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A Randomized, Controlled Pilot Trial of the Emotional Faces Memory Task: A Digital Therapeutic for Depression
Dr. Brian Iacoviello: Hello, and welcome to today's program. My name is Brian Iacoviello. I'm an Assistant Professor in the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai. It's my pleasure to discuss the background and results of a trial that were published in an article titled, A Randomized Controlled Pilot Trial of the Emotional Faces Memory Task: A Digital Therapeutic for Depression. This article was published by myself and my colleagues at Mt. Sinai in 2018.
I'm joined today by Sagar Parikh, who is a John F. Greden Professor of Depression and Clinical Neuroscience, Professor of psychiatry, and Professor of Health Management and Policy in the School of Public Health at the University of Michigan. This program is sponsored by Otsuka Pharmaceutical Development and Commercialization, Inc.
Dr. Sagar Parikh: Thank you for the introduction, Dr. Iacoviello. I'm looking forward to this conversation.
Dr. Brian Iacoviello: Great, let's get started.
Dr. Brian Iacoviello: Before we dig into the study itself, we'll give an overview of unmet needs in MDD management, as well as introduce the cognitive training intervention called the Emotional Faces Memory Task, or EFMT. Major depressive disorder, or MDD, is a serious condition of the brain that considerably increases morbidity and mortality rates among affected individuals. It also contributes to high public health costs. There continues to be an unmet need for effective treatments for MDD. Currently, 20 to 30% of people with MDD do not achieve adequate therapeutic response. To address this concern, a National Institute of Mental Health Strategic Plan for Research recently suggested a focus on developing novel interventions that address cognitive and behavioral correlates of depression. The plan described a vision for clinically validated and portable devices that were easily accessed by the general public. These digital devices, such as cognitive-emotional training, may show considerable promise in MDD treatment, because they can target and address specific neural network dysfunctions that are seen in patients with MDD. These abnormalities include decreased activity in the dorsal cortical regions that control cognition, and increased activity in the amygdala, which controls emotional processing. This has been most studied and observed in working memory and facial affect processing tasks.
EFMT is an example of a digital cognitive emotional training intervention for MDD that targets the brain's dorsolateral prefrontal cortex, the DLPFC, as well as the amygdala. It engages these areas of the brain through working memory and facial affect identification tasks, and thus supports cognitive control and emotional regulation.
We could think of EFMT, like an exercise that you might do in the gym for a particular muscle. With EFMT, we have identified a certain neural network in the brain involved in cognitive control and emotion processing that's very relevant for major depressive disorder. The EFMT task is like an exercise designed to target and exercise and strengthen that muscle or that neural network. So that cognitive control and emotion processing capabilities can be improved and ultimately improving symptoms of depression.
Dr. Parikh, can you give an example of how EFMT works?
Dr. Sagar Parikh: Certainly. Here is an example trial in the EFMT. Specifically, the EFMT digital software presents a series of face pictures, 1 at a time for 1 second, followed by a fixation cross for 1 second. Participants are required to identify the emotion of each face and remember the sequence of emotions. The image on this slide shows an example trial in the EFMT task.
Prior to today’s study, results from an initial pilot study had demonstrated proof-of-concept regarding efficacy of EFMT for MDD. In that study, 21 patients with MDD had been randomized to receive EFMT 2 times a week for 4 weeks or a sham training task as a control.
Outcomes showed that, compared to sham, EFMT was associated with a greater decline in symptoms of MDD and negative affective bias. However, improvements in working memory were similar across both groups.
These promising findings led to today’s study, which had intended to explore whether the first study’s outcomes could be replicated with a larger sample size. This study was a double-blind, randomized, controlled pilot study that explored EFMT as an intervention for major depression compared to control.
I’ll pass it on to Dr. Iacoviello to give an overview of the study participants.
Dr. Brian Iacoviello: Thank you. In the study, the 51 patients in the intention-to-treat, or ITT, population were unmedicated, with a current episode of MDD that was moderate to severe, as measured by the Hamilton Depression Rating Scale with 17 items, or the HAM-D. As you can see on this slide, the mean age in the ITT sample was approximately 35 years. Most patients were women in both groups. The mean baseline depression severity score, as measured by the HAM-D, was approximately 19 in both groups, and the mean current MDD episode duration was approximately 20 months in the EFMT group and 11 months in the control group. Overall, patients across both groups had experienced approximately three MDD episodes throughout their lifetime. Dr. Parikh, could you give an overview of the study design?
Dr. Sagar Parikh: Absolutely. In the study, 28 patients were randomized to receive EFMT and 22 patients to receive an active control that involved a cognitive training paradigm matched for time and attention, which used neutral shapes instead of emotional faces or stimuli, and thereby did not induce additional amygdala activity. The intervention and control were given three times a week over six weeks, with 18 sessions total. Out of the 51 patients, 48 completed at least one week in the study and were part of the modified intention-to-treat, or ITT, analysis. Throughout the study, patients were disqualified for participation if they missed more than two sessions in a week or missed more than three sessions total. By the end of the study, 37 patients, or 73%, had completed all sessions, with 20 patients in the EFMT group and 17 in the CT group. As Dr. Iacoviello will share on the next slide, EFMT was associated with considerable symptom improvement.
