The Role of Digital Biomarkers in Clinical Trials 

Digital biomarkers provide several advantages over traditional clinical outcome assessments (COAs). They offer continuous monitoring, real-time data collection, and improved participant engagement. These features are particularly valuable in clinical trials, where accurate and timely data collection is crucial for assessing the efficacy and safety of investigational treatments. 

One of the primary benefits of digital biomarkers is their potential to offer more objective evidence and improve signal detection. Trials in many areas of neuroscience, including psychiatry often suffer from high placebo response rates and low drug-placebo separation due to factors such as misdiagnosis, enrollment pressures, and subjective assessments. Digital biomarkers may prove to be vital tools to addressing these longstanding issues. 

Types of Digital Biomarkers 

Several types of digital biomarkers have been identified as valuable in clinical trials. These include vocal biomarkers, facial expression analysis, movement biomarkers, and physiological measures. 

• Vocal Biomarkers: Vocal biomarkers analyze speech patterns, including speech latency, tone, and other vocal features. These biomarkers have shown promise in psychiatric and neurological clinical trials ¹. For example, speech latency variables have been used to enrich participant selection in depression studies, enhancing the primary outcome effect size². Vocal biomarkers can also identify data quality issues and duplicate subjects, improving the overall quality of the trial data. 
• Facial Expression Analysis: Facial expressions can reveal significant insights into psychiatric and neurological conditions. AI-powered facial expression analysis can extract, analyze, and interpret complex behavioral and physiological signals, providing a rich source of objective, quantifiable data ³. This technology is particularly useful in early detection and proactive intervention for conditions such as schizophrenia, dementia, and anxiety disorders. 
• Movement Biomarkers: Movement biomarkers assess motor function and human behavior through wearable devices. These biomarkers are valuable in trials for conditions such as Parkinson’s disease and other neurological disorders. They provide continuous monitoring and real-time data, allowing for a more comprehensive assessment of treatment efficacy. 
• Physiological Measures: Physiological biomarkers include heart rate, blood pressure, and other vital signs measured through wearable devices. These biomarkers offer continuous monitoring and can provide early indicators of treatment efficacy and safety. They are particularly useful in trials for cardiovascular and metabolic disorders. 

Case Examples 

• Depression and Schizophrenia Trials: In a recent depression study, the incorporation of speech latency variables enabled an enrichment strategy for participant selection. The results were startling, enhancing the primary outcome effect size by 52%². This indicates that speech latency is an objective marker of depression, schizophrenia, and other psychiatric conditions that can feasibly be used for enrichment. Additionally, a follow-up study demonstrated similar results using a modification of the same speech latency measure, showing dramatic improvements in signal detection for schizophrenia⁴. Taken together, these findings support our understanding of speech latency as an objective marker in psychiatric conditions. 
• Parkinson’s Disease Trials: Movement biomarkers have been extensively used in Parkinson’s disease trials. Wearable devices that monitor motor function provide continuous data on tremors, gait, and other motor symptoms. This real-time data collection allows for a more accurate assessment of treatment efficacy and can identify subtle changes in motor function that may not be captured through traditional assessments. 
• Cardiovascular Trials: Physiological biomarkers such as heart rate and blood pressure are critical in cardiovascular trials. Wearable devices that continuously monitor these vital signs provide early indicators of treatment efficacy and safety. This continuous monitoring can detect adverse events earlier, allowing for timely intervention and improving patient safety. 

Challenges and Considerations 

While digital biomarkers offer significant advantages, there are also challenges and considerations to address. One of the primary challenges is the validation and standardization of digital biomarkers. Ensuring that these biomarkers are reliable, reproducible, and clinically meaningful is crucial for their successful integration into clinical trials. 

Another consideration is the potential for data overload. Digital biomarkers generate vast amounts of data, which can be overwhelming to analyze and interpret. Advanced data analytics and machine learning algorithms are essential for extracting meaningful insights from this data. 

Additionally, there are ethical and privacy concerns related to the use of digital biomarkers. Ensuring that patient data is securely collected, stored, and used is paramount. Clear guidelines and regulations are needed to address these concerns and protect patient privacy. 

Future Directions 

The future of digital biomarkers in clinical trials looks promising. Advances in artificial intelligence and machine learning will continue to enhance the accuracy and reliability of digital biomarkers. New, low-burden approaches to the assessment of clinically relevant features of speech, motor function, and human behavior are expected to emerge. 

Moreover, the integration of digital biomarkers with other digital health technologies, such as telemedicine and remote monitoring, will further improve patient engagement and trial efficiency. The use of digital biomarkers in decentralized and hybrid clinical trials is also expected to increase, providing more flexibility and convenience for participants. 

Conclusion 

Digital biomarkers offer substantial value in clinical trials by providing objective, continuous, and real-time data. They enhance the accuracy and efficiency of trials, reduce placebo response, and improve patient engagement. Vocal biomarkers, facial expression analysis, movement biomarkers, and physiological measures are among the most promising digital biomarkers in clinical trials. While there are challenges to address, the future of digital biomarkers in clinical trials looks bright, with continued advancements in technology and data analytics paving the way for more effective and efficient clinical research. 

References 

1. Cohen, A., Rodriguez, Z., Opler, M., Kirkpatrick, B., Milanovic, S., Piacentino, D., Szabo, S. T., Tomioka, S., Ogirala, A., Koblan, K. S., Siegel, J. S., Hopkins, S. Evaluating speech latencies during structured psychiatric interviews as an automated objective measure of psychomotor slowing. Psychiatry Res. 2024 Oct; 340:116104.

2. Siegel, J., Cohen, A., Szabo, S., Tomioka, S., Opler. M., Kirkpatrick, B., Hopkins, S. (2024). Enrichment using speech latencies improves treatment effect size in a clinical trial of bipolar depression. Journal of Psychiatry Research, 340, 5. https://www.sciencedirect.com/science/article/abs/pii/S0165178124003901   

3. Cowan, T., Rodriguez, Z. B., Strauss, G. P., Raugh, I. M., Cohen, A.S. Eur Arch Psychiatry Clin Neurosci. 2024 Oct;274(7):1771-1775.

