Repetitive Transcranial Magnetic Stimulation for Adolescent Depression: Efficacy, Predictive Biomarkers, and Mechanisms: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Repetitive Transcranial Magnetic Stimulation for Adolescent Depression: Efficacy, Predictive Biomarkers, and Mechanisms (NCT02611206), a non-randomized na study. The primary outcome is Change in Score on Child Depression Rating Scale - Revised (CDRS-R).

2. Clinical Question

The study’s stated focus joins safety and tolerability with a depression-severity measure. Its brief description explains a 3+3 escalation approach: participants were to begin at 80% of MT, with intensity increased in 20% steps after safe completion at a level, subject to stopping rules for major safety events. That plan describes how investigators intended to explore intensity; it does not itself establish that every level was used or that all enrolled participants completed treatment.

The registry also lists secondary measures concerning depression, suicide severity, pleasure, anxiety and depression symptoms, and mania. The record does not give their observed results. Accordingly, the available description identifies the questions and measures but does not provide evidence with which to estimate treatment-associated changes or compare them with an untreated or alternative-treatment group.

3. Trial Design

This completed study is registered as NCT02611206 and is sponsored by the University of Minnesota. The record lists the phase as NA, a non-randomized allocation, no masking, and a single-group model. Enrollment is listed as 24. The study start is recorded as 2015-10 and primary completion as 2021-12-01. These record details describe the study’s registration and status; they do not supply participant-level results.

The brief summary describes an open-label course of active rTMS lasting 6 weeks, with 30 sessions and a fixed frequency of 10 Hz. The listed interventions use 80%, 100%, and 120% of MT. The planned intensity sequence was safety-oriented: begin at 80% of MT, increase by 20% after three participants safely completed treatment at a level, and enroll additional participants at the same level if a major safety event occurred in one of the initial three. The summary says that reaching two major safety events at a level would stop enrollment at that level; further steps depended on whether the level was initial or higher.

Those descriptions are protocol plans, not confirmation of the treatment each participant received. Actual enrollment by intensity, dose changes, completion by period, and the number treated at each intensity are not reported in the registry record. Nor is it reported whether the planned 3+3 rules were followed without modification.

Because the study was non-randomized, unmasked, and single-group, it does not provide a randomized contrast against a control treatment. Changes over time could not be separated from the influence of treatment using a concurrent randomized comparison. The intensity periods also should not be read as randomized groups: eligibility for later periods depended on the sequence and safety experience described in the plan. Actual group composition and the comparability of participants across intensity levels are not reported in the registry record.

The study is marked completed, but completion status alone does not show that the primary endpoint or every planned measure was analyzed. The registry lists 17 outcome measures and no analyses. The statistical analysis plan, any changes to the planned design, and the final analysis populations are not reported in the registry record.

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 Change in Score on Child Depression Rating Scale - Revised (CDRS-R), measured over Baseline to post-treatment.

The primary endpoint is change in score on the Child Depression Rating Scale-Revised (CDRS-R), from baseline to post-treatment. The record describes the CDRS-R as a clinician-completed measure based on interviews with the child or adolescent and their parent. It covers 17 symptom areas, with item ratings on a Likert scale ranging from 1 to 5 or 7. The raw summary score ranges from 17 to 113, and higher scores indicate more severe depression and a worse outcome.

The registry defines change by subtracting the post-rTMS score from the baseline score. Under that convention, a positive value means the score decreased between baseline and post-treatment. It is important to retain this direction when reading any reported change: positive change does not mean that the post-treatment score was higher.

A clinician-rated symptom scale can provide a structured way to describe severity at assessment points. A change score expresses how the recorded measure differs over time for participants with the required assessments. It remains a measure on the scale, not by itself a description of why scores changed or whether the change was caused by treatment. In this single-group, open-label study, the endpoint would not create a randomized treatment-versus-control comparison.

The registry does not report the observed primary mean change, standard deviation, number contributing to the endpoint, or a confidence interval. It therefore does not report the magnitude or precision of the primary result. The CDRS-R description refers to adolescents and children ages 6 to 12, while the study is described as concerning adolescents; participant ages and any measure-specific eligibility details are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry names a continuous primary measure summarized as a mean, with standard deviation as the dispersion measure. No mean, standard deviation, or analysis result is reported for the primary endpoint. The following concepts explain how such statistics are generally read; they are not claims about analyses performed in this study.

