More Personalized, Precision Medicine Needed In Psychiatry Clinical Trials
By Joel Raskin, MD, and Greg Rigdon, Ph.D., Arrivo Bioventures
Clinical trials for psychiatric illnesses have historically enrolled broad populations under the assumption that all people with a given disease are the same. We assume they have the same underlying pathophysiology, and the same responses to treatments. But in contrast to other physical diseases, psychiatric illnesses are diverse, classified by a broad list of symptoms split into diagnostic categories. Consequently, patients diagnosed with the same psychiatric illness may present a significant heterogeneity from one another in their clinical presentation. Combined with our incomplete knowledge of these illnesses’ physiological mechanisms, this heterogeneity contributes to the enrollment of a broad group of subjects that don’t truly represent the target illness, leading to reduced efficacy and increased trial failure rates. One possible solution to this enrollment challenge is precision medicine.
Precision medicine focuses on using genetic and molecular information to identify which therapeutic approaches will be most effective for a given group of patients. Even with gaps in our knowledge of the underlying biology of psychiatric illness, we should nevertheless proactively study biological subsets of patients during the clinical trial phase, rather than relying solely on post-hoc identification of patient subsets that respond to treatment. Even early-stage trials that don’t achieve endpoints can help identify appropriate patient populations for further research; they can provide a foundation for consistent efficacy across scales and a biological underpinning for the results. With these “reasons to believe,” our industry should embrace genetic or molecular data to identify target patient populations for early research phases.
3 Ways Researchers Can Find Right-Fit Participants
According To Phenotypes
For psychiatric illnesses, there are several ways to create more homogeneous clinical trial populations. The first is for trial sponsor companies to prospectively identify phenotypes, as we already do in schizophrenia research with positive or negative symptoms or those with cognitive deficits. Depression phenotypes are also available for study but are rarely studied prospectively, perhaps because animal models do not exist for them. Women with depression are the exception, with postpartum depression and premenstrual dysphoria subtypes having been studied. More commonly, however, sponsors will optimistically progress negative or failed studies with subset results into another study. But without a physiological mechanism of action — a “reason to believe” — to explain the subset result, moving forward means running the risk of subsequent trial failure.
With Biomarkers
While the field of biomarkers remains nascent, we could subtype potential research subjects using various biomarkers to identify homogeneous illness subsets within a clinical trial population. For example, researchers could use biomarkers for risk susceptibility (single nucleotide polymorphisms, epigenetics such as sex, age, childhood experience, ethnicity), diagnosis (neuroimaging, qEEG, immune markers), pharmacodynamics (BDNF, receptor function), prediction (micro and circular RNAs), and safety (cytochromes). Not only would exploring these biomarkers increase the odds of a positive study, but it also supports the identification of a population more likely to benefit from an investigational drug.
Of course, the challenge is that many of these biomarkers are not fully validated and can be expensive. Not to mention that some of the subpopulations are considered too small a market. Depending on the circumstance, the subpopulations can be as small as 5% or as “large” as 30% or more. While the first two points are valid, surely a drug that is more effective for a specific subpopulation could still succeed, particularly where there is an unmet need.
By Sex
“Sex at birth” is one of the most understudied subpopulations. Most would agree that men and women are wired differently and, yet they are usually studied the same way. Let’s look at two disorders: schizophrenia and major depression.
With schizophrenia, there are well-documented sex differences across various domains — onset, symptoms, course, and outcomes. The age of onset in women is often between 25 and 35 years, with a second peak around menopause, as estrogen is thought to have a protective effect. For men, onset occurs in late teens to early 20s. Women exhibit more positive symptoms and affective expression, while men have more prominent negative symptoms and more cognitive deficits. There are structural brain differences as well, with men tending to show greater reductions in gray matter volume and more pronounced ventricular enlargement. Women typically have a better overall prognosis with a better treatment response, again possibly related to estrogen's role.