4. Cohen, A., Kirkpatrick, B., Opler, M., Sedway, J., Tatsumi, K., Bhat, S., Bhat, L. Enrichment based on speech latency enhances treatment effects in a phase III study of brilaroxazine. Poster., 2024 Nov. 

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The following Insight is a featured article from WCG’s 2025 Trends & Insights Report. If you would like to read more insights from this report, please click here.

In 2018, at a National Academy workshop, Stroud and colleagues presented a compelling case that digital biomarkers and the field of mobile assessment were at risk of “overpromising.”¹ They warned researchers and technology developers to avoid hype in favor of rigorous methods if they hoped to bring meaningful innovation to clinical research. In the six years that have followed, while some interesting and intriguing developments have surfaced in the use of AI-based methods and complex, multimodal measures of behavior, for the most part, these have been peripheral to drug development. It is fair to say that the fervor around digital approaches has not yet brought substantive change to measurement in neuroscience clinical trials, particularly in psychiatry.  

In 2024, however, several developments with the potential to alter the landscape have begun to surface, notably in mood disorders and psychosis. First, groundbreaking work published by Cohen et al. on the development and validation of vocal biomarkers as tools for enrichment in depression demonstrated a significant potential for the selection and characterization of patients.² The post-hoc analysis of a bipolar depression trial showed that speech latency, a simple, generalizable feature, can be reliably calculated across countries, languages, and cultures. Their measure of pauses in speech, specifically the delay in speech generation, was shown to improve signal detection by 50 to 100% when applied at screening.³ 

A follow-up study by Cohen, Kirkpatrick, and colleagues used data from Reviva Pharmaceuticals’ Phase III trial of brilaroxazine, a novel antipsychotic treatment.⁴ In that study, they demonstrated similar results using a modification of the same speech latency measure, showing dramatic results not only on total pathology, but also on negative symptoms and functioning as well.  

The story of the last six years in digital biomarkers has been one of machine learning models and “black box” proprietary technologies. We submit that this approach has not yielded significant solutions to the enduring problems of neuroscience drug development. Simplicity, transparency, a return to the fundamentals of psychometrics, and old-fashioned methodological rigor will do what complexity and AI have not yet been able to do. Look out for novel, but low-burden approaches to the assessment of clinically relevant features of speech, motor function, and human behavior.   

In 2025, we predict that the wearables will come off, the apps will be uninstalled, and the fanfare will fade. The next wave of innovation in this space might be focused on things as simple and understated as silence, but the impact will be deafening.  

References:

1. Stroud C, Onnela JP, Manji H. “Harnessing digital technology to predict, diagnose, monitor, and develop treatments for brain disorders.” NPJ Digit Med. https://pmc.ncbi.nlm.nih.gov/articles/PMC6550158/.  
2. Siegel, J., Cohen, A., Szabo, S., Tomioka, S., Opler, M., Kirkpatrick, B., Hopkins, S. “Enrichment using speech latencies improves treatment effect size in a clinical trial of bipolar depression.” Journal of Psychiatry Research, Volume 340, 116105, ISSN 0165-1781. https://doi.org/10.1016/j.psychres.2024.116105. 
3. Cohen, A., Rodriguez, Z., Opler, M., Kirkpatrick, B., Milanovic, S., Piacentino, D., Szabo, S., Tomioka, S., Ogirala, A., Koblan. K., Siegel, J., Hopkins, S. “Evaluating speech latencies during structured psychiatric interviews as an automated objective measure of psychomotor slowing.” Journal of Psychiatry Research, Volume 340, 116104, ISSN 0165-1781. https://doi.org/10.1016/j.psychres.2024.116104. 
4. Cohen, A., Kirkpatrick, B., Opler, M., Tatsumi, K., Bhat, S., Bhat, L. “Enrichment Based on Speech Latency Enhances Treatment Effects in a Phase III Study of Brilaroxazine.” Poster Presented at the 2024 CNS Summit.   

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Psychedelics, the most exciting new trend in neuroscience, are not exactly new – they have been used all over the world for thousands of years, predating the rise of modern industrial medicine. Legal and conceptual frameworks to allow their use in neuroscience research have only recently permitted widespread study, bringing them to the brink of potential approval by the FDA for therapeutic applications.  

In parallel with the rise of psychedelics and the continued advances in new treatments for schizophrenia, PTSD, and anxiety disorders, we have seen the evolution of a new area of technologies collectively referred to as digital biomarkers. The confluence of these two trends, coupled with recent research on novel mechanisms of action, will likely help foster large-scale changes in how neuroscience studies are conducted, particularly in the field of psychiatry.  

The central challenges of psychiatry clinical trials have been two-fold: first, the eternal limitations of finding appropriate research participants for disorders that are diagnosed based on subjective criteria and syndromic presentations; and second, the difficulty of determining efficacy with measurement tools which require significant training and resources to use correctly, and even in the hands of an expert are often inaccurate and prone to bias. Rapid-acting antidepressant research has catalyzed a re-examination of study endpoints² and hints at a new method for bridging the gap between objective evaluations, which will enable efficient, sensitive evaluations at scale and the existing validated methods of symptom assessment has emerged in the form of vocal analytics. This field has roots in the 1960s and 70s when researchers used pauses in speech as a measure for neuromotor function.³

Recent publications by Johns Hopkins University and others point to the use of simple, valid measures, such as speech latency, as being useful methods for automating objective markers of pathology in depression and bipolar disorder. Future work on this approach may lead to smaller, more accurate trials that have meaningfully better statistical power and can be conducted more efficiently and ethically.⁴ 

The next year will bring more reports of continued success with psychedelics and a further crystallization of their unique modality. They may increasingly come to be appreciated as “synaptogenics,” or compounds that promote the reorganization of the brain, while also demonstrating renewed attention to non-drug therapies as most psychedelics are being packaged with various structured psychotherapies and supportive therapies. An unintended benefit of the psychedelic revolution might well be the renewed interest in holistic approaches to treatment and a rediscovery of the psychiatric patient as a psychosocial entity, not simply a neurobiological test subject. 

Progress is not without its problems. While the past decades have been a time of incredible technological transformation of neuroscience research, the impact on investigative site staff has been challenging. A poster by Cohen et al.⁵ shows that the stress of managing technology burdens falls disproportionately on the shoulders of those clinicians assessing patient symptoms. The demand for high-throughput data collection at scale with strong reliability and accuracy, on top of all the other tasks required by investigators, may finally force the field to consider the limits of this approach. 

