Study of the Effects of an Antidepressant Medication and Placebo on the Brain Functioning of Normal Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of the Effects of an Antidepressant Medication and Placebo on the Brain Functioning of Normal Subjects (NCT00634283), a randomized phase 4 study. The primary outcome is Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (4 Weeks)..

2. Clinical Question

The study’s stated purpose was to examine brain functioning in normal subjects using recordings of brain electrical activity. Its hypotheses concern long-term brain effects after a course of antidepressant treatment, pharmaco-conditioning effects related to tolerance or sensitization, and responses to initial versus subsequent antidepressant trials. These are aims, not reported findings.

The enrollment was 6. The primary outcome description identifies 2 antidepressant-experienced subjects and 4 antidepressant-naive subjects. The registry record does not report numerical outcome estimates that would establish the direction or size of a difference between those groups. Nor does it report a confidence interval or a p-value for the primary outcome. Thus, the clinical question can be described, but its answer cannot be judged from the posted numerical results.

3. Trial Design

This is a Phase 4, randomized, triple-masked, parallel study sponsored by the University of California, Los Angeles. The registry lists venlafaxine as the drug intervention and describes a study of antidepressant medication and placebo in normal subjects. The study status is completed. The recorded start is 2008-02, and primary completion is 2009-02.

The arm descriptions are based on prior exposure. The antidepressant treatment-experienced group had previously been exposed to active venlafaxine. The antidepressant treatment-naive group had previously been exposed to placebo only and had never been exposed to active antidepressant medication. These labels should not be mistaken for a complete account of current treatment assignment. Details linking prior exposure, randomization, and the medication or placebo given during the study are not reported in the registry record.

Randomized allocation means the record identifies the study as randomized, but the sequence-generation method, allocation concealment, and assignment procedures are not reported in the registry record. The record also does not identify who was masked under the triple-masked designation or how masking was maintained. These omissions limit assessment of how the design was implemented; they do not establish that any particular procedure was or was not used.

The parallel model indicates separate groups rather than a reported crossover comparison. The enrollment was 6, with the primary outcome population described as 2 experienced and 4 naive subjects. The registry record does not report a sample-size justification, recruitment details, eligibility criteria beyond the description of normal healthy subjects, or the planned duration of treatment. It also does not report an analysis plan that would clarify how the small groups were intended to address the stated hypotheses.

The record lists 2 outcome measures and 2 analyses. However, numerical results for the primary outcome are not reported in the registry record. The study’s status and dates establish that it was completed, but do not by themselves indicate whether the intended comparisons were conclusive.

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: Subjects were required to wash out from any exclusionary medication for at least two weeks. Subjects taking fluoxetine were required to wash out for at least 30 days prior to treatment assignment.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Antidepressant-experienced subjects; n=2 and antidepressant-naive subjects; n=4

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 Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (4 Weeks)., measured over Average over 4 weeks.

The primary endpoint is change over time in quantitative electroencephalogram (qEEG) prefrontal cordance, summarized as a mean in z-score units. The timeframe is an average over 4 weeks. The analysis description focuses on baseline change in theta-band cordance in the prefrontal region, using electrodes Fp1, Fpz, and Fp2. The frequency band is specified as 8-12Hz.

Cordance combines normalized absolute and relative EEG power. In the described procedure, power values are calculated using a re-attributional electrode montage, then absolute and relative power are z-transformed within each electrode site and frequency band for a recording. Those transformed values are summed to form a cordance intensity value. This produces a measure of electrical activity expressed relative to the relevant recording-level values, rather than a direct measure of a clinical symptom.

The endpoint is used to characterize a physiologic response in the brain and to examine whether that response differs with prior antidepressant exposure. The registry assigns a directional interpretation: positive change represents an increased physiologic and behavioral response to the drug, labelled sensitization, while negative change represents increased tolerance to the drug, labelled habituation. These definitions describe how the study interprets the measure; they do not establish that a change is beneficial or harmful.

