Journal Club Presentation

1. Journal Club Presentation
Presenter : Dr. Saran A K
Preceptor : Dr Yogesh Kumar
12 January 2024
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3. Overview
1. Introduction
2. Aim and Objectives
3. Methodology
4. Statistical Analysis
5. Results
6. Discussion
7. Conclusion
Critical Analysis
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4. 1. Introduction
• Depression is a chronic, recurring, and progressive disorder
affecting 300-350 million people worldwide.
• Leading cause of disability, and is a major contributor to the
overall global burden of disease (WHO Fact Sheet No. 369 -
Reviewed April 2016)
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5. Diagnostic and Statistical Manual of Mental Disorders,
5th Edition (DSM-5) - Diagnostic Criteria MDD
• Persistently low or depressed mood
• Anhedonia
• Feelings of guilt or worthlessness
• Lack of energy
• Poor concentration or indecisiveness
• Appetite changes
• Psychomotor retardation or agitation
• Sleep disturbances
• Suicidal thoughts
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6. • Poorer neurophysiological performance on tests of memory,
attention and executive functions in patients with depression.
• Can affect their psychosocial functioning.
• Cognitive impairment can persist even during periods of symptom
remission after anti-depressant therapy.
• The treatment options for providing benefit to patients with MDD
having cognitive deficits are limited.1
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7. Available treatment options for Major Depressive Disorder
and their effect on cognitive impairment
Pharmacological Non Pharmacological
• Most pharmacological treatment provide
little to no benefit. 1
• Vortioxetine - objective cognitive
assessment showed positive effect on
processing speed.
• Cognitive Behavioral Therapy
• Problem Solving Therapy
• Predominantly affective symptoms.
• Limitation : difficulty of access
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8. • Siegal et.al.2 reported that a metacognitive attention task aimed at
enhancing prefrontal regions resulted in improvement of cognitive
control and affective symptoms.
• Mobile technologies that provide home based personalized
cognitive treatment may be particularly useful in overcoming this
constraint.
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9. Pathophysiology – Cognitive deficits in MDD
• Associated with the inefficient functioning of the fronto-
parietal cognitive control networks. 3
• These have high degree of connectivity across brain regions and
can rapidly modify functional connections in response to changing
internal and environmental demands.
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10. Malfunction Regions involved Function
Hypoconnectivity Within the frontoparietal network
(FN)
A set of regions involved in
cognitive control of attention and
emotion regulation
Hypoconnectivity Between frontoparietal systems and
parietal regions of the dorsal
attention network (DAN)
Involved in attending to the
external environment.
Hyperconnectivity Within the default network (DN) A network believed to support
internally oriented and self-
referential thought
Hyperconnectivity Between frontoparietal control
systems and regions of the default
network
Kaiser RH, Andrews-Hanna JR, Wager TD, et al: Large-scale network dysfunction in major depressive disorder:
a meta-analysis of resting-state functional connectivity. JAMA Psychiatry 2015; 72: 603–611
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11. Hasenkamp, W. (2014). Using first-person reports during meditation to investigate basic
cognitive experience. In S. Schmidt & H. Walach (Eds.), Meditation — Neuroscientific
approaches and philosophical implications (pp. 75–93). Springer International Publishing.
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12. AKL-T03 (Developed by Akili Interactive)
• It is an investigational digital therapeutic design to activate the
frontoparietal networks of the brain to improve attention and
related attentional control processes.
• Through a video game based interface, displaying two tasks that
are to be done in parallel.
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13. Users are presented
1. Sensory motor navigation task in which they must
continuously adjust their location to interact with or avoid
positional targets.
2. A perceptual discrimination targeting task in which they must
respond to the designated stimulus targets and ignore the
stimulus distractors (similar to a go/no-go task)
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14. Kollins SH, DeLoss DJ, Cañadas E, Lutz J, Findling RL, Keefe RSE, Epstein JN, Cutler AJ, Faraone SV. A
novel digital intervention for actively reducing severity of paediatric ADHD (STARS-ADHD): a
randomised controlled trial. Lancet Digit Health. 2020 Apr;2(4)
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15. 2. Aim
To evaluate whether AKL-T03 would improve cognitive
performance in adults with depression and demonstrated
cognitive impairment when compared with an educational styled
digital control intervention.
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16. 3. Methodology
• Randomized, Double blind, Parallel group, 6 week-controlled
trial.
• Trial was conducted at four sites in the United States from October
16, 2017, to December 14, 2018 after appropriate ethics clearance.
• Written informed consent was obtained from all participants included
in the study.