In conclusion, 2024 may be the year that neuroscience clinical research rediscovers its future in the promises of the past. From the approval of psychedelics known to humanity for thousands of years for their potent neuroactive properties to the renewal of speech analysis as a method of evaluating patient status and the promise of smaller, more humane studies that allow patients and investigators to fully participate in the benefits of our work. With hope and optimism that is hopelessly old-fashioned, we look forward to the coming year. 

References: 

1. Goodwin et al, “Single Dose Psylocibin for a Treatment-Resistant Episode of Major Depression” New England Journal of Medicine, November 3, 2022.
2. Yavorsky et al, “Recommendations for Selection and Adaptation of Rating Scales for Clinical Studies of Rapid-Acting Anti-Depressants,” Front Psychiatry, June 2023.
3. E. Szabadi et al, “Elongation of Pause Time in Speech: A Simple, Objective Measure of Motor Retardation in Depression,” Cambridge University Press, January 2018.
4. Cohen et al, “Measuring Depression Using an Automated Natural Speech Analysis Pipeline: A Potential Clinical Trial Enrichment Tool,” Poster Presented at the 2022 ISCTM Meeting
5. Cohen, E. A., Montero, J., Grindell, V. M., Wyka, K., Hassman, H. H., Walling, D.P., Blanchard, C. L., Opler, M. G., Michoulon, D., and Ereshefsky, L. (November, 2023). Global raters’ work stress and task burnout: An empirical exploration of our primary endpoint evaluators. Poster presented at the Annual CNS Summit Scientific Meeting, Boston, MA.

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In 2019 the U.S. Federal Drug Administration (FDA) approved esketamine for treatment-resistant depression and brexanolone for postpartum depression. By targeting new synaptic sites, these rapid-acting antidepressants (RAADs) challenge our previous understandings of how antidepressants work. Yet, for the most part, depression rating scales haven’t kept pace. Clinicians and researchers continue to use instruments designed for a different era; these include the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS).

The Assessment Methods and Endpoints for Rapid-Acting Antidepressants-RAADs Working Group of the International Society for CNS Clinical Trials and Methodology addressed this issue, documented their findings in a review recently published in Frontiers in Psychiatry.[1] This paper focuses on the emerging field of RAADs and the challenges in effectively evaluating their effects due to the use of older rating instruments designed for traditional antidepressants.

RAAD: Defying Measurement, Defying Definition

Recent developments in antidepressant treatments include drugs that act on new molecular targets, resulting in faster responses (hours or days compared to weeks or months). These targets include the N-methyl-D-glutamate receptor antagonist ketamine (and its enantiomers and derivatives) and allosteric modulators of GABA receptors. The authors also note the renewed interest in psychedelic compounds that affect various receptor sites, including D1, 5-HT7, KOR, 5-HT5A, Sigma-1, NMDA, and BDNF.

These treatments have faster onset of action compared to conventional antidepressants, and they also have the potential to resolve symptoms more quickly. They also have different symptom response patterns, potentially including effects on language use and feelings of “calm alertness.” Conventional scales may not adequately capture the experience of patients using these treatments. Scales measuring subjective experience may offer additional insight into the treatment effect, although they are typically secondary outcomes in clinical trials.

The working group recognized the need for shorter measurement intervals and real-time evaluations, as well as the need to address unresolved questions regarding what constitutes a clinically meaningful response. Discussions within the working group highlighted the need for precision in defining the concept of response as it applies to RAADs, taking into consideration factors such as the duration of symptom resolution, the number of symptoms that need to resolve, and the heterogeneity of symptom resolution.

They explored the adaptation of existing scales, the development of new ones, and the use of digital measurements to supplement existing scales.

Modification of Existing Scales

As noted, current rating scales, including HDRS and MADRS, were developed for older generations of antidepressants and typically evaluate symptoms over a 7-day period. With certain adaptations, some of them can capture certain symptomatic changes in the RAAD timeframe. Overall, however, “they remain inherently limited by their structure (items such as sleep and appetite), timeframe of retrospective review of symptoms (usually 7 days) and conceptual biases.” Thus, the working group concluded, “it is likely that these measures fail to capture some aspects of the patient experience following treatment with RAADs.”

Development of New Scales

Novel scales, such as the Symptoms of Major Depressive Disorder Scale (SMDDS) and the McIntyre And Rosenblat Rapid Response Scale (MARRRS), have been developed specifically to measure the effects of RAADs. In particular, MARRRS — a 14-item self-report scale designed to measure rapid treatment response — has shown promising psychometric characteristics, including high internal consistency and significant convergent validity. It will be used in an upcoming Phase II clinical trial.

The authors also discussed the potential of digital measurements, such as ecological momentary assessments (EMA), sleep and activity trackers, and applications using facial and vocal metrics. While these methods are not ready to replace traditional scales, they can provide valuable supplementary data and real-time assessments.

Moving Forward: Radical Change Required

Although existing rating instruments can be adapted to measure RAADs, their usefulness is limited. Newly developed scales — SMDDS and MARRRS in particular– have significant potential to address these limitations. Digital technologies could initially supplement and cross-validate items in existing or new scales.

Much more work is needed, the authors concluded.

“Further development of new measures that meaningfully evaluate the novel effects of RAADs will require new approaches, as radical as the departure was from the older generations of drugs to the newer ones, they write. “To ensure we are fully and objectively measuring what matters most to patients, clinicians and other stakeholders, our rating instruments and perhaps even our most basic assumptions about what they are and how they work may also have to adapt to keep up with the remarkable pace of change in the field of RAADs.”

The full article can be accessed here.

[1] Yavorsky C, Ballard E, Opler M, et al. Recommendations for selection and adaptation of rating scales for clinical studies of rapid-acting antidepressants. Frontiers in Psychiatry. 2023;14:1135828. doi:https://doi.org/10.3389/fpsyt.2023.1135828

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About this episode:

In major depressive disorder, researchers have used remote assessments for decades. As a result, many of these studies have had an easier time adapting to the new clinical trial landscape. But that doesn’t mean they are pandemic-proof. 

