============================================================ TITLE: Why Do Mood Disorder Trials Enroll the Wrong Participants? TYPE: article VERSION: 1 VERSION_ID: 7e269c55-da06-4fdd-9082-be69d2929ad8 GENERATED_AT: 2026-06-19T15:04:43.816Z SUMMARY: Dropout rates of 15-30% in AOM trials threaten regulatory submissions. Evidence-based strategies to improve participant retention in anti-obesity trials. AUTHOR: Signant Health DATE PUBLISHED: June 19, 2026 DATE MODIFIED: June 19, 2026 READING TIME: 13 min WORD COUNT: 2480 KEYWORDS: Key Points SOURCE URL: https://signanthealth.com/resources/why-do-mood-disorder-trials-enroll-the-wrong-participants ============================================================ KEY TAKEAWAYS: * Key Points * AUTHOR BIO Back to Resource Hub Video Why Do Mood Disorder Trials Enroll the Wrong Participants? Signant Health Jun 19, 2026 Video Diagnostic reliability for major depressive episodes is poor, not modest, and the gap between who a protocol says should be enrolled and who gets randomized is one of the most consequential and least addressed sources of trial failure in mood disorder research.   In this conversation, Dr. Gary Sachs, Clinical Vice President and Therapeutic Area Leader for Bipolar Disease and Mood Disorders at Signant Health, presents validated, replicated data showing that improving diagnostic confidence at screening can double or triple drug-placebo effect sizes, and describes how sponsors are now operationalizing undisclosed eligibility criteria to prevent the bias that standard screening processes cannot control.  Key Points  DSM-5 field trial data show the diagnostic reliability of major depressive episode between two raters seeing the same patient on the same day is low, meaning studies routinely randomize participants who do not have the target condition, directly reducing the probability of a positive trial. Mapping MADRS scores to DSM-5 criteria allows diagnostic confidence to be quantified at the item level, enabling a reproducible, validated measure of how many criteria a participant meets with confidence rather than relying on binary eligibility determination alone. Across multiple replicated datasets, restricting enrolment to participants with high diagnostic confidence has produced drug-placebo effect sizes that are double to triple those observed in unrestricted samples, a finding that has now been replicated three times on unblinded data. Knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments. Undisclosed eligibility criteria, where neither the participant nor the site investigator knows the specific thresholds being applied, directly address this source of bias. Tandem readings combining two independent sources of eligibility information, and restricting randomization to participants where both sources confirm eligibility, produce better effect sizes and a higher probability of a positive trial outcome. The video contains Dr. Sachs's complete framework for diagnostic confidence measurement, the operational model for undisclosed eligibility criteria, including real-time API-based eligibility adjudication, and the evidence base across the datasets that have validated these approaches.   What the Video Covers: From Diagnostic Confidence to Undisclosed Criteria     For a participant entering a mood disorder trial who does not actually meet the diagnostic criteria for the condition being studied, their presence in the randomized population does not simply add noise. It actively compresses the drug-placebo gap. The more participants enrolled without a genuine major depressive episode, the lower the signal the study is powered to detect. When a trial fails under those conditions, the investigational product may have been effective in the population it was designed to treat. The study simply never enrolled enough of them. That failure has direct consequences beyond the trial itself. Development programs are halted. Treatments that may work for patients who need them do not reach approval. The time and contribution of participants who genuinely had the target condition produced no usable evidence. Placebo response rates in mood disorder trials have increased over decades, a trend documented extensively in psychiatric clinical research literature. The factors driving that increase include the awareness effect: when participants and investigators know what criteria must be met for enrolment, reporting adjusts toward those criteria. Controlling for that effect is now technically feasible in a way it has not been before. For sponsors designing mood disorder programs today, that capability is available and being adopted. The question is whether to build it into the protocol from the start.  