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17. Sample size - 40 participants per intervention (would be sufficient
to detect an effect size of 0.70 with >90% confidence and an alpha
criterion of 0.05 on the primary outcome)
a. Study Participants
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18. Inclusion Criteria
 Age 25-55 years of age
 Confirmed diagnosis of MDD (DSM-5 criteria)
 Confirmed via Mini International Neuropsychiatric Interview version 7.0.2
 Hamilton Depression Rating Scale 14-22
 Symbol Coding T Score less than or equal to 50
 Antidepressant medication for ≥ 8 weeks prior to screening and baseline,
with a stable dosage for ≥4 weeks prior to baseline.
Exclusion criteria
o Significant comorbid psychiatric diagnoses
o Active suicide risk or ideation as measured by the Columbia-Suicide
Severity Rating Scale.
b.
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19. c. Randomization and Blinding
• Participants were randomized in a 1:1 ratio to receive AKLT03 or a
digital control.
• Randomization scheme –Software generated pseudo random
numbers.
• Unblinded staff at clinical sites enrolled patients, obtained the
randomized intervention, and trained patients on the assigned
device.
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20. To minimize bias
1. Participants were informed that the study was evaluating the effect of
two different investigational interventions.
2. Expectancy analysis showed comparable expectation of benefit
from both.
3. Participants were discouraged from discussing their randomized
intervention with anyone other than an unblinded study coordinator.
4. Investigators and other blinded site staff were restricted from
access to source documents and case report forms.
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21. d. Intervention Training and Adherence
• Both the AKL-T03 and control conditions were administered using
Apple iPad mini 2 tablets.
• After randomization, eligible participants were trained in the use
of their intervention by unblinded study staff – 10 min.
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22. • Participants assigned to AKL-T03 were instructed to complete
five sessions at least 5 days per week for 6 weeks, for a total
of approximately 25 minutes of game-play per day.
• The software automatically locked after the five sessions were
completed, to preclude excessive use of the intervention.
• Same duration for control intervention.
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23. Adherence was ensured by
1. Monitored remotely by unblinded study coordinators using an
electronic dashboard created by Akili.
2. Devices generated automatic reminders - 24 hours.
3. Unblinded study coordinators notified participants and
reminded them if they had not performed over a 48-hour
period.
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24. e. Digital Interventions
1. AKL-T03
• Investigational digital therapeutic
• Akili’s proprietary algorithm - Selective Stimulus Management
Engine (SSME)
• Designed to train interference management at an adaptive
and personalized degree of difficulty.
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25. 2. Control intervention
• An engagement-, expectancy-, and time-on-task-matched
software program – Video Game
• To connect letters in a grid on the screen horizontally, vertically,
or diagonally to form as many words of at least two letters as
possible during a 25-minute period.
• Points awarded in the game are based on increasing difficulty.
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26. f. Outcome Measures
• The priori primary outcome was change from baseline in
cognitive performance between the two groups.
• It is measured by change in sustained attention using the Test of
Variables of Attention (T.O.V.A)
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27. T.O.V.A (Test of Variables of Attention)
1. A type of FDA cleared Continuous Performance Test
2. Tool for assessing sustained attention and inhibitory control
3. 21.6 min long – simple yet boring computer game
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29. T.O.V.A (Test of Variables of Attention)
1. A type of FDA cleared Continuous Performance Test
2. Tool for assessing sustained attention and inhibitory control
3. 21.6 min long – simple yet boring computer game
4. Variables
• Response Time Variability (ms)
• Response Time (ms)
• Commission Errors (%)
• Omission Errors (%)
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30. TOVA H1
• First half of TOVA – Infrequent/Vigilance Mode
• Target appear randomly and infrequently
• With a target: non target ratio of 1:3.5
• Easily bored (low arousal) persons do poorly during this half (10.8
min)
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31. Change from baseline scores from the first half of the TOVA
between day 0 (baseline) and day 42 (study exit) were compared
between the two intervention groups.
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32. Secondary outcome measures included the
1. Symbol coding test from the Brief Assessment of Cognition
2. Trail Making Test parts A and B (Trails A and B)
3. Letter number sequencing task
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33. Symbol Coding Test
• Subjects assign numbers to non meaningful
symbols with the use of the key provided.
• Outcome Measure : No of items completed
correctly in 90 s
• Speed of processing
Trail Making Test A and B
• Complex Attention
Letter Number Sequencing Task
• Working Memory
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34. • Post hoc analysis was performed to evaluate the overall
impact on cognition.
• Composite score a simple average of the z-scores from each
cognitive test.
• In exploratory analyses, changes in mood, subjective
cognitive symptoms, and quality of life was assessed.
