A randomized, controlled pilot trial of the Emotional Faces Memory Task: a digital therapeutic for depression

A randomized, controlled pilot trial of the Emotional Faces Memory Task: a digital therapeutic... www.nature.com/npjdigitalmed ARTICLE OPEN A randomized, controlled pilot trial of the Emotional Faces Memory Task: a digital therapeutic for depression 1,2 2,3,4 2 2 2 5 Brian M. Iacoviello , James W. Murrough , Megan M. Hoch , Kathryn M. Huryk , Katherine A. Collins , Gary R. Cutter , 2,6,7 2,3,8 Dan V. Iosifescu and Dennis S. Charney There is an urgent need for more effective treatments for major depressive disorder (MDD). Digital therapeutics, such as computerized cognitive–emotional training interventions, represent a promising new strategy for treating MDD. Here we report a replication of efficacy of a digital cognitive–emotional training intervention designed to enhance cognitive control for emotional information-processing. In a randomized, double-blind, controlled study design, 51 participants with MDD in a current major depressive episode were randomly assigned to participate in a digital cognitive–emotional training regimen (Emotional Faces Memory Task (EFMT); n = 28) involving 18 sessions over 6 weeks, or an active control condition (CT; n = 23) involving computerized working memory training. MDD symptoms were assessed weekly using a clinician-rated measure (Hamilton Depression Rating Scale; Ham-D); and neurocognition (working memory), at baseline and study outcome. Mixed-effects model for repeated measures (MMRM) analysis of all participants randomized revealed a significantly greater reduction in MDD symptom severity (Ham-D) from baseline to outcome in the EFMT group (8.65 points) compared to the CT group (4.77 points) (F(6,205) = 3.23, p = .005, d = 0.46). Ten of 28 EFMT participants achieved clinical response (≥50% reduction in symptoms) compared to 4 of 23 in CT. Both groups exhibited similar, small improvements in working memory. This replicated the preliminary efficacy of a digital cognitive–emotional training approach for the treatment of MDD. EFMT may be a feasible and effective intervention strategy for MDD, but future studies to elucidate its mechanism of action are warranted. This study is registered with Clinicaltrials.gov (NCT: 01934491). npj Digital Medicine (2018) 1:21 ; doi:10.1038/s41746-018-0025-5 INTRODUCTION identification tasks, which have been shown to elicit activity in 8 9 the DLPFC and amygdala, respectively. A version of this task There is an urgent public health need for more effective confirmed simultaneous activation of the DLPFC and amygdala in treatments for major depressive disorder (MDD), a disabling a sample of healthy volunteers, but the activation effects in MDD condition associated with significant morbidity, mortality and 1,2 patients have not yet been confirmed. public health costs. Twenty to 30% of patients fail to achieve An initial pilot study provided proof-of-concept for the efficacy adequate therapeutic response to currently available treat- 3,4 of EFMT in MDD. In that study the EFMT intervention was ments. To address the problems in treating MDD with currently administered to a sample of 21 MDD patients twice per week for available therapies, a recent National Institute of Mental Health 4 weeks, in line with previous cognitive training regimens Strategic Plan for Research calls for the development of novel 11,12 reported in the literature. Half of the sample was randomly interventions that focus upon known cognitive and behavioral assigned to an active sham training task, which involved a correlates of depression, and suggests development of interven- straightforward working memory training (adaptive N-back task tions that are portable and accessible to the general public and with shapes as the stimuli, instead of emotional faces) that would reduce development times, but that are also clinically validated. In elicit DLPFC activation (but not amygdala as no emotion line with this, digital interventions have begun to emerge for a processing is occurring). The efficacy of EFMT was evaluated variety of conditions including MDD and have shown promising using a battery of measures to assess changes in cognitive biases indicators of efficacy. and rumination, neurocognition/working memory, and MDD An example of a digital intervention for MDD with preliminary symptoms. At study outcome, EFMT had elicited significantly validation is a cognitive–emotional training intervention for MDD: greater reductions in MDD symptoms and negative affective bias 6,7 the Emotional Faces Memory Task (EFMT). EFMT was designed compared to the control group. Both groups, however, showed to simultaneously engage the dorsolateral prefrontal cortex similar improvements in working memory, indicating that (DLPFC) and amygdala, which subserve cognitive control and cognitive improvement alone was not driving the MDD symptom emotion regulation impairments commonly observed in MDD. To improvement. These findings suggested that cognitive–emotional do so, EFMT combines working memory and facial affect training holds the promise of enhancing cognitive control for 1 2 Click Therapeutics, Inc., New York, NY, USA; Department of Psychiatry, Mood and Anxiety Disorders Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3 4 Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New 5 6 York, NY, USA; Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA; Department of Psychiatry, NYU School of 7 8 Medicine, New York, NY, USA; Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA Correspondence: Brian M. Iacoviello (brian@clicktherapeutics.com) Received: 5 September 2017 Revised: 7 March 2018 Accepted: 9 March 2018 Published in partnership with the Scripps Translational Science Institute A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. affective information processing and modulating the underlying Table 1. Demographic and clinical characteristics of the study sample neural networks that are involved in these processes. The current study was designed to replicate the initial pilot study findings in a All randomized participants larger sample that was powered to detect the expected symptom- EFMT CT improvement difference between EFMT and the sham-training group. A second, larger pilot was recommended by the funding n 28 23 agency (NIMH) as the initial study was considered a demonstration Age (years) 35.43 (10.66) 34.57 (11.72) of feasibility and they wanted to see positive results in a larger Gender (% female) 75.0% 60.9% pilot trial prior to funding a large-scale clinical trial. Thus, a second pilot study was conducted to investigate whether the initial pilot Race study results could be replicated, in a new sample of 51 MDD Asian 4 2 participants who enrolled in a randomized study of EFMT Hawaiian or Pacific islander 0 1 compared to a sham-control condition involving working memory Black/African American 5 9 training. White/Caucasian 14 8 More than one race 4 2 RESULTS Unknown/Unreported 1 1 Between August 2013–April 2017, 55 currently un-medicated MDD Baseline MDD severity 19.25 (2.55) 19.48 (2.64) participants signed consent to participate in the study, and study (Ham-D) follow-up visits occurred through June 2017 until the sample of n Current MDD episode 18.61 (19.69) 11.04 (11.60) > 50 was achieved. Four of these participants exited the study duration (months) prior to commencing the training regimen and were not Number of MDD episodes 3.19 (3.35) 3.61 (3.12) randomized, two due to scheduling conflicts and inability to (lifetime) commit to the study visit regimen, and two due to no longer Axis I comorbidities (current) Dysthymia 14.29% Dysthymia 4.35% meeting eligibility criteria to participate (symptom severity). The Social phobia Social phobia 8.7% intention-to-treat (ITT) evaluation sample included the 51 MDD 10.71% participants randomized, with 28 randomized to EFMT and 23 to CT. Three participants failed to complete at least two training Generalized anxiety Specific phobia disorder 3.57% 8.7% sessions in week 1 and were discontinued from the protocol prior to the week 1 assessment. Forty-eight participants completed at Body dysmorphic least 1 week of training and were included in the modified disorder 3.57% intention-to-treat (m-ITT) analysis, 26 in EFMT and 22 in CT. Thirty- seven participants (73%) completed all study visits including the Modified ITT sample outcome assessments, 20 in the EFMT group (71%) and 17 in the EFMT CT CT group (77%). Table 1 provides the demographic and clinical characteristics of the study sample. n 26 22 Age (years) 35.46 (10.22) 33.68 (11.19) MDD symptom severity Gender (% female) 76.9% 63.6% Mixed-effects model for repeated measures (MMRM) analysis of all Baseline depression severity (Ham-D) 19.35 (2.56) 19.23 (2.41) 51 participants randomized revealed significant group × time Current MDD episode duration (months) 19.73 (19.99) 11.14 (11.87) interactions for change in HAM-D score (F(6, 205) = 3.23, p = 0.005, d = 0.46). Least squares means were tested between Number of MDD episodes (lifetime) 3.36 (3.43) 3.65 (3.22) groups, with significant Ham-D mean differences at week 3 of Values indicate n’s or mean (SD) unless otherwise indicated 3.15 (se 1.34; t(205) = 2.36, p = 0.019, d = 0.23) and week 6 of 3.87 (se 1.32; t(205) = 2.93, p = 0.004, d = 0.30) demonstrating EFMT to have superior reduction in Ham-D score compared to the CT group. Table 2 provides the least squares means Ham-D score Table 2. EFMT and CT Ham-D score difference in least square means difference between EFMT and CT by week, along with the by week standard error, t-value, degrees of freedom, and corresponding p- value for the least squares means comparisons. Figure 1 depicts Week Difference Standard error dft-value p-value the least squares means change in Ham-D score from baseline over time for EFMT and CT groups. From baseline to outcome, Baseline 0.2283 1.1963 205 0.19 0.8489 EFMT participants showed a mean reduction of 44.94% in Ham-D Week 1 −0.7493 1.257 205 −0.60 0.5517 score (from 19.25 to 10.60); CT participants showed a 24.49% Week 2 0.3586 1.3246 205 0.27 0.7869 mean reduction in Ham-D score (from 19.48 to 14.71). Ten of the Week 3 3.1462 1.3355 205 2.36 0.0194 28 EMFT participants showed at least 50% reduction in Ham-D Week 4 0.8958 1.3596 205 0.66 0.5107 from baseline (meeting “clinical responder” criteria) while only 4 of the 23 CT participants achieved “responder” status. Week 5 1.7720 1.3737 205 1.29 0.1985 Sensitivity analysis in the m-ITT sample revealed a significant Week 6 3.8681 1.3181 205 2.93 0.0037 group × time effect on Ham-D score (F(1, 44) = 4.698, p = 0.036) indicating superior Ham-D reduction in the EFMT group compared to the CT group, controlling for baseline depression severity and the number of training sessions completed. These results were Post-hoc analyses investigated dose-response effects by analyz- corroborated by the self-reported depression severity measure ing the effect of the number of training sessions completed and BDI-II, on which the EFMT group demonstrated a significantly the performance on the cognitive