A naturalistic, descriptive study of treatment response to ketamine or esketamine in patients with treatment-resistant depression

Introduction

In recent years, ketamine and esketamine have emerged as therapeutic options for the treatment of treatment-resistant depression, notable for their rapid onset of action, which is particularly relevant in patients with severe depressive symptoms and suicidal ideation [1,2]. However, the results of clinical trials may not fully reflect the efficacy and tolerability of these treatments in routine clinical practice [3]. The aim of this study is to describe the antidepressant response associated with these treatments and to analyse the possible association with various clinical variables in real-world care settings and heterogeneous populations.

Methods

An observational, naturalistic and descriptive study was conducted, including patients with treatment-resistant major depression treated with ketamine or esketamine. Socio-demographic and clinical data were collected. Treatment response was assessed by the change in score on the Montgomery–Åsberg Depression Rating Scale (MADRS) before and after treatment. The paired-sample t-test was used to compare MADRS scores. A multivariate regression analysis was performed to explore the association between clinical variables and treatment response. Using an analysis of covariance (ANCOVA) adjusted for baseline MADRS score and gender, the final score was compared between treatments.

Results

Sixty-four patients were included, of whom 49 received esketamine and 15 ketamine. The mean age was 53.6 years (SD 10) and 54% were women (n = 35). Ketamine was administered in six sessions (two per week) at a dose of 0.5 mg/kg per day, and esketamine was administered for seven months (one month of induction and six months of maintenance) at doses ranging from 28 to 84 mg, at the maximum tolerated dose. The final sample for the efficacy analysis consisted of 47 patients with complete data. A statistically significant reduction in the MADRS score was observed, which decreased from a mean of 35 points (SD=4.92) to 21 points (SD=12.06), representing a mean reduction of 13.83 points (p<0.001).

Higher baseline severity was associated with higher final scores (B=0.80; p=0.024). Similarly, higher final scores were observed in patients with single depressive episode compared to patients with bipolar disorder in a depressive episode (B=13.21; p=0.031). No significant effect on the final MADRS score was observed with other analysed variables (age, gender, age of onset of the depressive episode, duration of the episode, number of previous treatments or presence of a comorbid diagnosis). No statistically significant differences in efficacy were observed between ketamine and esketamine after adjusting for baseline score (p=0.174) and gender (p=0.724). The treatment was well tolerated, with only 3 discontinuations due to adverse effects.

Conclusions

Ketamine and esketamine are effective treatments in real-world clinical practice for the treatment of treatment-resistant major depression. A diagnosis of bipolar depression and lower baseline severity may be predictive factors for a better clinical response. Given the observed heterogeneity of response, studies with larger samples are needed to optimise therapeutic personalisation protocols.

References

1. Ouyang, Y., Li, J., 2025. Efficacy of esketamine nasal spray for treatment-resistant depression: A meta-analysis of randomized controlled studies. Medicine 104 (9), e41495.
2. Sapkota, A., Khurshid, H., Qureshi, I.A., Sarwar, S., Patel, R.S., 2021. Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review. Cureus 13 (8), e17352.
3. Sarlon, J., Thomi, D., Brühl, A.B., Liwinski, T., Lang, U.E., 2026. Real-world comparison of intranasal racemic ketamine and esketamine in treatment-resistant depression: a retrospective observational study. J. Affect. Disord. 121208.