What the Video Covers: From Instrument Selection to Submission-Ready Data   Sponsors designing mood disorder trials have historically accepted diagnostic variability as an inherent feature of psychiatric research, not a design variable that can be controlled. The replicated data Dr. Sachs presents challenges that assumption directly and provides a practical pathway from validation to implementation. Dr. Sachs describes how the MADRS, already the most widely used primary endpoint scale in major depressive disorder trials, can be used not just as an outcome measure but as a screening tool. Because every item is rated on a zero to six scale and eight of the nine DSM-5 criteria for depression map directly to MADRS items, a cut-off score for each item enables quantification of diagnostic confidence at screening.  That quantification, when used as an eligibility criterion rather than simply a severity threshold, produces improvements that have now been replicated across three independent datasets. The operationalization of undisclosed eligibility criteria is described in specific terms. Real-time eligibility adjudication through API-based data exchange means that a site can receive an eligibility determination in milliseconds without the investigator or participant knowing which criteria drove it. Several studies have adopted this approach. The resistance Dr. Sachs anticipated from sponsors and sites has not materialized at the scale predicted. For mood disorder program teams evaluating whether this approach is feasible for their next study, the video provides the clinical rationale, the evidence base, and the operational model.   "Clinical trials are a contest between the investigational product and the placebo. The way we communicate with subjects can increase the placebo response and lessen the signal. Giving people the idea of what the entry criteria are can influence their self-assessment and the rater's assessment of their scores."- Gary Sachs, MD, Clinical Vice President and Therapeutic Area Leader, Bipolar Disease and Mood Disorders, Signant Health  How does diagnostic confidence affect drug-placebo separation in depression trials? Restricting randomization to participants with high diagnostic confidence, quantified by mapping MADRS item scores to DSM-5 criteria, has produced drug-placebo effect sizes that are double to triple those observed in unrestricted samples. This finding has been replicated across three independent unblinded datasets, moving it from a theoretical quality metric to a validated, reproducible predictor of trial success.  What are undisclosed eligibility criteria in clinical trials, and how do they work? Undisclosed eligibility criteria are screening thresholds that are not communicated to either the participant or the site investigator. Because knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments, withholding that information prevents systematic bias toward meeting the criteria. Eligibility adjudication is conducted in real time through API-based data exchange, allowing a site to receive a randomization decision in milliseconds without knowing the specific criteria applied. How can the MADRS be used to improve participant selection in depression trials? The MADRS can be used as a diagnostic confidence tool at screening because eight of the nine DSM-5 criteria for major depressive episode map directly to MADRS items, each scored on a zero to six scale. Setting an item-level cut-off to determine whether each criterion is met with confidence enables quantification of how many DSM-5 criteria are clearly present, providing a reproducible eligibility measure that goes beyond binary diagnostic determination and has been validated across multiple datasets. AUTHOR BIO  Name: Gary Sachs,Title and Credentials: MD, Clinical Vice President at Signant HealthBio: Gary Sachs, MD, is Clinical Vice President at Signant Health, where he serves as Therapeutic Area Leader for Bipolar Disease and Mood Disorders. He brings extensive experience in rater training and methodologies of mood and anxiety disorder research to support clinical studies across these indications.   This conversation is hosted by Dawie Wessels, MD, Chief Medical Officer at Signant Health.   WATCH THE VIDEO Designing a participant selection strategy for an upcoming major depressive disorder or bipolar disorder trial? Speak to Gary Sachs, MD, about diagnostic confidence measurement, undisclosed eligibility criteria, and tandem rating implementation for mood disorder programs. # Why Do Mood Disorder Trials Enroll the Wrong Participants? Jun 19, 2026 Diagnostic reliability for major depressive episodes is poor, not modest, and the gap between who a protocol says should be enrolled and who gets randomized is one of the most consequential and least addressed sources of trial failure in mood disorder research.   In this conversation, Dr. Gary Sachs, Clinical Vice President and Therapeutic Area Leader for Bipolar Disease and Mood Disorders at Signant Health, presents validated, replicated data showing that improving diagnostic confidence at screening can double or triple drug-placebo effect sizes, and describes how sponsors are now operationalizing undisclosed eligibility criteria to prevent the bias that standard screening processes cannot control.  