Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression
Reanalysis of a placebo‑controlled double‑blind RCT of intravenous ketamine in 31 adults with treatment‑resistant depression found that later age of depression onset predicted a greater antidepressant response three days after infusion, whereas age, sex, baseline severity and dissociative scores showed no association. The authors propose that impaired glutamatergic signalling and reduced neuroplasticity in earlier‑onset cases may explain the diminished ketamine response.
Authors
- Yonezawa, K.
- Uchida, H.
- Yatomi, T.
Published
Abstract
Introduction
Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials.
Methods
Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i. e., 0.5 and 1.0 mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score.
Results
This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (β=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration.
Discussion
Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response.
Research Summary of 'Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression'
Introduction
Ketamine, an NMDA receptor antagonist, has shown rapid antidepressant effects in clinical trials for major depressive disorder (MDD) and bipolar depression, but real-world response rates vary widely. Previous reviews and cohort studies have suggested a range of clinical predictors of ketamine response — including family history of alcohol use disorder, body mass index, younger chronological age, number of prior treatment failures, biomarkers such as BDNF, and neuroanatomical measures — yet findings across studies have been inconsistent and study designs heterogeneous. Notably, the roles of age at illness onset and acute dissociative symptoms after infusion remain underexplored in homogeneous samples of treatment-resistant depression (TRD). Yonezawa and colleagues conducted a post-hoc analysis of a double-blind, placebo-controlled randomized trial (NCT01920555) to identify clinical factors associated with acute antidepressant response to therapeutic doses of intravenous ketamine (0.5 and 1.0 mg/kg) in adults with TRD. The investigators hypothesised that age at onset and dissociative symptoms after infusion would relate to treatment response, and they examined demographic and clinical predictors using regression models with change in the HAM-D-6 score and a binary response definition as outcomes. This study aims to clarify predictors in a diagnostically uniform TRD sample drawn from a high-quality trial dataset.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Yonezawa, K., Uchida, H., Yatomi, T., Ohtani, Y., Nomoto-Takahashi, K., Nakajima, S., Mimura, M., & Tani, H. (2024). Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression. Pharmacopsychiatry, 57(01), 35-40. https://doi.org/10.1055/a-2179-8884
References (7)
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