Ketamine as an Adjunctive Therapy for Major Depression: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ketamine as an Adjunctive Therapy for Major Depression (NCT03256162), a randomized phase 1 study. The primary outcome is The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24).

2. Clinical Question

3. Trial Design

KARMA-Dep is described in the registry as a randomized, controlled, parallel-group pilot trial of ketamine versus midazolam as adjunctive therapy for depression. It is listed as phase 1, with quadruple masking and a planned enrollment of 25. The registry status is completed. The stated main purpose of the pilot was to assess trial processes to help inform a future definitive trial; the record therefore places emphasis on feasibility and processes, rather than presenting the study as a definitive test of treatment effect.

The ketamine arm was assigned four once-weekly infusions at 0.05mg/kg, and the midazolam arm four once-weekly infusions at 0.045mg/kg. A consultant anaesthetist was to administer all infusions. Details of the randomization sequence, allocation concealment, masking procedures, and how masking was assessed are not reported in the registry record.

The primary outcome was the HRSD-24 score at week 15. The registry describes measurements at baseline, one week after each of the four weekly infusions, and follow-up after another five and eleven weeks; week 15 is the reported time point. Six secondary outcomes are named, covering self-reported depressive symptoms, dissociative symptoms, psychiatric symptoms, a mania mood item, side effects, and cognitive assessment. The record does not describe the detailed analysis plan, participant flow, or how outcomes were handled when measurements were unavailable.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: Treatment-as-usual, by the participants' treating teams, continued throughout the entire trial.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24), measured over 15 weeks.

The primary endpoint is the mean score on the 24-item Hamilton Rating Scale for Depression, or HRSD-24, at week 15. The scale assesses the severity of depressive symptoms. Its score range is 0-77, with higher scores reflecting a greater burden of symptoms. The registry describes the HRSD as commonly used to measure depression severity.

A continuous score retains information about symptom severity across the scale, rather than reducing each participant’s result to a response or remission category. The registry also describes response, remission, and relapse criteria based on changes from baseline and score thresholds, but those criteria are not the reported primary outcome in this record. The endpoint is the mean HRSD-24 score at the specified follow-up time.

The registry reports a mean and 95% confidence interval for each arm. Such summaries describe the group-level scores and the uncertainty around each estimated mean; they do not, by themselves, quantify the uncertainty in the difference between groups. No between-group primary-outcome analysis is posted in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: each participant’s HRSD-24 is a score, and the registry reports a group mean. For a continuous outcome, a mean describes the average score in the group, while individual scores may vary around that average. The group mean is not the score of a typical individual by definition, and it does not describe the full distribution of scores.

What do the confidence intervals describe?

A confidence interval expresses the statistical uncertainty around an estimated quantity. In this record, each interval is attached to an arm-specific mean. In general, a narrower interval indicates greater precision for that estimate, while a wider interval indicates less precision. These intervals concern the means, not the spread of individual participant scores. The posted intervals are 6.2 to 16.2 for ketamine and 7.8 to 25.3 for midazolam.

The registry does not report a confidence interval for the difference between the arm means. That distinction matters: uncertainty about each mean is not identical to uncertainty about the contrast between means. A direct comparison would use an estimate of the between-group difference and its uncertainty, with methods appropriate to the trial analysis. Neither that estimate nor a p-value for the primary outcome is posted. It would be inappropriate to infer a formal comparison from the separate summaries alone.

What does randomization contribute?

Random allocation is intended to support a fair comparison by assigning participants to study groups through a chance-based process. In a well-conducted randomized trial, this can reduce systematic differences between groups at allocation. Randomization does not guarantee that the groups will have identical baseline characteristics, particularly in a pilot with small groups. The registry does not report baseline characteristics, sequence generation, allocation concealment, or details that would allow those aspects of implementation to be assessed.

What does masking mean in this record?

The registry labels the trial quadruple masked. Masking is generally intended to limit the influence of expectations or knowledge of assigned treatment on participants, clinical care, outcome assessment, or analysis. The record does not specify which roles were masked, how masking was maintained, or whether it was successful. The label alone cannot answer those implementation questions.

