Oral ketamine reduces the experience of stress in people with chronic suicidality

Suicide is presented as a major public health problem, and the authors situate chronic stress as a key neurobiological risk factor that can produce structural and functional brain changes implicated in suicidal behaviour. They describe how chronic stress is associated with HPA-axis dysregulation, inflammatory changes, altered glutamate signalling, synaptic loss and reductions in NMDA and AMPA receptor expression. Prior research indicates that ketamine, an NMDA receptor antagonist, can reverse some stress-induced brain changes by increasing BDNF, enhancing AMPA function, promoting synaptogenesis and restoring neural connectivity. Clinical trials have demonstrated ketamine's antidepressant and anxiolytic effects, but treatment options specifically targeting suicidality and stress-related pathology remain limited. Dutton and colleagues set out to examine whether a six-week course of subanaesthetic oral ketamine would reduce self-reported stress in adults with chronic suicidality. The study tested the primary hypothesis that weekly oral ketamine over six weeks would produce a significant reduction in the Depression Anxiety Stress Scale (DASS-21) Stress subscale, and additionally assessed concurrent changes in the DASS Depression and Anxiety subscales and the relationship between stress change and suicidality responder status (as defined on the Beck Scale for Suicide Ideation). The trial aimed to extend earlier pilot work on oral ketamine in this population and to explore durability of effects at a four-week no-treatment follow-up.

The study reported here is an open-label clinical trial conducted at the Thompson Institute, University of the Sunshine Coast, registered with the Australia and New Zealand Clinical Trials Registry. Adults aged 18 or older with chronic suicidal ideation and a Beck Scale for Suicide Ideation (BSS) score ≥ 6 were recruited from primary and psychiatric services. Exclusion criteria included current psychosis, mania/hypomania, acute suicidality requiring urgent intervention, uncontrolled cardiovascular disease, neurological pathology, abnormal liver function, pregnancy or breastfeeding. Sixty-four people were screened, 40 met eligibility criteria, 32 completed the six-week active treatment phase and 30 completed the full 10-week protocol (six weeks active treatment plus four weeks follow-up). Reasons for withdrawal included inability to attend visits, urinary abnormalities before first treatment, failure to meet suicidality criteria and incidental MRI findings. Ethics approvals and informed consent are reported. Intervention consisted of a single, subanaesthetic oral racemic ketamine dose administered once weekly for six weeks. Participants started at 0.5 mg/kg and doses were titrated by the study psychiatrist, usually in 0.2–0.5 mg/kg increments up to a maximum of 3.0 mg/kg by the sixth treatment; dose reductions of 0.2–0.7 mg/kg were permitted for tolerability. Ketamine was delivered as a compounded oral liquid taken with apple juice. The treatment was an augmentation strategy and participants could remain on concomitant psychotropic and other medications; concomitant medication details are referenced to a previous publication. After six active doses there was a four-week no-treatment follow-up phase. Primary outcome assessment for the analyses reported here used the self-rated Depression Anxiety Stress Scale-21 (DASS-21) administered at pre-ketamine (week 0), post-ketamine (4–7 days after the final dose) and follow-up (28–32 days after the last dose). The three subscales (Depression, Anxiety, Stress) each range 0–42 after scoring adjustments; the Stress subscale measures chronic nonspecific arousal and difficulty relaxing. Suicidality responder definitions (based on the BSS) were prespecified: ‘response’ as ≥50% BSS improvement or BSS ≤ 6 at post-ketamine, and ‘prolonged response’ as ≥50% BSS improvement or BSS ≤ 6 at follow-up. Safety monitoring included pathology, urinalysis and vital signs (blood pressure and heart rate) pre- and post-treatment. Statistical analyses comprised repeated measures ANOVA with time (pre, post, follow-up) as the within-subjects factor for each DASS subscale; Mauchly's test assessed sphericity and Huynh–Feldt correction was applied where needed. Post-hoc pairwise comparisons used Bonferroni correction. Clinically significant change was evaluated using the Reliable Change Index (RCI) at a 95% confidence level, calculated using pre-treatment standard deviations and reported subscale reliabilities (r = 0.91 for Depression, 0.80 for Anxiety, 0.84 for Stress). Two-way mixed ANOVA tested time by responder (and time by prolonged-responder) effects on DASS Stress scores. Paired t-tests compared pre-to post-treatment blood pressure and heart rate. Significance was set at p < .05 for all tests.

