Biological Psychiatry - Vol. 2

Meir Steiner, Edward Dunn, Leslie Born

The lifetime prevalence of mood disorders in women is approximately twice that of men. This higher incidence of depression in women is primarily seen from puberty on and is less marked in the years after menopause (Weissman and Olfson, 1995), with the exception of an additional perimenopausal blip (Kessler et al, 1993). The underlying causality of this gender difference in moodrelated disorders is not clear at this time. Since mood disorders occur in both men and women it is assumed that a unified basis for the development of these diseases exists. The principal constituent of this unified theory is believed to be related to genetic predisposition. Multiple environmental stressful events cause biochemical changes in a host of neuroendocrine systems and neuroanatomical areas. The genetic predisposition, which is multi-factorial, determines how stressful life events are interpreted and predicts the response, which can lead to the development of mood disorders (Heim and Nemeroff, 2001).

Notwithstanding, marked variations in the presentation of depression, comorbidity and treatment point to meaningful underlying sex differences. Women are about twice as likely as men to suffer from major depression or dysthymia (Kessler et al., 1994; Weissman et al, 1991). Women are prone to depressive episodes triggered by hormonal fluctuations related to reproductive events, such as during the premenstrual period, during pregnancy or the post-partum period, and around the menopause. Clinically, women present with a notably different depression symptom profile and more often develop a seasonal pattern to their depression (Ernst and Angst, 1992; Frank et al, 1988; Leibenluft et al, 1995; Moldin et al, 1993; Whybrow, 1995). The burden of illness in women with chronic depression is profound (Kornstein et al, 2000), while men may be more likely to 'forget' depressive episodes over time, a phenomenon which in turn may serve to protect them against recurrence (Ernst and Angst, 1992; Nolen-Hoeksema, 1987). Sex differences in the efficacy and tolerability of antidepressant medications is suggested by placebo-controlled and comparative studies (Kornstein, 1997, 2001; Kornstein and Wojcik, 2000). Moreover, there are marked differences between men and women in the pharmacokinetic and pharmacodynamic parameters of a number of psychotropic agents, including antidepressants (Kornstein and Wojcik, 2000; Yonkers et al, 1992).

Collectively, the literature points to a higher prevalence of mood disorders in women related to an increased genetic predisposition, an increased vulnerability/exposure to stressful life events, modulation of the neuroendocrine system by fluctuating gonadal hormones, or a combination of any or all of these factors.

A biological susceptibility hypothesis has been previously proposed, to account for gender differences in the prevalence of mood disorders based on the idea that there is a disturbance in the interaction between the hypothalamic-pituitary-gonadal (HPG) axis and other neuromodulators in women (Dunn and Steiner, 2000; Meller et al, 2001; Steiner and Dunn, 1996; Young et al, 2000). According to this hypothesis, the neuroendocrine rhythmicity related to female reproduction is vulnerable to change and is sensitive to psychosocial, environmental and physiological factors. Thus, premenstrual dysphoric disorder (PMDD), depression with post-partum onset (PPD), and mood disorders associated with the perimenopause or with menopause may all be related to hormone-modulated changes in neurotransmitter function.

Control of mood and behaviour involves many different neurotransmitter systems, including glutamate, gamma aminobutyric acid (GABA), acetylcholine (ACh), serotonin (5-HT), dopamine (DA), noradrenalin (NA) and neuropeptides. Given the observation that prevalence and symptomatology of mood disorders is often different between males and females, it is presumed that gonadal steroid hormones are somehow involved. For example, declining levels of oestrogen in women have been associated with post-natal depression and postmenopausal depression, and the cyclical variations of oestrogens and progesterone are probably the trigger of premenstrual complaints in women with premenstrual syndrome (Fink et al, 1996). The interaction between neurotransmitters and steroid hormones is extremely complex and delicately balanced. Each system appears to have a modulatory function on the other, and changes in one system may have dramatic effect on the other systems.

Glucocorticoid and gonadal steroid receptors are abundant in different areas of the brain. Gonadal steroid receptors are found in the amygdala, hippocampus, basal forebrain, cortex, cerebellum, locus ceruleus, midbrain raphe nuclei, pituitary gland and hypothalamus (Stomati et al, 1998). Oestrogen receptors are also located in the preoptic area and amygdala (McEwen, 1988) and in the ventromedial nucleus and arcuate nucleus of the hypothalamus (Herbison et al, 1995).

Activation of cholinergic, dopaminergic or adrenergic neurotransmitter systems can alter concentrations of cytosolic hypothalamic oestrogen receptors. Muscarinic agonists and antagonists can increase oestrogen-binding sites in the female rat hypothalamus (Lauber and Whalen, 1988). Oestrogen, progesterone and glucocorticoid receptors can also be activated by insulin-like growth factor 1 (IGF–1), epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), cyclic AMP (cAMP), protein kinase activators and by various neurotransmitters (Culig et al, 1995). Thus activation of neurotransmitter systems can have a direct modulatory effect on binding of gonadal hormones in the central nervous system (CNS).

Conversely, steroid hormones can modulate neuronal transmission by a variety of mechanisms. They may affect the synthesis and/or release of neurotransmitters, as well as the expression of receptors, membrane plasticity and permeability. It has been suggested that steroid hormone receptors function as general transcription factors to achieve integration of neural information in the CNS (Mani et al, 1997; Stahl, 2001a). Steroids are believed to act primarily by classical genomic mechanisms through intracellular receptors to modulate transcription and protein synthesis. This

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