Low-Dose Naltrexone (LDN) for Depression Relapse and Recurrence: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Low-Dose Naltrexone (LDN) for Depression Relapse and Recurrence (NCT01874951), a randomized phase 2 study. The primary outcome is Change in HAM-D-17 Total Score.

2. Clinical Question

The trial addresses a specific clinical research question: whether adding low-dose naltrexone to ongoing antidepressant therapy is associated with a different short-term change in depressive symptom scores than adding placebo for people experiencing breakthrough symptoms. The registry describes the study as a randomized, proof-of-concept trial in major depressive disorder. Its hypothesis was that the naltrexone group would show higher response rates, but the posted primary endpoint is change in HAM-D-17 total score, not response rate.

HAM-D-17 is a depression symptom measure. The primary outcome is the mean change from baseline to week 3, with negative change defined in the registry as a lower score at the end of treatment and therefore improvement on the scale. The posted results give group means and standard deviations for study completers. They do not provide an estimable two-arm comparison for this continuous endpoint. Consequently, the group summaries alone do not establish the size or statistical uncertainty of the treatment comparison.

The question is also limited by the short treatment period and the small number of participants. Findings from this pilot study describe the observed completers in this trial; they do not, by themselves, settle how the approach would perform in a larger or different population.

3. Trial Design

This was a phase 2, randomized, quadruple-masked, parallel-group trial sponsored by Massachusetts General Hospital. The registry lists an enrollment of 12 participants. The study began in 2013-06, had primary completion in 2015-06, and is marked completed. The registry identifies the condition as major depressive disorder and also lists unipolar depression, recurrence, and relapse.

Participants were assigned to naltrexone or placebo. Both arms were described as three-week treatment periods: low-dose naltrexone for the intervention group and placebo for the comparator group. The official title describes augmentation of antidepressants, and the trial summary specifies breakthrough depression while taking an antidepressant regimen containing a pro-dopaminergic agent. Further details about the background antidepressant regimens are not reported in the registry record.

Quadruple masking indicates that the registry classifies the trial as masked across four roles, but the identities of those roles are not reported in the registry record. The record labels the allocation randomized and the model parallel. Further details about sequence generation, allocation concealment, or how masking was maintained are not reported in the registry record.

The primary outcome was change in HAM-D-17 total score from baseline to week 3. The outcome population is identified as study completers. The arm summaries list six participants in each group. The registry also lists seven secondary outcomes: changes in HAM-D28, MADRS-10, MADRS-15, and CGI-S scores, final CGI-I score, response rate, and remission rate. Results for those secondary outcomes are not included in the posted result information considered in this analysis.

The registry describes this as a pilot or proof-of-concept study. A formal sample-size justification, the planned target effect, and detailed protocol methods are not reported in the registry record. Randomization and masking support a structured comparison, but they do not remove the uncertainty that follows from the small number of participants and the absence of a reported comparative estimate for the primary endpoint.

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: 21 prospective subjects were screened. The following were excluded: sub-threshold Hamilton-D (HAMD) scores (n=3); too recent changes in medication regimen (n=2); cerebrovascular accident in past 5 years (n=1); no history of past treatment response (n=1); inappropriate antidepressant (n=1); antidepressant dose too low and duration too short (n=1).

Overall Study

Analysis population for the primary outcome, as defined in the registry: Study completers.

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.

Population: Twenty-one patients were screened, of which twelve patients were admitted into the study, all men and women with major depressive disorder who had relapsed on a pro-dopaminergic antidepressant regimen.

6. Primary Endpoint

The registry lists the primary outcome as Change in HAM-D-17 Total Score, measured over Change from baseline to week 3.

The primary endpoint is change in Hamilton Depression Scale-17 total score (HAM-D-17) from baseline to week 3, measured in units on the scale. It is summarized as a mean with a standard deviation. The registry says the analysis population consists of study completers. Change scores represent the end-of-treatment score relative to the initial score; a negative value means the score was lower at the end, a positive value means it was higher, and zero means no change.