Key Points  DSM-5 field trial data show the diagnostic reliability of major depressive episode between two raters seeing the same patient on the same day is low, meaning studies routinely randomize participants who do not have the target condition, directly reducing the probability of a positive trial. Mapping MADRS scores to DSM-5 criteria allows diagnostic confidence to be quantified at the item level, enabling a reproducible, validated measure of how many criteria a participant meets with confidence rather than relying on binary eligibility determination alone. Across multiple replicated datasets, restricting enrolment to participants with high diagnostic confidence has produced drug-placebo effect sizes that are double to triple those observed in unrestricted samples, a finding that has now been replicated three times on unblinded data. Knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments. Undisclosed eligibility criteria, where neither the participant nor the site investigator knows the specific thresholds being applied, directly address this source of bias. Tandem readings combining two independent sources of eligibility information, and restricting randomization to participants where both sources confirm eligibility, produce better effect sizes and a higher probability of a positive trial outcome. The video contains Dr. Sachs's complete framework for diagnostic confidence measurement, the operational model for undisclosed eligibility criteria, including real-time API-based eligibility adjudication, and the evidence base across the datasets that have validated these approaches.   What the Video Covers: From Diagnostic Confidence to Undisclosed Criteria     For a participant entering a mood disorder trial who does not actually meet the diagnostic criteria for the condition being studied, their presence in the randomized population does not simply add noise. It actively compresses the drug-placebo gap. The more participants enrolled without a genuine major depressive episode, the lower the signal the study is powered to detect. When a trial fails under those conditions, the investigational product may have been effective in the population it was designed to treat. The study simply never enrolled enough of them. That failure has direct consequences beyond the trial itself. Development programs are halted. Treatments that may work for patients who need them do not reach approval. The time and contribution of participants who genuinely had the target condition produced no usable evidence. Placebo response rates in mood disorder trials have increased over decades, a trend documented extensively in psychiatric clinical research literature. The factors driving that increase include the awareness effect: when participants and investigators know what criteria must be met for enrolment, reporting adjusts toward those criteria. Controlling for that effect is now technically feasible in a way it has not been before. For sponsors designing mood disorder programs today, that capability is available and being adopted. The question is whether to build it into the protocol from the start.  What the Video Covers: From Instrument Selection to Submission-Ready Data   Sponsors designing mood disorder trials have historically accepted diagnostic variability as an inherent feature of psychiatric research, not a design variable that can be controlled. The replicated data Dr. Sachs presents challenges that assumption directly and provides a practical pathway from validation to implementation. Dr. Sachs describes how the MADRS, already the most widely used primary endpoint scale in major depressive disorder trials, can be used not just as an outcome measure but as a screening tool. Because every item is rated on a zero to six scale and eight of the nine DSM-5 criteria for depression map directly to MADRS items, a cut-off score for each item enables quantification of diagnostic confidence at screening.  That quantification, when used as an eligibility criterion rather than simply a severity threshold, produces improvements that have now been replicated across three independent datasets. The operationalization of undisclosed eligibility criteria is described in specific terms. Real-time eligibility adjudication through API-based data exchange means that a site can receive an eligibility determination in milliseconds without the investigator or participant knowing which criteria drove it. Several studies have adopted this approach. The resistance Dr. Sachs anticipated from sponsors and sites has not materialized at the scale predicted. For mood disorder program teams evaluating whether this approach is feasible for their next study, the video provides the clinical rationale, the evidence base, and the operational model.   "Clinical trials are a contest between the investigational product and the placebo. The way we communicate with subjects can increase the placebo response and lessen the signal. Giving people the idea of what the entry criteria are can influence their self-assessment and the rater's assessment of their scores."