Effects of Weekly Dosing of D-cycloserine on Cognitive Function in Individuals With Schizophrenia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effects of Weekly Dosing of D-cycloserine on Cognitive Function in Individuals With Schizophrenia (NCT00455702), a randomized phase 4 study. The primary outcome is Main Outcome Measure: The Change From Baseline to Week 8 on the SANS.

2. Clinical Question

3. Trial Design

The registry describes a randomized, quadruple-masked, parallel-group phase 4 trial of d-cycloserine and placebo in individuals with schizophrenia. Massachusetts General Hospital is listed as the sponsor. The study is marked completed, with enrollment of 38. The recorded start is 2004-07 and primary completion is 2007-04.

The arm descriptions list 50 mg d-cycloserine and 50 mg placebo. The registry summary says the study aimed to assess single-dose and repeated weekly dosing of d-cycloserine, but the posted arm descriptions do not establish the full dosing schedule used in the primary comparison. Other stated aims included evaluating cognitive and memory functioning, positive and negative symptoms, tolerability, and side effects. The primary outcome focused on negative symptoms, while a posted secondary outcome concerned the Positive Syndrome Subscale of the PANSS.

Randomization is intended to create groups that are comparable on average, while masking is intended to reduce the influence of expectations on study conduct or assessment. These design features do not remove uncertainty, particularly when the outcome samples are small. The registry does not report the randomization procedure, the roles included in quadruple masking, or details of adherence and follow-up.

The primary outcome data include 16 participants assigned to d-cycloserine and 17 assigned to placebo. The secondary outcome data include 16 in each group. These outcome-specific counts should not be taken as a full account of participant flow: reasons for differences in available outcome counts and the analysis populations are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

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 Main Outcome Measure: The Change From Baseline to Week 8 on the SANS, measured over Baseline score vs. Week 8.

The primary endpoint was change from baseline to week 8 in the SANS total score, reported as a mean with standard deviation. The SANS assesses negative symptoms. Its total score ranges from 0 to 100 and is computed by adding scores across five subscales: affective flattening or blunting, alogia, avolition-apathy, anhedonia-asociality, and attention. Higher scores indicate more prominent negative symptoms.

For the change score, the registry defines the calculation as baseline score minus week 8 score. A positive change therefore means the week 8 score was lower than baseline, which the registry describes as greater improvement. This direction matters when reading the group means: positive and negative values do not mean the same thing as the underlying SANS score itself.

Negative symptoms were a target of the study’s stated aims, making the SANS a measure directly related to the primary clinical question. A change score captures the difference across the specified assessment period, rather than the score at week 8 alone. The registry does not report a threshold for interpreting a change as clinically important, so the estimated mean difference should be read in score units, with uncertainty, rather than treated as proof of a particular level of meaningful benefit.

7. Results Posted in the Registry

• D-cycloserine: mean 2.06 versus -2.11 on control; difference 4.17 (95% CI 0.01 to 8.33), standardized effect d = 0.68; z-test p = 0.049.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Treatment Effects on the Positive Syndrome Subscale of the PANSS

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • D-cycloserine: mean 0.19 versus -0.19 on control; difference 0.38 (95% CI -2.12 to 2.88), standardized effect d = 0.11; z-test p = 0.766.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between D-cycloserine and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary outcome concerns the PANSS Positive Subscale, complementing the primary SANS outcome by addressing positive symptoms. Across the posted outcomes, the primary estimate is positive in the direction defined as improvement on the SANS, while the secondary estimate is close to zero relative to its uncertainty. This difference in pattern does not by itself show that effects truly differ between symptom domains. Comparing whether one result appears more notable than another is not the same as formally testing whether the effects differ.

The secondary estimate has a confidence interval that includes zero and extends to differences in both directions. That broad uncertainty means the result offers limited evidence about the size or direction of a difference in positive-symptom change. It should not be described as proof of equivalence, absence of an effect, or contradiction of the primary result. The endpoints measure different symptom domains, so they need not produce identical estimates.

Secondary findings generally carry less confirmatory weight than a designated primary endpoint because they may be among several outcomes considered. Testing multiple outcomes can increase the chance of a seemingly notable result arising by chance. The registry lists one secondary outcome and reports no analyses, but does not state whether additional outcomes or tests were considered in the study’s analysis plan. A multiplicity adjustment or prespecified hierarchy is not reported in the registry record.