What a mean change represents

For a continuous measure, a mean is the arithmetic average of observed values in the analyzed group. For a change endpoint, the mean change describes the average of participant-level changes when those changes are available. Here, the registry specifies the direction as baseline CDRS-R score minus post-treatment CDRS-R score. The scale description makes clear that higher scores indicate greater depression severity, so positive change under this convention corresponds to a decrease in score.

A group mean does not show how similar or different individual participants’ changes were. Participants may have changes near the average or far from it. The standard deviation describes the spread of observations around the mean. A larger standard deviation indicates more variation in the measured values; a smaller one indicates less variation. The registry does not report the primary endpoint’s mean or standard deviation, so neither the average nor the variability can be characterized from this record.

What a confidence interval would convey

General explanation: a confidence interval gives a range of values compatible with the data and the method used to calculate it. Its width communicates precision: a wider interval indicates greater uncertainty about the estimated value, while a narrower interval indicates more precision under the analysis assumptions. A confidence interval is not reported for the primary endpoint in the registry record. Therefore, the precision of the primary estimate cannot be evaluated.

A confidence interval would not, by itself, resolve the design limitation. In a single-group study, an interval around mean pre-to-post change would quantify uncertainty about that group’s change estimate under the chosen method. It would not create a randomized comparison or separate change associated with treatment from other possible influences over time.

Why the escalation design matters

The brief summary describes a 3+3 safety and tolerability design. Participants were to enter cohorts at successive intensity levels according to rules tied to completion and major safety events. In general, this kind of rule-based escalation is intended to guide decisions about whether to increase, hold, or stop an exposure while monitoring safety. It is not the same as random assignment across treatment levels. Later cohorts can differ from earlier ones for reasons related to the sequence, eligibility, calendar time, or other factors; which of these applied cannot be determined from the registry record.

The listed levels are 80%, 100%, and 120% of MT, and the summary describes 20% increases between levels. Actual numbers treated at each intensity, actual escalation decisions, and outcome summaries by intensity are not reported in the registry record. Thus, the planned rule should not be mistaken for observed adherence or evidence that all listed levels were reached.

Why over-dispersion can matter

General explanation: over-dispersion occurs when observed variation is greater than assumed by a statistical model. When a model understates variability, its uncertainty estimates can be too small, making results appear more precise than they are. The registry identifies the primary measure as continuous and names a standard deviation, but it does not report a model, residual checks, or information that would show whether over-dispersion was assessed. It would be inappropriate to infer that any particular model or diagnostic was used.

Planning calculations are not observed evidence

The assumptions accompanying the planning illustration describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect defined as a stated proportion of an observed effect. Those assumptions are not a description of the registered single-group design, which has no randomized two-arm comparison. No planning sample-size values are reported in the registry record. A planning illustration based on an observed effect is not an observed trial result, and a sample-size calculation is not evidence that the study achieved a particular level of power.

General explanation: power is a design-stage probability defined under specified assumptions about the effect, variability, sample size, and analysis. It is not a measure of how likely a result is to be true after the study. Retrospective calculations based on an observed estimate can be especially difficult to interpret because the estimate itself is uncertain. The record does not report a protocol sample-size justification or any study-specific power calculation.

What is missing for statistical interpretation

The registry lists 17 outcome measures and no analyses. For the primary endpoint, the record does not report the analyzed sample size, missing-data handling, estimate, standard error, confidence interval, hypothesis test, or model. It also does not report whether the analysis adjusted for baseline score or other variables. These details matter because the same endpoint can be analyzed in different ways, and those methods can affect the estimate and its uncertainty.

