Role of Magnesium Supplementation in the Treatment of Depression: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Role of Magnesium Supplementation in the Treatment of Depression (NCT02466087), a randomized phase 2, phase 3 study. The primary outcome is Patient Health Questionnaire-9.

2. Clinical Question

3. Trial Design

This was a randomized crossover study, listed in phases II and III, with no masking. The registry lists the study as completed, with enrollment of 126. The study start is recorded as 2015-05 and primary completion as 2016-05. The sponsor was the University of Vermont.

Participants were followed for 12 consecutive weeks. According to the study summary, they were randomized to start supplementation at week 1 or week 7, and took magnesium for 6 consecutive weeks. The other 6-week period was the control period, described as no intervention. This sequence means that each assigned start schedule included a supplementation period and a period without intervention. The record does not report further details about sequence generation, concealment of allocation, or procedures for managing possible period or carryover effects.

The summary describes two supplement doses taken two times a day, for a total of 248 mg elemental magnesium daily, in the form of magnesium chloride. The arm description instead states 500mg Mg Cl per day. These are distinct descriptions in the registry record; it does not explain how they relate. Volunteers were asked to maintain their normal diet over the 12 weeks.

The primary outcome was the PHQ-9 score, measured over a 12-week timeframe. Secondary outcomes listed in the record were the Generalized Anxiety Disorder 7 Item Questionnaire and change in headaches while taking supplements. There are three outcome measures listed, but only two secondary outcomes are named in the registry record. More detail about how and when secondary outcomes were analyzed is 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.

First Intervention: Weeks 1-6

Second Intervention: Weeks 7-12

Analysis population for the primary outcome, as defined in the registry: Number of participants with analyzable data.

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 Patient Health Questionnaire-9, measured over 12 weeks.

The primary endpoint was the change in Patient Health Questionnaire-9 score. The PHQ-9 is a questionnaire used to assess depressive symptoms; the registry describes it as validated and notes its sensitivity and specificity for diagnosing depression. Scores can range from 0 to 27, with categories recorded as 0-4 None, 5-9 Mild, 10-14 Moderate, 15-19 Moderate to Severe, and 20-27 Severe.

The endpoint was defined as change from week 1 to week 6 and change from week 7 to week 12, analyzed as a difference in differences. The intent of this form of endpoint is to compare change across the supplementation and control periods, rather than interpreting a single score in isolation. Because the study used different randomized start times, the two periods correspond to supplementation and control in different sequences.

The posted arm summaries give mean changes and 95% confidence intervals: MgCl, -4.28 with interval -4.99 to -3.56; Control, -0.09 with interval -0.9 to 0.72. These are arm-level summaries. They do not, by themselves, provide the uncertainty for the paired or adjusted comparison between periods. The record describes the primary outcome population as participants with analyzable data, but further detail on the endpoint’s scoring rules or handling of incomplete questionnaires is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: it is a score on a scale, and the registry reports means with 95% confidence intervals. In general, a mean summarizes the central value of observations, while a confidence interval expresses uncertainty in the estimated mean. The interval’s width depends on factors such as the variability and amount of analyzable data, as well as the analysis method. The record does not report the standard deviations or individual-level data for this endpoint, so those features cannot be independently assessed from the arm summaries.

What does a difference in differences represent?

In general, a difference-in-differences analysis compares changes across two conditions or periods. It is designed to focus on the contrast between changes, rather than on a single endpoint measurement. In a crossover study, the same participants may contribute observations under more than one condition, so the analysis may need to account for the relationship between measurements from the same person. The registry identifies the sponsor’s method as linear regression and its parameter as difference in differences, but does not report the model specification, covariates, treatment of repeated observations, or assumptions used.

The primary outcome description names changes in the week 1 to week 6 and week 7 to week 12 periods. The registry does not provide the period-specific raw scores, participant-level change values, or the exact model contrast. Consequently, the reported arm means cannot establish the sponsor estimate by direct inspection, and a recalculation is not available for this continuous two-arm comparison. The registry does not report whether period or sequence effects were assessed, or how possible carryover was handled.

