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

Study design and participants

The Karma-Dep (Ketamine as an adjunctive therapy for major depression) trial was a randomised controlled pragmatic pilot trial of four once-weekly ketamine infusions (0.5 mg/kg over 40 minutes) compared to midazolam infusions (0.045 mg/kg over 40 minutes) as an adjunctive therapy in hospitalised depressed patients. Midazolam was used as an active placebo to help with blinding¹⁴. Patients who were admitted to St Patrick’s University Hospital for treatment of a depressive episode between September 2017 and June 2018 and who met eligibility criteria for the trial were approached by the research team within 10 days of admission. Depressive episodes were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders – fifth edition, DSM-5²⁹, and confirmed using the Mini International Neuropsychiatric Interview (MINI; updated Version 7 for DSM-5)³⁰. After participants provided written and informed consent, they were invited to be randomised to a course of four once-weekly ketamine or midazolam (active comparator) infusions that began at the next clinic, which took place every Wednesday morning in St Patrick’s University Hospital. Treatment-as-usual, directed by the participants’ treating teams, continued throughout the entire trial. Psychotomimetic, physical, and cognitive outcomes were monitored before, during and after infusions. Participants were followed up for 12 weeks after the final infusion.

This clinical trial was approved by the Research Ethics Committees of both the Mater Misericordiae Hospital, Dublin, and St Patrick’s University Hospital, Dublin. This trial was also approved by the Health Products Regulatory Authority (HPRA) of Ireland, the relevant national body under the European framework for clinical trials (EudraCT 2016-004764-18 on 30/11/2016) and was registered with ClinicalTrials.gov (NCT03256162 on 21/08/2017).

Eligible participants were inpatient ≥18 years old, being treated for an acute depressive episode and met DSM-5 criteria for major depressive disorder (MDD) or bipolar affective disorder (current episode depression) and scored ≥21 on the 24-item Hamilton Rating Scale for Depression (HRSD-24). To be eligible for inclusion, subjects must have met each of the above criteria at screening and baseline assessments. Exclusion criteria were current involuntary admission, active suicidal intention, dementia, history of Axis 1 diagnosis other than a major depressive episode, ECT administered within the last two months, a Montreal Cognitive Assessment (MoCA) score <24, alcohol/substance dependence in the previous six months, pregnancy or inability to confirm use of adequate contraception during the trial, breastfeeding women and any medical condition rendering the patient unfit for ketamine/midazolam. Contraindications to ketamine, as per summary of product characteristics, included hypersensitivity to the active substance, uncontrolled hypertension, severe coronary or myocardial disease, cerebrovascular accident and cerebral trauma. Contraindications to midazolam included known hypersensitivity to benzodiazepines, severe respiratory failure or acute respiratory depression. All candidates meeting any of the exclusion criteria at screening/baseline were excluded from study participation.

Randomisation and blinding

Block randomisation was performed by another researcher within St Patrick’s University Hospital and who was not otherwise associated with the Karma-Dep pilot trial. Randomisation was done in blocks of two and four. This randomisation list was stored in a locked cabinet to which only the anaesthetist (ES) had access. A protocol was in place to allow emergency unblinding.

Study treatment assignment was blinded for both the raters and the participants as well as the regular treating teams. To ensure patient safety during infusions and in the post-infusion period, the anaesthetist administering the ketamine/midazolam infusions was not blinded but was not involved in assessments or data analysis. Infusions were prepared by the anaesthetist in a location separate to the infusion area and labelled as “trial infusion” prior to transfer to the infusion area. Success of blinding for patients and raters was assessed after the first treatment.