The registry summary also mentions cognition and memory, tolerability, and side effects as study aims, but the posted results do not provide a full account of those aims. The available secondary result therefore gives only a limited view of the broader questions described in the summary. It is most appropriately read as additional, uncertain context alongside the primary outcome, not as an independent confirmation of the primary finding.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Treatment Effects on the Positive Syndrome Subscale of the PANSS

9. Statistical Interpretation

10. Statistical Methods Explained

The primary result is a difference between group means for a continuous outcome. The outcome is the change in SANS total score from baseline to week 8. The treatment-group mean change was 2.06, and the placebo-group mean change was -2.11. The posted mean difference was 4.17, defined in the direction of d-cycloserine relative to placebo. Since higher change scores represent greater improvement under the registry’s definition, a positive difference favors d-cycloserine on this scale.

What does a mean difference describe?

A mean is the arithmetic average of the observations in a group. A mean difference compares those averages in the outcome’s original units. Here, the unit is SANS scale units. This makes the estimate directly interpretable as a difference in average change, but it does not show how much participants varied or whether every participant had a change in the same direction. The standard deviations, 5.03 and 7.05, describe spread within the two outcome groups; they are not measures of uncertainty in the mean difference itself.

What does the confidence interval add?

A confidence interval expresses uncertainty around an estimated effect. The 95% interval for the primary mean difference is 0.01 to 8.33. It shows that the data are compatible with a range of possible differences, from a value very close to no difference to a larger advantage on the stated scale. The interval does not assign a probability to the true effect being inside its particular endpoints. Rather, it indicates how uncertain the estimate is under the statistical procedure used to construct the interval.

The interval’s lower endpoint is close to zero, so the evidence does not pin down the size of the difference precisely. A p-value answers a related but different question: under a specified null model, how unusual would a result at least this extreme be? The reported unadjusted p-value is 0.049. It should not be interpreted as the probability that the null hypothesis is true, nor as a measure of the size or importance of the estimated effect.

Why does variation matter?

Variation in individual outcomes affects how precisely group averages can be compared. When outcomes vary widely, the group means are less informative about the underlying average difference unless there are enough observations to estimate them precisely. Standard deviations describe this variation in the observed groups. The standard errors listed for the outcome means, 1.258 for d-cycloserine and 1.71 for placebo, describe uncertainty in those means rather than the spread of individual values. The registry does not report participant-level data, so the shapes of the outcome distributions cannot be assessed from these summaries alone.

Over-dispersion is a general concern when observed variation is greater than a statistical model expects. For a continuous outcome, an analysis that understates the true variation can make uncertainty look too small. The posted summaries include group standard deviations, but the registry record does not describe a model that assessed over-dispersion or a diagnostic procedure. No conclusion about such a procedure can be drawn from the available record.

What does the secondary estimate show?

The secondary PANSS Positive Subscale comparison is also a difference between group means. Its estimated difference was 0.38 units, with a 95% confidence interval from -2.12 to 2.88 and an unadjusted p-value of 0.766. The interval covers zero and includes possible differences in both directions. The estimate is therefore not precise enough to distinguish a small difference from a larger one in either direction. This is not equivalent to demonstrating that the groups are identical.

What does “unadjusted” mean?

An unadjusted comparison refers to the posted comparison without a stated correction for multiple outcomes or tests. Adjustment can be used when many hypotheses are tested, because the chance of finding an apparently notable result can increase as tests accumulate. Whether any adjustment was used in the trial’s original analysis is not reported in the registry record. The posted outcome comparison should not be interpreted as evidence that a particular statistical plan was followed.

The trial is randomized and parallel-group, but the record does not describe the exact method used to estimate the confidence intervals, the randomization procedure, or whether covariates were included in any analysis. The displayed estimates are not a substitute for a complete protocol or statistical analysis plan. They provide a readable summary of the reported group means and the stated comparative estimates, with uncertainty that should remain central to interpretation.

11. Confidence Intervals and Precision

Precision concerns how narrowly the data constrain the plausible size of an effect. For the primary SANS change comparison, the mean difference was 4.17 units and the 95% confidence interval was 0.01 to 8.33. The interval extends from a difference near zero to a larger difference favoring d-cycloserine. Thus, while the point estimate is positive, the magnitude is not tightly determined. The near-zero lower endpoint is especially relevant: modest changes in the data or analysis could affect how strongly the result separates from no difference.

The outcome groups were small, with 16 participants in the d-cycloserine group and 17 in the placebo group. Small samples generally provide less precise estimates than larger samples when other conditions are similar. The standard deviations were 5.03 and 7.05, indicating appreciable variation in the observed change scores. These factors help explain why the uncertainty around the mean difference matters, although the registry does not provide enough detail to attribute the interval width to any one cause.

The secondary PANSS Positive Subscale mean difference was 0.38 units, with a 95% confidence interval from -2.12 to 2.88. This interval includes zero and effects in either direction, so the estimate does not identify a clear direction or a narrow range of possible effects. It should not be read as proof of no difference.

