Childhood trauma is one of the biggest risk factors for major depressive disorder; in fact, studies have shown that it increases the risk of depression by more than twofold (Li, D’Arcy and Meng 2016, Otte et al 2016). Concerningly, it also increases the risk of developing ‘treatment-resistant depression’ (or perhaps difficult-to-treat depression if we want to be less stigmatising), which has more severe and long-lasting symptoms, and is less effectively treated by conventional antidepressants (Nelson et al 2017; Nanni, Uher and Danese 2012).
In hope of solving this problem, ketamine has been proposed as a possible solution. Ketamine has been shown to be effective in treating treatment-resistant depression, providing an antidepressant effect which is both rapid and lasting – music to the ears of people who have been struggling with depression for a long time (Nikolin et al 2023; Alnefeesi et al 2022; McIntyre et al 2021). However, studies which have investigated the relationship between childhood trauma and treatment effects have shown mixed results (O’Brien et al 2023; O’Brien et al 2021).
This study by Johnson et al (2025) aims to shed further light on this, analysing the relationship between childhood trauma and treatment effectiveness in a community-based sample of adults receiving ketamine for ‘treatment resistant depression’.
This study seeks to resolve an argument: can ketamine be helpful in resolving treatment-resistant depression in the community, for people who have experienced childhood trauma earlier in life?
Methods
The study is a retrospective analysis of 83 patients with a primary diagnosis of ‘treatment-resistant depression’ who received ketamine infusions at a community outpatient clinic. Treatment-resistant depression was defined as having inadequately responded to “at least two major classes of antidepressants at a sufficient length and dosage”. They were given four ketamine infusions intravenously over 8-14 days; the first two infusions were given at 0.5mg/kg and the last two between 0.5mg/kg and 0.75mg/kg, titrated flexibly based on clinical response and drug tolerance.
Culminative trauma load was measured using the ECHO-wide Cohort version of the Childhood Trauma Questionnaire (CTQ). This involves six yes/no questions on the following topics: death of a close friend or family member, major upheaval between parents, traumatic sexual experience, victim of violence, severe illness or injury, and other major upheavals before 18. This enables a minimum score of 0 and maximum of 6. Those who scored from 0-2 were placed in the “low load” category and 3-6 in the “high load” category. Patients who experienced at least one of the trauma types were also asked to rate the severity from a scale of 1-7 (1 = Not at All Traumatic to 7 = Extremely Traumatic).
Depression symptoms were measured using the Quick Inventory of Depressive Symptomatology Self-Report 16-item (QIDS-SR16) questionnaire, which covers symptoms related to sleep, mood, weight and appetite, concentration, suicidal ideation, interest, fatigue and psychomotor changes.
Validated psychometric tools were used to assess the extent of childhood trauma and depressive symptoms experienced by people receiving ketamine infusion treatment in a community clinic.
Results
Patients with high (n = 46) and low (n = 37) trauma loads did not experience significant differences in reduction of depression symptoms (p = 0.572) as well as response and remission rates (p = 0.230 and p = 0.397, respectively). Response was defined as a reduction in QIDS-SR16 scores of greater than or equal to 50% while remission was defined as the patient having a QIDS-SR16 score of less than or equal to 5 after all four ketamine infusions.
Type of childhood trauma also had no significant impact on these outcomes. The researchers used a chi-squared test to investigate the relationship between specific types of childhood trauma and response or remission rates, and found that all 6 subcategories (death of a close friend or family member, major upheaval between parents, traumatic sexual experience, victim of violence, severe illness or injury, and other major upheavals) had no effect on response (p = 0.113, p = 0.205, p = 0.710, p = 0.379, p = 0.073 and p = 0.662), and remission (p = 0.395, p = 0.667, p = 0.346, p = 0.597, p = 0.638 and p = 0.193) rates.
| Subcategory | Response rate | Remission rate |
| Death of a close friend or family member | p = 0.113 | p = 0.395 |
| Major upheaval between parents | p = 0.205 | p = 0.667 |
| Traumatic sexual experience | p = 0.710 | p = 0.346 |
| Victim of violence | p = 0.379 | p = 0.597 |
| Severe illness or injury | p = 0.073 | p = 0.638 |
| Other major upheavals | p = 0.662 | p = 0.193 |
Note: a p-value under 0.05 usually means the result is considered “statistically significant.” In the above table, all the p-values are well above 0.05 (e.g., 0.113, 0.205, 0.710, etc.), which means none of these life events had a significant effect on whether someone responded to or recovered with treatment.
Similarly, severity of childhood trauma had no significant effect. There was no significant correlation between culminative trauma severity and change in depressive symptoms (p = 0.312) or between mean trauma severity and change in depressive symptoms (p = 0.266). In fact, they only explained 1.25% and 1.54% of the variance in symptom change, respectively.
There was, however, a significant effect of time on depression symptoms (p < 0.001) with a large effect size (η²p = 0.41), meaning that in patients receiving ketamine infusions for ‘treatment-resistant depression’, depressive symptoms significantly decreased over time – irrespective of childhood trauma type, load or severity.
No matter which type of major life stressor someone had experienced, it didn’t seem to make a difference to how likely they were to benefit from the ketamine treatment.
