Abstract

Cognitive Control Predicts Alleviation of OCD Symptoms by Ketamine

Van Roessel P, Asgari S, Jo B, Williams L, Rodriguez C
61st Annual Meeting of the American College of Neuropsychopharmacology. 2022.

Abstract

Background: Obsessive-compulsive disorder (OCD) is a common and impairing illness. First-line pharmacologic treatment with serotonin reuptake inhibitors helps most patients, yet benefit may take weeks to accrue, and many patients don’t achieve adequate response. Ketamine and other glutamatergic interventions offer great promise as alternative and more rapidly acting treatments. The growing diversity of treatment options, however, increases the need for data to support goals of precision medicine, matching the right treatment to the right patient.

OCD has been associated with alterations in both cognitive and affective processing, assessed using both neuroimaging and behavioral tests. These alterations include deficits in cognitive control and a valence bias reflected in increased threat responsivity and decreased reward responsivity. In secondary analysis of data from a randomized, active-placebo-controlled trial of intravenous ketamine for treatment of OCD, we explored whether validated behavioral measures of cognitive control and valence processing have utility as predictive biomarkers or as clinically meaningful targets of treatment.

Methods: Data were analyzed from N = 45 unmedicated individuals with DSM-5 obsessive-compulsive disorder who participated in a randomized controlled trial exploring the mechanisms of ketamine as a rapid-acting treatment. Participants were randomized 2:1 to receive a single 40 min intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg). Clinical OCD symptoms were assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, at post-infusion Day 1, and at post-infusion Day 7. Participants additionally completed a validated, computer-based neurocognitive test battery (‘WebNeuro’) one day prior to and one day after infusion. Testing included measures of cognitive control (performance on Stroop color-word interference and Go/No-Go tests) and of valence processing (performance on tests of emotion identification and of implicit priming by facial expressions of fear and happiness), quantified as z-scores relative to age-, sex-, and years of education-matched healthy norms. We explored whether baseline performance on cognitive control and valence processing tests moderate symptom alleviation in response to ketamine vs midazolam, and whether pre-post change in test performance is associated with symptom alleviation. MacArthur criteria were used to define potential moderator and mediator variables.

Results: Treatment had a significant effect on OCD symptoms at Day 1 (β = -7.894, p = .004, representing a nearly 8 point mean difference in Y-BOCS change for ketamine vs midazolam) and at Day 7 (β = -6.048, p = .005). In moderation analyses, the interaction between a measure of Stroop interference by response speed and treatment had a significant effect on the change in Y-BOCS at Day 1 (β = -4.0618, Cohen’s f2 = 0.14, p = .04), but not at Day 7. That is, the effect of treatment at Day 1 was considerably larger for those with faster normalized performance on a color-naming relative to color word-reading task. Performance on the Go/No-Go and valence processing tests did not moderate the treatment effect on outcomes at Day 1 or Day 7. In mediation analyses, treatment did not have a significant effect on pre-post change in cognitive control or valence processing; these measures did not fulfill criteria as potential mediators of Y-BOCS change. Pre-post change in Stroop interference by response speed did, however, correlate with change in Y-BOCS at Day 1 (r = 0.36, p = .03).

Conclusions: Ketamine robustly reduced symptoms of OCD at Day 1 and Day 7 post-infusion, compared to the active-placebo midazolam. Our data suggest that the short-term effect of ketamine vs midazolam on Y-BOCS may be influenced by baseline inhibitory cognitive control, such that greater control (less Stroop interference for color-naming) predicted greater benefit from ketamine vs midazolam. Our data may accord with published findings suggesting that Stroop task performance moderates the effectiveness of other OCD treatment modalities (e.g., cognitive behavioral therapy vs fluoxetine).