Many stress-related mental disorders, including depression and post-traumatic stress disorder occur more often in women than in men. While social and cultural factors certainly contribute to these differences, neurobiological sex differences seem to also play an important role. A rapidly burgeoning literature from basic and clinical research documents sex differences in brain anatomy, chemistry and function, as well as in stress and drug responses. For example, some clinical studies have reported that women may have a better outcome when treated with selective serotonin re-uptake inhibitors, in comparison to tricyclic antidepressants. Furthermore, relatively limited basic research has been devoted to developing animal models and consequently describing drug treatments which are sensitive to sex differences. In this MiniReview, we discuss sex differences in behavioural aspects, as well as neurochemical, neurobiological and pharmacological findings that we have collected from several different animal models and tests of depression. These are the forced swim test, the chronic mild stress and the learned helplessness models, the Flinders sensitive line rats, which is a genetic model of depression and the lipopolysaccharide-induced sickness behaviour, a putative inflammatory model of depression. Collectively, our data have shown that in all animal models assayed, serotonergic neurochemical responses were differently affected in males and females, ultimately producing sex-dependent behavioural effects. In addition, Flinders sensitive line rats exhibited a sexually dimorphic response to chronic antidepressant treatment. These sex-differentiated neurochemical and behavioural alterations lend support to a major role of serotonin in the mediation of sexually dimorphic responses.Men and women differ in the occurrence and symptomatology of several psychiatric disorders. Specifically, major depression, which is a significant cause of morbidity worldwide, is twice as common in females as in males [1]. Interestingly, prior to puberty, there are no sex differences in rates of major depression. Many theories, biological, psychosocial and sociological, attempt to explain this dramatic increase in the prevalence of depression among women, but none is fully satisfactory. Furthermore, while the preponderance of women suffering from depressive disorders is well-established, considerably less attention has been given to gender differences in the presentation and features of depression and in response to antidepressant treatment. This is not unrelated to the fact that women were under-represented in clinical trials prior to 1993 [2].A further difficulty is that the neurobiology of depression itself is still not fully understood. Most reports implicate abnormalities in the monoaminergic systems (i.e. serotonergic, noradrenergic and dopaminergic), but recent data show that many other systems are also involved in the pathophysiology of depression [3]. For example, depression is now commonly viewed as an impairment of neural plas...
