Gender differences: The new challenge for the next years

The prevalence, age at onset, and clinical symptoms of many neuropsychiatric diseases substantially differ between males and females. Examples of female-biased conditions include emotional disorders such as depression, anxiety disorder, or anorexia nervosa, which usually starts around puberty or later in life; examples of male-biased conditions include early-onset disorders that involve a certain degree of neurodevelopmental impairment, such as autism, attention deficit/hyperactivity disorder, conduct disorder, specific language impairment, and Tourette syndrome or schizophrenia.[1] Factors influencing the relationships between brain development and function and sex/gender may help to understand the differences between males and females in terms of risk or resilience factors to brain diseases. Epigenetic modifications involving DNA methylation and histone deacetylation are also essential for feminization or masculinization of sexual behavior.[2,3] Unfortunately, in preclinical research, in most cases, researchers do not use female animals and consider that there are no sex differences in brain function outside of reproductive behavior. Single sex studies of male animals outnumber those of females: 5.5–1.3. In addition, clinical studies conducted in both sexes frequently forget to analyze results by sex/gender.[4,5]

The mean rate of depressive disorders for females is approximately twice that of males (1.63–3.89)[6,7] (and almost 3 times higher in South Asia, including India). Most of anxiety disorders are more common in women than men (2–3 fold increase in the occurrence of generalized anxiety disorder and panic disorder; social anxiety disorder is also more frequent in women with an odds ratio of 1.2–1.5). Anxiety disorders are more likely to be chronic, often complicated by other comorbid psychiatric disorders, and associated with more functional impairment in women.[8] Concerning schizophrenia, the male/female incidence approximates 1.4/1 but after 50-year-old women predominate; the functional outcome is usually better in women.[9] Finally, the prevalence of dependence or harmful use of alcohol and the prevalence of tobacco or illicit drug use are generally higher in adult men. However, epidemiological studies indicate an alarming narrowing in this gender gap, especially in adolescents. These behavioral changes may reflect changes in sociocultural patterns rather than biology. In fact, women are gradually losing the protection they had from historic social roles. In most countries, the mean level of alcohol use has gradually decreased over time, but in some countries such as India, China, Russia, some Latin American countries, and Eastern Europe, the mean consumption has increased from 2000 to 2013 (https://dx.doi.org/10.1787/health-data-fr). Health consequences significantly differ according to sex/gender. There are also important gender differences in terms of pharmacokinetics and pharmacodynamics. For example, the World Health Organization has defined different risks for occasional and chronic alcohol use, which are significantly lower in women: low risk (<20 g/day), moderate risk (>20–40 g/day), and high risk (>40 g/day). There is no safe level for tobacco or illicit drug use. Cardiovascular diseases are the most important cause of alcohol-attributable mortality in women. The risk of breast cancer increases according to the daily dose of alcohol use with a relative risk (RR) of 5–9 with one standard drink daily and of 41 with 3–6 standard drinks daily.[10] The protective cardiovascular effect of alcohol at low dose is less clear in women compared with men, in whom a clear decrease in RR of ischemic heart disease is observed at doses lower than 2–3 standard drinks daily. In the US, Jemal et al.[11] have reported an important decrease in annual age-adjusted death rates from almost all cancers among females (including breast cancer) except for lung and bronchus cancer, which has dramatically increased since the 1930s. These findings were confirmed by Pirie et al.[12] in a cohort of 1.2 million women followed for 12 years in the UK. In addition, heavy drinking puts women at risk of injuries and death from accidents, as well as unsafe sex, sexual assaults, and violence. Yet, the small number of studies on gender differences in addiction is surprising when considering the modulatory role of estradiol in decision-making and its interplay with dopamine in modulating reward, motivation, and cognitive processes. Men and women are also differentially affected by environmental triggers for relapse to drug-taking. As compared to men, women use more often psychoactive substances to cope with stress and negative feelings. Women are also more likely to have a lower socioeconomic status, which might also be a risk factor for addictive disorders. Potenza et al.[13] reported sex differences in the neural correlates of cocaine-induced craving. Corticostriatal-limbic hyperactivity was linked to stress cues in women but to drug cues in men. In the same way, women are also less sensitive to the reinforcing effects of nicotine but more sensitive to social cues. Young women are seen everywhere by the alcohol and tobacco industry as a potential growth market.

Finally, women's consumption of tobacco, alcohol, or illicit substances during pregnancy may be associated with serious birth and developmental consequences in newborns. Despite the international consensus recommending total abstinence of psychoactive drug use during pregnancy, prenatal alcohol, tobacco, or illicit drug exposure remains a major public health issue. In particular, alcohol consumption during pregnancy is associated with a large range of adverse effects including spontaneous abortion, stillbirth, weight and growth deficiencies, birth defects, prematurity, and fetal alcohol spectrum disorder. On the basis of data obtained in seven countries (Australia, Canada, Croatia, France, Italy, South Korea, and the US) on the prevalence of both alcohol use during pregnancy and resulting fetal alcohol syndrome (FAS), Popova et al.[14] estimated that one in every 67 mothers who consumed alcohol during pregnancy gave birth to a child with FAS. Prematurity and low birth weight are also frequently associated with tobacco exposure during pregnancy (smoking or secondhand smoke). The International Association of Women's Mental Health and the World Federation of Societies of Biological Psychiatry have recently published guidelines for the management of alcohol use during pregnancy.[15]

Female outpatients are still underrepresented in specialized treatment settings, particularly for the treatment of addictive disorders. Training care providers in primary care and mental health settings may help to identify and refer women to psychiatry and specialty addiction services. Providing services, such as child care, also help keeping women in treatment. Finally, raising public awareness about the risks of alcohol, tobacco, and illicit drug use during pregnancy is crucial, especially in all women of childbearing age.