Assessments

The primary clinical outcome measure for this study was the change in the 24-item Hamilton Rating Scale for Depression (HRSD-24)³¹. HRSD-24 scores were obtained 60 minutes (-60 mins) before the infusion began (0 mins) and at 120 and 240 minutes after the start of the infusion. Scores on items such as sleep and appetite were carried over from the -60 mins HRSD-24 as they were unable to change in such a short period of time. The first pre-infusion HRSD-24 scores served as the baseline scores while subsequent pre-infusion scores served as weekly HRSD-24 scores with the end of treatment score taken one week after the final infusion. Follow-up assessments using the HRSD-24 were completed at six and 12 weeks after the final infusion. HRSD-24 interrater reliability was assessed before the study began and six-months into the recruitment period with intraclass correlation coefficient scores of ≥0.95.

Response to treatment was defined as achieving a ≥60% decrease from baseline HRSD-24 and a score ≤16. Remission criteria were ≥60% decrease in HRSD-24 from baseline and a score ≤10 on two consecutive weekly ratings. Criteria for relapse were a ≥10 point increase in HRSD-24 compared to responders’ end of treatment score and a HRSD-24 score of ≥16. A readmission to hospital for psychiatric treatment or episode of self-harm was also considered a relapse of a depressive episode. The 16-item Quick Inventory of Depressive Symptoms, self-report version (QIDS-SR 16) was used at all the same time points as the HRSD-24 to measure subjective depression ratings³².

Patient demographic information was collected pre-randomisation and included age, weight, education, marital status and socioeconomic group. Clinical variables included age of onset of depression, previous number of episodes, duration of index episode, prescribed psychotropic medications and length of hospital stay. Additional baseline assessments included the Maudsley Staging Method for Treatment Resistant Depression (MSMTRD), which is scored from 3 to 15 with higher numbers indicating a greater degree of treatment resistance³³.

To capture any side-effects participants may have experienced during or after the infusion period, we used a number of instruments before (-60mins), during (+30 mins) and after (+60 mins) the infusions. The Clinician-Administered Dissociative States Scale (CADSS)³⁴ was used to capture dissociative effects and is scored out of a maximum of 92. The positive symptoms subscale of the Brief Psychiatric Rating Scale (BPRS) was used to measure psychotomimetic effects³⁵. This 4-item positive symptoms subscale measures suspiciousness, hallucinations, unusual thought content and conceptual disorganisation and is scored out of a maximum of 28. We used the Young Mania Rating Scale (YMRS; mood item)³⁶ to assess for mood elevation with a maximum score of 4.

Heart rate, blood pressure, pulse oximetry, and ECG were recorded to measure haemodynamic changes before and during infusions and for a further 200 minutes. These vital signs measures were taken at baseline and every 10 minutes during the infusion period. When the infusion ended, they were taken every 20 minutes for a further 80 minutes and then every 40 minutes until the end of the four-hour monitoring period. Infusions were discontinued by the anaesthetist if there were persisting haemodynamic changes (i.e. heart rate >110/minute or systolic/diastolic blood pressure >180/100 or >20% increase above pre-infusion BP for more than 15 minutes) that did not respond to beta-blocker therapy.

The Patient-Rated Inventory of Side Effects (PRISE) was used to document other general adverse events by patients before (-60mins), during (+30 mins) and after (+60 mins) infusions³⁷.

Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA)³⁸ at baseline, one day after the first and final infusions and at the final follow-up 12 weeks after the last infusion.

Interventions

Ketamine (0.5 mg/kg) and midazolam (0.045 mg/kg) were made up as 50 ml colourless saline solutions and administered as slow infusions over 40 minutes using an infusion pump, as previously described³⁹. Like ketamine at 0.5 mg/kg, midazolam at 0.045 mg/kg has anaesthetic effects and causes some sedation with a similar time course. Participants were asked to fast for 8 hours prior to infusion clinics. All patients were monitored for heart rate, blood pressure, pulse oximetry and ECG before, during and after infusions. A researcher contacted each participant 24 hours after each infusion to check for additional potential adverse effects.

Patients were withdrawn from the trial if an infusion was discontinued for haemodynamic reasons or other serious medical contra-indications, e.g. over-sedation, hypoxia, intolerable adverse physical reactions; the patient developed mania or psychosis; the patient became severely depressed and/or suicidal. All infusions took place while participants were inpatients.

