Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial)

Depression is described as a highly prevalent disorder that causes substantial disability, reduced life expectancy and elevated suicide risk. Gallagher and colleagues note that conventional antidepressant treatments targeting monoamine systems can take weeks to exert effects and often leave many patients without remission, highlighting the need for faster-acting interventions. Ketamine, an NMDA receptor antagonist that modulates glutamate signalling, has repeatedly shown rapid but transient antidepressant effects at subanaesthetic intravenous doses; however, uncertainty remains about whether repeated (serial) infusions can prolong benefit and how adjunctive ketamine performs in patients receiving routine care. This pilot trial set out to assess the feasibility of a pragmatic randomised controlled design testing four once-weekly intravenous ketamine infusions (0.5 mg/kg over 40 minutes) versus an active comparator, midazolam (0.045 mg/kg), as add-on treatment for inpatients admitted with a depressive episode. The main objectives were to evaluate recruitment, retention and procedural aspects to inform a definitive trial, and to estimate the 95% confidence interval for differences in depression scores at end of treatment. The investigators hypothesised the protocol would be feasible and used midazolam to improve blinding compared with saline placebo.

The Karma-Dep trial was a pragmatic, patient- and rater-blinded randomised controlled pilot study conducted at St Patrick's University Hospital. Eligible participants were adults (≥18 years) admitted for an acute depressive episode meeting DSM-5 criteria for major depressive disorder or bipolar depression, scoring ≥21 on the 24-item Hamilton Rating Scale for Depression (HRSD-24), and screened with the MINI interview. Key exclusions included involuntary admission, active suicidal intent, recent ECT (within two months), MoCA <24, recent substance dependence, pregnancy or medical contraindications to ketamine or midazolam. Block randomisation (blocks of two and four) was performed by an independent researcher; allocation was held by the anaesthetist who administered infusions and could be unblinded for safety. Participants continued treatment-as-usual directed by their treating teams throughout the trial. Infusions were delivered weekly for four weeks, each as a 50 ml saline solution infused over 40 minutes; ketamine 0.5 mg/kg or midazolam 0.045 mg/kg. The anaesthetist was unblinded for safety monitoring but did not perform assessments or analysis. Blinding success for patients and raters was assessed after the first infusion. The primary clinical outcome was change in HRSD-24, measured pre-infusion (-60 minutes), and at 120 and 240 minutes after infusion start, with weekly pre-infusion scores used as week-by-week measures and end-of-treatment taken one week after the final infusion. Follow-up HRSD-24 assessments occurred at six and 12 weeks. Response was defined as ≥60% decrease from baseline HRSD-24 and score ≤16; remission required ≥60% decrease and score ≤10 on two consecutive weekly ratings. Secondary safety and tolerability assessments included CADSS for dissociation, the positive symptom subscale of the BPRS for psychotomimetic effects, the YMRS mood item for mania, the PRISE for patient-rated side-effects, vital signs and ECG monitoring, and MoCA for cognition at multiple time points. Researchers contacted participants 24 hours post-infusion to check adverse effects. Statistical analysis was descriptive in this pilot context. Baseline characteristics were summarised with means (SD) or medians (range) and variables tested for normality with the Kolmogorov-Smirnov test. The investigators calculated 95% confidence intervals for between-group differences at end of treatment. Analyses were performed using IBM SPSS Statistics v24.0. Recruitment target had initially been 40 participants to allow biomarker work, but recruitment stopped after 25 enrolees because this number was judged sufficient for pilot aims; the team regarded ~12 participants per arm as adequate for a pilot trial.

