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 Iloperidone Augmentation of SSRIs for Patients With Major Depressive Disorder With Residual Anger and Irritability (NCT01464229), a randomized phase 4 study. The primary outcome is SQ Anger/Hostility Scale.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01464229 |
| Phase | Phase 4 |
| Condition | Major Depressive Disorder |
| Allocation | Randomized |
| Design model | Crossover |
| Masking | Triple |
| Enrollment | 20 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Maurizio Fava, MD |
| Results posted | Yes |
2. Clinical Question
Population
Adults with major depressive disorder in partial remission who continued to experience residual anger and irritability. The registry describes the intended participants as outpatients receiving SSRI treatment.
Intervention
Iloperidone added to an SSRI antidepressant. The registry identifies iloperidone as the study drug; it does not report additional details about dosing or treatment schedules.
Comparator
Placebo added to standard SSRI antidepressant treatment. The study is described as placebo-controlled, with iloperidone and placebo compared in a crossover design.
Primary question
Does the change from baseline to endpoint in the Symptom Questionnaire Anger/Hostility Scale differ between the iloperidone and placebo treatment conditions? The registry states this as a hypothesis, not as a reported finding.
The primary measure is the total score on the Anger/Hostility Scale, and the listed timeframe is 9 weeks. Higher scores represent greater anger and hostility. The study was randomized and triple masked. In a crossover design, participants receive more than one treatment condition, so the intended comparison concerns responses under both conditions rather than a comparison of separate groups alone. The registry does not report the treatment sequence, details of any transition between conditions, or the statistical method used to make that comparison.
Twenty patients were randomized, and the outcome description says data were analyzed for 13 completers. A numerical treatment contrast, uncertainty interval, and p-value are not reported in the registry record. As a result, the record documents the question and the intended measure but does not establish the size or precision of an observed difference.
3. Trial Design
This completed phase 4 trial is identified as NCT01464229. It used randomized allocation, triple masking, and a crossover model to compare iloperidone augmentation of SSRI treatment with placebo augmentation. The registry lists an enrollment of 20. The study start is listed as 2012-04, and primary completion is listed as 2014-12.
The planned population was adults with major depressive disorder in partial remission who had residual anger and irritability while receiving SSRI treatment. The intervention descriptions identify iloperidone added to an SSRI and placebo added to standard SSRI treatment. The registry does not give further detail about treatment dose, duration by condition, assignment sequence, washout, or the roles covered by triple masking. Those elements are not reported in the registry record.
The primary outcome is the Symptom Questionnaire Anger/Hostility Scale, with a listed timeframe of 9 weeks. The outcome description says that the scale is a 23-item subscale of the 92-item Symptom Questionnaire. Although 20 patients were randomized, the registry says outcome data were analyzed for 13 completers. It does not explain the reasons for noncompletion or describe how missing observations were handled.
The trial status is completed, but completion status alone does not convey the result. The registry lists one outcome measure and no analyses. No numerical comparison of treatment conditions or inferential result is reported. Further information about the protocol, allocation sequence, sample-size justification, interim monitoring, and prespecified statistical analysis 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.
Overall Study
| Stage | Iloperidone, Then Placebo | Placebo, Then Iloperidone |
|---|---|---|
| STARTED | 10 | 10 |
| COMPLETED | 5 | 8 |
| NOT COMPLETED | 5 | 2 |
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 | Iloperidone, Then Placebo | Placebo, Then Iloperidone | Total |
|---|---|---|---|---|
| Participants analysed | 10 | 10 | 20 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 10 | 10 | 20 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Sex/Gender, Customized: Females | Participants | 6 | 8 | 14 |
| Sex/Gender, Customized: Males | Participants | 4 | 2 | 6 |
6. Primary Endpoint
The registry lists the primary outcome as SQ Anger/Hostility Scale, measured over 9 weeks.
| Element | Registry entry |
|---|---|
| Result type | Mean |
| Measure of spread | Standard Deviation |
| Unit | Score on Anger/Hostility Scale |
| Endpoint classification | Continuous Endpoint |
The primary endpoint is the total score on the Symptom Questionnaire Anger/Hostility Scale. The registry describes it as a 23-item subscale within the 92-item Symptom Questionnaire. Its score ranges from 0 to 23, with higher values representing higher anger and hostility. The listed timeframe is 9 weeks, and the stated parameter is the mean, with standard deviation as the measure of dispersion.
This measure is relevant to the study question because the target symptoms were residual anger and irritability in people with major depressive disorder in partial remission. A scale score provides a structured way to quantify these symptoms rather than relying only on a general description. In principle, comparing change from baseline to endpoint can describe whether scores shifted during each treatment condition.