training task (mean N-level greater reduction (31.28 (SD = 1.72) to 20.0 (2.28)) compared to CT achieved across blocks in a session) in the m-ITT sample. The EFMT (28.71 (1.77) to 25.29 (2.34)), F(1, 33) = 7.392, p = 0.011. and CT groups did not demonstrate significantly different npj Digital Medicine (2018) 21 Published in partnership with the Scripps Translational Science Institute 1234567890():,; A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. outcome, both groups reported similar scores to baseline and again not significantly different between groups and relatively unchanged from baseline (EFMT mean = 3.94 (1.24); CT = 3.71 (0.91); t(28) = 0.555, p = 0.583). At study outcome, EFMT and CT groups provided similar ratings for perceived helpfulness with attention and concentration (EFMT mean = 2.75 (1.13); CT = 3.14 (1.10); t(28) = 0.964, p = 0.343), perceived helpfulness with controlling thoughts (EFMT mean = 2.81 (1.17); CT = 3.14 (1.41); t(28) = 0.703, p = 0.488) and improv- ing depressed mood (EFMT mean = 2.69 (1.01); CT = 2.86 (1.23); t (28) = 0.414, p = 0.682). The CT group reported greater perceived helpfulness with improving memory at outcome compared to EFMT (EFMT mean = 2.56 (1.21); CT = 3.79 (1.05); t(28) = 2.936, p = 0.007). DISCUSSION Fig. 1 Change in depression severity over time. Least squares The current study replicated the results of our initial proof-of- means change in Ham-D total score from baseline demonstrate superior reduction in the EFMT group compared to CT. Error bars concept study of the efficacy of a digital cognitive–emotional indicate ±1 standard error of the mean. *p < 0.05 between groups training intervention for MDD. Compared to an active working memory training control condition (CT), the EFMT group demon- numbers of sessions completed (EFMT: 14.46 (SD = 5.27), CT: 14.91 strated greater MDD symptom reduction after completing a 6- (4.33); t(46) = 0.318, p = 0.752) or significantly different perfor- week regimen of the training task, in both clinician-rated and self- mance on the training task (mean N-level achieved; EFMT: 3.37 report measures of MDD symptoms. A dose-response effect was (1.73), CT: 4.40 (2.03); t(46) = 1.892, p = .065) although the CT also detected, with the number of training sessions showing a group appeared to show an estimated greater performance on strong and significant correlation with symptom improvement in the CT task. There was a significant correlation between number of the EFMT group. The magnitude of MDD symptom response in sessions completed and percent Ham-D response in the EFMT both groups was similar to that observed in the previously group (r = −0.497, p = 0.01) with more sessions completed published study (49% reduction in Ham-D score in study one vs. associated with greater Ham-D response (a negative value) that 45% in study two in the EFMT groups; 28% reduction vs. 25% in was not present in the CT group (r = 0.152, p = 0.501). Perfor- the CT groups). It is noteworthy that this is a second pilot study to mance on the training task was not significantly correlated with yield a large effect size for EFMT, with this study revealing a Ham-D response in either group (EFMT: r = −0.365, p = 0.066; CT: greater than 3.8-point difference in Ham-D improvement between r = 0.406, p = 0.061) although the correlations were in opposite EFMT and CT. This difference would be described as clinically directions: greater performance was associated with greater Ham- significant—a reduction of >2 points on the Ham-D is generally considered clinically significant (meaning the patient and clinician D improvement in the EFMT group and lesser improvement in the will typically note “improvement” when Ham-D scores have CT group. improved by 2 or more points); in addition, 2–4 point differences in Ham-D scores between groups are typically observed and Working memory effects interpreted as clinically significant in antidepressant treatment Both groups demonstrated average working memory capabilities trials. However, the relatively small sample size still limits the at baseline (mean scaled score on WAIS subtests DSF, DSB and generalizability of the current findings. LNS) that were not significantly different between groups (10.79 This study investigated changes in working memory capacity, (SD = 0.85) for CT, 11.00 (0.78) for EFMT; t(46) = 0.366, p = 0.716). and found that both EFMT and CT groups demonstrated similar, Both groups demonstrated an improvement in working memory small improvements in working memory from baseline to from baseline to outcome (outcome score: 12.01 (0.85) for CT, outcome that were not significantly different between groups. 11.63 (0.79) for EFMT), with a significant effect of time (F(1, 35) = Thus, the symptom improvement observed is not explained by 6.56, p = 0.015) but were not significantly different at outcome (t improvement in cognition or working memory specifically. Both (35) = 0.399, p = 0.692). There was no significant group-by-time groups estimated cognitive training to be “somewhat acceptable” interaction (F(1, 35) = 0.798, p = 0.378) suggesting both groups (3 on a 5-point Likert-scale) at baseline with no significant working memory scores improved similarly during the course of difference between groups and no significant change from the study. baseline to outcome. At study outcome, both groups reported similar ratings for perceived helpfulness of the training interven- tion with improving attention, improving control over thinking Symptom-level analysis and improving mood, with ratings in the “somewhat helpful” Analysis of baseline-to-outcome change in individual Ham-D range (3 on a 5-point Likert-scale). The CT groups reported greater symptoms in the m-ITT sample revealed significant group × time perceived helpfulness with improving memory compared to the interactions for the following Ham-D items: item #2 (Rumination/ EFMT group, even though both groups demonstrated similar feelings of guilt) (F(1, 46) = 4.462, p = 0.04)); item #7 (Work and improvements in working memory during the study period. This activities) (F(1, 46) = 4.078, p = 0.049)); and item #11 (Somatic could be due to the fact that the CT group practiced a regimen of anxiety) (F(1, 46) = 6.11, p = 0.017)). a working memory training task, whereas the dual task of emotion recognition and working memory in the EFMT task may have Acceptability and perceived helpfulness of the interventions obscured the perceived benefit for memory training in that group. At baseline, both EFMT and CT groups indicated that a cognitive The EFMT task aims to enhance cognitive control for emotional training intervention “could be acceptable as a treatment for information processing and was designed to target abnormal MDD,” with mean ratings just above 3 = “somewhat acceptable” activation patterns in DLPFC and amygdala. Given these neural (EFMT mean = 3.79 (0.98); CT = 3.81 (1.22); t(33) = 0.062, targets, certain MDD symptoms would be expected to respond to p = 0.951). When rating the acceptability of the intervention at the intervention, such as symptoms related to cognition and Published in partnership with the Scripps Translational Science Institute npj Digital Medicine (2018) 21 A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. emotion, while others, such as neurovegetative symptoms, would poorly-matched control conditions, short-lived results and exag- not be expected to show quite as large of a response. For gerated generalizability of findings. example, symptoms related to perseverative thinking (rumination There are limitations acknowledged in this study. First, the study and dwelling) and mood disturbance (chronic sad mood or relied on in-person visits to complete the training sessions and a anxious mood) might show more response than symptoms such relatively small sample size, which limits the generalizability of the as sleep and appetite disturbance. In line with this hypothesis, current findings; future study of the feasibility of administering exploratory analysis of all 17 Ham-D symptoms, using a liberal EFMT remotely in a “real world” setting, and in a large sample, is threshold for significance of p < 0.05 not corrected for multiple needed. Attrition in the current study was difficult to assess comparisons, identified three symptoms that survived this thresh- precisely due to the discontinuation criterion in the study protocol old: rumination/guilt, motivation/activity, and somatic anxiety whereby participants were discontinued if they missed more than symptoms. These symptoms demonstrating a group-by-time one session in any week or missed more than three sessions interaction effect in favor of the EFMT group that are consistent cumulatively. Still, 7 of 55 participants that signed consent with the mechanistic hypothesis of the cognitive–emotional discontinued the study by the end of the first week and were training intervention, which targets cognitive control for emo- not included in the m-ITT sample, providing an estimate of tional information-processing. expected attrition in similar studies in the future. An ITT analysis Taken together, these results support the continued evaluation and secondary “completer” analysis were conducted to investigate of EFMT as an intervention for MDD, and support the develop- potential non-attrition bias (participants that completed the ment of training exercises designed to target cognitive–emotional treatment might be “special” compared to non-completers and processing abnormalities and the neural networks associated with confer exaggerated results); the consistency of results between these processes in mood and anxiety disorders. Other groups have the ITT and completer analyses suggests a minimal non-attrition reported on cognitive training interventions for depression: for bias in these results. Another limitation of the current study example, computerized exercises that aim to enhance functioning includes that it was conducted at a single site; future multi-center of prefrontal cortical brain regions by use of a metacognitive trials are indicated to adequately investigate the effectiveness of exercise, or improve attention inhibition deficits in dysphoric EFMT as an intervention for MDD. The lack of a matched passive individuals using a working memory training exercise. A recent comparison group means that the possibility that the effects meta-analysis of computerized cognitive training (CCT) interven- observed are due to non-specific factors shared by both groups, tion studies for depression suggests small to large effects for CCT including the behavior activation involved in study participation, on depressed mood, daily functioning, and certain cognitive can not be ruled out. In addition, the data collected in the present domains (attention, working memory, and global functioning), trial do not allow for investigation of the mechanism of action for suggesting that CCT may be an effective treatment option for this intervention. We hypothesize that the training confers adult depression. However, the mechanism by which this occurs functional connectivity changes between the DLPFC