Placebo-controlled Trial of 5-hydroxytryptophan and Creatine for SSRI or SNRI Augmentation in Treatment Resistant Depression in Females: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Placebo-controlled Trial of 5-hydroxytryptophan and Creatine for SSRI or SNRI Augmentation in Treatment Resistant Depression in Females (NCT02922725), a randomized phase 4 study. The primary outcome is Change From Baseline in Hamilton Depression Rating Scale.

2. Clinical Question

The record identifies this as a phase 4, randomized, triple-masked, parallel-group trial. Its title and summary situate the question in females with treatment-resistant depression associated with hypobaric hypoxia. The posted primary comparison concerns the HAM-D score, not the imaging or spectroscopy measures. The registry record does not report the precise hypothesis, the anticipated direction of change, or how a change score was coded. Those omissions matter when interpreting whether a positive or negative change within an arm represents improvement or worsening.

3. Trial Design

The registry describes a randomized, triple-masked, parallel-group, placebo-controlled phase 4 study. It lists 32 as the enrollment and gives the status as terminated. The listed start is 2016-11 and the primary completion is 2020-05. The reason for termination is not reported in the registry record, so the status alone does not explain why the trial ended.

The intervention was oral 5-HTP and creatine added to existing SSRI or SNRI treatment, as described in the trial summary. The planned course was 8 weeks, with the primary outcome assessed at that timeframe. The comparison was placebo. The registry names the trial as concerning females, and the official title links the depression to hypobaric hypoxia. Further details about setting, recruitment, eligibility rules, randomization procedure, allocation concealment, and the people or roles covered by triple masking are not reported in the registry record.

For the primary result, the registry reports 11 participants in the study-drug arm and 12 in the placebo arm. These are the arm counts attached to the reported outcome; they should not be treated as a complete account of enrollment or as evidence about why other enrolled participants are not represented in the outcome. The record does not report participant flow, withdrawals, or the number with missing primary outcome data.

The trial summary describes an additional interest in functional connectivity measured by resting-state fMRI and brain metabolism inferred from phosphorus-31 magnetic resonance spectroscopy. The registry posts one outcome measure and no secondary posted outcomes. Results for the imaging and spectroscopy measures are not reported in the registry record. Nor are protocol deviations, adherence, or details of any changes made after trial initiation reported.

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

Reasons for not completing this period:

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 From Baseline in Hamilton Depression Rating Scale, measured over 8 weeks.

The primary endpoint is change from baseline in the Hamilton Depression Rating Scale, reported at 8 weeks. The HAM-D is a clinician-rated measure of depressive symptom severity. The registry describes a total score ranging from 0 to 54 and states that higher total scores indicate more severe depression. It also lists score ranges for mild, mild to moderate, and moderate to severe depression. The posted endpoint is the change in score, rather than the final score alone.

Using a common measure in both groups allows the randomized comparison to focus on the difference in the measured outcome between the study-drug and placebo arms. The trial summary identifies the 17-item HAM-D as the instrument for assessing hypoxia-related depressive symptoms. A continuous score retains gradations of symptom severity, rather than reducing the result to a yes-or-no classification.

Interpretation of change scores depends on the coding convention: for example, whether change is calculated as follow-up minus baseline or in the reverse order. That convention is not reported in the registry record. The arm means are posted as 6.8 for study drug and 7.3 for placebo, with standard deviations of 5.5 and 5.4, respectively. These values describe the reported change measure; without the coding convention, their sign alone does not establish the direction of symptom change. The record does not describe the endpoint’s assessment procedures or handling of incomplete measurements.

7. Results Posted in the Registry

• Depressed Patients Receiving Study Drug: mean 6.80 versus 7.30 on control; difference -0.50 (95% CI -4.96 to 3.96), standardized effect d = -0.09; z-test p = 0.826.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary measure is continuous: each participant’s HAM-D change is represented by a numeric score, and the registry summarizes each arm with a mean and standard deviation. In general, a mean describes the center of a set of measurements. A standard deviation describes how dispersed individual measurements are around that mean. These are different summaries: the standard deviation is not the uncertainty in the arm mean, and it does not by itself describe the precision of the between-group estimate.

What does the mean difference represent?

The registry reports a mean difference of -0.5 for study drug compared with placebo. In general, a difference between group means expresses the estimated contrast on the original measurement scale, here units on the HAM-D change measure. The estimate is reported alongside arm means of 6.8 and 7.3. The registry does not describe the change-score coding convention, so the sign should be read as the direction of the reported contrast, not automatically as improvement or worsening.