Dr. Brian Iacoviello: Yes. As Dr. Parikh said, results with the ITT population demonstrated a nearly two times greater symptom improvement among patients in the EFMT group versus those in the control group from baseline to week six. Specifically, the mean HAM-D score reduced by 44.9% from 19.25 to 10.6 in the EFMT group, and by 24.49%, from 19.48 to 14.71 in the control group. Of the 28 patients in the EFMT group, 10 met the clinical responder criteria, which was defined as a reduction in the HAM-D from baseline by at least 50%. By comparison, only four of 23 patients in the control group achieved that status. Findings from a sensitivity analysis in the modified ITT sample similarly showed a greater reduction in HAM-D score achieved by the EFMT group than the control group when controlling for baseline MDD severity and number of sessions completed. These results were supported by findings from the patient self-reported measure, the Beck Depression Inventory, on which EFMT was associated with a significantly greater score reduction from 31.28 to 20, than that of the control group from 28.71 to 25.29, with a P value equal to 0.011.
Dr. Sagar Parikh: This table offers greater detail regarding the EFMT and control HAM-D scores, detailing the differences by least square means from the baseline through week six. Here, I want to call out that the reduction in HAM-D score with EFMT versus that with control was significant at week three, at which point the difference in least square means between the groups was 3.15 and the P value equaled 0.01. It was also significant at six weeks, at which point the difference in least square means was 3.87 and the P value equaled 0.003. Outcomes from a post-hoc analysis that evaluated dose-response effects found a significant correlation between the number of EFMT sessions patients completed and the percent HAM-D response, with P value equal to 0.01. In other words, a higher number of completed sessions was associated with a greater HAM-D response. This correlation was not demonstrated with control sessions.
In the post hoc analysis findings, performance was not correlated with HAM-D response in either group. Now I've said a couple of things which may be confusing. I've just said, that outcomes showed a dose response curve that was significant. That is the more you had sessions, the better you did. But then I just said performance on the actual test did not make a difference. What by that, I can explain by an analogy. If you were working out in the gym, if you go to the gym two or three times a week, you're going to have better results than if you go only once a week. But whether you lift 40 pounds or 50 pounds may not make the difference. The difference in performance was whether you were using 40 pounds or 50 pounds, that didn't matter. It was the frequency of going to the gym, or in this case, the number of sessions that you actually completed that made the difference.
Dr. Brian Iacoviello: Dr. Parikh, Thanks for that clarification. It's a feature of the EFMT task that it keeps the patient in what we call a zone of proximal challenge. So really, it's just a matter of you have to try to get the effect. It doesn't matter if you're trying to lift the 10 pounds or the 50 pounds, it's just that you're trying, and you'll get the exercise and get the effect from it.
Dr. Sagar Parikh: That's very helpful, Dr. Iacoviello. Could you share the specific symptoms that improve the most with EFMT?
Dr. Brian Iacoviello: Certainly. With results from a symptom level analysis test of the modified ITT sample. The HAM-D items that most notably improved from baseline to week six were rumination or feelings of guilt, work and activities and somatic anxiety. This is understandable considering the EFMT was designed to improve cognitive control for processing emotional information by targeting abnormal activation patterns in the dlPFC and the amygdala. Thus, symptoms associated with cognition and emotion such as rumination and dwelling or feelings of sadness or anxiety would be more likely to improve than neurovegetative symptoms, such as changes in sleep or appetite.
Dr. Sagar Parikh: It makes sense that symptoms associated with cognitive function and emotional processing would improve the most. This brings us to conclusions.
The authors of the study surmised that these outcomes were in line with the initial pilot study demonstrating improvement with MDD symptoms among patients who received EFMT that were greater than that of those who received the control.
The authors concluded that cognitive emotional training shows promise as a novel approach to addressing symptoms of MDD. Of note studies regarding cognitive training interventions come with certain inherent limitations, such as poorly matched controls and exaggerating the generalizability of results.
In this study with its small sample size and in-person sessions, generalizability was limited, although there is a need for future study in real world remote settings with a larger sample size.
Limitations for this study included difficulty in accurately determining attrition being located at a single site, not including a group for passive comparison, and not allowing for evaluating the mechanism of action of EFMT.
Dr. Brian Iacoviello: Thank you for that summary, Dr. Parikh.
On one final point to address the obstacles that patients with depression have in terms of accessing effective treatments for their symptoms of depression. Developing these kinds of cognitive emotional training exercises as interventions for depression could actually help overcome some of these accessibility barriers. If we create interventions that are on devices or computers that are in the hands of patients already and enable them to access a treatment at the time and place of their choosing, we can really overcome some of the barriers that have prevented patients with depression from accessing effective treatments.
Dr. Brian Iacoviello: This concludes our conversation today regarding EFMT as a cognitive training intervention for MDD. Thank you for joining us today for this important conversation.