Recruitment and retention: Over nine months (September 2017–June 2018), 1,581 inpatient admissions were screened for eligibility, 125 (8%) met initial criteria and 25 (20% of eligible) consented to participate. Thirteen participants were randomised to ketamine and 12 to midazolam. Sixteen participants (64%) completed all four infusions, eight in each arm. End-of-treatment HRSD-24 assessments were obtained for 11/13 (85%) in the ketamine group and 12/12 (100%) in the midazolam group. Follow-up retention was 18/25 (72%) at six weeks and 19/25 (76%) at 12 weeks, with similar rates between groups. Primary depression outcomes: Both groups showed reduced HRSD-24 scores at end of treatment compared with baseline and followed a similar trajectory over time. The mean difference in HRSD-24 between ketamine and midazolam at end of treatment was -2.6 points (95% CI -8.26 to 3.03), favouring ketamine numerically but with a confidence interval that included no effect. QIDS-SR16 self-report scores tracked similarly to HRSD-24. No participants met response criteria within four hours of the first infusion for either group. Response and remission rates: At end of treatment, responders numbered 6/11 (55%) in the ketamine arm and 6/12 (50%) in the midazolam arm; remission was achieved in 2/11 (18%) versus 4/12 (33%), respectively. At 12-week follow-up responders were 7/10 (70%) in the ketamine group and 4/9 (44%) in the midazolam group, with remissions 2/10 (20%) and 2/9 (22%). The investigators note small sample sizes and that the trial was not powered to detect statistical differences. Safety and tolerability: No serious adverse events or reactions occurred. Dissociative and psychotomimetic symptoms, assessed with CADSS and BPRS positive symptoms, were more prevalent with ketamine, particularly during the first infusion, and diminished with subsequent infusions. The most common new-onset physical symptoms after the first ketamine infusion were anxiety and dizziness (each reported by 31%), restlessness, fatigue, poor co-ordination and dry mouth. Two ketamine participants found anxiety and nausea/vomiting distressing and withdrew after the first infusion; overall 3/25 (12%) discontinued due to side-effects. Vital-sign monitoring showed transient haemodynamic effects: mean systolic blood pressure change from baseline to 40 minutes in infusion 1 was +16.6 (11.5) mmHg for ketamine and -13.3 (17.1) mmHg for midazolam. Nine participants had ≥20% systolic BP increases during the first infusion (eight ketamine, one midazolam); all resolved without pharmacological intervention and returned to within 20% of baseline on repeat measurement. No participants had heart rate >110/min during infusion monitoring and oxygen saturation and ECG remained stable. MoCA scores showed no clear differences over time between groups. Blinding and other procedural outcomes: Blinding appeared imperfect: after the first infusion 10/13 (76.9%) ketamine participants and 7/12 (58.3%) midazolam participants correctly guessed allocation; raters guessed correctly for 10/13 (76.9%) ketamine and 10/12 (83.3%) midazolam cases. Reasons for discontinuation included side-effects (3/9), initiation of ECT (2/9), scheduling conflicts (1/9) and discharge before completing infusions (3/9).

Gallagher and colleagues interpret the findings primarily through the lens of feasibility. Recruitment and retention rates were judged satisfactory for a definitive trial, with 20% of eligible inpatients consenting and acceptable adherence to the four-infusion schedule for most participants. Using midazolam as an active comparator was highlighted as a strength because it may better preserve blinding than saline and increases the generalisability of results by evaluating ketamine as an adjunct to routine inpatient care rather than after a medication washout. In terms of efficacy, the investigators did not observe a clear superior antidepressant effect of serial ketamine infusions compared with midazolam in this small sample; both groups showed similar reductions in depression scores and no rapid response within hours of the first infusion. They place these results in the context of prior trials that have yielded inconsistent findings for repeated ketamine dosing and note that a sustained benefit from serial infusions remains uncertain. Safety findings aligned with existing literature: dissociation and transient haemodynamic changes were more common with ketamine but were generally short-lived and diminished across repeated infusions; no episodes of mania, psychosis or serious adverse events occurred. The authors acknowledge several limitations. As a pilot study, it was underpowered to detect clinically important differences in depression outcomes. The single-centre inpatient setting and the requirement that infusions occur while hospitalised limit generalisability to other populations and outpatient settings. Continuing treatment-as-usual, including medication changes and multidisciplinary care, complicates attribution of effects specifically to ketamine. Blinding was imperfect based on participant and rater guesses after the first infusion. Finally, the sample included both unipolar and bipolar depression but excluded those with prior psychotic illness, which constrains applicability. Implications the authors discuss focus on trial design: a definitive trial appears feasible but should consider strategies to improve tolerability (for example, dose titration), preserve blinding and account for concurrent treatments. They also recommend larger studies to clarify whether serial adjunctive ketamine confers sustained antidepressant benefit and to monitor longer-term safety with repeated dosing.

The investigators conclude that a definitive randomised trial of adjunctive ketamine for inpatients with a depressive episode is feasible. Recruitment and retention were satisfactory in this pilot, and four once-weekly ketamine infusions were generally well tolerated; 3/25 (12%) discontinued because of side-effects. The authors call for further studies to evaluate longer-term effects and safety of repeated ketamine administration.