How should the pilot purpose shape interpretation?

The registry states that the main purpose was to assess trial processes to inform a future definitive trial. Pilot findings can help describe whether trial procedures were undertaken and can offer preliminary outcome summaries. They are not automatically a definitive estimate of treatment effect. Here, the posted primary outcome information is limited to arm-specific means and confidence intervals, and there is no reported comparison analysis. This supports descriptive reading, not a firm conclusion about the comparative effect.

What are the planning illustrations?

Any sample-size illustrations associated with the results are planning calculations based on the observed effect, not results observed in this trial and not the trial’s own design justification. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is expressed as a fraction of the observed effect. Such illustrations describe hypothetical planning under those assumptions. They are not observed power, and they do not show that the pilot was designed or powered to detect a particular effect. The registry does not report a sample-size justification or the assumptions used in the original design.

More generally, calculations that use observed effects for planning can be uncertain, especially when estimates come from a small pilot. They should be treated as scenarios for planning rather than reliable forecasts of a future study’s result. The registry does not report a prespecified statistical analysis plan, an interim analysis plan, or the details of any recalculated comparison. The posted arm summaries should therefore remain separate from hypothetical planning work.

10. Multiplicity, Missing Data and Analysis Populations

The registry names six secondary outcomes in addition to the primary HRSD-24 outcome. These cover the QIDS-SR16, CADSS, BPRS, YMRS mood item, PRISE, and MoCA. The record lists seven outcome measures overall, but reports no analyses for the secondary outcomes in the posted results. It does not describe a multiplicity strategy or state how testing across several outcomes would be interpreted. When multiple outcomes are examined, the chance of at least one apparently unusual result can increase; a prespecified approach can help clarify how evidence across outcomes should be assessed. The applicable approach is not reported in the registry record.

The record also does not report the statistical analysis plan, the analysis population for the primary endpoint, or whether analyses followed the assigned groups. It does not describe how missing outcome data were handled, whether any imputation was used, or how many participants had unavailable measurements at week 15. The number contributing to each posted primary mean is 8 in each arm, but the registry does not explain the relationship between those outcome summaries and the planned enrollment.

Without these details, readers cannot assess whether exclusions or missing measurements may have affected the summaries, or whether the reported endpoint analysis followed prespecified procedures. No interim analysis information is reported in the registry record. These gaps are particularly relevant to interpretation of a pilot, where transparent reporting of participant flow and analysis methods helps distinguish feasibility findings from outcome comparisons.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry reports serious adverse events affecting 0 participants among the 13 at risk in the ketamine group and 0 participants among the 12 at risk in the midazolam group. It also records 0 deaths in each group. No serious adverse event terms are listed. These figures describe what was recorded in the registry for the stated groups and should not be read as proof that no safety events could occur.

The registry also lists 0 other adverse events affecting participants among the 13 at risk in the ketamine group and 0 among the 12 at risk in the midazolam group. The record does not provide further event-level detail in the information. Counts of affected participants are distinct from counts of event episodes, and the registry figures should be understood according to the categories it reports.

Safety counts from a pilot are descriptive. The small numbers at risk limit how much can be inferred about uncommon events, and the record does not report a comparative statistical analysis of safety outcomes. These figures do not establish equivalent safety between groups.

12. What the Result Does, and Does Not, Mean

The primary results show the week 15 HRSD-24 mean and 95% confidence interval in each randomized arm. They provide a descriptive view of symptom-severity scores among the participants contributing to those summaries. The registry does not post a direct estimate or inferential test of the between-group difference, so the summaries do not establish whether the arms differed statistically or how precise a comparative effect might be.

The trial’s stated purpose was to assess processes that could inform a future definitive trial. Its pilot status is important: the posted arm summaries can be informative as preliminary outcome data, but they should not be interpreted as a definitive efficacy conclusion. The registry does not report the detailed analysis plan, baseline outcome summaries, or handling of missing data, all of which would help contextualize the endpoint results.

