This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders (NCT01720316), a randomized phase 2 study. The primary outcome is Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01720316 |
| Phase | Phase 2 |
| Condition | Schizo-affective Disorder, Bipolar Disorder |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Quadruple |
| Enrollment | 2 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Mclean Hospital |
| Results posted | Yes |
2. Clinical Question
Population
Two psychotic patients with a triplication, described as 4 copies, of the gene encoding glycine decarboxylase (GLDC). The registry lists schizo-affective disorder and bipolar disorder as conditions.
Intervention
Oral glycine, up to 0.8 g/kg per day on a TID dosing schedule. The protocol description includes a double-blind treatment period and a later open-label glycine period.
Comparator
Placebo, administered on a TID schedule during the double-blind treatment period. The crossover design means participants were assigned treatment periods rather than remaining in only one treatment group.
Primary question
How positive and negative symptom scores change from baseline and across scheduled assessments during glycine and placebo intervention periods, and during open-label glycine. The registry does not report a single reduced comparison or numerical treatment-effect estimate for this question.
The study was intended to assess glycine augmentation in people with this uncommon genetic finding and psychotic disorders. Its stated primary measure is symptom scores assessed at baseline and at 2 weeks, 4 weeks, and 6 weeks within treatment periods, as well as after each period. The record describes glycine and placebo treatment in a double-blind crossover phase, followed by open-label glycine. A 2-week period without treatment separated the two double-blind arms.
This setup makes the question exploratory and specific to the enrolled participants. It is not a broad test across a representative group of people with psychotic disorders. The record reports enrollment as 2 and does not provide a primary-outcome analysis that combines the repeated observations into a treatment comparison. Consequently, the registry record does not establish the size or precision of a difference between glycine and placebo.
3. Trial Design
This was a randomized, quadruple-masked, crossover study listed as Phase 2. The registry records enrollment of 2 and a completed status. McLean Hospital is listed as the sponsor. The study began on 2012-12-10, and the primary completion date is recorded as 2017-05-31.
The protocol description says participants first entered a double-blind, placebo-controlled clinical trial with one 6-week glycine arm and one 6-week placebo arm. Glycine was given up to 0.8 g/kg on a TID schedule; placebo was also given on a TID schedule. A 2-week period without treatment was planned between these arms. The record then describes a 6-week open-label glycine period. It does not state the sequence assigned to each participant or provide a participant-level account of treatment completion.
Assessments were planned at baseline and at 2 weeks, 4 weeks, and 6 weeks during each intervention period, and after each treatment period. The protocol description also lists imaging, electrophysiology, symptom, neurocognitive, amino-acid, and psychotropic-drug assessments. These procedures and measures indicate a broad pilot investigation, but the registry does not give results for most of them in the record summarized by the outcomes.
A crossover design compares treatments received by the same participants at different times. In general, that can reduce the influence of stable differences between participants, but it makes the treatment comparison dependent on the period sequence and the handling of effects that may persist after a treatment period. The registry describes a 2-week no-treatment interval but does not report a statistical model or explain how sequence, period, or carryover effects were handled. It also does not report a sample-size justification.
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.
Double-Blind Glycine Placebo Crossover
| Stage | Glycine, Then Placebo | Placebo, Then Glycine |
|---|---|---|
| STARTED | 1 | 1 |
| COMPLETED | 1 | 1 |
| NOT COMPLETED | 0 | 0 |
Open-label Glycine
| Stage | Glycine, Then Placebo | Placebo, Then Glycine |
|---|---|---|
| STARTED | 1 | 1 |
| COMPLETED | 1 | 1 |
| NOT COMPLETED | 0 | 0 |
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.
| Characteristic | Unit | Glycine, Then Placebo | Placebo, Then Glycine | Total |
|---|---|---|---|---|
| Participants analysed | 1 | 1 | 2 | |
| Age, Continuous: age | years | 59 (NA to NA) | 32 (NA to NA) | 45.5 (32 to 59) |
| Sex: Female, Male: Female | Participants | 1 | 0 | 1 |
| Sex: Female, Male: Male | Participants | 0 | 1 | 1 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 1 | 1 | 2 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 1 | 1 | 2 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Region of Enrollment: United States | Participants | 1 | 1 | 2 |
6. Primary Endpoint
The registry lists the primary outcome as Positive and Negative Symptom Scores at Baseline and at 2 Weeks, 4 Weeks, and 6 Weeks During Intervention 1 (Glycine or Placebo), Intervention 2 (Glycine or Placebo), and During Open-label Glycine, measured over baseline and at 2 weeks, 4 weeks, and 6 weeks within each treatment period and after each treatment period.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | units on a scale |
| Endpoint classification | not reduced to a single comparison |
The registered primary outcome concerns positive and negative symptom scores measured at baseline and at scheduled points during the intervention periods. The stated timing is baseline and 2 weeks, 4 weeks, and 6 weeks within each treatment period, with assessment after each treatment period. The registry identifies the Positive and Negative Symptom Scale (PANSS) and describes its positive-symptom component: the sum of ratings for seven positive symptoms, on a scale from 7-49, where 7 means no symptoms and 49 means severe symptoms.
