Prior Expectations of Volatility Following Psychotherapy for Delusions: A Randomized Clinical Trial.

Importance: Persecutory delusions are common, distressing, and difficult to treat. Testing computational neuroscience models of delusions can identify new therapeutic targets. Objective: To determine whether change in delusion severity is associated with a corresponding change in volatility priors and brain activation estimated during a belief updating task. Design, Setting, and Participants: This randomized clinical trial was conducted from April 9, 2021, to December 5, 2023, within the Vanderbilt University Medical Center Psychiatric Hospital and at a community mental health center in Nashville, Tennessee. Participants were adults (aged between 18 and 65 years) with schizophrenia spectrum or delusional disorder and an active, persistent (≥3 months) persecutory delusion with strong conviction (>50%). Participants were randomly assigned 1:1 to either cognitive behavioral therapy for psychosis (CBTp)-based intervention or befriending therapy. Intention-to-treat analysis was performed from June 1 to October 31, 2024. Intervention: The CBTp was a manualized intervention targeting persecutory delusions. The befriending therapy involved engaging in conversations and activities focused on neutral topics. Both interventions were provided in person, lasted for 8 weeks, and included standard care. Standard care consisted of medication management and ancillary services. Main Outcomes and Measures: Primary outcomes were volatility priors (ie, prior expectations of volatility) derived from a 3-option probabilistic reversal learning task; persecutory delusion severity measured by the Psychotic Symptom Rating Scales (PSYRATS delusion subscale; score range: 0-16, with the highest score indicating severe preoccupation, distress, conviction, and functioning impact); and brain activation in the striatum and prefrontal cortex measured by blood oxygenation level-dependent signal change. Associations between volatility priors, clinical improvement, and change in neural activation were examined. Results: Sixty-two participants (median [range] age, 31 [19-63] years; 38 males [61%]) were randomly assigned to the CBTp (n = 32) or befriending therapy (n = 30) arms. A subgroup of 35 participants (57%) completed functional magnetic resonance imaging. Volatility priors decreased following treatment (F1,112 = 7.7 [P = .006]; Cohen d = 0.52 [95% CI, 0.15-0.90]), as did delusion severity (F1,112 = 59.7 [P < .001]; Cohen d = 1.50 [95% CI, 1.00-1.90]), across both groups. The decrease in volatility priors was not associated with clinical improvement in PSYRATS scores (F1,102.8 = 1.8 [P = .18]; Cohen d = 0.26 [95% CI, -0.12 to 0.65]). Activation in the caudate and prefrontal cortex significantly decreased following treatment. Decreased caudate activation was associated with decreased volatility priors (F1,58.3 = 16.6 [P < .001]; Cohen d = 1.07 [95% CI, 0.51-1.61]) but not with PSYRATS total scores. Associations remained significant after controlling for antipsychotic medication (F1,53 = 13.77; P < .001). Conclusions and Relevance: This randomized clinical trial found that elevated volatility priors and associated activation in the caudate nucleus were amenable to change. Volatility priors could be a potential target for intervention in psychosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04748679.