Why is it important to further investigate sex and gender in the neuroscience of mental health?

With regards to sex and gender there are three important differences in relation to mental health:

• There are sex differences in the prevalence of mental health and neurodiverse conditions (e.g. females are more likely to be diagnosed with depression).
• There are sex differences in the expression of symptoms. This could be a reflection of differential biological susceptibility in the brain and/or sociocultural gender-related expectations that interact with biological factors.
• There are sex differences in the life span course of mental health conditions. 

The underlying mechanisms for these differences are difficult to disentangle and poorly understood. This lack of understanding has negative consequences for those with mental health problems.

Which sex-related factors can cause differences in the emergence, expression and diagnosis of mental health conditions?

We can differentiate between genetic factors and sex hormones.

• With regards to genetic factors you can think of the Y-chromosome, the 1 versus 2 X-chromosomes, imprinting, random X silencing in females, Y homologue genes, epigenetic sex effects, and X-inactivation and escape genes.
• With regards to sex hormones you can think of prenatal/postnatal/pubertal surges, pregnancy, daily fluctuations and age-related decline in males, pubertal timing, and fluctuations in the menstrual cycle, peripartum period and menopause transition.

Which gender-related factors can cause differences in the emergence, expression and diagnosis of mental health conditions?

There are many environmental factors that can cause these differences, but a few examples are social-cultural gender roles, stereotypes and expectations, socioeconomic status, integrity of social relationships, education, diet, nutrition and physical activity, and occupational and leisure activities. 

How do the sex- and gender-related factors interact in the emergence, expression and diagnosis of mental health conditions?

The sex- and gender-related factors interact and converge mechanisms that shape neurodiverse conditions. The sex- and gender-related factors moderate and mediate the behavioral and cognitive manifestations of neurodevelopmental health conditions and shape brain development.

What are the main barriers that withhold researchers from addressing and understanding sex- and gender-related mechanisms?

Three key domains with barriers are research methods, diagnosis/treatment, and stakeholder collaborations.

Research methods:

A variety of research methods can withhold researchers from addressing and understanding sex- and gender-related mechanisms:

• Conflated terminology. Terminology regarding sex and gender is often incorrectly used interchangeably. Also, the term gender is multifaceted and has diverse definitions. For example, gender identity and gender expectations are different constructs that may affect different mechanisms in the brain, and they need their own dimensionalities and conceptualizations.
• Non-binary sex differences. Biological sex and sociocultural gender constructs are often studied in binary terms, but these constructs may very well contain nonbinary end points. Think of X-inactivation in females, testosterone fluctuations, and gonadal hormones.
• Sex and gender vary under different conditions and sex and gender mechanisms interact. Sex is highly correlated with sociocultural gender differences and research designs cannot always distinguish between sex- and gender-related factors.

Diagnosis/treatment:

Diagnosis and treatment can withhold researchers from addressing and understanding sex- and gender-related mechanisms through:

• The gap between neuroscience and clinical practice. There is no direct mapping from fundamental insights from neuroscience to daily clinical practice, which tends to use more of a holistic approach.

• Group-based models and binary approaches are limited and do not capture the full complexity of underlying populations. The traditional classification of mental health disorders ignores the heterogeneity and high co-occurrence of mental health conditions.

Stakeholder collaborations:

Stakeholder collaborations can also withhold researchers from addressing and understanding sex- and gender-related mechanisms:

• Sex and gender are socially sensitive subjects that often fall victim to societal opinions, controversy, and misunderstanding.
• Science communication and stakeholder involvement are time-consuming activities that are currently undervalued and unrewarded in academic, professional, and funding institutions.
• Funding agencies are not facilitating sex and gender research leading some research not to be done due to lack of funding.

What recommendations are made to better understand sex and gender in the neuroscience of mental health?

Sex and gender can be better understand in the neuroscience of mental health when:

• More explicit descriptions of sex and gender constructs are used in research articles. 
• Sex and gender recordings are improved.
• Underrepresented groups in the research process are included. 
• Sex- and gender-related mechanisms and their interactions are accurately reported and analyzed.
• Interdisciplinary collaborations that require time and financial investments are included.