Symptom scales are used to represent clinical features in a structured way, allowing ratings to be compared across assessment times. Repeated ratings can describe how scores change over time and can support a comparison between treatment periods if an analysis plan specifies how those observations are combined. General statistical interpretation depends on the chosen outcome definition, scoring, and analysis; the registry record does not report a single summary contrast for the primary outcome.
The outcome title refers to positive and negative symptom scores, while the posted scale description specifically explains the positive-symptom score. A separate definition of the negative-symptom scoring component is not reported in the registry record. Numerical scores, treatment contrasts, uncertainty intervals, and test results for the primary outcome are also not reported in the registry record. Thus, the outcome definition and planned assessment schedule are available, but the size and precision of any treatment difference cannot be read from this record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies a clinically focused primary outcome and a repeated-measures schedule, but it does not report numerical primary-outcome results or a statistical analysis. The outcomes listing indicates that no analysis results were reduced to a single comparison. There is therefore no posted treatment-effect estimate, confidence interval, or p-value for glycine versus placebo to interpret. The record does not establish whether symptom scores differed between treatment periods, how large any difference was, or how precisely it could be estimated.
Enrollment is recorded as 2, and the brief description specifies two psychotic patients with a GLDC triplication. This is a pilot with a very limited participant base, so even a numerical estimate, if available, would need to be interpreted in light of its uncertainty and narrow population. The posted record does not provide individual scores, variability measures, or a completed statistical comparison that would quantify that uncertainty. No inference about a wider population can be drawn from a treatment contrast that is not reported.
The crossover structure is relevant to interpretation. In a crossover trial, each participant can contribute observations under both treatments, and the treatment comparison can depend on the ordering and timing of those observations. General statistical practice requires consideration of period effects, treatment sequence, and possible carryover. Although the record describes a 2-week period without treatment between the double-blind arms, it does not report whether carryover was assessed or how these design features were handled in an analysis.
The record lists assessments at multiple time points and additional outcomes, including brain metabolite measures and auditory evoked potentials. Repeated measurements and multiple outcomes raise questions about which comparisons were primary, how missing observations were handled, and whether any adjustment for multiple testing was planned. The statistical plan and those handling details are not reported in the registry record. The outcome listing itself includes a secondary measure whose description says no data were collected.
Safety entries list no serious adverse events and no deaths in either the glycine or placebo group. Other adverse events are listed for the glycine group and not for placebo, but these counts do not establish that glycine caused an event or that the groups differ in risk. In a crossover study, group labels represent treatment exposures, and the record does not provide event narratives, timing, or an analysis accounting for repeated exposure. Overall, the posted record supports describing the trial design, planned outcomes, and recorded safety counts, but not an estimate of efficacy or comparative safety.
9. Statistical Methods Explained
Statistical interpretation depends on the question being estimated, the data collected, and the analysis used. The registry describes the randomized and masked crossover structure and a schedule of repeated symptom assessments. It does not report an analysis method, a treatment-effect estimate, a measure of uncertainty, or a test result for the primary outcome. The general concepts below explain what such methods would address; they are not a description of an analysis confirmed in this trial.
What does a treatment-effect estimate represent?
In general, a treatment-effect estimate summarizes the contrast relevant to the research question. For a crossover study, an analysis might compare outcomes under glycine with outcomes under placebo while accounting for the fact that the same participant may contribute observations to both treatment periods. The exact contrast depends on the outcome definition and analysis plan. Here, the registry does not report a single reduced comparison or numerical estimate, so no direction or size of a primary treatment effect can be stated.
What does a confidence interval tell a reader?
In general, a confidence interval describes the statistical uncertainty around an estimated effect under the assumptions of the method used. It is not a range containing every possible value, and it does not resolve limitations in the study design or the applicability of the participants to other populations. No confidence interval for the primary outcome is reported in the registry record. Without an estimate and its uncertainty, the precision of a glycine-placebo comparison cannot be assessed from the posted results.
Why does repeated measurement matter?