Major Depressive Disorder is about twice as common in women. Contributing factors include hormonal fluctuations, higher rates of trauma exposure, and sociocultural stressors. Major depression typically occurs in women in their late teens to early 20s, while for men, onset can occur slightly later, often in the mid to late 20s. Men and women also show different phenotypes. Women present with internalizing symptoms like sadness, guilt, anxiety, and fatigue, with more somatic symptoms like appetite changes, sleep issues, and pain. Men, on the other hand, typically show more atypical externalizing symptoms like irritability, anger, aggression, and substance use, with higher rates of anhedonia and psychomotor agitation. Women also show more chronic, recurrent depression with more self-harm attempts, while men have a higher rate of completed suicide. Women have higher rates of interpersonal trauma, such as childhood abuse or domestic violence, and more ruminative coping styles, both linked to longer depressive episodes. Research shows sex differences in neurobiology and brain imaging, including HPA axis activity (stress response system), and brain structure/function in areas related to mood regulation (e.g., hippocampus, amygdala, prefrontal cortex). Functional MRI shows different patterns of connectivity and response to emotional stimuli between the sexes. Even the treatment response also varies, as women may respond better to SSRIs, possibly due to serotonin modulation by estrogen. While these differences cannot be applied at an individual level yet, the group trends lend themselves to different research approaches.
Precision Medicine In Practice At Arrivo
At Arrivo, we are studying an oral epigenetic SIRT6 activator for major depression in women. This is based on an earlier Phase 2 placebo-controlled study that, in post-hoc analyses, showed women had a strong antidepressant effect consistent across all scales, while men exhibited placebo-like effects. In trying to understand these surprising results and looking for our “reasons to believe,” we soon realized that the results may not be surprising at all. The consistent results in women in all scales, both clinician- and subject-rated, along with the low placebo response, suggested this was a true effect and not a cherry-picked result. Physiologically, women and men with depression have over 1,020 genes that move in opposite directions, so a drug that has an epigemnetic effect could have opposite effects on women and men. SIRT6 plays a crucial role in DNA repair, mitochondrial health, metabolism, and inflammation, all implicated in major depression etiology. While many of its functions are shared across sexes, there is growing evidence of sex-specific roles of SIRT6, particularly in women, due to differences in hormones, gene regulation, and disease vulnerability. With these clinical and biological “reasons to believe,” we now hope to replicate these results and are proactively studying women in a Phase 2B/3 trial.
In other psychiatric illnesses, sex differences also exist, with important implications for how trials are designed. Women are more likely to experience most types of anxiety disorders, including generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobias. Eating disorders and post-traumatic stress disorder are also more common in women. For most of these conditions, women are also more likely to seek help, which may contribute to higher diagnosis rates and influence how clinical trial populations are enrolled.
A Call For Precision
The broad spectrum of phenotypes in patients diagnosed with the same psychiatric disorder and the overlap of traits between different disorders increase the heterogeneity of the clinical population being studied and boost the likelihood of clinical trial failure. Focusing on the identification of specific phenotypes or potential biomarkers earlier in the clinical drug development process and applying those insights at the clinical trial design stage could lead to more robust results. This would increase the chances of bringing forward more targeted, effective treatments, ultimately delivering on the promise of personalized and precision medicine in psychiatry.
About The Authors
Joel Raskin, MD, brings almost 40 years of clinical, academic, pharmaceutical research, and medical affairs experience to his role as chief medical officer to Arrivo. He was a community and academic psychiatrist, consultant to public and private industry, and the head of the depression clinic and clinical trials specialist in mood disorders at the Center for Addiction and Mental Health, University of Toronto before joining Eli Lilly in 1999. During his 20 years at Eli Lilly, Joel held various global team roles in neuroscience drug development and commercialization, working in mood and anxiety disorders, schizophrenia, chronic pain, Alzheimer’s, and migraine.
Joel has published nearly 100 articles and presented at international conferences and academic institutions. He continues to consult in drug development and mentors researchers at the University of Toronto Health Innovation Hub.
Greg Rigdon, Ph.D., brings over 30 years of pharmaceutical research, clinical development, and regulatory experience to his role as senior vice president of scientific affairs at Arrivo. He began his career at Burroughs Wellcome (later Glaxo Wellcome) as a Wellcome Fellow and head of the neuropharmacology laboratory, advancing programs in antidepressants, antipsychotics, and muscle relaxants through IND filings. He later led global, cross-functional teams as international product development team leader for a novel antiepileptic drug.
Greg went on to serve as vice president of new product development at Icagen, where he built and managed teams across key areas including drug metabolism, pharmacology, and toxicology. At Salix Pharmaceuticals, he was director of clinical research, designing trials and collaborating with regulatory authorities for GI and rare disease programs.
He holds a Ph.D. in pharmacology from Texas Tech University, has authored over 30 publications, holds four patents, and has lectured at UNC-Chapel Hill and Campbell University.