A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise (NCT02407704), a randomized phase 4 study. The primary outcome is Number of Participants Experiencing Remission.

2. Clinical Question

The study’s broader rationale was to investigate whether exercise-related changes in GABA function might mediate antidepressant effects, and to assess feasibility of the intervention and planned measurements. Its summary describes the work as a pilot and says it was not powered to test the full causal model. The listed secondary outcomes include inflammatory and genetic biomarkers, physical activity, cardiovascular fitness, functional MRI, and neurocognitive function.

3. Trial Design

This was a completed, randomized, parallel-group phase 4 study with no masking reported. The registry lists enrollment of 31. The study began in 2015-03, and primary completion was 2016-11. The sponsor is listed as Kirk Erickson, PhD. Randomization and the parallel model describe the intended study structure, but the registry record does not report the allocation sequence or concealment procedures.

The intervention groups were organized by age as well as treatment. In the 60-79 years of age groups, the registry lists Aerobic Exercise + Venlafaxine XR with 2 participants and Venlafaxine XR Only with 3 participants. In the 20-39 years of age groups, it lists 4 participants for Aerobic Exercise + Venlafaxine XR and 2 for Venlafaxine XR Only. The record does not explain how these group counts relate to the enrollment figure, or report a separate accounting of all randomized participants.

Venlafaxine XR was described as an oral medication with a target dose of 150mg/d and a response-dependent maximum of 300mg/d, for a minimum of 12 weeks. The exercise regimen was treadmill walking for 1 hour, 3 times/week for 12 weeks. In the medication-only description, lorazepam may be used for participants already taking it or needing it for sleep and/or anxiety. The complete rules governing medication adjustment, adherence, and co-interventions are not reported in the registry record.

The primary outcome was assessed from baseline, weekly for weeks 1 and 2, then biweekly for weeks 4-12. The record describes the MADRS as also being used to assess clinical response during the trial and to determine final medication dosage. At the end of week 6, participants with a MADRS score greater than 10 were to have venlafaxine XR increased from 150 mg/d to a maximum of 300 mg/d. Further details about the protocol’s operational conduct 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.

Before assignment: Participants were diagnosed using the SCID, and were excluded from participation if they did not meet criteria for Major Depressive Disorder. Participants were also excluded for presence of bipolar or psychotic disorders, alcohol/substance dependence within the past 3 months, or if they could not complete MRI.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 1 participant in the "Venlafaxine XR Only (20-39 Years of Age)" group was excluded from analyses as he/she discontinued the medication after week 8.

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 Number of Participants Experiencing Remission, measured over Baseline, weekly for weeks 1 and 2, then biweekly for weeks 4-12.

The primary endpoint was the number of participants experiencing remission. The registry defines remission as a MADRS score of 10 or less for at least two consecutive assessments, and says that study completers were classified as remitters or non-remitters. This is a binary classification at the participant level: each completer either met the stated rule or did not.

Repeated assessments matter to the definition. A single assessment meeting the score threshold would not, by itself, meet the stated requirement for remission; the threshold had to be met at consecutive assessments. The registry schedule began at baseline, continued weekly for weeks 1 and 2, and then continued biweekly for weeks 4-12. The record does not specify how the consecutive-assessment rule was applied when an assessment was missing.

A remission count is easy to interpret as a number of people meeting a prespecified clinical-state definition, but a count alone does not express the uncertainty around a treatment contrast. Interpretation also depends on the denominator and the definition of the analysis population. The registry lists the group counts and remission counts, and notes that one participant in the Venlafaxine XR Only (20-39 Years of Age) group was excluded from analyses after discontinuing medication after week 8. The exact analyzed denominators are not separately reported in the registry record.

The MADRS was also used to assess clinical response throughout the trial and to guide medication dosage, but the primary endpoint was remission rather than a continuous change score. Results for a continuous MADRS outcome are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is a binary participant-level outcome: remission or no remission under the registry definition. For this kind of outcome, a basic descriptive result is the number of participants with the event and the number of participants assessed. The registry gives remission counts alongside group counts, but it does not report an inferential analysis for the primary outcome. The absence of an inferential result means there is no posted estimate of a treatment contrast with which to quantify the difference between the exercise-plus-medication and medication-only groups.

What does a confidence interval add?

As a general statistical concept, a confidence interval expresses the uncertainty in an estimate under a specified model and sampling procedure. A narrow interval indicates greater precision than a wide interval, while an interval spanning a broad range of plausible effects signals substantial uncertainty. A confidence interval is not reported for the remission outcome in the registry record. With sparse binary data, estimates can be particularly uncertain, and the choice of method can matter; no method for interval estimation is reported.

What can be concluded from event counts?

Counts summarize what was observed in the listed groups, but they do not by themselves distinguish a treatment effect from chance variation or differences between participants. A treatment comparison generally requires a defined estimand, an analysis population, a method for comparing outcomes, and uncertainty measures. The registry record does not report a primary comparison estimate, a test statistic, a p-value, or a confidence interval. It reports 0 of 2, 2 of 3, 4 of 4, and 2 of 2 across the four groups. Those values are descriptive counts, not standalone evidence of a precise treatment contrast.