In general, a change-from-baseline endpoint asks whether participants’ measured status shifted during a specified period. It can describe the direction and average magnitude of within-participant change, while the between-group comparison is needed to assess whether the observed change differed between randomized assignments. A group’s mean change alone does not separate effects of treatment assignment from other influences over time.

HAM-D-17 is used as a symptom measure in this trial because the research question concerns depressive symptoms during a short period of treatment. The registry description gives theoretical score-change bounds based on the scale’s stated minimum and maximum, but it also notes that possible change depends on the starting and ending scores. Those bounds do not substitute for an observed comparative estimate. The posted summaries report a mean change of -5.8 with standard deviation 5.1 for placebo and -9.5 with standard deviation 6.9 for naltrexone. A two-arm comparison for this continuous endpoint is not reported as estimable in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a mean change describe?

In general, a mean change is the average of participants’ individual changes from baseline to follow-up. It compresses those individual observations into one group summary. Here, the registry defines a negative change as a decrease in HAM-D-17 score from baseline to week 3. The posted means are -5.8 for placebo and -9.5 for naltrexone. These values describe change within each group; they are not themselves the treatment contrast.

In a randomized parallel-group trial, the main comparative question is whether the outcome differs between the groups assigned to the two strategies. For a continuous endpoint such as change in score, that is ordinarily expressed through a between-group estimate, with an uncertainty measure. The registry record says values are missing or not estimable for a two-arm comparison of this continuous endpoint. No comparative estimate should be reconstructed or inferred from the arm summaries in place of the analysis that is not available.

What does the standard deviation tell a reader?

In general, a standard deviation describes how spread out participant-level values are around their group mean. A larger standard deviation indicates more variation in those observed values, but it is not a direct measure of uncertainty in the mean and does not show whether the group difference is statistically persuasive. The posted standard deviations are 5.1 for placebo and 6.9 for naltrexone. Because each arm has six participants, these summaries are based on a small set of observations.

In general, standard errors and confidence intervals address precision of an estimate, while standard deviations describe variation among observations. A confidence interval for the treatment comparison could show how compatible the observed data are with a range of possible comparative effects under specified assumptions. Such an interval is not reported in the registry record. The arm means and standard deviations do not justify presenting a confidence interval or p-value that the registry does not report.

How should randomization and masking be understood?

In general, random assignment aims to make treatment groups comparable in expectation, including for characteristics that are not measured. It does not guarantee that small groups will be balanced on every characteristic. Masking is intended to reduce the influence of expectations or knowledge of assignment on care, reporting, or assessment, depending on who is masked. The registry classifies this study as randomized and quadruple-masked. The specific randomization procedures, masked roles, and checks of masking are not reported in the registry record.

The parallel design means the registry presents separate groups assigned to naltrexone or placebo rather than describing a crossover sequence. The trial’s treatment period was three weeks in each arm. The registry’s descriptions identify the study as augmentation of antidepressant medication, but further detail on concomitant treatments and adherence is not reported in the registry record.

What can a small pilot trial establish?

In general, a proof-of-concept trial can provide early descriptive information and help identify whether a research question merits further evaluation. A small trial usually has limited precision for estimating a treatment effect, especially when outcomes vary among participants. Its results should not be mistaken for a definitive estimate merely because the group means differ. The record labels this study as a pilot and reports 12 enrolled participants; it does not report a formal sample-size justification or a target effect used to design the trial.

The planning illustrations associated with a trial are conceptually different from its observed findings. In general, a sample-size calculation depends on assumptions about the effect to detect, outcome variability, significance level, allocation, and method. The registry’s planning description states that its illustrations use the observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation; they are illustrations rather than the trial’s original design justification. Any such planned sample size is not observed power and does not add evidence to the observed treatment comparison.

Why are the analysis population and missing data important?

In general, an analysis population defines which participants contribute to an estimate. An analysis of completers can differ from an analysis that retains all randomized participants, especially if completion is related to outcome or treatment assignment. The registry identifies the primary endpoint population as study completers. It does not report the number of participants who completed treatment separately from the number listed in each arm, reasons for non-completion, or methods for handling missing measurements. Thus, the potential impact of incomplete follow-up cannot be assessed from the registry record.

