December 31, 2018
In a recent conversation on the current psychiatric clinical trials environment, Mark Opler, MD, chief research officer at WCG-MedAvante-ProPhase, had the opportunity to gather insights from noted clinical psychiatrist and researcher Christoph Correll, MD. Dr. Correll’s work focuses on the identification, characterization and treatment of adults and youths with severe psychiatric disorders. His particular area of expertise is psychopharmacology.
Dr. Opler: Could you tell us what you see as the top three challenges in our current clinical trials environment?
Dr. Correll: Unfortunately, we’ve seen many programs look promising but ultimately fail. The transition from Phase II to Phase III has been particularly difficult, and we need to understand that better. We get signals in smaller trials that are suggestive, but once they go into large explanatory Phase III trials, the results are disappointing.
One of the related big problems is the rising and enormous placebo effect that has really invaded and undermined the signal-to-noise detection. In schizophrenia, over 45 years the placebo effect has increased by 12.2 points and the drug effect by 1.2 points. When you have more and more sites and more study arms, the placebo response increases; we really need to get that under control. Perhaps there is more expectation bias — and maybe some baseline inflation. We need to have methodology that can deal with that. I think that’s a major challenge.
Another challenge is that we see patients intermittently and, based on their recall, we make judgments on how they actually behaved, what they felt and what they thought over a week or even longer. It’s still very subjective. We need a methodology that can get a much finer-grained assessment and also more objective data on behavior and the performance of patients.
A related one is cross-cultural psychiatry. We’re now getting approvals in many cultures, and psychiatry might be more culturally bound than we think. In some cultures, the placebo effect is even larger; especially when you only have a couple of patients per site. How do we deal with that? Researchers haven’t really tapped into that.
Dr. Opler: Could you share with us a couple of examples of developments in clinical research from the past year that you are particularly excited about?
Dr. Correll: I think the most exciting area at the moment — because approval appears to be right around the corner — is harnessing a glutamate system for depression. We’re seeing rapid-acting antidepressants. Esketamine is on the forefront, including as an IV and now as an intranasal treatment. We’ve learned that our hypothesis — that it takes several weeks until depression improves–is not necessarily right. If you have another receptor system and another approach, people feel better 40 minutes after a single IV dose and achieve the maximum effect after a day or two. That’s really exciting. Also, it is anti-suicidal; that opens different treatment paradigms. People who are currently helped in emergency rooms and are sent for admission could maybe be spared the admission. We actually get “speed jumps” into improvement and faster recovery.
Related to that is, we have basically now, for the first time in 40 or 50 years, an opening into different receptor systems. In psychiatry, it’s always been around serotonin or adrenalin or dopamine. Now, we can harness receptors related to abuse with ketamine or cannabinoids — and benefit the patient. That’s what I’m excited about.
Another important development — one that’s underappreciated — is that we can we use more technology to both assess and treat patients. Patients — and people in general — use technology all day, for many, many hours. Getting information for clinical trials from either the e-mental health tools that can be used as medical devices or maybe devices that measure and improve adherence. This is something I’m most excited about, that this could yield additional benefits for patients.
Dr. Opler: What do you see as the top three opportunities in clinical development for psychiatry? Where can we make a dent?
Dr. Correll: I just mentioned the use of technology. Wearables provide the opportunity to gather more objective data and to perform interactive assessments and momentary assessments. This will help us determine whether patients actually hear voices all of the time vs. only saying it when we have them at baseline. During screening, this could actually refine the patient population we want to enroll based on frequency and severity of certain symptoms. I think that’s exciting.
Another challenge is this: The field must move away from these broad-stroke diagnostic approaches for molecules. We must re-stratify medicine and stratify clinical trials. When a medication has a target engagement, let’s say an alpha-7 agonist in the nicotinic system, you want to see whether you can actually measure that system and only enroll patients who have the deficit.
For people who use an anti-inflammatory drug, just measure people with inflammation and enroll those patients. But what the companies are still doing is, they have a hypothesis, they take all patients and then run their biomarker afterwards — when it’s totally underpowered — to see if it could have yielded a result. I think that’s something where we really need to get into subgroups of patients. We might also need to reanalyze some data to see who are the super-responders; we can learn from even failed trials by identifying the potential subgroups.
These are two areas where progress can be made quickly. Other than that, obviously, I would say we need mobile mechanisms. We need also treatments for dimensions that are not captured in the current treatment algorithm, such as negative and cognitive symptoms for people with schizophrenia, treatments for the elderly who are agitated and aggressive, and treatments that have lower risks for increased mortality. These are lower-hanging fruit than, for example, understanding and treating dementia.
Christoph U. Correll, MD, is a Professor of Psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, and Medical Director of the Recognition and Prevention (RAP) Program at the Zucker Hillside Hospital in New York.
Mark Opler, MD, PhD, serves as Chief Research Officer, directing scientific research and development at MedAvante-ProPhase. Dr. Opler was the founder of ProPhase and served as its CEO and Chief Scientific Officer, among other positions. He holds the titles of Adjunct Assistant Professor of Psychiatry at New York University and Assistant Professor of Clinical Neuroscience at Columbia University’s College of Physicians and Surgeons.