How should the confidence intervals be read?

In general, a confidence interval expresses the precision of an estimate under the method’s assumptions. The arm-level intervals are attached to the separate means. They should not be read as intervals for the contrast between those means, nor as a test of the sponsor’s difference-in-differences estimate. For a comparison, the relevant interval would need to describe that contrast and account for the design and the covariance between measurements where appropriate. The sponsor analysis has a stated 95% confidence level, but the interval limits are not reported in the registry record.

The arm-level confidence intervals and the sponsor estimate answer different statistical questions. One summarizes each arm’s mean change; the other is reported as a regression-based difference in differences. Without details of the regression model and its uncertainty estimate, the 1.5 point estimate cannot be fully evaluated for precision. The posted arm means do not fill that gap.

What can the sample-size illustrations tell readers?

In general, sample-size planning asks how many participants might be needed to detect a specified effect under stated assumptions. The planning illustrations associated with this analysis use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with effects defined as stated proportions of the observed effect. For continuous outcomes, the reported planning quantities are participants per arm. These are hypothetical planning calculations based on the observed effect, not the trial’s own design justification and not observed power. The registry record does not report the original sample-size justification or identify a prospectively specified effect used for enrollment planning. The numerical planning results are not described in the registry information summarized for this interpretation, so no values can be quoted.

In general, the normal approximation is a simplifying assumption used in planning calculations. The adequacy of that approximation depends on the design and data characteristics. A crossover design also differs from a simple independent parallel-arm design because participants can contribute measurements in both conditions. The planning assumptions listed do not establish that the trial’s own analysis used the same assumptions, and the registry does not report a detailed connection between the planning calculations and the original design.

Why do distribution and design details matter?

In general, continuous-outcome methods can be affected by skewness, outliers, unequal variability, and dependence among repeated measurements. Over-dispersion is most often discussed for count outcomes; in general, it means that variability exceeds what a simpler model assumes, which can make standard errors too small if not addressed. The PHQ-9 is recorded as a score, and the registry does not report an over-dispersion assessment or any distributional diagnostics. No claim about such features can be made from the reported means alone.

The crossover structure makes sequence and timing relevant to interpretation. In general, a period effect occurs when outcomes differ over time for reasons separate from the intervention, and carryover refers to an effect from an earlier treatment period persisting into a later period. The registry record does not report whether either was evaluated or how either would be represented in the regression. This lack of detail limits assessment of the assumptions underlying the contrast, but does not by itself show that the analysis was inappropriate.

10. Analyses Reported by the Sponsor

The registry reports a sponsor analysis using linear regression, described as a difference in differences. Its point estimate is 1.5, with a confidence interval level of 95%. The interval limits and p-value are not reported in the registry record, and the record does not give the sign convention or model details needed to interpret the point estimate more fully.

No independent recalculated two-arm comparison is available from the posted summary statistics: the continuous endpoint comparison is marked as missing or not estimable. The reported means and intervals for MgCl and Control are separate arm summaries, not a substitute for the sponsor’s regression contrast. They cannot establish a recalculated estimate or its uncertainty without additional data and design details.

The record marks the discrepancy flag as false, so there is no stated discrepancy between a sponsor result and a recalculated comparison. In any event, a recalculated comparison is not available for this endpoint. The sponsor’s own analysis remains the registry’s reported comparative result, but its precision and inferential strength cannot be judged from the point estimate alone because the confidence interval limits and p-value are absent.

The arm summaries report 112 analyzable participants in each group, but the relationship between those counts and the crossover sequences is not described. The registry also does not report the regression model specification, so the extent to which the sponsor analysis accounts for repeated measurements, sequence, and period cannot be determined.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the PHQ-9 as the primary outcome and names two secondary outcomes: the Generalized Anxiety Disorder 7 Item Questionnaire and change in headaches while taking supplements. It also lists three outcome measures in total, but only two secondary outcomes are named. Results for those secondary outcomes are not included in the posted information described in the registry record.

