Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects (NCT02487485), a randomized phase 2 study. The primary outcome is Montgomery-Asberg Depression Rating Scale.

2. Clinical Question

The clinical question is therefore about the added treatment context around ketamine, not a comparison of ketamine with no ketamine: ketamine appears in both described conditions. The crossover structure means that the two combinations were administered to the same participants at different occasions, in differing orders as described by the arm labels. The registry record does not explain how order was assigned, whether periods were separated by a washout, or how order and period effects were handled in the statistical analysis. Those details matter when interpreting a crossover comparison, because an observed difference could reflect more than the treatment combination alone if period or carryover effects are present.

3. Trial Design

This was a Phase 2, randomized, triple-masked, crossover study sponsored by Yale University. The registry lists depression as the condition, an enrollment of 23, and a completed status. The record gives a start date of 2016-03 and a primary completion date of 2020-01. These dates describe the registered study timeline, not the timing of individual participants’ treatment or outcome measurements.

The intervention descriptions place ketamine in both conditions. In one, ketamine was paired with sirolimus; in the other, ketamine was paired with placebo. The arm descriptions state that participants were treated twice, with the other study medication given at the second occasion after two weeks. Thus, this is not described as a parallel comparison in which one group receives sirolimus and another receives placebo throughout. It is a crossover comparison of treatment occasions, with the order of sirolimus and placebo differing between the two arm descriptions.

Randomization and triple masking are recorded, but the registry record does not identify which people or roles were masked, how allocation was generated or concealed, or how the sequence was assigned. It also does not report a washout interval, a detailed visit schedule, or a statistical model for the crossover structure. A crossover design can make within-participant comparisons possible, but sound interpretation depends on the handling of treatment order, period effects, and possible carryover. The registry record does not report those details.

The primary outcome is MADRS score, with a timeframe of pretreatment and 2 week. Secondary outcomes include the Quick Inventory of Depressive Symptoms, Hamilton Anxiety Rating Scale, Clinician Administered Dissociative States Scale, the Positive subscale of the Positive and Negative Symptom Scale, and rapamycin and ketamine levels. The registry does not provide a reported primary-outcome analysis that resolves the multiple time points or categories noted in its outcome description.

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.

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 Montgomery-Asberg Depression Rating Scale, measured over Pretreatment and 2 week.

The primary endpoint is the Montgomery-Asberg Depression Rating Scale (MADRS), a standardized instrument used to assess depressed mood and neurovegetative signs and symptoms of depression. The registry describes the measure as a score on a scale ranging from 0-60, with higher scores indicating worse symptoms. A standardized rating scale gives investigators a structured way to quantify symptom severity rather than relying only on an unstructured impression.

The registry lists the primary timeframe as pretreatment and 2 week. Measurements at different times can describe symptom status and change over follow-up, but the record does not specify a single endpoint contrast, such as a particular change score or a particular visit comparison. Its note indicates that the primary outcome has several categories or time points and was not reduced to one comparison. Consequently, the stated endpoint identifies what was assessed but does not, by itself, establish which summary or contrast should be treated as the main result.

As a continuous measure, MADRS scores can be summarized by means and measures of variability. The registry identifies the parameter as a mean and the dispersion as a standard error, but does not post the actual values needed to interpret a treatment contrast. A mean describes the average score in the analyzed observations; a standard error describes uncertainty around an estimated mean, not the spread of individual scores. Without the posted group estimates, a contrast, and its uncertainty, the magnitude and precision of any primary-outcome difference cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Understanding the design and the reported endpoint helps clarify what statistical information would be needed to answer the trial’s question. The registry describes a randomized, triple-masked crossover study with a continuous primary measure. It does not report a primary treatment estimate, its uncertainty, or a specified analysis contrast. General statistical concepts can explain what those items would mean, but cannot supply the missing trial results.

What does a crossover comparison require?

In a crossover study, participants receive more than one condition at separate treatment occasions. Comparisons can use the fact that measurements come from the same participant, which can account for stable differences between people. But repeated measurements are not independent observations: they are linked within participant. A suitable analysis generally reflects that pairing rather than treating each treatment occasion as if it came from an unrelated person.

Period and sequence are also important. A period effect is a change associated with when a treatment is received, rather than with the treatment itself. A sequence effect concerns the order in which conditions are received. Carryover refers to an effect of an earlier condition that persists into a later period. These are general crossover-design concepts. The registry record does not report a washout, a model, or an analysis of period, sequence, or carryover, so it is not possible to say how those matters were handled in this trial.

What would a mean contrast describe?

The registry identifies the primary parameter as a mean. A mean is an average of the observed scores in the analysis population. A contrast between treatment conditions would express how those averages differ under a specified comparison. For MADRS, the registry states that higher scores are worse, so the direction of a contrast would need to be interpreted using that scoring rule. No such contrast is reported, and no direction or magnitude can be inferred from the design description.