Statistical analysis

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 research⁴⁰. 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 trial⁴¹. Data are presented as means (standard deviation (SD)) or medians (range).

Participants

The CONSORT diagram in Figure 1 summarises reasons for ineligibility, non-recruitment and dropouts at each stage of the trial. Recruitment took place over a nine-month period between September 2017 and June 2018 and follow-up assessments were completed by September 2018. During this time, 1581 admissions to St Patrick’s University Hospital were assessed for eligibility. Of these, 125 (8%) were potentially eligible to participate in the trial and 25 (20%) of these agreed to participate. In total, 13 patients were randomly assigned to the ketamine arm and 12 to the midazolam arm. Demographic and baseline clinical characteristics of the sample are summarised in Table 1. The randomised groups were reasonably balanced with no major obvious differences between age, gender, baseline depression scores and level of treatment resistance.

Figure 1. CONSORT flow diagram.

EOT, end of treatment.

A total of 16 participants (64%) completed all four infusions, eight in each group. In the ketamine group, four (30.8%) participants discontinued after one infusion. Of these, two dropped out due to dissociative side-effects, one chose to do a therapeutic programme and could no longer attend the infusion clinics and one had improved sufficiently to be discharged from hospital. One participant (7.8%) discontinued after two infusions as they were prescribed electroconvulsive therapy (ECT). In the midazolam group, three participants (25%) discontinued after the second infusion. One was due to side-effects (nightmares), one was referred for ECT and one had improved sufficiently to be discharged from hospital. One (8.3%) discontinued after the third infusion as they left hospital against medical advice. End of treatment assessments were obtained for 11/13 (85%) of patients in the ketamine group and 12/12 (100%) in the midazolam group. Retention rates of participants who agreed to remain in the trial for follow-up purposes were as follows: 18/25 (72%) at six weeks and 19/25 (76%) after 12 weeks. Retention rates in the ketamine group were 9/13 (69%) at six weeks and 10/13 (77%) at 12 weeks. In the midazolam group rates were 9/12 (75%) at week six and 9/12 (75%) at week 12.

When asked about treatment allocation after the first infusion session, 10/13 (76.9%) in the ketamine group and 7/12 (58.3%) in the midazolam group correctly guessed their treatment. For raters, 10/13 (76.9%) guesses for the ketamine group and 10/12 (83.3%) for the midazolam group were correct.

Depression outcomes

Figure 2 compares the HRSD-24 scores in the ketamine and midazolam groups at baseline, end of treatment and follow up at weeks six and 12. Both groups followed a similar pattern, with depression scores lower at end of treatment than at baseline. Figure 3 shows a more detailed breakdown of the HRSD-24 scores for both groups at -60, +120 and +240 minutes during infusion sessions 1 to 4. The mean difference in HDRS-24 scores between the ketamine and midazolam groups, at the end of the treatment phase was -2.6 (95% CI -8.26 to 3.03) points. The QIDS-16 SR scores followed a similar pattern to the HRSD-24 scores, as shown in Figure 4 and Figure 5. Data relating to the very first infusion sessions have been previously reported on in a study examining peripheral blood molecular changes related to ketamine⁴⁰.

Figure 2. Depression rating scores at end of treatment and follow up timepoints: 24-item Hamilton Rating Scale for Depression (HRSD-24) scores are presented as mean (SD) values.

FU, follow-up. Number of participants at each stage: Baseline - Ketamine n=13, Midazolam n=12; End of treatment - Ketamine n=11, Midazolam n=12; Follow-up at 6 weeks - Ketamine n=9, Midazolam n=9; Follow-up at 12 weeks - Ketamine n=10, Midazolam n=9.

Figure 3. Depression rating scores throughout the infusion sessions: 24-item Hamilton Rating Scale for Depression (HRSD-24) scores are presented as mean (SD) values.

