, etc. But certainly there is reason to believe there may be some improvement in cold cognitive processes with SSRIs, with the caveat that the study designs are very much limited, in terms of interpretability, vis-à-vis direct effects and pseudospecificity and that kind of thing. I agree that there is a subset of people who report either exacerbation of existing cognitive symptoms or other cognitive problems with SSRIs.

There seems to be a dampening-down, or apathy, or numbing-down type of syndrome that patients often experience. So, it does seem to be the case, that the SSRIs don’t necessarily possess the required clinical and potentially pharmacodynamic profile. But again, always with this statement there is the caveat that, I think, we just don’t have enough studies of SSRIs and cognition.

It may be even more surprising to learn that a similar lack of evidence exists with respect to bupropion, which has been with us for decades and enjoys a certain reputation for being capable of mitigating cognitive problems. Anecdotally, I wonder if, in part, that was because of the data that were obtained with bupropion in adult attention-deficit/hyperactivity disorder. I don’t know, but it being a stimulant derivative, and having a long history of off-label use for a variety of purposes including general cognitive processes – these things may have played a role in the development of that agent’s reputation.

However, like the SSRIs, bupropion has also not been subject to adequate scrutiny in the sense that one cannot say that there is any level 1 evidence, or for that matter level 2 evidence, to support a role as a pro-cognitive agent in depression. That is a claim that just hasn’t been studied sufficiently, and so these are important limitations. I think that there does seem to be a cognition story beginning to unfold in certain areas.

We have heard about vortioxetine, and certainly there are reasons to believe 5-hydroxytryptamine (5HT-7) may be a receptor that, when antagonized, may result in pro-cognitive effects. These areas perhaps also include agents that may be affecting immunoinflammatory systems, perhaps agents affecting gamma-aminobutyric acid (GABA) glutamate systems, or those that are affecting insulin or bioenergetics systems in the brain, and then extending into subpopulations of receptors.

But going back to the initial question in this topic, I think there still seems to be an algorithmic approach to the selection and sequencing of medicines in the treatment of depression that seems to be lacking in the differentiation of these products. At least, my sense is that the general impression is that they all seem to be similar, when in fact they are not similar. But I don’t think the level of refinement that we are seeking here is really one that goes on in everyday clinical practice. 



Greer TL, Furman JL, Trivedi MH. Evaluation of the benefits of exercise on cognition in major depressive disorder. Gen Hosp Psychiatry. 2017;Jul 6. pii: S0163-8343(17)30102-0. [Epub ahead of print]. Review.

McIntyre RS, Soczynska JZ, Woldeyohannes HO, et al. The impact of cognitive impairment on perceived workforce performance: results from the International Mood Disorders Collaborative Project. Compr Psychiatry. 2015;56:279-82.

National Academies of Sciences, Engineering, and Medicine (2015). Enabling discovery, development, and translation of treatments for cognitive dysfunction in depression. Workshop summary. Washington, DC: National Academies Press (US). Accessed July 31, 2017.

Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905-1917.

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