The primary outcome schedule includes measurements at baseline and multiple times during the intervention periods. Repeated observations from the same participant are generally correlated rather than independent. General statistical methods account for that within-participant relationship when estimating changes or treatment contrasts. Treating every observation as if it came from a different participant can misrepresent uncertainty. The record does not state which method, if any, was used to account for repeated measurements.
What issues arise in a crossover design?
General crossover analyses may need to account for treatment, period, and sequence. A period effect is a change associated with the time at which an intervention is given, rather than the intervention itself. Carryover refers to an effect of an earlier treatment that persists into a later period. A washout interval may be used to reduce that concern, but its presence alone does not show that carryover is absent. The protocol describes a 2-week no-treatment period between double-blind arms; analysis choices and any assessment of carryover are not reported in the registry record.
Why can over-dispersion matter?
General explanation: over-dispersion occurs when observed variability is greater than a statistical model assumes. If a model underestimates variability, its uncertainty estimates may be too small. This can make intervals appear narrower or tests appear more conclusive than warranted. Whether over-dispersion is relevant depends on the outcome and model. The registry does not describe a model for the symptom scores, and no variance or model diagnostics are reported.
What do sample-size illustrations mean?
General explanation: planning calculations describe how many participants per arm might be needed under specified assumptions about an effect, significance level, allocation, and statistical model. They are planning illustrations, not evidence of the study's observed ability to detect an effect. The record's planning assumptions describe a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect expressed as a stated fraction of the observed effect. No numerical planning counts or observed primary effect are reported in the registry record. The trial's enrollment of 2 should not be confused with a planning estimate or with observed power.
What can a p-value establish?
General explanation: a p-value measures how compatible the data are with a specified null hypothesis under the assumptions of a statistical test. It does not measure the probability that the null hypothesis is true, the size of an effect, or its clinical importance. No primary-outcome p-value is reported in the registry record. The absence of a reported test result means statistical significance cannot be assessed from the registry entry.
These concepts clarify why a design description is not a substitute for analyzed outcome data. The registry identifies a planned comparison and measurement schedule, but without the analysis details and numerical results, effect size and precision remain unknown.
10. Multiplicity, Missing Data and Analysis Populations
The primary outcome is assessed at multiple scheduled times, across glycine and placebo periods and during open-label glycine. The registry also lists multiple secondary outcomes, including brain glycine, glutamate and GABA measures, auditory evoked potentials, and other measures. When many outcomes or time-point comparisons are examined, the chance of a false-positive finding can increase if each is tested separately without an appropriate plan. General methods for addressing multiplicity include defining a primary contrast in advance, controlling an overall error rate, or treating analyses as exploratory. The registry record does not report a multiplicity strategy or an analysis hierarchy.
The record does not describe missing-data handling, reasons for missing assessments, or whether all scheduled measurements were collected. One secondary-outcome description explicitly states that no data were collected for change in magnocellular pathway function. Missing-data methods can affect results when observations are incomplete; the appropriate approach depends on why data are missing and on the analysis being used. Those details are not reported in the registry record.
Analysis populations are also not described. The record does not state whether an intention-to-treat, per-protocol, or other population was used, nor does it report participant flow or treatment-period completion. Such information would help clarify which observations contributed to an analysis. Since no primary analysis is reported, it is not possible to determine how outcome availability or analysis-population definitions affected a treatment comparison.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Glycine | 0 | 2 | 0.0% |
| Placebo | 0 | 2 | 0.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Glycine | 0 of 2 |
| Placebo | 0 of 2 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Glycine | 2 of 2 |
| Placebo | 0 of 2 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Glycine | Placebo |
|---|---|---|---|
| nausea | Gastrointestinal disorders | 2 of 2 | 0 of 2 |
| vomiting | Gastrointestinal disorders | 2 of 2 | 0 of 2 |
| diarrhea | Gastrointestinal disorders | 2 of 2 | 0 of 2 |
The registry lists serious adverse events for the glycine and placebo treatment groups. It records 0 serious adverse events and 0 deaths in each group. The entries list other adverse events affecting 2 in the glycine group and 0 in the placebo group. These are registry counts, not a statistical comparison or an estimate of the likelihood of harm.
The record does not provide descriptions, timing, severity details, or an assessment of whether events were considered related to treatment. In a crossover trial, participants can receive more than one treatment, so group entries should not automatically be interpreted as separate sets of people. The record does not explain the event-counting approach or how exposure periods were handled. The at-risk entries are listed as 2 for each treatment group; they should be read in the context of the crossover design rather than added together.