So what are the critical success factors for clinical depression programs—especially now? 

In his conversation with WCG President of Patient Advocacy Steve Smith, Mark Opler, PhD, MPH, Chief Research Officer at WCG MedAvante-ProPhase offers his insights on the future of clinical depression trials. This is the third episode in our podcast series, “Transforming CNS Trials During COVID-19—and Beyond.”

We’re headed in the right direction by enabling more patient-friendly evaluation, and — especially in light of the pandemic — we must continue to refine these systems with the input of patients, caregivers, and of course, the investigators who ultimately use these evaluations.

Among his recommendations: Ensure clinicians have the right assessment tools and that they are using them correctly so that the subjective evaluation of depression is being done in a reliable and compliant way. In other words, sponsors should not only leverage secure, remote assessments and electronic diaries, but they should also take care to monitor the health of the data captured throughout the course of the study. WCG’s Study Insight Analytics Platform provides such recourse by allowing sponsors to identify and mitigate data-quality risks before the results of the trial are threatened. In this way, clinicians and patients can keep research going—without compromising data validity and integrity.

Mark Opler, PhD, MPH, is Chief Research Officer at WCG MedAvante-ProPhase. Dr. Opler was the founder of ProPhase and served as its CEO and Chief Scientific Officer, among other roles. He serves as adjunct assistant professor of psychiatry at New York University and assistant professor of clinical neuroscience at Columbia University’s College of Physicians and Surgeons. He is also leading the development of the forthcoming edition of the PANSS Manual.

The post On the Future of Depression Trials: Part 3 of WCG’s Transforming CNS Trials Series appeared first on WCG.

About this episode:

Remote assessments have become a necessity across CNS trials, but some areas are more complicated than others. Schizophrenia provides one such example; the risk of variability is high, and sponsors are concerned. In this podcast, Mark Opler, PhD, MPH, Chief Research Officer at WCG MedAvante-ProPhase, sits down with WCG President of Patient Advocacy Steve Smith to discuss the topic. This is the second episode in our podcast series, “Transforming CNS Trials During COVID-19—and Beyond.”

PANSS—the gold standard rating scale for schizophrenia primary outcomes—is based largely on face-to-face interviews; it wasn’t developed for remote assessments. Is it still usable? Yes, says Dr. Opler. “I’m pleased to report that the anecdotal experience, as well as available data, suggests assessments conducted with patients with schizophrenia via video can be done reliably and can be done in a way that produces valid data.”

It can be done—the tools exist. But it’s the way sponsors and CROs approach remote assessments that can make or break data integrity—and he delves into that topic in this podcast. In particular, he shares how sponsors and CROs can leverage remote assessments in their next clinical trial.

Mark Opler, PhD, MPH, is Chief Research Officer at WCG MedAvante-ProPhase. Dr. Opler was the founder of ProPhase and served as its CEO and Chief Scientific Officer, among other roles. He serves as adjunct assistant professor of psychiatry at New York University and assistant professor of clinical neuroscience at Columbia University’s College of Physicians and Surgeons. He is also leading the development of the forthcoming edition of the PANSS Manual.

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About this episode:

The switch to remote methodologies as a response to COVID-19 has had a profound effect on the conduct of psychiatric disorder trials. Supporting these remote trials requires new tools, sophisticated technology and, most important, deep scientific and clinical expertise.

In this podcast, Mark Opler, PhD, MPH, Chief Research Officer at WCG MedAvante-ProPhase, sits down with WCG President of Patient Advocacy Steve Smith to explore how COVID-19 has forced everyone involved in psychiatric trials to reconsider not only the tools and technology they use, but the entire patient encounter.

That places a tremendous responsibility on sponsors, he says. “I think in this new environment … sponsors have the responsibility to ensure that the right technologies are in place to facilitate remote assessment. They need to be thoughtful and careful about which technologies they use and [ensure] all stakeholders, especially patients, are served and supported in that choice.”

Mark Opler, PhD, MPH, is Chief Research Officer at WCG MedAvante-ProPhase. Dr. Opler was the founder of ProPhase and served as its CEO and Chief Scientific Officer, among other roles. He serves as adjunct assistant professor of psychiatry at New York University and assistant professor of clinical neuroscience at Columbia University’s College of Physicians and Surgeons. He is also leading the development of the forthcoming edition of the PANSS Manual.

The post On the Future of Psychiatric Disorders: Part 1 of WCG’s Transforming CNS Trials Series appeared first on WCG.

In 2019, the treatment of depression changed forever, the result of decades of research by academia, industry and government agencies.

What happened? The US FDAapproved esketamine. It was a landmark moment: Approval of this new rapid-acting antidepressant formulated for intranasal use marked the beginning of a new era.

At present, depression—and major depressive disorder in particular—affects a startlingly high percentage of the population. In the United States, the estimated lifetime risk of a major depressive episode is almost 30%.¹ Roughly 30% of U.S. adults with depression reported moderate or extreme difficulty with work, home and social activities due to depression.² Major depressive disorder (MDD) is the third-leading cause of disability worldwide.³

Compounding these public health challenges is the fact that available treatments have thus far been inadequate; about a third of Americans with MDD aren’t receiving any treatment, while only a little more than half reported using medication.^4,5

To fully understand the reason this class of medications holds such promise for the future, it helps to understand the history of depression pharmacotherapy.

Millenia of Melancholia

Depression (or melancholia) has been recognized as a clinical disorder for more than 2,000 years. Hippocrates attributed it to the excess of black bile, one of the four basic humors – the others were blood, yellow bile and phlegm. In the centuries that followed, physicians, scholars, philosophers, among many others, referenced the condition in their works.⁶

As the 20^th century progressed, the advent of modern psychopharmacology brought together rigorous methods and serendipitous discoveries. In the 1950s and 1960s, clinical and pharmaceutical research into depression treatments boomed. Antidepressant drug development began with the discovery of monoamine oxidase inhibitors and tricyclic antidepressants and moved into selective serotonin reuptake inhibitors (SSRIs).⁷

Researchers stumbled on the first pharmacological antidepressant: In the 1950s, the FDA approved Iproniazid, a monoamine-oxidase inhibitor, as a tuberculosis therapy. However, physicians began using it off-label to treat patients with depression. The FDA approved imipramine for the treatment of depression in 1959, making it the first tricyclic antidepressant.⁸

It wasn’t until 1965 that depression therapy underwent the gold-standard of research: a double-blind, randomized, placebo-controlled trial. That study compared imipramine, phenelzine, electroconvulsive therapy and placebo.^9,10

In the late 1960s, researchers found evidence suggesting a significant role of serotonin in MDD. In 1987, fluoxetine became the first FDA-approved selective serotonin reuptake inhibitor.¹¹ Until the recent breakthrough with esketamine, SSRIs represented one of the most significant medical discoveries of the last half century.