Why does the age grouping matter?

The randomized groups are also partitioned into 20-39 and 60-79 years of age. An analysis combining these strata would require a stated approach to pooling or modeling age, and an analysis of treatment differences by age would require a defined interaction or stratified comparison. Neither approach is reported in the registry record. The results should therefore be understood as group-specific counts rather than as a pooled or age-adjusted estimate.

What does the planning illustration mean?

General sample-size planning asks how many participants would be needed to detect a prespecified effect with a chosen error rate and power under stated assumptions. The planning description associated with these results uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it describes the effect to detect as a stated fraction of the observed effect. Such planning values are illustrations based on the observed effect, not the trial’s original design justification and not observed power. In this case, the registry record indicates that values are missing or not estimable for a two-arm comparison of the binary endpoint. No participants-per-arm planning result is therefore available for interpretation, and no sample-size justification for the original study is reported in the registry record.

Why can over-dispersion matter?

As a general statistical concept, over-dispersion occurs when observed variation is greater than a model assumes. It can make standard errors too small and confidence intervals too narrow if the model fails to account for that extra variability. This issue is relevant to some count models, especially when modeling counts across repeated units. The primary outcome is reported as a binary classification summarized by participant counts, and the registry does not report an over-dispersion analysis or a model-based estimate. It would not be appropriate to assume that a count model or a particular variance adjustment was used.

The registry lists 0 analyses. It also lists six secondary outcomes, while the reported number of outcome measures is 7. The record does not provide analysis methods, covariate adjustments, missing-data procedures, or inferential results for the secondary outcomes. As a result, methodological interpretation is limited to the stated endpoint definition, assessment schedule, arm-level counts, and the explicit note about an exclusion.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Aerobic Exercise + Venlafaxine XR (60-79 Years of ", "Venlafaxine XR Only (60-79 Years of Age)", "Aerobic Exercise + Venlafaxine XR (20-39 Years of ", "Venlafaxine XR Only (20-39 Years of Age)")
n      <- c(2, 3, 4, 2)
events <- c(0, 2, 4, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Aerobic Exercise + Venlafaxine XR (60-79 Years of   2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  Venlafaxine XR Only (60-79 Years of Age)  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2
ARM  Aerobic Exercise + Venlafaxine XR (20-39 Years of   4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  Venlafaxine XR Only (20-39 Years of Age)  2  2  100.0  15.8  100.0  34.2  100.0  29.2  99.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six secondary outcomes: inflammatory biomarkers, genetic biomarkers, physical activity measured with a SenseWear Physical Activity-monitoring Armband, cardiovascular fitness measured by submaximal VO2, functional MRI, and neurocognitive function measured by a neuropsychological battery. The record lists seven outcome measures overall. It does not report results or analyses for these secondary outcomes, and does not describe a plan for controlling multiplicity across outcomes or comparisons. Whether any multiplicity adjustment was planned or used is not reported in the registry record.

The primary outcome is defined among study completers, which makes the treatment of participants who did not complete the study relevant to interpretation. The registry specifically notes that one participant in the Venlafaxine XR Only (20-39 Years of Age) group was excluded from analyses because medication was discontinued after week 8. The record does not describe how that participant’s outcome was handled, whether other participants had missing assessments, or how missing MADRS assessments affected the consecutive-assessment remission definition.

The analysis population is not fully specified beyond the statement that study completers were classified. An intention-to-treat analysis, a per-protocol analysis, or another analysis set is not identified in the registry record. The exact relationship between the listed group counts, enrollment, and analyzed denominators is also not explained. Procedures for imputation, sensitivity analyses, protocol deviations, and handling of missing data are not reported in the registry record. These omissions limit the ability to assess whether the reported counts represent all randomized participants or only those with evaluable completion data.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry lists serious adverse events for each of the four groups. It reports 0 serious adverse events among 2 participants at risk in Aerobic Exercise + Venlafaxine XR (60-79 Years of Age), 0 among 3 in Venlafaxine XR Only (60-79 Years of Age), 0 among 4 in Aerobic Exercise + Venlafaxine XR (20-39 Years of Age), and 0 among 4 in Venlafaxine XR Only (20-39 Years of Age). Deaths are listed as 0 in each group.

These are observed counts in small groups. A zero count means no serious adverse event was recorded among the listed participants at risk; it does not establish that the underlying risk is zero. The registry record does not report a comparative safety analysis or uncertainty estimates, so the counts do not quantify a difference between treatment groups.

Other adverse events are recorded separately from serious adverse events. The listed counts affected by other adverse events are 1 of 2, 3 of 3, 4 of 4, and 4 of 4 across the four groups, respectively. These figures should not be conflated with serious adverse events. Further descriptions of the other adverse events and their severity are not reported in the registry record.