and limbic is unclear due in part to treatments administered alongside CCT in system, and that these changes are associated with symptom several of the studies (participants were also treated with response. fMRI studies investigating this hypothesis are currently antidepressants, psychotherapy, or transcranial direct current underway. Lastly, the middling ratings observed for acceptability stimulation during these trials). Further development and of a cognitive training intervention as a treatment for MDD, which investigation is especially warranted as these types of exercises did not change after study completion despite significant can be delivered remotely over a computer or smart device symptom improvement in the EFMT group, may be seen as a (phone, tablet) at the time and place of one’s choosing, and can potential limitation to the dissemination of these interventions in therefore help to address the barrier to accessible and effective the future. However, the acceptability and perceived helpfulness interventions that patients with depression too often encounter. measures employed in this study may not have been sensitive or Additionally, the combination of cognitive training interventions sophisticated enough to elucidate actionable data regarding with traditional antidepressant medication treatment warrants EFMT’s acceptability and perceived helpfulness. Nonetheless, investigation, as there could be significant synergy between these patients’ motivation to adhere to a treatment regimen that is modes of treatment that could confer greater benefit to MDD rated as “somewhat acceptable” and implemented remotely patients than either treatment alone. Studies of cognitive training should be considered with caution when these interventions are interventions in patients with only partial response to antide- disseminated on a large scale. Commercial efforts to enhance the pressant medication treatment are also warranted to assess acceptability and helpfulness of this type of intervention, for whether this could bring about full remission. In 2017 Pear example by enhancing user engagement and other associated Therapeutics had the first software-as-a-medical-device (SaMD) features, will be a focus of EFMT development in the future. approved by the Food and Drug Administration as a class II In summary, cognitive–emotional training exercises hold the medical device for treatment of a psychiatric disease. Other promise of providing a novel paradigm for the treatment of MDD companies such as Akili Interactive Labs have been working to symptoms. A second study has now shown superior MDD develop SaMD to treat ADHD and other conditions. Thus, the symptom improvement associated with a cognitive–emotional stage has been set for subsequent SaMD devices to be developed, training intervention compared to an active control condition. The evaluated and approved for the treatment of psychiatric disorders magnitude of the effect was similar to a previously published pilot including MDD. study, and the specific symptoms that appear to respond to the There are strengths and limitations associated with this study. intervention are consistent with the hypothesized mechanism of Strengths of the study include the careful clinical characterization action. Further study is warranted, in large samples and multiple of the participant sample, randomization and blinding, and the sites, to confirm the effects of EFMT training, on specific symptom experience of the investigators having previously completed a effects, and to explore mechanisms of action via neuroimaging pilot study with the same methods. Finally, this study provides the brain changes that are associated with EFMT. support for the efficacy of an intervention that has the potential to be disseminated on a large scale by leveraging electronic or digital METHODS means (e.g., web-based delivery; inclusion in a digital therapeutic platform), and ultimately reaching MDD patients that might not Participants otherwise be able to access effective treatment. However, Participants, recruited through advertisements in newspapers and online cognitive training studies have some serious limitations that have for depression research studies, were between the ages of 18–55 and been highlighted previously in the literature. These include evaluated by trained clinicians using the Structured Clinical Interview for npj Digital Medicine (2018) 21 Published in partnership with the Scripps Translational Science Institute A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. 13 15 DSM-IV-TR Axis I Disorders (SCID ). Participants met criteria for MDD Intelligence Scale-3rd Edition. MDD symptoms were evaluated using the diagnosis with a current episode. They could have other Axis I diagnoses clinician-rated Ham-D, and the self-report measure Beck Depression (excluding psychotic disorders, bipolar disorders and substance abuse or Inventory (BDI-II ). Acceptability of a cognitive training intervention as a dependence within the past 6 months) as long as their MDD diagnosis was treatment for MDD was assessed using a 5-point Likert-scale (“Using the primary. MDD severity, as measured by the Hamilton Depression Rating scale below, please circle the number corresponding to how acceptable Scale—17-item version (Ham-D, ) had to be at least “moderate” (Ham-D ≥ cognitive training would be to you, for the treatment of your depression 16). Participants with very severe MDD (Ham-D >27) were excluded and symptoms, if cognitive training were a treatment option in the future.” 1: referred for treatment due to safety concerns surrounding participation in not at all acceptable; 3: somewhat acceptable; 5: very acceptable). a placebo-controlled study and in which the treatment intervention had Participants were randomly assigned to the EFMT or CT groups by a not yet been validated. Participants who had taken any antidepressant research coordinator using a pre-determined randomization sequence for group assignment, with balancing in blocks of six participants in the medications during their current MDD episode as well as those with a history of treatment non-response (2+ failures of an adequate trial of a sequence. Investigators and blinded study raters were kept blind to group standard antidepressant medication) were excluded from participation. assignment throughout the study. Participants were assigned to complete Cognitive–behavioral therapy attendance in the 6 weeks prior to, or at any 18 training sessions over 6 weeks (approximately 20–35 min each, three time during, the study, would also precipitate exclusion. Participants with times per week). Participants that failed to complete at least two sessions in any week, or that missed greater than three sessions during the course visual or motor impairments that were thought to interfere with of the study, were discontinued as per the study protocol. Weekly Ham-D performance on the computerized exercise were also excluded. Reading ability at the 8th grade or above was required for enrollment to ensure that assessments were conducted by PhD or MD-level clinicians who were blind participants could comprehend all study assessments and questionnaires to group assignment. Ham-D raters were extensively trained to administer that were written at-or-below 8th grade reading level. the assessment and demonstrated an ICC > 0.8 on two separate training The protocol and study procedures were approved by the Program for interviews. An outcome evaluation was conducted within 1 week of the Protection of Human Subjects at the Icahn School of Medicine at completing the training sessions, at which time the baseline assessments Mount Sinai (ISMMS) and were conducted in accordance with the were repeated. At the outcome evaluation, assessments of participants’ Declaration of Helsinki. After a pre-screening interview, eligible participants perceived acceptability of a cognitive-training intervention were again were informed about the study procedures and signed informed consent obtained, as were assessments of perceived helpfulness with improving to complete screening and baseline procedures. Participants were aware memory, improving attention and concentration, improving control over that the study would evaluate the effects of two different memory-training thoughts, and improving mood. Assessments were obtained using a 5- exercises on memory and MDD symptoms. They did not, however, know point Likert-scale (1: not acceptable; 3: somewhat acceptable; 5: very the specific differences between the cognitive–emotional and control acceptable). training (CT) paradigms, thereby maintaining the study blind. After completing the study, participants were debriefed, including a description Cognitive training exercises of the study blinding involved and the rationale. Participants were The EFMT is a combination of emotion identification and working memory reimbursed for each study session completed to compensate for time and tasks, designed to simultaneously engage the DLPFC and amygdala, which travel expenses. subserve cognitive control and emotion regulation impairments com- monly observed in MDD. To do so, EFMT combines working memory and Procedure facial affect identification tasks, which have been shown to elicit activity in 8 9 The study intervention was administered over 20 visits. At the first visit, the the DLPFC and amygdala, respectively. In this task participants must SCID and Ham-D were administered to confirm MDD diagnosis and identify the emotions they observe on a series of pictures of faces determine symptom severity. A subsequent baseline evaluation assessed presented one at a time on a computer screen for 1 s, followed by a reading level, attention and working memory, MDD symptom severity, and fixation cross for 1 s, and remember the sequence of emotions. Figure 2 participants’ perceived acceptability of a cognitive training exercise as an depicts an example stimuli sequence in the EFMT task. Using an N-back intervention for MDD. To measure reading ability, a Wide Range working memory training paradigm, after each face observed participants Achievement Test Reading test was administered. To assess attention are prompted to indicate whether the emotion on the face is the same as span and working memory, a composite score was calculated as the mean the emotion N faces prior. Each training session contains 15 blocks of the scaled score from the Digit-Span Forward (DSF), Digit-Span Backward (DSB) task during which the N level varies depending on the participant’s and Letter-Number Sequencing (LNS) subtests of the Wechsler Adult performance: the difficulty level increases or decreases across blocks as a Fig. 2 Example trial in the EFMT task. Participants observe an expression of facial affect shown on screen for 1 s and identify the emotion expressed. Participants then compare the observed emotion to the emotion observed N faces prior, in this case N = 2 faces prior. Copyright for the face images in the figure is owned by Adobe Systems Incorporated (http://stock.adobe.com) Published in partnership with the Scripps Translational Science Institute npj