2026 ECNP Congress

PS01-1201

Real-world evidence suggests rethinking continuation criteria for ketamine in treatment-resistant depression

Mark Berthold-Losleben — I. Autran, T.M. Kvam, O.A. Andreassen · Østfold Hospital Trust, DPS Nord, Moss, Norway

2026 ECNP Congress

Introduction

Treatment-resistant depression (TRD) remains a major clinical challenge. Repeated-dose intravenous (IV) ketamine, with induction followed by maintenance infusions, is increasingly used in clinical practice. However, most maintenance studies have restricted continuation to patients meeting conventional post-induction response criteria, usually defined as ≥50% symptom reduction from baseline [1]. Longer-term outcomes among patients who do not meet this threshold are less well characterised [2].

Aims

To describe clinical outcomes during induction and maintenance phases of IV racemic ketamine for TRD in a naturalistic outpatient setting, with emphasis on the relationship between post-induction response and post-maintenance outcome.

Methods

This retrospective observational study was conducted at a Norwegian outpatient ketamine unit from December 2020 to December 2025. Adults with TRD who received both induction and maintenance infusions were included. Treatment followed a naturalistic protocol with an intended induction course of six IV ketamine infusions over three weeks, titrated from 0.5 mg/kg to 1.0 mg/kg. Maintenance infusions were generally delivered at four-week intervals and adjusted according to clinical need. Maintenance initiation was guided by clinical evaluation, including symptoms, functioning, tolerability and patient-reported benefit, rather than by a predefined response threshold. The Montgomery–Åsberg Depression Rating Scale, self-report (MADRS-S), was assessed at baseline (T0), post-induction (T1) and post-maintenance (T2). Response was defined as ≥50% reduction from baseline, partial response as 30–<50%, non-response as <30%, and remission as MADRS-S ≤10. MADRS-S was analysed with linear mixed models with random intercept per patient: a time-only model across the three timepoints for overall change, and a time × post-induction response group interaction model adjusted for baseline MADRS-S.

Results

A total of 127 patients (mean age 45.0 years [SD 10.9]; 59.8% female; mean baseline MADRS-S 33.3 [SD 6.3]) met inclusion criteria. Induction was associated with a large reduction in depressive symptoms; at the group level these effects remained largely stable during maintenance, but individual trajectories varied. Estimated reductions from baseline were 18.55 points at post-induction (95% CI 16.72–20.38; p<.001) and 16.31 points at post-maintenance (95% CI 14.48–18.14; p<.001). Response and remission rates were 62.2% and 36.2% at post-induction, and 51.2% and 37.8% at post-maintenance. Of the 65 post-maintenance responders, 18 (27.7%) had not been responders at post-induction. Conversely, 32 of 79 post-induction responders (40.5%) no longer met response criteria after maintenance treatment. Maintenance trajectories differed significantly by post-induction response group (interaction χ²(2)=12.48, p=.002): responders worsened (+4.66 points, p<.001), partial responders remained stable (−0.10, p=.960), and non-responders showed numerical improvement (−4.71, p=.071).

Conclusions: In this real-world TRD cohort, post-induction response was associated with maintenance outcomes but did not fully determine them. Continuation decisions based on a single post-induction assessment may miss patients who later benefit from extended treatment. Future studies using predefined continuation criteria and repeated outcome assessments are needed to clarify how maintenance ketamine should be initiated, continued, or discontinued.

References

  1. Phillips, J.L., Norris, S., Talbot, J., Birmingham, M., Hatchard, T., Ortiz, A., Owoeye, O., Batten, L.A., Blier, P., 2019. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am. J. Psychiatry 176 (5), 401–409.
  2. McIntyre, R.S., Rosenblat, J.D., Nemeroff, C.B., Sanacora, G., Murrough, J.W., Berk, M., Brietzke, E., Dodd, S., Gorwood, P., Ho, R., Iosifescu, D.V., Lopez Jaramillo, C., Kasper, S., Kratiuk, K., Lee, J.G., Lee, Y., Lui, L.M.W., Mansur, R.B., Papakostas, G.I., Subramaniapillai, M., Thase, M., Vieta, E., Young, A.H., Zarate, C.A., Stahl, S., 2021. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am. J. Psychiatry 178 (5), 383–399.