The posted standardized effect estimate is -0.092, with a pooled standard deviation of 5.448. In general, standardizing a difference expresses it relative to the variability of measurements, which can help describe magnitude on a scale-independent basis. It does not replace the original-scale estimate, and it does not supply a clinical interpretation by itself. The registry does not state a threshold for interpreting a standardized effect as important.

What does the confidence interval add?

The reported 95% confidence interval for the mean difference is -4.961 to 3.961. In general, a confidence interval communicates the uncertainty around an estimate using a range of values compatible with the data and the statistical procedure. Its width reflects precision: a wider interval leaves more uncertainty about the size and direction of the contrast. The interval includes zero, so the reported result does not distinguish a nonzero difference from no difference at the conventional level associated with that interval. The interval is not a range containing 95% of individual participants’ scores.

How should the p-value be read?

The unadjusted p-value is 0.826. In general, a p-value measures how unusual data at least as incompatible with a specified null model would be if that model and the test assumptions held. It is not the probability that the null is true, and it is not a measure of the size or importance of the result. The registry calls this value unadjusted; the record does not describe a multiplicity adjustment or the precise test used to obtain it.

In general, randomization supports a between-group comparison by assigning participants to groups in a way intended to reduce systematic baseline differences. The registry states that allocation was randomized, but it does not report the sequence-generation method or allocation concealment procedure. Triple masking is listed, but which people were masked and how masking was maintained are not reported in the registry record. These missing procedural details prevent a fuller assessment of how the design was implemented.

The registry posts a mean-based comparison and arm-level standard deviations, but does not report whether the primary analysis adjusted for baseline HAM-D score, used a particular model, or followed an intention-to-treat approach. The record also does not report assumptions about the score distribution, residual diagnostics, or treatment of outliers. In general, the suitability of a mean-based analysis depends on the measurement and the distribution of the data; the posted summaries alone cannot establish whether those assumptions were checked.

In general, over-dispersion means that variability is greater than a model assumes. When a model underestimates variability, standard errors can be too small and confidence intervals too narrow; accounting for extra variability can improve uncertainty estimates. This is a general concept, not a reported feature of this trial. The outcome is continuous, and the registry does not report an over-dispersion assessment or identify such a concern.

The posted standard errors for the arm means are 1.658 for study drug and 1.559 for placebo. In general, a standard error describes the sampling uncertainty of an estimated quantity, whereas a standard deviation describes the spread of individual observations. These reported standard errors do not fill in missing details about the analysis model or the handling of missing data.

The registry lists no analyses in addition to the posted primary comparison. The exact analysis plan, prespecified covariates, handling of protocol deviations, and any interim analyses are not reported in the registry record. The result should therefore be interpreted as the registry’s posted summary rather than as a complete account of the trial’s statistical procedures.

10. Confidence Intervals and Precision

The mean difference is -0.5 HAM-D units, with a 95% confidence interval from -4.961 to 3.961. The interval is wide enough to include zero and values on both sides of zero. Thus, the estimate is not precise enough to locate the between-group difference narrowly. The result is compatible with a range of possible effects, not just the point estimate.

In general, a confidence interval describes uncertainty in an estimated group contrast, conditional on the data and the method used to calculate it. It does not show the range of individual participant outcomes, nor does it guarantee that the true value lies within the displayed endpoints. The registry does not report the method used to construct this interval. Its exact interpretation therefore depends on analysis details that are not reported in the registry record.

The arm-level standard deviations are 5.5 for study drug and 5.4 for placebo, compared with means of 6.8 and 7.3. These summaries indicate appreciable spread in the change scores relative to the difference between the posted means, but they do not establish the distribution of individual scores or explain the source of variation. The group outcome counts are 11 and 12. The registry does not give a missing-data account or the number assessed at each timepoint, making it difficult to determine how outcome availability affected precision.

The p-value of 0.826 is unadjusted and should not be read as a measure of precision or as evidence that the groups are equivalent. A conclusion of equivalence would require a stated equivalence margin and an analysis designed for that purpose; neither is reported in the registry record. The confidence interval is the more direct guide to the range of contrasts left plausible by the posted estimate, while its clinical meaning cannot be judged against a threshold absent from the record.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm, not total events. They are illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario targets a stated fraction of the observed effect. The original trial’s own sample-size assumptions and justification are not reported in the registry record.

The 80% power column gives the number of participants per arm used in the planning illustration to have an 80% chance of detecting the chosen effect under its assumptions. The 90% power column gives the corresponding per-arm planning count for a 90% chance. These are design calculations, not counts of participants observed in the trial and not evidence about the probability that the trial’s result is true.