Digital Medicine (2018) 21 A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. participant’s accuracy improves or declines (respectively). The first training investigated differences between groups in perceived acceptability of the session begins with a difficulty level of N = 1 and the starting difficulty intervention at baseline, and perceived helpfulness of the intervention at level for subsequent sessions is determined by performance at the prior study outcome on: depressed mood, attention and concentration, session. The task is therefore tailored to a participant’s ability, ensuring a controlling thinking, and memory. These secondary analyses were consistent challenge. N-back working memory tasks that are progressively conducted using t-tests between groups. Dose effects were investigated challenging have been shown to improve working memory performance. by analyzing correlations between the number of training sessions EFMT utilizes a progressively challenging working memory paradigm and completed or the difficulty levels achieved, and Ham-D change. For these incorporates emotional stimuli throughout the task. The CT task is an exploratory analyses, p < .05 was utilized as the critical alpha to identify target symptoms of interest for future investigation of this intervention, active comparator to EFMT that consists of an identical cognitive-training recognizing the multiple testing might increase our type I error. paradigm, except that stimuli in the CT task are neutral shapes (circle, square, etc.). Because the CT task does not include emotional stimuli, no additional amygdala activation is induced. Thus the EFMT task involves Data availability exerting cognitive control over emotional information processing and the The data reported in this manuscript are available from the corresponding simultaneous activation of amygdala and DLPFC, whereas CT involves author to facilitate replication. Access to the EFMT software can be granted working memory and associated DLPFC activation only. The CT task in this to qualified researchers interested in viewing it for research purposes. study was the same that was utilized in the prior pilot study. Study design ACKNOWLEDGEMENTS The study was designed as a double-blind, randomized, controlled trial to The authors would like to acknowledge the study participants for their time and replicate the effects of a regimen of cognitive–emotional training sessions effort participating in this trial, and the research staff at the Mood and Anxiety on MDD symptoms and working memory in MDD participants. Random Disorders Program at Mount Sinai for their assistance conducting the study. This assignment to group (targeted to 1:1) utilized a randomization sequence, research was supported by National Institute of Mental Health (Bethesda, MD) grant generated by a researcher not affiliated with this study, including random #5K23MH099223 to Brian M. Iacoviello, Ph.D. The sponsor was not involved with the sequences in blocks of six participants to maintain group equivalence over conduct or analysis of the study or the writing of this report. time. The randomization scheme also accounted for completion of the training regimen, factoring this into the algorithm when assigning group AUTHOR CONTRIBUTIONS status to aim for equivalent proportions of regimen completers in both groups. This was done due to a priori concern about unequal dropouts in Drs. Iacoviello and Charney contributed to the conceptualization, design and conduct favor of the control condition if participants suspected that the working of the study, the writing and revising of the manuscript, final approval of the memory training was not effective in addressing MDD. Randomization was completed version, and are accountable for all aspects of the work. Dr. Iacoviello is implemented by a research coordinator at the initial cognitive training the guarantor for this study and manuscript. Drs. Iosifescu, Murrough and Collins visit, who generated a unique login and password for each participant. This contributed to the conduct of the study and writing of the manuscript and approve enabled participants to access the cognitive training exercise to which they of the completed version. Ms. Hoch and Ms. Huryk were research coordinators and had been assigned on a computer in the clinic at each visit. Research contributed to the conduct of the study and writing of the manuscript and approve coordinators were not involved in any clinical ratings. All other study team of the completed version. Dr. Cutter contributed to the data analysis and writing of members remained blind to group assignment. the manuscript and approves of the completed version. Data analytic strategy ADDITIONAL INFORMATION The effect of EFMT vs. CT training on MDD symptom severity was the Competing interests: Dr. Brian Iacoviello (the Principal Investigator) is an adjunct primary analysis of interest in this study. Primary analysis was conducted faculty member of the ISMMS and is employed full time as the Director of Scientific using a MMRM of all study participants randomized, with treatment group, Affairs of Click Therapeutics. Prior to joining Click Therapeutics, Dr. Iacoviello (in his role visit, the interaction of treatment group and visit (used as a categorical as a full time faculty member at ISMMS) and Dr. Dennis Charney (Dean of the ISMMS) variable to allow for characterizing the temporal effects without assuming co-developed EFMT as a computer-based brain training exercise for the treatment of linearity), and participant as a random effect, using an unstructured depression. Drs. Iacoviello and Charney are named co-inventors on a patent filed by covariance matrix. Targeted sample size of 50 was calculated based on a ISMMS to develop this therapeutic approach as a mobile/remote program (app). There power analysis for the above repeated measures analysis using G*Power is a licensing agreement between Mount Sinai and Click Therapeutics to develop this 3.1 software, estimating a medium effect size, α = .05, power= 0.8, two technology; if a commercial product is developed, Mount Sinai, Dr. Iacoviello, and Dr. groups, two measurements, correlation between measures= 0.5, and Charney would benefit financially. A management plan was enacted proactively by the nonsphericity correction = 1. Sensitivity analyses were conducted in a m- Financial Conflicts of Interest in Research (FCOIR) board at Mount Sinai for this study to ITT sample that included all participants who were randomized to either mitigate conflicts of interest. According to this management plan, an independent EFMT or CT, who completed at least one week of training and for whom at statistical analyst (Dr. Gary Cutter) was secured to conduct all data analyses least 1 Ham-D score was obtained after the baseline assessment, with last independently of the study investigators. Dr. Cutter conducted the analyses and observation carried forward (LOCF). This analysis included baseline Ham-D provided the write-up and interpretations of the results to be included in the score and the number of training sessions completed as covariates. LOCF manuscript, to remove any potential bias of conflicted investigators conducting was utilized as a conservative means of addressing any missing Ham-D analyses or interpreting results. Dr. Cutter oversees the drafting of all manuscripts data in the m-ITT analysis. Self-reported depression severity was also including these results and interpretations and approves any manuscript prior to investigated using repeated-measures analysis of BDI-II scores between submission. Dr. Iacoviello has served as a consultant to Fortress Biotech, Inc., and groups. All data were checked to confirm assumptions required for reports grant funding from the National Institutes of Health and the Brain and Behavior statistical analyses conducted (e.g., normality, equal variances). Research Foundation. In the past 3 years, Dr. Murrough has served as a consultant to Secondary analyses aimed to evaluate changes in working memory and Fortress Biotech, Inc., Novartis, Janssen Research and Development and Genentech and symptom-level effects on Ham-D items between groups. Repeated has received research support from Avanir Pharmaceuticals, Inc.; he is named on a measures analysis at two time points (baseline and outcome) was patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and conducted to explore for group or group-by-time effects on working on a patent pending for the combination of ketamine and lithium for suicidal ideation memory (mean scaled score of WAIS subtests: DSF, DBS and LNS). and for relapse prevention following ketamine in patients with depression. He is an Symptom-level analysis was conducted to explore whether specific employee of the ISMMS and has received external funding from the National Institutes symptoms respond to the EFMT vs. CT training. We hypothesized that of Health, the Brain and Behavioral Research Foundation, the Doris Duke Charitable certain symptoms associated with cognitive control abnormalities for Foundation, and the American Foundation for Suicide Prevention. Dr. Collins performs emotion processing, such as sad mood, anxious mood, worry, and clinical trial assessments for ProPhase, LLC as an independent contractor. In the past rumination/dwelling, would be responsive to the EFMT intervention, five years, Dr. Iosifescu has consulted for Avanir, Axome, CNS Response, INSYS Therapeutics, Lundbeck, Otsuka, Servier, and Sunovion and he has received grant/ whereas other unrelated symptoms, such as sleep and appetite research support through the ISMMS from Alkermes, Astra Zeneca, Brainsway, disturbance, would not. To explore this, repeated measures analysis of Euthymics, Litecure, Neosync, Roche, Shire. Dr. Cutter, Ms. Hoch and Ms. Huryk symptom change from baseline to outcome was conducted to investigate declares no competing interests. group-by-time interactions in all 17 Ham-D items. Secondary analyses also npj Digital Medicine (2018) 21 Published in partnership with the Scripps Translational Science Institute A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims 13. First, M. B., Spitzer, R. L., Gibbon, M., Williams, J. B. W. Structured Clinical Interview in published maps and institutional affiliations. for DSM-IV Axis Disorders (SCID) (New York State Psychiatric Institute, Biometrics Research, New York, NY, 1995). 14. Hamilton, M. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62 (1960). REFERENCES 15. Wechsler, D. Wechsler Adult Intelligence Scale. 3rd edn, (The Psychological Cor- 1. Kessler, R. C. et al. The epidemiology of major depressive disorder: results from poration, San Antonio, TX, 1997). the national comorbidity survey replication (NCS-R). JAMA 289, 3095–3105 16. Beck, A. T., Steer, R. A. & Brown, G. K. 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Developing cognitive-emotional training exer- cises as interventions for mood and anxiety disorders. Eur. Psychiatry 30,75–81 Open Access This article is licensed under a Creative Commons (2015). Attribution 4.0 International License, which permits use, sharing, 8. Dima, D., Jogia, J. & Frangou, S. Dynamic causal modeling of load-dependent adaptation, distribution and reproduction in any medium or format, as long as you give modulation of effective connectivity within the verbal working memory network. appropriate credit to the original author(s) and the source, provide a link to the Creative Hum. Brain Mapp. 35, 3025–3035 (2014). Commons license, and indicate if changes were made. The images or other third party 9. Dima, D., Stephan, K. E., Roiser, J. P., Friston, K. J. & Frangou, S. 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Attention bias modification treatment: a meta-analysis toward the establishment of novel treatment for anxiety. Biol. Psychiatry 68, 982–99890 © The Author(s) 2018 (2010). Published in partnership with the Scripps Translational Science Institute npj Digital Medicine (2018) 21 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Digital Medicine Springer Journals