Confidence intervals represent uncertainty under the statistical method used to calculate them. They do not account automatically for every possible limitation, such as missing outcomes, selective reporting, or multiplicity. Those issues are not resolved by a confidence interval, and relevant analysis details are not reported in the registry record. The interval is useful, but it is not a complete measure of the certainty of the evidence.

12. 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 for the primary continuous outcome are participants per arm, not total events. They are illustrations based on the observed effect, rather than the trial’s original design assumptions. The stated planning assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to a stated fraction of the observed effect. The trial’s own sample-size justification and original design assumptions are not reported in the registry record.

For planning at 100% of the observed effect, the figures are 35 participants per arm for 80% power and 46 participants per arm for 90% power. At 75% of the observed effect, they are 61 participants per arm for 80% power and 82 participants per arm for 90% power. At 50% of the observed effect, they are 137 participants per arm for 80% power and 184 participants per arm for 90% power.

In general terms, 80% power means that a study designed under these assumptions would have an 80% chance of detecting an effect of the specified size at the stated significance level, if that effect were the true one and the assumptions held. The 90% column uses the same idea with a higher target chance of detection. Smaller effects require more participants because they are harder to distinguish from random variation. These counts are planning illustrations, not observed power: they do not describe the probability that this completed trial detected an effect or establish what its original sample-size plan was.

13. 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 = 4.170; pooled standard deviation σ = 6.156.
2. n = 2 × (1.96 + 0.842)² × 6.156² / 4.170² = 34.2, rounded up to 35 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 <- 4.17                      # observed difference in means
sigma <- 6.15591375780626                     # 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(455702)
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 = 35 (80% power), 46 (90% power)
 75% of observed effect: n per arm = 61 (80% power), 82 (90% power)
 50% of observed effect: n per arm = 137 (80% power), 184 (90% power)
power.t.test: 35.2 
Simulated power at n = 35 per arm: 0.793 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry designates change in SANS total score as the primary outcome and lists a secondary outcome for the PANSS Positive Subscale. It reports two outcome measures in total, while the number of posted analyses is zero and no reported analyses are listed for the secondary outcome. The record does not describe a prespecified statistical analysis plan, a testing hierarchy, or an adjustment for multiple comparisons. It is therefore not possible to determine from the registry record how multiplicity was handled in the trial’s own analyses.

Multiplicity matters when several outcomes, time points, or statistical tests are examined. The more opportunities there are to identify a result as notable, the more important it becomes to know which analyses were planned and whether the interpretation accounts for multiple testing. The unadjusted p-values are results for individual comparisons and should not be treated as if they were necessarily adjusted for all analyses undertaken. The absence of a reported adjustment is not proof that no adjustment was performed; the method is not reported in the registry record.

Missing-data handling is also not described. The primary outcome counts are 16 for d-cycloserine and 17 for placebo; the secondary outcome counts are 16 per group. The record does not explain why these counts differ, whether all randomized participants contributed to each analysis, how missing week 8 measurements were handled, or whether any imputation or sensitivity analyses were used. It also does not report an intention-to-treat or per-protocol analysis population.

These omissions affect how confidently the posted estimates can be connected to the randomized groups as a whole. If outcome availability is related to participants’ outcomes or treatment assignment, analyses limited to observed measurements may be affected. The registry record does not provide enough information to assess that possibility. The estimates remain useful descriptions of the posted outcome data, but their interpretation should acknowledge that the analysis population and missing-data approach are not reported.

15. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: worsening psychosis due to discontinuation of anti-psychotic (5.3%).

The registry lists serious adverse event figures for 19 participants at risk in each group. It records 1 affected in the d-cycloserine group and 0 in the placebo group. For other adverse events, it records 8 affected in the d-cycloserine group and 13 in the placebo group, again with 19 at risk in each group. These are counts as posted; they do not establish that an event was caused by the assigned treatment.

The registry names “Worsening psychosis due to discontinuation of anti-psychotic” as a top serious adverse event term and gives 5.3%. The record does not identify a group for this term in the listed summary, so it should not be assigned to either arm based on these figures. Death counts are not reported in the registry record.

Safety counts should be considered alongside the size of the groups and the trial’s limited outcome information. The registry does not provide event timing, severity details beyond the serious-event category, exposure duration, or a full narrative of how events were collected and assessed. These figures describe the posted record and are not, on their own, a complete comparison of safety.