- Gary Sachs, MD, Clinical Vice President and Therapeutic Area Leader, Bipolar Disease and Mood Disorders, Signant Health  How does diagnostic confidence affect drug-placebo separation in depression trials? Restricting randomization to participants with high diagnostic confidence, quantified by mapping MADRS item scores to DSM-5 criteria, has produced drug-placebo effect sizes that are double to triple those observed in unrestricted samples. This finding has been replicated across three independent unblinded datasets, moving it from a theoretical quality metric to a validated, reproducible predictor of trial success.  What are undisclosed eligibility criteria in clinical trials, and how do they work? Undisclosed eligibility criteria are screening thresholds that are not communicated to either the participant or the site investigator. Because knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments, withholding that information prevents systematic bias toward meeting the criteria. Eligibility adjudication is conducted in real time through API-based data exchange, allowing a site to receive a randomization decision in milliseconds without knowing the specific criteria applied. How can the MADRS be used to improve participant selection in depression trials? The MADRS can be used as a diagnostic confidence tool at screening because eight of the nine DSM-5 criteria for major depressive episode map directly to MADRS items, each scored on a zero to six scale. Setting an item-level cut-off to determine whether each criterion is met with confidence enables quantification of how many DSM-5 criteria are clearly present, providing a reproducible eligibility measure that goes beyond binary diagnostic determination and has been validated across multiple datasets. AUTHOR BIO  Name: Gary Sachs,Title and Credentials: MD, Clinical Vice President at Signant HealthBio: Gary Sachs, MD, is Clinical Vice President at Signant Health, where he serves as Therapeutic Area Leader for Bipolar Disease and Mood Disorders. He brings extensive experience in rater training and methodologies of mood and anxiety disorder research to support clinical studies across these indications.   This conversation is hosted by Dawie Wessels, MD, Chief Medical Officer at Signant Health.   WATCH THE VIDEO Designing a participant selection strategy for an upcoming major depressive disorder or bipolar disorder trial? Speak to Gary Sachs, MD, about diagnostic confidence measurement, undisclosed eligibility criteria, and tandem rating implementation for mood disorder programs. In this conversation, Dr. Gary Sachs, Clinical Vice President and Therapeutic Area Leader for Bipolar Disease and Mood Disorders at Signant Health, presents validated, replicated data showing that improving diagnostic confidence at screening can double or triple drug-placebo effect sizes, and describes how sponsors are now operationalizing undisclosed eligibility criteria to prevent the bias that standard screening processes cannot control. ## Key Points * DSM-5 field trial data show the diagnostic reliability of major depressive episode between two raters seeing the same patient on the same day is low, meaning studies routinely randomize participants who do not have the target condition, directly reducing the probability of a positive trial. * Mapping MADRS scores to DSM-5 criteria allows diagnostic confidence to be quantified at the item level, enabling a reproducible, validated measure of how many criteria a participant meets with confidence rather than relying on binary eligibility determination alone. * Across multiple replicated datasets, restricting enrolment to participants with high diagnostic confidence has produced drug-placebo effect sizes that are double to triple those observed in unrestricted samples, a finding that has now been replicated three times on unblinded data. * Knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments. Undisclosed eligibility criteria, where neither the participant nor the site investigator knows the specific thresholds being applied, directly address this source of bias. * Tandem readings combining two independent sources of eligibility information, and restricting randomization to participants where both sources confirm eligibility, produce better effect sizes and a higher probability of a positive trial outcome. * The video contains Dr. Sachs's complete framework for diagnostic confidence measurement, the operational model for undisclosed eligibility criteria, including real-time API-based eligibility adjudication, and the evidence base across the datasets that have validated these approaches. What the Video Covers: From Diagnostic Confidence to Undisclosed Criteria For a participant entering a mood disorder trial who does not actually meet the diagnostic criteria for the condition being studied, their presence in the randomized population does not simply add noise. It actively compresses the drug-placebo gap. The more participants enrolled without a genuine major depressive episode, the lower the signal the study is powered to detect. When a trial fails under those conditions, the investigational product may have been effective in the population it was designed to treat. The study simply never enrolled enough of them. That failure has direct consequences beyond the trial