In general, results are most interpretable when the analysis population, outcome definition, missing-data approach, and planned statistical method are clear. This is particularly relevant to a repeated-measures design, where participants may not have measurements at every assessment. The record does not state how incomplete baseline or post-treatment assessments were handled, whether all enrolled participants were included, or whether any sensitivity analyses were conducted. No particular method should be assumed.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Period 1: 80% of MT", "Period 2: 100% of MT", "Period 3: 120% of MT")
n   <- c(3, 3, 8)
m   <- c(12.33, 1.33, 22.13)
sp  <- c(6.03, 3.79, 4.29)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Period 1: 80% of MT  3  12.330  6.030  -2.649  27.309
CARM  Period 2: 100% of MT  3  1.330  3.790  -8.085  10.745
CARM  Period 3: 120% of MT  8  22.130  4.290  18.543  25.717

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures, including the primary CDRS-R change and secondary measures of depression, suicide severity, pleasure, symptom subscales, and mania. When several outcomes are examined, general statistical practice distinguishes the prespecified primary question from additional or exploratory questions. Testing many outcomes can increase the chance of at least one apparently notable result, depending on how the tests are conducted. Methods such as a prespecified hierarchy or multiplicity adjustment can address particular forms of this issue, but the choice depends on the study plan and intended interpretation.

The registry record does not report a multiplicity strategy, a testing hierarchy, or which outcomes were treated as confirmatory versus exploratory. It also does not report analyses or results for the listed secondary outcomes. The mere presence of multiple registered measures does not indicate that all were tested, how they were tested, or whether any adjustment was used.

Missing-data methods and analysis populations are also not reported in the registry record. The record does not say how many participants completed each assessment, how missing baseline or post-treatment scores were handled, or whether the primary analysis included all enrolled participants or a subset. It does not report imputation, complete-case analysis, sensitivity analysis, or reasons for missing assessments. These omissions matter because an analysis based only on participants with complete observations can differ from one that handles missing outcomes under explicit assumptions.

The enrollment is listed as 24, while the safety group lists 14 participants at risk. The registry does not explain this difference. It should not be assumed that the safety denominator is the endpoint analysis population or that all enrolled participants contributed to the primary outcome.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: suicide ideation (7.1%), suicide intent (7.1%), suicide attempt (7.1%), seizure (7.1%).

The registry reports a safety group titled Open Label rTMS. For serious adverse events, 14 participants are listed as at risk and 2 as affected. For other adverse events, 14 are listed as at risk and 14 as affected. Deaths are listed as 0. The most frequently listed serious-event terms are Suicide ideation, Suicide intent, suicide attempt, and seizure, each shown with 7.1%.

These are descriptive safety figures, not proof that rTMS caused an event or that an event was unrelated to treatment. The registry does not report event timing, intensity level at the time of an event, seriousness criteria, relatedness assessments, or whether a participant could contribute more than one event term. The listed terms and percentages should therefore not be interpreted as mutually exclusive categories or as evidence about causation.

The at-risk denominator for the safety group is 14, while overall enrollment is listed as 24. The reason for that difference is not reported in the registry record. The serious-event counts also do not establish how many participants completed treatment, how safety findings informed escalation, or whether the planned stopping rules were triggered. The registry’s listed counts should be read as the posted safety summary, with those details unresolved.

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

The registry record establishes that this was a completed, open-label, non-randomized, single-group study of active rTMS for treatment-resistant depression. It describes a planned 6-week course of 30 sessions, a fixed frequency of 10 Hz, and a safety-oriented intensity sequence using 80%, 100%, and 120% of MT. It also identifies the primary outcome as CDRS-R change from baseline to post-treatment and defines positive change as a decrease in score.

Those details do not supply the primary result. The registry does not report the observed change, standard deviation, confidence interval, or analysis. Without them, the amount of change and its precision cannot be assessed. The endpoint definition explains how a result would be interpreted, but it is not itself evidence that the score changed.

Even if a pre-to-post change estimate were available, the design would limit what it could establish. General explanation: in an uncontrolled group, an observed difference over time cannot isolate the effect of treatment from other influences. Randomization and a concurrent control group can help address that problem, but this study is listed as single-group and non-randomized. The record therefore does not support a randomized comparative estimate.

The planned escalation sequence also does not amount to a randomized comparison among intensities. Later treatment levels depended on earlier safety experience according to the described rules. Actual level-specific enrollment and outcomes are not reported, so the record does not establish comparative results across intensity levels.

The safety counts offer a separate descriptive view: the registry lists 2 serious adverse events among 14 participants at risk, 14 affected by other adverse events among 14 at risk, and 0 deaths. The listed serious-event terms each have a percentage of 7.1%. These figures do not establish causality, comparative risk, or the relationship between events and dose. The reason the safety group has 14 at risk while enrollment is 24 is not reported.

