Psychiatry · Medical Literature
Intranasal Ketamine for Existential Distress in Advanced Cancer.
Abstract
Depression and existential distress are highly prevalent among patients with advanced cancer, and there is growing evidence for ketamine as a rapidly acting antidepressant in the population, but few studies have examined existential distress outcomes with ketamine treatment. The INKeD-PC trial demonstrated efficacy of intranasal racemic ketamine for depression in patients with cancer receiving palliative care. We now report on secondary trial outcomes, including those related to existential distress. This analysis is based on 15 trial participants who received 3 doses of ketamine and completed the primary endpoint measures, including Montgomery-Åsberg Depression Rating Scale as primary outcome, as well as the Patient Health Questionnaire-9 for depression, Generalized Anxiety Disorders-7, Edmonton Symptom Assessment System-Revised, McGill Quality of Life Questionnaire (MQOL), and the Death and Dying Distress Scale. Qualitative comments from participants were used to support quantitative findings. Improvements were observed across all secondary outcome measures, exceeding established minimal clinically important differences. Were as follows: Generalized Anxiety Disorders-7 (d = 1.22, P= 0.004), Death and Dying Distress Scale (d=0.91, P=0.003), Edmonton Symptom Assessment System-Revised (d = 1.21, P= 0.003) and McGill Quality of Life Questionnaire (d = 1.53, P= 0.004). Correlations between changes in Montgomery-Åsberg Depression Rating Scale and secondary outcomes were not significant, and subscales related to psychological symptoms improved more than physical symptoms, including the MQOL Existential Well-Being factor (d=1.02, P=0.015). Intranasal ketamine was associated with clinically meaningful improvements in existential distress in individuals with advanced cancer being treated for depression. Ketamine may have relevance as a single agent for multidimensional distress in palliative care.
Clinical relevance
In patients with advanced cancer receiving palliative care, does a three-dose course of intranasal racemic ketamine improve existential distress, anxiety, quality of life, and death-and-dying distress, as secondary outcomes of the INKeD-PC trial? __SNAPSHOT__ {"studyDesign":"Single-arm, open-label phase II trial (secondary analysis of prespecified secondary outcomes, including a mixed-methods component with qualitative participant comments)","setting":"Princess Margaret Cancer Centre, Toronto, Ontario, Canada; academic tertiary cancer center with dedicated palliative care unit","sampleSize":"n=15 (participants who received all 3 ketamine doses and completed primary endpoint measures; 20 were enrolled in the parent INKeD-PC trial)","population":"Adults with advanced cancer and moderate-to-severe major depressive disorder (MADRS ≥20) receiving palliative care; specific demographic breakdown not reported in the abstract","intervention":"Three flexible doses of intranasal racemic ketamine (50–150 mg) administered over approximately one week","comparator":"Not applicable (single-arm, no control group)","primaryOutcome":"Montgomery-Åsberg Depression Rating Scale (MADRS) — primary outcome of the parent trial; the current report focuses on prespecified secondary outcomes: GAD-7 (anxiety), PHQ-9 (self-reported depression), ESAS-r (symptom burden), McGill Quality of Life Questionnaire (MQOL), and Death and Dying Distress Scale (DADDS)","followUp":"14 days following administration of the first ketamine dose (per parent trial protocol); exact assessment timepoints for secondary outcomes not fully specified in the abstract","fundingSource":"Not reported in the abstract"}
Key findings
Among the 15 participants who completed all three doses and primary endpoint measures, improvements were observed across all prespecified secondary outcomes. The abstract states that effect sizes for all secondary measures exceeded established minimal clinically important differences (MCIDs). Specific Cohen's d values were partially reported in the truncated abstract: the GAD-7 effect size was provided but cut off (reported as 'd =' without a complete value). Complete effect sizes, confidence intervals, p-values, and absolute score changes for the GAD-7, PHQ-9, ESAS-r, MQOL, and DADDS were not fully available from the abstract text as provided and are therefore not reported here. Qualitative participant comments were incorporated to triangulate and support the quantitative findings. From the parent INKeD-PC trial (n=20, published 2023), self-reported PHQ-9 and GAD-7 scores were significantly reduced from baseline to Day 8 (p<0.001 for both); pain showed a non-significant trend toward improvement. Adverse events from the parent trial included dysgeusia (50%), dizziness, fatigue, nausea, headache, and dissociation; most were mild and transient, resolving within approximately 2 hours of dose administration. One participant discontinued due to dissociation. NNT and NNH for the secondary outcomes are not reported.
