This first pragmatic randomised pilot trial of four once-weekly adjunctive ketamine infusions in hospitalised patients with major depression found the infusions were generally safe and well tolerated but produced no significant difference in HRSD-24 scores versus midazolam. The study indicates a definitive trial of adjunctive ketamine is feasible.
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Zanos, P., Gould, T. D. · Molecular Psychiatry (2018)
Background : Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response. Methods : The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression. The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick’s Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up. Results : In total, 1581 admissions to St Patrick’s Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions : This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration : ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.
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.
Baseline clinical and demographic characteristics are presented using descriptive statistics. Variables were examined for normality using the Kolmogorov-Smirnov test. 95% confidence intervals for the differences between the groups at the end of treatment phase were calculated. Descriptive and comparative statistics were performed using IBM SPSS Statistics, version 24.0 (IBM Corp, Armonk, NY). We initially planned to recruit 40 participants (20 per group) to also allow for some biomarker research. However, recruitment ended earlier than expected when 25 participants had been enrolled in good time, demonstrating that a larger definitive trial was clearly feasible. A sample size of 12 participants per group is adequate for the purpose of a pilot trial. Data are presented as means (standard deviation (SD)) or medians (range).
This is the first pragmatic trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. The aim of this pilot trial was to assess the feasibility of this study to inform a future definitive trial. Recruitment was successful and 20% of patients who were eligible for this study consented to take part. Adherence to interventions was also satisfactory with 8/13 participants completing all four ketamine infusions and 8/12 completing all four midazolam infusions. Overall, 16/25 (64%) of participants completed the intended four once-weekly infusions. Reasons for discontinuing included side-effects (3/9), commencing ECT (2/9), opting for doing an educational programme that coincided with clinic time (1/9) and being discharged from hospital before all four infusions were complete (3/9). Follow-up assessment rates were also adequate with 72% of participants completing the six-week and 76% completing the 12-week follow up. In general, ketamine and midazolam infusions were safe and well tolerated in our small patient sample. Dissociative side-effects were more prevalent in the ketamine group in line with results from previous trials. With each subsequent infusion, dissociative symptoms in the ketamine group diminished. Some trials have experimented with various doses of ketamine (lower than 0.5mg/kg) and have shown that some participants respond to ketamine at doses as low as 0.1mg/kg. Dose titration of ketamine may be an alternative way of minimising side-effects whilst optimising efficiency and therefore reducing dropouts as a result. There were no episodes of mania or psychosis during any of the infusions in this trial. Although increases in blood pressure were more common in the ketamine group, these were transient and had returned to baseline during the post infusion monitoring period. Increases in blood pressure in the ketamine group became less prevalent with subsequent infusion sessions. The most common physical side-effects reported in the ketamine group were anxiety and dizziness, however these also lessened with subsequent infusions. Physical symptoms reported in this pilot trial are in keeping with those documented in previous trials. In the midazolam group, the most commonly reported symptom was fatigue, the prevalence of which was maintained as the treatment course continued. The vast majority of new onset physical symptoms in both groups were considered to be tolerable. Apart from palpitations reported in the second ketamine infusion by one participant and dizziness on standing reported in the second midazolam session, there were no other new onset symptoms that emerged during the treatment course after the first infusion session. Previous studies have shown that a single infusion of subanaesthetic dose of ketamine has a fast acting antidepressant effect which is superior to placebo. This effect tends to start at 40 minutes after start of infusion, peak at day 1 and lose superiority at approximately day 10. Although this pilot trial was not sufficiently powered to detect differences in HRSD-24 depression scores, we did not observe the superior antidepressant effect of ketamine, with both groups having similar depression scores following each infusion period. No participants met response criteria within four hours of the first infusion session in either group. There have been very few trials that have examined serial ketamine infusions in depressed patients and results have been inconsistent in terms of its potential to prolong its antidepressant effects. As this is a pilot trial with a small number of participants, we were unable to establish differences in depression scores at the follow-up time points. Further research is required to establish the possible sustained antidepressant effect of serial ketamine infusions. Most previous trials that have used subanaesthetic doses of ketamine in the treatment of depression, have used saline as the placebo. There has been limited reporting of the success of blinding in many of these trials. In our pilot trial, 10/13 participants in the ketamine group correctly guessed their infusion and 7/12 in the midazolam group guessed correctly. Although these numbers are too small to interpret, it gives us some indication of the possible advantages of blinding when using midazolam as an active comparator. Midazolam mimics some of the psychoactive effects of ketamine making it potentially more acceptable as a placebo in clinical trials. A separate trial reported success of blinding in ketamine versus midazolam and had similar results to the Karma-Dep trial with 5/7 and 7/9 correctly guessing their allocated infusions to be ketamine and midazolam respectively. Strengths of this study include the use of midazolam as an active placebo, therefore, potentially helping with blinding and establishing an accurate treatment effect when compared to using only saline. Most other ketamine trials have used ketamine following a wash out period from other antidepressant therapies. As ketamine was used an as adjunctive treatment to other antidepressant medication and routine care in our trial, the results are more generalisable to real world practice. This trial has several limitations. As this is a pilot trial, it is not adequately powered to detect statistically significant differences between the depression scores of the two groups. Further limitations include eligibility being restricted to only inpatients within St Patrick's University Hospital and participants not being permitted to continue with the infusion clinics if discharged early from hospital. We included those with both unipolar and bipolar depressive disorders but excluded those with a previous psychotic illness. Treatment as usual was continued for all participants by their treating teams which included medication changes and multidisciplinary team input which makes it difficult to distinguish between the antidepressant effects of ketamine and those of other medication changes and therapies.
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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.