SSRIs have been successful for many people with depression, but they can take four to six weeks to have any effect. More concerning, they have a high non-response rate. It became clear that serotonin didn’t fully explain depression, and the drugs targeting serotonin couldn’t help everyone suffering with the disease.

Something had to change. Researchers turned their attention to other neurotransmitters such as GABA and glutamate–already known to play a role in seizure disorders and schizophrenia.¹²

Enter ketamine.

Above and Beyond Serotonin

Scientists and clinicians have known about ketamine’s antidepressant properties for some time, beginning with studies at Yale University and the National Institute of Mental Health.  It’s been used in clinical practice as an anesthetic since the 1960s,¹³ and many doctors have used it off-label to treat depression.¹⁴

But, until very recently, no one sought regulatory approval for it as an antidepressant.  That approval changed everything.

As we suggested earlier, there are now two eras in the psychopharmacology of depression. There is the pre-esketamine era—everything that came before FDA’s approval—and everything that comes after.

Until 2019, every antidepressant approved by the FDA targeted the biogenic amines, including dopamine, norepinephrine and serotonin. Ketamine—and now, esketamine—work on an entirely different mechanism of action. It’s an antagonist for the N-methyl-D-aspartate receptor. It triggers a surge in glutamate production, which makes the brain more adaptable and able to create new pathways.¹⁵

This novel mechanism of action likely underlies the ultra-rapid relief it provides. Traditional-acting antidepressants can take weeks to months to see full therapeutic effects of treatment – an especially salient consideration considering the rising suicide rate in the United States. Esketamine, in contrast, often acts within hours, and it’s effective in many patients for whom nothing else has worked.

The difficulty of adequately treating treatment-resistant depression coupled with its crippling effects make the success in esketamine clinical trials all the more groundbreaking, potentially transforming the treatment and remission for patients diagnosed with depression.

But this is just the beginning.

Unexplored Territory: New Domains, New Tools

We’re on the cusp of a new era in psychopathology and psychiatry. As more ketamine-like, rapid-acting antidepressants progress through different stages of research, we’ll gain a better understanding of the neurobiology of depression. However, we’ll need to develop better tools to capture outcomes and patient experience.

A new era in research and treatment requires new tools. Each treatment breakthrough in psychiatry typically brings new insights into measurement and assessment. That will be essential for rapid-acting antidepressants.

At present, we have a limited choice of outcome measures. The MADRS, the HDRS, BDI and the other tools we’ve long used were not built to capture treatment at the speed with which these new treatments work.

We need new tools that capture not only clinical outcomes, but also the patient experience. We cannot talk about antidepressant efficacy without talking about what matters to patients.

Addressing core symptoms that have been the focus of clinical attention in past decades is no longer adequate. Entire domains of psychopathology remain to be more fully explored, including anhedonia, cognition and functional recovery.

While the new frontiers of neurobiology that ketamine and esketamine have opened up are promising, perhaps the area crying out for the most innovation lies elsewhere: the patient experience and the patient voice. How do we better include patients, patient advocates, families and other stakeholders in development of new treatments? How do we create a true dialogue rather than the monologue that has characterized the history of drug development so far? How can we make sure everyone benefits?

We all must rise to that challenge on the cusp of this new era.

References

^1. Park LT, Zarate CA Jr. “Depression in the Primary Care Setting.” N Engl J Med. 2019 Feb 7;380(6):559-568. doi: 10.1056/NEJMcp1712493. Updated Feb. 2019

^2. National Center for Health Statistics Data Brief No. 303, February 2018

^3. Institute for Health Metrics and Evaluation (IHME). Findings from the Global Burden of Disease Study 2017. Seattle, WA: IHME, 2018.

^4. Hasin, DS, et al. “Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States.” JAMA Psychiatry, 75(4), 336. (2018)

^5. National Institute of Mental Health: Major Depression. Updated Feb. 2019

^6. Telles-Correia D, Marques JG. “Melancholia before the twentieth century: fear and sorrow or partial insanity?” Front Psychol. 2015 Feb 3;6:81. doi: 10.3389/fpsyg.2015.00081.

^7. Hanrahan, C. New, J. “Antidepressant medications: The FDA-approval process and the need for updates.” Mental Health Clinician 2014

^8. Hillhouse TM, Porter JH. “A brief history of the development of antidepressant drugs: from monoamines to glutamate.” Exp Clin Psychopharmacol. 2015;23(1):1–21.

^9. Khan, A. et al. “The conundrum of depression clinical trials: one size does not fit all.” International Clinical Psychopharmacology, 33(5), 239 (2018)

^10. Khan A, Detke M, Khan S et al. “Placebo response and antidepressant clinical trial outcome.” J Nerv Ment Dis 2003;191:211‐8

^11. Hillhouse TM, Porter JH. “A brief history of the development of antidepressant drugs: from monoamines to glutamate.” Exp Clin Psychopharmacol. 2015;23(1):1–21. d

^12. Chen, J. “How New Ketamine Drug Helps with Depression,” Yale Medicine, March 21, 2019

^13. Li, L & Vlisides, P. E. (2016). “Ketamine: 50 Years of Modulating the Mind.” Front. Hum. Neurosci., 10. doi: 10.3389/fnhum.2016.00612

^14. Wilkinson ST, Sanacora G. Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders. JAMA. 2017 Sep 5;318(9):793-794. doi: 10.1001/jama.2017.10697.

^15. Abdallah CG, et al. “Ketamine’s Mechanism of Action: A Path to Rapid-Acting Antidepressants.” Depress Anxiety. 2016;33(8):689–697

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About this Podcast

What’s the state of clinical trials in autism and neurodevelopmental disorders? What’s on the horizon?