itself. Development programs are halted. Treatments that may work for patients who need them do not reach approval. The time and contribution of participants who genuinely had the target condition produced no usable evidence. Placebo response rates in mood disorder trials have increased over decades, a trend documented extensively in psychiatric clinical research literature. The factors driving that increase include the awareness effect: when participants and investigators know what criteria must be met for enrolment, reporting adjusts toward those criteria. Controlling for that effect is now technically feasible in a way it has not been before. For sponsors designing mood disorder programs today, that capability is available and being adopted. The question is whether to build it into the protocol from the start. What the Video Covers: From Instrument Selection to Submission-Ready Data Sponsors designing mood disorder trials have historically accepted diagnostic variability as an inherent feature of psychiatric research, not a design variable that can be controlled. The replicated data Dr. Sachs presents challenges that assumption directly and provides a practical pathway from validation to implementation. Dr. Sachs describes how the MADRS, already the most widely used primary endpoint scale in major depressive disorder trials, can be used not just as an outcome measure but as a screening tool. Because every item is rated on a zero to six scale and eight of the nine DSM-5 criteria for depression map directly to MADRS items, a cut-off score for each item enables quantification of diagnostic confidence at screening.  That quantification, when used as an eligibility criterion rather than simply a severity threshold, produces improvements that have now been replicated across three independent datasets. The operationalization of undisclosed eligibility criteria is described in specific terms. Real-time eligibility adjudication through API-based data exchange means that a site can receive an eligibility determination in milliseconds without the investigator or participant knowing which criteria drove it. Several studies have adopted this approach. The resistance Dr. Sachs anticipated from sponsors and sites has not materialized at the scale predicted. For mood disorder program teams evaluating whether this approach is feasible for their next study, the video provides the clinical rationale, the evidence base, and the operational model. "Clinical trials are a contest between the investigational product and the placebo. The way we communicate with subjects can increase the placebo response and lessen the signal. Giving people the idea of what the entry criteria are can influence their self-assessment and the rater's assessment of their scores."- Gary Sachs, MD, Clinical Vice President and Therapeutic Area Leader, Bipolar Disease and Mood Disorders, Signant Health ### How does diagnostic confidence affect drug-placebo separation in depression trials? Restricting randomization to participants with high diagnostic confidence, quantified by mapping MADRS item scores to DSM-5 criteria, has produced drug-placebo effect sizes that are double to triple those observed in unrestricted samples. This finding has been replicated across three independent unblinded datasets, moving it from a theoretical quality metric to a validated, reproducible predictor of trial success. ### What are undisclosed eligibility criteria in clinical trials, and how do they work? Undisclosed eligibility criteria are screening thresholds that are not communicated to either the participant or the site investigator. Because knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments, withholding that information prevents systematic bias toward meeting the criteria. Eligibility adjudication is conducted in real time through API-based data exchange, allowing a site to receive a randomization decision in milliseconds without knowing the specific criteria applied. ### How can the MADRS be used to improve participant selection in depression trials? The MADRS can be used as a diagnostic confidence tool at screening because eight of the nine DSM-5 criteria for major depressive episode map directly to MADRS items, each scored on a zero to six scale. Setting an item-level cut-off to determine whether each criterion is met with confidence enables quantification of how many DSM-5 criteria are clearly present, providing a reproducible eligibility measure that goes beyond binary diagnostic determination and has been validated across multiple datasets. ## AUTHOR BIO Name: Gary Sachs,Title and Credentials: MD, Clinical Vice President at Signant HealthBio: Gary Sachs, MD, is Clinical Vice President at Signant Health, where he serves as Therapeutic Area Leader for Bipolar Disease and Mood Disorders. He brings extensive experience in rater training and methodologies of mood and anxiety disorder research to support clinical studies across these indications. This conversation is hosted by Dawie Wessels, MD, Chief Medical Officer at Signant Health. WATCH THE VIDEO Designing a participant selection