patient care perspectives

Major Depressive Disorder: Unpacking the Neural Bases of Cognitive Impairment

by Michael E. Thase, MD

Overview

As the field of psychiatry increasingly recognizes the importance of the cognitive symptoms of major depressive disorder (MDD), researchers explore the neural basis of related cognitive deficits. Investigators at Oxford University recently identified effects of an atypical antidepressant on the neural circuits thought to be important for executive function and working memory – effects that could not be accounted for by changes in subjective mood, and effects that were also observed in the healthy control group.

Expert Commentary

Michael E. Thase, MD

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

“I think that just the possibility of 1 medication with 1 difference in its sub-effect showing an advantage in improving cognitive symptoms that SSRIs, SNRIs, and other modern antidepressants don’t show is interesting.”

Michael E. Thase, MD

Using functional imaging, investigators at Oxford University recently found that vortioxetine, a newer multimodal antidepressant, modulates neural load during working memory in both patients with remitted MDD and in healthy controls. Findings were published in the May 2017 issue of Molecular Psychiatry.

MDD is associated with broad deficits in executive function, memory, and learning. This cognitive impairment may persist despite treatment with available agents, and may also be present during periods of symptom remission. There is ongoing debate as to whether such cognitive impairment represents an enduring or a possible trait vulnerability marker for depression; in either case, cognitive deficits in patients with MDD may act as crucial levers of functional impairment, preventing complete restoration and return to baseline occupational and psychosocial function. Thus, the neural bases for the cognitive deficits of depression are of great interest scientifically and in antidepressant drug development.

Vortioxetine is an approved antidepressant with a multi-modal mechanism of action different from that of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). The mechanism of the antidepressant action of vortioxetine is not fully understood. That is, there is inhibition of serotonin (5-HT) reuptake but also agonism at 5-HT1A receptors, partial agonism at 5-HT1B receptors, and antagonism at 5-HT3, 5-HT1D, and 5-HT7 receptors. The influence of each of these actions on the antidepressant effect is not clear.

Preclinical studies in animals suggested that there might be effects with vortioxetine that improve procognitive function when compared with other antidepressants. A meta-analysis of 3 randomized, controlled trials analyzed Digit Symbol Substitution Test (DSST) score performance and found that vortioxetine, but not duloxetine, significantly improved performance, independent of depressive symptoms. Interest also stems from an analysis of shared variance and findings that suggested that a large part of the improvement in cognitive function with vortioxetine was a direct, independent effect, rather than merely a broad-based symptom improvement in depression.

Collectively, these findings suggest the possibility of a functional pharmacology that may be beneficial for patients with MDD and specifically for the cognitive symptoms of MDD — a noteworthy prospect. I think that just the possibility of 1 medication with 1 difference in its sub-effect showing an advantage in improving cognitive symptoms that SSRIs, SNRIs, and other modern antidepressants don’t show is interesting.

In functional imaging studies of the brain, MDD and other neuropsychiatric disorders have been associated with abnormal function in several key brain networks (see figure). One such network is termed the default mode network (DMN), a system of linked brain regions that are more active during rest than during many attention-demanding tasks.

 

cognitive impairment_graphic

 

Depression has been associated with increased engagement of task-positive networks and reduced deactivation of the DMN compared with healthy controls when task performance is maintained. In addition, depressed patients seem to have difficulty in switching off the DMN, which is coupled with a compensatory overactivation of the task-positive network.

Thus, Oxford University researchers, J Smith and colleagues, performed fMRI to investigate these brain networks in subjects during cognitive tasks that have been well studied in depressed individuals. Forty-eight remitted MDD participants and 48 healthy control participants were recruited from 3 academic sites in the United Kingdom and randomized to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design.

One cognitive task measured in the study was N-back visual working memory task, which requires subjects to monitor a series of stimuli and indicate when the current stimulus matches the one from N steps earlier in the sequence. The demands of this task are associated with an increased engagement of a frontoparietal network and concomitant deactivation of the DMN, including the medial temporal lobe. This shift in activity from the DMN to the task-positive network is thought to reflect the reallocation of available neurons to regions that are required for working memory, thereby optimizing performance, according to the authors.

Effects on fMRI responses during an N-back working memory task were assessed at baseline and at the end of treatment with vortioxetine. Other neuropsychological measures of executive function, speed and information processing, attention, learning, and memory were also examined.

Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task. Vortioxetine also increased Trail Making Test (TMT) performance and self-reported cognitive function on the Perceived Deficits Questionnaire (PDQ).

Smith and colleagues reported that their findings supported direct effects of vortioxetine on the neural circuits important for executive function and working memory – effects that could not be accounted for by changes in subjective mood in the remitted group, and effects that were also observed in the healthy control group.

Investigators concluded that the results from the imaging tasks suggest that vortioxetine may improve the efficiency and reduce the effort required to complete executive tasks. It remains to be determined whether the effects of vortioxetine on cognition are specific to the cognitive deficits observed in depression or whether similar cognitive deficits associated with other psychiatric disorders such as schizophrenia may also be modulated.

Study authors noted several important limitations of this study. Participants were assessed at 2 weeks, which is a relatively short period of treatment, and most patients are likely to be treated chronically. Thus, it remains to be determined whether the effects of vortioxetine described are maintained following longer term administration and are predictive of changes in cognitive function.

“Smith and colleagues reported that their findings supported direct effects of vortioxetine on the neural circuits important for executive function and working memory – effects that could not be accounted for by changes in subjective mood in the remitted group, and effects that were also observed in the healthy control group.”

Michael E. Thase, MD

Additionally, there was no active comparator group in the present study, which prevents a direct comparison between the neurocognitive effects of vortioxetine with that of an alternative antidepressant. Investigators noted that a previous neuroimaging study of fluoxetine in depressed patients had found no effect of treatment in the circuitry identified in this study. The authors also stated that future studies would benefit from the inclusion of an active comparator.

The most commonly observed adverse reactions for vortioxetine in patients in 6- to 8-week placebo-controlled studies were nausea, constipation, and vomiting. The most common was nausea, with 21% at the 5-mg dose and 32% at the 20-mg dose, vs 9% with placebo.

References

Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RS. A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacol. 2015;40:2025-2037.

McIntyre R, 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.

Smith J, Browning M, Conen M, 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;May 23. doi: 10.1038/mp.2017.104. [Epub ahead of print]

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