Scott J. Hunter, PhD, Senior Scientific Expert in Neurodevelopmental Disorders and Rare Pediatric Diseases for WCG Clinical Endpoint Solutions, shared his insights during a recent conversation with Mark Opler, MD, PhD, Chief Research Officer at WCG-MedAvante-ProPhase. Dr. Hunter previously, for 22 years, was on the faculty at The University of Chicago, where he was Professor of Psychiatry, Behavioral Neuroscience, and Pediatrics and Director of Neuropsychology for UChicago Medicine.

The interview has been edited for clarity and length.

Podcast Transcript:

Dr. Opler: Can you give us an update on the overall state of the field in clinical trials in autism and neurodevelopmental disorders. What’s new and exciting?

Dr. Hunter: One of the most exciting things that I’ve been involved with is the identification of the risk and the range of severity of autism spectrum disorders and other neurodevelopmental challenges in children who have been born prematurely and at very low birth weight.

As a result of this ongoing research, we have a better understanding of the risk that exists for these individuals. In the past, they were very difficult to manage; now, with many changes in neonatal care, they are showing much greater advancements in their development.

In this population, it’s important to understand the risk for a range of challenges that are consistent with the identification of autism spectrum disorders and how to best look at ways of treating them, given that in many cases, autism spectrum disorder is actually more tied to a higher functional profile, one where there is greater prevalence of co-occurring ADHD. We’re seeing more work and greater understanding in this area.

What I’ve been most intrigued by is that we are beginning to better understand the broad range of phenotypic differences that contribute to making sense of what we classify as the autism spectrum disorders. We’re developing a better understanding of the different variables at play that predict risk, which then allows us to begin to better identify groups where different treatment approaches and different compounds may be the most useful.

Dr. Opler: There’s renewed interest in the gut and the GI microbiome as a potential target. Can you give us any insights?

Dr.  Hunter: I think one of the things that’s been very intriguing to me has been the growing investigation with individuals who are vulnerable to developing symptoms consistent with autism spectrum disorder and the relationship with the environmental factors; looking at the microbiome is giving us a new window into this.

Looking at the relationship between the environmental factors that may be at play prenatally and postnatally may give us a greater understanding of segregating different phenotypic expressions. I think we’re already beginning to see some of that play out.

Dr. Opler: Let’s move from the gut into symptomatology. There’s been a lot of focus on agitation and aggression and a certain amount of focus on attention. Are we finally moving beyond those domains? Are we getting to what some of us think are more core, such as the social impairments and impairments in social cognition and performance? Are there any signs of progress that merit discussion?

Dr. Hunter: Without a doubt, there are some indications coming from a series of different drug trials. We can begin now to focus much more directly on the social and the reciprocal communication considerations that are at play. We have a better understanding that one of the key features across autism spectrum disorders is this barrier to effectively make sense of information typically transmitted socially and through the face. There’s now a much greater emphasis on efforts to try to guide more effective interactions, and to do that from an earlier stage of development.

This means identifying individuals at later infancy and very early toddlerhood to begin intensive work on the behavioral side. But we’re also beginning to look at whether the compounds that address the anxiety and inattention features could support and better guide our ability to then address those social concerns.

I also am aware of the goal to better understand some of the neurochemical considerations that underlie social processing, looking at particular hormonal- and neurotransmitter-based for compound research.

Dr. Opler: Obviously Balovaptan has received considerable attention. This is a small molecule acting as a vasopressin receptor. It received breakthrough designation by the FDA early last year and has moved into phase three trials. Do you have any thoughts about Balovaptan to share?

Dr.  Hunter: I find this very exciting research. To be upfront, I’m involved with colleagues who are co-PIs on the Balovaptan studies. We’re now looking at late adolescence to young adulthood, focusing on individuals whose social challenges are of most concern. Given the research that’s been done already with this compound, this is a really promising area, and it’s an exciting one. I’m involved in helping do assessments for subjects in these studies, so it’s giving me a chance to get in on the ground floor and see what exactly is being focused on. And the key with this is really looking at adaptive social functioning, and research to date has been very promising.

We’re at a stage now where we are able address multiple challenges that are at play for individuals with autism spectrum disorder; that puts us in a very different place than we were even just 10 years ago.

Dr. Opler:  Do you have any news about the assessment of autism? For many years we’ve had the same measures, the same batteries.

Dr. Hunter: That’s a tougher one because right now I would say, specifically from the psychology realm, the emphasis continues to be on utilization of the Autism Diagnostic Observation Schedule. The decision to utilize the M-CHAT and other measures developed with pediatricians and with developmental clinicians, very early on, is important.

Several studies are now looking at both refining measures like the M-CHAT as well as measures that allow us to more effectively address certain behaviors and concerns like the autism diagnostic schedule and a number of other tools that have been traditionally less commonly used. One of the challenges has been having measures available that can be used in clinical trials and to gain the information in an effective way. And I think that’s an area that’s beginning to be refined.

Many of these measures are now being translated in other languages. I’m particularly interested in the movement to use the ADOS, the M-CHAT, the social responsiveness scale and SEQ in China.

Dr. Opler: I think one of the things that intrigues a lot of people in the area is the potential for moving beyond traditional scales and into technology. Is there a role, for example, for wearables? Is there a role for more automated methods of analysis that will help us transcend some of the challenges we’ve historically faced? Is there a role for technology as an outcome measure in treatment studies and intervention studies?

Dr. Hunter: Without a doubt. I think the research, looking at eye tracking, and that we now have methods for using eye tracking technologies in diagnostic settings, is something that is under investigation and is moving forward. The other interesting thing is the use of virtual reality as a component of assessment. Putting individuals into situations where they actually have to demonstrate live how they’re able to engage is proving to be very useful.

One of the things we have found about individuals with autism spectrum disorders is that they often are more comfortable engaging with technology. So not only do we see areas of challenge for them, but we also can use these tools. And at least in the empirical settings, they have been shown to be very helpful in understanding greater strengths that individuals actually have that we’re not necessarily able to pick up in a one-on-one social interaction, human to human.

Dr. Opler: How long will it be until these kinds of measures are ready for prime time? Whether it be in drug trials or other forms of intervention research?

