As the empirical method and the double-blind, randomized trial came to dominate medical research, the menstrual cycle and the possibility of pregnancy disqualified female subjects from most investigations— pregnancy because of the possibility of teratogenicity, and the menstrual cycle because it might complicate research findings. In 1993 the U.S. Congress mandated the inclusion of women in clinical trials. It is now essential that we look at gender differences in order to ensure that the treatments developed before 1993 work as well for our female patients as for the male patients on whom they were tested. Gender differences do complicate research, but they also offer a window into physiological and pathophysiological processes and raise questions that inform new research directions. Since the menstrual cycle, menopause, and administration of hormones, including oral contraceptives and exogenous "replacements" later in life, affect nonreproductive functions, including blood levels of psychopharmacologic agents, their effects tell us something about how those agents work. If men’s and women’s brains bind opioids differently, we may be able to use that difference to explore the process of opioid binding. If men and women react differently to traumatic early experiences, we may come to understand where and how a traumatic experience is handled, both in the psyche and in the central nervous system.

Men and women are more alike than they are different. But because men and women differ in chromosomes, anatomy, and physiology, as well as in social expectations, gender roles, life experiences, and personal psychology, gender-based research is complex. However, adding gender to the research equation can force us and help us to address critical questions at the interfaces of biology, psychology, and sociology. Why is it that the same gene can have different effects depending on whether it comes from the male or the female parent? How do differences in hormones interact with differences in rearing and circumstances to cause differences in behavior both simple and complex (parenting being behavior that is fundamental to survival of the species but very complex)?

The study by Räsänen and colleagues in this issue of the Journal demonstrates a relationship between prenatal exposure to maternal smoking and later violent criminal behavior in male offspring. This raises a host of gender-related questions. Why is the male fetus more vulnerable to this exposure, and why does the vulnerability result in an increase in violent, but not in nonviolent, criminality? If we find the embryonic neurodevelopmental factors, the brain loci or processes affected, the way in which they differ between males and females, and the mechanisms by which they are damaged by maternal smoking, we might have important clues to the genesis, prevention, and treatment of violence—and to the effects of nicotine on central nervous system development and function.

The mothers in that study were interviewed during pregnancy. European record keeping, which begins prenatally and extends throughout each citizen’s medical history and, if applicable, criminal justice history, allows for the examination of correlations that elsewhere in the world, including the United States, are very expensive in time and money. But many subtle or not-so-subtle differences in the mothers’ postpartum behavior could not have been captured in those interviews. For what behaviors and circumstances might smoking be a marker: the mother’s trait or state anxiety, depression, inadequate care and supervision during her own childhood, poor social networks and supports, even a relative lack of interest in the well-being of her child, or an inability to conform her behavior to that interest? Although data continue to accumulate, smoking during pregnancy has been considered deleterious to pregnancy outcome for decades. Why did these mothers smoke? Perhaps we can research the factors that contribute to successful mothering, as well as better strategies for preventing girls from beginning to smoke and helping women to stop.

Gender-related research takes many forms. There is research focused on conditions that like postpartum depression and premenstrual symptoms, occur only in women; or that like depression, anxiety disorders, and eating disorders, occur more commonly in women; or that like schizophrenia, tend to be milder and of later onset in women; or that like sociopathy and substance abuse, are manifested differently in women than in men. There are studies of the differential effects of toxins or medications or psychotherapies by gender. A study focused on female addicts, such as the one by Rutherford and associates in this issue, can cast light on inconsistencies in our diagnostic systems and raise questions about the applicability of diagnostic criteria to diverse populations.

Why is a sociopath not a psychopath? Is sociopathy gender-bound, or is it manifested differently in men and women? Could it even be that prenatal maternal smoking is a marker for maternal sociopathy? And, if so, what would be the public policy implications? We have only recently emerged from the era of the "schizophrenogenic mother," and in much of the United States, pregnant women who abuse substances risk incarceration and criminal prosecution despite the fact that there are far fewer openings in treatment programs than women who seek treatment, and despite the fact that these punitive approaches deter women from obtaining prenatal care. Therefore, the American Psychiatric Association has taken a formal stance against such approaches. Both parents are important, and we must always be aware of the potential uses and abuses of our research findings.

The psychiatric consequences of trauma, in both childhood and adulthood, have become a major research focus. Gender may affect memory and reporting as well as vulnerability to abuse and shock. Depression is twice as common in women as in men. There are probably effects in both directions; childhood experiences increase adult vulnerability to depression, and depression increases the likelihood that childhood experience will be remembered as negative or that negative experiences will be remembered at all. Men may be both socially and biologically more vulnerable than women to committing violence and sexual abuse against female children, and women may be more socially and biologically vulnerable to expressing pathological sequelae from that abuse. These differences offer insights into the mechanisms by which trauma occurs and changes feelings, thoughts, and behaviors.

The labor of research into gender-based biology is beginning to bear fascinating and rewarding fruits. Our research subjects, whether human or animal, include both males and females, and that inclusion can result in research findings that will benefit both males and females. We need to go beyond inclusion to gender analysis and the publication of that analysis, to further the research agenda, raise new questions, and refine the clinical applications of our findings. Differences and variations in the social and hormonal milieu shape our diagnostic criteria and affect the pharmacokinetics, the metabolism, and the effectiveness of our treatments. No area is richer in intellectual and clinical challenges and possibilities.