Stages of symptoms in schizophrenia: an interview with Dr. Mark Opler, ProPhase

insights from industryDr. Mark Opler, PhD, MPHChief Scientific Officer at ProPhase

Please can you give a brief overview of the spectrum of symptoms associated with schizophrenia?

I think there's a perception that schizophrenia is principally a disorder that involves hallucinations such as hearing voices, seeing things and believing things that aren't real. These are indeed part of the phenomenon, but the condition is much broader than that.

As well as those odd experiences, which we refer to as positive symptoms, patients with schizophrenia also experience negative symptoms. Negative symptoms include difficulty expressing emotion, difficulty communicating on a non-verbal level and difficulty enjoying things that were enjoyed previously.

Another domain that is of critical importance in targeting new treatments is cognitive deficit. For example, the ability to pay attention and the ability to remember important things may be lost. Another important feature that develops in some patients is depression.

Finally, agitation and a preoccupation with different aspects of the environment or different ideas are also not uncommon. Overall, there’s a very broad range of symptoms to consider, certainly a lot more than many people realize.

How much was previously known about the stages of the disorder and the types of symptoms experienced over time?

I think the field has recognized for a long time that this disease changes over time. We've recognized that the first episode patients’ experience is different than the experience of those in the stabilization phase and different again to the experience in the chronic phase, especially as patients age.

There are many excellent studies reporting on the possibility of recovery over time but what hasn't been recognized is how specific clusters of symptoms change over time. There's been a general sense that there's a change, but we've been lacking that quantitative element and not looked at how the disease really evolves over the life course.

Please can you outline the main findings of the recently published research article: "The evolution of illness phases in schizophrenia: A non-parametric item response analysis of the Positive and Negative Syndrome Scale" (PANSS) in Schizophrenia Research: Cognition?

What we've done is to validate the broad idea that symptoms in patients with schizophrenia change over time and differ according to the phase of the disease. What we've asked here is exactly what symptoms do in fact change and we are using a very carefully constructed, highly quantitative approach.

For example, knowing what the truly critical symptoms in first episode patients are gives us the opportunity to focus treatments more meaningfully on the same continuum. Ambulatory outpatients have a very different symptom profile. For instance, their anxiety, their agitation is considerably different, and perhaps a less important target than other domains.

The other thing that we're doing here is not simply looking to see which symptoms are prominent and which symptoms are less prominent. We're looking to see what domains are valuable and recognising that there is a lot of variability between individual patients and even within the same disease phase.

While we are very excited about the results of our research, we still need to recognize the importance of tailoring treatment to the individual. There's a lot of well-grounded and well-founded interest in personalized medicine. Our work takes a step in that direction.

What we must never lose sight of, especially when we think about the treatment of individual patients, is that every single person with schizophrenia is an individual.

Is it true that most clinical trials in schizophrenia rely on a general symptom rating scale regardless of the stage of the disorder? Do you think this research will change the way clinical trials are conducted going forwards?

That's a very good question. The brief answer to both questions is yes, with some exceptions. For instance, there are researchers in the field who are making a very concerted effort to develop treatments that target specific domains.

For example, negative symptoms are vitally important in developing effective treatments and some research is focused on those efforts. My hope is that our research will also get people to shift from simply thinking about individual features of the disease to thinking about the life course of the disease.

We need to think more concretely about patients and how their underlying pathology is evolving, rather than simply considering a collection of symptoms. Studies should be focused on multiple axes such as where the patient is in the life course of their personal evolution and their disorder, rather than just the symptom profile the patient is presenting with.

The other thing I hope it will do is get people excited about continuing this kind of research. I'm very excited about our results and about the interest that it's generating, but I have to remind myself and everyone else that this is hopefully just the beginning of a larger conversation.

We need to recognize the complexity of schizophrenia and how it isn't simply one disease, but is highly heterogeneous and perhaps even a collection of disorders that changes over time, as patients evolve.

What further research is needed to improve our understanding of the way schizophrenia evolves over the life course?

I think we need to do a better job in terms of moving away from the relatively narrow perspective that we have for trials. We tend to focus on the doctor’s evaluation and what they think of the patient's disease.

We need to consider the perspectives of the patient and of the caregiver or caregivers who are responsible for and focused on the care and well-being of the patient day to day. Other perspectives that are often lost include that of the community the patient lives in and those of other observers who are important in the patient's life.

My hope is that our work challenges several assumptions. We're challenging the assumption that an individual’s symptom profile at a given time is the only point of concern and introducing the idea that their stage in the life course of the disease merits consideration.

I hope we also participate in a conversation about what aspects of measurement are being missed in our evaluation of new interventions and new treatments. We always have to be aware that our understanding is incomplete and we need to test our assumptions.

What are ProPhase’s plans for the future?

Our plan is to continue this line of work. It’s very important to really be engaged with other schools of thought and other ways of looking at the world and the things that we study.

Right now, we are reinvesting in new perspectives and in our focus on the fundamentals of measurement science. That means working with patients and their families to better understand their perspectives of the disorder.

For example, one area where we see a deficit in schizophrenia is social cognition. Social cognition is the processing of information about social interactions, such as being able to recognize what another person’s emotional state is or being able to understand their intentions. We need better tools for evaluating this and for understanding how patients perceive themselves.

Stigma is another very important area that's been underappreciated in clinical trials. The role of stigma in the remission of symptoms and ultimately recovery is something that people in adjacent disciplines have known about and focused on for a while now; yet, it’s only played a minor role, if any, in mainstream clinical trials.

We need to be dragging these things out of the shadows and into the light, so we can find out if they have a place in improving the work that we do to develop  treatments.

I would also like to encourage people everywhere to get involved, wherever possible in clinical research. We're very devoted to what we do, but we desperately need involvement, the input of the world at large.

I would like to hear from anyone and everyone from all walks of life, all disciplines, all professions and anyone who's interested in improving the way that clinical research is done to make it more valuable for patients.

I'm eager to hear from people with their own personal perspectives on this disease, as well as practicing professionals in the field.

If innovative medications are ever going to really advance, they've got to become part of the public’s interest. Anyone who wants to get involved is welcome to contact me. There are so many things that need to be done and we need everyone's help to do it.

Where can readers find more information?

Our article in Schizophrenia Research: Cognition can be found here:

About Mark Opler

Dr. Mark Opler serves as Chief Scientific Officer, managing and directing scientific research and development at ProPhase. Dr. Opler 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.

His academic research focuses on the etiology, phenomenology, and treatment of serious and persistent mental disorders. He is also leading the development of the new upcoming edition of the PANSS Manual©.

Dr. Opler is a former “NARSAD Young Investigator” recipient and has recently completed a 5-year research grant from the US NIH to establish an international cohort in Finland to investigate the role of paternal reproductive health in the onset of mental disorders.

He has co-authored over 40 peer-reviewed publications and has contributed to multiple book chapters and review articles on schizophrenia and mental health research. He received his BSc at SUNY Stony Brook and his MPH and PhD from Columbia University.

He is also a graduate of the Psychiatric Epidemiology Training Program at Columbia University and completed his Postdoctoral Fellowship at the New York State Psychiatric Institute.

April Cashin-Garbutt

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April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.


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