Dr. Hunter: I’m going to be optimistic here: I think within five-10 years we’re actually going to see a much greater opportunity for using technologically based assessment tools. One of the things that’s taking place right now that’s a little bit of a challenge, in terms of making the adjustment, is that most of the traditional measures for looking at cognition and looking at a number of the various psychological functions are moving to technological models as opposed to traditional, interactive, pencil-and- paper types of model assessments.

And I do believe that with challenges in the neurodevelopmental area–including autism spectrum disorders and some of the intellectual disability syndromes–we’re finding that we can gain more information by moving to iPad-based presentations and using more computer-based systems. And I think that really, by 10 years from now, they’re going to be in a whole new world with doing assessment. I think that will allow us to do far more real-time consideration and actual consideration within the environments that the people interact in on a day-to-day basis.

Dr. Opler: Now, let’s shorten our horizon a little bit: What do we have to look forward to in, say, the next year or two that you think is going to be exciting for clinical research and for treatment of folks with autism spectrum?

Dr. Hunter: Well I think, without a doubt, within the next two years, we’re going to have some very intriguing data from a number of ongoing studies, many supported through the NIH and through the ECHO Consortium. Looking at biomarkers that help us better understand the relationship between the environment and risk by both looking at information regarding the microbiome but also even more directly at neurofunction, in tandem with looking at a series of different serums and other biomarkers.

I also think that within the next two years, we’re going to have a really good understanding about the usefulness of the compounds that have to do with addressing social functioning and how we can take advantage of those in conjunction with more active and assertive behavior interventions, and start to do some pretty interesting real-time investigations.

The post The State of Clinical Trials in Autism and Neurodevelopmental Disorders with Dr. Scott Hunter appeared first on WCG.

About this Podcast: 

Dr. Andrew J. Cutler shares his insights on the current challenges and opportunities for CNS therapies during an energizing conversation with Dr. Mark Opler, Chief Research Officer at WCG MedAvante-ProPhase.

Dr. Cutler is a member of WCG’s Scientific Leadership Team, and a recognized expert in CNS therapies and clinical trials. Dr. Cutler is a sought-after speaker about the evaluation and treatment of mental illnesses such as ADHD, Bipolar Disorder (Manic-Depression), Major Depression, Anxiety Disorders and Schizophrenia. He conducts clinical trials for Phase I-IV studies. Indications include ADHD in children, adolescents and adults, depression, anxiety, bipolar disorder, schizophrenia and other neuropsychiatric and medical conditions. In addition to being the Chief Medical Officer for Meridien Research, Dr. Cutler is a Courtesy Assistant Professor of Psychiatry at the University of Florida.

Podcast Transcript:

The interview has been edited for clarity and length.

Dr. Opler: Dr. Cutler, could you tell us a bit about how you got into our field, what your research focus is, and why it matters? What is it about our work that inspires you?

Dr. Cutler: I always wanted to be a doctor. My father was a physician, and I grew up loving biology and science. I also loved detective stories like Sherlock Holmes and even Encyclopedia Brown when I was young. So when I went to medical school, I imagined myself going into internal medicine, which I saw as detective work. You get the data and you make the diagnosis, which is like solving a mystery. Then I took neuroscience and neuro-anatomy, and I realized that the brain is the most interesting organ in the body. When I did my psychiatry rotation, I really fell in love with psychiatry, especially brain chemistry. This was at the dawn of the modern psychopharmacology era. So I was really excited about these new developments and new medicines that were coming out that seemed to promise even better efficacy and safety.

I was at the University of Virginia at the time, and I decided to do a combined internal medicine and psychiatry residency. I ended up getting board certified in both. Along the way I also did research training on dopamine receptor pharmacology. I wanted to do research and be a professor. That’s where I saw my career going.

I started out my academic career at the University of Chicago doing psychopharmacology research. I discovered it was difficult being junior faculty. My research kept getting put on the back burner. Then I was recruited to a hospital in Orlando, Florida, that had a psychiatry division and wanted to do clinical trials. So I went there and started doing clinical trials privately. My goal was to do academic quality research in a private setting with best business practices–and less bureaucracy.

I really caught a wave because that was a time when a lot of pharmaceutical companies were looking at doing research in private settings. It was one of those lucky “right place at the right time” kind of things.

I’d say my primary research focus has been an outgrowth of my dopamine receptor research. The four areas clinically that involve dopamine dysregulation that I’ve done work, and published, in are schizophrenia, bipolar disorder, depression, and ADHD.

This matters personally to me: Not only because of the patients I have met along the way, but I also have a lot of family members with mental illnesses including bipolar disorder and ADHD. Some small part of me hopes to find great treatments to help them and others.

Dr. Opler: Specifically, what do you see as the top three challenges in our current trial methodologies and the execution of studies?

Dr. Cutler: This is my 26th year of doing clinical trials; over that time, they have become a lot more complicated. Of course, the problem we have, especially in CNS drug development, is separating drug from placebo. We’re trying to detect a signal and minimize noise. Over the years, what has happened, not only in the U.S. but across the world, is we’re seeing placebo response rising. The problem in the U.S. is we’re not only seeing placebo response rise, we’re actually seeing drug response drop.

There are many reasons for this.

One of the problems is identifying the appropriate patient and, even more than that, the appropriate biological target, for your potential intervention. The problem in psychiatry is the brain is so darn complicated. We’re forced to use diagnoses that are clinical diagnoses, and not necessarily biologic targets. So over time, I have seen many interesting and unique drugs fail–although they probably work well for a subset of people with a particular clinical condition–for instance, schizophrenia. I like to say, it’s not schizophrenia but schizophrenias. There are many different pathologies here. It’s not only a failure of the drug, it’s a failure of our ability to select the right patients that have the target we’re aiming for.

Another challenge we face is minimizing noise. The problem is, of course, is people have been chasing this smaller signal. So they’ve done things like ramp up the number of patients and the number of sites in a study. Paradoxically, this introduces more noise, making it even harder to detect a signal.

Along those lines, we had a lot of issues with payers for new treatments. Early on, companies are asking, “How do we start generating data that’s going to help us get this medication paid for in the marketplace.” That’s a very reasonable thing. Meanwhile, they’re also focused on marketing considerations that end up adding measures such as quality of life and healthcare economics and things like that.  But again, what we’re trying to do is detect a signal. The more of these kinds of outcomes and variables that get put in, the more potential noise gets put into the system. That’s something I think about and worry about as well.

