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.
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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.
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.
This study is a post-hoc secondary analysis of data from a previously conducted placebo-controlled, double-blind, randomised trial (NCT01920555) of single 40-minute intravenous infusions in adults with current major depressive episodes meeting DSM-IV criteria for MDD and exhibiting treatment-resistant depression (TRD). TRD was defined as less than 50% improvement after at least two adequate antidepressant courses in the current episode, and enrolled participants had a MADRS total score ≥20 at screening and baseline. In the original trial 99 participants were randomised across five arms: ketamine 0.1 mg/kg, 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, and midazolam 0.045 mg/kg as an active placebo. For this reanalysis the investigators restricted the sample to participants who received a single therapeutic ketamine dose (0.5 or 1.0 mg/kg) and who had baseline HAM-D-17 and HAM-D-6 assessments as well as HAM-D-6 at day 3. The primary clinical outcome here was treatment response on day 3, defined as a ≥50% reduction in HAM-D-6 total score versus baseline; percentage change in HAM-D-6 from baseline to day 3 was analysed as a continuous secondary outcome. Dissociative symptoms were measured with the Clinician-Administered Dissociative States Scale (CADSS) at 40 minutes after infusion and used as an explanatory variable. Logistic regression was used to examine associations with binary response status, and multiple linear regression was applied to the percentage change outcome. Explanatory variables included age, age at illness onset, sex, baseline HAM-D-6 total score, and CADSS total score at 40 minutes. Statistical significance was set at two-tailed p < 0.05, analyses were performed in R version 4.1.0, and variance inflation factors were inspected to assess multicollinearity. Ethical approvals and informed consent were obtained for the original trial; this secondary analysis used anonymised data and did not seek additional approval.
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. Trial Registration Data used in this secondary analysis were obtained from ClinicalTrials.gov, identifier: NCT01920555. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Article published online: 2023-10-16 Several predictors of the efficacy of intravenous ketamine therapy have been reported.reviewed 12 studies to identify potential predictors of a successful response to intravenous ketamine infusion in patients with treatment-resistant depression (TRD). In their analysis, patients with MDD and BD with a family history of alcohol use disorder showed a greater improvement in the total scores of the Montgomery-Asberg Depression Scale (MADRS) after ketamine infusion than in patients without these factors. Moreover, higher body mass index was correlated with a greater reduction in the 17-item Hamilton Depression Rating Scale (HAM-D-17) total score at 1 d and 230 min after ketamine infusion in patients with MDD and BD. Other studies have reported the association of following factors with better response to ketamine treatment: lower number of treatment failures and lower baseline severity of illness, younger age and no history of neuromodulation treatment, lower baseline intelligence quotient, lower pretreatment working memory function, lower adiponectin, higher brain-derived neurotrophic factor (BDNF) after ketamine administration, single nucleotide polymorphism (SNP) in the Val/Val BDNF allele at rs6265, and smaller left hippocampal volume. However, these studies had several limitations, such as the study design heterogeneity (e. g., a combination of open-label and randomized placebo-controlled trials, including both MDD and BD). Recently, Alnefeesi et al. (2022) conducted a systematic review and meta-analysis of studies evaluating the real-world clinical effectiveness of ketamine in patients with TRD. They reported that the mean number of failed antidepressants and depressive symptomatology scores at baseline were negatively correlated with remission rates, whereas the mean age was positively correlated with symptom improvement in the meta-regression analysis. However, other clinically relevant variables, such as age at onset and dissociative symptoms, have not been thoroughly investigated. While one study reported that earlier onset age was predictive of favorable treatment response after ketamine administration in patients with TRD, the findings from previous studies examining the association between age of onset and response to antidepressant treatment in patients with MDD have been inconsistent. In addition, the lack of agreement among previous studies is also the case for the association between dissociative symptoms and treatment response to ketamine infusion. To fill this gap in the literature and examine the factors associated with treatment response, we conducted a post-hoc analysis of data from a placebo-controlled, double-blind, randomized controlled trial that assessed the acute efficacy of ketamine infusion versus an active placebo in patients with TRD. We hypothesized that dissociative symptoms and age of onset would be related to treatment response in this homogeneous diagnostic group.
