Single, Fixed-Dose Intranasal Ketamine for Alleviation of Acute Suicidal Ideation. An Emergency Department, Trans-Diagnostic Approach: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Trial

Acute suicidal patients frequently present to emergency departments but lack rapid, specific pharmacological options; these individuals are often hospitalised for short stabilisation and discharged before conventional treatments have time to act. Suicide can cut across diagnostic categories, and a trans-diagnostic framing—treating suicidal ideation as a separable clinical target—may be especially useful in the emergency setting where immediate management is required. Earlier research indicates that ketamine, a glutamatergic modulator with a rapid antidepressant effect, can reduce suicidal ideation for hours to days after administration, and intranasal esketamine has been studied and approved for resistant depression, motivating investigation of intranasal routes for acute suicidality. Domany and colleagues set out to evaluate whether a single fixed dose of intranasal racemic ketamine is feasible, tolerated and efficacious for rapidly reducing acute suicidal ideation in adults presenting to an emergency department who required psychiatric hospitalisation, irrespective of their diagnostic category. The study aimed to test a practical emergency-department intervention (40 mg intranasal ketamine) and to assess suicidal ideation, depressive symptoms, remission rates and safety across a 28-day follow-up period.

This was a randomised, double-blind, placebo-controlled proof-of-concept trial conducted at the University of Cincinnati Medical Center between August 2016 and April 2018. Forty-five patients with suicidal ideation requiring psychiatric hospitalisation were screened and 30 met inclusion criteria and were randomised 1:1 to receive either intranasal racemic ketamine 40 mg or matched saline placebo; 15 subjects were allocated to each arm and all were analysed. Inclusion required age 18–65, BSS first five items score of at least 3 (indicating at least a death wish) and a Columbia-Suicide Severity Rating Scale (C-SSRS) score >2 (active suicidal plans). Exclusion criteria included schizophrenia-spectrum or dissociative disorders, pervasive developmental or cognitive disorders, acute intoxication or withdrawal, homicidal risk, pregnancy/breastfeeding, hypersensitivity to ketamine and significant medical conditions that would contraindicate ketamine. Randomisation and blinding were maintained by having the pharmacist prepare syringes; the pharmacist was the only non-blinded person. Investigators originally planned IV weight-based dosing but switched to a fixed intranasal dose for practicality and based on reported intranasal bioavailability (~45%); the chosen dose was 40 mg delivered via a mucosal atomisation device as four 0.1 ml squirts (10 mg each) across both nostrils with a 10-minute separation. Vital signs were monitored for four hours post administration, after which participants were admitted to psychiatric units; discharge decisions were made by a blinded non-study physician. Treating clinicians provided standard psychiatric care and could change treatments as clinically indicated. Primary outcome was change in suicidal ideation over four weeks assessed with both a self-report (Beck Scale for Suicidal Ideation, BSS) and a rater-based single item from the Montgomery–Åsberg Depression Rating Scale (MADRS-SI). Assessments occurred at baseline, 30, 60, 120 and 240 minutes post-administration and on days 1, 2, 3, 4, 5, 7, 14, 21 and 28. Secondary outcomes included change in depressive symptoms (MADRS), remission from suicidal ideation (MADRS-SI = 0), length of hospitalisation and harms. Side effects were recorded using a Ketamine Side Effects Scale (KSES). Data were collected in REDCap. Statistical analyses used SPSS with two-sided tests at alpha = 0.05; normality checks were applied. Linear mixed models were used for group-by-time comparisons, while 4-hour outcomes were analysed with independent t-tests; remission rates used chi-square and length of stay used Mann–Whitney U. The trial had been planned for n = 60 but recruitment was terminated early after the principal investigator left the institution.

Thirty participants were randomised and there were no reported baseline differences between groups on demographics or baseline scores (MADRS, MADRS-SI, BSS) in the extracted text. All randomised subjects (15 per arm) were included in analyses. At four hours post administration the rater-based MADRS-SI showed a statistically significant advantage for ketamine: mean difference 1.267 (ketamine group reduction 4.89 ± 0.4 versus placebo 3.35 ± 0.5), 95% CI 0.1–2.43, p < 0.05. The self-reported BSS showed a larger numerical reduction in the ketamine arm (17.4 ± 9.4) than placebo (10.5 ± 8.21) but this did not reach statistical significance (p = 0.086). A linear mixed model for group-by-time interaction did not reach significance. Remission of suicidal ideation (MADRS-SI = 0) at four hours occurred in 12/15 (80%) of ketamine-treated subjects versus 5/15 (33%) of controls (p < 0.01). Depressive symptoms measured by MADRS at four hours favoured ketamine with a mean difference of 9.75 (95% CI 0.72–18.79, p < 0.05). Length of hospitalisation showed a non-significant trend favouring ketamine: median 5 days (25th–75th percentiles 4–8.5) versus 9 days (5.5–10.5) for placebo (p = 0.089). Safety assessments indicated more side effects in the ketamine group at one hour post dose on the KSES, but differences were not statistically significant; by two hours there was no evidence of side effects. No participants developed psychotic symptoms. One participant with baseline dissociative symptoms reported worsening dissociation but also reported overall improvement in suicidal measures. The authors note the study is underpowered for definitive safety conclusions.

Domany and colleagues interpret their findings as supporting that a single fixed 40 mg intranasal dose of ketamine can reduce suicidal ideation and improve depressive symptoms within four hours in a trans-diagnostic cohort presenting to an emergency department, and that the intervention induced remission in a substantial proportion of participants. They position the results as consistent with prior ketamine work in both emergency and non-emergency contexts and suggest intranasal administration may offer a pragmatic, potentially safer route than intravenous delivery. The investigators emphasise that the trial has limitations that temper conclusions: recruitment was terminated early yielding a small sample, the linear mixed model did not detect a significant group-by-time interaction, and effective masking is difficult in ketamine trials because of its psychomimetic and cardiovascular effects; the absence of an active placebo is noted. They also acknowledge lack of blood ketamine levels and that post-intervention psychotropic treatments were not recorded in the extracted text, which limits interpretation of durability and dosing adequacy. A notable observation was the sustained low suicidal-ideation scores in the ketamine arm over the 28-day follow-up, but the authors caution this may reflect inpatient support and is not conclusive given the study’s limited power. Clinical implications discussed by the authors include the potential for rapid symptom relief to influence immediate risk management, possibly reducing need or duration of hospitalisation and easing emergency department loads; nevertheless they call the observations preliminary. The study team recommends larger, adequately powered trials with improved blinding strategies (for example an active comparator), blood-level monitoring and careful recording of subsequent treatments, as well as consideration of ambulatory pathways to manage the sub-acute period after an emergency intervention.

The authors conclude that single fixed-dose intranasal ketamine was feasible and appeared safe in this emergency-department, trans-diagnostic sample and produced rapid reductions in suicidal ideation and depressive symptoms at four hours, including higher remission rates and a trend toward shorter hospital stays. They stress the results are inconclusive because the trial was underpowered and a linear mixed model did not demonstrate a significant group-by-time effect. Domany and colleagues recommend larger-scale studies to establish whether this paradigm can be recommended for acute management of suicidal patients.