Understanding Why Men and Women Differ in Medication and Treatment Response

In part 2 of this interview, Patricia Pelufo Silveira, MD, PhD, associate professor at the Department of Psychiatry at McGill University in Montreal, Canada, continues to discuss her study, what clinicians should take away from the results, and where future research needs to go. 

"A sex-specific genome-wide association study of depression phenotypes in UK Biobank" was recently published in the journal Molecular Psychiatry. 

Catch up on part 1 here: Genetic Variance in Depressive Phenotypes Found to Vary by Sex

Editor's Note: Answers have been lightly edited for clarity. 

Patricia Pelufo Silveira, MD, PhD, is an associate professor at the Department of Psychiatry at McGill University in Montreal, Canada. Dr Silveira obtained an MD (2001) and specialized in pediatrics (2002-2006). She received a MSc (2004) and a PhD (2007) in neurosciences from the Universidade Federal do Rio Grande do Sul (UFRGS), Brazil. She also completed a postdoctoral fellowship (2007–2009) in Dr Meaney´s Lab at the Douglas Institute. Before joining McGill and returning to the Douglas Institute in 2016, Dr Silveira was an assistant professor in the UFRGS Pediatrics Department (2009-2016) and led the externally funded lab, the DOHaD Porto Alegre group.

A pediatrician and neuroscientist with extensive research, teaching and clinical experiences, Dr Silveira has also shown significant leadership in preparing tomorrow’s research leaders, supervising over 30 PhD and MSc students and mentoring several post-doctoral fellows.

Dr Silveira’s research focuses on how perinatal and early-childhood environments can shape and modulate both health and disease across the lifespan, into old age. Her aim is to identify genetic/epigenetic markers that interact with environmental adversities in childhood, modifying endophenotypes (impulsivity, sensitivity to reward, food choices) that ultimately affect healthy growth and neurodevelopment, increasing an individual’s risk for developing chronic diseases and mental illnesses across their lifespan.

Read the Transcript: 

Patricia Silveira, MD, PhD: My name is Patricia Pelufo Silveira. I'm an associate professor at the department of psychiatry at McGill University here in Montreal, Canada. And my lab is focused on gene-environment interactions and how early life adversity or stress influences the risk for disease in the long term. We work a lot with genetics data, functional genomics, but also with the environment and early life adverse.

Evi Arthur, DepressionCare 360: Were any of the outcomes you found different than you expected them to be?

Dr Silveira: We were surprised by the fact that while the genes associated with depression were commonly linked to certain biological processes in both men and women. Depression affects how the genes are expressed in the cells in both sexes. But this happened through specific mechanisms, for example, activating specific molecular pathways in men and women. These were different in the 2 sexes. In males, these molecular pathways involved epigenetic mechanisms that are more linked to the response to the environment, and especially variants in genes that called for histone proteins that again, are molecular processes involved in the response to the environment. And in females, these pathways involve neurotransmitter systems like the dopaminergic system of the brain, glutamatergic systems. These differences may help us understand why men and women differ in their responses to medications and treatment in general.

Arthur: What practical applications of your findings exist for clinicians treating patients with depression?

Dr Silveira: We learned a bit more about the mechanisms involved in the differences in the clinical presentation of the depressive phenotypes between men and women, and identified some genes and pathways that are important specifically for men and women. This may inform the development of new drugs that may more specifically target these sex-specific mechanisms. Beyond that, our study can also highlight the relevance of the metabolic aspects associated with depression, especially in women, confirming that metabolic diseases should be carefully investigated, prevented, and promptly treated, especially in this group.

Arthur: Are you conducting any more research on this area? What other studies do you think are needed?

Dr Silveira: We continued investigating the genetic and early environmental causes of psychopathology and their metabolic comorbidities, hoping to shed a light on the mechanisms by which these diseases co-occur. It is possible that certain drugs are more likely to benefit women and some other drugs more likely to benefit men. And this is still a matter to be researched in the future, but our study opens a venue for this type of investigation.

Arthur: Any final thoughts or takeaways for clinicians?

Dr Silveira: I hope that our paper contributes to the larger recent effort in considering sex and gender as important variables in research. In our case, we were focused on biological sex and how men and women differ in terms of the genetic background linked to the depressive phenotype. But the same approach can be used in other areas of health and medicine too. And the better understanding of sex-specific effects and biological processes can benefit the health of both men and women.