Intranasal Ketamine for Existential Distress in Advanced Cancer

Advanced cancer is frequently accompanied by depressive symptoms, and cancer-related depression can be difficult to treat, particularly in palliative care where standard treatments may act too slowly to help patients with limited life expectancy. The paper also highlights existential distress as a broader and less well-studied source of suffering in advanced cancer, involving fear, helplessness, loss of meaning, death anxiety, demoralisation and the wish to hasten death. Although ketamine has emerging evidence as a rapidly acting antidepressant, the authors note that existential distress outcomes have rarely been examined in ketamine studies, and most prior work has focused on intravenous administration rather than intranasal delivery. Aguiar and colleagues set out to report the secondary outcomes of the INKeD-PC trial, asking whether intranasal racemic ketamine might improve not only depression but also existential distress, anxiety, quality of life and broader symptom burden in patients with advanced cancer receiving palliative care. They present this work as addressing an important gap in the literature by extending the trial beyond depressive symptoms to multidimensional distress outcomes relevant to palliative care.

The study was a single-centre, 14-day, open-label, flexible-dose, single-arm clinical trial conducted at the Princess Margaret Cancer Centre in Toronto. It was approved by the University Health Network Research Ethics Board and Health Canada and registered on ClinicalTrials.gov. The trial enrolled patients with advanced cancer and moderately severe major depressive disorder, defined here as a clinician-rated MADRS score above 20 and an expected prognosis of less than 1 year. Participants received three doses of intranasal racemic ketamine on Days 1, 4 and 7, with individual dose titration from 50 mg to 150 mg. The ketamine was delivered using a mucosal atomisation device. Concomitant psychiatric medication was allowed, but doses could not be changed in the 2 weeks before or during the trial. No formal psychotherapeutic intervention was included, beyond the general study setting. Dosing took place either in an inpatient room or in a standard outpatient oncology clinic, with vital signs and adverse-effect monitoring for 4 hours after each dose. The primary outcome of the parent trial was change in clinician-rated depression measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). In this secondary analysis, the researchers examined self-reported anxiety, depression, palliative symptom burden, quality of life and death-related distress using the GAD-7, PHQ-9, ESAS-r, McGill Quality of Life Questionnaire (MQOL) and Death and Dying Distress Scale (DADDS), including relevant subscales. Secondary outcomes were collected at baseline and Day 8, the primary endpoint, to reduce burden. Qualitative comments from participants and family members were also recorded. The authors used paired-sample t-tests for pre-post comparisons, Cohen’s d to estimate effect sizes, Bonferroni-Holm correction for multiple testing, and Pearson correlations to explore relationships between change in MADRS and changes in secondary outcomes. A sensitivity analysis using all 20 enrolled participants applied a last observation carried forward responder/non-responder approach based on minimal clinically important differences where available.

Twenty participants were enrolled, and 15 completed all three ketamine doses and had secondary outcome data available. The main depression outcome showed a large and statistically significant improvement: mean MADRS scores fell from 32.27 at baseline to 11.00 on Day 8, with an average reduction far exceeding the minimal clinically important difference and a large effect size (d = 2.66, p = 0.006). All reported secondary outcomes improved significantly and by clinically meaningful amounts. PHQ-9 depression scores decreased by 7.73 points (d = 1.86, p = 0.005) and GAD-7 anxiety scores by 6.64 points (d = 1.22, p = 0.004). Death and Dying Distress Scale scores fell by 10.73 points (d = 0.91, p = 0.003), total MQOL increased by 38.47 points (d = 1.53, p = 0.004), and total ESAS-r symptom burden decreased by 16.00 points (d = 1.21, p = 0.003). In the subscales, psychological symptoms tended to improve more than physical symptoms. For ESAS-r, the psychological subscale improved slightly more than the physical subscale; for PHQ-9, the cognitive/affective component improved more than the somatic component. Within DADDS, the process-of-dying subscale improved more than the finitude subscale. MQOL subscales showed significant gains in physical symptoms, psychological symptoms and existential well-being, whereas social support did not change significantly. Correlational analyses found that change in total MQOL was significantly correlated with change in MADRS (r = -0.72, p = 0.045), but the other secondary outcomes were not significantly correlated with MADRS change. Qualitative comments from 12 participants or family members described noticeable improvements in mood and mental state, while physical symptoms and cancer-related worries often persisted. One participant summarised the change by saying: “I’m still dying. The sadness and knowledge is there, but now I can go to it, instead of it coming to me all the time.” In the sensitivity analysis including all 20 participants and treating missing data as non-response, the secondary outcomes still met statistical significance and exceeded minimal clinically important differences.

Aguiar and colleagues interpret these findings as suggesting that intranasal ketamine may help not only with depression but also with broader psychological and existential distress in advanced cancer. They emphasise that the treatment appeared to affect multiple dimensions of suffering, including general anxiety, death anxiety, quality of life and overall symptom burden, and note that psychological symptoms improved more strongly than physical symptoms. They also highlight the apparent dissociation between improvements in existential distress and the change in depression scores, pointing out that the correlation analyses did not show significant relationships for most secondary outcomes. The authors place their results alongside earlier research showing ketamine’s rapid antidepressant effects and mention a previous retrospective report of an anxiolytic effect in palliative patients receiving ketamine for pain. They argue that their findings extend the literature because existential distress outcomes have rarely been measured in ketamine studies and have previously appeared mainly in case reports. They further suggest that the greater improvement in the MQOL existential well-being domain and the larger change in the DADDS “Dying” subscale may indicate that ketamine reduces distress about the process of dying more than concern about death itself. They also note that social support did not improve, which they interpret as consistent with a mainly intrapsychic effect rather than a change in external support systems. The authors acknowledge several limitations: the open-label design, very small sample, short follow-up, and missing secondary outcome data for some participants. Because secondary outcomes were only measured at baseline and endpoint, they could not conduct a true intention-to-treat analysis for these measures, meaning the observed effects may be biased towards participants able to tolerate and complete treatment. They also state that the study was underpowered for mediation analyses, so it is not possible to determine whether changes in depression explained the existential distress improvements. Other limitations included the lack of detailed experiential or dissociative measures, no control for standard palliative or psychosocial support, and limited generalisability beyond patients with advanced cancer. The authors conclude that the findings are promising but preliminary, and they call for a Phase III randomised controlled trial of intranasal ketamine for poly-symptom control in palliative care, as well as comparisons with ketamine-assisted psychotherapy.

The authors conclude that intranasal ketamine showed rapid antidepressant effects and was also associated with improvements in existential and psychological distress among people with advanced cancer. They suggest that ketamine may have promise as a single agent for multidimensional distress in palliative care and propose further Phase III randomised research, including comparison with ketamine-assisted psychotherapy.