Conclusions
The results of this study suggest that neither the type nor the severity of childhood trauma have an impact on clinical response to ketamine. This challenges studies which show that people with significant trauma-load respond more, while replicating studies which show similar results. All in all, it is a helpful contributor to the study of ketamine for managing ‘treatment-resistant depression’.
In a small prospective trial of people receiving ketamine infusions in a community setting, childhood trauma type, load or severity had no impact on ketamine’s effect in alleviating depressive symptoms.
Strengths and limitations
Strengths
While this paper does not decisively spell the end of this question, this is an important study due to two key reasons. First, it specifically studies a community-based population, allowing ketamine’s effectiveness to be evaluated in a realistic setting. This is important as other study types may have exclusion criteria that render the studied population unrealistic e.g. excluding people with comorbidities when mental health conditions are often comorbid.
Second, it is known that negative or equivocal results are less likely to be published, also known as the file-drawer problem (Pautasso 2010; Rosenthal 1979). Publishing this study allows it to be included and analysed in future meta-analyses, which will take into account how similar and different it is to other such studies. Together, these studies can then help inform the question of what the effect of childhood trauma on ketamine antidepressant effectiveness truly is, as well as what may amplify or attenuate this effect.
Limitations
First, the childhood trauma questionnaire having only 6 yes/no questions can understandably feel reductive when capturing the complexity of trauma. While efforts were made to address both the range and severity of trauma by having patients rate each category on a scale from 1 to 7, this approach still feels insufficient. Other concerns include issues with self-reporting as individuals might repress or understate the severity of their trauma as a coping mechanism. Another key omission is also that it does not capture experiences of complex PTSD, such as those arising from prolonged neglect or emotional abuse. One could also argue that any significant trauma constitutes a meaningful trauma load. All that said, however, it may be that the very nature of trauma makes it difficult to adequately measure, and many of these may be inherent limitations of trying to do so. As such, it remains a challenge to find a comprehensive way of assessing the severity of trauma, and for now it remains important to compare and contrast studies with each other, in hope that they can patch the gaps in each other.
This methodological limitation may also help explain why the findings of this study differ from others, given that the version of the Childhood Trauma Questionnaire (CTQ) used differs from other studies (e.g. O’Brien et al 2019).
Second, while the study does show a decrease in depression symptoms over time after treatment with ketamine, the lack of a control group limits the validity of this result. In particular, there may have been a strong expectancy affect as participants were aware of their treatment and paid for it either via insurance or directly. Regression to the mean and recall biases may also have occurred. However, note that there is existing evidence for ketamine’s effectiveness, and this was not the main focus of this study.
Lastly, the study has a relatively small sample size, limiting its statistical power in detecting population-level effects and allowing for demographic breakdowns . However, these demographics data are still important to collect, as future meta-analyses may be able to make use of them in combined samples.
This study publishes small results, without a control group, that don’t look sensational on paper, but challenge the conventional narrative on the effect of trauma on the utility of ketamine therapy.
Implications for practice
Despite its limitations, this study does provide more evidence for ketamine’s effectiveness in a real-world setting, which is important for translating research into practice. This aligns with previous meta-analyses demonstrating ketamine’s effectiveness (Nikolin et al 2024, Alnefeesi et al 2022). It being effective for both people with high and low childhood trauma loads suggests that it can be used broadly for people with ‘treatment-resistant depression’, providing much-needed hope.
Ketamine itself is also already a well-known medication in healthcare due to its use in anaesthesia and pain management. This familiarity means that its side effects and contraindications are relatively well understood, potentially making it “safer” in some respects compared to newer, less-studied drugs. However, it is important to compare and contrast the mode of delivery, dosing, and other considerations in psychiatric settings, and particularly in the community clinic setting as in this study compared to other more intensive tertiary care contexts before making firm conclusions on its safety profile in mental health treatment.
From a practical research perspective, the use of the QIDS-SR16 may also raise some difficulty for some readers as it is a less well-known questionnaire and not used as often in UK clinical research. To clarify, the QIDS-SR16 is a self-report questionnaire designed to capture depression symptoms, much like the Beck Depression Inventory (BDI), which may be more familiar. The key difference is that while the BDI covers a broader range of depressive symptoms, the QIDS-SR16 specifically targets the core criteria for depression as defined in the DSM. While the BDI is more well-established and validated, the QIDS-SR16 remains a valid and useful measure, particularly for quick self-assessment and symptom tracking.
All in all, this study does provide some evidence for ketamine being useful clinically for ‘treatment resistant depression’, regardless of extent of childhood trauma, though it would be best examined alongside other studies. This provides helpful information for making decisions about the provision and regulation of ketamine as an antidepressant as an alternative to electroconvulsive therapy, especially since it is already available privately in Scotland (Jarvis 2025), while also being aware of concerns about its side effects and risks of recreational use.
This study provides objective evidence for the promise that ketamine therapy can improve depressive symptoms over time for adults in the community – regardless of type or extent of childhood trauma.
Statement of interests
No conflicts of interest.
Links
Primary paper
Johnson DE, Rodrigues NB, Mansur RB, McIntyre RS, Rosenblat JD. (2025) The Influence of Childhood Trauma on the Real‐World Effectiveness of Ketamine in Adults With Treatment‐Resistant Depression. Acta Psychiatrica Scandinavica. 2025 Apr 16.
Other references
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