The illustration uses 100%, 75%, and 50% of the observed effect. For 100% of the observed effect, the listed figures are 1,864 participants per arm for 80% power and 2,495 for 90% power. For 75% of the observed effect, the figures are 3,314 and 4,436. For 50% of the observed effect, they are 7,455 and 9,980. Smaller effects need more participants to detect under otherwise unchanged assumptions.

These figures are not observed power. They are planning illustrations derived from the effect estimate in a small outcome set, and may change substantially if the true effect differs from the observed estimate. They should not be interpreted as the trial’s planned enrollment target or as a retrospective measure of what the completed study could detect.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = -0.500; pooled standard deviation σ = 5.448.
2. n = 2 × (1.96 + 0.842)² × 5.448² / -0.500² = 1,863.6, rounded up to 1,864 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- -0.5                      # observed difference in means
sigma <- 5.4478479805376                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2922725)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 1,864 (80% power), 2,495 (90% power)
 75% of observed effect: n per arm = 3,314 (80% power), 4,436 (90% power)
 50% of observed effect: n per arm = 7,455 (80% power), 9,980 (90% power)
power.t.test: 1864.5 
Simulated power at n = 1,864 per arm: 0.799 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry posts one outcome measure and no secondary posted outcomes. The trial summary describes intended imaging and spectroscopy examinations, but results for these measures are not reported in the registry record. The absence of posted secondary results does not establish whether those measures were collected, analyzed, or omitted; their status is not reported.

Multiplicity arises when multiple outcomes, timepoints, groups, or statistical tests create several opportunities to find a nominally notable result. In general, a prespecified approach to multiplicity can help control the chance of false-positive conclusions across a set of tests. The record does not report a multiplicity strategy, a hierarchy of outcomes, or a family of hypotheses. The primary comparison is labeled unadjusted, and the posted p-value is 0.826.

The record does not report how missing HAM-D measurements were handled, whether any participants withdrew, or how many participants were assessed at the endpoint. It also does not report whether the analysis used all randomized participants, participants who completed treatment, or another analysis population. These details are important because missing outcomes and decisions about inclusion can affect the estimate and its uncertainty.

Participant flow from randomization through the primary assessment is not reported in the registry record. Although enrollment is listed as 32, the outcome counts are 11 for study drug and 12 for placebo. The record does not explain the relationship between those figures, so no conclusion about attrition or the reasons for the outcome counts can be drawn from them alone.

The trial’s statistical analysis plan, protocol deviations, baseline comparability, interim analyses, and any changes to planned analyses are not reported in the registry record. The record therefore does not support a detailed assessment of whether the posted comparison follows a prespecified analysis plan or whether unreported outcomes or analyses were considered.

14. 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.

For the study-drug group, the registry reports 0 serious adverse events among 11 at risk, 0 other adverse events among 11 at risk, and 0 deaths. For the placebo group, it reports 0 serious adverse events among 12 at risk, 0 other adverse events among 12 at risk, and 0 deaths. The record also lists a healthy-control group with 0 serious adverse events among 8 at risk, 0 other adverse events among 8 at risk, and 0 deaths.

These figures describe events recorded in the registry for the listed groups. A zero count means that no events of that category are reported for that group in this record; it does not establish that no symptoms or events occurred outside the categories captured or reporting period. The registry does not provide event definitions, follow-up duration for safety, severity details, or a description of how events were collected. No serious adverse event terms are listed.

The healthy-control group is not the placebo comparison group for the depression outcome. Its safety count should not be combined with the randomized treatment groups or interpreted as part of the primary efficacy comparison. The safety figures alone do not establish comparative safety, particularly without fuller information about exposure and ascertainment.

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

The primary registry result describes the average difference in HAM-D change between the study-drug and placebo groups at 8 weeks. The estimate is -0.5 units, with a confidence interval from -4.961 to 3.961 and an unadjusted p-value of 0.826. The interval crosses zero and is broad, leaving uncertainty about both the size and direction of the contrast. This is a description of the posted result, not a conclusion that the treatments are equivalent.

The record identifies the study population as females with treatment-resistant depression associated with hypobaric hypoxia and describes augmentation with 5-HTP and creatine alongside SSRI or SNRI treatment. The posted result does not establish what the estimate means for other populations, treatment settings, or durations. The record does not report a clinically important difference threshold or the change-score coding convention, so the result cannot be translated reliably into a statement about clinically meaningful symptom improvement.