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Wilkinson, S. T., Katz, R. B., Toprak, M. et al. · Journal of Clinical Psychiatry (2018)
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Alnefeesi, Y., Chen-Li, D., Jawad, M. Y. et al. · Journal of Psychiatric Research (2022)
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Papers in Blossom that reference this study
Gutierrez, G., Kang, M. J. Y., Vasquez, G. · Psychiatry Research (2024)
Thirty-one participants met the inclusion criteria for this post-hoc analysis (ketamine 0.5 mg/kg: n = 17; 1.0 mg/kg: n = 14). The sample comprised 13 women with a mean age of 48.4 years (standard deviation reported elsewhere as 10.9). Treatment response on day 3 — defined as ≥50% reduction in HAM-D-6 — was the primary endpoint for the predictive analyses. Logistic regression identified a positive association between age at illness onset and treatment response at day 3 (β = 0.08, p = 0.037), indicating that a later age of onset predicted a greater likelihood of achieving the predefined response. No statistically significant relationships were observed between response and chronological age, sex, baseline HAM-D-6 total score, or CADSS total score measured 40 minutes after infusion. In the multiple linear regression examining percentage change in HAM-D-6 from baseline to day 3, none of the evaluated variables showed a significant association. Variance inflation factors for the explanatory variables were all below five, suggesting multicollinearity was not a concern in these models.
Yonezawa and colleagues interpret their principal finding — that later age at illness onset was associated with better acute antidepressant response to therapeutic-dose ketamine at three days — as suggesting biological heterogeneity between early-onset and late-onset TRD. They propose that earlier-onset MDD may index chronicity or a longer duration of illness, both of which have been associated with poorer response to conventional antidepressant treatments and may likewise reduce responsiveness to ketamine. The authors consider neurobiological mechanisms that might underlie this effect, emphasising evidence for impaired glutamatergic signalling and diminished AMPA receptor expression and synaptic spine density in chronic stress and depression models. Because ketamine's antidepressant action is thought to involve AMPA receptor activation and synaptogenic pathways, a longer disease course or early-onset disease could plausibly attenuate ketamine’s effectiveness via reduced neuroplasticity. The discussion notes the recent development of an AMPA-specific PET tracer ([11C]K-2) as a potential tool for future studies investigating receptor expression and treatment response. Regarding dissociative symptoms, the study found no correlation between CADSS total score at 40 minutes post-infusion and antidepressant response at day 3. The authors acknowledge that prior studies report mixed results on this relationship; they suggest that the CADSS may not sensitively capture ketamine-induced dissociation and that observed discrepancies across studies may reflect differences in sample size, study design, timing, and measurement instruments. Key limitations acknowledged by the investigators include the post-hoc design, small sample size, restriction to a single early assessment time point (day 3), and lack of data on duration of the index depressive episode. They also note that other potentially relevant predictors reported in prior work — such as family history of alcohol use disorder and body mass index — were not available in the dataset. Strengths highlighted include the use of data from a rigorously conducted, double-blind randomised trial and a diagnostically uniform TRD sample. The authors recommend larger, prospectively designed studies that include measures of illness duration, more sensitive dissociation instruments, and biomarker assessments to clarify predictors and mechanisms of ketamine response.
A later age at onset of depression was associated with a better short-term antidepressant response three days after a single therapeutic infusion of ketamine (0.5 mg/kg or 1.0 mg/kg) in this sample of patients with treatment-resistant depression. The authors suggest that early-onset TRD may represent a biologically distinct subgroup with greater resistance to ketamine, potentially due to impaired glutamatergic transmission and reduced neuroplasticity after a long disease course. They call for further research to identify reliable predictors of ketamine response and to elucidate the underlying mechanisms of its antidepressant effect.