-60, 60 minutes before infusion begins; 120, 120 minutes post start of infusion; 240, 240 minutes post start of infusion. Number of participants at each infusion: Infusion 1 - Ketamine n=13, Midazolam n=12; Infusion 2 - Ketamine n=9, Midazolam n=12; Infusion 3 - Ketamine n=8, Midazolam n=9; Infusion 4 - Ketamine n=8, Midazolam n=8.

Figure 4. Patient-rated depression scores at end of treatment and follow up timepoints: 16-item Quick Inventory of Depressive Symptoms, self-report version, (QIDS-SR 16) scores are presented as mean (SD) values.

FU, follow-up. Number of participants at each stage: Baseline - Ketamine n=13, Midazolam n=12; End of treatment - Ketamine n=11, Midazolam n=12; Follow-up at 6 weeks - Ketamine n=9, Midazolam n=9; Follow-up at 12 weeks - Ketamine n=10, Midazolam n=9.

Figure 5. Patient-rated depression scores throughout the infusion sessions: 16-item Quick Inventory of Depressive Symptoms, self-report version, (QIDS-SR 16) scores are presented as mean (SD) values.

-60, 60 minutes before infusion begins; 120, 120 minutes post start of infusion; 240, 240 minutes post start of infusion. Number of participants at each infusion: Infusion 1 - Ketamine n=13, Midazolam n=12; Infusion 2 - Ketamine n=9, Midazolam n=12; Infusion 3 - Ketamine n=8, Midazolam n=9; Infusion 4 - Ketamine n=8, Midazolam n=8.

The rates of responders and remitters in both groups are shown in Table 2. There were no participants, in either group, who met response criteria during the first infusion session at either +120 or +240 minutes post start of infusion. At the end of treatment assessment, the proportion of responders in the ketamine and midazolam groups were 6/11 (55%) and 6/12 (50%) while remission rates were 2/11 (18%) and 4/12 (33%), respectively. By the 12-week follow-up, the proportion of responders in the ketamine and midazolam groups were 7/10 (70%) and 4/9 (44%) and proportion of remitters were 2/10 (20%) and 2/9 (22%) respectively.

Safety and tolerability

Several instruments were used before, during and after infusion sessions to assess for psychotomimetic side-effects. Figure 6 summarises the CADSS dissociative symptom scores obtained from the ketamine and midazolam groups at various time points during infusion sessions. Participants receiving ketamine tended to score higher than those in the midazolam group. During the first infusion, the mean CADSS score (at 30 minutes) was 17.8 (15.0) in the ketamine group and 3.4 (4.4) in the midazolam group. The peak CADSS scores within the ketamine group declined with each subsequent infusion session and returned towards pre-infusion levels at the +60 minute time point (i.e. 20 minutes after infusions finished) for each of the four infusions sessions (Table 3). Psychosis (BPRS) and mania (YMRS) scores are shown in Table 3. No participants in either group experienced psychosis or elevated mood during any of the infusion sessions.

Figure 6. Dissociative symptoms during infusion sessions: The graph shows the total mean (SD) scores for the Clinician-Administered Dissociative States Scale (CADSS) during allocated infusion sessions.

-60, 60 minutes prior to commencement of infusion; 30, 30 minutes post start of infusion: 60, 60 minutes post start of infusion. Number of participants at each infusion: Infusion 1 - Ketamine n=13, Midazolam n=12; Infusion 2 - Ketamine n=9, Midazolam n=12; Infusion 3 - Ketamine n=8, Midazolam n=9; Infusion 4 - Ketamine n=8, Midazolam n=8.

