Sex-related differences: do they matter?

Sex differences in the incidence of psychiatric disorders have been well recognized and documented. It is known that depression, anxiety disorders and eating disorders occur more commonly in women. Sex-specific syndromes such as post partum depression and premenstrual dysphoric disorder have recently been characterized as distinct psychiatric disorders. Yet, until the early 1990s, women were often excluded from clinical trials of new psychotropic drugs. Women of child-bearing age were generally not included in the testing of new drugs, particularly in the early stages of drug development, because of potential harm to the fetus. In addition, the menstrual cycle was thought to complicate the results of the trials. Since the US Congress mandated the inclusion of women in clinical trials in 1993, regulatory agencies require that the make-up of patient samples for clinical trials of new drugs reflect that of the intended target population. Most of the preclinical studies on the efficacy and safety of new agents, as well as on neurochemical correlates of behaviour and the mode of action of psychotropic drugs, have been done with male animals. Again, the reason was the concern that the estrus cycle might complicate experimental results. Some of the currently prevailing theories of the mode of action of antidepressants were based on the results of experiments with male rats only. Research in biological psychiatry and psychopharmacology is now focusing more on the analysis of sex influences. New evidence emerging from these studies indicates that sex differences at biological and genetic levels may have an important impact on our understanding of brain functioning and on the clinical use of psychopharmacological agents. A recent study on the forced swimming test,3 which is widely used in screening of antidepressants, showed that sex differences exist in some of the behaviours scored in the test. For instance, duration of immobility and head shake frequency were much lower in female than in male animals. These differences will obviously have to be taken into account when analyzing the effect of tested drugs. Another recent study suggests that sex differences in the prevalence of attention deficit with hyperactivity disorder (ADHD) may be attributable to sex differences in dopamine receptor density. In male rats, striatal dopamine D2-receptor density increases 144% between 25 and 40 days of age (the onset of puberty), whereas the increase in females is only 31%. The rise of male, but not female, striatal dopamine receptor density parallels the early developmental appearance of motor symptoms of ADHD and may explain why prevalence rates are 2to 4-fold higher in boys than in girls. Serotonergic mechanisms are thought to be involved in the etiology of some psychiatric disorders, particularly major depression and anxiety, in impulsivity and suicidal behaviour, as well as in the action of antidepressant, antianxiety and some newer antipsychotic drugs. There are several reports in the literature of sex differ-