In this post-hoc analysis, we examined the clinical variables associated with the treatment response to intravenous ketamine therapy in patients with TRD. Our study used data from a placebo-con-trolled, double-blind, randomized controlled trial that assessed the acute efficacy of ketamine infusion compared to an active placebo. In patients who received 0.5 mg/kg or 1.0 mg/kg ketamine infusion, the age of onset was positively correlated with treatment response according to the HAM-D-6 total score change 3 d after ketamine infusion. That is, a later onset of illness was associated with a better treatment response. This finding suggests that the onset of depression may reflect the treatment response of patients with TRD to intravenous ketamine therapy. The findings of previous studies were inconsistent regarding the associations between age of onset and response to antidepressant treatment in patients with MDD. In contrast to our result, Chen and colleagues (2021) demonstrated that earlier age of onset was one of the predictors of good treatment response 2 d after a single 0.5 mg/kg intravenous ketamine administration in 73 patients with TRD. The discrepancy between their findings and our result may partly be due to the differences in the study design. Chen et al. included patients who were resistant to treatment for both MDD and BD, and conducted a regression tree analysis using binary classification. They demonstrated that an earlier age of onset was predictive of good treatment response among patients who had a current depressive episode for 24 months or less and a baseline HAM-D-17 total score of 23 or less; however, the present age was not included as a covariate in their analysis. Thus, to clarify the relationship between age at onset and treatment response after ketamine infusion, future studies should adjust for the age in a uniform diagnostic group. The worse treatment response associated with an earlier onset of illness may be because MDD with an earlier age of onset may be related to chronic depression. According to the DSM-5, chronic depression is defined as depression that has persisted for at least two years,. Compared to non-chronic depression, chronic depression is associated with an earlier age of onset and more frequent episodes of depression. Moreover, patients with chronic depression often do not respond to pharmacotherapy and psychotherapyand need higher dosages to achieve improvement. In the present study, it may be possible that MDD patients with an earlier age of onset had characteristics of chronic depression and were more resistant to ketamine treatment than other MDD patients. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. As another explanation for the association between an earlier onset of illness and a worse treatment response is that an earlier age at onset is associated with a longer duration of illness in MDD. Previous studies have found that a longer duration of illness is associated with a lower treatment response to antidepressant treatment in patients with MDD. Thus, the higher resistance to ketamine treatment in early-onset patients with TRD in the present study may possibly be attributed to the longer duration of illness. Preclinical and clinical evidence support impaired glutamatergic pathways in patients with MDD. Some postmortem studies have reported that compared to controls, patients with MDD have decreased expression of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit in the perirhinal cortex, cornu ammonis (CA)1, and dentate gyrus. Moreover, animal studies have demonstrated that exposure to chronic stress causes a reduction in AMPA receptor subunit expression in these brain regions. Furthermore, the number of apical dendrite spines of CA1 and CA3 pyramidal cells was progressively reduced over 3 w in a depression model consisting of chronically and unpredictably stressed mice. The antidepressant effects of ketamine are assumed to occur via the activation of AMPA receptors and synaptogenic signaling pathways. The long course of the disease may have impaired glutamatergic signaling transmission, disturbed neuroplasticity, and developed ketamine resistance. However, the relationship between illness duration and AMPA receptor expression in patients with MDD has not been clarified, since no technique to measure AMPA receptors in living humans is available. Recently, [ 11 C] K-2, the first positron emission tomography tracer that specifically binds to AMPA receptors, was developed. Future studies are warranted to investigate the relationship between the treatment response to ketamine and AMPA receptor expression before and after ketamine infusion in the context of neural plasticity. This study found no association between the total CADSS score 40 min after ketamine administration and treatment response 3 d after ketamine infusion. The relationship between the dissociative side effects of ketamine and antidepressant effects has been examined in several previous studies, but their findings are inconsistent. For example, in a single-blind study of 10 patients with MDD, no association was found between the maximum change in the CADSS total score and the change in the HAM-D-17 total score at any time point after administering a single dose of ketamine at a subanesthetic dose. However,studied 108 patients with TRD and found that a higher CADSS total score 40 min after ketamine administration was correlated with a percentage decrease in the HAM-D-17 total score 7 d and 230 min after ketamine infusion. Later, Phillips et al. (2019) conducted a randomized, double-blind crossover trial in which participants received a single dose of 0.5 mg/kg ketamine infusion over 40 min. They found that the increase in the CADSS total score 40 min after ketamine administration correlated with the MADRS total score reduction at 24 h post-infusion. The discrepancy between these findings and our result may possibly be due to the small sample size and lack of power of the present study. Additionally, the CADSS may not have fully captured the dissociative symptoms of ketamine because it was initially developed to assess dissociative symptoms of post-traumatic stress disorder. To elucidate the relationship between treatment response and dissociative symptoms after ketamine administration, further studies should include larger sample sizes and utilize more sensitive and specific rating scales that measure dissociative symptoms after ketamine administration. The strengths of this study were that the original trial had a robust study design, and the study participants consisted of a uniform diagnostic group (i. e., TRD), resulting in high-quality data. However, our study had several limitations. First, this was a posthoc analysis and was not originally designed to investigate the predictors of treatment response after ketamine infusion. Second, the sample size was small. Third, the study evaluated depressive symptoms only 3 d after ketamine administration and did not assess them at other time points. Fourth, the data on the duration of the index episode were not available; therefore we could not analyze the effect of this factor on the treatment outcome. Finally, previous studies reported that a positive family history of alcohol use disorder and body mass index were associated with treatment response to ketamine; however, these factors were not assessed in the current study.