Sample characteristics: Of the treated cohort, 53% were female at birth and the mean weight at first treatment was 91.1 ± 24.8 kg. All participants met criteria for major depressive disorder and had chronic suicidality; comorbidities included borderline personality disorder, generalized anxiety disorder, post-traumatic stress disorder and obsessive-compulsive disorder. Most participants (all but five) were taking psychotropic medications at baseline. At the pre-ketamine assessment, 72% (n = 23) reported severe or extremely severe stress levels on the DASS Stress subscale. DASS outcomes: At the whole-group level (n = 32), all three DASS subscales (Stress, Depression, Anxiety) showed statistically significant reductions at post-ketamine and at follow-up compared with pre-ketamine scores. Omnibus repeated measures ANOVA reached significance (p < .05) and post-hoc pairwise comparisons indicated highly significant pre-to-post and pre-to-follow-up reductions for each subscale (post-hoc pairwise comparisons all p < .001). However, there were small but significant increases from post-ketamine to follow-up on each subscale, indicating partial relapse after the nil-ketamine phase. Categorical mean changes across timepoints were: Depression moved from ‘extremely severe’ (pre) to ‘moderate’ (post) to ‘severe’ (follow-up); Anxiety from ‘extremely severe’ to ‘normal’ to ‘moderate’; Stress from ‘severe’ to ‘normal’ to ‘mild’. Only the Stress subscale mean reached the normal range at the post-ketamine timepoint. Reliable Change Index: RCI analysis at the 95% confidence level showed clinically significant change in 78% of participants (n = 25) on the DASS Stress subscale, 84% (n = 27) on Depression, and 63% (n = 20) on Anxiety. Half the cohort (50%, n = 16) demonstrated clinically significant change across all three subscales. Responder-status analyses: A two-way mixed ANOVA for responders versus non-responders (with Huynh–Feldt correction) showed a significant main effect of time on DASS Stress [F(1.63,45.7) = 30.5, p < .001], but no significant main effect of responder status nor time-by-responder interaction. Inspection of timepoints revealed responders had significantly lower Stress scores than non-responders at post-ketamine (p < .001), but this difference was not maintained at follow-up. For prolonged responders versus prolonged non-responders, mixed ANOVA revealed significant main effects of time [F(2,56) = 51.7, p < .001] and prolonged responder status [F(1,28) = 11.7, p < .01], and a significant time-by-prolonged-responder interaction [F(2,56) = 7.0, p < .01]. Prolonged responders showed sustained reductions in DASS Stress from post-ketamine to follow-up, whereas prolonged non-responders relapsed; prolonged responders differed significantly from prolonged non-responders at both post-ketamine (p < .05) and follow-up (p < .001). Paired testing indicated prolonged responders maintained lower stress levels between post and follow-up (paired t-test p = .88). Physiological and safety outcomes: Mean systolic blood pressure did not change significantly pre-to post-treatment, while mean diastolic blood pressure decreased significantly (p < .05); mean heart rate remained stable. The treatment was generally well tolerated with no serious adverse events reported. Common acute effects included transient dissociation during treatment sessions and tiredness/decreased energy in the first 24 hours; these effects subsided and were described as mild. Urinalysis did not identify ketamine-related cystitis; one participant had transient urinary hypersensitivity on one occasion and another had intermittent haemolysed urine that was judged unrelated to ketamine. Vital signs showed transient hyperdynamic changes during treatment sessions that rapidly normalised. Thirty-two participants completed the active phase and 30 completed the full 10-week protocol.

Dutton and colleagues interpret their findings as evidence that a six-week course of low-dose oral ketamine substantially reduced self-reported stress in adults with chronic suicidality, with the Stress subscale showing the most pronounced clinical change. At the group level the mean DASS Stress score fell into the normal range after treatment, whereas mean Depression and Anxiety scores improved but did not uniformly return to normal. The authors highlight that Reliable Change Index calculations supported clinically meaningful change across the cohort, but note that depression remained at a higher categorical level despite many individuals showing reliable improvement. The investigators link their clinical findings to preclinical work suggesting ketamine can enhance resilience to stress and protect against stress-induced pathology. They suggest that repeated weekly dosing may produce more durable effects than single-dose administrations, and emphasise the potential of glutamatergic agents to target stress-related neurobiological mechanisms implicated in suicidality. Anecdotal reports from three participants who experienced serious life events during the treatment phase suggested improved coping and functional responses compared with their pretrial behaviour; the authors stress these reports were volunteered and not systematically collected, limiting firm conclusions. Limitations acknowledged by the authors include the small sample size, open-label design, absence of a control arm, potential effects of concomitant medications and the possibility of expectancy effects. They also note strengths: outcome assessment at least four days after the last dose reduced the likelihood that acute ketamine sensorium obscured clinically meaningful behavioural change. Recommendations for future research include larger, controlled trials, use of multilevel models to characterise individual differences in response over time, systematic assessment of life events during treatment, incorporation of objective physiological stress measures (for example HPA-axis markers such as cortisol) and exploration of genetic or epigenetic biomarkers (for example CRH or FKBP5 measures) and neuroimaging to identify predictors of risk and treatment response. The authors conclude that further investigation is warranted into oral ketamine for stress-related disorders and suicidality, with a focus on objective stress measures and biomarkers.

The study concludes that low-dose oral ketamine administered weekly for six weeks produced significant reductions in self-reported stress, depression and anxiety in adults with chronic suicidality, with the Stress subscale showing the most robust clinical response reaching the normal range post-treatment. For participants classified as prolonged responders, improvement in stress persisted through the four-week no-treatment follow-up. The authors recommend larger controlled studies incorporating objective physiological measures of stress to clarify ketamine's therapeutic potential in stress-related mental disorders and suicidality.