A randomized, controlled pilot trial of the Emotional Faces Memory Task: a digital therapeutic for depression

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www.nature.com/npjdigitalmed ARTICLE OPEN A randomized, controlled pilot trial of the Emotional Faces Memory Task: a digital therapeutic for depression 1,2 2,3,4 2 2 2 5 Brian M. Iacoviello , James W. Murrough , Megan M. Hoch , Kathryn M. Huryk , Katherine A. Collins , Gary R. Cutter , 2,6,7 2,3,8 Dan V. Iosifescu and Dennis S. Charney There is an urgent need for more effective treatments for major depressive disorder (MDD). Digital therapeutics, such as computerized cognitive–emotional training interventions, represent a promising new strategy for treating MDD. Here we report a replication of efficacy of a digital cognitive–emotional training intervention designed to enhance cognitive control for emotional information-processing. In a randomized, double-blind, controlled study design, 51 participants with MDD in a current major depressive episode were randomly assigned to participate in a digital cognitive–emotional training regimen (Emotional Faces Memory Task (EFMT); n = 28) involving 18 sessions over 6 weeks, or an active control condition (CT; n = 23) involving computerized working memory training. MDD symptoms were assessed weekly using a clinician-rated measure (Hamilton Depression Rating Scale; Ham-D); and neurocognition (working memory), at baseline and study outcome. Mixed-effects model for repeated measures (MMRM) analysis of all participants randomized revealed a significantly greater reduction in MDD symptom severity (Ham-D) from baseline to outcome in the EFMT group (8.65 points) compared to the CT group (4.77 points) (F(6,205) = 3.23, p = .005, d = 0.46). Ten of 28 EFMT participants achieved clinical response (≥50% reduction in symptoms) compared to 4 of 23 in CT. Both groups exhibited similar, small improvements in working memory. This replicated the preliminary efficacy of a digital cognitive–emotional training approach for the treatment of MDD. EFMT may be a feasible and effective intervention strategy for MDD, but future studies to elucidate its mechanism of action are warranted. This study is registered with Clinicaltrials.gov (NCT: 01934491). npj Digital Medicine (2018) 1:21 ; doi:10.1038/s41746-018-0025-5 INTRODUCTION identification tasks, which have been shown to elicit activity in 8 9 the DLPFC and amygdala, respectively. A version of this task There is an urgent public health need for more effective confirmed simultaneous activation of the DLPFC and amygdala in treatments for major depressive disorder (MDD), a disabling a sample of healthy volunteers, but the activation effects in MDD condition associated with significant morbidity, mortality and 1,2 patients have not yet been confirmed. public health costs. Twenty to 30% of patients fail to achieve An initial pilot study provided proof-of-concept for the efficacy adequate therapeutic response to currently available treat- 3,4 of EFMT in MDD. In that study the EFMT intervention was ments. To address the problems in treating MDD with currently administered to a sample of 21 MDD patients twice per week for available therapies, a recent National Institute of Mental Health 4 weeks, in line with previous cognitive training regimens Strategic Plan for Research calls for the development of novel 11,12 reported in the literature. Half of the sample was randomly interventions that focus upon known cognitive and behavioral assigned to an active sham training task, which involved a correlates of depression, and suggests development of interven- straightforward working memory training (adaptive N-back task tions that are portable and accessible to the general public and with shapes as the stimuli, instead of emotional faces) that would reduce development times, but that are also clinically validated. In elicit DLPFC activation (but not amygdala as no emotion line with this, digital interventions have begun to emerge for a processing is occurring). The efficacy of EFMT was evaluated variety of conditions including MDD and have shown promising using a battery of measures to assess changes in cognitive biases indicators of efficacy. and rumination, neurocognition/working memory, and MDD An example of a digital intervention for MDD with preliminary symptoms. At study outcome, EFMT had elicited significantly validation is a cognitive–emotional training intervention for MDD: greater reductions in MDD symptoms and negative affective bias 6,7 the Emotional Faces Memory Task (EFMT). EFMT was designed compared to the control group. Both groups, however, showed to simultaneously engage the dorsolateral prefrontal cortex similar improvements in working memory, indicating that (DLPFC) and amygdala, which subserve cognitive control and cognitive improvement alone was not driving the MDD symptom emotion regulation impairments commonly observed in MDD. To improvement. These findings suggested that cognitive–emotional do so, EFMT combines working memory and facial affect training holds the promise of enhancing cognitive control for 1 2 Click Therapeutics, Inc., New York, NY, USA; Department of Psychiatry, Mood and Anxiety Disorders Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 3 4 Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New 5 6 York, NY, USA; Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA; Department of Psychiatry, NYU School of 7 8 Medicine, New York, NY, USA; Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA and Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA Correspondence: Brian M. Iacoviello (brian@clicktherapeutics.com) Received: 5 September 2017 Revised: 7 March 2018 Accepted: 9 March 2018 Published in partnership with the Scripps Translational Science Institute A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. affective information processing and modulating the underlying Table 1. Demographic and clinical characteristics of the study sample neural networks that are involved in these processes. The current study was designed to replicate the initial pilot study findings in a All randomized participants larger sample that was powered to detect the expected symptom- EFMT CT improvement difference between EFMT and the sham-training group. A second, larger pilot was recommended by the funding n 28 23 agency (NIMH) as the initial study was considered a demonstration Age (years) 35.43 (10.66) 34.57 (11.72) of feasibility and they wanted to see positive results in a larger Gender (% female) 75.0% 60.9% pilot trial prior to funding a large-scale clinical trial. Thus, a second pilot study was conducted to investigate whether the initial pilot Race study results could be replicated, in a new sample of 51 MDD Asian 4 2 participants who enrolled in a randomized study of EFMT Hawaiian or Pacific islander 0 1 compared to a sham-control condition involving working memory Black/African American 5 9 training. White/Caucasian 14 8 More than one race 4 2 RESULTS Unknown/Unreported 1 1 Between August 2013–April 2017, 55 currently un-medicated MDD Baseline MDD severity 19.25 (2.55) 19.48 (2.64) participants signed consent to participate in the study, and study (Ham-D) follow-up visits occurred through June 2017 until the sample of n Current MDD episode 18.61 (19.69) 11.04 (11.60) > 50 was achieved. Four of these participants exited the study duration (months) prior to commencing the training regimen and were not Number of MDD episodes 3.19 (3.35) 3.61 (3.12) randomized, two due to scheduling conflicts and inability to (lifetime) commit to the study visit regimen, and two due to no longer Axis I comorbidities (current) Dysthymia 14.29% Dysthymia 4.35% meeting eligibility criteria to participate (symptom severity). The Social phobia Social phobia 8.7% intention-to-treat (ITT) evaluation sample included the 51 MDD 10.71% participants randomized, with 28 randomized to EFMT and 23 to CT. Three participants failed to complete at least two training Generalized anxiety Specific phobia disorder 3.57% 8.7% sessions in week 1 and were discontinued from the protocol prior to the week 1 assessment. Forty-eight participants completed at Body dysmorphic least 1 week of training and were included in the modified disorder 3.57% intention-to-treat (m-ITT) analysis, 26 in EFMT and 22 in CT. Thirty- seven participants (73%) completed all study visits including the Modified ITT sample outcome assessments, 20 in the EFMT group (71%) and 17 in the EFMT CT CT group (77%). Table 1 provides the demographic and clinical characteristics of the study sample. n 26 22 Age (years) 35.46 (10.22) 33.68 (11.19) MDD symptom severity Gender (% female) 76.9% 63.6% Mixed-effects model for repeated measures (MMRM) analysis of all Baseline depression severity (Ham-D) 19.35 (2.56) 19.23 (2.41) 51 participants randomized revealed significant group × time Current MDD episode duration (months) 19.73 (19.99) 11.14 (11.87) interactions for change in HAM-D score (F(6, 205) = 3.23, p = 0.005, d = 0.46). Least squares means were tested between Number of MDD episodes (lifetime) 3.36 (3.43) 3.65 (3.22) groups, with significant Ham-D mean differences at week 3 of Values indicate n’s or mean (SD) unless otherwise indicated 3.15 (se 1.34; t(205) = 2.36, p = 0.019, d = 0.23) and week 6 of 3.87 (se 1.32; t(205) = 2.93, p = 0.004, d = 0.30) demonstrating EFMT to have superior reduction in Ham-D score compared to the CT group. Table 2 provides the least squares means Ham-D score Table 2. EFMT and CT Ham-D score difference in least square means difference between EFMT and CT by week, along with the by week standard error, t-value, degrees of freedom, and corresponding p- value for the least squares means comparisons. Figure 1 depicts Week Difference Standard error dft-value p-value the least squares means change in Ham-D score from baseline over time for EFMT and CT groups. From baseline to outcome, Baseline 0.2283 1.1963 205 0.19 0.8489 EFMT participants showed a mean reduction of 44.94% in Ham-D Week 1 −0.7493 1.257 205 −0.60 0.5517 score (from 19.25 to 10.60); CT participants showed a 24.49% Week 2 0.3586 1.3246 205 0.27 0.7869 mean reduction in Ham-D score (from 19.48 to 14.71). Ten of the Week 3 3.1462 1.3355 205 2.36 0.0194 28 EMFT participants showed at least 50% reduction in Ham-D Week 4 0.8958 1.3596 205 0.66 0.5107 from baseline (meeting “clinical responder” criteria) while only 4 of the 23 CT participants achieved “responder” status. Week 5 1.7720 1.3737 205 1.29 0.1985 Sensitivity analysis in the m-ITT sample revealed a significant Week 6 3.8681 1.3181 205 2.93 0.0037 group × time effect on Ham-D score (F(1, 44) = 4.698, p = 0.036) indicating superior Ham-D reduction in the EFMT group compared to the CT group, controlling for baseline depression severity and the number of training sessions completed. These results were Post-hoc analyses investigated dose-response effects by analyz- corroborated by the self-reported depression severity measure ing the effect of the number of training sessions completed and BDI-II, on which the EFMT group demonstrated a significantly the performance on the cognitive training task (mean N-level greater reduction (31.28 (SD = 1.72) to 20.0 (2.28)) compared to CT achieved across blocks in a session) in the m-ITT sample. The EFMT (28.71 (1.77) to 25.29 (2.34)), F(1, 33) = 7.392, p = 0.011. and CT groups did not demonstrate significantly different npj Digital Medicine (2018) 21 Published in partnership with the Scripps Translational Science Institute 1234567890():,; A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. outcome, both groups reported similar scores to baseline and again not significantly different between groups and relatively unchanged from baseline (EFMT mean = 3.94 (1.24); CT = 3.71 (0.91); t(28) = 0.555, p = 0.583). At study outcome, EFMT and CT groups provided similar ratings for perceived helpfulness with attention and concentration (EFMT mean = 2.75 (1.13); CT = 3.14 (1.10); t(28) = 0.964, p = 0.343), perceived helpfulness with controlling thoughts (EFMT mean = 2.81 (1.17); CT = 3.14 (1.41); t(28) = 0.703, p = 0.488) and improv- ing depressed mood (EFMT mean = 2.69 (1.01); CT = 2.86 (1.23); t (28) = 0.414, p = 0.682). The CT group reported greater perceived helpfulness with improving memory at outcome compared to EFMT (EFMT mean = 2.56 (1.21); CT = 3.79 (1.05); t(28) = 2.936, p = 0.007). DISCUSSION Fig. 1 Change in depression severity over time. Least squares The current study replicated the results of our initial proof-of- means change in Ham-D total score from baseline demonstrate superior reduction in the EFMT group compared to CT. Error bars concept study of the efficacy of a digital cognitive–emotional indicate ±1 standard error of the mean. *p < 0.05 between groups training intervention for MDD. Compared to an active working memory training control condition (CT), the EFMT group demon- numbers of sessions completed (EFMT: 14.46 (SD = 5.27), CT: 14.91 strated greater MDD symptom reduction after completing a 6- (4.33); t(46) = 0.318, p = 0.752) or significantly different perfor- week regimen of the training task, in both clinician-rated and self- mance on the training task (mean N-level achieved; EFMT: 3.37 report measures of MDD symptoms. A dose-response effect was (1.73), CT: 4.40 (2.03); t(46) = 1.892, p = .065) although the CT also detected, with the number of training sessions showing a group appeared to show an estimated greater performance on strong and significant correlation with symptom improvement in the CT task. There was a significant correlation between number of the EFMT group. The magnitude of MDD symptom response in sessions completed and percent Ham-D response in the EFMT both groups was similar to that observed in the previously group (r = −0.497, p = 0.01) with more sessions completed published study (49% reduction in Ham-D score in study one vs. associated with greater Ham-D response (a negative value) that 45% in study two in the EFMT groups; 28% reduction vs. 25% in was not present in the CT group (r = 0.152, p = 0.501). Perfor- the CT groups). It is noteworthy that this is a second pilot study to mance on the training task was not significantly correlated with yield a large effect size for EFMT, with this study revealing a Ham-D response in either group (EFMT: r = −0.365, p = 0.066; CT: greater than 3.8-point difference in Ham-D improvement between r = 0.406, p = 0.061) although the correlations were in opposite EFMT and CT. This difference would be described as clinically directions: greater performance was associated with greater Ham- significant—a reduction of >2 points on the Ham-D is generally considered clinically significant (meaning the patient and clinician D improvement in the EFMT group and lesser improvement in the will typically note “improvement” when Ham-D scores have CT group. improved by 2 or more points); in addition, 2–4 point differences in Ham-D scores between groups are typically observed and Working memory effects interpreted as clinically significant in antidepressant treatment Both groups demonstrated average working memory capabilities trials. However, the relatively small sample size still limits the at baseline (mean scaled score on WAIS subtests DSF, DSB and generalizability of the current findings. LNS) that were not significantly different between groups (10.79 This study investigated changes in working memory capacity, (SD = 0.85) for CT, 11.00 (0.78) for EFMT; t(46) = 0.366, p = 0.716). and found that both EFMT and CT groups demonstrated similar, Both groups demonstrated an improvement in working memory small improvements in working memory from baseline to from baseline to outcome (outcome score: 12.01 (0.85) for CT, outcome that were not significantly different between groups. 11.63 (0.79) for EFMT), with a significant effect of time (F(1, 35) = Thus, the symptom improvement observed is not explained by 6.56, p = 0.015) but were not significantly different at outcome (t improvement in cognition or working memory specifically. Both (35) = 0.399, p = 0.692). There was no significant group-by-time groups estimated cognitive training to be “somewhat acceptable” interaction (F(1, 35) = 0.798, p = 0.378) suggesting both groups (3 on a 5-point Likert-scale) at baseline with no significant working memory scores improved similarly during the course of difference between groups and no significant change from the study. baseline to outcome. At study outcome, both groups reported similar ratings for perceived helpfulness of the training interven- tion with improving attention, improving control over thinking Symptom-level analysis and improving mood, with ratings in the “somewhat helpful” Analysis of baseline-to-outcome change in individual Ham-D range (3 on a 5-point Likert-scale). The CT groups reported greater symptoms in the m-ITT sample revealed significant group × time perceived helpfulness with improving memory compared to the interactions for the following Ham-D items: item #2 (Rumination/ EFMT group, even though both groups demonstrated similar feelings of guilt) (F(1, 46) = 4.462, p = 0.04)); item #7 (Work and improvements in working memory during the study period. This activities) (F(1, 46) = 4.078, p = 0.049)); and item #11 (Somatic could be due to the fact that the CT group practiced a regimen of anxiety) (F(1, 46) = 6.11, p = 0.017)). a working memory training task, whereas the dual task of emotion recognition and working memory in the EFMT task may have Acceptability and perceived helpfulness of the interventions obscured the perceived benefit for memory training in that group. At baseline, both EFMT and CT groups indicated that a cognitive The EFMT task aims to enhance cognitive control for emotional training intervention “could be acceptable as a treatment for information processing and was designed to target abnormal MDD,” with mean ratings just above 3 = “somewhat acceptable” activation patterns in DLPFC and amygdala. Given these neural (EFMT mean = 3.79 (0.98); CT = 3.81 (1.22); t(33) = 0.062, targets, certain MDD symptoms would be expected to respond to p = 0.951). When rating the acceptability of the intervention at the intervention, such as symptoms related to cognition and Published in partnership with the Scripps Translational Science Institute npj Digital Medicine (2018) 21 A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. emotion, while others, such as neurovegetative symptoms, would poorly-matched control conditions, short-lived results and exag- not be expected to show quite as large of a response. For gerated generalizability of findings. example, symptoms related to perseverative thinking (rumination There are limitations acknowledged in this study. First, the study and dwelling) and mood disturbance (chronic sad mood or relied on in-person visits to complete the training sessions and a anxious mood) might show more response than symptoms such relatively small sample size, which limits the generalizability of the as sleep and appetite disturbance. In line with this hypothesis, current findings; future study of the feasibility of administering exploratory analysis of all 17 Ham-D symptoms, using a liberal EFMT remotely in a “real world” setting, and in a large sample, is threshold for significance of p < 0.05 not corrected for multiple needed. Attrition in the current study was difficult to assess comparisons, identified three symptoms that survived this thresh- precisely due to the discontinuation criterion in the study protocol old: rumination/guilt, motivation/activity, and somatic anxiety whereby participants were discontinued if they missed more than symptoms. These symptoms demonstrating a group-by-time one session in any week or missed more than three sessions interaction effect in favor of the EFMT group that are consistent cumulatively. Still, 7 of 55 participants that signed consent with the mechanistic hypothesis of the cognitive–emotional discontinued the study by the end of the first week and were training intervention, which targets cognitive control for emo- not included in the m-ITT sample, providing an estimate of tional information-processing. expected attrition in similar studies in the future. An ITT analysis Taken together, these results support the continued evaluation and secondary “completer” analysis were conducted to investigate of EFMT as an intervention for MDD, and support the develop- potential non-attrition bias (participants that completed the ment of training exercises designed to target cognitive–emotional treatment might be “special” compared to non-completers and processing abnormalities and the neural networks associated with confer exaggerated results); the consistency of results between these processes in mood and anxiety disorders. Other groups have the ITT and completer analyses suggests a minimal non-attrition reported on cognitive training interventions for depression: for bias in these results. Another limitation of the current study example, computerized exercises that aim to enhance functioning includes that it was conducted at a single site; future multi-center of prefrontal cortical brain regions by use of a metacognitive trials are indicated to adequately investigate the effectiveness of exercise, or improve attention inhibition