Interpretation should also distinguish a prespecified primary endpoint from secondary endpoints. The primary endpoint focuses the main question, while secondary measures can provide additional perspectives. Testing or emphasizing multiple outcomes can increase the chance of findings that appear notable by chance unless the statistical approach accounts for multiplicity. The record lists seven secondary outcomes, but a multiplicity adjustment or hierarchy is not reported in the registry record. Results for those secondary outcomes are not available in the posted results.

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("Placebo", "Naltrexone")
n   <- c(6, 6)
m   <- c(-5.8, -9.5)
sp  <- c(5.1, 6.9)
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  Placebo  6  -5.800  5.100  -11.152  -0.448
CARM  Naltrexone  6  -9.500  6.900  -16.741  -2.259

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary endpoint, change in HAM-D-17 total score from baseline to week 3, and lists seven secondary outcomes. The secondary measures include changes in other depression scales, clinician ratings, response rate, and remission rate. Considering several outcomes raises a general multiplicity issue: the more statistical comparisons examined, the greater the opportunity for chance findings to appear noteworthy. In general, researchers may address this by prespecifying a hierarchy or using an adjustment. Whether such a plan was used is not reported in the registry record.

The primary endpoint population is described as study completers. The record lists six participants in each arm, but it does not report whether those counts represent all randomized participants or only those with complete endpoint data. The number of randomized participants who did not complete treatment, reasons for missing data, and methods for handling missing outcomes are not reported in the registry record. It is therefore not possible to assess whether the completer summaries could be affected by attrition or missingness.

The registry does not report an estimable two-arm comparison for the continuous primary endpoint. It also does not report a confidence interval or p-value for that comparison. A single analysis is listed, but the detailed statistical analysis plan, including model specification and any prespecified handling of covariates, is not reported in the registry record. Interim analyses and stopping rules are also not reported in the registry record.

These omissions limit assessment of how the primary comparison was conducted and how secondary results, if available, should be interpreted. They do not establish that a particular method was or was not used; they mean that the relevant details cannot be confirmed from the registry record.

12. 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 5% reporting threshold.

Most frequent non-serious adverse event terms

The posted serious adverse event figures list zero serious adverse events among six participants at risk in the placebo group and zero among six participants at risk in the naltrexone group. The registry lists no serious adverse event terms. Death counts are not reported in the registry record.

Each group also lists six participants at risk for other adverse events and six participants affected. These are counts of participants with at least one event, as represented in the registry summary; they do not give the total number of events or describe their severity, duration, or relationship to treatment. The specific non-serious adverse events are not reported in the registry record.

In general, an observed count of zero serious events in a small study does not establish that the risk is absent. It only describes what was recorded among the participants monitored in this trial. With six participants at risk per group, these figures cannot precisely characterize uncommon harms or support a strong comparison of safety between groups. The registry’s safety summaries should be read as limited descriptive data, not as a complete safety profile.

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

The result describes mean HAM-D-17 change among study completers over a three-week treatment period. The placebo group mean was -5.8, with a standard deviation of 5.1, and the naltrexone group mean was -9.5, with a standard deviation of 6.9. In the registry’s definition, negative change means a lower score at the end of treatment than at baseline. These summaries show the direction and spread of observed changes within each arm.

They do not provide an estimable comparison between the groups. The registry record does not report a comparative estimate, confidence interval, or p-value for this primary endpoint. The means should not be treated as if they alone establish the size, precision, or statistical significance of a treatment effect. The trial’s stated hypothesis concerned response rates, but response and remission results are not reported in the registry record.

The study enrolled 12 participants and lists six in each arm. This small scale limits how precisely the results can characterize average changes and how well they can represent the broader population described by the research question. The endpoint population is study completers, and the handling of missing outcomes is not reported. These considerations make the scope of the observed summaries narrower than a complete account of all randomized participants might be.

