1/2 A Brief Automated Neurocognitive Training to Enhance the Real-World Impact of Ketamine's Rapid Antidepressant Effect

Project Summary. Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse symptoms by rapidly enhancing neuroplasticity. Although community-based ketamine clinics have proliferated in the US and

worldwide in recent years, a significant barrier to clinical adoption is the lack of evidence-based strategies to enhance the

durability of ketamine’s effects, creating substantial barriers to access and longer-term maintenance of gains. In a previous efficacy study among depressed outpatients, we posited that ketamine would rapidly increase plasticity within the information processing domain, allowing for rigid, negative biases in cognition (specifically, negative self-

representations) to be rapidly made malleable. We further expected these neurocognitive changes would provide a clinical window of opportunity in which to introduce digital cognitive training techniques, which would consolidate adaptive

forms of cognitive processing (specifically, positive implicit representations of self) while neuroplasticity remains high. By instantiating adaptive forms of processing after first 'priming' the brain with ketamine, we developed a novel

synergistic treatment approach (ketamine + Automated Self Association Training; ‘ASAT’) that extended the acute effects of a single ketamine infusion far beyond its typical 7-14 day window, showing statistically significant effects on

depression [relative to saline paired with ASAT (no-drug control arm)] that persisted for 3 months after a single infusion of ketamine—an approximately 9-fold increase in durability of effect relative to ketamine paired with sham digital

training (no-training control arm). In the current multi-site ‘Hybrid Type 1’ effectiveness-implementation randomized

controlled trial, 600 ketamine-seeking depressed outpatients receiving intravenous ketamine ‘induction’ (6-12 serial

infusions over 3-8 weeks) at one of 8 well-established real-world clinics throughout the US will be randomized to receive

either adjunctive active ASAT or sham ASAT. After an initial in-clinic ‘onboarding’ session, patients will self-administer

ASAT (or sham) at home, in three ‘bursts’ (each ‘burst’ = eight ~15min sessions delivered 2x/day over 4 consecutive

days), sequenced to begin just after (1) the first ketamine induction dose (Aim 1), (2) the last ketamine induction dose (Aim 2), and (3) 3 months after the first dose (Exploratory Aim). Patients will complete depression severity measures and performance-based measures of cognitive target engagement (implicit self-associations), acutely and across a 12-

month naturalistic follow-up, enabling comprehensive assessment of ASAT’s potential enhancing (Aim 1) and extending (Aim 2) effects on depression relief. Validated data-driven ‘combined moderator’ methods will be used to identify baseline patient profiles (Aim 3) that predict favorable response to ketamine (all patients) and specific response to

ketamine+ASAT (relative to ketamine+sham). Comprehensive, mixed methods feasibility, acceptability, appropriateness, and cost data will be captured from both patients and providers (Aim 4). This study will provide novel effectiveness, feasibility/acceptability, and long-term (12-month), systematic follow-up data among heterogeneous real-world patients

seeking ketamine treatment under real-world conditions in the community, and will synergistically combine ketamine with a portable digital intervention in an effort to exploit and extend ketamine's rapid antidepressant effects.