The numerical mean change, standard deviation, and between-group comparison are not reported in the registry record. The endpoint’s measurement process and interpretation are described, but the posted results do not show how much cordance changed or how precisely it was estimated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a continuous measure, summarized using a mean and standard deviation. General explanation: a mean is the arithmetic average of recorded values, and a standard deviation describes the distribution of those values around the average. A mean is useful for expressing the central tendency of a continuous measure, but it does not by itself show the spread of observations or the uncertainty around a comparison.

The endpoint is expressed in z-score units. The registry describes transforming absolute and relative EEG power values to measure deviation from mean values for each electrode site and frequency band within a recording. The transformed absolute and relative values are then added to form cordance. As a result, cordance is a constructed signal measure based on the recorded EEG power values; it is not a direct scale of depression symptoms or treatment benefit. The registry record does not report validation details or a clinical threshold for interpreting a particular cordance value.

The analysis focuses on changes from baseline in the prefrontal theta band, with the region defined by electrodes Fp1, Fpz, and Fp2. The specified band is 8-12Hz, and the reported timeframe is an average over 4 weeks. General explanation: a change-from-baseline analysis compares follow-up measurement with a starting measurement, while an average over time summarizes the period rather than describing every individual measurement. The record does not explain how repeated recordings were combined to produce the four-week average, or how missing recordings, if any, were handled.

A group comparison of means would ordinarily need a defined contrast and an estimate of uncertainty. General explanation: a confidence interval provides a range of plausible values for the underlying effect under the stated model and assumptions. A p-value describes how incompatible the observed data are with a specified null model; it is not the probability that the null hypothesis is true and does not measure the size or clinical importance of an effect. No numerical group contrast, confidence interval, or p-value for the primary outcome is reported in the registry record, so these quantities cannot be interpreted for this study.

The record identifies randomization, triple masking, and a parallel model. General explanation: randomization is intended to reduce systematic differences between assigned groups, and masking is intended to limit the influence of knowledge of assignment on care, measurement, or assessment. The labels alone do not establish how these protections were implemented. The randomization method, concealment approach, masking roles, and any assessment of whether masking was maintained are not reported in the registry record.

The group sizes described for the endpoint are n=2 and n=4. General explanation: very small samples often provide limited information about between-person variability and can yield imprecise estimates. Statistical methods can calculate a mean from a small group, but the existence of a calculated average would not ensure that it is stable or broadly representative. The record does not report precision estimates that would allow readers to assess uncertainty directly.

The sample-size assumptions describe a planning illustration, not the trial’s own design justification. They specify a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect targeted as a stated fraction of the observed effect. The illustration is not observed power, and it does not explain why the trial enrolled 6 participants. The planning output values and the trial’s own sample-size justification are not reported in the registry record. General explanation: planning calculations depend on assumptions about the target effect, variability, significance level, and allocation; changing assumptions changes the number of participants needed. Such calculations should not be read as evidence that the completed study had a particular probability of detecting an effect.

The registry lists 2 analyses, but the numerical results and the methods attached to those analyses are not reported in the registry record. It is therefore not possible to establish whether the analysis used a pooled-variance approach, a repeated-measures model, an adjusted comparison, or another method. General explanation: a model for repeated measurements can account for the correlation between observations from the same participant, whereas a simple comparison that treats all observations as independent may understate or misstate uncertainty. The record does not specify which approach was used.

General explanation: over-dispersion occurs when observed variability exceeds what a statistical model assumes. When that happens, standard errors from an overly restrictive model may not represent the data’s variability well. This is a general consideration, not a reported feature of this trial; the registry does not provide enough outcome data or model detail to assess over-dispersion.