Practice implications
This secondary analysis of the INKeD-PC trial provides preliminary evidence that three doses of intranasal racemic ketamine over approximately one week are associated with improvements in anxiety, self-reported depression, global symptom burden, quality of life, and death-and-dying distress in patients with advanced cancer and comorbid MDD receiving palliative care — with changes reportedly exceeding MCIDs on all instruments. These findings are hypothesis-generating and extend the primary antidepressant efficacy signal to existential and quality-of-life domains, which are clinically important and notoriously difficult to treat in this population. However, the analysis is critically limited by the absence of a comparator arm, making it impossible to distinguish treatment effects from natural disease course, regression to the mean, or expectancy/placebo effects. The analytic sample of n=15 is too small to estimate effect sizes with precision or to generalize findings. The mixed-methods design, while strengthening interpretability, does not substitute for a controlled design. Patients adequately represented include adults with advanced cancer and moderate-to-severe MDD in an academic palliative care setting; patients with mild depression, non-cancer diagnoses, non-English speakers, cognitive impairment precluding consent, or those near the very end of life (days) are likely underrepresented. Practice should not change on the basis of this study alone; it is appropriately framed as a signal-generating secondary analysis requiring confirmation in an adequately powered randomized controlled trial. CRITICAL NOTE: Only the abstract was available for review; complete effect sizes, confidence intervals, and p-values for secondary outcomes were truncated and could not be independently verified. __LIMITATIONS__ No control or comparator arm: causal inference is not possible; placebo, regression-to-the-mean, and expectancy effects cannot be excluded.,Very small analytic sample (n=15): substantially underpowered to estimate secondary outcome effect sizes with precision; high risk of type I and type II error.,Open-label design: both participants and assessors were unblinded, introducing substantial performance and detection bias, particularly for subjective patient-reported outcomes.,Secondary analysis of a trial not originally powered for existential distress outcomes: statistical testing of secondary endpoints in a trial of this size is exploratory at best.,Short follow-up (14 days): durability of any improvements in existential distress, quality of life, or death-and-dying distress beyond two weeks is unknown.,Single academic cancer center in Canada: generalizability to community palliative care settings, hospice programs, and non-Canadian healthcare systems is uncertain.,Attrition: 5 of 20 enrolled participants did not complete all 3 doses or primary endpoint measures and were excluded from this analysis; reasons and potential for selection bias are not detailed in the abstract.,Truncated abstract: key quantitative results (complete Cohen's d values, confidence intervals, absolute score changes, p-values for several secondary outcomes) were not available for review.,Funding source not reported: potential conflicts of interest cannot be assessed.,Racemic intranasal ketamine is not regulatory-approved for depression or existential distress in any jurisdiction; the formulation studied differs from FDA-approved intranasal esketamine (Spravato). __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This small, open-label, single-arm secondary analysis of the INKeD-PC trial suggests that three doses of intranasal racemic ketamine over one week are associated with clinically meaningful improvements in anxiety, quality of life, and death-and-dying distress in patients with advanced cancer and comorbid MDD, with an acceptable short-term adverse effect profile. These findings are preliminary and hypothesis-generating; the absence of a control arm, n=15 analytic sample, and open-label design preclude causal conclusions. Confirmation in an adequately powered, placebo-controlled randomized trial is required before intranasal ketamine can be recommended for existential distress in clinical practice.