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

The primary estimate indicates a higher average SANS change score in the d-cycloserine group than in the placebo group over the period from baseline to week 8. Under the registry’s scoring definition, higher change means a greater decrease in SANS score. The estimated between-group mean difference was 4.17 units. Its 95% confidence interval, 0.01 to 8.33, shows that the magnitude remains uncertain and includes values close to no difference.

This result does not establish that every participant improved, that the difference was clinically important, or that the same estimate would be observed in another trial. The registry does not report a threshold for a clinically important SANS change. The small outcome groups and variation in change scores are reasons to avoid treating the point estimate as a precise prediction.

The posted secondary comparison does not clearly distinguish the groups, but that is not proof of no effect on positive symptoms. Its uncertainty is broad, and the registry does not report a multiplicity strategy or a complete analysis plan. The trial summary describes broader aims related to cognition, memory, tolerability, and side effects, but the posted results do not provide a complete results account for all those aims.

Randomization and masking are important design features, but their presence does not answer every question about the quality and completeness of the evidence. The registry does not report participant flow, analysis populations, missing-data methods, or the details of the original statistical plan. The appropriate reading is therefore limited to the estimates and uncertainty recorded for these outcomes, without extending them into claims about treatment recommendations or effects beyond the trial’s reported measures and time frame.

17. Why This Trial Matters Statistically

This trial illustrates why an estimated difference and its uncertainty should be read together. The primary mean difference is positive on the registry’s improvement-oriented scale, but the confidence interval begins very close to zero and extends to a larger value. A single point estimate cannot express that range of plausible effects. The interval helps distinguish an estimate that is precise from one whose magnitude remains uncertain.

It also illustrates the limits of threshold-focused interpretation. The unadjusted p-value for the primary comparison is 0.049, near the conventional 0.05 threshold. That value does not measure clinical importance, and it does not tell readers the probability that the result is true. The estimated effect, interval, sample size, and outcome variability all contribute to a more informative interpretation than a binary significant-or-not label.

Small randomized trials can provide useful comparative estimates, but estimates from small outcome groups may be imprecise. The planning illustrations show how the number of participants needed depends on the effect size being targeted and the desired power under stated assumptions. They are not evidence about the trial’s original planning or a retrospective measure of its success.

Finally, registry results are easier to interpret when the analysis plan, missing-data approach, outcome populations, and multiplicity handling are clearly documented. Those details are not reported in the registry record. Their absence does not invalidate the posted summaries, but it limits how fully readers can evaluate the analysis and its relationship to the broader study aims.

18. Limitations

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

The primary outcome data are available for 16 participants in the d-cycloserine group and 17 in the placebo group, within an enrollment of 38. The registry does not report participant flow or explain why the outcome counts do not account for the full enrollment. As a result, the extent and handling of missing primary outcome data cannot be assessed from the record.

The registry provides means and standard deviations but not participant-level outcomes or distributional summaries. This limits assessment of unusual values, skew, or whether group averages represent a typical participant. The record also does not describe the precise statistical procedure used to construct the confidence interval or whether the estimate was adjusted for baseline scores or other covariates.

The study summary describes single-dose and repeated weekly dosing aims, but the arm descriptions list only 50 mg d-cycloserine and 50 mg placebo. The dosing schedule relevant to the primary comparison is therefore not fully clear from the record. The roles covered by quadruple masking, adherence, and exposure are also not described.

Only one secondary outcome is posted, and the record reports no analyses. It does not establish whether other outcomes or analyses were considered, how multiplicity was addressed, or whether the reported comparisons followed a prespecified plan. The registry also does not provide a clinically important difference threshold for the SANS. These gaps limit assessment of clinical relevance, analysis choices, and the completeness of the results, beyond the uncertainty already reflected in the confidence intervals.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Effects of Weekly Dosing of D-cycloserine on Cognitive Function in Individuals With Schizophrenia — NCT00455702.
• Registry record last updated 2014-08-07; status last verified 2014-07.
• Results first posted 2014-08-07.
• 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.

22. Record Summary

The registry identifies a completed, randomized, quadruple-masked, parallel-group phase 4 trial sponsored by Massachusetts General Hospital. It lists enrollment of 38 and compares 50 mg d-cycloserine with 50 mg placebo in individuals with schizophrenia.

The primary outcome is change in SANS total score from baseline to week 8, with higher change scores indicating greater improvement. The posted mean difference is 4.17 units, with a 95% confidence interval from 0.01 to 8.33 and an unadjusted p-value of 0.049. One secondary outcome, the PANSS Positive Subscale, is also posted.

The registry record does not report the trial’s original sample-size justification, analysis populations, missing-data approach, multiplicity strategy, or a full account of analyses. These omissions limit assessment of the posted estimates beyond their reported values and uncertainty.