By Kari Nations and Paul Greene

The National Institutes of Mental Health report that in 2015, approximately 16 million adults in the U.S. had experienced a major depressive episode in the past year. [1] The World Health Organization calculations put that number at 300 million, again about four to five percent. [2] What an extraordinary number, meaning that one in every 20 people with whom we work – our friends, employees, bosses, our parents and certainly our children – may have suffered from depression some time very recently, not to mention at some point in their lifetime. For those of you who have been touched by depression, either yourself or your loved ones, you know how incapacitating it can be. Often cited, but perhaps underappreciated, is the World Health Organization report that depression is the leading cause of disability around the globe, which means that the disorder can render a person unable to work or function as they normally would. More than 50 percent of all suicides occur in people with a diagnosis of depression, and suicide is the second cause of death in young people, age 15-29.

All of these statistics and frightening numbers are to say that the depression phenomenon is in no way solved, and Syneos Health takes it very personally. The exceptional research efforts by our combined academic and drug development communities has been a whirlwind of discovery, hope and advancement; but to be honest, that excitement has often been offset by disappointment. New drugs with true novel mechanisms of action are struggling to reach the important success bars set by our regulators. Empirically based psychotherapeutic treatments, as well as innovations like transcranial magnetic stimulation, are highly effective but often inaccessible to everyone. Big paradigm shifts in how we approach treatment, personalized biomarker-based approaches, and maintenance of recovery once our treatments have shown an effect are slow to develop and not yet clearly in sight.

Depression research has been a career foundation for most every colleague we have in CNS Clinical Development at Syneos Health. Our team includes 20 licensed clinical psychologists and psychiatrists who not only work in depression research but have, at some point, treated patients themselves. Many of us have published extensively in this area, not just on research outcomes but also on the methodological challenges in this work. And we literally have thousands of combined years of depression trial experience within our operational personnel ranks. Part of that is surely driven by substantial interest over years by pharmaceutical companies in new treatments for depression but it is also much more familiar and personal than that. We have all been touched by someone with depression in our lives. We recognize it; we understand the hopelessness and the isolation that comes with it. The very pervasiveness of the disorder means that it touches – and in some cases scars – nearly all of us in some way. And so we take it personally and commit our work and intellectual effort to finding new and better therapies.

While we may be daunted by the unmet need that still exists, we in the CNS Team at Syneos Health are excited about what is to come.

Expanded Focus for Drug Development – Historically, pharmaceutical trials have focused on treatments for the core mood symptoms of depression. However, we observe that more focus on the full impact of depression is emerging. For example, patients with depression also often see deficits in cognitive and executive function. These symptoms are very real and negatively impact their ability to work and keep up at home. We are excited to see new interest in medicines that target the cognitive deficits. Our Clinical Surveillance Team is deep with experience in this area and is bringing that experience to new trials.

Taking on Suicidality – Suicide is a tragic and far too frequent event in patients with depression. We are excited to see movement in the field towards treatments that are targeted for suicidal ideation and behavior. This shows a willingness on the part of both regulators and drug developers to think creatively to bring novel mechanisms to bear on a significant public health problem.

Minimizing Placebo Response – A negative study for a medication that is, in reality, effective is not only expensive but it delays the result that we all want which is getting new treatment options in the hands of the medical community faster. Trials of medications to treat depression are plagued with high failure rates because of high placebo response, which means that trial participants are experiencing improvement without actually receiving the treatment itself. This would be an exceptional outcome in a clinical setting, but for research, it complicates our ability to clearly see the effect of an investigational medication. At Syneos Health, we aim to take the issue head on. We have successfully implemented complex study designs that have the effect of increasing the signal to noise ratio and improving the ability of a study to detect a real difference. We also believe that decreasing noise begins with making sure you have the right patients in the study. Looking at historic depression studies, we have demonstrated that more than nine percent of subjects who the investigator believes are ready to randomize are, in fact, not appropriate for the study.

Syneos Health focuses much of its screening efforts on identifying those subjects and eliminating them from the study prior to randomization. This leads to less noise and a clearer signal.

Recognizing the tremendous advances in depression research should not distract us from the fact that there is yet so much that can still be done. And when we combine experience, passion, vision, and a real connection to patients, we know we are unstoppable.



About the Authors

Kari Nations, PhD, Senior Vice President, Clinical Development, CNS, Syneos Health™

Dr. Kari Nations, PhD, is a licensed clinical psychologist with 27 years of experience in the pharmaceutical industry. During that period, she has accumulated significant breadth of experience serving in multiple operational and scientific leadership roles in both CROs and pharmaceutical companies, all of which she directly applies to her current position as Head of the Syneos Health Clinical Surveillance Team. Her past work included clinical development for novel compounds in depression and other psychiatric disorders. Dr. Nations has a keen interest in the methodological issues that impact CNS trials and has actively contributed to a number of industry/academic consortia addressing measurement and variability challenges and their impact on signal detection and placebo response. She is a frequent speaker and trainer on these topics, and has delivered these messages back to the university setting to ensure young researchers can learn from industry experience. Dr. Nations holds an appointment of Clinical Assistant Professor at the University of Texas at Austin, Department of Psychology, where most of her adjunct work has focused on teaching and mood disorders research.

Paul Greene, PhD, Senior Vice President, Clinical Development, CNS

Dr. Greene is a seasoned pharmaceutical research professional with success in both large pharmaceutical companies and in CROs. He has a PhD and post-doctoral training in biopsychology, with a focus on the neuroanatomical and neurochemical bases of learning and memory. His career has spanned the full range of clinical development in CNS from pre-clinical pharmacology through late-stage clinical development, successful NDA and MAA submissions, and post approval commitments and label extensions. Dr. Greene has published numerous manuscripts and more than thirty abstracts, all focused in CNS describing both laboratory and clinical work.

Paul has more than 25 years of experience in the pharmaceutical industry, first as a Lilly Fellow at the Universitè Louis Pasteur in Strasbourg, France, then in roles of progressing responsibility at major pharmaceutical companies and CROs. He has experience across a range of CNS disease states with very deep concentrations in mood disorders (bipolar disorder and major depressive disorder), schizophrenia, cognitive dysfunction in schizophrenia, Alzheimer’s disease, epilepsy, ADHD and autism. He has worked extensively in pediatric and elderly populations including special institutional environments (nursing homes and psychiatric inpatient facilities). Dr. Greene led the clinical team through the creation and execution of a clinical development plan for a major marketed product for bipolar disorder. He also led the submission team for a successful NDA and MAA for that product and wrote the Integrated Summary of Efficacy and the Integrated Summary of Benefits and Risks. Having led both global project management teams and a rater training enterprise at a major CRO, Dr. Greene brings both scientific and operational expertise to the programs under his management. Paul is currently the head of NeuroPsych in the CNS Business Unit at Syneos Health.

Therapeutic Area Experience: Alzheimer’s disease, agitation associated with Alzheimer’s disease, ADHD, autism, bipolar disorder (mania, bipolar depression, rapid cycling, acute and maintenance therapy), schizophrenia (acute treatment and cognitive dysfunction), major depressive disorder, migraine, generalized anxiety disorder, epilepsy, and metabolic syndrome in bipolar disorder.