The registry's hypothesis concerns a greater reduction in the total score under iloperidone than under placebo. That wording describes the planned direction of the question; it does not report an observed result. The record does not provide group or condition means, standard deviations, a treatment contrast, or a confidence interval. It also does not provide a numerical endpoint result from which the magnitude or precision of any change could be assessed.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry identifies the primary question, scale, and analysis population description, but it does not report the numerical primary-outcome result. It states that data were analyzed for 13 completers among the 20 randomized patients. No mean scores, standard deviations, estimated treatment contrast, confidence interval, or p-value are reported in the registry record. The direction and size of the observed difference therefore cannot be evaluated from the registry information.
The stated hypothesis is that iloperidone augmentation would produce a greater reduction in Anger/Hostility Scale score than placebo augmentation. This is a hypothesis, not evidence that such a reduction occurred. Without the posted outcome values and a defined comparison estimate, it is not possible to assess whether the observed data favored either condition, how large any contrast was, or how uncertain it was. The hypothesis should not be read as a conclusion.
The crossover model is important to interpretation. In a crossover study, each participant can contribute observations under multiple treatment conditions. A suitable analysis generally needs to account for the relationship between observations from the same participant, as well as the order and timing of conditions. General statistical practice also considers whether a previous condition could influence measurements in a later condition. The registry does not report the sequence, transition procedures, or analysis details needed to determine how those considerations were addressed.
The completer count also limits what can be inferred. The outcome description says that 13 completers contributed analyzed data, while 20 patients were randomized. The record does not explain why some randomized patients did not complete the study, whether their available measurements were used, or whether missing data could have influenced the comparison. The completer result, even if numerical values were available, would need to be understood in light of those omissions.
The safety entries report serious adverse events affecting 2 participants in the iloperidone group and 0 in the placebo group, with 13 at risk in each group. Other adverse events are listed for 13 participants in the iloperidone group and 5 in the placebo group. These are descriptive counts in a small trial; they do not by themselves establish whether an event was caused by treatment or how the safety experience would generalize beyond the participants recorded.
Overall, the registry supports a description of the study question and its design, not a conclusion about comparative efficacy. No numerical primary-outcome result is available in the registry record, and no statistical precision measure is reported. Any claim about the magnitude, direction, or certainty of a treatment effect would go beyond the recorded results.
9. Statistical Methods Explained
The registry describes a randomized, triple-masked crossover trial and names a continuous primary outcome summarized by a mean and standard deviation. Those descriptors establish the broad design and measurement type, but they do not specify the statistical analysis actually used. The record lists no analyses and does not report a numerical comparison for the primary endpoint.
What does randomization contribute?
Randomization assigns treatment conditions using a chance process. In general, this is intended to reduce systematic differences related to treatment assignment. In a crossover study, randomization may determine the order in which participants receive conditions, but the registry does not report the sequence or allocation procedures. It is therefore not possible to describe the implementation beyond the registry's randomized designation.
How does a crossover comparison differ?
A crossover design observes participants under more than one condition. Because the same participant can contribute measurements in both conditions, the comparison can use within-participant information. This can help account for stable differences between participants, but it also creates correlated observations: measurements from the same person are generally not independent. A suitable analysis should reflect that structure rather than treating all observations as though they came from unrelated participants.
Order and timing can also matter. For example, a condition received earlier could affect a later measurement, or responses could differ by period. These are general design considerations, not reported findings about this trial. The registry does not describe the treatment sequence, period-specific data, transition or washout procedures, or whether the analysis assessed order or carryover effects. It is not possible to determine from the record how these design issues were handled.
What do the mean and standard deviation describe?
A mean describes the arithmetic average of observed scores in a group or condition. The standard deviation describes the spread of individual scores around that mean. They answer different questions: the mean characterizes the central level, while the standard deviation describes how variable participants' scores are. The registry identifies these as the outcome's summary parameter and dispersion measure, but it does not give their values for either treatment condition.
A treatment comparison would ordinarily need to make clear what quantity is being contrasted, such as a difference in change or another prespecified summary of the repeated observations. The registry's hypothesis refers to change from baseline to endpoint in the crossover design, but the record does not provide the exact estimator or model. No effect estimate is available to interpret.
How should uncertainty be described?
A confidence interval is a general statistical tool for expressing the precision of an estimated effect. It gives a range of values compatible with the observed data under the assumptions of the analysis. A narrow interval indicates greater precision than a wide interval, while an interval that includes no difference can indicate that the data do not distinguish the estimate from no difference at the chosen confidence level. This is a general explanation; no confidence interval is reported for this trial.