A standard error is a measure of the statistical uncertainty in an estimated quantity, such as a mean. It is not the same as the spread of individual scores. A confidence interval uses an estimate and its uncertainty to describe a range of values compatible with the data under the analysis assumptions. The registry identifies standard error as the dispersion measure but does not post the underlying mean estimates or a confidence interval for a treatment contrast. Therefore, the precision of the primary comparison is not assessable from the registry record.

Why does endpoint definition matter?

An outcome name and a measurement timeframe do not fully specify an estimand, the precise quantity an analysis is intended to estimate. For example, a comparison could focus on change from pretreatment, a score at follow-up, or a model-based contrast across repeated measurements. These are general examples, not descriptions of the analysis used in this trial. The registry lists pretreatment and 2 week, and notes that the primary outcome has several categories or time points but was not reduced to one comparison. It does not report which contrast, population, or handling of events after randomization was intended for the primary analysis.

That distinction matters because results from different contrasts need not answer the same question. A change score uses each participant’s baseline value as a reference. A follow-up comparison focuses on scores at a particular assessment. A repeated-measures model can incorporate multiple observations, but its interpretation depends on model structure and assumptions. Without the chosen analysis definition, numerical results would be difficult to interpret even if isolated score summaries were available.

How should uncertainty and significance be read?

A confidence interval communicates both the estimated effect and its precision. A narrow interval indicates greater precision than a wide interval, while the values within the interval show which effect sizes remain compatible with the data under the method’s assumptions. A p-value addresses how compatible the observed data are with a specified null model; it does not quantify the probability that a treatment works, nor does it measure clinical importance. These are general explanations. The registry record does not report a p-value or confidence interval for the primary outcome.

Statistical significance and clinical importance are different considerations. A small effect can be estimated precisely, while a larger effect can remain uncertain when data are limited. Clinical interpretation also depends on the scale, context, and a meaningful-change threshold. No threshold for interpreting MADRS change is reported in the registry record, and no effect estimate is available to compare with one.

What can planning calculations tell a reader?

A sample-size planning illustration asks how many participants per arm might be needed under specified assumptions to detect a target effect with a chosen power and significance level. Such an illustration is prospective, not a report of how the trial performed. In this record, the stated assumptions include a two-sided significance level of 0.05, equal allocation, and a normal approximation; the target effect is expressed as a fraction of the observed effect. Those planning assumptions do not establish the trial’s original design rationale, because the record says the illustration is computed from the observed effect and is not the trial’s own design. A planning calculation is never observed power.

The registry record does not report the protocol’s sample-size justification, whether any interim analyses occurred, or the statistical analysis plan. It also does not provide the primary effect estimate needed for a reader to interpret a recalculation independently. The posted results identify no primary analysis to compare with an unadjusted recalculation. Accordingly, the design description and general statistical principles can guide questions to ask, but they cannot replace the unreported analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome measured at pretreatment and 2 week and notes that the outcome has several categories or time points but was not reduced to one comparison. It does not report which time point or contrast was designated for the primary statistical test. This leaves the primary analysis target unclear in the registry record.

Multiplicity arises when several outcomes, time points, or comparisons are assessed. If many hypotheses are tested, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for the number and structure of those tests. This is a general statistical concern; the registry record does not say whether multiplicity adjustment was planned or performed. It also does not report a hierarchy of primary and secondary analyses, or an approach for interpreting the several listed measures together.

The record names secondary measures covering depressive symptoms, anxiety, dissociative symptoms, positive symptoms, and drug levels. It does not provide results or analysis details for these measures. Their presence in the registry does not establish that each was analyzed or that any particular result was prespecified as confirmatory.

Missing-data methods and analysis populations are not reported in the registry record. The enrollment entry does not establish how many participants had usable MADRS observations, completed both treatment occasions, or were included in a particular analysis. The record does not describe missing visits, withdrawals, exclusions, imputation, or sensitivity analyses. These omissions limit assessment of possible bias and of how well the analyzed data represent the randomized participants.

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.

Most frequent non-serious adverse event terms

The registry reports serious adverse events for the listed treatment groups. For Ketamine + Sirolimus, the at-risk entry is 20, serious events affected 0, other adverse events affected 6, and deaths were 0. For Ketamine + Placebo, the at-risk entry is 20, serious events affected 0, other adverse events affected 6, and deaths were 0. These are the registry’s recorded figures for each group; they should not be combined into a new total.

“At risk” describes the denominator recorded for the adverse-event entries, while “affected” is the count of participants recorded with an event in the relevant category. Serious and other adverse events are distinct reporting categories in the registry. The record lists no serious adverse-event terms, but it does not provide the terms for the other adverse events in this summary.

