Skip to content

Neural Mechanisms Underlying Sex Differences in Risk and Resilience for Mental Illness

NAMHC Concept Clearance


Janine Simmons, M.D., Ph.D.
Chief, Affect, Social Behavior and Social Cognition Program
Division of Neuroscience and Basic Behavioral Science (DNBBS)

Stacia Friedman-Hill, Ph.D.
Chief, Mechanisms of Cognitive Dysfunction Program and Trajectories of Neurocognitive Functioning Program
Division of Developmental Translational Research (DDTR)


The purpose of this initiative is to support basic and translational research on the neurobiology of sex differences in order to expand our understanding of the etiology and developmental trajectories of mental disorders in males and females, and to inform novel approaches to individualized interventions and treatment across the lifespan.


It is well established that an individual's sex can influence susceptibility, prevalence, and age of onset for mental disorders. Disorders that emerge early in development, such as autism spectrum disorder, attention deficit hyperactivity disorder, Tourette syndrome, and early-onset schizophrenia, tend to be more prevalent in males. Disorders with onset in adolescence or adulthood, such as major depression, anxiety, and eating disorders, are more prevalent in females. Despite these clear epidemiological trends, very little is known about the precise timing, neural circuitry, or mechanisms underlying the expression of sex differences in mental disorders. Analysis of the NIMH portfolio suggests that explicit testing for sex differences is rarely proposed, whether in basic or translational research, and that there are very few translational studies that compare the etiology of mental disorders between males and females. Particularly lacking are theoretical models of disease that attempt to explain how neurobiological sex differences at particular points in development interact with other biological or environmental factors to confer risk and resilience for mental disorders. Moreover, sex differences are likely to contribute significantly to individual differences in response to treatment and intervention. Research on sex differences in the developmental etiology of mental disorders will provide information fundamental to the development of personalized interventions.

Anticipated outcomes include:

  • Increased understanding of how interactions between sex chromosomes, steroid hormones, and environment shape sexually dimorphic neural pathways and behavior;
  • Stimulation of research on neurodevelopmental sex differences that confer vulnerability or protection in individuals at familial/genetic risk for mental disorders; and,
  • Identification of sexually-dimorphic points of vulnerability and developmental divergence that influence the onset and symptoms of mental disorders.

Submit Comments