A p-value, in general, describes how unusual data at least as inconsistent with a specified null hypothesis would be if that hypothesis and the analysis assumptions were true. It does not measure the probability that a treatment works, nor does it describe the size or clinical importance of an effect. The registry does not report a p-value or identify a completed inferential analysis for the primary comparison.
Why do analysis details matter?
Repeated measurements, incomplete follow-up, and crossover order affect which observations are included and how their dependence is represented. Different reasonable methods can produce different estimates or uncertainty when data are incomplete or assumptions differ. General good practice is to define the analysis population, outcome contrast, model, missing-data approach, and treatment of period or sequence effects in advance. These details are not reported in the registry record, so the analysis cannot be independently reconstructed from its entries.
The registry describes 13 completers as the basis for analyzed data, but does not state whether the analysis included only completers or used any additional observations. It also does not report the reasons for noncompletion or the handling of missing endpoint measurements. No interim analysis or sample-size justification is reported in the registry record.
Sample-size planning illustrations, when used, are planning aids rather than results from participants. The stated assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of an observed effect. These assumptions do not establish that they were used to design this trial. The registry does not report the trial's own sample-size justification, and the illustration assumptions should not be mistaken for an observed-power analysis or a trial result.
10. Multiplicity, Missing Data and Analysis Populations
The record does not report a complete multiplicity strategy. Multiplicity arises when analyses cover more than one outcome, time point, subgroup, or comparison: examining more possibilities can increase the chance that at least one result appears notable by chance. General approaches can prespecify a primary comparison, adjust inferential thresholds, or treat additional analyses as exploratory. The registry does not state which approach, if any, was planned for this trial.
The record lists one primary outcome measure, but its skip note says the outcome has multiple categories or time points and was not reduced to a single comparison. The registry does not identify a single numerical contrast that resolves those categories or time points. It also does not report results for a particular time point or a procedure for controlling multiplicity.
For missing data, the outcome description states that 13 completers contributed analyzed data, out of 20 randomized patients. The registry does not report why the remaining patients did not complete, how much outcome information was missing, whether observations from noncompleters were retained, or what assumptions underpinned any missing-data method. A completer-only analysis can be affected if completion is related to symptoms, treatment experience, or other factors; this is a general concern, not a finding about this trial.
The analysis population and handling of incomplete crossover sequences are not reported in the registry record. Nor are sensitivity analyses, interim analyses, or a detailed statistical analysis plan. Without these details and the numerical outcome results, the robustness of a treatment comparison cannot be assessed.
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 |
|---|---|---|---|
| Iloperidone | 2 | 13 | 15.4% |
| Placebo | 0 | 13 | 0.0% |
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 |
|---|---|
| Iloperidone | 13 of 13 |
| Placebo | 5 of 13 |
Most frequent serious adverse event terms
| Event term | Organ system | Iloperidone | Placebo |
|---|---|---|---|
| Palpitations | Cardiac disorders | 1 of 13 | 0 of 13 |
| Increased Irritability | General disorders | 1 of 13 | 0 of 13 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Iloperidone | Placebo |
|---|---|---|---|
| Dry Mouth | Skin and subcutaneous tissue disorders | 6 of 13 | 1 of 13 |
| Somnolence | Nervous system disorders | 2 of 13 | 2 of 13 |
| Headaches | Nervous system disorders | 2 of 13 | 1 of 13 |
| Nausea | Gastrointestinal disorders | 2 of 13 | 1 of 13 |
| Cramping | Gastrointestinal disorders | 1 of 13 | 0 of 13 |
Serious events with the highest arm-level rate: palpitations (7.7%), increased irritability (7.7%).
The registry lists 13 participants at risk in each treatment group for serious adverse events. Serious adverse events affected 2 participants in the iloperidone group and 0 in the placebo group. For other adverse events, the listed counts are 13 in the iloperidone group and 5 in the placebo group. Death counts are not reported in the registry record.
The listed serious-event terms are Palpitations and Increased Irritability, each shown as 7.7%. The registry entry does not connect these term-specific percentages to a treatment group in the information available. They should be read as recorded terms, not as evidence that a particular treatment caused them.
These are counts from a small study, not a definitive comparison of safety. Counts do not describe event severity beyond the registry's serious-event classification, timing, duration, or whether participants experienced multiple events. They also do not establish causation. The registry record does not provide enough detail to determine how these events were assessed or to characterize risks beyond the participants and follow-up recorded.
12. What the Result Does, and Does Not, Mean
The registry establishes that the study asked whether iloperidone added to an SSRI was associated with a greater reduction in anger and hostility scores than placebo added to SSRI treatment. It identifies a randomized, triple-masked crossover design and a symptom scale aligned with the residual symptoms of interest. It also records that 20 patients were randomized and that the outcome description refers to data analyzed for 13 completers.