When a study evaluates multiple outcomes or multiple comparisons, the chance of at least one apparently unusual result can increase. In general, multiplicity procedures can control or otherwise address that issue, depending on the analysis plan. The registry record does not report whether multiplicity was considered, whether any outcomes were prioritized beyond identifying the primary measure, or whether an adjustment was planned. It would be inappropriate to assume that an adjustment was or was not used.

The primary endpoint population is described as participants with analyzable data. Arm summaries list 112 participants each, while enrollment is 126. The registry does not report how missing observations were handled, whether the analysis included all randomized participants, how many participants completed both periods, or whether any imputation or sensitivity analysis was conducted. Reasons for missing data and their distribution by randomized start time are also not reported in the registry record.

In general, missing outcome data can affect an estimate if the availability of measurements is related to treatment, outcome, or participant characteristics. The potential effect depends on why values are missing and on the analysis assumptions. Without information about missingness and analysis populations, the degree to which the analyzable results represent all enrolled participants cannot be assessed. This is a reporting limitation, not evidence about the direction or size of any resulting bias.

The registry does not report an interim-analysis plan, stopping rule, or a detailed statistical analysis plan. It also does not report whether the endpoint, secondary outcomes, and analysis choices were prespecified in a protocol. These matters therefore remain unknown from the registry record.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

The registry reports serious adverse events for 62 participants at risk in the magnesium supplementation group and 64 at risk in the control group. It records zero serious adverse events in each group. The same at-risk counts are listed for other adverse events, with zero recorded in both groups, and deaths are listed as zero in both groups.

These figures describe the adverse-event entries in the registry record. They do not establish that no symptoms or events occurred outside the categories or collection procedures reflected in those entries. The record does not provide event definitions, surveillance methods, timing, severity grading, or detail about whether events were assessed during both periods in the same way.

The adverse-event at-risk counts differ from the 112 participants listed in each arm for the primary outcome. The registry does not explain the relationship between these counts, including which participants were included in safety monitoring or how exposure during the crossover periods was attributed. The safety figures should therefore be interpreted using their own reported denominators, rather than assumed to describe every participant with analyzable PHQ-9 data.

Zero recorded events in these groups is a statement about the reported counts, not proof that an event is impossible or that the intervention has no risk. The record does not report further safety analyses or provide enough information to compare event rates across the two exposure periods.

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

The results describe mean PHQ-9 changes in the two reported arms and a sponsor-reported regression estimate for a difference-in-differences analysis. The MgCl arm mean change is -4.28, with a 95% confidence interval from -4.99 to -3.56. The Control arm mean change is -0.09, with a 95% confidence interval from -0.9 to 0.72. The sponsor’s reported estimate is 1.5, with a stated 95% confidence level but no interval limits or p-value.

Those results do not, on their own, establish the precision of the sponsor’s comparative estimate. The arm-level confidence intervals describe the separate means, not the crossover contrast. Because the registry does not report interval limits for the regression estimate and a recalculated comparison is unavailable, the uncertainty of that contrast cannot be evaluated from the posted summaries.

The registry record also does not report a threshold for a clinically important PHQ-9 difference. The PHQ-9 severity categories help describe score ranges, but they do not establish how meaningful the reported change or comparison is for participants. Nor does a change in a questionnaire score alone establish broader effects beyond the outcome measured.

The study’s crossover design, missing analysis details, and incomplete reporting of the analyzable population all matter to interpretation. The registry does not report enough information to assess period effects, carryover, missing-data assumptions, or the regression model in detail. These gaps do not prove that the results are biased, but they prevent a complete appraisal of the analysis from the registry record alone.