deficits in dysphoric EFMT as an intervention for MDD. The lack of a matched passive individuals using a working memory training exercise. A recent comparison group means that the possibility that the effects meta-analysis of computerized cognitive training (CCT) interven- observed are due to non-specific factors shared by both groups, tion studies for depression suggests small to large effects for CCT including the behavior activation involved in study participation, on depressed mood, daily functioning, and certain cognitive can not be ruled out. In addition, the data collected in the present domains (attention, working memory, and global functioning), trial do not allow for investigation of the mechanism of action for suggesting that CCT may be an effective treatment option for this intervention. We hypothesize that the training confers adult depression. However, the mechanism by which this occurs functional connectivity changes between the DLPFC and limbic is unclear due in part to treatments administered alongside CCT in system, and that these changes are associated with symptom several of the studies (participants were also treated with response. fMRI studies investigating this hypothesis are currently antidepressants, psychotherapy, or transcranial direct current underway. Lastly, the middling ratings observed for acceptability stimulation during these trials). Further development and of a cognitive training intervention as a treatment for MDD, which investigation is especially warranted as these types of exercises did not change after study completion despite significant can be delivered remotely over a computer or smart device symptom improvement in the EFMT group, may be seen as a (phone, tablet) at the time and place of one’s choosing, and can potential limitation to the dissemination of these interventions in therefore help to address the barrier to accessible and effective the future. However, the acceptability and perceived helpfulness interventions that patients with depression too often encounter. measures employed in this study may not have been sensitive or Additionally, the combination of cognitive training interventions sophisticated enough to elucidate actionable data regarding with traditional antidepressant medication treatment warrants EFMT’s acceptability and perceived helpfulness. Nonetheless, investigation, as there could be significant synergy between these patients’ motivation to adhere to a treatment regimen that is modes of treatment that could confer greater benefit to MDD rated as “somewhat acceptable” and implemented remotely patients than either treatment alone. Studies of cognitive training should be considered with caution when these interventions are interventions in patients with only partial response to antide- disseminated on a large scale. Commercial efforts to enhance the pressant medication treatment are also warranted to assess acceptability and helpfulness of this type of intervention, for whether this could bring about full remission. In 2017 Pear example by enhancing user engagement and other associated Therapeutics had the first software-as-a-medical-device (SaMD) features, will be a focus of EFMT development in the future. approved by the Food and Drug Administration as a class II In summary, cognitive–emotional training exercises hold the medical device for treatment of a psychiatric disease. Other promise of providing a novel paradigm for the treatment of MDD companies such as Akili Interactive Labs have been working to symptoms. A second study has now shown superior MDD develop SaMD to treat ADHD and other conditions. Thus, the symptom improvement associated with a cognitive–emotional stage has been set for subsequent SaMD devices to be developed, training intervention compared to an active control condition. The evaluated and approved for the treatment of psychiatric disorders magnitude of the effect was similar to a previously published pilot including MDD. study, and the specific symptoms that appear to respond to the There are strengths and limitations associated with this study. intervention are consistent with the hypothesized mechanism of Strengths of the study include the careful clinical characterization action. Further study is warranted, in large samples and multiple of the participant sample, randomization and blinding, and the sites, to confirm the effects of EFMT training, on specific symptom experience of the investigators having previously completed a effects, and to explore mechanisms of action via neuroimaging pilot study with the same methods. Finally, this study provides the brain changes that are associated with EFMT. support for the efficacy of an intervention that has the potential to be disseminated on a large scale by leveraging electronic or digital METHODS means (e.g., web-based delivery; inclusion in a digital therapeutic platform), and ultimately reaching MDD patients that might not Participants otherwise be able to access effective treatment. However, Participants, recruited through advertisements in newspapers and online cognitive training studies have some serious limitations that have for depression research studies, were between the ages of 18–55 and been highlighted previously in the literature. These include evaluated by trained clinicians using the Structured Clinical Interview for npj Digital Medicine (2018) 21 Published in partnership with the Scripps Translational Science Institute A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. 13 15 DSM-IV-TR Axis I Disorders (SCID ). Participants met criteria for MDD Intelligence Scale-3rd Edition. MDD symptoms were evaluated using the diagnosis with a current episode. They could have other Axis I diagnoses clinician-rated Ham-D, and the self-report measure Beck Depression (excluding psychotic disorders, bipolar disorders and substance abuse or Inventory (BDI-II ). Acceptability of a cognitive training intervention as a dependence within the past 6 months) as long as their MDD diagnosis was treatment for MDD was assessed using a 5-point Likert-scale (“Using the primary. MDD severity, as measured by the Hamilton Depression Rating scale below, please circle the number corresponding to how acceptable Scale—17-item version (Ham-D, ) had to be at least “moderate” (Ham-D ≥ cognitive training would be to you, for the treatment of your depression 16). Participants with very severe MDD (Ham-D >27) were excluded and symptoms, if cognitive training were a treatment option in the future.” 1: referred for treatment due to safety concerns surrounding participation in not at all acceptable; 3: somewhat acceptable; 5: very acceptable). a placebo-controlled study and in which the treatment intervention had Participants were randomly assigned to the EFMT or CT groups by a not yet been validated. Participants who had taken any antidepressant research coordinator using a pre-determined randomization sequence for group assignment, with balancing in blocks of six participants in the medications during their current MDD episode as well as those with a history of treatment non-response (2+ failures of an adequate trial of a sequence. Investigators and blinded study raters were kept blind to group standard antidepressant medication) were excluded from participation. assignment throughout the study. Participants were assigned to complete Cognitive–behavioral therapy attendance in the 6 weeks prior to, or at any 18 training sessions over 6 weeks (approximately 20–35 min each, three time during, the study, would also precipitate exclusion. Participants with times per week). Participants that failed to complete at least two sessions in any week, or that missed greater than three sessions during the course visual or motor impairments that were thought to interfere with of the study, were discontinued as per the study protocol. Weekly Ham-D performance on the computerized exercise were also excluded. Reading ability at the 8th grade or above was required for enrollment to ensure that assessments were conducted by PhD or MD-level clinicians who were blind participants could comprehend all study assessments and questionnaires to group assignment. Ham-D raters were extensively trained to administer that were written at-or-below 8th grade reading level. the assessment and demonstrated an ICC > 0.8 on two separate training The protocol and study procedures were approved by the Program for interviews. An outcome evaluation was conducted within 1 week of the Protection of Human Subjects at the Icahn School of Medicine at completing the training sessions, at which time the baseline assessments Mount Sinai (ISMMS) and were conducted in accordance with the were repeated. At the outcome evaluation, assessments of participants’ Declaration of Helsinki. After a pre-screening interview, eligible participants perceived acceptability of a cognitive-training intervention were again were informed about the study procedures and signed informed consent obtained, as were assessments of perceived helpfulness with improving to complete screening and baseline procedures. Participants were aware memory, improving attention and concentration, improving control over that the study would evaluate the effects of two different memory-training thoughts, and improving mood. Assessments were obtained using a 5- exercises on memory and MDD symptoms. They did not, however, know point Likert-scale (1: not acceptable; 3: somewhat acceptable; 5: very the specific differences between the cognitive–emotional and control acceptable). training (CT) paradigms, thereby maintaining the study blind. After completing the study, participants were debriefed, including a description Cognitive training exercises of the study blinding involved and the rationale. Participants were The EFMT is a combination of emotion identification and working memory reimbursed for each study session completed to compensate for time and tasks, designed to simultaneously engage the DLPFC and amygdala, which travel expenses. subserve cognitive control and emotion regulation impairments com- monly observed in MDD. To do so, EFMT combines working memory and Procedure facial affect identification tasks, which have been shown to elicit activity in 8 9 The study intervention was administered over 20 visits. At the first visit, the the DLPFC and amygdala, respectively. In this task participants must SCID and Ham-D were administered to confirm MDD diagnosis and identify the emotions they observe on a series of pictures of faces determine symptom severity. A subsequent baseline evaluation assessed presented one at a time on a computer screen for 1 s, followed by a reading level, attention and working memory, MDD symptom severity, and fixation cross for 1 s, and remember the sequence of emotions. Figure 2 participants’ perceived acceptability of a cognitive training exercise as an depicts an example stimuli sequence in the EFMT task. Using an N-back intervention for MDD. To measure reading ability, a Wide Range working memory training paradigm, after each face observed participants Achievement Test Reading test was administered. To assess attention