What the record does not establish is the answer to the comparative question. It reports no numerical score summaries, treatment contrast, confidence interval, or p-value. The stated hypothesis is not a finding. Without an estimated difference and its uncertainty, the direction, magnitude, and precision of any observed change cannot be assessed from the registry record.
The record also does not establish that any difference, if one was observed, would be clinically important. Statistical evidence and clinical importance are distinct: an estimate can be statistically distinguishable from no difference yet have limited practical importance, or be potentially meaningful but estimated imprecisely. Assessing that distinction would require the results and an interpretation grounded in an appropriate clinical threshold; neither is reported in the registry record.
The design and completer information further shape interpretation. Crossover data require methods that account for repeated observations within participants and consider condition order. The registry does not describe those methods or explain incomplete participation. Safety counts are descriptive and do not establish causation or predict outcomes outside the recorded participants.
Accordingly, the appropriate reading is limited: the registry describes the research question, design, endpoint, and some safety counts, but does not provide the primary efficacy result needed to judge the comparison. It supports neither a claim that iloperidone reduced these symptoms more than placebo nor a claim that the treatments were equivalent.
13. Why This Trial Matters Statistically
This trial is statistically notable for its crossover structure and its focus on a symptom scale tied to residual anger and irritability. In crossover studies, each participant may contribute information under multiple conditions. That structure can make within-participant comparisons informative, but the analysis must account for dependence between repeated observations and the order in which conditions are received. Those requirements make the design and analysis details important to interpretation.
The registry also makes the distinction between enrollment and analyzed completion visible: 20 patients were randomized, while the outcome description says data were analyzed for 13 completers. That difference raises questions about the analysis population and missing observations. Without information about why participants did not complete or how their data were handled, readers cannot judge how incomplete follow-up may have affected the estimated comparison.
A further statistical lesson is that a clearly stated hypothesis is not the same as a reported result. The registry gives the intended direction of the primary question and describes the scale, but it does not give the numerical outcome comparison or its uncertainty. Statistical interpretation depends on estimates and their precision, not solely on the study rationale or design labels.
The record therefore illustrates why registration details and results reporting serve different purposes. Design information explains what investigators set out to study. Outcome estimates and analysis details are needed to assess what the collected data show. In this case, the former is described more fully than the latter, limiting the conclusions that can be drawn from the registry record.
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 main limitation for interpreting the primary outcome is that the registry record does not report numerical results. Means, standard deviations, treatment contrasts, confidence intervals, and p-values are not given. The stated hypothesis therefore cannot be evaluated against a posted estimate.
The outcome description reports data analyzed for 13 completers among 20 randomized patients, but does not explain noncompletion or missing-data handling. The analysis population is not described in enough detail to determine which measurements contributed to the analysis. The registry also does not report whether incomplete crossover data were included.
Important crossover details are absent. Treatment order, period-specific information, transition or washout procedures, and analysis of sequence or carryover effects are not reported in the registry record. The statistical model and the exact treatment contrast are also not specified, so the handling of repeated measurements cannot be assessed.
The record does not report a sample-size justification, interim analyses, or a detailed statistical analysis plan. It notes multiple categories or time points for the primary outcome without reducing them to a single comparison. This leaves uncertainty about which comparison was intended to carry the main inference and how multiplicity was addressed.
Finally, the enrollment was 20, and the registry reports analyzed data for 13 completers. The available safety counts are descriptive, and the registry does not provide enough event-level detail to assess timing, recurrence, or causality. These limitations constrain both efficacy interpretation and broader generalization.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Iloperidone Augmentation of SSRIs for Patients With Major Depressive Disorder With Residual Anger and Irritability — NCT01464229.
- Registry record last updated 2017-04-11; status last verified 2017-02.
- Results first posted 2017-04-11.
- 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.
Continue through the Clinical Biostats statistical pathway
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18. Record Summary
NCT01464229 is a completed phase 4 randomized, triple-masked crossover study of iloperidone augmentation of SSRI treatment versus placebo augmentation for residual anger and irritability in major depressive disorder. The registry lists enrollment of 20 and a primary outcome timeframe of 9 weeks. The primary measure is the Symptom Questionnaire Anger/Hostility Scale, a 23-item subscale with scores ranging from 0 to 23; higher values represent higher anger and hostility.
The outcome description says data were analyzed for 13 completers. The registry does not report a numerical primary-outcome comparison, statistical uncertainty, or a detailed analysis plan. Serious adverse events affected 2 participants in the iloperidone group and 0 in the placebo group, with 13 at risk in each group. The record supports a description of the study design and recorded counts, but not a conclusion about the comparative primary outcome.