The safety entries show zero serious adverse events, zero other adverse events, and zero deaths in the listed groups. Those counts should be read as registry-reported events among the specified at-risk participants, not as a guarantee that no events occurred under other definitions or observation procedures. Taken together, the posted information supports a description of the recorded outcome and safety summaries; it does not resolve the uncertainty around the comparative estimate or establish a clinical conclusion.

14. Why This Trial Matters Statistically

This trial is statistically interesting because it uses a randomized crossover structure for a continuous symptom score. In a crossover design, participants can contribute information under both an intervention period and a control period. That can make within-participant comparisons relevant, while also making the analysis dependent on how repeated measurements, timing, and sequence are handled.

The registry’s primary outcome definition explicitly focuses on change across two periods and describes the sponsor analysis as a difference in differences. This makes the distinction between arm-level summaries and a comparative estimate especially important. Separate means can describe changes within the listed groups, but they do not supply the uncertainty for the regression contrast. The sponsor’s reported point estimate therefore cannot be fully evaluated without its interval limits and model details.

The record also illustrates why analyzable sample sizes and enrollment are not interchangeable descriptions. Enrollment is 126, while the primary outcome summaries list 112 in each arm. Because the registry does not explain the relation between those numbers or how participants contributed across the periods, the analysis population remains difficult to reconstruct.

Finally, the intervention is described in two different ways: the summary gives 248 mg elemental magnesium daily, while the arm description lists 500mg Mg Cl per day. The registry does not explain the relationship between these statements. Clear reporting of intervention dose, outcome definition, model specification, and missing-data handling is important for understanding a clinical trial result and assessing whether it can be reproduced or interpreted in context.

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 registry record leaves several trial-specific questions unresolved. Most importantly, it contains two descriptions of the supplementation amount: 248 mg elemental magnesium daily in the study summary and 500mg Mg Cl per day in the arm description. These refer to different stated quantities, and the record does not explain their relationship. The distinction matters for understanding what exposure the outcome summaries represent.

The crossover analysis is not described in enough detail to reconstruct. The record identifies linear regression and a difference-in-differences parameter, but does not report the model equation, covariates, handling of repeated observations, sequence terms, period terms, or carryover assessment. The sponsor estimate of 1.5 has no interval limits or p-value in the registry record. A recalculated comparison is unavailable because the continuous two-arm comparison is marked as missing or not estimable.

The endpoint summaries are reported for 112 participants in each arm, while enrollment is 126. The registry does not report how these counts correspond to randomization sequences, whether the same participants contributed to both periods, or why some enrolled participants are absent from the analyzable summaries. Missing-data handling, reasons for missing observations, and sensitivity analyses are not reported.

The record also does not report a sample-size justification, interim-analysis procedures, a detailed statistical analysis plan, or methods for addressing multiple outcomes. Although secondary outcomes are named, their results are not reported in the information. Participant characteristics and more detailed safety-collection methods are also not reported in the registry record. These limitations restrict the statistical and clinical interpretation of the posted results without establishing that any particular bias occurred.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Role of Magnesium Supplementation in the Treatment of Depression — NCT02466087.
• Registry record last updated 2019-05-08; status last verified 2019-04.
• Results first posted 2019-05-08.
• 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 a completed randomized, unmasked crossover study sponsored by the University of Vermont, with enrollment of 126. Participants were followed for 12 weeks and assigned to begin 6 weeks of magnesium supplementation at week 1 or week 7; the other period was described as no intervention. The registry gives different descriptions of the magnesium amount, which it does not reconcile.

The primary outcome was PHQ-9 change over the two periods. Arm-level mean changes were -4.28 for MgCl and -0.09 for Control, with reported 95% confidence intervals. The sponsor’s linear-regression difference-in-differences estimate was 1.5; interval limits and a p-value are not reported. No recalculated comparison is available from the posted summary statistics.

The registry lists two secondary outcomes and reports zero serious adverse events, zero other adverse events, and zero deaths in the listed safety groups. Details about the regression model, missing data, the analysis population, and multiplicity are not reported in the registry record.