Table 4 shows the numbers of participants who experienced physical symptoms during each of the four infusion sessions as recorded by the PRISE. The most common new-onset side-effects that occurred during the first infusion session in the ketamine group were anxiety (31%), dizziness (31%), restlessness (23%), fatigue (23%), poor co-ordination (23%) and dry mouth (23%). These symptoms became less prevalent in subsequent infusion sessions. One participant reported new onset palpitations in the second ketamine infusion; however, this episode was short lived, was not distressing and was not described as a side-effect in subsequent infusions. There were no other new onset side-effects reported during subsequent ketamine infusions. The PRISE records whether the participants found the symptoms to be ‘tolerable’ or ‘distressing’. Two of the participants in the ketamine group reported anxiety as a new symptom in the first infusion session and found it to be distressing. The same two participants also experienced nausea and vomiting and reported this as distressing. Both participants dropped out of the trial after the first infusion session due to poor tolerability but agreed to be followed-up. All of the other symptoms reported in the ketamine group were considered to be tolerable.

The most common side-effects that were reported during the first infusion session in the midazolam group were sleeping too much (33%) and fatigue (42%). Fatigue continued to be reported in the midazolam group in subsequent sessions with 38% reporting it in the fourth infusion. One participant reported new onset dizziness on standing during the second midazolam infusion; however, this was not reported in subsequent infusions. There were no participants who described any physical symptom in the midazolam group as ‘distressing’. There were no obvious differences in terms of new onset physical symptoms between the two groups.

Of the 32 physical symptoms that were specifically inquired about, there were no new onset of symptoms for 15 of these in either group during any of the four infusions. There were no participants who experienced new onset urinary symptoms in either group.

Vital signs were closely monitored and recorded throughout each infusion session. Table 5 shows the mean scores for systolic blood pressure (SBP), diastolic blood pressure, heart rate and oxygen saturation for baseline and 10, 20, 30, 40 and 60 minutes post start of infusion for each of the four infusion sessions in both groups. Mean changes in SBP from baseline to 40 minutes into the infusion were calculated for both groups during the first infusion session. In the ketamine group, the mean change in SBP between these two time points was 16.6 (11.5) mm Hg. In the midazolam group, the mean change was -13.3 (17.1) mm Hg. SBP tended to increase at 40 minutes in the ketamine group while SBP decreased at 40 minutes in the midazolam group. Nine participants in total (36%) had an increase in SBP of ≥20% from baseline during the first infusion session. Eight of these received ketamine and one received midazolam. Three participants (14%) had an increase in SBP of ≥20% from baseline during the second infusion – all three were in the ketamine group. Two participants (12%) had ≥20% increase in SBP from baseline during the third infusion session – one from each group, and, two participants (13%) had this increase in SBP in the fourth infusion session and both were in the midazolam group. Blood pressures were measured again 10 minutes after these elevated readings, and all elevated blood pressures had returned to within 20% of their baseline measures at this time. No pharmacological intervention was required for any of the increases in BP. There were no participants with a heart rate above 110 per minute during the infusion phase or up to 200 minutes after the infusion. Stable oxygen saturation and electrocardiogram rhythm were observed in all participants during the monitoring period before, during and after the infusions for up to 200 mins. There were no serious adverse events or reactions throughout the trial.

The MoCA was used to assess cognitive function at four time points during the trial (Table 6). There were no obvious differences between the scores of the two groups at the four time points and scores did not appear to differ from baseline.

Underlying data

Access to raw data is restricted under Research Ethics Committees approval as even de-identified data may contain information that could potentially identify a participant which may present a potential breech in General Data Protection Regulation (GDPR). As a result, this data cannot be made available publicly. To access the data, please contact Bronagh Gallagher (bgallag@tcd.ie) or the Principal Investigator (d.mcloughlin@tcd.ie). Researchers must provide a written proposal on how the data will be used in research before access is granted.

Extended data

Zenodo: Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial). https://doi.org/10.5281/zenodo.4302297⁴³

This file contains the following data:

Reporting guidelines

Zenodo: CONSORT checklist for pilot studies for ‘Ketamine as an adjunctive therapy for major depression - a randomised controlled pragmatic pilot trial (Karma-Dep Trial)’ https://doi.org/10.5281/zenodo.4302297⁴³

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).