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35. After each intervention, participants completed the
1. HAM-D
2. Patient Health Questionnaire–9 (PHQ-9)
3. Cognitive and Physical Functioning Questionnaire (CPFQ)
4. Work and Social Adjustment Scale (WSAS), and
5. Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)
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38. Cognitive and Physical Functioning Questionnaire (CPFQ)
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39. Work and Social Adjustment Scale (WSAS) Quality of Life Enjoyment and Satisfaction Questionnaire
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40. 4. Statistical Analysis
• Prespecified statistical analysis plan.
• Intent-to-treat analysis - to include each participant who was
randomized to an intervention and began the at-home portion of
treatment.
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41. • Between-group statistical tests were conducted on each
metric using an analysis of covariance (ANCOVA)
• On the difference between post- treatment (day 42) and
pretreatment (day 0) scores
• With age, sex, and the baseline score of the corresponding
metric included as covariates.
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42. • Statistical comparisons for secondary endpoints were adjusted for
multiple comparisons using the Hochberg step-up method.
• Effect sizes (partial eta-squared) were interpreted as small=0.01,
medium=0.06, and large=0.14.
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43. Results
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44. Adherence
• There was no statistical difference between the two groups in
the proportion of participants who adhered to the ≥50% of the
recommended sessions.
• However, total number of sessions played in each group –
statistically significant difference, control group being more.
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F=8.550, df=69,
partial η2 =0.11 medium

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48. Safety
• Two (5.5%) of the 37 patients in the AKL –T03 group reported
an intervention related adverse event (headache).
• There were no serious intervention related adverse event in
either group.
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49. 6. Discussion
• AKL-T03, significantly improved performance on the primary outcome
measure of sustained attention compared with the control.
• Post hoc analysis indicated a significant difference between interventions
on composite measure of cognition (AKL-T03)
• Both interventions were well tolerated.
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50. • AKL-T03 shows promise for reducing cognitive
impairment during a current episode of depression.
• Further research looking at longitudinal data and durability of effect is
needed to confirm the hypothesis.
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51. No differences between AKL-T03 and the control intervention on
secondary and exploratory measures.
1. Both interventions required continued perseverance through
failure. May have trained coping and reappraisals skills or
even increased the sense of self-efficacy and mastery.
2. Expectations of efficacy have been shown to moderate
intervention effects. May partially explain improvement in both
groups.
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52. Statistically significant difference in total number of sessions
played in each group maybe due to the active engagement
required to complete AKL-T03 compared to the self paced
control.
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53. 7. Conclusion
Limitations Strengths
1. Randomization - HAM-D scores at
baseline, the control group being
more depressed.
2. Recruitment from clinical research
centers with specific inclusion and
exclusion criteria, which may limit
the generalizability.
Minimization of potential biases and
differences in expectation of benefit
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54. Future directions
1. Include the effectiveness of a sham control to reduce perceived
subjective benefit.
2. Development of a treatment condition inherently more enjoyable
for this population.
3. An examination of the durability of the effect of treatment beyond
the 6-week treatment period.
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55. In summary,
• AKL-T03 was found to have significant improvement in
primary objective measure of cognition in MDD patients.
• The intervention is a well tolerated intervention and its digital
nature could increase access for patients.
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56. Critical Analysis
Serial
No
Questions Yes/No
1 Achieved Aim Yes
2 Study design appropriate for stated aim Yes
3 Was consent taken Yes
4 Were objectives defined achieved Yes
5 Was measures taken to address loss of data Not specified
6 Were outcomes measured in a reliable way Yes
7 Was sample size appropriate/adequate/justified Yes
8 Was appropriate statistical analysis used/explained Yes
9 Were results properly presented/can be generalized Yes/No
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57. References
1. Keefe RSE, McClintock SM, Roth RM, et al: Cognitive effects of pharmacotherapy for
major depressive disorder: a systematic review. J Clin Psychiatry 2014; 75:864–876
2. Siegle GJ, Ghinassi F, Thase ME: Neurobehavioral therapies in the 21st century:
summary of an emerging field and an extended example of cognitive control training
for depression. Cogn Ther Res 2007; 31:235–262
3. Kaiser RH, Andrews-Hanna JR, Wager TD, et al: Large-scale network dysfunction in
major depressive disorder: a meta-analysis of resting-state functional connectivity.
JAMA Psychiatry 2015; 72: 603–611
4. Leark RA, Dupuy TR, Greenberg LM, et al: TOVA Professional Manual: Test of Variables
of Attention Continuous Performance Test, 2016.
5. Atkins AS, Tseng T, Vaughan A, et al: Validation of the tablet administered Brief
Assessment of Cognition (BAC App). Schizophr Res 2017; 181:100–106
6. Gold JM, Carpenter C, Randolph C, et al: Auditory working memory and Wisconsin
Card Sorting Test performance in schizophrenia. Arch Gen Psychiatry 1997; 54:159–165
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58. THANK YOU !
saran.adhoc@gmail.com
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