The stated outcome interpretation assigns meaning to positive and negative changes, but no numerical result is available to apply those definitions. Without a reported estimate and its uncertainty, the method description can clarify what was intended to be measured, but it cannot show whether the data support a particular direction or how precisely any effect was estimated.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 2 outcome measures and 2 analyses. The primary outcome description specifies a four-week average, while the registry’s analysis note indicates that the primary outcome has several categories or time points and was not reduced to one comparison. The numerical results for the primary outcome are not reported in the registry record. The full set of outcome definitions and analysis contrasts is therefore not available for assessing how many statistical tests were conducted or how they relate to one another.

General explanation: multiplicity arises when several outcomes, time points, subgroups, or statistical comparisons are examined. If many tests are considered, the chance of at least one apparently unusual result can increase. Methods such as designating a primary comparison in advance or adjusting for multiple tests can address this issue, but their suitability depends on the study question and analysis plan. A multiplicity strategy, a hierarchy among outcomes, and any adjustment procedure are not reported in the registry record. No claim can be made that the analyses were or were not adjusted.

Missing-data methods are also not reported in the registry record. The record does not state whether every enrolled subject contributed endpoint data, how missing recordings were handled, or whether any imputation or sensitivity analysis was used. The outcome population is described as n=2 experienced subjects and n=4 naive subjects, but this does not by itself establish the completeness of each participant’s repeated measurements.

The analysis population is not defined in the registry record. It does not specify whether the analysis followed randomized assignment, included only subjects who completed the study, or used another population. The number of participants enrolled and the group counts in the outcome description should therefore not be treated as proof that all enrolled participants were included in every analysis. These omissions limit interpretation of both the intended comparisons and their reliability.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 1% reporting threshold.

The registry lists serious adverse events by group. For the antidepressant treatment-experienced group, 0 serious adverse events were reported among 2 at risk. For the antidepressant treatment-naive group, 0 serious adverse events were reported among 4 at risk. The record lists no serious adverse event terms.

For other adverse events, the registry likewise reports 0 affected among 2 at risk in the experienced group and 0 affected among 4 at risk in the naive group. These are counts in the posted record; they do not establish that the risk of an adverse event is absent. With small groups, zero reported events provides limited information about the range of possible event rates or about differences between groups. General explanation: observing no events in a small sample does not rule out events in a larger population.

The death counts are not reported in the registry record. A blank or null death count should not be interpreted as a reported count of zero. The record does not provide event descriptions beyond the absence of listed serious terms, nor does it report the duration of safety monitoring or a detailed method for collecting adverse events. These figures describe what is recorded, not a complete estimate of safety risk.

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

The posted record establishes that a completed, randomized, triple-masked, parallel Phase 4 study was designed to examine venlafaxine and placebo effects on brain electrical activity in normal subjects. It also specifies an endpoint: mean change in prefrontal qEEG cordance, averaged over 4 weeks, with an interpretation tied to sensitization or habituation. These details identify the question and the measurement, but they do not supply the numerical answer.

The primary outcome’s group means, variability, comparison estimate, confidence interval, and p-value are not reported in the registry record. Therefore, the posted information does not establish whether cordance increased or decreased, whether the groups differed, or how precise any difference might be. No result should be inferred from the stated hypotheses, study completion, or the endpoint’s directional definitions.

The record describes subjects with different prior exposure histories, but does not fully explain the relationship between those histories and current randomized treatment. This makes it important not to assume that the listed group contrast is a straightforward comparison of current venlafaxine against current placebo. The exact contrast and analysis model are not reported in the registry record.

The population also sets a boundary on interpretation. The study summary describes normal healthy subjects, and the endpoint is a physiologic EEG measure. The record does not report a direct clinical symptom outcome that would allow this result to be interpreted as a change in depression symptoms. The registry lists Depression as a condition, but the summary’s healthy-subject description should remain part of the context.

The safety listing reports no serious or other adverse events in the small groups, while death counts are not reported in the registry record. These counts are not proof that such events cannot occur. Overall, the record is useful for understanding the study’s intended measurement and design labels, but it does not support a conclusion about the magnitude, precision, clinical meaning, or safety implications of an observed treatment effect.

