Repeated intranasal ketamine for treatment-resistant depression - the way to go? Results from a pilot randomised controlled trial

Five participants were enrolled before suspension: three randomised to ketamine and two to midazolam. The sample was treatment resistant, with a mean of 3 (SD 1.7) failed antidepressants in the current episode and a mean of 5 (SD 2.6) failed lifetime. Feasibility: All three ketamine recipients experienced motor incoordination that interfered with self-administration from as early as the second spray (after ~20 mg delivered); none were able to self-administer all ten sprays at any session. By contrast, both midazolam participants self-administered the full ten sprays at every session. Several ketamine sessions required extension of treatment time under the operational protocol; midazolam sessions did not. Acute side effects and tolerability: Ketamine recipients generally had higher CADSS (dissociation) scores than midazolam recipients, with one ketamine participant showing markedly elevated CADSS after each session; CADSS scores returned to baseline by 4 h in all participants. Peak blood pressure values were higher in the ketamine group, with three ketamine participants and one midazolam participant recording peak BP ≥150/80 at various sessions; these episodes required only longer intervals between sprays in the ketamine group and no pharmacological intervention. No increases in selected BPRS positive symptoms or orientation impairments at 4 h were observed. Other acute physical side effects were more common with ketamine than midazolam. Cumulative safety: There were no clinically important changes in liver function tests, PRISE scores, or BPIC-SS urinary symptom scores over the treatment course in either group. Neuropsychological testing showed only isolated decrements: one ketamine participant had slower choice reaction time (Identification Task) and one midazolam participant showed poorer working memory on the n-back task; no systematic cognitive decline was evident. Pharmacokinetics and variability: Ketamine and norketamine plasma concentrations sampled 20 min after the last spray in the first session varied by approximately two-fold between participants. The participant with the highest plasma concentrations (k1) also experienced the poorest acute tolerability. Mood outcomes: Two participants met response (and remission) criteria at the end of the treatment course—one in the ketamine group (k1) and one in the midazolam group (m2). At one month follow-up only the ketamine participant k1 remained a responder. Inspection of MADRS trajectories suggested an antidepressant effect after the first and second ketamine sessions but little maintenance of benefit thereafter across sessions for most ketamine recipients. Comparison with subcutaneous (SC) ketamine within-subjects: Two participants who received both IN and subsequent SC ketamine under the same study design reported and objectively experienced fewer and less severe acute side effects with SC administration. Peak BP and peak CADSS scores were lower with SC than with IN dosing for these participants, and several acute symptoms (palpitations, sweating, blurred vision, oral numbness/tingling, dry mouth) were reported only with IN ketamine. Participants spontaneously commented that SC administration felt better than the sprays.

Gálvez and colleagues interpret these pilot data to show that, with the specific drug formulation and atomiser device used here, a fixed 100 mg intranasal ketamine regimen was not a practical approach for TRD. Acute tolerability problems—particularly motor incoordination, dissociation and transient blood pressure elevations—occurred at low cumulative exposure (as early as after 20 mg in some participants), prevented self-administration of the intended dose and sometimes prolonged administration beyond the planned 45 min. The investigators contrast their findings with a prior IN trial that used 50 mg and reported fewer adverse effects, noting that the prior study achieved lower plasma concentrations; thus they attribute differences to dosing and to the effective speed and extent of nasal absorption rather than to the intranasal route per se. The authors note substantial inter-individual variability in plasma ketamine and norketamine concentrations following a fixed IN dose, with up to two-fold differences between participants; the highest concentrations correlated with the greatest side-effect burden but also with the single ketamine remitter at one month. They therefore argue that weight-based or individually titrated dosing may be preferable to a one-size fixed dose, and they highlight that IN administration lends itself to titration because dose can be adjusted by number of sprays during a session. The study team also reports that, for two participants who later received subcutaneous ketamine in the same design, SC administration was better tolerated and led to fewer and milder acute effects. Longer-term safety signals were not observed in this small sample: no hepatic, cognitive or urinary adverse changes were detected after eight treatments, and no participants spontaneously reported subsequent drug craving or misuse when followed at 12 months (follow-up response 4/5). The authors acknowledge the primary limitation is the very small sample size due to early termination, which prevents reliable efficacy conclusions. They further emphasise that tolerability and efficacy with IN ketamine are likely to depend on multiple factors including drug formulation, delivery device, insufflation technique and individual nasal anatomy or vascularity. The investigators conclude that while the IN route remains of interest, careful optimisation of formulation, device and dosing strategy (for example titration or weight-based dosing) will be needed before repeated IN ketamine can be recommended for routine clinical use.