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

The primary results describe remission classifications among participants in four small age-by-treatment groups. The counts show that remission was recorded for 0 of 2 participants in the older exercise-plus-medication group, 2 of 3 in the older medication-only group, 4 of 4 in the younger exercise-plus-medication group, and 2 of 2 in the younger medication-only group. These are observations from the registry record, not a demonstrated treatment effect. No inferential comparison or uncertainty interval is reported.

The results do not establish that adding exercise changes remission outcomes. The age groups are distinct, the numbers in each group are small, and the record does not report a pooled or age-adjusted comparison. The result also cannot establish whether age modifies treatment effects because no interaction analysis is reported. The registry’s explicit description of the study as a pilot not powered to test the full causal model further limits the conclusions that can be drawn about causal mechanisms.

The remission measure is based on repeated MADRS assessments, with a threshold of 10 or less required at two consecutive assessments. The registry says the primary classification concerns study completers and notes one exclusion following medication discontinuation. Because the handling of missing assessments and the analysis population are not fully described, the counts should be interpreted in light of that reporting gap.

The study was also intended to assess feasibility and measurement acquisition and included secondary outcomes spanning biomarkers, physical activity, fitness, imaging, and cognition. The registry does not report analyses for these outcomes. Accordingly, the posted primary counts do not answer questions about those domains, nor do they establish the proposed GABA-related causal pathway. They provide a limited descriptive record of remission counts and safety events for the listed groups.

14. Why This Trial Matters Statistically

This trial illustrates why design labels and outcome counts need to be read alongside the analysis actually reported. Randomization describes the planned allocation structure, but it does not by itself provide a treatment-effect estimate. The registry presents outcome counts in four groups but reports no analysis for the binary comparison. A reader therefore has descriptive data without a corresponding estimate of comparative effect or its precision.

The study also highlights the importance of matching conclusions to a pilot’s stated purpose. The registry summary describes feasibility and acquisition of measures as central aims and explicitly says the study was not powered to test the full causal model. That context distinguishes the pilot’s exploratory role from a definitive test of mediation or treatment effect. Sample-size planning illustrations based on observed effects cannot replace the original design rationale, which is not reported in the registry record.

Age-stratified reporting adds another interpretive consideration. Counts from 20-39 and 60-79 years of age groups should not automatically be pooled or treated as evidence of an age interaction. Such conclusions require an analysis plan and adequate data to support the relevant comparison; neither is reported in the registry record.

Finally, a remission endpoint based on consecutive assessments raises practical questions about completion and missing measurements. The registry identifies one exclusion after medication discontinuation but does not detail the analysis population or missing-data procedures. Clear reporting of denominators, analytic methods, and uncertainty is essential for readers to judge how robust an observed count may be. Those details are not reported for the primary comparison in this 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 primary outcome is presented as counts without a reported treatment-effect estimate, confidence interval, p-value, or inferential method. The very small listed groups make the counts intrinsically limited for assessing comparative effects. The registry itself describes the study as a pilot and says it was not powered for testing the full causal model.

Although enrollment is listed as 31, the four primary outcome groups list 2, 3, 4, and 2 participants. The relationship between enrollment, randomization, group counts, and the analysis population is not explained in the registry record. It also notes one participant in the younger medication-only group was excluded from analyses after discontinuing medication after week 8, while the exact analyzed denominator is not separately clarified.

The registry does not report the allocation sequence, allocation concealment, adherence, protocol deviations, missing-data methods, or whether the primary analysis followed an intention-to-treat principle. It does not specify how missing assessments would affect the requirement for remission at consecutive assessments. The absence of these details constrains evaluation of potential bias and reproducibility.

Secondary outcomes are listed, but analyses and results are not reported. Multiplicity handling, covariate adjustment, and any prespecified subgroup analyses are also not described in the registry record. No original sample-size justification is reported. The reported results therefore support only a cautious descriptive reading of the primary counts and safety figures, not broad conclusions about efficacy, mechanism, or age-specific effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Multi-level Life-span Characterization of Adult-depression and Effects of Medication and Exercise — NCT02407704.
• Registry record last updated 2018-05-23; status last verified 2018-04.
• Results first posted 2018-05-23.
• 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

This completed randomized, parallel-group phase 4 study compared venlafaxine XR alone with aerobic exercise plus venlafaxine XR in groups aged 20-39 years and 60-79 years. Enrollment was 31, and the study had no masking reported. The primary outcome was the number of study completers meeting a remission definition of MADRS score 10 or less at two consecutive assessments.

The registry lists remission counts of 0 of 2, 2 of 3, 4 of 4, and 2 of 2 across the four groups. It reports no inferential analysis for the primary outcome. Serious adverse event counts and deaths are listed as 0 in all four groups. One participant in the younger medication-only group was excluded from analyses after medication discontinuation after week 8.

The registry describes the work as a pilot focused in part on feasibility and measurement acquisition. Analysis methods, missing-data procedures, a sample-size justification, and results for the listed secondary outcomes are not reported in the registry record.