Distinct therapeutic profiles of ketamine in treatment-resistant depression: an exploratory analysis

Intravenous ketamine demonstrates rapid efficacy for treatment-resistant depression (TRD). However, its impact on individual depressive symptoms and whether the degree of treatment resistance moderates these effects remain unclear. This study aimed to dissect symptom-specific trajectories and examine the moderating role of the degree of treatment resistance.

We conducted a post-hoc analysis of pooled data from two randomized, double-blind, controlled trials involving 154 adults with TRD receiving subanesthetic ketamine or control. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) over 15 days. Linear mixed-effect models (LMM) analyzed total scores, while generalized estimating equations (GEE) assessed item-level improvement. The Maudsley Staging Method (MSM) was used to quantify the degree of treatment resistance and evaluate its moderating effect.

Ketamine elicited a significant reduction in MADRS total scores (P < .001). Item-level analysis revealed significant improvements in seven symptoms, including apparent sadness, inner tension, and suicidal thoughts (P < .05). Crucially, a significant treatment × MSM interaction was found for apparent sadness (P = .002) and inner tension (P = .024), indicating attenuated efficacy in patients with higher resistance. Conversely, anti-suicidal efficacy was robust and not significantly moderated by resistance severity (P = .083).

Ketamine demonstrates broad efficacy in TRD but may exhibit symptom-specific divergence: anti-suicidal effects appear robust across resistance levels, whereas improvements in apparent sadness and inner tension may be attenuated by greater resistance severity. These exploratory findings warrant confirmation in prospective studies.

UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 (registered June 30, 2016), UMIN000023581 (registered December 31, 2018), and UMIN000033916 (registered November 30, 2021). Significant outcomes 1) Intravenous ketamine showed rapid anti-suicidal efficacy in patients with treatment-resistant depression (TRD), which was not significantly moderated by the baseline severity of treatment resistance. 2) Improvement in apparent sadness and inner tension was significantly moderated by the degree of treatment resistance, with attenuated efficacy observed in patients with higher Maudsley Staging Method (MSM) scores. 3) These exploratory findings raise the hypothesis that a symptom-specific stratified therapeutic approach may be warranted. Future research should examine whether ketamine could serve as an acute intervention for suicidal crises across the resistance spectrum, and whether improvements in specific affective symptoms may require augmentation strategies in highly refractory cases. Limitations 1) Limited generalizability: The study population consisted exclusively of Han Chinese patients from a single medical center, which may restrict the applicability of these symptom-specific findings to other ethnic groups or cultural contexts, given potential genetic and cultural variations. 2) Methodological constraints: This was a post-hoc analysis of pooled data with a heterogeneous control group (saline or midazolam). Functional unblinding may have occurred in both treatment directions, and formal blinding assessment was not conducted in either contributing trial. Sensitivity analyses adjusting for study source confirmed the robustness of all primary findings. 3) Study design duration: The protocol involved a single infusion with a short 15-day follow-up period, precluding conclusions regarding the long-term durability of the observed symptom divergence or the efficacy of repeated dosing regimens.