No serious adverse-event terms are listed. That absence does not establish that no adverse experiences occurred: the registry separately records other adverse events in the glycine group. Conversely, the difference in the listed other-event counts does not show that treatment caused those events. The small enrollment and lack of event-level detail limit comparative safety interpretation.
12. What the Result Does, and Does Not, Mean
The record documents a randomized, quadruple-masked crossover pilot of oral glycine and placebo, followed by open-label glycine. It identifies the target population as psychotic patients with a GLDC triplication and lists positive and negative symptom scores as the primary outcome. The schedule and several planned assessments are described, and the record includes group-level safety entries.
What the record does not provide is a numerical primary-outcome result. No single treatment comparison, effect estimate, confidence interval, or p-value is reported. It is therefore not possible to say whether the symptom scores were higher or lower under one treatment, how large any difference may have been, or how precisely it was estimated. A completed status indicates the registry's status designation; it does not itself provide evidence of a treatment effect.
The entry also does not establish a result for the many listed secondary outcomes. One secondary measure states that no data were collected, and other outcomes do not have analysis results in the registry record. The recorded safety counts describe events by treatment group, but do not provide event narratives or a causal assessment. Neither efficacy nor comparative safety can be concluded from those counts alone.
More broadly, a pilot in this narrowly described population cannot, without further evidence, establish how results apply to other people with psychotic disorders or to people without the genetic finding. The registry record is useful for understanding the design and intended measurements, but the lack of reported statistical results leaves the central treatment comparison unanswered.
13. Why This Trial Matters Statistically
This study raises statistical issues that are especially visible in a small crossover pilot. The design asks participants to receive glycine and placebo in separate treatment periods, allowing within-participant comparison in principle. That structure can be useful when participant characteristics are highly specific, but it requires careful attention to timing, treatment order, period effects, and possible carryover. The registry describes a no-treatment interval but does not report the analysis approach used to address these issues.
The trial also combines a repeated symptom scale with multiple assessment times and a broad set of biological and electrophysiological measures. Such a design can generate informative exploratory observations, but it also creates many possible comparisons. Clear outcome prioritization and transparent multiplicity handling are important for distinguishing a planned primary question from exploratory findings. Those analysis details are not reported in the registry record.
Finally, the record illustrates the difference between a completed study and a reported estimate. The registry gives a primary outcome definition and design, but no reduced primary comparison or numerical uncertainty measure. Without those, readers cannot evaluate effect size or precision. For a small, specialized pilot, reporting participant-level flow, analysis methods, and estimates with uncertainty would be particularly important to interpret what the collected data can support.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The most direct limitation for statistical interpretation is the absence of a reported primary-outcome analysis. The registry lists a repeated symptom outcome but provides no numerical scores, treatment contrast, uncertainty interval, or test result. The outcomes listing indicates that the primary measure was not reduced to one comparison. The magnitude and precision of any difference therefore remain unknown.
Enrollment is recorded as 2, and the study concerns a highly specific population with a GLDC triplication and psychotic disorders. This narrow, small pilot is not a basis for broad population-level conclusions. The record does not report participant flow, individual treatment sequence, period completion, or analysis populations, limiting assessment of how the planned crossover comparison was implemented.
The crossover design raises questions about treatment period, sequence, and carryover. The protocol description includes a 2-week period without treatment, but does not report how the analysis addressed these design features. The statistical plan, handling of repeated measurements, missing-data methods, and multiplicity strategy are not reported in the registry record.
Outcome reporting is incomplete for interpretation: the primary outcome title includes positive and negative symptom scores, while the accompanying scale description explains the positive-symptom component. A separate description of negative-symptom scoring is not reported. The registry also notes that no data were collected for one secondary measure. Safety entries lack event descriptions and timing, and do not establish causation. These limitations are specific to the information available in the registry record and do not determine what may appear in other study documents.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders — NCT01720316.
- Registry record last updated 2017-09-19; status last verified 2017-09.
- Results first posted 2017-04-18.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
The registry describes a completed Phase 2 randomized, quadruple-masked crossover pilot sponsored by McLean Hospital. Enrollment is recorded as 2. The protocol includes double-blind glycine and placebo treatment periods, a 2-week period without treatment between them, and a later open-label glycine period.
The primary outcome concerns positive and negative symptom scores measured at baseline and at scheduled points during treatment. The record does not report a single reduced primary comparison or numerical analysis results. It lists 0 serious adverse events and 0 deaths for both treatment groups, and other adverse events affecting 2 in the glycine group and 0 in the placebo group. These entries do not establish causality or a comparative safety effect. Missing-data methods, analysis populations, the primary statistical model, and multiplicity handling are not reported in the registry record.