In general, randomized assignment is a design feature intended to support a fair group comparison, but interpretation still depends on the availability and quality of the outcome analysis. Here, the record identifies randomized allocation and quadruple masking, while several operational and analysis details are not reported. The posted data can be read as preliminary descriptive evidence from a proof-of-concept study. They do not by themselves establish that one assigned strategy is superior, equivalent, or ineffective, and they do not settle the study’s response-rate hypothesis.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between descriptive arm summaries and a comparative treatment estimate. The posted means describe average change within each group. The central randomized-trial question, however, concerns the contrast between assigned groups and the uncertainty around that contrast. Because the registry record does not provide an estimable two-arm comparison for the continuous endpoint, readers cannot judge that contrast directly from the reported result.

The trial also illustrates why precision matters alongside direction. The arm summaries come from six participants per group, and the standard deviations show variation in observed changes. In general, a small study can produce unstable estimates, and the observed mean may be sensitive to individual outcomes. A confidence interval would help communicate uncertainty, but one is not reported for the primary comparison.

A further statistical lesson is that the outcome named in a trial hypothesis and the endpoint with posted results may not be the same type of measure. The registry summary hypothesizes higher response rates with naltrexone, while the primary posted endpoint is continuous change in HAM-D-17 score. Response and remission are listed among secondary outcomes, but their results are not reported in the registry record. Keeping these distinctions clear prevents a continuous mean change from being mistaken for a response-rate finding.

Finally, the record highlights the importance of analysis-population and missing-data reporting. The primary outcome is for study completers, but the flow from enrollment to endpoint analysis and the missing-data approach are not described. Those details matter when interpreting who contributed to an estimate. Together, these features make the study useful for understanding the limits of early, small-sample evidence and the information needed for a more precise comparison.

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 most direct limitation is the size of the study: enrollment was 12, with six participants listed in each arm. The results therefore summarize a small group of completers. The registry does not report a formal sample-size justification, so the planned precision or target effect cannot be evaluated from the record.

The comparative primary result is not available as an estimable two-arm analysis. No treatment contrast, confidence interval, or p-value for change in HAM-D-17 is reported. The group means and standard deviations are descriptive and cannot replace that missing comparative analysis. Without the comparison and its uncertainty, the magnitude and precision of any difference between assignments remain unclear.

The primary endpoint population is study completers, but the registry does not report completion counts separately, reasons for missing measurements, or a missing-data method. It is therefore not possible to assess whether the analyzed participants represent all randomized participants. The detailed statistical plan, including model specification and any covariate adjustment, is not reported in the registry record.

The intervention period was three weeks, so the posted endpoint addresses change over that period only. Longer-term outcomes are not reported in the registry record. The registry lists several secondary outcomes, but their results and any approach to multiplicity are not reported. The safety summary gives counts but does not identify non-serious event types or report deaths.

Other details relevant to interpreting implementation—including the exact masked roles, allocation procedures, adherence, and background antidepressant regimens—are not reported in the registry record. These absences limit assessment of design and conduct; they should not be read as evidence that a particular procedure was not used.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Low-Dose Naltrexone (LDN) for Depression Relapse and Recurrence — NCT01874951.
• Registry record last updated 2017-02-24; status last verified 2017-01.
• Results first posted 2017-02-24.
• 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

The registry record describes NCT01874951 as a completed, randomized, quadruple-masked, parallel-group phase 2 pilot trial sponsored by Massachusetts General Hospital. It enrolled 12 participants with major depressive disorder and breakthrough symptoms on antidepressant therapy. Participants were assigned to three weeks of low-dose naltrexone or placebo.

The primary endpoint was change in HAM-D-17 total score from baseline to week 3 among study completers. The posted mean changes were -9.5 with standard deviation 6.9 for naltrexone and -5.8 with standard deviation 5.1 for placebo; negative values indicate lower scores at follow-up. The registry does not report an estimable two-arm comparison for this continuous endpoint.

Seven secondary outcomes are listed, but their results are not reported in the registry record. Serious adverse events were recorded for zero participants in each arm, while other adverse events were recorded for all six participants at risk in each arm. The record does not give further details on those other events. Overall, the posted information supports a descriptive reading of a small pilot study, not a precise estimate of the comparative effect.