are prompted to indicate whether the emotion on the face is the same as span and working memory, a composite score was calculated as the mean the emotion N faces prior. Each training session contains 15 blocks of the scaled score from the Digit-Span Forward (DSF), Digit-Span Backward (DSB) task during which the N level varies depending on the participant’s and Letter-Number Sequencing (LNS) subtests of the Wechsler Adult performance: the difficulty level increases or decreases across blocks as a Fig. 2 Example trial in the EFMT task. Participants observe an expression of facial affect shown on screen for 1 s and identify the emotion expressed. Participants then compare the observed emotion to the emotion observed N faces prior, in this case N = 2 faces prior. Copyright for the face images in the figure is owned by Adobe Systems Incorporated (http://stock.adobe.com) Published in partnership with the Scripps Translational Science Institute npj Digital Medicine (2018) 21 A randomized, controlled pilot trial of the Emotional Faces BM Iacoviello et al. participant’s accuracy improves or declines (respectively). The first training investigated differences between groups in perceived acceptability of the session begins with a difficulty level of N = 1 and the starting difficulty intervention at baseline, and perceived helpfulness of the intervention at level for subsequent sessions is determined by performance at the prior study outcome on: depressed mood, attention and concentration, session. The task is therefore tailored to a participant’s ability, ensuring a controlling thinking, and memory. These secondary analyses were consistent challenge. N-back working memory tasks that are progressively conducted using t-tests between groups. Dose effects were investigated challenging have been shown to improve working memory performance. by analyzing correlations between the number of training sessions EFMT utilizes a progressively challenging working memory paradigm and completed or the difficulty levels achieved, and Ham-D change. For these incorporates emotional stimuli throughout the task. The CT task is an exploratory analyses, p < .05 was utilized as the critical alpha to identify target symptoms of interest for future investigation of this intervention, active comparator to EFMT that consists of an identical cognitive-training recognizing the multiple testing might increase our type I error. paradigm, except that stimuli in the CT task are neutral shapes (circle, square, etc.). Because the CT task does not include emotional stimuli, no additional amygdala activation is induced. Thus the EFMT task involves Data availability exerting cognitive control over emotional information processing and the The data reported in this manuscript are available from the corresponding simultaneous activation of amygdala and DLPFC, whereas CT involves author to facilitate replication. Access to the EFMT software can be granted working memory and associated DLPFC activation only. The CT task in this to qualified researchers interested in viewing it for research purposes. study was the same that was utilized in the prior pilot study. Study design ACKNOWLEDGEMENTS The study was designed as a double-blind, randomized, controlled trial to The authors would like to acknowledge the study participants for their time and replicate the effects of a regimen of cognitive–emotional training sessions effort participating in this trial, and the research staff at the Mood and Anxiety on MDD symptoms and working memory in MDD participants. Random Disorders Program at Mount Sinai for their assistance conducting the study. This assignment to group (targeted to 1:1) utilized a randomization sequence, research was supported by National Institute of Mental Health (Bethesda, MD) grant generated by a researcher not affiliated with this study, including random #5K23MH099223 to Brian M. Iacoviello, Ph.D. The sponsor was not involved with the sequences in blocks of six participants to maintain group equivalence over conduct or analysis of the study or the writing of this report. time. The randomization scheme also accounted for completion of the training regimen, factoring this into the algorithm when assigning group AUTHOR CONTRIBUTIONS status to aim for equivalent proportions of regimen completers in both groups. This was done due to a priori concern about unequal dropouts in Drs. Iacoviello and Charney contributed to the conceptualization, design and conduct favor of the control condition if participants suspected that the working of the study, the writing and revising of the manuscript, final approval of the memory training was not effective in addressing MDD. Randomization was completed version, and are accountable for all aspects of the work. Dr. Iacoviello is implemented by a research coordinator at the initial cognitive training the guarantor for this study and manuscript. Drs. Iosifescu, Murrough and Collins visit, who generated a unique login and password for each participant. This contributed to the conduct of the study and writing of the manuscript and approve enabled participants to access the cognitive training exercise to which they of the completed version. Ms. Hoch and Ms. Huryk were research coordinators and had been assigned on a computer in the clinic at each visit. Research contributed to the conduct of the study and writing of the manuscript and approve coordinators were not involved in any clinical ratings. All other study team of the completed version. Dr. Cutter contributed to the data analysis and writing of members remained blind to group assignment. the manuscript and approves of the completed version. Data analytic strategy ADDITIONAL INFORMATION The effect of EFMT vs. CT training on MDD symptom severity was the Competing interests: Dr. Brian Iacoviello (the Principal Investigator) is an adjunct primary analysis of interest in this study. Primary analysis was conducted faculty member of the ISMMS and is employed full time as the Director of Scientific using a MMRM of all study participants randomized, with treatment group, Affairs of Click Therapeutics. Prior to joining Click Therapeutics, Dr. Iacoviello (in his role visit, the interaction of treatment group and visit (used as a categorical as a full time faculty member at ISMMS) and Dr. Dennis Charney (Dean of the ISMMS) variable to allow for characterizing the temporal effects without assuming co-developed EFMT as a computer-based brain training exercise for the treatment of linearity), and participant as a random effect, using an unstructured depression. Drs. Iacoviello and Charney are named co-inventors on a patent filed by covariance matrix. Targeted sample size of 50 was calculated based on a ISMMS to develop this therapeutic approach as a mobile/remote program (app). There power analysis for the above repeated measures analysis using G*Power is a licensing agreement between Mount Sinai and Click Therapeutics to develop this 3.1 software, estimating a medium effect size, α = .05, power= 0.8, two technology; if a commercial product is developed, Mount Sinai, Dr. Iacoviello, and Dr. groups, two measurements, correlation between measures= 0.5, and Charney would benefit financially. A management plan was enacted proactively by the nonsphericity correction = 1. Sensitivity analyses were conducted in a m- Financial Conflicts of Interest in Research (FCOIR) board at Mount Sinai for this study to ITT sample that included all participants who were randomized to either mitigate conflicts of interest. According to this management plan, an independent EFMT or CT, who completed at least one week of training and for whom at statistical analyst (Dr. Gary Cutter) was secured to conduct all data analyses least 1 Ham-D score was obtained after the baseline assessment, with last independently of the study investigators. Dr. Cutter conducted the analyses and observation carried forward (LOCF). This analysis included baseline Ham-D provided the write-up and interpretations of the results to be included in the score and the number of training sessions completed as covariates. LOCF manuscript, to remove any potential bias of conflicted investigators conducting was utilized as a conservative means of addressing any missing Ham-D analyses or interpreting results. Dr. Cutter oversees the drafting of all manuscripts data in the m-ITT analysis. Self-reported depression severity was also including these results and interpretations and approves any manuscript prior to investigated using repeated-measures analysis of BDI-II scores between submission. Dr. Iacoviello has served as a consultant to Fortress Biotech, Inc., and groups. All data were checked to confirm assumptions required for reports grant funding from the National Institutes of Health and the Brain and Behavior statistical analyses conducted (e.g., normality, equal variances). Research Foundation. In the past 3 years, Dr. Murrough has served as a consultant to Secondary analyses aimed to evaluate changes in working memory and Fortress Biotech, Inc., Novartis, Janssen Research and Development and Genentech and symptom-level effects on Ham-D items between groups. Repeated has received research support from Avanir Pharmaceuticals, Inc.; he is named on a measures analysis at two time points (baseline and outcome) was patent pending for neuropeptide Y as a treatment for mood and anxiety disorders and conducted to explore for group or group-by-time effects on working on a patent pending for the combination of ketamine and lithium for suicidal ideation memory (mean scaled score of WAIS subtests: DSF, DBS and LNS). and for relapse prevention following ketamine in patients with depression. He is an Symptom-level analysis was conducted to explore whether specific employee of the ISMMS and has received external funding from the National Institutes symptoms respond to the EFMT vs. CT training. We hypothesized that of Health, the Brain and Behavioral Research Foundation, the Doris Duke Charitable certain symptoms associated with cognitive control abnormalities for Foundation, and the American Foundation for Suicide Prevention. Dr. Collins performs emotion processing, such as sad mood, anxious mood, worry, and clinical trial assessments for ProPhase, LLC as an independent contractor. In the past rumination/dwelling, would be responsive to the EFMT intervention, five years, Dr. Iosifescu has consulted for Avanir, Axome, CNS Response, INSYS Therapeutics, Lundbeck, Otsuka, Servier, and Sunovion and he has received grant/ whereas other unrelated symptoms, such as sleep and appetite research support through the ISMMS from Alkermes, Astra Zeneca, Brainsway, disturbance, would not. To explore this, repeated measures analysis of Euthymics, Litecure, Neosync, Roche, Shire. Dr. Cutter, Ms. Hoch and Ms. Huryk symptom change from baseline to outcome was conducted to investigate declares no competing interests. group-by-time interactions in all 17 Ham-D items. 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npj Digital MedicineSpringer Journals

Published: Jun 6, 2018

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