In short, the record permits a careful account of the registered design, outcome definition, and posted safety figures. It does not report the primary efficacy estimate, analysis details, missing-data approach, or a control comparison. Those absences prevent a judgment about the size, precision, or cause of any change in depression scores.

14. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a safety-oriented escalation design and a conventional randomized efficacy comparison. The registry describes a 3+3 sequence in which changes in intensity depended on safety experience in preceding participants. Such a design addresses decisions about exposure and tolerability, while the primary endpoint is a measure of depression severity over time. These are related but distinct questions: monitoring safety during escalation does not, on its own, estimate a treatment effect against a control condition.

The single-group, open-label structure also makes the interpretation of a pre-to-post endpoint especially important. A change score can describe how measurements differ over time, but it cannot isolate the reason for the change without an appropriate comparison and supporting assumptions. This is a general design principle, not a claim about the direction or size of this study’s results. The registry does not report the primary outcome estimate needed even to describe the observed group change.

The record also illustrates why a named outcome and a completed status are not equivalent to a reported analysis. It specifies the CDRS-R, its score direction, and baseline-to-post-treatment timeframe, yet does not report a mean, variability, or inferential result. Without those quantities, readers cannot assess precision or determine how much information the data contribute.

Finally, the difference between the total enrollment of 24 and the safety group’s 14 at risk is a consequential reporting gap. It prevents a clear account of how the safety denominator relates to the enrolled population. Together, these features make it important to keep design, planned procedures, observed outcomes, and statistical inference distinct when interpreting the record.

15. 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 principal limitation for interpretation is that the registry record does not report the primary endpoint result or any analyses. It provides no mean change, standard deviation, confidence interval, hypothesis test, or number of participants contributing to the primary measure. The size and precision of any observed CDRS-R change are therefore unknown from the record.

The study is listed as single-group, non-randomized, and unmasked. There is no randomized control comparison, so a pre-to-post change would not by itself distinguish treatment-associated change from other changes over time. The intensity periods are part of a planned sequence governed by safety experience, not randomized groups. Actual treatment by intensity and results by intensity are not reported.

The registry does not state whether the planned 3+3 rules were followed, how many participants completed treatment, or why the safety group’s at-risk count of 14 differs from the enrollment of 24. It does not describe the analysis population, missing-data handling, or participant flow. These gaps limit interpretation of both endpoint and safety denominators.

Although 17 outcome measures are listed, the analysis plan, multiplicity approach, and results for secondary outcomes are not reported. The record does not identify confirmatory and exploratory analyses or state whether any adjustment for multiple testing was planned. It also does not report a protocol sample-size justification.

The CDRS-R description refers to adolescents and children ages 6 to 12, but the registry does not report participant ages or clarify how the scale description relates to study eligibility. Safety event timing, attribution, intensity level, and details of event overlap are likewise not reported. These omissions make it difficult to connect the posted safety terms to the planned escalation process.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Repetitive Transcranial Magnetic Stimulation for Adolescent Depression: Efficacy, Predictive Biomarkers, and Mechanisms — NCT02611206.
• Registry record last updated 2023-05-18; status last verified 2023-04.
• Results first posted 2023-05-18.
• 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.

19. Record Summary

NCT02611206 is a completed, University of Minnesota-sponsored, non-randomized, open-label, single-group study of active rTMS for treatment-resistant depression. Enrollment is listed as 24; the phase is listed as NA. The study start is recorded as 2015-10, with primary completion on 2021-12-01.

The planned treatment was 6 weeks and 30 sessions at a fixed frequency of 10 Hz, with stimulation intensity levels of 80%, 100%, and 120% of MT described in a 3+3 safety and tolerability escalation plan. The primary endpoint was change in CDRS-R score from baseline to post-treatment, with positive change defined as a score decrease.

The record lists 17 outcome measures and no analyses. It does not report the primary endpoint result, statistical analysis details, missing-data methods, or actual enrollment and outcomes by intensity. For safety, it lists 14 at risk and 2 affected by serious adverse events, 14 at risk and 14 affected by other adverse events, and 0 deaths. The explanation for the safety denominator is not reported in the registry record.