Esketamine With or Without Integration Therapy for Treatment-Resistant Depression

This Phase IV, randomised, single-masked, parallel trial (n=20) will assess whether adding brief, structured preparation and integration therapy to FDA‑approved intranasal esketamine (Spravato®) improves depressive symptoms in adults aged 21–65 with treatment-resistant depression; the primary outcome is change in Montgomery‑Åsberg Depression Rating Scale (MADRS) score from baseline to the end of acute treatment at 8 weeks. Participants will be randomised to receive intranasal esketamine administered under medical supervision per FDA guidelines (twice weekly in weeks 1–4, then weekly or biweekly in weeks 5–8 based on clinical response) with standard post-dose monitoring of at least two hours. The experimental arm also receives brief, manualised preparation and integration sessions delivered by trained clinicians before and after each dosing session; the comparator arm receives esketamine with standard clinical monitoring and psychiatric care only. Key secondary measures include emotional regulation, therapeutic alliance, treatment acceptability and dissociative experiences, with exploratory assessments of participant engagement, perceived coherence of experience and satisfaction. Eligibility includes adults 21–65 with major depressive disorder meeting treatment‑resistance criteria (failure of ≥2 antidepressants) and baseline MADRS ≥30; the study is single-site and lasts approximately 8 weeks per participant.