Then there is integrating technology. We all know technology is going to change what we do in clinical trials. We just don’t know how yet. There is a variety of these emerging technologies I think people are trying to figure out.

Dr. Opler: To shift gears a little bit–it’s been a remarkable past 12 months. What are the developments you think are most exciting, and who do you think it will have an impact on the lives of our patients?

Dr. Cutler: I have to agree. I’d like to say that the past year or two has made me the most excited I have been about clinical trials in CNS and psychiatry since I got started all those years ago.

I’ve been thinking about the development of technology such as wearables, which allow you to collect so much more data in a less intrusive way. Not just activity level and sleep, but even monitoring cell phone usage and social media activity. How many phone calls are you making? Are you getting more active? Wearables are going to revolutionize not only research, but people’s lives.

I am excited about two areas in the field of depression. For a long time, we focused on medications that are basically ways to manipulate the three classic monoamines: serotonin, epinephrine and dopamine. We’ve gone at it in different ways, but the treatments have not worked well for a lot of patients. Finally, in the past year or two, we have had some very positive data come out on a couple of very different mechanisms.

One of them is esketamine, which is inhaled nasally. This works through the glutamate system, a totally different chemical. Janssen has that, but other companies have other kinds of glutamate-type, ketamine-like drugs.

Sage has a drug that is working on Gaba A receptors. Glutamate and Gaba are the two predominate chemicals in our brain. Glutamate is the major excitatory nerve transmitter. Gaba is the major inhibitory nerve transmitter. Both have been shown to have rapid effects–I’m talking hours–a day or two at the most. Traditionally, with the monoamine medications, you have to wait several weeks to see anything. So I’m really excited about this possibility of helping a lot more patients get better faster.

The other therapeutic area that’s really exciting to me right now is schizophrenia. Very positive results on a study with a very different mechanism of action were recently announced: a drug that works through receptors called TAR 1 receptors–trace amino receptors. This is a chemical system in the brain that has recently been discovered.

There’s one other thing I should mention: In 2017, we had two new drugs approved to treat tardive dyskinesia, which is a consequence of our antipsychotics. These work through a very interesting mechanism called VMAT2 inhibition. Most of our medicines work on the outsides of cells; this one works inside. That opens the door to possibilities.

Dr. Opler: What’s coming next? What do you see as the top three opportunities in clinical development in neuroscience?

Dr. Cutler: In addition to further developing this idea of rapid onset, or rapidly acting anti-depressants, I think we have to refine that quite a bit. We need ones that are, ideally, taken orally and have less risk and toxicity. Some of these rapid treatments now are intravenous.

We have a huge need for the treatment of schizophrenia in general and especially those symptoms that are most impairing– negative symptoms and cognitive impairment. These are the symptoms that keep someone from meaningfully engaging socially or occupationally. Schizophrenia is an especially pernicious illness because it hits people in their late teens, early twenties right when they’re getting ready to launch into their life.

As science evolves, I think we might be making progress. I was recently on an advisory board with a company that has developed a new medicine that is in front of the FDA right now. It has some very interesting intercellular mechanisms and may indirectly be affecting the glutamate system. That may help some people with schizophrenia who haven’t previously been helped.

The other one is in the ADHD field, which is another interest of mine. What the world needs, I like to say, is a non-stimulant that actually works reliably because we do have stimulants that are very effective, but they come with significant baggage–things like abuse and diversion as well as significant cardiovascular risk. There are a couple of non-stimulants that I’m excited about.

Another big need is bipolar depression. We have many approved to treat mania, but not for depression. And bipolar disorder is an illness predominately of depression. More depression, more recurrent depression and that’s what holds people back. We really need more effective treatments and more options for the depressive phase in particular.

Dr. Opler: To finish up, let me ask you about your predictions. Are there particular programs that you are excited to see read out one way or another in the next 12 months?

Dr. Cutler: One area I haven’t talked about yet is digital therapeutics. What that means is actual digital treatments, digital interventions. One that we’re working on for ADHD is a video game that is developed based on the principles of neuroscience that adapts as the child — or even adult –plays it. This video game has been used for ADHD, but it is starting to be looked at for autism and for adults with Alzheimer’s-related dementia. So as a person interacts with the game and plays the game, the game adapts and gets a little harder and more challenging. Theoretically, what you’re doing is training the brain and developing and strengthening circuits of attention and potentially inhibiting unwanted impulses. It’s almost like you’re working out your muscle. You lift weights, you work out your muscle. You can gradually lift more and more. So I’m very excited about that kind of possibility. For so long we thought of treatments and medications as pills. But obviously, we can administer medications intravenously, intranasally, as patches and various other ways. But potentially, we can have interventions and treatments that are digital and not a medication. These are things that are coming right now.

And as I mentioned, wearables also fascinate me. There is a wealth of data and information there that we can use that may lead to further treatments, further ways of monitoring the treatments, that maybe unlock some more of the clues and mysteries of how the brain works.

One other quick thing about technology: There is a technology that is not brand new, but it is being used increasingly. It assists in measuring improvement in patients on medications. It may detect changes even before the patient notices anything. One of those is a facial-recognition software. Patients who are depressed have something called negative cognitive bias, so everything seems more negative. If they look at a picture of a face that’s neutral, they will often misinterpret it as sad or anxious. Now if someone is given effective medication, they can more accurately identify the emotion of the face within a day or two, well before they notice feeling better. So I think about the potential of this to identify someone who is responding or potentially going to respond well to a treatment early on, then you can stay on the right track. Then if they’re not responding, rather than having to wait and potentially have the illness progress, maybe we can switch treatments and do something else.

Another way of applying this is something I heard about a couple of years ago. Computers can analyze people’s voices and accurately predict if someone is going into a depressive episode or becoming psychotic. So potentially we can catch people before they slip into a serious mental state that makes it harder to treat. Maybe we can do things prophylactically or very early on to prevent negative consequences. That’s very exciting.

The post Podcast: Exciting Developments in Psychopharmacology with guest Andrew Cutler, MD appeared first on WCG.