Addressing the gender bias in mental health research

Women and men respond differently to stress

Significant differences in the body’s stress management systems between women and men

Ruter Van der Gaag (Radboud University, Nijmegen, The Netherlands) opened the session by describing significant differences in the body’s stress management systems (neurological, endocrinological and immunological) between women and men. In response to mental stress, men demonstrate greater changes in physiological measures such as blood pressure, whereas women have increased stress-induced myocardial ischemia and higher probability of thrombus¹.  Men react with more acute infections whereas women with more chronic infections and autoimmune diseases². Fewer women than men have died in the current COVID-19 pandemic, and the female immune system may be less prone to developing the ‘cytokine storm’ associated with poor outcomes³.

Women often respond to stressors with ‘psychological’ diseases, whereas men present with ‘physical’ diseases such as hypertension, cardiovascular disease and diabetes. In a woman, somatic symptoms of headache and palpitations may be disguising an anxiety disorder, or fatigue and myalgia may have an underlying diagnosis of depression.

Patterns of medication use

Florence Thibaut (University of Paris, France) gave a gender-sensitive perspective on pharmacology. More women than men receive medication for a mental health condition⁴.  This pattern is true for antidepressants and anxiolytics, but also for adult ADHD medication and atypical anti-psychotics, where the related conditions have higher prevalence in men⁴.

More women than men receive medication for a mental health condition

Impact of differences in pharmacokinetics and pharmacodynamics

Historically, women have largely been excluded from clinical trials due to concerns over potential teratogenic effects. This has led to medications only being studied in men, and efficacy and safety data being extrapolated to women. Yet differences in pharmacokinetics and pharmacodynamics between the sexes can impact on adverse event reporting⁵:

• Women are more frequently overdosed due to smaller volume of distribution, larger free fraction of drug, and slower clearance from the body.
• Women are more sensitive to drugs due to alterations in receptor number and binding and signal transduction pathways.
• Alterations in pharmacokinetics and pharmacodynamics result in women taking greater amount of medications with increased risk of drug interactions.

Pharmacokinetic and pharmacodynamic properties can differ according to sex

Psychotropic drugs showing sex differences in pharmacokinetics⁵ include clozapine, olanzapine, and selective serotonin reuptake inhibitors (SSRIs), as well as substances such as ethanol, methadone and morphine. Women usually have higher responses to SSRIs than tricyclic antidepressants (whilst the reverse is true for men) and require lower doses of typical antipsychotics to control symptoms than men. The incidence of anti-psychotic adverse events is greater in women⁶.

Future direction for clinical practice and research

Gender-specific medicine will increase understanding of how dis-ease is expressed in the different sexes. This includes bridging the psychological/somatic gap to allow patients of both genders to be treated appropriately.

Further research is needed into differences in disease mechanisms between the sexes

Further research is needed into differences in disease mechanisms between the sexes so treatments can be focused accordingly. Guidance is available regarding the study of gender differences in clinical drug trials⁷, and women of reproductive age should be included, providing there is adequate risk protection regarding pregnancy.