These counts are descriptive. They do not establish whether an event was caused by a treatment, whether the groups differ statistically, or whether all events were captured and reported. The registry record does not describe event definitions, severity grading, exposure-adjusted rates, or a comparative safety analysis. The figures should therefore be read as recorded counts, not as proof of absence of risk or as evidence that one condition is safer.

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

The registry record establishes that a randomized, triple-masked crossover trial was completed and that MADRS was designated as the primary measure. It also describes two treatment occasions involving ketamine paired with sirolimus or placebo. Those details explain the question the study was intended to address, but they do not answer it quantitatively.

No primary-outcome estimate, treatment contrast, confidence interval, or test result is reported in the registry record. The direction and size of a difference between conditions are therefore unknown from the posted results. It is not possible to conclude from the record whether the scores differed, how precisely a difference was estimated, or whether any observed difference would be clinically meaningful.

The record’s note that the primary outcome has several categories or time points and was not reduced to one comparison adds uncertainty about what result should represent the main endpoint. The listed timeframe is pretreatment and 2 week, but the record does not identify a single reported contrast. The registry also does not describe how the crossover features, missing observations, or multiplicity were handled in an analysis.

The safety entries report no serious adverse events and no deaths in either listed group, with other adverse events recorded in each. Those entries are not an efficacy result and do not establish causal safety differences. A small descriptive count also cannot establish that unreported events did not occur.

Planning illustrations, where shown, answer a different question from an analysis of trial outcomes. They describe sample sizes under assumptions and should not be treated as observed power or as evidence about treatment effects. Overall, the record supports a description of the study’s design, aims, and recorded adverse-event counts, but not a conclusion about the primary treatment comparison.

13. Why This Trial Matters Statistically

This trial is statistically interesting because it uses a crossover structure to compare two treatment combinations in the same participants across separate occasions. In general, within-participant designs can reduce the influence of stable differences between people, but they require careful treatment of repeated observations and of possible period, sequence, and carryover effects. The registry’s description makes those considerations relevant, while the absence of a reported model leaves their handling unknown.

The study also illustrates why naming an outcome is not the same as specifying an analysis. MADRS is a recognized standardized measure, and the registry gives its direction and range. Yet the listed pretreatment and 2 week timeframe and the note about several categories or time points do not define one primary contrast. A clear estimand and analysis plan are needed to connect a clinical question to a reproducible statistical result.

Another statistical lesson is the distinction between a completed trial and an interpretable result. The status is completed, but the registry record does not report a primary-outcome estimate or its uncertainty. Without these, readers cannot assess effect size or precision. A completed study can still have an incomplete public statistical record for the question it was designed to address.

Finally, planning calculations should be kept separate from observed evidence. A sample-size illustration based on an observed effect and stated assumptions is not the original design justification and is not observed power. Recognizing that distinction prevents planning quantities from being mistaken for a trial’s primary findings.

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 main limitation for statistical interpretation is that the registry record does not report a primary MADRS analysis. It names the measure and timeframe, but provides no outcome estimate, contrast, confidence interval, or p-value. It also notes multiple categories or time points without reducing them to one comparison, so the primary result to interpret is not specified in the posted record.

The crossover design creates additional questions that the registry does not resolve. The record does not describe the treatment sequence-generation procedure, a washout interval, period or carryover assessment, or the statistical model. It states that treatment order differed, but does not explain the allocation sequence or how the analysis accounted for repeated observations.

The analysis population and missing-data procedures are not reported. Enrollment does not establish the number contributing data to the primary outcome, and the registry does not describe incomplete visits, withdrawals, exclusions, imputation, or sensitivity analyses. These details are important for assessing possible selection and missing-data bias.

The registry record also does not report a multiplicity strategy, a sample-size justification for the trial’s own design, an interim-analysis plan, or a full statistical analysis plan. The planning illustration is identified as an illustration computed from the observed effect, not as the trial’s original design. Finally, the adverse-event summary does not provide event terms beyond the serious-event listing, event definitions, or a comparative analysis. These limitations concern what can be learned from the registry record and should not be taken as claims about information that may exist elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects — NCT02487485.
• Registry record last updated 2020-07-16; status last verified 2020-07.
• Results first posted 2020-07-07.
• 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

NCT02487485 is a completed Phase 2, randomized, triple-masked crossover study sponsored by Yale University. The registry lists depression as the condition and an enrollment of 23. The study began in 2016-03, with primary completion in 2020-01.

The trial compared ketamine given with sirolimus against ketamine given with placebo across two treatment occasions. MADRS was the primary outcome, with pretreatment and 2 week listed as the timeframe. The registry record does not report a primary-outcome comparison or specify one primary contrast across the listed time points.

Serious adverse events and deaths are recorded as 0 in each listed group; other adverse events affected 6 in each group. These are descriptive registry counts. The record does not report the primary statistical analysis, analysis population, missing-data approach, or multiplicity handling.