strategy for an upcoming major depressive disorder or bipolar disorder trial? Speak to Gary Sachs, MD, about diagnostic confidence measurement, undisclosed eligibility criteria, and tandem rating implementation for mood disorder programs. ### Get notified on new marketing insights Here mention the benefits of subscribing ------------------------------------------------------------ FREQUENTLY ASKED QUESTIONS: Q: How does diagnostic confidence affect drug-placebo separation in depression trials? A: Restricting randomization to participants with high diagnostic confidence, quantified by mapping MADRS item scores to DSM-5 criteria, has produced drug-placebo effect sizes that are double to triple those observed in unrestricted samples. This finding has been replicated across three independent unblinded datasets, moving it from a theoretical quality metric to a validated, reproducible predictor of trial success. Restricting randomization to participants with high diagnostic confidence, quantified by mapping MADRS item scores to DSM-5 criteria, has produced drug-placebo effect sizes that are double to triple those observed in unrestricted samples. This finding has been replicated across three independent unblinded datasets, moving it from a theoretical quality metric to a validated, reproducible predictor of trial success. What are undisclosed eligibility criteria in clinical trials, and how do they work? Undisclosed eligibility criteria are screening thresholds that are not communicated to either the participant or the site investigator. Because knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments, withholding that information prevents systematic bias toward meeting the criteria. Eligibility adjudication is conducted in real time through API-based data exchange, allowing a site to receive a randomization decision in milliseconds without knowing the specific criteria applied. Q: What are undisclosed eligibility criteria in clinical trials, and how do they work? A: Undisclosed eligibility criteria are screening thresholds that are not communicated to either the participant or the site investigator. Because knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments, withholding that information prevents systematic bias toward meeting the criteria. Eligibility adjudication is conducted in real time through API-based data exchange, allowing a site to receive a randomization decision in milliseconds without knowing the specific criteria applied. Undisclosed eligibility criteria are screening thresholds that are not communicated to either the participant or the site investigator. Because knowledge of eligibility criteria influences how participants report symptoms and how raters score assessments, withholding that information prevents systematic bias toward meeting the criteria. Eligibility adjudication is conducted in real time through API-based data exchange, allowing a site to receive a randomization decision in milliseconds without knowing the specific criteria applied. How can the MADRS be used to improve participant selection in depression trials? The MADRS can be used as a diagnostic confidence tool at screening because eight of the nine DSM-5 criteria for major depressive episode map directly to MADRS items, each scored on a zero to six scale. Setting an item-level cut-off to determine whether each criterion is met with confidence enables quantification of how many DSM-5 criteria are clearly present, providing a reproducible eligibility measure that goes beyond binary diagnostic determination and has been validated across multiple datasets. Q: How can the MADRS be used to improve participant selection in depression trials? A: The MADRS can be used as a diagnostic confidence tool at screening because eight of the nine DSM-5 criteria for major depressive episode map directly to MADRS items, each scored on a zero to six scale. Setting an item-level cut-off to determine whether each criterion is met with confidence enables quantification of how many DSM-5 criteria are clearly present, providing a reproducible eligibility measure that goes beyond binary diagnostic determination and has been validated across multiple datasets. The MADRS can be used as a diagnostic confidence tool at screening because eight of the nine DSM-5 criteria for major depressive episode map directly to MADRS items, each scored on a zero to six scale. Setting an item-level cut-off to determine whether each criterion is met with confidence enables quantification of how many DSM-5 criteria are clearly present, providing a reproducible eligibility measure that goes beyond binary diagnostic determination and has been validated across multiple datasets. ------------------------------------------------------------ ABOUT THIS CONTENT ------------------------------------------------------------ Source: https://signanthealth.com/resources/why-do-mood-disorder-trials-enroll-the-wrong-participants Author: Signant Health Published: June 19, 2026 This content is provided for informational purposes. Please visit the original source for the most up-to-date information.