The primary endpoint is one part of the trial’s stated aims. Although the brief summary also describes planned resting-state fMRI and phosphorus-31 magnetic resonance spectroscopy assessments, their results are not reported in the registry record. The primary HAM-D comparison therefore does not answer the imaging or brain-metabolism questions.

The trial is listed as terminated, and the reason is not reported in the registry record. The available result also lacks participant flow, missing-data methods, and analysis-population details. Those gaps limit assessment of how representative the analyzed outcome is of the randomized groups and how robust the estimate may be to missing observations or analytic choices.

Accordingly, the posted findings should be read as an uncertain estimate from the reported comparison, rather than a definitive statement about benefit, lack of benefit, or equivalence. The registry result alone cannot establish a treatment recommendation or resolve the trial’s broader biological questions.

16. Why This Trial Matters Statistically

This trial raises a statistical question that is common in small clinical studies: how much information does a difference in group averages provide when the estimate is imprecise? The posted mean difference is -0.5, and its confidence interval spans values below and above zero. That contrast between a single point estimate and a broad interval is central to interpretation. A non-significant result does not by itself show that groups are the same; uncertainty and the range of effects compatible with the data also matter.

The posted arm counts for the primary outcome are 11 and 12, while the registry lists enrollment as 32. The relationship between those counts is not explained in the registry record. Without participant flow, missing-data details, and a clear analysis population, readers cannot fully assess how the available outcome data relate to the randomized groups. Such reporting is important for interpreting both the estimate and its precision.

The planning illustration highlights how sample-size requirements depend on the effect a future study aims to detect. It is based on the observed effect and stated planning assumptions, rather than on the trial’s original design justification. Its large per-arm figures make clear that planning around a small observed contrast can imply substantial information needs, but the illustration is not evidence that the trial was designed to those targets.

The trial also connects a symptom-scale endpoint with planned imaging and spectroscopy measures. Because those additional results are not posted, the available record supports interpretation of the HAM-D comparison only. Distinguishing reported outcomes from unreported aims is important: a biological rationale or planned measurement cannot substitute for outcome evidence.

17. Limitations

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

The registry record gives limited detail about how the primary endpoint was analyzed. It does not report the statistical model, whether baseline HAM-D scores were included, the change-score coding convention, the analysis population, or the approach to missing outcomes. These omissions restrict assessment of the assumptions underlying the estimate and make the meaning of the sign of the change scores less certain.

Outcome counts attached to the primary result are 11 in the study-drug group and 12 in the placebo group, while enrollment is listed as 32. No participant flow or explanation of the difference is reported in the registry record. It is therefore not possible to determine from this record why the outcome counts differ from enrollment or how missing results may have affected the comparison.

The trial status is terminated, but the reason for termination is not reported. The record does not provide details about adherence, treatment exposure, withdrawals, protocol deviations, recruitment, or masking procedures beyond the triple-masked designation. It also does not report the trial’s original sample-size assumptions, interim analyses, or full statistical analysis plan.

The record posts one primary outcome and no secondary outcomes. Although the summary describes planned imaging and spectroscopy assessments, results for these measures are not posted. The absence of these results limits evaluation of the trial’s broader stated objectives. No clinical importance threshold is reported for the HAM-D contrast, and the interval therefore cannot be judged against a trial-defined threshold for a meaningful difference.

Finally, the registry’s safety figures list zero events in the reported categories, but provide little information about event collection or duration of follow-up. Those counts should be interpreted as registry reporting, not as a comprehensive characterization of safety.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Placebo-controlled Trial of 5-hydroxytryptophan and Creatine for SSRI or SNRI Augmentation in Treatment Resistant Depression in Females — NCT02922725.
• Registry record last updated 2022-05-31; status last verified 2022-05.
• Results first posted 2022-05-31.
• 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.

21. Record Summary

The registry record describes a phase 4 randomized, triple-masked, parallel-group trial of 5-HTP and creatine augmentation versus placebo for females with treatment-resistant depression associated with hypobaric hypoxia. It lists enrollment as 32, status as terminated, a start of 2016-11, and primary completion in 2020-05. The reason for termination is not reported.

The primary endpoint was change from baseline in HAM-D score at 8 weeks. The reported group means are 6.8 for study drug and 7.3 for placebo. The mean difference is -0.5, with a 95% confidence interval from -4.961 to 3.961 and an unadjusted p-value of 0.826. The registry does not report the change-score coding convention or detailed analysis methods.

The primary outcome counts are 11 and 12 for the respective arms. The relationship between these counts and enrollment, and the handling of missing outcomes, are not reported in the registry record. No secondary outcomes are posted, and results for the imaging and spectroscopy aims are not reported.