The Combination of Oxytocin with Mindfulness-Based Group Therapy Reduces Negative Symptoms in Schizophrenia Spectrum Disorders: A Triple-Blind, Placebo-Controlled, Randomized, Controlled Clinical Pilot Trial (OXYMIND)

Background Negative symptoms in schizophrenia spectrum disorders (SSD) remain insufficiently treated and require novel therapeutic approaches. Oxytocin may improve negative symptoms, although its effects appear highly context-dependent according to the social salience hypothesis. We conducted a randomized, triple-blind, placebo-controlled pilot study combining intranasal oxytocin with mindfulness-based group therapy (MBGT), hypothesizing that the positive social context of MBGT would enhance oxytocin-related effects. Methods 47 participants with SSD (34% female) were randomized to receive either 24 IU oxytocin (MBGT+OXT; n = 26) or placebo (MBGT+PLA; n = 21) before four MBGT sessions. Primary outcome was negative symptoms assessed with the Positive and Negative Syndrome Scale negative subscale (PANSS-N) at post-intervention and 4-week follow-up. Secondary outcomes included the Brief Negative Symptom Scale (BNSS), Self-Evaluation of Negative Symptoms Scale (SNS), and additional clinical measures. Linear mixed models estimated within- and between-group effects. Results Overall dropout rate was 14.89%, with one dropout potentially treatment-related. Blinding was successful. Participants completed 95.63% of sessions. Only the MBGT+OXT group showed significant improvements in PANSS-N from baseline to post-intervention (d = -0.74) and follow-up (d = -0.77), with a small between-group effect at follow-up (d = 0.39). BNSS total improved significantly only in the MBGT+OXT group from baseline to post-intervention (d = -0.88) and follow-up (d = -0.91), with between-group effects favoring MBGT+OXT at follow-up (d = -0.38). No serious adverse events occurred. Conclusions These findings suggest, oxytocin combined with MBGT may improve negative symptoms in SSD and support further large-scale trials. Clinical Trials Registration: https://clinicaltrials.gov/study/NCT06136390, Registration number: NCT06136390