¹Institute of Psychiatry, Psychology and Neuroscience- King's College London, Psychological Medicine, London, United Kingdom

Background: Ketamine has rapid antidepressant and anti-suicidal effects in treatment-resistant depression (TRD), but optimal implementation, route selection, and longer-term maintenance strategies remain areas of active clinical development. At the Maudsley Advanced Treatment Service (MATS), ketamine and esketamine are delivered within a specialist governance framework, using multiple formulations/routes to individualise treatment for complex, difficult-to-treat affective disorders.

Aims & Objectives: 

1. To describe the MATS clinical model and governance for ketamine/esketamine prescribing and administration in TRD and TR Bipolar Depression.
2. To summarise real-world service experience across ketamine routes (intranasal esketamine; sublingual/oral racemic ketamine; subcutaneous racemic ketamine and s-ketamine where indicated).
3. To highlight MATS-linked clinical research activity in oral ketamine development (KET-IR) and its relevance for scalable hospital-to-home pathways.

Method: Service evaluation narrative plus clinical trajectories from MATS ketamine since service inception. Patients referred with TRD or bipolar depression are assessed by the MDT; decisions regarding formulation/route and dosing are made collaboratively with patients and families, supported by controlled-drug governance, monitoring protocols, and informed consent for off-label use. MATS research activity is summarised using findings from a randomised, double-blind, placebo-controlled Phase 1 study of immediate-release oral ketamine (KET-IR) in healthy volunteers and protocol for Phase 2 in TRD and Bipolar Depression type II

Results: Since 2019, 42 patients (mean age 49.2 years, SD 10.8) have received ketamine-based interventions at MATS; most had TRD (76.2%, n=32) with a minority with bipolar depression (23.8%, n=10). Clinical complexity was high, including prior suicide attempts (n=25), previous psychiatric admissions (n=22), and prior ECT exposure (n=16). Routes used included intranasal esketamine (n=15), sublingual racemic ketamine (n=18), intravenous ketamine (n=6), subcutaneous s-ketamine (n=8), and subcutaneous racemic ketamine (n=12); note that some patients received more than one route as part of sequencing or optimisation. Dosing ranges reflected formulation (e.g., intranasal esketamine 28–84 mg; sublingual racemic ketamine 80–240 mg; IV/subcutaneous ketamine 0.5–1.0 mg/kg). It demonstrated sustained symptom reduction with maintenance strategies combining subcutaneous dosing and ongoing oral/sublingual regimens, as tracked by MADRS over time, with periods of remission-level scores and symptom variability. Clinical research (KET-IR): In the Phase 1 KET-IR study (40–240 mg), ascending doses were generally well tolerated with no serious adverse events reported; adverse events were mild/moderate and dose-related dissociation was observed, peaking around 1 hour post-dose, with most measures returning to baseline within hours. Pharmacokinetics were dose proportional across the evaluated range.

Discussion & Conclusions: MATS demonstrates a specialist, governance-led model for delivering ketamine/esketamine across routes to meet the needs of highly complex TRD and bipolar depression populations, integrating structured consent, controlled-drug oversight, and physiological monitoring. Real-world experience supports the pragmatic sequencing of routes and the feasibility of longer-term maintenance in selected individuals, while ongoing uncertainties exist about optimal duration, long-term safety, and best maintenance algorithms. Parallel MATS-linked research on oral KET-IR provides early supportive safety/PK/PD signals that may enable scalable oral strategies and future hospital-to-home models, warranting further efficacy trials in TRD and Bipolar Depression.