The findings also do not establish that the two treatments are equivalent. A lack of a reported comparison is not evidence that there is no difference. Nor do the reported means alone justify a claim that one treatment works or does not work. The confidence intervals describe uncertainty around the group means, not a guarantee about individual outcomes or a direct measure of comparative uncertainty.

The registry’s safety figures record no serious adverse events or deaths in either group during the reported accounting. Those counts are descriptive and do not rule out risks that a small pilot could not characterize. Likewise, the named secondary outcomes cannot expand the interpretation because their analyses are not reported in the registry record. The appropriate reading is therefore limited to the information actually posted: group-level week 15 scores and recorded safety counts, within a process-focused pilot whose comparative outcome analysis is unavailable.

13. Why This Trial Matters Statistically

This trial illustrates why a clinical trial result needs to be read in light of its stated purpose and the analysis actually reported. KARMA-Dep is described as a pilot intended to assess trial processes and inform a future definitive trial. The primary endpoint summaries offer preliminary information about week 15 HRSD-24 scores, but the registry does not report a direct comparison of the randomized groups. Separating descriptive summaries from inferential comparisons prevents an arm-specific mean from being mistaken for a treatment-effect estimate.

The record also highlights the role of uncertainty. A mean is a compact description of group outcomes, while its confidence interval shows uncertainty around that estimated average. Neither is a substitute for a between-group estimate with its own uncertainty. This distinction is central when readers encounter results for parallel groups and need to know whether an apparent difference has been formally evaluated.

Finally, the registry identifies several secondary outcomes but does not post their analyses, and it does not describe multiplicity, missing-data handling, or the analysis population. Transparent reporting of these methods is important for understanding how robustly trial results answer their intended question. The example underscores a basic statistical lesson: a completed pilot can yield useful descriptive information without resolving the comparative question that a larger definitive study would address.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record gives limited detail for evaluating the primary outcome beyond the arm-specific means, confidence intervals, and numbers contributing to those summaries. It does not report a between-group estimate, p-value, baseline HRSD-24 values, or an adjusted analysis. The methods used to calculate the confidence intervals are not described in the posted outcome information.

Participant flow and missing-data handling are also not reported. The record does not explain why the number contributing to each primary outcome summary is as listed, whether all randomized participants were included in the analysis, or whether unavailable measurements were imputed. Without those details, it is difficult to assess how the reported summaries relate to the trial’s planned enrollment or whether missing outcomes could affect interpretation.

Important design and implementation details are absent, including the randomization sequence method, allocation concealment, and which roles were masked. Although the registry labels the trial quadruple masked, it does not explain the masking procedures or report whether masking was maintained. The record does not describe a statistical analysis plan, sample-size justification, interim analyses, or a multiplicity strategy for the named secondary outcomes.

The trial is identified as a pilot focused on trial processes, and the primary outcome summaries are based on small groups. The record does not post analyses for the six secondary outcomes. Together, these limitations leave the comparative effect and the broader outcome pattern uncertain. They do not negate the descriptive information, but they constrain conclusions that can be drawn from the registry results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Ketamine as an Adjunctive Therapy for Major Depression — NCT03256162.
• Registry record last updated 2020-01-18; status last verified 2020-01.
• Results first posted 2020-01-18.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

KARMA-Dep is a completed, randomized, quadruple-masked, parallel-group phase 1 pilot trial comparing ketamine with midazolam as adjunctive therapy for depression. Its stated main purpose was to assess trial processes to inform a future definitive trial.

The primary endpoint was mean HRSD-24 score at week 15. The ketamine group mean was 11.2, with a 95% confidence interval from 6.2 to 16.2; the midazolam group mean was 16.6, with a 95% confidence interval from 7.8 to 25.3. The registry does not post a direct comparison analysis. Six secondary outcomes are named, but their analyses are not reported in the registry record. Safety entries record 0 serious adverse events and 0 deaths in each group.