SYNERGISTIC BIOBEHAVIORAL TREATMENTS TO REDUCE DEPRESSION AND COMPULSIVITY

Approximately 40-60% of psychiatric patients exhibit treatment resistance to first-line interventions. This is associated with high burden on the health care system and longer suffering for the patients. As such, novel psychiatric interventions that are fast-acting and rooted in disorder pathophysiology are needed. One novel approach is to combine rapid-onset, plasticity enhancing biological interventions with digital behavioral trainings to achieve a synergistic effect. This talk will outline examples of our recent and ongoing work aimed at developing and testing such synergistic treatment combinations in refractory clinical populations. The first example explores adding a brief cognitive training (automated self-association training; ASAT), designed to mechanistically target low selfworth, to enhance the therapeutic effects of ketamine. In a published study, 154 adults with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active ASAT; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One day after a single infusion of intravenous ketamine (0.5 mg/kg over 40 minutes) or inert placebo (saline), active ASAT—targeting self-worth through automated “evaluative conditioning” training delivered by computer—or sham ASAT (consisting of identical computer tasks that included no positive or self-referential stimuli) was given, delivered twice daily over 4 consecutive days (eight total sessions, ≤20 minutes per session). Results of this trial showed that depression scores in the ketamine+ASAT group remained significantly and stably low relative to those of the saline+ASAT group for a total of 90 days (p < 0.05). By contrast, depression improvements following ketamine+sham treatment were far more transient, remaining significantly improved for < 12 days. These results suggested that after priming the brain with ketamine, training positive self-associations could provide an efficient, low-cost, portable, noninvasive, and highly dissemination-ready strategy for leveraging and extending ketamine’s rapid antidepressant effects. Several ongoing lines of work seek to expand on these promising initial findings, including studies testing the effectiveness of this treatment pairing in real-world populations and settings (e.g., among inpatients hospitalized following a suicide attempt; or when embedding ASAT into real-world specialty ketamine clinics); and a randomized controlled trial pairing ASAT with a novel, investigational NMDA compound in lieu of ketamine. In another line of research focused on compulsive behaviors, we have built directly on optogenetic studies in mice, using non-invasive brain stimulation techniques (Theta Burst Stimulation), paired with computer-based cognitive training, as a novel combination treatment approach. Our first published study showed a beneficial effect of continuous Theta Burst Stimulation (cTBS) followed by a computerized ‘habit override’ task on idiographic compulsive behaviors measured in the lab among 70 patients, with improvements persisting for 1 week following our ultra brief (single session) combination treatment (p’s < 0.05). This talk will include results of ongoing work in a larger cohort of > 200 patients which leveraged a fully crossed (2x2) factorial design to compare outcomes following a single session of either cTBS or sham TBS paired with either our computer-based ‘habit override’ task or a sham variant of the training.

References

Price RB, Wallace ML, Mathew SJ, Howland RH. One-year outcomes following intravenous ketamine plus digital training among patients with treatmentresistant depression: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2023;6(5):e2312434. Price RB, Gillan CM, Hanlon C, et al. Effect of experimental manipulation of the orbitofrontal cortex on short-term markers of compulsive behavior: a theta burst stimulation study. Am J Psychiatry. 2021;178(5):459-468.