13. Why This Trial Matters Statistically

This trial raises several statistical issues that are important when interpreting small studies of physiologic outcomes. Its primary endpoint is not a direct clinical symptom measure: it is a constructed qEEG cordance measure based on normalized absolute and relative power. Understanding the endpoint’s calculation and its study-specific interpretation is necessary before attaching meaning to a direction of change.

The design includes subjects with different prior antidepressant exposure histories, while the study summary describes medication and placebo. That combination makes clear reporting of the target comparison especially important. Randomization and masking are useful design features, but their labels do not tell the reader which contrast was analyzed or how current assignment related to previous exposure. The registry record does not report those details.

The groups are very small, with n=2 and n=4 in the primary outcome description. General statistical consideration: a small study can be informative about feasibility, measurement, and the structure of a research question, but it may have limited precision for estimating group differences. Statistical interpretation requires the estimate and uncertainty, not merely a statement that an analysis was conducted. Those numerical results are not reported in the registry record.

The record also illustrates the distinction between study planning and study evidence. The sample-size assumptions describe a planning illustration based on an observed effect, but the illustration is not the trial’s own sample-size justification and is not observed power. A planning calculation cannot replace the completed study’s effect estimate and uncertainty.

Finally, the record lists multiple outcomes and analyses, yet does not report the results or a multiplicity strategy. Transparent reporting of the analysis population, missing-data handling, comparisons, estimates, and uncertainty would be needed to understand how the hypotheses were evaluated. These considerations matter because statistical conclusions depend not only on the endpoint and design, but also on what was measured, which comparisons were made, and how much information the data contain.

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.

A central limitation is that the numerical primary outcome results are not reported in the registry record. Without group means, standard deviations, an effect estimate, or its uncertainty, readers cannot assess the observed direction, size, or precision of the endpoint change. The record’s statement that analyses exist does not supply those results.

The outcome groups are small: the registry describes n=2 antidepressant-experienced subjects and n=4 antidepressant-naive subjects. This limits the information available about variation among subjects and makes any estimate potentially sensitive to individual observations. The registry does not report confidence intervals or other precision measures that could quantify this uncertainty.

The record describes the groups according to prior exposure but does not fully explain how that history relates to current randomized allocation. It also does not report the randomization procedure, masking roles, analysis contrast, or model. These gaps make it difficult to reconstruct the comparison and assess whether the statistical analysis matches the study question.

The study summary describes normal healthy subjects, whereas the registry lists Depression as a condition. The record does not provide further detail to resolve that context. The endpoint is a physiologic EEG measure, and no numerical clinical symptom result is reported. Generalization to a clinical population or to clinical outcomes is therefore not established by this record.

Other important details are not reported in the registry record, including eligibility criteria, missing-data handling, analysis populations, multiplicity procedures, a sample-size justification, and the handling of repeated recordings. Death counts are also not reported. These limitations concern the information available in the registry record; they should not be taken as proof that the study did not address these issues in other materials.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of the Effects of an Antidepressant Medication and Placebo on the Brain Functioning of Normal Subjects — NCT00634283.
• Registry record last updated 2020-03-09; status last verified 2020-02.
• Results first posted 2020-02-18.
• 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

The record describes a completed Phase 4 randomized, triple-masked, parallel study of venlafaxine and placebo in normal healthy subjects. Enrollment was 6. The study was sponsored by the University of California, Los Angeles; its recorded start was 2008-02 and primary completion was 2009-02.

The primary endpoint is mean change in prefrontal theta-band qEEG cordance, expressed in z-score units and averaged over 4 weeks. The outcome population is described as 2 antidepressant-experienced and 4 antidepressant-naive subjects. The numerical primary outcome findings and their precision are not reported in the registry record.

The registry reports 0 serious and 0 other adverse events in each group; death counts are not reported. Details about the analysis population, missing data, multiplicity, and the precise relationship between prior exposure and current treatment assignment are not reported in the registry record.