expert roundtables

Cognitively Sparing Compounds vs Procognitive Therapies

by Joseph F. Goldberg, MD, Roger McIntyre, MD, Michael E. Thase, MD


Evidence related to the cognitive profiles of the various antidepressant drug therapies has traditionally been lacking; ie, approval of new agents indicated for the treatment of major depressive disorder (MDD) is often based on depression symptom score improvement, and there is not yet any single gold standard test of cognition. With growing recognition of the importance of functional outcomes in MDD, however, clinicians and researchers are now devoting more attention to the cognitive profiles of the various pharmacotherapies used in depression.

Q: How do you conceptualize the various drug therapies for MDD in regard their cognitive profiles?

Michael E. Thase, MD

Professor of Psychiatry
Director, Mood and Anxiety Disorders
Treatment and Research Program
University of Pennsylvania
Philadelphia, PA

“[This is] an intriguing story. Vortioxetine and lurasidone are the 2 agents with clinically meaningful 5-HT7 effects, and both of them are showing some benefit in cognitive functioning.”

Michael A. Thase, MD

Treating depression is procognitive, and all of the various antidepressant therapies have been proven effective in treating depression; thus, they all have at least some modest, nonspecific benefits in association. That said, things do not always turn out as one would hope. There was a very large study of donepezil in late-life depression, for instance, in which donepezil actually made outcomes worse. The group that received concomitant donepezil along with antidepressant therapy was much more likely to become ill again.

Joseph F. Goldberg, MD

Clinical Professor of Psychiatry
Icahn School of Medicine
Mount Sinai
New York, NY

Dr McIntyre just published a narrative review looking at levels of evidence for different antidepressant strategies targeting cognition, in which the double blind, prospective data really fell only to vortioxetine (Pan et al 2017):

 I believe they examined the extent to which open trials have tried to extract out what hopefully is not pseudospecificity in looking at cognition with SSRIs and SNRIs.

Additionally, if we borrow from the bipolar disorder literature, there is an interesting story that relates to the 5-HT7 receptor: it may be worth noting the lurasidone studies in euthymic patients with bipolar type I disorder that were published earlier this year in Lancet Psychiatry by Lakshmi Yatham and colleagues, in which they found a signal with lurasidone adjunctive therapy (mean dose was 48 mg/d, with SD of 15 to 90 mg/d) vs placebo. They did not really find, as I recall, individual domains of cognition improving with lurasidone, but they did see improvements on global cognitive functioning—there was a strong signal with a reasonable effect size.

It does inspire some interest, owing to the 5-HT7 aspects that relate to vortioxetine, and whether or not there is some inference to be made about the mechanism of action of vortioxetine on cognition. With vortioxetine, there are also some data showing—presumably via 5-HT7, but we don’t know if that’s the case for sure—that the molecule itself seems to exert a benefit on the Digit Symbol Substitution Test in attentional processing and psychomotor speed, independent of its effect on depression.

Q: When cognitive improvements are seen, is it a restoration to baseline, then?

Dr Goldberg:
I don’t know that we have any drugs that could be called nootropic. I think we have cognitively sparing and cognitively impairing compounds. Vortioxetine seems to improve some of the cognitive symptoms associated with depression, but I do not know if that is the same as calling it a cognitive enhancer, any more than I think acetaminophen is an antipyrogenic enhancer.

Roger McIntyre, MD

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

A distinct but related consideration here is that treatments that are primarily procognitive may also be antidepressant. But, you know, Dr Goldberg, on that note of enhancing cognition, in terms of whether or not an agent could theoretically be considered a nootropic, one would want to test that, presumably in healthy control subjects. And there is evidence to suggest that you do get some enhancement of performance with stimulants in healthy controls, at least in some cognitive domains, and also with modafinil. More recently, a vortioxetine study by Dr Goodwin and his team (Smith et al 2017), in patients with remitted depression and healthy control subjects, demonstrated a benefit in cognition in the healthy controls, as well. And, while we are on the topic, insulin has been shown to be procognitive in people who don’t have type 2 diabetes. We consider these and other procognitive strategies, and it seems that it may not be a “strictly monoamine thing,” even though that is where the focus has been, and maybe we can make procognitive inroads in some of the other areas. I think that those 3 (including modafinil, and stimulants as a class—obviously, some more than others) do have procognitive findings in healthy controls.


Lam RW, Iverson GL, Evans VC, et al. The effects of desvenlafaxine on neurocognitive and work functioning in employed outpatients with major depressive disorder. J Affect Disord. 2016;203:55-61.

Pan Z, Grovu RC, Cha DS, et al. Pharmacological treatment of cognitive symptoms in major depressive disorder. CNS Neurol Disord Drug Targets. 2017 Sep 18. doi: 10.2174/1871527316666170919115100. [Epub ahead of print].

Reynolds CF, Butters MA, Lopez O, et al. Maintenance treatment of depression in old age: a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy. Arch Gen Psychiatry. 2011;68(1):51-60.

Smith J, Browning M, Conen S, et al. Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls. Mol Psychiatry. 2017. doi: 10.1038/mp.2017.104. [Epub ahead of print].

Yatham LN, Mackala S, Basivireddy J, et al. Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study. Lancet Psychiatry. 2017;4(3):208-217.

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